Study Title: Hypo COMPASS
Clinical Study Protocol
Prevention of Recurrent Hypoglycaemia: a Definitive RCT
Comparing Optimised MDI and CSII with or without Adjunctive
Real-time Continuous Glucose Monitoring: hypo COMPASS
ISRCTN No: 52164803
Eudract No: 2009-015396-27
Date: 26 Apr 2012
Version 3.1
Protocol ID NCTU:ISRCTN52164803
Version 3.1. 26 Apr 2012
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Study Title: Hypo COMPASS
1
PROTOCOL CONTACTS
Sponsor:
Newcastle upon Tyne Hospitals NHS Foundation Trust
Ms Amanda Tortice
Head, Newcastle Joint Research Office
Joint Research Office
Level 6 Leazes Wing
Royal Victoria Infirmary
Newcastle upon Tyne
NE1 4LP
Tel: 0191 282 5959
Fax: 0191 282 0064
Email: Trust.R&D@nuth.nhs.uk
Chief Investigator:
Professor James Shaw
Professor of Diabetes and Consultant Physician
Diabetes Research Group
4th Floor William Leech Building
The Medical School
Newcastle University
Framlington Place
NE2 4HH
Tel: 01912228129
Fax: 01912220723
Email: jim.shaw@ncl.ac.uk
Statistician:
Dr Thomas Chadwick
Newcastle Clinical Trials Unit
Institute of Health & Society
Newcastle University
Baddiley-Clark Building
Richardson Road
Newcastle upon Tyne
NE2 4AX
Tel: 0191 222 6039
t.j.chadwick@ncl.ac.uk
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Study Title: Hypo COMPASS
Trial Managers:
Dr Julia Stickland (Trial Manager until July 2011)
Newcastle Clinical Trials Unit
Institute of Health & Society
4th Floor William Leech Building
The Medical School
Newcastle University
Framlington Place
NE2 4HH
Mr Chris Speed
Newcastle Clinical Trials Unit
Institute of Health & Society
4th Floor William Leech Building
The Medical School
Newcastle University
Framlington Place
NE2 4HH
Tel: 0191 222 6054
e-mail: chris.speed@ncl.ac.uk
Miss Catherine Brennand
Newcastle Clinical Trials Unit
Institute of Health & Society
4th Floor William Leech Building
The Medical School
Newcastle University
Framlington Place
NE2 4HH
Tel: 0191 222 7258
e-mail: cath.brennand@ncl.ac.uk
Principal Investigators:
Dr J. Begley
Consultant Chemical Pathologist, Poole
Hospital NHS Trust and Royal Bournemouth &
Christchurch NHS Foundation Trust
Clinical Biochemistry Department,
Poole Hospital NHS Foundation Trust,
Longfleet Road,
Poole
BH15 2JB
Tel: 01202-442155
Email: joe.begley@poole.nhs.uk
Prof David Kerr (Co-Investigator)
Consultant Physician and Honorary Senior
Lecturer
Bournemouth Diabetes & Endocrine Centre
Royal Bournemouth Hospital
Castle Lane East, Bournemouth
Dorset
BH7 7DW
Tel: 01202 704603
Email: david.kerr@rbch.nhs.uk
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Professor Simon Heller
Professor of Clinical Diabetes
Academic Unit of Diabetes, Endocrinology and Metabolism
Room OU141
School of Medicine and Biomedical Sciences
Beech Hill Road
Sheffield
S10 2RX
Tel: 0114 271 2521
Email: s.heller@sheffield.ac.uk
Dr Mark Evans
Lecturer and Honorary Consultant Physician
Institute of Metabolic Science
Metabolic Research Laboratories
University of Cambridge
Box 289, Level 4
Addenbrooke’s Hospital
Cambridge CB2 0QQ
United Kingdom
Tel: 01223 336994
Email: mle24@cam.ac.uk
Dr Daniel Flanagan
Consultant Physician / Honorary Senior Lecturer
Department of Endocrinology
Level 10
Derriford Hospital
Derriford Road,
Crownhill,
Plymouth
Devon
PL68DH
Tel: 01752517578
Email: Daniel.Flanagan@phnt.swest.nhs.uk
Dr Jane Speight
Chartered Health Psychologist
AHP Research Ltd
Brunel Science Park
Kingston Lane
Uxbridge UB8 3PQ
UK
Tel: 01895273599
Email: Jane.speight@ahpresearch.com
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2 PROTOCOL SIGNATURE PAGE
2.1
Protocol Authorisation Signatories
Signature ……………………………………. Date……………………….
Professor James Shaw, Chief Investigator
Signature ……………………………………. Date……………………….
Dr Thomas Chadwick, Statistician
Signature ……………………………………. Date……………………….
Mr Chris Speed, Trial Manager
Signature ……………………………………. Date……………………….
Ms Amanda Tortice, Sponsor’s Representative
2.2
Principal Investigator’s Signature
I confirm that I have read and understood protocol version 3.1 dated 26 April 2012.
I agree to comply with the study protocol, the principles of GCP and the appropriate reporting
requirements.
Signature ……………………………………. Date……………………….
Print Name ………………………………
Site Name/I.D. ………………………………
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3 CONTENTS
1
2
3
4
5
6
7
PROTOCOL CONTACTS .................................................................................................................... 2
PROTOCOL SIGNATURE PAGE ........................................................................................................ 5
CONTENTS ......................................................................................................................................... 6
GLOSSARY ......................................................................................................................................... 8
RESPONSIBILITIES ............................................................................................................................ 9
PROTOCOL SUMMARY ................................................................................................................... 14
BACKGROUND................................................................................................................................. 16
7.1 Introduction ................................................................................................................................ 16
7.2 Rationale for the Study ............................................................................................................. 18
7.3 Risk – Benefit Assessment ....................................................................................................... 18
8 OBJECTIVES .................................................................................................................................... 19
8.1 Primary Objective ...................................................................................................................... 19
8.2 Secondary Objectives ............................................................................................................... 19
9 SUBJECT POPULATION .................................................................................................................. 20
9.1 Study Centres ............................................................................................................................ 20
9.2 Identification, recruitment, and characterisation of those with severe hypoglycaemia ....... 20
9.3 Eligibility Criteria ....................................................................................................................... 21
9.4 Withdrawal of Participants........................................................................................................ 22
9.5 Participant Identification and Randomisation ......................................................................... 22
9.6 Participant Recruitment ............................................................................................................ 22
10 STUDY DESIGN .............................................................................................................................. 23
10.1 Overview .................................................................................................................................. 23
10.2 Primary Endpoint..................................................................................................................... 23
10.3 Secondary Endpoints .............................................................................................................. 23
10.4 Definition of the end of study ................................................................................................. 23
10.5 Qualitative interview study ..................................................................................................... 24
10.6 Study Timeline and Visit Schedule......................................................................................... 24
11 STUDY DRUGS AND DEVICES .................................................................................................... 34
11.1 Drugs General Information ..................................................................................................... 34
11.2 Insulin for MDI Participants .................................................................................................... 34
11.2.1 Insulin Aspart (Novorapid) ................................................................................................... 34
11.2.2 Insulin Glargine (Lantus)...................................................................................................... 35
11.2.3 Insulin Lispro (Humalog)...................................................................................................... 35
11.3 Insulin for use in CSII Groups ............................................................................................... 36
11.4 Study Drug Administration .................................................................................................... 37
11.4.1 Packaging and labelling ........................................................................................................ 37
11.6 Expected Adverse Reactions.................................................................................................. 38
11.7 Insulin Titration Protocols ...................................................................................................... 38
11.7.1 Blood Glucose Targets (for all patients in CSII and MDI groups): .................................... 38
11.7.2 Glargine titration in MDI Group............................................................................................ 38
11.7.3 Introduction of twice daily glargine .................................................................................... 39
11.7.4 Basal Insulin titration in CSII Group ................................................................................... 39
11.7.5 Meal time insulin bolus in all groups (CSII and MDI): ....................................................... 40
11.9 Real Time Continuous Glucose Monitors .............................................................................. 41
11.10 Standard Continuous Glucose Monitors ............................................................................. 42
12 BLINDING ..................................................................................................................................... 42
13 STUDY DATA ................................................................................................................................ 43
14 STATISTICAL METHODS ............................................................................................................. 48
14.1 Power and sample size considerations ................................................................................. 48
14.2 Statistical analysis .................................................................................................................. 48
15 COMPLIANCE AND WITHDRAWAL............................................................................................. 50
15.1 Participant Compliance ............................................................................................................ 50
15.2 Participant Withdrawal ............................................................................................................. 50
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16 INTERIM ANALYSIS AND DATA MONITORING .......................................................................... 51
16.1 Discontinuation rules ........................................................................................................... 51
16.2 Trial Coordination, monitoring, quality control and assurance ........................................ 51
16.2.1 Data monitoring and Ethics Committee .............................................................................. 51
16.2.2 Trial Steering Committee ..................................................................................................... 51
16.2.3 Trial Management Group...................................................................................................... 52
16.2.4 Principal Investigators ......................................................................................................... 52
16.2.5 Trial Monitoring .................................................................................................................... 52
17 PHARMACOVIGILANCE AND ADVERSE EVENTS ....................................................................... 54
17.1 Definition .................................................................................................................................. 54
17.2 Causality .................................................................................................................................. 55
17.3 Follow up period of adverse events ........................................................................................ 56
17.4 Protocol Specifications ............................................................................................................ 56
18 THE REPORTING OF ADVERSE EVENTS..................................................................................... 57
18.1 Reporting of Non serious adverse events ............................................................................ 57
18.2 Reporting of Serious Adverse Events ................................................................................... 57
18.3 Flow chart of adverse event reporting .................................................................................. 59
18.4 Pregnancy during Trial period ............................................................................................... 59
19 ETHICAL CONSIDERATIONS ....................................................................................................... 60
19.1 Subject Payments..................................................................................................................... 60
20 FINANCE AND INSURANCE .......................................................................................................... 60
21 STUDY REPORT ............................................................................................................................. 60
22 CLINICAL TRIAL PROTOCOL AMENDMENTS ............................................................................. 61
23 STUDY CONDUCT .......................................................................................................................... 61
24 REFERENCES ................................................................................................................................ 62
25 APPENDICES.................................................................................................................................. 64
APPENDIX 1: Hypoglycaemia Experience and Awareness Questionnaires ................................... 64
APPENDIX 2 Modified Clarke/Edinburgh Hypo Awareness score ................................................... 65
APPENDIX 3 ADA/WHO Definition of Diabetes Mellitus ................................................................... 67
APPENDIX 4 Protocol for stepped hyperinsulinaemic hypoglycaemic clamp ............................... 68
APPENDIX 5 – Questionnaires (The Gold Score, Edinburgh Hypoglycaemia Survey, Hypo
Awareness Questionnaire, Guy’s and St Thomas’ Minimally Modified Clarke
Hypoglycaemia Survey, Fear of Hypoglycaemia Survey, High Blood Sugar Survey
(FoHyper Questionnaire), Hypo Cues Questionnaire, Attitudes to Awareness of
Hypos Questionnaire, Hypo Burden Questionnaire, Quality of Life Questionnaire,
Diabetes Treatment Satisfaction Questionnaire (the DTSQs version), Blood Glucose
Monitoring Questionnaire, Insulin Treatment Satisfaction Questionnaire, EQ-5D
Questionnaire and the Perceived Control of Diabetes Scales ................................... 74
APPENDIX 6 Summary of Product Characteristics (SmPC) for Novorapid flexpen 100 U/mL
solution for injection in pre-filled pen and Novorapid 100 U/mL solution for injection
in vial............................................................................................................................ 108
APPENDIX 7 SmPC for Lantus 100 U/mL solution for injection in a pre-filled pen ...................... 124
APPENDIX 8 SmPC for Humalog 100 U/mL solution for injection in a vial and Humalog 100 U/mL
Kwikpen, solution for injection .................................................................................. 142
APPENDIX 9 Schedule of Events ..................................................................................................... 160
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4 GLOSSARY
AE
AFT
AR
BGAT
BH
BP
CANTAB
CGM
CI
CRF
eCRF
CSII
CTA
DKA
DMEC
EQ-5D
GCP
HR
IAH
IMP
MDI
MHRA
MREC
NCTU
PI
QoL-Q
RCT
R&D
RT
SAE
SH
SMBG
SmPC
SUSAR
SWM
T1DM
TSC
TSH
4CRT
Adverse Event
Autonomic Function Tests
Adverse Reaction
Blood Glucose Awareness Training
Biochemical Hypoglycaemia
Blood Pressure
Cambridge Neuropsychology Test Automated Battery
Continuous Glucose Monitoring
Chief Investigator
Case Report Form
Electronic Case Report Form
Continuous Subcutaneous Insulin Infusion
Clinical Trial Authorisation
Diabetic Ketoacidosis
Data Monitoring and Ethics Committee
Euro QoL (Quality of Life)
Good Clinical Practice
Heart Rate
Impaired Awareness of Hypoglycaemia
Investigational Medicinal Product
Multiple Daily Insulin Injections
Medicines and Healthcare products Regulatory Agency
Multicentre Research Ethics Committee
Newcastle Clinical Trials Unit
Principal Investigator (at each site)
Quality of Life Questionnaire
Randomised Control Trial
Research and Development
Real Time Continuous Glucose Monitoring
Serious Adverse Event
Severe Hypoglycaemia
Self Monitoring Blood Glucose
Summary of Product Characteristics
Suspected Unexpected Serious Adverse reaction
Spatial Working Memory
Type 1 Diabetes Mellitus
Trial Steering Committee
Thyroid Stimulating Hormone
4 Choice Reaction Time
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5 RESPONSIBILITIES
Responsibility to:
Responsible
Party:
1.Study
Preparation
a) Ensure that insurance or
indemnity arrangements are in place
to cover liabilities.
b) Secure and administer funding for
the study.
c) Secure the contract for the
supply of resources including
medicinal products/devices/contract
research services.
d) Ensure that the appropriate
contracts and agreements are in
place for the study.
2. Applications
and
Registration
3. Protocol
Amendments
e) Notify the substantive employers
of investigators in writing, in advance
of the study commencing, of their
participation in the study.
a) Ensure that the protocol has
undergone independent scientific and
statistical review and is compliant
with the relevant regulations /
guidelines.
If responsibility is
delegated, name body
/ individual that it is
delegated to:
Sponsor
Sponsor
Chief Investigator
Sponsor
Chief Investigator/
Newcastle Clinical trials
unit
Sponsor
Institution
Sponsor
b) Prepare participant information
sheet and consent form, including
where appropriate consent to
providing participant tissue, sample,
medical data or other material to the
sponsor and other relevant
documents prior to ethics
submission.
Sponsor
Chief Investigator/
Newcastle Clinical
Trials Unit
c) Prepare and submit ethics
application.
Sponsor
Chief Investigator/
Newcastle Clinical
Trials Unit
d) Register the study with an
appropriate protocol registration
scheme.
Sponsor
Chief Investigator/
Newcastle Clinical
Trials Unit
e) Obtain NHS permission.
Institution
f) Prepare and submit application for
clinical trial authorisation to MHRA
Sponsor
Chief Investigator/
Newcastle Clinical
Trials Unit
a) Prepare and submit proposed
substantial amendments of the
protocol to the regulatory
authority(ies), relevant ethics
Sponsor
Chief Investigator/
Newcastle Clinical
Trials Unit
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Responsibility to:
Responsible
Party:
If responsibility is
delegated, name body
/ individual that it is
delegated to:
committee and NHS Site.
b) Ensure all investigators are
aware of dates of approval and
implementation of all such
amendments.
4. Study Conduct
Sponsor and
Institution
a) Ensure that legislation in relation
to research is followed within the site.
Institution
b) Ensure that the study site team
members are appropriately qualified
and experienced to undertake the
conduct of the study and that they
have current substantive or honorary
employment contracts in place,
where required.
Institution
c) Ensure that no participant is
recruited until a favourable ethical
opinion has been provided.
Sponsor and
Institution
d) Ensure that no participant is
recruited to the study until
satisfied that all relevant
regulatory permissions and
approvals have been obtained.
e) Put and keep in place
arrangements to allow all
investigators to conduct the
study in accordance with the
protocol.
Chief Investigator/
Newcastle Clinical
Trials Unit
Sponsor and
Institution
Sponsor and
Institution
f) Ensure that the study is
managed, monitored and
reported as agreed in the
protocol.
Sponsor and
Institution
g) Ensure that the rights of
individual participants are
protected and that they receive
appropriate medical care whilst
participating in the study.
Institution
h) Maintain and archive study
documentation at the site.
i) Ensure that all data and
documentation are available for
the purposes of monitoring,
inspection or audit and that the
appropriate consent has been
provided by the participant.
Institution
Institution
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Study Title: Hypo COMPASS
Responsibility to:
Responsible
Party:
5.Adverse Events
j) Inform appropriate health or
social care professionals if their
patient is a participant in the study in
accordance with the research
governance framework.
Institution
k) Ensure adequate facilities,
resources and support are
available to conduct the study at the
site.
Institution
l) Report suspected research
Sponsor misconduct.
Sponsor and
Institution
m) Notify the regulatory
authority(ies) of the end of the study.
Sponsor
n) Notify the regulatory
authority(ies) and relevant ethics
committee if the study is terminated
early.
Sponsor
a) Maintain detailed records of all
adverse events as specified in the
protocol.
Sponsor and
Institution
b) Report adverse events as
agreed in the Protocol and to legal
requirements and in
accordance with Trust policy.
Sponsor and
Institution
c) Promptly inform regulatory
authorities, ethics committees and
investigators of any urgent safety
measures taken to protect
participants in the study.
d) Ensure that annual safety
reports and end of study reports are
generated and submitted to the
regulatory authority and relevant
ethics committee within
the required time frames.
e) Ensure that all investigators are, at
all times, in possession of the current
relevant safety information for the
study.
6.Data
Management
a) Design of case report forms and
database and report generating
functionality
Sponsor
If responsibility is
delegated, name body
/ individual that it is
delegated to:
Chief Investigator /
Newcastle Clinical
Trials Unit
Chief Investigator /
Newcastle Clinical
Trials Unit
Chief Investigator/
Newcastle Clinical
Trials Unit
Chief Investigator/
Newcastle Clinical
Trials Unit
Chief Investigator/
Newcastle Clinical
Trials Unit
Sponsor
Chief Investigator/
Newcastle Clinical
Trials Unit
Sponsor
Chief Investigator/
Newcastle Clinical
Trials Unit
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
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Study Title: Hypo COMPASS
Responsibility to:
Responsible
Party:
If responsibility is
delegated, name body
/ individual that it is
delegated to:
b) Ensure appropriate analysis of
data.
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
7. Publication
a) Initiate and coordinate review
and submission of abstracts,
posters and publications.
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
8.Archiving
a) Ensure that all Study records are
archived appropriately on conclusion
of the study and retained for 15
years.
a) Ensure that the Study is
conducted in accordance with
the principles of Good Clinical
Practice (GCP).
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
b) Request Clinical Trials
Authorisation from the
regulatory authority (MHRA in
the UK).
Sponsor and
Institution
c) Ensure that Investigational
Medicinal Product (IMP) is not
used for any purposes other
than the conduct of the Study
and is used in strict accordance
with the Protocol.
Institution
9.Clinical Trials
involving
medicinal
Products
d) Ensure that all Serious Adverse
Events (SAE), other than those
specified in the Protocol as not
requiring immediate reporting,
are promptly assessed as
regards the requirement for
expedited reporting to the
regulatory authority and relevant
ethics committee.
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
Chief Investigator /
Newcastle Clinical
Trials Unit
e) Ensure that SAEs are reviewed by
an appropriate committee for the
monitoring of trial safety.
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
f) Ensure that all Suspected
Unexpected Serious Adverse
Reactions (SUSAR) are
identified and fully reported to
the regulatory authority and
relevant ethics committee within
the required timelines.
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
g) Ensure that investigators are
aware of any SUSARs occurring
in relation to the Investigational
Medicinal Product (IMP).
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
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Responsibility to:
h) Ensure Investigational Medicinal
Product (IMP) is provided and
labelled in accordance with the
Medicines for Human Use
(Clinical Trials) Regulations
2004.
i) Ensure that IMP is stored in
appropriate and secure
conditions and that detailed
records are maintained
regarding its movement from
delivery to return/destruction.
Responsible
Party:
If responsibility is
delegated, name body
/ individual that it is
delegated to:
Sponsor
Chief Investigator /
Newcastle Clinical
Trials Unit
Institution
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Study Title: Hypo COMPASS
6 PROTOCOL SUMMARY
Full Title:
Prevention of recurrent hypoglycaemia: a definitive RCT comparing optimised MDI
and CSII with or without adjunctive real-time continuous glucose monitoring
Acronym:
hypo COMPaSS (Comparison of Optimised MDI and Pump with and without
Sensors in Severe hypoglycaemia)
Protocol Version:
3.1
Protocol date:
26 April 2012
Chief Investigator:
Professor James Shaw
Sponsor:
Newcastle upon Tyne Hospitals NHS Foundation Trust
Funder:
Diabetes UK
Study Design:
Interventional multicentre randomised controlled trial, 2 x 2 factorial design
Study intervention:
All participants will participate in a uniform structured education programme
targeted at the rigorous avoidance of hypoglycaemia.
Participants will then be randomised to one of 4 intervention groups for a 24 week
randomised control trial:
1. MDI (multiple daily insulin injections)
2. MDI with RT (real time continuous glucose monitoring)
3. CSII (continuous subcutaneous insulin infusion)
4. CSII with RT (real time continuous glucose monitoring)
Objectives:
To demonstrate that by optimising conventional management in subjects with type
1 diabetes mellitus complicated by severe hypoglycaemia, rigorous prevention of
biochemical hypoglycaemia will restore hypoglycaemia awareness.
Primary Outcome
Measure:
The restoration of hypoglycaemia awareness as determined by quantitative
questionnaire analysis.
Study Sites:
1. Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust
2. Royal Bournemouth Hospital, The Royal Bournemouth and Christchurch Hospitals
NHS Foundation Trust
3. Derriford Hospital, Plymouth Hospitals NHS Trust
4. Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust
5. Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust
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Study Population:
100 eligible male and females inclusive aged 18-74 years.
Study Duration:
3 years
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7 BACKGROUND
7.1 Introduction
Diabetes Mellitus is a group of metabolic disorders characterised by chronic hyperglycaemia. Type 1
diabetes mellitus (T1DM) is characterised by an absolute deficiency of insulin caused by immunologically
mediated damage to the beta cells in the pancreas.
Type 1 diabetes mellitus accounts for 5-10% (1) of those with diabetes and is caused by a cellular
mediated autoimmune destruction of the beta cells of the pancreas. This type of diabetes mellitus can
occur at any age but most often occurs in children, adolescents and young adults. T1DM is complicated
by microvascular disease of the kidneys, eyes and nervous tissue in addition to macrovasular disease
such as ischaemic heart disease, cerebrovascular disease and peripheral vascular disease.
As there is no cure for T1DM the management entails the regulation of blood glucose levels with insulin
replacement therapy and dietary modification. Despite more than 85 years’ clinical experience with
insulin replacement therapy in T1DM, SH (severe hypoglycaemia) remains the major factor limiting tight
glycaemic control, necessary to prevent long-term microvascular and macrovascular complications.
Severe hypoglycaemia (SH) affects up to 30% of individuals with established T1DM each year and
remains one of the most feared complications as it can result in collapse without warning, fits, or even
sudden death (2). Tight glycaemic control in the landmark DCCT trial attained by MDI (multiple daily
injections) or CSII (continuous subcutaneous insulin infusion) was associated with a three- fold increase
in SH (3). Established risk factors for severe hypoglycaemia include age, duration of diabetes, tight
glycaemic control, previous severe hypoglycaemia and IAH (impaired awareness of hypoglycaemia). IAH
occurs in 25% of those with T1DM and is characterised by diminished autonomic warning symptoms of
impending hypoglycaemia with a six fold increased risk of SH (4). Antecedent biochemical
hypoglycaemia including silent nocturnal hypoglycaemia can induce IAH in addition to diminished
counter-regulatory hormone response in non-diabetic individuals as well as in those with established
diabetes (5).
In insulinoma patients, surgical resection restores normal symptomatic and neuroendocrine response to
hypoglycaemia providing further evidence of the direct causative role of BH (biochemical hypoglycaemia)
in IAH and SH. Rigorous avoidance of hypoglycemia by relaxing glycaemic targets while maintaining
conventional MDI therapy has been shown to restore hypoglycaemia awareness with normalisation of
glycaemic thresholds for symptoms and neuroendocrine responses during a stepped hyperinsulinemic–
hypoglycemic clamp
(6,7)
. This was, however, associated with a 0.5-1.1% increase in HbA 1c . Moreover,
success has previously been confined to those with relatively short duration of diabetes
(6)
or transiently
following a brief period of absolute hypoglycaemia avoidance in those with longer disease duration (7).
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Study Title: Hypo COMPASS
The potential for reducing nocturnal and late post-prandial hypoglycaemia by employing rapid-acting
(8)
insulin analogues pre-prandially has been demonstrated
. In addition, reduced nocturnal hypoglycemia
(9)
has been reported in insulin glargine trials
. Evidence is accruing for a reduction in HbA 1c with
optimized rapid- and long-acting insulin analogue therapy, including insulin glargine, in comparison to
MDI regimens with conventional insulin preparations
(10)
. Individuals with a previous history of SH and
longer duration of diabetes have typically been excluded from randomized clinical trials investigating
insulin analogues. The National Institute for Health and Clinical Excellence (NICE) in the UK has
recommended further studies to assess the impact of insulin analogues on duration and severity of
hypoglycaemia and on quality of life (QoL) (11).
In randomized trials of CSII versus MDI, a relatively modest improvement in HbA 1c has been
demonstrated in addition to the potential for reduction in the incidence of severe hypoglycaemia
(12,13)
.
There have been relatively few trials to date with glargine as the basal insulin in the MDI comparator
group
(13,14)
. Individuals with established SH have again often been excluded from prospective studies,
despite a reported sustained reduction in the incidence of SH in a non-randomized, retrospective study
(15)
. NICE recommend CSII therapy where achievement of optimal glycaemic control has been precluded
by disabling hypoglycaemia but has emphasized the absence of studies in high-risk individuals with the
need for randomized control trials to assess biomedical and psychosocial outcomes of both analogue
MDI and CSII in those with established SH (16).
The potential role of real time continuous glucose monitoring (RT) has generated considerable interest in
clinicians and those with T1DM since its recent introduction. Improved overall glycaemic control has
been reported
(17)
. In a short term study, use of RT glucose trend analysis and low glucose alarms
enabled 21% reduction in duration of BH
(18)
. Sustained avoidance of BH achieved through feedback
from intermittent RT use with the aim of restoring hypoglycaemia awareness and preventing risk of
further SH in high risk individuals with T1DM has not been assessed.
Blood glucose awareness training (BGAT) is a psychoeducational intervention focussed on a
multifactorial approach to improve detection of hypo- and hyperglycaemia (19). It is particularly effective in
those with IAH and sustained reduction in SH has been confirmed. It has not been formally evaluated in
conjunction with optimised insulin replacement.
Despite implicit acknowledgement amongst health care professionals that SH impairs an individual’s
QoL, there is little formal evidence for this in the literature. Davis et al., have demonstrated the major
impact of SH on perceived health and well-being
(20)
but the full impact of SH on QoL has not been
assessed adequately. Relatively few studies have directly assessed impact of successful prevention of
further SH in addition to differential effects according to therapeutic intervention.
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7.2 Rationale for the Study
A 6 month randomised prospective pilot study in individuals with T1DM complicated by SH has been
completed comparing rigorous BH avoidance with optimised analogue MDI; CSII; or education alone
(EDUC)
(21)
. This demonstrated absolute prevention of recurrent SH in 71% in all groups. Quantitative
improvement in IAH using the validated Clarke questionnaire in addition to restored symptomatic
response to clamp-induced hypoglycaemia was confirmed. Concomitant improvement in glycaemic
control, diabetes-related QoL and fear of hypoglycaemia was achieved with MDI (HbA1c: 7.6%) and CSII
(HbA1c: 7.4%) but not EDUC (HbA1c: 8.3%).
These pilot data provide the rationale, robust power
calculation and proven study design for this definitive RCT without the requirement for an education
alone arm.
7.3 Risk – Benefit Assessment
This study will use existing conventional management for Type 1 DM within licenced indications to
demonstrate definitively whether severe hypoglycaemia can be successfully prevented. Consequently
the investigators believe that there is no added risk to participants compared to current management
within the NHS.
This research will provide the participants with a period of intensive, multidisciplinary management of
their diabetes mellitus. The education programme is extensive and it is hoped that this will improve the
patients' overall diabetes control for many years after the end of the study.
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8 OBJECTIVES
8.1 Primary Objective
To demonstrate that by optimising conventional management, including the use of real time continuous
glucose monitors, in subjects with type 1 diabetes mellitus complicated by severe hypoglycaemia,
rigorous prevention of biochemical hypoglycaemia will restore hypoglycaemia awareness. This will be
determined by use of quantitative questionnaire analysis.
8.2 Secondary Objectives
•
To quantify and compare biochemical hypoglycaemia identified by SMBG (self monitored blood
glucose) and CGM (continuous glucose monitoring) profiles during each intervention.
•
To quantify and compare overall glycaemic control and glucose lability in each group by analysis
of HbA1C, SMBG and CGM.
•
To quantify and compare total daily doses of insulin before and after the intervention period.
•
To compare symptomatic, counter-regulatory and cognitive response to hypoglycaemia in gold
standard clamp study in each group after intervention.
•
To compare health utility, well being and quality of life during each intervention using validated
measures.
•
To compare cardiac autonomic function before and after the intervention period.
•
To perform sub-group analyses of those who continue to experience severe hypoglycaemia and
impaired awareness of hypoglycaemia (IAH) despite successful avoidance of biochemical
hypoglycaemia to evaluate associated risk factors.
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9 SUBJECT POPULATION
9.1 Study Centres
This is a multicentre study and recruitment will be conducted at the following hospitals:
1.
2.
3.
4.
5.
Royal Victoria Infirmary, Newcastle upon Tyne
Royal Bournemouth Hospital
Derriford Hospital, Plymouth
Addenbrooke’s Hospital, Cambridge
Northern General Hospital, Sheffield
9.2 Identification, recruitment, and characterisation of those with severe hypoglycaemia
100 patients in total will be recruited from across 5 UK tertiary referral and established academic
hypoglycaemia/CSII centres. The patients will be aged 18-74 with established Type 1 DM (C-peptide
negative) with severe hypoglycaemia and or IAH (Impaired Awareness of Hypoglycaemia).
Patients will be identified from existing clinics and research databases held at each centre. Potential
participants may be identified using the brief Hypoglycaemia Screening Questionnaire (comprising
hypoglycaemia history (Appendix 1) and Clarke / Edinburgh validated IAH questionnaires (Appendix 2))
to ascertain whether they fulfil the SH / IAH inclusion criteria. These questionnaires are in established
clinical use in the participating centres.
Potential participants will be provided with written information, along with opportunity for questions and
will have a minimum of 24 hours to decide whether or not to take part. Informed written consent will be
taken by a member of the research team at each site adhering to guidelines of Good Clinical Practice.
The original signed consent form will be retained in the Investigator Site File, with a copy in the clinical
notes and a copy provided to the participant. The participant will specifically consent to their GP being
informed of their participation in the study.
The right to refuse to participate without giving reasons must be respected.
Trial entry will be notified to the co-ordinating centre within 5 working days of enrolment by the local
principal investigator or member of site staff with delegated authority.
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9.3 Eligibility Criteria
Inclusion Criteria
1. Male or female aged 18-74 years inclusive at start of the trial.
2. Diagnosis of diabetes mellitus according to ADA and WHO criteria (see Appendix 3) and
consistent with a clinical diagnosis of Type 1 diabetes mellitus.
3. Fasting serum C-peptide below the quality assured limit of detection for the assay and laboratory
with simultaneous exclusion of biochemical hypoglycaemia (glucose <4.0 mmol/L) by laboratory
glucose level analysis on a sample taken at the same time point.
4. History of severe hypoglycaemia in the preceding one year (as defined by the American Diabetes
Association (22): an event requiring assistance of another person to actively administer
carbohydrate, glucagons or other resuscitative actions. These episodes may be associated with
sufficient neuroglycopaenia to induce seizure or coma. Plasma glucose measurements may not
be available during such an event, but neurological recovery attributable to restoration of plasma
glucose to normal is considered sufficient evidence that the event was induced by low plasma
glucose concentration) and / or impaired awareness of hypoglycaemia as confirmed by a score of
≥ 4 in the Gold score (included in the Edinburgh hypoglycaemia awareness score) See appendix
2.
Exclusion Criteria:
1. Any condition that in the investigator’s judgement is likely to cause the subject to be unable to
understand the information in the Informed Consent Document or provide informed consent.
2. A level of English below that to enable the participant to understand both verbal and written
information required by the study. Due to the complexity of the education programme to be
given and the degree of training that the educators will need to give the programme it is not
possible to invite patients to take part in this trial who in the opinion of the investigator do not
have a sufficient level of understanding of English.
3. Unwilling to undertake intensive insulin therapy including the use of CSII, optimised MDI regimen
and use of real time continuous glucose monitoring.
4. Unwilling to undertake glucose profiles using the subcutaneous continuous glucose monitoring
(CGM) equipment.
5. Unwilling to monitor home blood glucose levels at least 4 times daily.
6. Unwilling to monitor and record signs and symptoms of hypoglycaemia.
7. A history of intolerance to insulin glargine.
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9.4 Withdrawal of Participants
Subjects will be withdrawn from the study if they withdraw consent to participate. No reason needs to be
given for withdrawal of consent.
The reason for withdrawal will be recorded in the CRF and the subject’s medical records.
The investigator will make every reasonable effort to contact subjects lost to follow up.
9.5 Participant Identification and Randomisation
Each participant will be given a subject identification number.
Upon enrolment and completion of baseline measurements / education each subject will be assigned a
unique randomisation number.
Randomisation will be administered centrally via Newcastle Clinical Trials Unit using a secure web based
system.
The randomisation method: Computer based third party concealed randomisation, stratified by centre.
Participants will be informed of their allocated treatment group following randomisation.
9.6 Participant Recruitment
The study has a target population of 100 participants. Each of the 5 sites will recruit 20 participants
ideally within 4 months of the first participant recruitment but within a 6 month recruitment window.
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10 STUDY DESIGN
10.1 Overview
This will be an interventional multicentre prospective randomised controlled trial comparing
hypoglycaemia avoidance with optimised subcutaneous insulin analogue regimen (MDI) and insulin
pump therapy (CSII) with or without adjunctive real-time continuous subcutaneous glucose monitoring
(RT) in a 2x2 factorial design. All end points will be analysed at the end of the RCT (24 weeks) and then
at 6, 12 and 18 months after the RCT unless otherwise stated.
.
10.2 Primary Endpoint
IAH (Impaired Awareness of Hypoglycaemia) score at 24 weeks– calculated from analysis of validated
quantitative questionnaires.
10.3 Secondary Endpoints
•
Change in diary rates of mild symptomatic hypoglycaemia, severe hypoglycaemia and change in
experience of symptoms of hypoglycaemia
•
Change in HbA1c.
•
Change in mean SBGM and mean CGM.
•
Change in symptomatic, cognitive and counter regulatory hormone response to a stepped
hypoglycaemic clamp study before and after 24 week RCT period.
•
Change in heart rate variability, baroreceptor sensitivity and ambulatory blood pressure, derived
by undertaking detailed autonomic function tests, before and after RCT period.
•
Detailed sub group analysis will be undertaken to determine the underlying clinical and
psychological phenotypes of those who continued to experience SH and IAH despite BH
avoidance enabling such individuals to be more easily identified in routine clinical practice. The
analysis of these subgroups will centre on data from autonomic function tests and the
hyperglycaemia avoidance index questionnaire.
•
Change in total daily dose of insulin.
•
Change in health utility, well being and quality of life during each intervention using validated
measures.
10.4 Definition of the end of study
The end of the randomised control trial (RCT) will be the last assessment of the last participant at 24
weeks. The end of the study will be the last follow up visit of the last participant scheduled for 18 months
after the 24 week RCT.
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10.5 Qualitative interview study
Forty hypo COMPASS participants will be recruited for a follow-on interview sub-study of experience of
hypoglycaemia, treatment, diabetes management and diabetes control during the hypo COMPASS
Randomised Control Trial. Participants will be recruited to comprise approximately 10 participants per
study arm, equal male and female participants, 8 per site.
A broad interview guide has been developed to guide discussions. Using this interview guide, semistructured interviews will be conducted, using an adapted grounded theory approach in which early
interviews inform the narrative prompts of later interviews so as to elicit the most complete coverage of
participants’ experience of treatment. Interviews will be recorded digitally and verbatim transcription will
be conducted. Two investigators will code interviews, analyse the data and compare emerging themes.
A third investigator will review their summaries and discuss the emerging themes.
10.6 Study Timeline and Visit Schedule
There will be a 4 week wash in period as outlined below before the 24 week randomised control trial
(RCT) period. Participants will be followed up at study visits every 4 weeks during the RCT. Participants
will be invited to attend for further follow up 6, 12 and 18 months after the RCT.
Potential participants will be identified from clinical referrals or from the clinical databases held at each of
the centres. Participant information sheets (hypo COMPASS Participant Information Sheet version 1.0
10.09.09) will be provided to potential participants at least 24 hours before being invited to attend
baseline screening visit. Before any study specific procedure is performed, valid informed consent must
be obtained as described in section 9.1.
Visit 1: Recruitment (Wash-in Week 0, 4 week wash in period starts at visit 1)
1. Determine patient’s eligibility for study inclusion (i.e. eligibility criteria). The Hypoglycaemia
Screening Questionnaire (Appendix 1) will be completed by the potential participant or results
reviewed if previously completed.
2. Explain the nature and purpose of the trial.
3. Check that patient has read both the Participant Information Sheet and Informed Consent form
(Clinical Trial hypo COMPASS Participant Information Sheet version 1.0 10.09.09).
4. A separate Participant Information Sheet will be provided regarding the (optional) hypoglycaemic
clamp studies (hypo COMPASS clamp study Participant Information Sheet version1.0 10.09.09).
This will be provided to all participants unless any of the exclusion criteria for undertaking a
clamp study are met (see Appendix 4 for full clamp protocol).
5. Ensure that the patient has had their questions about the trial answered adequately.
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6. If patient is ready to do so, obtain their written consent.
7. If they need more time to consider study participation, this should be allowed and, if necessary, a
return visit arranged to complete the process.
8. Complete the standardised enrolment or the “eligible but declined” information on the CRF. No
reason needs to be given if participation is declined however if a reason is given this should be
recorded on the CRF.
9. Issue the patient with their unique trial number for the trial.
10.Patients will be provided with a hand-held glucometer and educated in the use of prospective
Self Monitoring Blood Glucose (SMBG) / Hypoglycaemia diaries (hypo COMPASS Glucose/hypo
diary version 1.0 10.09.09) to measure daily 4 point profiles and weekly 8 point profiles in
addition to clinical details of all glucose levels less than 4 mmol/L and symptomatic
hypoglycaemic events during a 4 week wash in period.
11.Blood to be taken for HbA1c together with C-peptide and random glucose to confirm absence of
endogenous insulin secretion.
Visit 2: CGMS placement (Wash-in Week 3)
Participants attend for placement of subcutaneous sensor for 7 day blinded continuous glucose
monitoring (CGM). At this visit the patient will also provide a first morning urine sample for albumin:
creatinine ratio and undergo dilated retinal photography. The retinal screening only needs to be done if
the participant has not had retinal screening performed within the preceding 6 months. If necessary to
accommodate the participant’s needs, individual components of this visit can be performed on separate
days. Severity of diabetes complications will not preclude participation in the study.
Visit 3: Baseline / Clamp Visit (Wash-in Week 4, end of 28 day wash-in period)
The participant will attend after 7 days blinded CGMS and completion of the 4 week glucose /
hypoglycaemia diary. (hypo COMPASS Glucose/hypo Diary version 1.0 10.09.09)
Full clinical history and examination together with detailed history of SH number and consequences over
the preceding 12 months will be taken. Modified Clarke and Edinburgh questionnaire will be repeated
when completing full study questionnaire pack (Appendix 5).
The 4 week glucose / hypoglycaemia paper diary will be copied and placed within the CRF with the
original remaining with the participant.
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Validated patient-reported outcome questionnaires in addition to new instruments designed to be
sensitive to changes related to study interventions will be completed (see 13.2 Data Collection).
Blood will be taken for HbA1c, U&Es, liver function tests and lipid profile.
All history/examination/investigation data will be recorded on GCP compliant Case Report Forms.
Questionnaires will be completed within designated study packs.
If the participant is willing to proceed with the hypoglycaemic clamp study, separate consent will be
obtained. Participants will be provided with written information, along with opportunity for questions and
will have a minimum of 24 hours to decide whether or not to take part. Informed written consent will be
taken by a member of the research team at each site adhering to guidelines of Good Clinical Practice.
The original signed consent form will be retained in the Investigator Site File, with a copy in the clinical
notes and a copy provided to the participant. The participant will specifically consent to their GP being
informed of their undertaking of a hypoglycaemic clamp study.
The right to refuse to participate without giving reasons must be respected.
If participants do not meet clamp study exclusion criteria (see Appendix 4) and consent to undertaking a
clamp study their CGM profile will be reviewed to determine whether any antecedent biochemical
hypoglycaemia (BH) occurred over the preceding 24 hour period. Studies will be postponed to another
day if any CGM and/or self-monitored capillary glucose below 3.0mmol/l are detected during 24 hours
prior to the study. If this is the case, participants will be asked to be fitted for a further 72 hours CGMS
and to reduce their basal insulin by 25% if on Detemir insulin and by 50% if on Glargine on the night
before the rescheduled clamp study, in addition to making other targeted self-management adjustments
to absolutely prevent glucose levels <3.0mmol/L over the preceding 24 hours.
Participation in the clamp study will require fasting (other than water) from 10pm the evening before,
early morning arrival (approximately 7-8am) and departure after lunch (which will be provided) at
approximately 3 pm. Total additional blood sample volume will be approximately 165ml (about 1 cup full).
See Appendix 4 for full protocol for clamp studies.
Visit 4: Autonomic Function Tests
(visits 4 and 5 may be on the same day)
Participants will be given an appointment to attend for detailed cardiac autonomic function tests (AFTs)
which will be carried out at the established dedicated laboratory at each centre. Participants will be
asked to refrain from smoking and caffeine ingestion on the day of the investigation. The autonomic
function tests are non-invasive and take approximately 45-60 minutes to complete.
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Visit 5: Autoimmune Disease Screening
Participants will attend for a short synacthen test. This test is performed to screen for adrenocortical
insufficiency. 2ml of blood will be taken to measure basal cortisol (0 mins). This will be followed by
intravenous 250µg (in 1 ml) synacthen. 2mls of blood will be taken at 30 mins and 60 mins for cortical
analysis. At this visit a sample will also be taken for serum TSH (Thyroid Stimulating Hormone)
measurement to exclude thyroid disease and for anti-endomysial antibody analysis to exclude coeliac
disease. New diagnoses of other autoimmune diseases will not preclude participation in the study. If
indicated participants with newly diagnosed autoimmune disease will be referred to an appropriate
specialist for further investigation and management. Thyroxine, hydrocortisone/fludrocortisone and/or
gluten free diet will be commenced prior to the RCT intervention period.
Visit 6: Education session
The results of the SMBG (self monitoring blood glucose) diary will be discussed with all participants
forming the basis for the uniform structured re-education programme to be undertaken at each site by
the trained research fellow, specialist nurse and dietician specifically targeted at rigorous avoidance of
BH (biochemical hypoglycaemia) while maintaining overall glycaemic control. This education
programme has been validated in the pilot study and includes carbohydrate counting and discussion of
the glycaemic indices of foods, the effect of exercise on blood glucose, the importance of detection and
prevention of nocturnal hypoglycaemia, self adjustment of insulin doses in light of carbohydrate intake,
SMBG and planned activity, recommendation for oral carbohydrate administration for all glucose levels
less than 4 mmol/L and aspects of blood glucose awareness training (BGAT).
Where feasible, this session will be run in small groups including up to 4 study participants. Individual
one-to-one sessions will, however, be arranged if any participant would prefer this. This will be a single
session lasting no more than 3 hours.
Randomisation
Participants will be allocated by third party concealed randomisation to 24 weeks CSII using insulin
aspart (or insulin lispro if previous intolerance / negative experience with insulin aspart) or MDI using
glargine and insulin aspart (or insulin lispro if previous intolerance / negative experience with insulin
aspart). 50% of each of these two groups will be randomised to the use of real time continuous glucose
monitoring (RT). Therefore there will be four intervention groups with 25 participants in each group as
detailed below.
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Intervention group 1 - CSII with RT
Intervention group 2 – CSII without RT
Intervention group 3 – MDI with RT
Intervention group 4 – MDI without RT
Intervention period
The primary goal of titration throughout will be the absolute avoidance of all glucose levels <3mmol/L as
determined by CGM and SMBG. This will be achieved by setting ‘4 as the floor’ with all glucose levels
<4mmol/L treated by 15g glucose with repeat SMBG every 15 minutes until glucose >4mmol/L in
addition to consideration of insulin dose reduction.
Where attainable without hypoglycaemia, SMBG before breakfast and 4am targets will be 5-7 mmol/L
with other pre-prandial targets 4.5-7 mmol/L and post-prandial targets 6-8 mmol/L (see 11.7 ‘insulin
titration protocol’).
During the intervention period all participants will be telephoned daily for the first week post
randomisation for support in starting their new regimen, to review SMBG values and offer guidance in
initial insulin dose adjustment. Thereafter participants will be telephoned weekly for the remainder of the
randomised control trial period. Participants will have contact numbers for study personnel to contact
between telephone calls/visits if further advice is needed.
Visit 7: Insulin Administration Educational Session / RCT commencement (RCT Week 0)
All patients will have an educational session solely on the technical aspects of the insulin administration
equipment they will be using during the intervention period. The session for
participants randomised to CSII will be restricted to technical aspects of insulin pump management. The
external pump, consumables and insulin will be provided. The session for participants randomised to
MDI will be restricted to insulin device (pen) use and injection site care.
Each participant will be provided with their appropriate titration regimens (11.7). Where feasible, this
session will be run in small groups including up to 4 study participants undertaking the study in parallel.
Individual one-to-one sessions will, however, be arranged if any participant would prefer this. This will be
a single session lasting no more than 3 hours.
On this day, study insulin will be provided using study specific prescriptions with commencement of 24
week RCT of new intervention and 4 week glucose-monitoring / hypoglycaemia diary (hypo COMPASS
Glucose/Hypo Diary version 1.0 100909).
All participants will be telephoned daily over the following 6 days for support in starting their new
regimen, to review SMBG values and offer guidance in initial insulin dose adjustment.
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Visit 8: Review/Blood Glucose Monitoring Session (RCT Week 1)
At this visit, in addition to reviewing progress over the first week, using glucose data to achieve the
primary goal of avoiding biochemical hypoglycaemia will be discussed together with reinforcement of the
other educational tenets of the study.
All participants randomised to real time glucose monitoring will be given an educational session on the
technical aspects of using the RT monitors including trend analysis and the use of the hypoglycaemia
and hyperglycaemia alarms. They will be encouraged to wear the sensor continuously (resiting every 7
days) but flexibly with a minimum of 7 days continuous monitoring in the last week of each month.
Participants not randomised to RT will have an educational session on self blood glucose monitoring.
At this visit arrangements for all participants to upload their anonymised data onto a central server
(Carelink, Medtronic) will be discussed to facilitate optimised self-management (with the research team
also having access to the data to support self management). Participants do not need to consent to this
in order to participate in the study. The use of Carelink is only to facilitate self management and none of
the data collected from Carelink will be used in the study.
Telephone Contact
Participants will be contacted by telephone weekly after visit 8 throughout the RCT to reinforce the
primary goal of biochemical hypoglycaemia avoidance, provide clinical review / support, and ensure
diary completion.
Visit 9: CGMS placement (RCT Week 3)
Participants will attend for placement of subcutaneous sensor for 7 day blinded CGM.
Visit 10: Week 4 follow up (RCT Week 4):
Week 4 attendance for collection of Glucose/Hypo diary; SMBG / CGM data download, HbA1c. Data /
self management review to include review of Carelink data if being uploaded by participant. Clinical
discussion and further participant education. A short ‘4 week questionnaire’ pack will be given to the
participant for later completion and return to the Health Psychology Team (who will be blinded to the
randomised intervention). Participant to return any unused insulin from previous follow up visit and will
be issued with new study specific prescription for the following 4 weeks along with glucose monitoring
strips and real time sensors where applicable.
Visit 11: CGMS placement (RCT Week 7)
Participants will attend for placement of subcutaneous sensor for 7 day blinded CGM.
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Visit 12: week 8 follow up (RCT Week 8):
Week 8 attendance for collection of Glucose/Hypo diary; SMBG / CGM data download, HbA1c. Data /
self management review to include review of Carelink data if being uploaded by participant. Clinical
discussion and further participant education. Participant to return any unused insulin from previous follow
up visit and will be issued with new study specific prescription for the following 4 weeks along with
glucose monitoring strips and real time sensors where applicable.
Visit 13: CGMS placement (RCT Week 11)
Participants will attend for placement of subcutaneous sensor for 7 day blinded CGM.
Visit 14: week 12 follow up (RCT week 12)
Week 12 attendance for collection of Glucose/Hypo diary; SMBG / CGM data download, HbA1c. Data /
self management review to include review of Carelink data if being uploaded by participant. Clinical
discussion and further participant education. Participant to return any unused insulin from previous follow
up visit and will be issued with new study specific prescription for the following 4 weeks along with
glucose monitoring strips and real time sensors where applicable.
Visit 15: CGM placement (RCT Week 15)
Participants will attend for placement of subcutaneous sensor for 7 day blinded CGM.
Visit 16: week 16 follow up (RCT Week 16)
Week 16 attendance for collection of Glucose/Hypo diary; SMBG / CGM data download, HbA1c. Data /
self management review to include review of Carelink data if being uploaded by participant. Clinical
discussion and further participant education. Participant to return any unused insulin from previous follow
up visit and will be issued with new study specific prescription for the following 4 weeks along with
glucose monitoring strips and real time sensors where applicable.
Visit 17: CGMS placement (RCT Week 19)
Participants will attend for placement of subcutaneous sensor for 7 day blinded CGM.
Visit 18: week 20 follow up (RCT Week 20)
Week 20 attendance for collection of Glucose/Hypo diary; SMBG / CGM data download, HbA1c. Data /
self management review to include review of Carelink data if being uploaded by participant. Clinical
discussion and further participant education. Participant to return any unused insulin from previous follow
up visit and will be issued with new study specific prescription for the following 4 weeks along with
glucose monitoring strips and real time sensors where applicable.
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At visit 18 those participants who had a hypoglycaemic clamp prior to intervention will be given a new
copy of the clamp Participant Information Sheet ( Hypo COMPASS clamp Participant information Sheet
version 1.0 10.09.09) to consider participation at the end of the RCT.
Visit 19: CGMS Placement (RCT Week 23)
Participants will attend for placement of subcutaneous sensor for 7 day blinded CGM.
Visit 20: week 24 (RCT Week 24, end of randomised control trial)
Week 24 attendance for collection of Glucose/Hypo diary; SMBG / CGM data download, HbA1c. Data /
self management review to include review of Carelink data if being uploaded by participant.
Questionnaire packs to be repeated at this visit.
On the same day, participants will be invited to attend for end of study stepped hyperinsulinaemic
hypoglycaemic clamp (see clamp protocol Appendix 4).
If the participant had a baseline clamp, does not meet any exclusion criteria (see Appendix 4) and is
willing to proceed with the hypoglycaemic clamp study, separate consent will be obtained. Participants
will be provided with written information, along with the opportunity for questions and will have a
minimum of 24 hours to decide whether or not to take part. Informed written consent will be taken by a
member of the research team at each site adhering to guidelines of Good Clinical Practice. The original
signed consent form will be retained in the Investigator Site File, with a copy in the clinical notes and a
copy provided to the participant. The participant will specifically consent to their GP being informed of
their undertaking of a hypoglycaemic clamp study.
The right to refuse to participate without giving reasons must be respected. Participants can refuse to
participate even if they consented to participate before the intervention period.
If participants consent to undertaking a clamp study their CGM profile will be reviewed to determine
whether any antecedent biochemical hypoglycaemia (BH) occurred over the preceding 24 hour period.
Studies will be postponed to another day if any CGM and/or self-monitored capillary glucose below
3.0mmol/l are detected during 24 hours prior to the study. If this is the case, participants will be asked to
be fitted for a further 72 hours CGM and to reduce their basal insulin by 50% if on glargine on the night
before the rescheduled clamp study, in addition to making other targeted self-management adjustments
to absolutely prevent glucose levels <3.0mmol/L over the preceding 24 hours. See Appendix 4 for full
clamp protocol.
Visit 21: Post RCT Autonomic Function Tests
At end of intervention period patients will be asked to attend for repeat autonomic function tests. These
will be the same tests as described at visit 4.
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Optional exit interview: Experience of the hypo COMPASS Randomised Control Trial (Interview Sub-
study)
When participants complete the 24 week RCT they will be asked if they are willing to participate in an
interview exploring their experiences of taking part in the trial.
Post RCT follow-up
At the end of the 24 week RCT participants will return to routine clinical care within the NHS. Those
participants randomised to the MDI regimen during the trial can be considered for CSII therapy. Those
participants randomised to CSII can continue with this therapy if they wish as by meeting the eligibility
criteria for this study NICE (National Institute for Clinical Excellence) criteria for CSII therapy will have
also been satisfied. After the patient has returned to routine care they will be invited to attend 3 follow up
visits 6, 12 and 18 months after the RCT has finished. Each visit will be preceded by a 7 day CGM
study. Those participants who were given the real time glucose monitor will be able to keep it for the next
18 months (post-Randomised Controlled Trial follow-up period) with sensors provided for intermittent
use. As these are not currently available on the NHS, no sensors will be provided beyond the end of the
overall 2 year study.
Visit 22: CGM placement (6 months-1week after RCT completion)
Participants will attend for placement of subcutaneous sensor for 7 day blinded CGM.
Visit 23: 6 month follow up visit
One month prior to this visit a letter will be sent to the participant with appointment details and with a new
blood glucose/hypo diary (hypo COMPASS Glucose/Hypo Diary version 1.0 10.09.09) to be completed
for 4 weeks before attending. This letter is to be followed up with a telephone call to remind the
participant about the blood glucose/hypo diary.
Attendance for collection of Glucose/Hypo diary; SMBG / CGM data download, HbA1c. Data / self
management review to include review of Carelink data if being uploaded by participant. Clinical
discussion. Questionnaire packs to be repeated at this visit.
Visit 24: CGM placement (12 months-1week after RCT completion)
Participants will attend for placement of subcutaneous sensor for 7 day blinded CGM.
Visit 25: 12 month follow up visit
One month prior to this visit a letter will be sent to the participant with appointment details and with a new
blood glucose/hypo diary ( hypo COMPASS Glucose/Hypo Diary version 1.0 10.09.09) to be completed
for 4 weeks before attending. This letter will be followed up with a telephone call to remind the
participant about the blood glucose/hypo diary.
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Attendance for collection of Glucose/Hypo diary; SMBG / CGM data download, HbA1c. Data / self
management review to include review of Carelink data if being uploaded by participant. Clinical
discussion. Questionnaire packs to be repeated at this visit.
Visit 26: CGM placement (18 months-1week after RCT completion)
Participants will attend for placement of subcutaneous sensor for 7 day blinded CGM.
Visit 27: 18 month follow up visit (last study visit)
One month prior to this visit a letter will be sent to the participant with appointment details and with a new
blood glucose/hypo diary ( hypo COMPASS Glucose/Hypo Diary version 1.0 10.09.09) to be completed
for 4 weeks before attending. This letter will be followed up with a telephone call to remind the
participant about the blood glucose/hypo diary.
Attendance for collection of Glucose/Hypo diary; SMBG / CGM data download, HbA1c. Data / self
management review to include review of Carelink data if being uploaded by participant. Clinical
discussion. Questionnaire packs to be repeated at this visit.
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11
STUDY DRUGS AND DEVICES
11.1 Drugs General Information
In accordance with the Medicines for Human Use (Clinical Trials) Regulations 2004 and Directive
2001/20/EC the drugs under investigation in the above trial fall under the definition of ’investigational
medicinal product’ (IMP). As with all medication for people with diabetes mellitus these drugs will be
supplied free of charge. Although the insulins used during this trial fall under the definition of IMPs they
will be used under existing licence agreements.
Packaging, labelling and distribution will be performed by the Sponsor or Sponsor’s designees in
accordance with regulatory guidelines and all local legal requirements. Each study centre will maintain a
drug disposition log in which they will record all information regarding the administration of study drug
and return of unused vials.
The responsibility for study drug control, administration and accountability rests with the Principal
Investigator at each site. Study drug administration and/or maintenance of study drug accountability
records may be delegated to trained, qualified staff members, but these responsibilities remain with the
Principal Investigator.
11.2 Insulin for MDI Participants
11.2.1 Insulin Aspart (Novorapid)
For the participants randomised to MDI (Multiple Daily Injections) Insulin Aspart will be given as follows:
Formulation: 3 ml cartridge 100 Units/mL in a pre-filled pen (Flexpen).
Insulin aspart (novorapid) is a recombinant human insulin analogue that is a rapid acting parenteral blood
glucose-lowering agent. Aspart is a clear, colourless aqueous solution for SC injection. Each millilitre of
Aspart injection contains 100 Units of insulin aspart. Aspart must not be mixed with any other insulin
including Glargine. Separate injections of the different insulins must be given. Novorapid Flexpen is a
pre-filled insulin delivery device for use of insulin aspart. This device allows dose dialling in one-unit step
increments between one unit and a maximum of 60 units.
The prefilled devices will be stored between 2°C and 8°C in a refrigerator until use and will be allowed to
warm up to room temperature before the first injection. Participants will be told that in use the device
needs to be stored at room temperature below 30°C without the needle attached. Once punctured it can
be used for up to 28 days and cannot be exposed to excessive heat or sunlight. The pen cap should
always be replaced to avoid dust and dirt from getting into the pen. The needle will be removed after
every injection and the device will be stored without a needle attached. This prevents contamination
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and/or infection, or leakage of insulin, and will ensure accurate dosing. Participants will be told that a
new needle should be used for each injection to prevent contamination.
Please see Appendix 6 for summary of product characteristics of Novorapid flexpen 100U/mL solution
for injection in pre-filled pen.
11.2.2 Insulin Glargine (Lantus)
For the participants randomised to MDI the glargine will be given as follows:
Formulation: 3 ml cartridge 100 Units/mL in a pre-filled pen (SoloStar).
Glargine is a recombinant human insulin analogue that is a long acting parenteral blood glucoselowering agent. Glargine is a clear, colourless aqueous solution for SC injection. Each millilitre of
glargine injection contains 100 Units of insulin glargine. Lantus SoloStar is a pre-filled delivery device
containing 3 mL insulin glargine. This device allows dose dialling in one-unit step increments between
one unit and a maximum of 80 units.
The glargine prefilled devices will be stored between 2°C and 8°C in a refrigerator until use and
participants will be told that the device should be allowed to warm up to room temperature before the first
injection. In use the prefilled device should be stored at room temperature below 25°C without the needle
attached. The prefilled device should be protected from moisture and direct heat. Participants will be told
that the pen cap should always be replaced to avoid dust and dirt from getting into the pen. The prefilled
device can be used for up to 28 days under normal conditions.
See Appendix 7 for summary of product characteristics of Lantus 100U/mL solution for injection in a prefilled pen.
11.2.3 Insulin Lispro (Humalog)
For the participants randomised to MDI (Multiple Daily injections) Insulin Aspart will be the rapid acting
insulin analogue of choice. However for those patients who have had a previous negative experience or
adverse effect with insulin aspart the alternative of insulin lispro will be offered
Formulation: 3 ml cartridge 100 Units/mL in a pre-filled pen (Kwikpen).
Insulin lispro (humalog) is a recombinant human insulin analogue that is a rapid acting parenteral blood
glucose-lowering agent. Lispro is a clear, colourless aqueous solution for SC injection. Each millilitre of
Lispro injection contains 100 Units of insulin lispro. Lispro must not be mixed with any other insulin
including Glargine. Separate injections of the different insulins must be given. Humalog Kwikpen is a
pre-filled insulin delivery device for use of insulin lispro. This device allows dose dialling in one-unit step
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increments between one unit and a maximum of 60 units. Pharmacokinetics and pharmacodynamics of
insulin Lispro are equivalent to those of insulin Aspart.
The prefilled devices will be stored between 2°C and 8°C in a refrigerator until use and will be allowed to
warm up to room temperature before the first injection. Participants will be told that in use the device
needs to be stored at room temperature below 30°C without the needle attached. Once punctured it can
be used for up to 28 days and cannot be exposed to excessive heat or sunlight. The pen cap should
always be replaced to avoid dust and dirt from getting into the pen. The needle will be removed after
every injection and the device will be stored without a needle attached. This prevents contamination
and/or infection, or leakage of insulin, and will ensure accurate dosing. Participants will be told that a
new needle should be used for each injection to prevent contamination.
See Appendix 8 for summary of product characteristics of Humalog 100U/mL Kwikpen, solution for
injection
11.3 Insulin for use in CSII Groups
For participants randomised to CSII, insulin aspart (novorapid) will be the insulin used.
Formulation: 10 ml vial 100 Units/mL
Insulin aspart (novorapid) is a recombinant human insulin analogue that is a rapid acting parenteral blood
glucose-lowering agent. Aspart is a clear, colourless aqueous solution for SC injection. Each millilitre of
aspart injection contains 100 units of insulin aspart. When used for CSII aspart must not be mixed with
any other insulins. The vials will be stored between 2°C and 8°C in a refrigerator until use and will be
allowed to warm up to room temperature before being used to fill the insulin pump’s reservoir.
Participants will be given training on the technical aspects of how this is done during an educational
session. During the education session participants will be told that the remaining insulin aspart in the
pump’s reservoir should be changed every 48 hours as insulin degradation may occur after this time.
The insulin aspart should not be exposed to temperatures greater than 37°C. See appendix 6 for
summary of product characteristics of Novorapid 100u/ML solution for injection in 10mL vial.
Insulin lispro can be used instead of insulin aspart in the CSII group for those participants who have had
previous negative experience / adverse effect with aspart. Insulin lispro should not be exposed to
temperature greater than 37°C. Insulin lispro for use in the CSII group will be provided in 10ml vials 100
Units/mL. Prior to opening the vial it should be stored between 2°C and 8°C in a refrigerator and then
allowed to warm to room temperature before being used to fill the insulin pump’s reservoir. The
remaining insulin lispro in the pump’s reservoir should be changed every 48 hours. Open vials of insulin
lispro can be kept for up to 28 days before being discarded.
Insulin lispro: formulation 10 ml vial 100 Units/mL
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See Appendix 8 for summary of product characteristics of humalog 100U/mL solution for injection in
10mL vial.
11.4 Study Drug Administration
11.4.1 Packaging and labelling
This is an open study and the treatments will not be blinded. The packaging and labelling is under the
Sponsor’s responsibility.
Insulin Glargine (Lantus) will be packaged in boxes of 5 SoloStar pens.
Insulin Aspart (Novorapid) will be packaged in boxes of 5 FlexPens for those participants in MDI group.
Insulin Lispro (Humalog) will be packaged in boxes of 5 KwikPens for those participants in MDI Group.
Insulin Aspart (Novorapid) and Insulin Lispro (Humalog) will be packaged in boxes of single 10 mL vials
for those participants in CSII group.
The content of the labelling is in accordance with the local regulatory specifications and requirements.
The hospital pharmacist at each study site will be responsible for ensuring that the Investigational
Product used in the clinical trial is securely maintained as specified in the pharmacy manual and in
accordance with the applicable regulatory requirements.
All Investigational Product shall be dispensed in accordance with the Investigator's prescription and it is
the Investigator's responsibility to ensure that an accurate record of Investigational Product issued and
returned is maintained. Any quality issue noticed with the receipt or use of an Investigational Product
(deficient IP in condition, appearance, pertaining documentation, labelling, expiry date, etc.) should be
promptly notified to the Sponsor, who will initiate a complaint procedure.
11.5 Concomitant Medications
At visit 1 as part of full clinical history a full medication history will be taken. Information recorded will be
generic name, route of administration, dose and frequency. All medications other than the study drugs
that the subject takes from 1 month before the first dose of the study drug are considered concomitant
medications. These include:
•
Prophylaxis medications
•
Herbal preparations
•
Nutritional supplements
At each follow up visit subjects will be asked what concomitant medications they are taking.
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11.6 Expected Adverse Reactions
When insulin is used for subcutaneous injection possible side effects include local reactions including
transient oedema of the injection site and fat hypertrophy. Rarely hypersensitivity reactions can occur
such as urticaria and rash.
11.7 Insulin Titration Protocols
11.7.1
Blood Glucose Targets (for all patients in CSII and MDI groups):
Fasting blood glucose (FBG) :
5.0 - 7.0 mmol/L
Pre-prandial blood glucose:
4.5 - 7.0 mmol/L
3am blood glucose:
5.0 – 7.0 mmol/L
Post-prandial glucose*:
6.0 – 8.0 mmol/L
Bedtime blood glucose**:
6.0 – 8.0 mmol/L
*postprandial blood glucose: measurement made 2 hours after the start of a meal
**bedtime blood glucose: measurement made within 30 minutes of retiring to bed for the night.
11.7.2
Glargine titration in MDI Group
Insulin glargine will be self-administered and the following titration protocol will be followed.
•
Take within 30 minutes of retiring to bed for night / no need for snack
•
Aim for stable (not falling) glucose through the night
•
Reduce dose if any hypoglycaemic episodes or glucose <5mmol/L between 4am and before
breakfast
•
Target glucose of 5-7mmol/l before breakfast – adjust dose by 1-2 units to maintain target if
necessary with primary aim being absolute avoidance of BH (Biochemical Hypoglycaemia)
During periods of illness, basal insulin doses may need to be altered and this will be guided by SMBG
levels.
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11.7.3 Introduction of twice daily glargine
Participants randomised to MDI already on twice daily glargine will continue on this from the outset of the
RCT.
In other MDI participants, if glucose is consistently >7mmol/L before evening meal or highly variable
between breakfast and evening meal, add second dose of insulin glargine before breakfast. Initial dose
will be 4 units but can be adjusted in light of participant’s current insulin doses. If glucose has been
falling through the night, a 2-4 unit reduction in evening glargine dose will be actioned before bed on the
day of commencing the morning dose. The addition of a second daily glargine dose will be considered in
all participants on the MDI group. This can be initiated between study visits if necessary, eg after
telephone advice.
Morning insulin glargine will be self-administered and adjusted as below:
•
Take within 30 minutes of rising from bed for the morning
•
Aim for stable (not falling) glucose through the afternoon
•
Reduce dose if any hypoglycaemic episodes or glucose <5mmol/L between 2 hours after lunch
and evening meal
•
Target glucose of 5-7mmol/l before evening meal – adjust dose by 1-2 units to maintain target if
necessary with primary aim being absolute avoidance of BH
11.7.4
Basal Insulin titration in CSII Group
The basal insulin delivery rate will be titrated according to fasting, bedtime, pre-prandial and 4am
glucose levels ensuring absence of recurrent low glucose levels at these times (checkpoints). Increased
or decreased delivery will be commenced from the previous basal insulin checkpoint level i.e. if low at
4am – decrease from bedtime; if high fasting increase from 4am.
Mean fasting; bedtime; 4am and pre-prandial blood glucose:
Within target:
No change to basal delivery rate
Above target:
Increase basal insulin by 0.1 U/hr from
previous check point
Below target or unexplained late post-
Decrease basal insulin by 0.1 U/hr from
prandial hypoglycaemia:
previous check point
During periods of illness, basal insulin rates may need to be altered and this will be guided by SMBG
levels.
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11.7.5 Meal time insulin bolus in all groups (CSII and MDI):
All participants will be taught carbohydrate counting and bolus dose adjustment in light of current blood
glucose level / individualised insulin carbohydrate ratios. Aspart or lispro will be delivered either by
subcutaneous injection or as a subcutaneous pump bolus before all meals and potentially before
carbohydrate containing snacks.
Insulin: carbohydrate ratios will be calculated for all individuals using the ‘500 rule’ and using total daily
insulin doses pre-randomisation. The ‘500 rule’ is:
500 divided by the TDD (Total Daily Dose of insulin) = grams of carbohydrate covered by one unit
of aspart or lispro
In the event of high pre-prandial glucose levels corrective doses should also be given with meals as part
of the meal time bolus. This will be calculated using the ‘100 rule’ for estimation of Insulin Sensitivity
Factor. The ‘100 rule’ is
100 divided by the TDD (Total daily Dose of insulin) = glucose drop in mmol/L per 1 unit of aspart
or lispro.
This will be presented to all patients as ‘1 unit of aspart/lispro will reduce your blood glucose by x
mmol/L’.
Corrective doses with all pre-main meal boluses / prandial insulin injections will be encouraged
according to the 100 rule when glucose level is above target.
If glucose level is consistently below or above target 2 hours after a bolus / prandial insulin injection,
Insulin: Carbohydrate ratio and Insulin Sensitivity Factor for that period of the day will be adjusted
accordingly.
If any unexplained hypoglycaemic event occurs 2 hours after a bolus / prandial insulin injection, Insulin:
Carbohydrate ratio and Insulin Sensitivity Factor for that period of the day will be adjusted accordingly.
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11.8
Insulin Pumps
Fifty percent of participants will be randomised to continuous subcutaneous insulin infusion therapy
(CSII). The pump being used is the CE-marked Medtronic Veo pump (Medtronic). All participants
randomised to CSII (insulin pump therapy) will be given a single additional session restricted to technical
aspects of pump management. Patients will be advised of the need to change the infusion set at least
every 72 hours.
Initial basal rate calculation:
All participants commencing insulin pump therapy will start on a single basal insulin infusion rate. This
will be calculated using the following:
Pre-pump total daily dose, reduced by 25%, divided by 2, (1/2 for total basal, ½ for total
bolus), divided by 24 (hours in the day) = estimated hourly basal rate.
Further basal rates will be introduced if necessary to achieve BH avoidance and glycaemic targets.
Otherwise, equivalent education and support will be given to the CSII group as the MDI group.
As with all participants in the study, patients starting on CSII therapy will be contacted by the diabetes
team daily for the first week after randomisation to review their blood glucose values and weekly
thereafter. If there is a frequent or prolonged episode of hypoglycemia or hyperglycemia both MDI and
CSII participants will be instructed to contact the diabetes team immediately for further advice.
11.9 Real Time Continuous Glucose Monitors
Fifty percent of all participants will be randomised to real time monitoring. The monitor being used is the
CE-marked REAL time continuous glucose monitor (Medtronic). All participants will have an educational
session on the recording of home blood glucose monitoring but for those participants randomised to real
time continuous glucose monitoring (RT) this session will include the technical aspects of using the
monitor. This includes trend analysis, hypoglycaemia and hyperglycaemia alarms. Participants will be
given written instructions on how to use the data provided by continuous glucose monitors to make realtime adjustments of insulin doses and on the use of computer software (for those with a home computer)
to retrospectively review the glucose data to alter future insulin doses. Participants randomised to RT will
be encouraged to wear the sensor continuously but flexibly with a minimum of 7 days continuous
monitoring in the last week of each month. Those participants randomised to RT will be advised to resite the sensor every 7 days.
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11.10 Standard Continuous Glucose Monitors
CGM will be undertaken using the CE-marked Medtronic wireless iPro system. The monitor will be fitted
to patients at the study visits as outlined in the visit schedule. These will be used in the 4 week wash in
period and during the last seven days of every month. The patients are blinded to the results of this
monitoring system until the data is downloaded at the end of the 7 days. The results of the CGM are then
used to form part of the individualised education programme at each of the study visits
12
BLINDING
This is an open study with both participants and investigators aware of the treatment groups.
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13 STUDY DATA
13.1
Time Line of Assessments and Data Collection
See schedule of events (Appendix 9) for a full outline of the data collection at each visit.
13.2
The Assessments
Two dedicated questionnaire booklets will be completed pre-randomisation, at RCT completion and at
post-RCT follow-up visits: 24 weeks, 12 months, and 18 months. The first will comprise the measures
relating to hypoglycaemia experience, namely: the Gold Score, Edinburgh Hypoglycaemia Survey,
Hypoglycaemia Awareness Questionnaire (HypoA-Q), Guy’s and St Thomas’ Minimally Modified Clarke
Hypoglycaemia Survey, Fear of Hypoglycaemia Survey (FHS), High Blood Sugar Survey (FoHyper
Questionnaire), Hypoglycaemia Cues Questionnaire (HypoC-Q), Attitudes to Awareness of Hypos
Questionnaire, Hypoglycaemia Burden Questionnaire (HypoB-Q). The second will comprise the health
and well-being measures, namely: Quality of Life Questionnaire (QoL-Q), Diabetes Treatment
Satisfaction Questionnaire (status; DTSQs 1), Blood Glucose Monitoring Questionnaire (BGM-Q), Insulin
Treatment Satisfaction Questionnaire (ITSQ) 2, EQ – 5D and the Perceived Control of Diabetes Scales.
Please see appendix 5 for copies of these questionnaires.
While these questionnaire measures may be considered relatively burdensome, taking up to 45 minutes
each to complete, our experience has been that this is well-tolerated by those with Type 1 diabetes
mellitus participating in complex trials of this nature. Participants are motivated to help researchers
understand the full impact of diabetes and its treatments on outcomes of importance to the individual
participants and often welcome the opportunity to share their experiences, finding it a gratifying
experience.
The Hypo Awareness Questionnaire has been designed with patient and clinician input to assess
patient-reported awareness (or impaired awareness) of hypoglycaemia. The Hypo Burden
Questionnaire has also been designed with patient and clinician input to assess the perceived frequency,
severity and burden of autonomic and neuroglycopenic symptoms of hypoglycaemia.
Both these measures (awareness and burden) are intended to improve upon the previously wellestablished but limited measures of IAH and hypoglycaemic symptoms. These instruments have been
finalised for use following patient input, including a pilot study in this patient population which involved
detailed cognitive debriefing of the instruments to assess patient understanding as well as
comprehensiveness and the need to modify or remove any items.
1
The DTSQs will be administered unless ceiling effects are observed at baseline, in which case the ‘change
version’ (DTSQc) will be administered
2
Two full subscales only relating to hypoglycaemia and insulin delivery method
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Blood Glucose levels (SMBG)
Participants will use paper blood glucose diaries (Clinical Trial hypo COMPASS Glucose/hypo diary
version 1.0 10.09.09) at home to record their blood sugar readings. Subjects will be expected to check
their blood glucose at least 4 times daily for the duration of the study period. Participants will also be
asked to record weekly 8 point profiles.
HbA1c
HbA1c will be recorded at visits as shown in the schedule of events (Appendix 9). HbA1c is a secondary
endpoint. This sample will be analysed locally and reported in both IFCC units (mmol/mol) and derived
NGSP units (%) using the IFCC-NGSP master equation.
Continuous Glucose Monitoring Results
Each participant will undertake a CGM for a target period of 7 days every month as shown in the
schedule of events in addition to a 7 day period in the 4 week wash in period. The data from these will
be recorded on the CRF.
Autonomic Function tests
Participants will be asked to undertake autonomic function tests before the RCT period and at 24 weeks
+/- 10 days. These will be done at dedicated laboratories at each centre. Change in results from
autonomic function tests will be a secondary endpoint.
Clamp data (biochemical: C-peptide, plasma catecholamines, cortisol, Growth Hormone,
Glucagon, Insulin)
These samples will be analysed centrally at Newcastle in the dedicated endocrinology research
laboratory.
Glucagon:
2.5 mL of whole blood drawn into tube containing 0.25mL Trasylol and EDTA. A
sequential radioimmunoassay will be used for glucagon assay
Catecholamines:
4mL of whole blood drawn into Lithium heparin tube. A non competitive enzyme
linked immunosorbent assay kit will be used to measure epinephrine or
norepinephrine in plasma.
Cortisol:
2.5mL of whole blood drawn. ADVIA Centaur Cortisol Assay will be used to
measure cortisol in the serum samples.
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Growth hormone:
3 mL of whole blood drawn. GH measured using a Nichols Advantage assay
using a two-site chemiluminescence immunoassay procedure.
Insulin:
Blood samples for insulin will be collected as 3ml samples in EDTA tubes, and
centrifuged at 2500 rpm for 2 minutes. Equal volumes of a polyethylene glycol
(PEG) buffer will be added, samples vortexed and then spun for 30 minutes to
remove the precipitated globulin fraction. The supernatant will be frozen for assay
(stored at -20) and free insulin measured by double-antibody enzyme linked
immunosorbent assay.
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Clamp data (cognitive function tests)
See Appendix 4 for the protocol for the clamp study and the details of the cognitive function tests.
Body weight and BMI
Body weight and height will be recorded at visits as shown in the schedule of events. Body mass index
will be recorded as: BMI = weight (kg) [height (m)] 2
C-peptide levels
A C-peptide level will be checked at screening. The sample will be analysed locally. A fasting serum Cpeptide level below the quality assured limit of detection for the assay and laboratory with simultaneous
exclusion of biochemical hypoglycaemia (glucose <4.0 mmol/L) by laboratory glucose level analysis on a
sample taken at the same time point will be required to meet eligibility criteria.
Physical Examinations
A general clinical examination will be carried out at baseline, RCT completion and at 6, 12 and 18 month
post RCT follow up visits. This will be focussed towards the detection of complications of diabetes
mellitus such as autonomic dysfunction.
Medical Histories
A complete medical history will be obtained at baseline visit, completion of RCT visit and at 6, 12 and 18
month post RCT follow up visits. The medical history will be obtained by the principal investigator or a
sub investigator who has been trained on this study. It will include evaluations of insulin regimen and
mean total daily dose, past experience of hypoglycaemic episodes, substance misuse, allergies, family
history of diabetes mellitus, details of any cohabitants who also have diabetes mellitus and details of any
symptoms of the respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, dermatological and
genitourinary systems.
13.3
Data Handling
Power Trial’s Symphony web software will be used for data collection and management. Access to this
system will be restricted and staff accessing the database via secure login will not have access to any
identifier data other than study ID number. This system provides electronic case report forms (eCRFs)
that allow remote data entry, source document verification, query resolution and audit trail of all entries,
compliant with GCP regulations. Data will be held on a secure server and automated failover and
backup will be provided. Only authorised users with appropriate access permissions will be able to
enter/view/edit data.
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The quality and retention of study data will be the responsibility of the Newcastle Clinical Trials Unit.
Data will be collected to standards required by the latest Directive on GCP (2005/28/EC) and local policy
and will adhere to the Data Protection Act 1998. All study data will be archived in line with Trust policy
(currently 15 years).
All Investigators and their participating institutions must permit site monitoring, audits, REC and MHRA
review and must provide direct access to source data and documents as required for these purposes.
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14
STATISTICAL METHODS
14.1 Power and sample size considerations
The sample size was determined pragmatically based on what was thought to be achievable in the time
proposed. However, using pilot study data, the sample size of 100 (25 in each of the four groups) would
give 80% power at a significance level of 0.05 to detect a difference of 1.1 between the IAH scores of the
50 patients randomised to either of the CSII arms and the 50 randomised to either of the MDI arms. A
difference of greater than 1 is considered to be a clinically relevant change on the IAH scale. The
calculation is based on the use of the 2-sample t-test and the assumption, taken from the pilot data, that
the standard deviation of the IAH score is 2 (Pilot data for mean±SD was 2.57±1.90 in the CSII arm and
4.0±1.79 in the MDI arm).
14.2 Statistical analysis
The IAH (Impaired Awareness of Hypoglycaemia) score at 24 weeks is the primary endpoint; this will be
obtained from the validated Gold psychosocial questionnaire measure. This measure will then be
compared with the Clarke psychosocial questionnaire measure and an additional newly devised
psychosocial questionnaire measuring hypoglycaemia awareness.
The principal analysis will examine the factorial structure of the treatment and monitoring regimen effects
on the difference in the IAH score at 24 weeks using Analysis of Covariance (ANCOVA). Baseline IAH
and stratification (centre and baseline HbA1c) variables will be included among the covariates in addition
to suitable summaries of questionnaire scores and glucose monitoring data collected at baseline prior to
randomisation. The glucose monitoring data to be collected includes both time spent and area under the
curve for the following separate ranges: <2.5 mmol/L, <3mmol/L, <4mmol/L, >7mmol/L, >10 mmol/L,
between 4 and 7 mmol/L and between 3 and 10 mmol/L. The inclusion of baseline HbA1c as a covariate
will additionally, enable the examination of possible interactions between effects observed and these
values.
Wherever possible patients who elect to withdraw from the study will be followed up so that final
outcome data is obtained; this will then allow their inclusion in analysis by Intention to Treat (ITT).
Similar methods will be used to examine the association between the results of the clamp test at 24
weeks and the corresponding IAH score. Additional analyses using HbA1c and the separate glucose
monitoring measures as outcome variables will also be undertaken as will an analysis of the number of
participants no longer defined as having IAH after the intervention according to the Gold questionnaire
(i.e. a score < 4).
A number of exploratory analyses will also be undertaken. Specifically, logistic regression will be used to
assess factors associated with non-response to study interventions. Non-responders will be defined as
those from all interventions with no improvement in IAH score. Responders will be defined as those
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(allocated to any interventional arm) with improved IAH score. It is hypothesised that risk factors for nonresponse include (irreversible) autonomic neuropathy and preference for rigorous avoidance of high
glucose levels at the expense of ongoing biochemical hypoglycaemia. Autonomic neuropathy will be
assessed using scores from validated questions which will be compared between the groups of patients
defined as responders and non-responders. Similar analyses will be undertaken to compare other
measures of autonomic function in addition to scores from the Hyperglycaemia Fear Questionnaire, the
Hypo Cues Questionnaire and the Attitudes to Awareness of Hypos Questionnaire.
In addition, analyses will be undertaken to examine the joint distributions of questionnaire score against
both HbA1c values and time longitudinally.
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15
COMPLIANCE AND WITHDRAWAL
15.1 Participant Compliance
Compliance of study medication will be estimated by using the returned insulin pens and vials.
Quantitative assessment will not be possible as insulin doses will vary during the study and between
patients. Treatment exposure will be presented as the total dose of insulin received and the total
duration of the randomised therapy.
15.2 Participant Withdrawal
Participants have the right to withdraw from the study at any time for any reason. The investigator also
has the right to withdraw patients from the study in the event of significant inter-current illness, AEs,
SAE’s, SUSARs, protocol violations, administrative reasons or other reasons. It is understood by all
concerned that an excessive rate of withdrawals can render the study uninterpretable; therefore,
unnecessary withdrawal of patients should be avoided. Level of withdrawal from the study should be
confirmed with patients when the decision to withdraw trial therapy is made; if possible patients should
be followed on an ‘intention-to treat’ basis, with repeat testing at the same intervals as if they had
continued on therapy. Any such patients will complete the full follow-up schedule and will be analysed on
an ‘intention-to-treat’ basis in the group to which they were originally allotted.
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16
INTERIM ANALYSIS AND DATA MONITORING
16.1 Discontinuation rules
The trial may be prematurely discontinued on the basis of insufficient recruitment to power the trial, new
safety information, or for other reasons given by the Trial Steering Committee (TSC) / Data Monitoring
and Ethics Committee (DMEC), regulatory authority or ethics committee concerned.
If the study is prematurely discontinued active participants will be informed and no further participant
data will be collected.
The randomisation list will be held centrally by the NCTU. The person with responsibility for the list is
independent of the trial.
16.2 Trial Coordination, monitoring, quality control and assurance
The Trial will be managed through the Newcastle Clinical Trials Unit (NCTU), Newcastle University,
where the trial manager will be based and from where data management will be controlled and data
analysed. The NCTU has extensive experience of conducting multi-centre clinical trials in all health
service sectors.
16.2.1 Data monitoring and Ethics Committee
An independent data monitoring and ethics committee (DMEC) (2 physicians not connected to the trial
with at least one with expertise in hypoglycaemia, one statistician and one patient representative) will be
convened to undertake independent review. The purpose of this committee would be to monitor efficacy
and safety endpoints. The DMEC will have full access to unblinded study data. The committee will meet
at least 3 times, at the start, middle and completion of the randomised control period. At least one of
these visits should be in person the others may be via teleconference. At the first meeting, DMEC will
discuss and advise on the inclusion of an interim analysis and possible adoption of a formal stopping rule
for efficacy or safety.
16.2.2 Trial Steering Committee
A Trial Steering Committee (TSC) will supervise the trial, to ensure it is conducted to high standards in
accordance with the protocol, the principles of GCP, and with regard to participant safety. This
committee will have an independent chair with expertise in hypoglycaemia and in addition to the Chief
Investigator (Professor James Shaw) and principal investigators (Professor S Heller, Dr M Evans, Dr D
Flannagan, Dr D Kerr, Dr J Speight) will consist of a Sponsor/Funder representative, representatives of
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the Newcastle Clinical Trials Unit (including Dr Thomas Chadwick, NCTU Statistician, & Dr Julia
Stickland NCTU Trial Manager) Ruth Wood, Database Manager and two consumer representatives.
The TSC will meet prior to the recruitment of the first patient, at the conclusion of the Randomised
Control trial Period, 1 year after the RCT and finally 2 years after the RCT. A teleconference will be
arranged for 3 months after the first patient is recruited. The TSC will also consider safety issues for the
trial and relevant information from other sources, ensuring at all times that ethical considerations are met
when recommending the continuation of the trial.
16.2.3 Trial Management Group
A trial management group consisting of the Chief Investigator, Trial Manager, Statistician, Trial Data
Manager and Newcastle Clinical Research Associate will meet quarterly to discuss the operational
aspects of the trial.
16.2.4 Principal Investigators
The Principal Investigators will be responsible for the day-to-day study conduct at site. The Trial
Manager will provide day-to-day support for the sites and provide training through Principal Investigator
meetings, site initiation and routine monitoring visits.
16.2.5 Trial Monitoring
The Trial Manager will ensure that the study is conducted in accordance with GCP through a
combination of central monitoring and site monitoring visits. A monitoring plan will be written and agreed
prior to randomisation.
Central monitoring will include:
•
Reviewing (for accuracy and completeness prior to submission) all applications for study
authorisations.
•
Reviewing (for accuracy and completeness prior to submission) all submissions of
progress/safety reports.
All documentation essential for study initiation will be reviewed prior to site authorisation.
Site monitoring will include:
•
The presence of essential documents in the study file will be checked
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•
Consent forms will be reviewed as part of the site study file and the presence of a copy in the
treatment notes confirmed
•
Consent forms will be compared against the study participant identification list
•
All reported serious adverse events will be verified against treatment
•
Notes/medical records
•
Drug accountability & management will be checked
All monitoring findings will be reported and followed up with the appropriate persons in a timely manner.
A final site visit (close-out visit) will be performed at the end of the study
•
To complete final monitoring requirements, as above
•
To review archiving of study documentation
•
Final drug reconciliation and destruction/return
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17
PHARMACOVIGILANCE AND ADVERSE EVENTS
17.1 Definition
An adverse event is any untoward medical occurrence in a subject who has received an investigational
product and which does not necessarily have a causal relationship with this treatment. An adverse event
(AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use of an investigational product, whether or not
related to the product.
A serious adverse event (SAE) is an AE that results in any of the following outcomes:
1. Death
2. A life threatening adverse drug experience
3. Inpatient hospitalisation or prolongation of existing hospitalisation
4. A persistent or significant disability/incapacity
5. A congenital anomaly/birth defect
Life-threatening in the definition of a serious adverse event or serious adverse reaction refers to an event
in which the subject was at risk of death at the time of the event; it does not refer to an event which
hypothetically might have caused death if it were more severe. Medical judgement should be exercised
in deciding whether an adverse event or reaction is serious in other situations.
Important adverse events or reactions that are not immediately life-threatening or do not result in death
or hospitalisation but may jeopardise the subject or may require intervention to prevent one of the other
outcomes listed in the definition above, should also be considered serious.
An ‘adverse reaction’ is an untoward or unintended response to an investigational medicinal product
(IMP) related to any dose administered.
A ‘suspected unexpected serious adverse reaction’ (SUSAR) is an adverse reaction that is both serious
and unexpected. An adverse reaction is unexpected when its nature or severity is not consistent with the
applicable product information. The PI at the site responsible for the care of the participant will assess
the expected or unexpected nature of any serious adverse reactions.
Important medical events that do not meet this definition may be considered serious when based upon
appropriate medical judgement, they may jeopardise the subject and may require medical or surgical
interventions to prevent one of the outcome listed in the definition.
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17.2 Causality
The adverse events and adverse drug reactions that occur in this study, whether they are serious or not,
will be due to the nature of treatment with insulin used in this study. The assignment of the causality
should be made by the local investigator responsible for the care of the participant using the definitions
in the table below. All participants judged as having a reasonable suspected causal relationship (i.e.
definitely, probably or possible) are considered to be adverse reactions. If any doubt about the causality
exists the local investigator should inform the study coordination centre who will notify the Chief
Investigator to adjudicate. In cases of real difficulty the DMEC will act as final arbitrator.
Relationship Description:
Relationship
Unrelated
Unlikely
Possible
Probable
Definitely
Not
assessable
Description
There is no evidence of any causal relationship
There is little evidence to suggest there is a causal relationship (e.g. the event
did not occur within a reasonable time after administration of the trial
medication). There is another reasonable explanation for the event (e.g. the
participant’s clinical condition, other concomitant treatment).
There is some evidence to suggest a causal relationship (e.g. because the
event occurs within a reasonable time after administration of the trial
medication). However, the influence of other factors may have contributed to
the event (e.g. the participant’s clinical condition, other concomitant
treatments).
There is evidence to suggest a causal relationship and the influence of other
factors is unlikely.
There is clear evidence to suggest a causal relationship and other possible
contributing factors can be ruled out.
There is insufficient or incomplete evidence to make a clinical judgement of the
causal relationship.
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17.3 Follow up period of adverse events
The period during which adverse events will be reported is defined as the period from the beginning of
the RCT either with CSII or MDI to the end of the randomised control trial period at 24 weeks when the
professional responsibility for the ongoing diabetes care will return to patient’s pre-study medical team.
The investigator will continue to follow all AEs until resolution, until the condition stabilizes, until the
event is otherwise explained, or until the subject is lost to follow up. The follow up of AEs may therefore
extend after the end of the RCT. However no new AEs will be reported after the 24 week RCT period. A
full clinical history will be taken at follow up visits 6, 12 and 18 months after the RCT but there will be no
interim reporting between these visits.
17.4 Protocol Specifications
For purposes of this protocol:
•
All non-serious adverse events will be systematically elicited and recorded on the relevant eCRF
(electronic case report form) at each of the 4 weekly appointments for the duration of the trial (as
will any such adverse reactions spontaneously reported by participants between follow-up visits).
•
Any serious adverse events will be recorded throughout the duration of the trial, until 4 weeks
after trial therapy is stopped or the outcome of any necessary management is established.
•
Serious adverse events exclude any pre-planned hospitalisations not associated with clinical
deterioration.
•
Serious adverse events exclude routine treatment or monitoring of the studied indication, not
associated with any deterioration in condition.
•
Serious adverse events exclude elective or scheduled treatment for pre-existing conditions that
did not worsen during the study.
•
Serious adverse events exclude severe hypoglycaemia not requiring hospital admission (this is a
secondary outcome measure, already documented and monitored within study)
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18
THE REPORTING OF ADVERSE EVENTS
All AEs, including those the subject reports spontaneously, those the Investigators observe, and those
the subject reports in response to questions must be recorded in the source documents. Pregnancies
must be reported but are not necessarily classified as AEs.
18.1 Reporting of Non serious adverse events
Adverse Event (including Adverse Reaction): All non-serious adverse events / reactions during drug
treatment will be reported on paper AE forms to be held within the participants’ study file. These will also
be uploaded to the eCRF by the central study team. Severity of AEs will be graded on a three-point
scale: mild, moderate, severe (see below). Relation of the AE to the treatment should be assessed by
the principal investigator at each site. The individual investigator at each site will be responsible for
managing all adverse events / reactions according to local protocols.
Severity:
The following classification will be used.
•
Mild: transient or mild discomfort, no limitation in activity, no medical intervention/therapy required
•
Moderate: Mild to moderate limitation in activity, some assistance may be needed, no or minimal
medical intervention required
•
Severe: Marked limitation in activity, some assistance usually required, medical intervention
required, hospitalisation possible.
All non serious AE reports must be faxed within 7 days of discovering the event. These will be used to
collate reports as requested by the Trial Steering Committee and Data Monitoring and Ethics Committee.
18.2 Reporting of Serious Adverse Events
Serious Adverse Event / Reaction (SAE/SAR, including SUSARs):
All SAEs, SARs & SUSARs during drug treatment, as specified by the protocol above, shall be reported
to the Newcastle Clinical Trial’s Unit within 24 hours of learning of its occurrence. Reports will be made
via a secure fax line using a paper based SAE report form. SAE Reports will then be uploaded to the
eCRF by the central study team. The serious advent report should contain the following information*:
1. Study identifier (EudraCT number)
2. Participant’s unique study number
3. Date of birth
4. Event Description
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5. Start date of event
6. Current status
7. Laboratory tests used for the SAE
8. Medical Interventions used to treat the SAE
9. Whether administration of the study drug or use of the insulin pump or RT (Real Time Continuous
Glucose Monitoring) was discontinued.
10. Reason for seriousness (i.e death, life threatening, hospitalisation, disability/incapacity or other)
11. Presumed causality to IMP (glagine, aspart, lispro)
12. Reporter’s name, date and signature
*In the case of incomplete information at the time of initial reporting, all appropriate information should be
provided as follow-up as soon as this becomes available.
Relationship of the SAE to the treatment should be assessed by the investigator at site, as should the
expected or unexpected nature of any serious adverse reactions.
Each SAE report will be reviewed by the Trial Management Group which will meet every two weeks
during the RCT. The event, the severity and the duration will be reviewed however the TMG will be
anonymised to treatment group.
The MHRA and main REC will be notified of all SUSARs occurring during the study according to the
following timelines; fatal and life-threatening within 7 days of notification and non-life threatening within
15 days. All investigators will be informed of all SUSARs occurring throughout the study on a case-bycase basis.
The Chief Investigator will ensure the Newcastle upon Tyne Hospitals Trust is notified of any SUSARs in
accordance with local trust policy.
Local investigators should report any SUSARs and / or SAEs as required by their Local Research Ethics
Committee and/or Research & Development Office.
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18.3 Flow chart of adverse event reporting
Adverse event
Not Serious
Unrelated
Not sure
Related
Serious
Unrelated
Related
Expected
Unexpected
Complete
Complete
Complete
Complete and fax
Complete
Complete
and fax
and fax
and fax
SAE form
and fax
and fax SAE
AE form
AE form
SAE form or
SAE form
form
contact CI
18.4
Pregnancy during Trial period
If it is learned during the intervention period that a subject is pregnant the investigator will report the
pregnancy to the Sponsor within 2 weeks. The subject will be immediately referred to the joint diabetes /
obstetric clinic. The participant will remain in the study for data collection but diabetes management and
glucose monitoring may be changed to achieve optimal care. The subject will be followed to learn the
outcome of pregnancy. The investigator will notify the sponsor if the pregnancy is terminated. If the
subject gives birth, information on the health status of the mother and child will be forwarded to the
sponsor.
Pregnancy, childbirth and elective termination of pregnancy are not necessarily considered AEs.
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19 ETHICAL CONSIDERATIONS
The conduct of this study will be in accordance with the ethical principles set out in the Declaration of
Helsinki (2004). Regulatory and ethical approval of the protocol will be sought prior to commencement of
the study. Local approvals (site specific assessments and local R&D approval) will be sought before
recruitment may commence at each site. Participants will provide written informed consent before any
study procedures are carried out and a participant information sheet will be provided. As part of the
consent process participants must agree to researchers & regulatory representatives having access to
their medical records. Participants will also be informed that they have the right to withdraw from the
study at any time.
19.1 Subject Payments
There will be no payments available to participants for taking part in this study. Participants will however
receive expenses for travel costs incurred while attending study visits.
20 FINANCE AND INSURANCE
Diabetes UK is funding this study.
NHS Indemnity for clinical trials conducted with NHS permission will apply for clinical negligence that
harms individuals towards whom the NHS has a duty of care. Indemnity in respect of protocol authorship
will be provided through a combination of NHS schemes (for those protocol authors who have
substantive NHS employment contracts) and through Newcastle University’s public liability insurance (for
those who have their substantive contracts of employment with the University). There is no provision for
indemnity in respect of non-negligent harm.
21 STUDY REPORT
The results of the study will be submitted to Diabetes UK annual conference for consideration of peer
reviewed presentation and will be submitted as a report and as research papers to academic journals.
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22 CLINICAL TRIAL PROTOCOL AMENDMENTS
All appendices attached hereto and referred to herein are made part of this Clinical Trial Protocol. The
Investigator should not implement any deviation from, or changes of the Clinical Trial Protocol without
agreement by the Sponsor and prior review and documented approval/favourable opinion from the
Ethics committee of an amendment, except where necessary to eliminate an immediate hazard(s) to
Clinical Trial Patients, or when the change(s) involves only logistical or administrative aspects of the trial.
Any change agreed upon will be recorded in writing, the written amendment will be signed by the
Investigator and by the Sponsor and the signed amendment will be filed with this Clinical Trial Protocol.
Any amendment to the Clinical Trial Protocol requires written approval/favourable opinion by the Ethics
Committee prior to its implementation, unless there are overriding safety reasons. In some instances, an
amendment may require a change to the Informed Consent Form. The Investigator must receive an
Ethics Committee approval/favourable opinion concerning the revised Informed Consent Form prior to
implementation of the change.
23 STUDY CONDUCT
The investigator will ensure that all study personnel are adequately qualified and informed about the
protocol, any amendments to the protocol, the study treatments and procedures and their study related
duties. The investigator will maintain a list, using the form supplied by the sponsor, of sub investigators
and other personnel to whom significant study related duties have been delegated.
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24
REFERENCES
1. Forouhi N.G, Merrick D, Goyder E, Ferguson B.A, Abbas J, Lachowycz K, Wild S.H, Diabetes Prevalence
in England, 2001 Estimates from an epidemiological model. Diabetic Medicine 2006; 23:189-197
2. Cryer, P.E., S.N. Davis, and H. Shamoon, Hypoglycemia in diabetes. Diabetes Care, 2003. 26(6): p. 190212.
3. DCCT, The effect of intensive treatment of diabetes on the development and progression of long-term
complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial
Research Group. N Engl J Med, 1993. 329(14): p. 977-86.
4. Geddes, J. and B.M. Frier, An evaluation of methods of assessing impaired awareness of hypoglycemia in
Type 1 diabetes: response to pedersen-bjergaard et Al. Diabetes Care, 2007. 30(11): p. e113.
5. Veneman, T., et al., Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia.
Diabetes, 1993. 42(9): p. 1233-7.
6. Fanelli, C.G., et al., Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and
magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during
hypoglycemia in intensively treated patients with short-term IDDM. Diabetes, 1993. 42(11): p. 1683-9.
7. Cranston, I., et al., Restoration of hypoglycaemia awareness in patients with long-duration insulindependent diabetes. Lancet, 1994. 344(8918): p. 283-7
8. Holleman, F., et al., Reduced frequency of severe hypoglycemia and coma in well-controlled IDDM patients
treated with insulin lispro. The Benelux-UK Insulin Lispro Study Group. Diabetes Care, 1997. 20(12): p.
1827-32.
9. Ratner, R.E., et al., Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes.
U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care, 2000. 23(5): p. 639-43.
10. Ashwell, S.G., et al., Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre,
randomized, cross-over trial in people with Type1 diabetes Diabetic Medicine, 2006. 23(3): p. 285-292.
11. National Institute for Clinical Excellence Appraisal Consultation Document: The clinical effectiveness and
cost effectiveness of long acting Insulin analogues for Diabetes. www.nice.org.uk 2002.
12. Boland, E.A., et al., Continuous subcutaneous insulin infusion. A new way to lower risk of severe
hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes.
Diabetes Care, 1999. 22(11): p. 1779-84.
13. Doyle, E.A., et al., A randomized, prospective trial comparing the efficacy of continuous subcutaneous
insulin infusion with multiple daily injections using insulin glargine. Diabetes Care, 2004. 27(7): p. 1554-8.
14. Hirsch, I.B., et al., Continuous subcutaneous insulin infusion (CSII) of insulin aspart versus multiple daily
injection of insulin aspart/insulin glargine in type 1 diabetic patients previously treated with CSII. Diabetes
Care, 2005. 28(3): p. 533-8.
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Study Title: Hypo COMPASS
15. Bode, B.W., R.D. Steed, and P.C. Davidson, Reduction in severe hypoglycemia with long-term continuous
subcutaneous insulin infusion in type I diabetes. Diabetes Care, 1996. 19(4): p. 324-7.
16. National Institute for Clinical Excellence Full guidance on the use of continuous subcutaneous insulin
infusion for diabetes. www.nice.org.uk Technology Appraisal Guidance No. 57, 2003.
17. Deiss D, Bolinder J, Riveline JP, Battelino T, Bosi E, Tubiana-Rufi N, Kerr D, Phillip M, Improved glycemic
control in poorly controlled patients with type 1 diabetes using real-time continuous glucose monitoring.
Diabetes Care, 2006 29: p2730-2
18. Garg S, Zisser H, Schwartz S, Bailey T, Kaplan R, Ellis S, Jovanovic L. Improvement in glycemic
excursions with a transcutaneous, real-time continuous glucose sensor: a randomized controlled trial.
Diabetes Care, 2006 29(1): p44-50.
19. Cox, D.J., et al., Blood glucose awareness training (BGAT-2): long-term benefits. Diabetes Care, 2001.
24(4): p. 637-42.
20. Davis, R.E., et al., Impact of hypoglycaemia on quality of life and productivity in type 1 and type 2 diabetes.
Curr Med Res Opin, 2005. 21(9): p. 1477-83.
21. Thomas RM, Aldibbiat A, Griffin W, Cox MA, Leech NJ, Shaw JA. A randomized pilot study in Type 1
diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin
analogue therapy, CSII or education alone. Diabet Med, 2007 24(7): p778-83
22. Workgroup:, A.D.A., Defining and reporting hypoglycemia in diabetes: A report from the American Diabetes
Association Workgroup on Hypoglycemia. Diabetes Care 28:1245-1249, 2005.
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25 APPENDICES
APPENDIX 1: Hypoglycaemia Experience and Awareness Questionnaires
A study has been planned to assess whether by using modern insulins, insulin pumps and continuous blood
glucose meters to effectively prevent low blood glucose levels (hypoglycaemia), awareness of falling glucose can
be restored thus preventing future episodes of severe hypoglycaemia. You have been asked to complete this short
questionnaire as you may be eligible to take part. If you are interested in taking part please take away an
accompanying information sheet. If you have any questions about the study or would like to speak to one of the
study doctors for more information please phone .................... and ask to speak to ......................(Dr XXXXXXXX).
Thank you very much.
Initials:
Sex:
Date of Birth:
Age:
Date:
All of the following questions relate to your experience in the last 12 months
1. Have you had episodes of hypoglycaemia (glucose <4mmol/L) with
symptoms:
A) while awake during the day?
Yes
No
B) while sleeping at night?
Yes (how many times?)
No
2a. Have you had episodes of hypoglycaemia (glucose <4mmol/L) when you have lost consciousness; had a fit; or
needed help from someone else?
A) while awake during the day?
Yes (how many times?)
No
B) while sleeping at night?
Yes (how many times?)
No
2b. Have you required hospital or paramedic assistance during an episode of hypoglycaemia?
Yes (how many times?)
No
Please describe what happened during your worst episode of hypoglycaemia in the last year:
..............................................................................................................
..............................................................................................................
...............................................................................................................
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APPENDIX 2
Modified Clarke / Edinburgh
Hypo Awareness Score (HAS)
Study Centre:
Today’s date:
/
/
(dd/mm/yy)
Patient ID #:
Patient DOB:
/
/
(dd/mm/yy)
Guy’s and St Thomas’ Minimally Modified Clarke Hypoglycaemia Survey
1.
Tick the category that best describes you (tick one only):
I always have symptoms when my blood sugar is low
I sometimes have symptoms when my blood sugar is low
I no longer have symptoms when my blood sugar is low
2.
Have you lost some of the symptoms that used to occur when your blood sugar was low?
Yes
No
In the past 6 months, how often have you had hypoglycaemic episodes, where you might feel
confused, disorientated, or lethargic and were unable to treat yourself?
Never
Once or twice
Every other month
Once a month
More than once a month
3.
4.
In the past year, how often have you had hypoglycaemic episodes, where you were unconscious
or had a seizure and needed glucagon or intravenous glucose?
Never
1 time
2 times
3 times
4 times
5.
6.
7.
8.
5 times
6 times
7 times
8 times
9 times
10 times
11 times
12 or more
times
How often in the last month have you had readings <3.5mmol/l with symptoms?
Never
1-3 times
1 time/week
2-3 times/week
4-5 times/week
Almost daily
How often in the last month have you had readings <3.5mmol/l without any symptoms?
Never
1-3 times
1 time/week
2-3 times/week
4-5 times/week
Almost daily
How low does your blood sugar need to go before you feel symptoms?
3.4-3.9mmol/l
2.8-3.3mmol/l
2.2-2.7mmol/l
<2.2 mmol/l
To what extent can you tell by your symptoms that your blood sugar is low?
Never
Rarely
Sometimes
Often
Always
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Edinburgh Hypoglycaemia Survey (including The Gold Score)
1.
Please score the extent to which you experience the following symptoms during a typical
daytime hypoglycaemic episode (circle a number for each symptom)
Not present
2.
Present a great deal
Confusion
1
2
3
4
5
6
7
Sweating
1
2
3
4
5
6
7
Drowsiness
1
2
3
4
5
6
7
Weakness
1
2
3
4
5
6
7
Dizziness
1
2
3
4
5
6
7
Warmth
1
2
3
4
5
6
7
Difficulty Speaking
1
2
3
4
5
6
7
Pounding heart
1
2
3
4
5
6
7
Inability to concentrate
1
2
3
4
5
6
7
Blurred vision
1
2
3
4
5
6
7
Hunger
1
2
3
4
5
6
7
Nausea
1
2
3
4
5
6
7
Anxiety
1
2
3
4
5
6
7
Tiredness
1
2
3
4
5
6
7
Tingling lips
1
2
3
4
5
6
7
Trembling
1
2
3
4
5
6
7
Headache
1
2
3
4
5
6
7
Do you know when your hypos are commencing? Please circle a number:
Always aware
Awareness
1
Never aware
2
3
4
5
6
7
Comments:
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APPENDIX 3 ADA/WHO Definition of Diabetes Mellitus
1. FPG ≥ 7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.
OR
2. Symptoms of hyperglycemia and a casual plasma glucose ≥11.1 mmol/l. Casual is defined as any
time of day without regard to time since last meal. The classic symptoms of hyperglycemia include
polyuria, polydipsia, and unexplained weight loss.
OR
3. 2-h plasma glucose ≥ 11.1 mmol/l during an OGTT. The test should be performed as described by the
World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose
dissolved in water.
In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a
different day.
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APPENDIX 4
Protocol for stepped hyperinsulinaemic hypoglycaemic clamp
Exclusion Criteria for clamp study
All participants from the hypo COMPASS trial will be asked to consider participating in the clamp study
unless they meet any of the following exclusion criteria:
•
Age >60
•
History of Epilepsy (seizures not primarily induced by hypoglycaemia)
•
Known Ischaemic Heart Disease
•
Other significant disease which in the judgement of the investigators which would increase the
risks associated with taking part in the study
Day before Study
Subjects will have been fitted with a retrospective CGM sensor to be worn for the 7 days preceding the
study day. This will be downloaded on the morning of the study to determine whether any antecedent
biochemical hypoglycaemia (BH) occurred over the 24 hour period prior to the clamp. Studies will be
postponed to another day if any CGM and/or self-monitored capillary glucose below 3.0mmol/l are
detected during 24 hours prior to the study. If this is the case, participants will be asked to be fitted for a
further 72 hours CGM and to reduce their basal insulin by 25% if on Detemir insulin (this applicable only
to clamp studies carried out before the intervention period) and by 50% if on glargine on the night before
the rescheduled clamp study, in addition to making other targeted self-management adjustments to
absolutely prevent glucose levels <3.0mmol/L over the preceding 24 hours.
Day of Study
Participants will be admitted to the research unit at 0700Hrs on the study day following an overnight fast
from 10 pm. An intravenous cannula will be inserted in the antecubital vein of the non-dominant arm and
another retrogradely sited in a vein on the dorsum of the hand on the same side using local anaesthetic.
From 7am to 10. 30am, blood glucose will be stabilized with sliding scale insulin infusion aiming initially
for blood glucose reading of 6.0 – 7.0 mmol/l, but bringing down to between 5 and 6 mmol/L between
10.30 and 11 am for start of clamp.
The retrograde cannula will be used for sampling, both during initial stabilization and during clamp study.
A slow intravenous infusion of saline will be used as needed to keep the sampling line patent. During
this period of stabilization, participants will be shown how to perform the brain (cognitive) function tests
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and asked to practice the tests till they achieve consistent results (typically 5 practice sessions). The
distal non-dominant hand will be heated using hot box starting at least 30 min prior to start of clamp
(10.30 am at latest) and continued throughout study.
Clamp
At 11 am, a primed infusion of 60 mU/m-2 /min actrapid insulin will be started via the non-dominant
antecubital vein catheter.
To do this, insulin will made up between 10.00am and 11 am using either:
1) total volume 50mls if using syringe driver: normal saline with 2mls of autologous blood (add
saline first then blood and insulin last)
2) total volume 100ml in bag if using infusion pump: remove volume of saline from 100 ml bag, add
4 mls of autologous blood then insulin last!
The insulin dose will be calculated and will be run through the side arm of a 3-way tap. Priming rates are
(i)
(ii)
(iii)
insulin infusion at 48 mls/hr from 0 to 4 min
insulin infusion at 32 ml/h from 4 to 7 min
insulin infusion at 16 ml/hr from 7 min onwards
20% glucose will also be infused via the same antecubital cannula (best through “straight” arm of 3 way
tap at a variable rate to keep the blood glucose at the desired level. This is varied but a “typical” starting
protocol might be:
0 min
0
mg/kg/min
4 min
2
mg/kg/min
7 min
2.5
mg/kg/min
9 min
3
mg/kg/min
11 min
4
mg/kg/min
Plasma glucose will be sampled from sample drawn from retrograde cannula every 5 minutes (2ml dead
space drawn, then the sample for analysis and then dead space sample returned), spun rapidly and
assayed using Yellow Springs glucose analyzer. Dextrose infusion rates will be adjusted as needed
aiming for stabilization at 5.0mmol/l at 40mins and lowered in a step wise manner by variable glucose
infusion to 3.8mmol/L, 3.4mmol/l 2.8mmol/l and 2.4mmol/l. Each step will consist of 40 min allowing 20
minutes to fall to target and 20 minutes for stabilization at that level. Participants will be blinded to
glucose levels throughout the study.
In addition to samples for plasma glucose, additional arterialised venous blood samples for insulin,
catecholamines, growth hormones, glucagon and cortisol will be drawn spun and stored at 0,10,20,30
and 40 minutes at start of clamp. Thereafter, these extra samples will be drawn at 20 minute intervals.
Sampling details/ collection are detailed below. Also heart rate and BP recorded every 20 minutes so
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easiest for timings to have a consistent time pattern of recording HR, draw samples and then inflate BP
cuff as flushing line. Suggested pattern of activity for each glucose step (other than 0 to 40 min where
additional basal hormone sampling) in figure below:
Plasma glucose
falling
Target Glucose
Symptoms
Cognitive
function
Heart rate/
Samples/
BP
0 min
+20
+30
+40 min
Following Clamp
At the end of the study, dextrose infusion will be increased to raise blood glucose to euglycaemia, and
then tapered off gradually during meal (typically halved halfway through eating then discontinued at end
of meal). For insulin;
(1) for pump patients, the iv insulin infusion will be reduced to approximate basal infusion
rates and pump reconnected with meal bolus as below but allowing 30 minutes overlap
for pump site to kick in before stopping iv insulin (halve iv insulin infusion rate after 15
minutes)
(2) For MDI patients, iv insulin infusion will be reduced to approximate basal infusion rates
and meal injection given as below. Allow 30 mins overlap between bolus and stopping iv
insulin (halve iv insulin infusion rate after 15 minutes).
A carbohydrate rich meal will be consumed with 80% of usual prandial insulin bolus given. Frequent
blood glucose measurements will be made (every 10 minutes) until glucose levels are stable (at least 45
minutes after end of meal).
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Participants will be discharged home with advice about their subsequent insulin dose. Specifically (1)
warned increased risk of hypo during subsequent 24-48 hour period (2) MDI patients warned that it may
take up to 3 days to restabilise baseline, to monitor frequently and to make small corrections only.
Measures
Blood:
Plasma glucose will be analysed by Yellow Springs analyser (Yellow Springs, Ohio, USA).
Hormone analysis of samples from all centres will be performed in the quality assured Diabetes
Research Laboratory at Newcastle University.
Blood samples for insulin will be collected as 3ml samples in EDTA tubes, and centrifuged at 2500 rpm
for 2 minutes. Equal volumes of a polyethylene glycol (PEG) buffer will be added, samples vortexed and
then spun for 30 minutes to remove the precipitated globulin fraction. The supernatant will be frozen for
assay (stored at -20) and free insulin measured by double-antibody immunoassay.
For glucagon, 2.5ml blood will be collected in a tube containing 0.25ml aprotinin (trasylol) and EDTA
which will have been stored in a refrigerator. A sequential radioimmunoassay will be used for Glucagon
assay.
Blood samples for cortisol will be collected as 2.5ml samples in glass white topped tubes. ADVIA
Centuar Cortisol assay will be used to measure cortisol in the serum samples.
For catecholamines 4 mls of whole blood will be drawn into a Lithium Heparin tube. A non competitive
enzyme linked immunosorbent assay kit will be used to measure epinephrine or norepinephrine in
plasma.
Blood samples for growth hormone assays will be collected as 3ml samples in EDTA tubes. GH will be
measured using a Nichols Advantage assay using a two-site chemiuminescence immunoassay
procedure.
Physiological measurements
Electrocardiograph monitoring will be performed continuously throughout the clamp studies using three
electrodes. One electrode will be placed on either side of the sternum and one in the V5 position. The
signal will be amplified and displayed on a monitor with the integrated heart rate displayed digitally.
Heart Rate, blood pressure and 2 minutes ECG trace will be formally recorded every 20 minutes.
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In some studies, monitoring of skin perspiration and limb tremor will be undertaken intermittently using
non-invasive previously validated sensors. This is not expected to cause any added discomfort or
inconvenience for the recipient.
Hypoglycaemia Symptom Score
The participants will complete a symptom questionnaire at the end of each glucose step (i.e. every 40
minutes). Each symptom will be graded on a visual analogue scale (1-7).
Hypoglycaemia symptoms will be classified into 3 groups:
Autonomic: palpitations, sweating, shaking and hunger
Neuroglycopenic: confusion, drowsiness, odd behaviour, speech difficulty and inco-ordination
Non-specific: nausea and headache
Cognitive function
Participants will undertake three cognitive function tests at the end of each step of the clamp study (and
practiced at least 5 times as described above prior to start of clamp between 7 and 11 am- the practice
data will also be recorded to show that performance is stable), consisting of 4CRT (4 Choice Reaction
Time), N-back and SWM (Spatial Working Memory) performed always in this order:
Four choice reaction time:
Four-choice reaction time is a test of attention, discrimination and motor speed reaction. In this test, the
subject is presented with a computer screen divided into four quadrants. A computer-generated signal
appears randomly in one quadrant at a time and the subject has to clear it by pressing a corresponding
button on a box. Up to 500 signals are presented in 5 min. The mean time of the reactions and accuracy
(the percentage of correct responses) are recorded. The measures of speed and accuracy used in this
test have previously been demonstrated to change by less than 1% on repeated measures at
euglycaemia (Maran A, 1993)
N-back:
In this task, the subject is shown a rapid series of randomly chosen letters and responds when the letter
presented is the same as either the last or the next to last or the previous to the next to last letter in the
series.
Spatial Working Memory:
Spatial Working Memory (SWM) task involves searching for a token hidden behind a circle by pressing a
touch sensitive computer screen. Once the token is found, a new trial will start and participants are
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informed that another token is hidden behind a different circle, therefore they should avoid touching the
circle where the previous token was found. The SWM test has been shown to be sensitive to hormonal
manipulations. For example, chronic administration of cortisol to healthy subjects leads to an increase in
the within-search errors and impairs the use of appropriate cognitive strategies (Young, AH; Sahakian
BJ; Robbins TW; Cowen PJ (1999). "The effects of chronic administration of hydrocortisone on cognitive
function in normal male volunteers." Psychopharmacology 145(3): 260-266).
More recently, a more challenging SWM test has been developed in Newcastle and this has been found
to be sensitive to acute cortisol administration demonstrating a detrimental effect of cortisol on the withinsearch task, an effect that was attenuated by a selective serotonin reuptake inhibitor pre-treatment
(Alhaj, HA; Arulnathan, VE; Gallagher, P; Marsh, RA; Massey, AE; Pariante, CM; McAllister-Williams,
RH (2009). "Citalopram Modulation of the Effects of Cortisol on Attention and Memory." Journal of
Psychopharmacology 23(6): TE18.).
This is an in house adaptation of the SWM task from the CANTAB battery of cognitive tests. See
www.camcog.com/camcog/default.as
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Appendix 5 - Questionnaires
The Gold Score
1.
Do you know when your hypos are commencing? Please circle a number:
Always aware
Awareness
1
Never aware
2
3
4
5
6
7
Edinburgh Hypoglycaemia Survey
2.
Please score the extent to which you experience the following symptoms during a typical
daytime hypoglycaemic episode (circle a number for each symptom)
Not present
Present a great deal
Confusion
1
2
3
4
5
6
7
Sweating
1
2
3
4
5
6
7
Drowsiness
1
2
3
4
5
6
7
Weakness
1
2
3
4
5
6
7
Dizziness
1
2
3
4
5
6
7
Warmth
1
2
3
4
5
6
7
Difficulty Speaking
1
2
3
4
5
6
7
Pounding heart
1
2
3
4
5
6
7
Inability to concentrate
1
2
3
4
5
6
7
Blurred vision
1
2
3
4
5
6
7
Hunger
1
2
3
4
5
6
7
Nausea
1
2
3
4
5
6
7
Anxiety
1
2
3
4
5
6
7
Tiredness
1
2
3
4
5
6
7
Tingling lips
1
2
3
4
5
6
7
Trembling
1
2
3
4
5
6
7
Headache
1
2
3
4
5
6
7
Comments:
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The Hypo Awareness Questionnaire
These questions are about your recent experience of hypoglycaemia, also known as low
blood glucose, having a ‘hypo’ or going ‘low’. Please tick the one box  on each line that
best describes your experience. There are no right or wrong answers. We just want to know
about your experiences.
In the past week, how often have you had any hypo
1. (mild or severe, day or night)?
____ times (please enter a number)
2. In the past 6 months, how often did you have a hypo where …
a) ... you needed help / were unable to treat yourself?
____ times (please enter a number)
b) ... emergency services were called to help you?
____ times (please enter a number)
c) … you were taken to hospital (A&E) for treatment?
____ times (please enter a number)
d) … you were admitted to hospital (overnight or longer)?
____ times (please enter a number)
A. ‘Hypos’ when you are awake
3.
Never
Once or
twice
Three or
four times
About once
or twice a
month
About
once a
week
More
than once
a week
Never
Once or
twice
Three or
four times
About once
or twice a
month
About
once a
week
More
than once
a week
In the past 6 months, how often have
you had any ‘hypo’ when awake?
In the past 6 months, how often have
4. you had any ‘hypo’ when awake
where you …
a) … had symptoms and were able to
treat yourself?
b) … had symptoms and were unable
to treat yourself?
c) … needed someone else to give
you sugar by mouth (e.g. a drink,
carbohydrate, glucose gel)?
d) … needed someone else to give
you a glucagon injection?
In the past month, have you had blood glucose
5. readings (in mmol/l) …
a) … 3.5 to 3.9?
Yes
No
Don’t know
b) … 3.0 to 3.4?
Yes
No
Don’t know
c) … 2.5 to 2.9?
Yes
No
Don’t know
d) … less than 2.5? Yes
No
Don’t know
If yes, how often did you have hypo symptoms?
Never
Rarely
Sometimes
Often
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Always
Study Title: Hypo COMPASS
6. How low does your blood glucose
usually need to be before you feel any
of the following symptoms?
4.0mmol/l
or above
3.5-3.9
mmol/l
3.0-3.4
mmol/l
2.5 -2.9
mmol/l
Below
2.5mmol/l
I do not
have these
symptoms
Never
Rarely
Sometimes
Often
Always
Strongly
disagree
Disagree
Neither
agree nor
disagree
Agree
Strongly
agree
a) Trembling, shakiness, pounding
heart, warmth, sweating, hunger
b) Weakness, lack of coordination,
confusion, dizziness, inability to
concentrate, difficulty speaking,
blurred vision, drowsiness,
tiredness, irritability, odd behaviour
c) Nausea, tingling, headache
7. I have symptoms when my blood glucose is low
8.
I ‘just know’ when I am going hypo by the way
that I feel
9. I check my blood glucose level if I feel ‘low’
10. Other people recognise I am hypo before I do
11. I am less aware of my hypos coming on than I
used to be
12. I have lost symptoms I used to have when my
blood glucose is low
13. In the past 6 months, I have been more aware
of my hypos coming on than I used to be
14. Is there anything else you would like to mention about your hypos or your awareness of hypos
when you are awake? If so, please write it in this box.
B. ‘Hypos’ when you are asleep
Never
Less than About once About once
one a
or twice a a week
month
month
About
twice a
week
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Most
days
Study Title: Hypo COMPASS
15.
In the past 6 months, how often have
you had a hypo during your sleep?
16.
In the past 6 months, how often have
you had a hypo during your sleep …
Never
Less than About once About once
one a
or twice a a week
month
month
About
twice a
week
Most
days
Never
Less than About once
one a
or twice a
month
month
About
once a
week
About
twice a
week
Most
days
Often
Always
Not
Applicable
a) ... and were unable to treat yourself
when you woke up?
b) ... and someone else gave you
sugar by mouth (e.g. a drink,
carbohydrate, glucose gel)?
c) … and someone else gave you a
glucagon injection?
d) … which led to a major problem
(e.g. a fit, tongue biting, fall,
collapse, incontinence)?
e) … where you stayed asleep and
only later realised that you had
been hypo?
During my sleep...
Never
Rarely
Sometimes
17. ... I have symptoms which wake me
when my blood glucose is low
18. ... other people recognise that I am
hypo before I do
19. … my insulin pump / monitoring device
wakes me when my blood glucose
is low
20. Is there anything else you would like to mention about your hypos or your awareness of hypos
when you are asleep? If so, please write it in this box.
Thank you. Please check that you have answered all the questions.
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Guy’s and St Thomas’ Minimally Modified Clarke Hypoglycaemia
Survey
2.
Tick the category that best describes you (tick one only):
I always have symptoms when my blood sugar is low
I sometimes have symptoms when my blood sugar is low
I no longer have symptoms when my blood sugar is low
2.
Have you lost some of the symptoms that used to occur when your blood sugar was
low?
Yes
No
9.
In the past 6 months, how often have you had hypoglycaemic episodes, where you
might feel confused, disorientated, or lethargic and were unable to treat yourself?
Never
Once or twice
Every other
month
Once a month
More than once a month
10.
In the past year, how often have you had hypoglycaemic episodes, where you were
unconscious or had a seizure and needed glucagon or intravenous glucose?
Never
5 times
10 times
1 time
6 times
11 times
2 times
7 times
12 or more
times
3 times
8 times
4 times
9 times
11.
How often in the last month have you had readings <3.5mmol/l with symptoms?
Never
1-3 times
1 time/week
2-3 times/week
4-5 times/week
Almost daily
12.
How often in the last month have you had readings <3.5mmol/l without any symptoms?
Never
1-3 times
1 time/week
2-3 times/week
4-5 times/week
Almost daily
13.
How low does your blood sugar need to go before you feel symptoms?
3.4-3.9mmol/l
2.8-3.3mmol/l
2.2-2.7mmol/l
14.
<2.2 mmol/l
To what extent can you tell by your symptoms that your blood sugar is low?
Never
Rarely
Sometimes
Often
Always
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Adult Low Blood Sugar Survey (University of Virginia) / Fear of
Hypoglycaemia Survey
I. Behaviour: Below is a list of things people with diabetes sometimes do in order to avoid
low blood sugar and its consequences. Tick the box that best describes what you have done
during the last 6 months in your daily routine to AVOID low blood sugar and its
consequences. (Please do not skip any!).
To avoid low blood sugar and how it affects
me, I …
Never
Rarely Sometimes
Often
1. ate large snacks
2. tried to keep my blood sugar 4mmol/L or above
3. reduced my insulin when my blood sugar was low
4. measured my blood sugar six or more times a day
5. made sure I had someone with me when I go out
6. limited my out of town travel
7. limited my driving (car, truck or bicycle)
8. avoided visiting friends
9. stayed home more than I liked
10. limited my exercise / physical activity
11. made sure there were other people around
12. avoided sex
13. kept my blood sugar higher than usual in social
situations
14. kept my blood sugar higher than usual when
doing important tasks
15. had people check on me several times during the
day or night
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Almost
always
Study Title: Hypo COMPASS
Worry: Below is a list of concerns people with diabetes sometimes have about low blood sugar.
Please read each item carefully (do not skip any). Tick the box that best describes how often in the
last 6 months you WORRIED about each item because of low blood sugar.
Because my blood sugar could go low, I worried
about…
Never
Rarely Sometimes
Often
16. not recognising / realising I was having low blood
sugar
17. not having food, fruit or juice available
18. passing out in public
19. embarrassing myself or my friends in a social
situation
20. having a hypoglycaemic episode while alone
21. appearing stupid or drunk
22. losing control
23. no-one being around to help me during a
hypoglycaemic episode
24. having a hypoglycaemic episode while driving
25. making a mistake or having an accident
26. getting a bad evaluation or being criticised
27. difficulty thinking clearly when responsible for
others
28. feeling lightheaded or dizzy
29. accidentally injuring myself or others
30. permanent injury or damage to my health or body
31. low blood sugar interfering with important things
32. becoming hypoglycaemic during sleep
33. getting emotionally upset and difficult to deal with
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Almost
always
Study Title: Hypo COMPASS
High Blood Sugar Survey
PART 1: The items below describe things people may do in their daily diabetes management in order to
avoid high blood glucose levels. Please tick one box  on each line that best describes how often you
do each of these in your diabetes management.
How often do you …
1.
try to lower your blood glucose when it is
higher than 10mmol/l?
2.
choose to take a little more insulin rather
than risk taking too little?
3.
choose to under-treat low blood glucose
rather than risk high blood glucose later?
4.
keep your blood glucose below 7mmol/l?
5.
give extra insulin when you know your blood
glucose is above 7mmol/l?
6.
exercise to lower your blood glucose when
you know it is high?
7.
avoid restaurants / social situations that
tempt you to have food / drink which raise
your blood glucose?
8.
miss meals when you know your blood
glucose is high?
9.
avoid stressful situations that might raise
your blood glucose?
Never
Rarely
Sometimes
Often
10. check your blood glucose more often when
you think it is high?
11. choose to keep your blood glucose low
rather than risk being high?
12. keep your blood glucose low because you
want to avoid unpleasant symptoms?
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Always
Study Title: Hypo COMPASS
PART 2: The items below describe concerns and feelings you may have about high blood glucose.
Please tick one box  on each line that best reflects how often you feel that way.
Never
How often do you …
Rarely
Sometimes
Often
Always
1. worry about complications of high glucose,
e.g. blindness, kidney failure, amputation?
2. worry that you might die early due to
diabetes?
3. worry about high blood glucose?
4. feel upset (e.g. frustrated, distressed) when
your blood glucose is too high?
5. feel comfortable about being hypo if that is
what it takes to avoid high blood glucose?
6. worry about going into DKA (diabetic
ketoacidosis)?
7. worry about losing your health due to your
diabetes?
8. worry about not recognising when your
blood glucose is high?
9. feel annoyed at yourself when your blood
glucose is high?
10. worry about not knowing how to lower your
blood glucose when it is high?
11. worry about your doctor’s reaction if your
blood glucose is high?
12. worry that you will experience unpleasant
symptoms if your blood glucose is high?
On a typical day, what is the highest blood glucose level that you would feel comfortable with?
____ mmol/l (please write a number)
HbA 1c is a measure of average blood glucose over the past 6-8 weeks. What is the highest HbA 1c that
you would feel comfortable with?
____ % (please write a number)
OR
____ mmol/mol (please write a number)
I don’t know
Thank you for completing this questionnaire.
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Study Title: Hypo COMPASS
The Hypo Cues Questionnaire
These questions are about your experience of hypoglycaemia, also known as low blood glucose, having
a ‘hypo’ or going ‘low’. There are no right or wrong answers because everyone has their own
experiences of hypos, which are unique to them.
1.
Sometimes people go ‘hypo’ but still end up unable to treat it themselves or needing someone
else’s help. Does this ever happen to you?
No, I don’t have severe hypos
Yes, because I don’t have any warning symptoms
Yes, I have warning symptoms but I think this happens to me because…(please write in the box)
For the rest of the questions, please tick the one box  on each line that best describes your experience
Neither
Strongly
Strongly
Disagree agree nor
Agree
disagree
agree
disagree
I prefer to keep my blood glucose levels low
2.
rather than high
Having hypos doesn’t concern me; its just one of
3.
the things you have to put up with
Hypos don’t bother me much unless they’re
4.
severe
I prefer to have low blood glucose than to risk
5.
putting on weight because of snacking
6. Being hypo gives me a break from my diabetes
7. Avoiding hypos is just too difficult
If I keep my blood glucose low, I don’t have to
worry about long-term complications
Hypos are inevitable if I’m to have good control
9.
of my diabetes
8.
10. I never feel panicky or worried about going hypo
11.
12.
13.
14.
15.
Sometimes letting the hypo take over is easier
for me than coping with it
When I have a hypo, I just don’t want to have to
deal with it
The other stresses of life sometimes make
dealing with hypos too hard
There are some advantages in letting my blood
glucose levels go low
Long-term complications (e.g. blindness, kidney
failure, amputation) worry me more than hypos
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If I go hypo, its because...
Strongly
disagree
Disagree
Neither
agree nor
disagree
Agree
Strongly
agree
Never
Rarely
Sometimes
Most of
the time
Always
16. … I’ve been exercising or doing a lot physically
17. … I’ve not eaten or drunk enough
18. … my insulin doses are not quite right
19. … my blood glucose is unpredictable
20. … I’ve been drinking alcohol earlier
21.
… I’ve over-estimated the amount of carbs I’ve
eaten
22. … I just haven’t reacted to the warning signs
23. … I’ve missed ‘that moment’ to treat it early
24.
… I’ve taken extra insulin due to high glucose
levels
25. … I miss subtle symptoms until it’s too late
… I’ve not checked my blood glucose even
though I’ve had some warning signs
… I haven’t checked my blood glucose at a time
when hypos are more likely (e.g. after
27.
exercise, alcohol or at night)
26.
When I first start to go hypo ...
28. ... I am able to think clearly and act quickly
29. … I treat it straight away
30. … I find it difficult to recognise the signs
31.
… my symptoms are so mild that I feel I can
delay treating it
32. … I wait a while before treating it
33. ... I find it difficult to get to my glucose / food
34.
… I am relaxed about it, knowing there is time
to treat it
35. ... I am caught up in doing something else
36.
… I ignore the warning signs, thinking I can
treat it ‘in a minute’
37. … it’s impossible to stop it becoming severe
38. … I am distracted by other things
39. ... I miss the warning signs because I’m relaxing
40. ... carbohydrates or glucose are within reach
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Study Title: Hypo COMPASS
Attitudes to Awareness of Hypos
For the purposes of this questionnaire only, please use the following definitions:
• A ‘hypo’ is defined as having a blood glucose level below 3.5mmol/l, whether you have
symptoms or not.
• Having ‘impaired awareness’ means you are not experiencing symptoms (or warning signs)
until your blood glucose is below 3.0mmol/l when you are awake.
Q1
Based on this definition, do you think you have 'impaired awareness’?
Please circle one response
Yes
No
Unsure
If No or Unsure, please comment below why you gave this answer, and then skip to
question 6. If Yes, go on to question 2
Q2
Why do you believe you have lost your hypo awareness (warning signs)?
Q3
How strongly do you believe it is possible for you to get your hypo awareness (warning
signs) back?
Please tick one box

Not at all
Slightly
Somewhat
A lot
Extremely
Q4
How concerned are you about having 'impaired awareness'?
Please tick one box
Not at all
Q5
Slightly
Somewhat
A lot

Extremely
How motivated do you feel to get your hypo awareness (warning signs) back?
Please tick one box
Not at all
Slightly
Somewhat
A lot

Extremely
Below is a list of ideas people with diabetes sometimes have about low blood sugar.
Please tick one box for each question.
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Study Title: Hypo COMPASS
How true do you consider the following
statements for you personally:
Not at all
true
Slightly
true
I don't need to treat a hypo, unless I
feel symptoms
I'd rather die living life to the full,
than be too cautious about my
diabetes
Good diabetes control is mainly
about avoiding high blood glucose
levels












Q9
I don't need to worry about hypos
because I don't get them very often




Q10
There are no serious consequences
to leaving mild hypos untreated
Someone will always be around to
sort me out, if I go low








It's more important to avoid going
high than going low
I'm not too bothered about warning
signs because severe hypos are rare
for me
I can function ok with low (below 3)
blood sugar levels
Treating hypos when I don't have
symptoms, is an unnecessary fuss
















Q16
I get frustrated and/or worried when
I see high blood glucose readings




Q17
I don't believe I'll have a severe hypo
in the future
I don't get worried very easily about
hypos
Sometimes I know that I am giving
myself more insulin than I really
need












Q6
Q7
Q8
Q11
Q12
Q13
Q14
Q15
Q18
Q19
Moderately
true
Thank you. Please check you have answered each question.
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Very
true
Study Title: Hypo COMPASS
The Hypo Burden Questionnaire
During a ‘hypo’, you may experience some of the following symptoms. If you do not have the symptom,
tick the ‘No’ box  and then move on to the next question. If you do have this symptom, please tick the
boxes that best describe your experience.
Do you have
this symptom
during a hypo?
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
3. Warmth
No
4. Sweating
No
5. Nausea
No
6. Weakness
No
7. Tingling
No
8. Headache
No
Yes
9. Lack of
co-ordination
No
Yes
10. Confusion
No
Yes
11. Dizziness
No
…does it help you to
identify and treat
your hypo early?
…does it bother you
much?
2. Pounding
heart
No
... how often does it
happen?
… how severe is it?
1. Trembling /
shakiness
No
If you have this symptom…
Yes
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Do you have
this symptom
during a hypo?
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
Yes
14. Blurred
vision
No
15. Drowsiness
No
16. Hunger
No
17. Tiredness
No
Yes
18. Irritability
No
Yes
19. Odd
behaviour
No
20. Mood
swings
No
…does it help you to
identify and treat
your hypo early?
…does it bother you
much?
13. Difficulty
speaking
No
... how often does it
happen?
… how severe is it?
12. Inability to
concentrate
No
If you have this symptom…
Do you have any other symptoms during a ‘hypo’ that are not listed above? If so, please write them in
the spaces below and tick the boxes  that best describe your experience.
Another
symptom I have
is:
When you have this symptom…
... how often does it
happen?
… how severe is it?
…does it bother
you much?
…does it help you
to identify and treat
your hypo early?
21. __________
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
22. __________
Rarely
Sometimes
Almost always
Mild
Moderate
Severe
No
Yes, a little
Yes, a lot
Never
Often
Almost always
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Study Title: Hypo COMPASS
Your Quality of Life
Please think about your life right now. Whether your life is good or bad, we still want to know. Think
about your blood glucose control and what you currently need or don’t need to do (eg blood tests,
insulin, waiting for a transplant, anti-rejection medication). Please tick one box  on each line.
My blood glucose and what I need to do to
manage it mean …
Neither
Strongly
Disagree agree nor Agree
disagree
disagree
Strongly
Agree
1. …I can have the sort of relationship I
would like with my family
eg parents, brothers, sisters, children,
grandchildren
2. …I can have the sort of relationship I
would like with friends
eg visiting, mutual support, shared
interests / experiences
3. …I can go out or socialise as I would
like
eg cinema, concerts, eat or drink with
friends, go to busy or crowded places
4. …I can have the sort of relationship I
would like with a partner / spouse
eg mutual support, sharing interests /
experiences
5. …I can enjoy sexual activity as I would
like
eg spontaneity, frequency, ability
6. …I can be as physically active as I
would like
eg walking, gardening, shopping, sports
7. …I feel as well as I would like
eg feel fit and healthy, no symptoms,
healthy weight, enough energy
8. …I feel as in control of my body as I
would like
eg no highs and lows, can start a family
9 …I look as good as I would like
eg look healthy, wear the clothes I want
(no worries about hiding pump)
10. …I can have the holidays I would like
eg accommodation, location, travelling
11. …I can work as I would like
eg have responsibility, earn money,
progress in my career, full- or part-time
12. …I have enough money
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N/A
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My blood glucose and what I need to do to
manage it mean …
Neither
Strongly
Disagree agree nor Agree
disagree
disagree
Strongly
Agree
N/A
Neither
Strongly
Disagree agree nor
disagree
disagree
Strongly
Agree
N/A
eg to pay bills, transport costs, food,
gifts
My blood glucose and what I need to do to
manage it mean …
Agree
13. …I can drive as much as I would like
eg to go shopping, give lifts to
people, get to work, go out alone
14. …I can practise my religion / follow my
beliefs as I would like
eg go to my place of worship, be part of
the community
15. …I can look after my home as I would
like
eg cooking, cleaning, decorating, repairs
16. …I can enjoy relaxing pastimes as I
would like
eg TV, hobbies, reading, computer games
17. …I can sleep as I would like
eg get to sleep, stay asleep, feel rested
18. …I can eat as I would like
eg when, where, what, as much or as
little as I want
19. …I can look after or be as useful to
others as I would like
eg family, friends, colleagues,
pets / animals, volunteering
20. …I can enjoy being with my pets /
animals as much as I would like
eg exercising, grooming, playing
21. …I can be as independent as I would
like
eg look after myself, go out alone, work
or stay at home alone
22. …I can control my life as I would like
eg freedom, choices, planning ahead,
keeping appointments
23. …I can be as spontaneous as I would
like
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eg go out without notice, stay out as
long as I want
24. …I can do “normal” things
eg enjoy everyday life, do what other
people do without worry
25. …I am treated as “normal”
eg trusted to look after myself, capable,
like any other person my age
26. …I have the confidence I would like
eg alone or with others, able to take on
challenges
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Study Title: Hypo COMPASS
Your Quality of Life – Importance
Please think about your life right now and how important each aspect of life is to you.
Please tick  one box on each line.
Extremely
Not at all
Important
important
important
1. Family relationships
2. Friendships
3. Going out or socialising
4. Partner / spouse relationship
5. Enjoying sexual activity
6. Being physically active
7. Feeling well
8. Feeling in control of my body
9. Looking good
10. Having holidays
11. Working
12. Affording the things I would like
13. Driving
14. Practising my religion
15. Looking after my home
16. Enjoying relaxing pastimes
17. Sleeping
18. Eating as I would like
19. Looking after or being useful to others
20. Pets / animals
21. Being independent
22. Being in control of my life
23. Being spontaneous
24. Doing “normal” things
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25. Being treated as “normal”
26. Having confidence
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Study Title: Hypo COMPASS
Diabetes Treatment Satisfaction Questionnaire: DTSQs
The following questions are concerned with the treatment for your diabetes (including insulin,
tablets and/or diet) and your experience over the past few weeks. Please answer each
question by circling a number on each of the scales.
1. How satisfied are you with your current treatment?
very satisfied
6
5
4
3
2
1
0
very dissatisfied
2. How often have you felt that your blood sugars have been unacceptably high recently?
most of the time
6
5
4
3
2
1
0
none of the time
3. How often have you felt that your blood sugars have been unacceptably low recently?
most of the time
6
5
4
3
2
1
0
none of the time
4. How convenient have you been finding your treatment to be recently?
very convenient
6
5
4
3
2
1
0
very inconvenient
0
very inflexible
0
very dissatisfied
5. How flexible have you been finding your treatment to be recently?
very flexible
6
5
4
3
2
1
6. How satisfied are you with your understanding of your diabetes?
very satisfied
6
5
4
3
2
1
7. Would you recommend this form of treatment to someone else with your kind of diabetes?
Yes, I would definitely
recommend the
treatment
6
5
4
3
2
1
0
No, I would definitely
not recommend the
treatment
8. How satisfied would you be to continue with your present form of treatment?
very satisfied
6
5
4
3
2
1
0
very dissatisfied
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Study Title: Hypo COMPASS
The Blood Glucose Monitoring Questionnaire (BGM-Q)
The items below describe views that people with diabetes may have about blood glucose monitoring.
Please tick one box  on each line that best describes your views right now.
Part A. These questions are about your general likes and dislikes about monitoring.
Strongly
disagree
Disagree
Neither
agree nor
disagree
Agree
Strongly
agree
Agree
Strongly
agree
1. During the day, I like to keep a close eye on
my blood glucose levels
2. I wish I could take time off from monitoring
3. Too much information about my blood
glucose levels makes me feel anxious
4. I don’t like my sleep being disrupted by
monitoring
5. I like having lots of information about my
blood glucose control
Part B. These questions are about your current method of monitoring.
What is the name of your monitoring device? ________________________
My current method of monitoring …
Strongly
disagree
Disagree
Neither
agree nor
disagree
6. … is easy to do
7. … takes a lot of time
8. … gives me the confidence to do what I
want
9. … is convenient
10. … is discreet
11. … disrupts my sleep
12. … lets me be as physically active as I like
13. ... is accurate
14. … reassures me
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My current method of monitoring …
Strongly
disagree
Disagree
Neither
agree nor
disagree
Agree
Strongly
agree
Strongly
disagree
Disagree
Neither
agree nor
disagree
Agree
Strongly
agree
15. … makes me feel like a robot / machine
16. … makes me feel uncomfortable about how
my body looks
17. … gives me too much information
18. … causes other people to react negatively
(e.g. to stare / ask intrusive questions)
19. … means I am constantly looking at my
blood glucose levels
20. … means I have an accurate snapshot of
my blood glucose levels
21. ... helps me keep my blood glucose
levels within target
22. … makes me feel anxious about my
blood glucose levels
23. ... helps me to avoid hypos during the day
24. … gives me enough information
25. … causes me pain or discomfort
26. ... helps me to avoid high blood glucose
27. … helps me know in which direction my
blood glucose is moving (falling / rising)
28. … helps me to avoid hypos when I am
asleep
29. … gives me confidence to make changes
in my treatment
30. … gives me freedom in my everyday life
31. Overall, my current method of monitoring
suits me well
32. What are the best things (up to three) about your current method of monitoring?
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33. What are the worst things (up to three) about your current method of monitoring?
34. Is there anything that could improve your monitoring device or that you wish it could do?
Thank you. Please check that you have answered each question.
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Insulin Treatment Satisfaction Questionnaire (ITSQ) – abridged version
People who take insulin can have many different experiences with their treatment. Some people who
take insulin may find it difficult and burdensome, while others feel that it is not much of a bother at all.
The following questions are about your perceptions of your current insulin treatment and how it affects
you in your daily life. When you think of your insulin treatment, please keep in mind the type of insulin
you take, the dose or amount of insulin, your schedule for taking insulin, and the device or method you
use to give yourself insulin.
Please think about your experiences during the past 4 weeks when you answer the questions.
Please answer each question by circling the number  that best represents your answer. If you are
unsure about how to answer a question, please give the best answer you can.
1.
How confident are you that you can avoid symptoms of low blood sugar (such as
sweating, trembling, dizziness, blurred vision) with your current insulin treatment?
Extremely confident
Not at all confident
1
2.
5
6
7
2
3
4
5
6
7
2
3
4
5
6
7
How much do you feel that the insulin you are currently using increases the chances that
you will experience low blood sugar?
Not at all
Extremely
1
5.
4
In general, how bothered are you by symptoms of low blood sugar (such as sweating,
trembling, dizziness, blurred vision) due to the insulin you currently use?
Not at all bothered
Extremely bothered
1
4.
3
How confident are you that you can avoid severe episodes of low blood sugar that result
in loss of consciousness (fainting or passing out) with the insulin you currently use?
Extremely confident
Not at all confident
1
3.
2
2
3
4
5
6
7
How worried are you about experiencing low blood sugars during the night with the
insulin you currently use?
Not at all worried
Extremely worried
1
2
3
4
5
6
7
The following questions are about your perceptions of your current method of taking insulin and
how it affects you in your daily life. For these questions, you should only think about the device or
method you use to give yourself insulin.
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6.
How easy is it for you to take the correct amount of insulin each time with your current
method of taking insulin?
Extremely easy
Not at all easy
1
7.
2
3
4
5
6
How convenient is your current method of taking insulin when you are away from home?
Extremely convenient
1
8.
2
3
4
5
6
7
2
3
4
5
6
7
How comfortable are you taking insulin in a public place (where people might see you
with your current method of taking insulin)?
Extremely
Not at all comfortable
comfortable
1
10.
Not at all convenient
How much pain or other physical discomfort do you experience with your current method
of taking insulin?
No pain or
A tremendous amount of
discomfort
pain or discomfort
1
9.
7
2
3
4
5
6
7
How much emotional distress or anxiety do you experience related to your method of
taking insulin?
A tremendous amount of
No distress or anxiety
distress or anxiety
1
2
3
4
5
6
7
11. Overall, how satisfied are you with your current method of taking insulin?
Extremely satisfied
1
Not at all satisfied
2
3
4
5
6
7
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EQ-5D
By placing a tick in one box in each group below, please indicate which statements best
describe your own health state today.
Mobility
I have no problems in walking about
I have some problems in walking about
I am confined to bed
Self-Care
I have no problems with self-care
I have some problems washing or dressing myself
I am unable to wash or dress myself
Usual Activities (e.g. work, study, housework, family or leisure activities)
I have no problems with performing my usual activities
I have some problems with performing my usual activities
I am unable to perform my usual activities
Pain / Discomfort
I have no pain or discomfort
I have moderate pain or discomfort
I have extreme pain or discomfort
Anxiety / Depression
I am not anxious or depressed
I am moderately anxious or depressed
I am extremely anxious or depressed
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The Perceived Control of Diabetes Scales
The following questions are about the causes of situations which might happen to you. We ask
you to imagine that the events described have happened to you recently.
While events may have many causes, we want you to pick only one - the major cause of the
situation as you see it. Please write this cause in the space provided after each event.
Next, we want you to answer some questions about the cause by circling the most appropriate
number on a sliding scale from 6 to 0.
Imagine that you have recently experienced a hypo.
Write down the single most likely cause of the hypo in the space below.
________________________________________________________________________
_________________________________________________________________________
Now rate this cause on the following scales:
1.
To what extent was the cause due to something about you?
Totally due to me
2.
2
1
0
Not at all due to me
6
5
4
3
2
1
0
Not at all due
to treatment
recommended
6
5
4
3
2
1
0
Not at all due
to other people
or circumstances
6
5
4
3
2
1
0
Not at all due
to chance
2
1
0
Totally uncontrollable
by me
1
0
Totally uncontrollable
by my doctor
To what extent was the cause controllable by you?
Totally controllable
by me
6.
3
To what extent was the cause due to chance?
Totally due
to chance
5.
4
To what extent was the cause something to do with other people or circumstances?
Totally due
to other people
or circumstances
4.
5
To what extent was the cause due to the treatment recommended by your doctor?
Totally due
to treatment
recommended
3.
6
6
5
4
3
To what extent was the cause controllable by your doctor?
Totally controllable
by my doctor
6
5
4
3
2
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7.
To what extent do you think you could have foreseen the cause of the hypo?
Totally foreseeable
by me
6
5
4
3
2
1
0
Totally unforeseeable
by me
Imagine that your diabetes has been well controlled for a period of several weeks, during which
time there has been little fluctuation in blood glucose, no reactions and you have felt fit and well.
Write down the single most likely cause of this period of good control in the space below.
___________________________________________________________________________________
___________________________________________________________________________________
Now rate this cause on the following scales:
1.
To what extent was the cause due to something about you?
Totally due to me
2.
1
0
Not at all due to me
6
5
4
3
2
1
0
Not at all due
to treatment
recommended
6
5
4
3
2
1
0
Not at all due
to other people
or circumstances
6
5
4
3
2
1
0
Not at all due
to chance
6
5
4
2
1
0
Totally uncontrollable
by me
1
0
Totally uncontrollable
by my doctor
3
To what extent was the cause controllable by your doctor?
Totally controllable
by my doctor
7.
2
To what extent was the cause controllable by you?
Totally controllable
by me
6.
3
To what extent was the cause due to chance?
Totally due
to chance
5.
4
To what extent was the cause something to do with other people or circumstances?
Totally due
to other people
or circumstances
4.
5
To what extent was the cause due to the treatment recommended by your doctor?
Totally due
to treatment
recommended
3.
6
6
5
4
3
2
To what extent do you think you could have foreseen the cause of the period of good diabetes
control?
Totally foreseeable
by me
6
5
4
3
2
1
0
Totally unforeseeable
by me
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Imagine that for several days you have found high levels of sugar when you tested your blood or
urine.
Write down the single most likely cause of the high sugar levels in the space below.
___________________________________________________________________________________
___________________________________________________________________________________
Now rate this cause on the following scales:
1.
To what extent was the cause due to something about you?
Totally due to me
2.
1
0
Not at all due to me
6
5
4
3
2
1
0
Not at all due
to treatment
recommended
6
5
4
3
2
1
0
Not at all due
to other people
or circumstances
6
5
4
3
2
1
0
Not at all due
to chance
6
5
4
2
1
0
Totally uncontrollable
by me
1
0
Totally uncontrollable
by my doctor
3
To what extent was the cause controllable by your doctor?
Totally controllable
by my doctor
7.
2
To what extent was the cause controllable by you?
Totally controllable
by me
6.
3
To what extent was the cause due to chance?
Totally due
to chance
5.
4
To what extent was the cause something to do with other people or circumstances?
Totally due
to other people
or circumstances
4.
5
To what extent was the cause due to the treatment recommended by your doctor?
Totally due
to treatment
recommended
3.
6
6
5
4
3
2
To what extent do you think you could have foreseen the cause of the high sugar levels?
Totally foreseeable
by me
6
5
4
3
2
1
0
Totally unforeseeable
by me
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Imagine that good control of your diabetes is restored after a period of poor control.
Write down, in the space below, the single most likely cause of good control being restored.
___________________________________________________________________________________
___________________________________________________________________________________
Now rate this cause on the following scales:
1.
To what extent was the cause due to something about you?
Totally due to me
2.
1
0
Not at all due to me
6
5
4
3
2
1
0
Not at all due
to treatment
recommended
6
5
4
3
2
1
0
Not at all due
to other people
or circumstances
6
5
4
3
2
1
0
Not at all due
to chance
6
5
4
2
1
0
Totally uncontrollable
by me
1
0
Totally uncontrollable
by my doctor
3
To what extent was the cause controllable by your doctor?
Totally controllable
by my doctor
7.
2
To what extent was the cause controllable by you?
Totally controllable
by me
6.
3
To what extent was the cause due to chance?
Totally due
to chance
5.
4
To what extent was the cause something to do with other people or circumstances?
Totally due
to other people
or circumstances
4.
5
To what extent was the cause due to the treatment recommended by your doctor?
Totally due
to treatment
recommended
3.
6
6
5
4
3
2
To what extent do you think you could have foreseen the cause of good control being restored?
Totally foreseeable
by me
6
5
4
3
2
1
0
Totally unforeseeable
by me
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Imagine that you have successfully avoided the complications of diabetes such as problems with
your feet.
Write down, in the space below, the single most likely cause of the successful avoidance of diabetic
complications such as problems with your feet.
___________________________________________________________________________________
___________________________________________________________________________________
Now rate this cause on the following scales:
1.
To what extent was the cause due to something about you?
Totally due to me
2.
1
0
Not at all due to me
6
5
4
3
2
1
0
Not at all due
to treatment
recommended
6
5
4
3
2
1
0
Not at all due
to other people
or circumstances
6
5
4
3
2
1
0
Not at all due
to chance
6
5
4
2
1
0
Totally uncontrollable
by me
1
0
Totally uncontrollable
by my doctor
3
To what extent was the cause controllable by your doctor?
Totally controllable
by my doctor
7.
2
To what extent was the cause controllable by you?
Totally controllable
by me
6.
3
To what extent was the cause due to chance?
Totally due
to chance
5.
4
To what extent was the cause something to do with other people or circumstances?
Totally due
to other people
or circumstances
4.
5
To what extent was the cause due to the treatment recommended by your doctor?
Totally due
to treatment
recommended
3.
6
6
5
4
3
2
To what extent do you think you could have foreseen the cause of successfully avoiding
complications?
Totally foreseeable
by me
6
5
4
3
2
1
0
Totally unforeseeable
by me
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Imagine that you have recently become unacceptably overweight.
Write down, in the space below, the single most likely cause of becoming overweight.
___________________________________________________________________________________
___________________________________________________________________________________
Now rate this cause on the following scales:
1.
To what extent was the cause due to something about you?
Totally due to me
2.
1
0
Not at all due to me
6
5
4
3
2
1
0
Not at all due
to treatment
recommended
6
5
4
3
2
1
0
Not at all due
to other people
or circumstances
6
5
4
3
2
1
0
Not at all due
to chance
6
5
4
2
1
0
Totally uncontrollable
by me
1
0
Totally uncontrollable
by my doctor
3
To what extent was the cause controllable by your doctor?
Totally controllable
by my doctor
7.
2
To what extent was the cause controllable by you?
Totally controllable
by me
6.
3
To what extent was the cause due to chance?
Totally due
to chance
5.
4
To what extent was the cause something to do with other people or circumstances?
Totally due
to other people
or circumstances
4.
5
To what extent was the cause due to the treatment recommended by your doctor?
Totally due
to treatment
recommended
3.
6
6
5
4
3
2
To what extent do you think you could have foreseen the cause of becoming overweight?
Totally foreseeable
by me
6
5
4
3
2
1
0
Totally unforeseeable
by me
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Imagine that you have managed your diabetes successfully, living life as you wished while also
keeping your glucose (sugar) levels under control.
Write down, in the space below, the single most likely cause of managing your diabetes successfully.
___________________________________________________________________________________
___________________________________________________________________________________
Now rate this cause on the following scales:
1.
To what extent was the cause due to something about you?
Totally due to me
2.
1
0
Not at all due to me
6
5
4
3
2
1
0
Not at all due
to treatment
recommended
6
5
4
3
2
1
0
Not at all due
to other people
or circumstances
6
5
4
3
2
1
0
Not at all due
to chance
6
5
4
2
1
0
Totally uncontrollable
by me
1
0
Totally uncontrollable
by my doctor
3
To what extent was the cause controllable by your doctor?
Totally controllable
by my doctor
7.
2
To what extent was the cause controllable by you?
Totally controllable
by me
6.
3
To what extent was the cause due to chance?
Totally due
to chance
5.
4
To what extent was the cause something to do with other people or circumstances?
Totally due
to other people
or circumstances
4.
5
To what extent was the cause due to the treatment recommended by your doctor?
Totally due
to treatment
recommended
3.
6
6
5
4
3
2
To what extent do you think you could have foreseen the cause of managing your diabetes
successfully?
Totally foreseeable
by me
6
5
4
3
2
1
0
Totally unforeseeable
by me
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APPENDIX 6 SmPC for Insulin Aspart
Novo Nordisk Limited
Broadfield Park, Brighton Road, Crawley, West Sussex, RH11 9RT
Telephone: +44 (0)1293 613555
Fax: +44 (0)1293 613535
Medical Information Direct Line: +44 (0)845 600 5055
Medical Information e-mail: ukmedicalinfo@novonordisk.com
Customer Care direct line: +44 (0)845 600 5055
Medical Information Fax: +44 (0)1293 613211
Summary of Product Characteristics last updated on the eMC: 18/08/2009
SPC NovoRapid 100 U/ml, NovoRapid Penfill 100 U/ml, NovoRapid FlexPen 100 U/ml
Table of Contents
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
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•
•
•
•
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•
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
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•
LEGAL CATEGORY
1. NAME OF THE MEDICINAL PRODUCT
NovoRapid 100 U/ml solution for injection in vial.
NovoRapid Penfill 100 U/ml solution for injection in cartridge.
NovoRapid FlexPen 100 U/ml solution for injection in pre-filled pen.
Go to top of the page
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of the solution contains 100 U of insulin aspart* (equivialent to 3.5mg). 1 vial contains
10 ml equivalent to 1,000 U.
1 ml of the solution contains 100 U of insulin aspart* (equivialent to 3.5mg). 1 cartridge
contains 3 ml equivalent to 300 U.
1 ml of the solution contains 100 U of insulin aspart* (equivialent to 3.5mg). 1 pre-filled pen
contains 3 ml equivalent to 300 U.
*Insulin aspart is produced by recombinant DNA technology in Saccharomyces cerevisiae.
For a full list of excipients, see section 6.1.
Go to top of the page
3. PHARMACEUTICAL FORM
Solution for injection in vial.
Solution for injection in cartridge. Penfill.
Solution for injection in pre-filled pen. FlexPen.
Clear, colourless, aqueous solution.
Go to top of the page
4. CLINICAL PARTICULARS
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4.1 Therapeutic indications
Treatment of diabetes mellitus in adults and adolescents and children aged 2 to 17 years.
Go to top of the page
4.2 Posology and method of administration
NovoRapid is a rapid-acting insulin analogue.
Posology
NovoRapid dosing is individual and determined in accordance with the needs of the patient.
It should normally be used in combination with intermediate-acting or long-acting insulin
given at least once a day. Blood glucose monitoring and insulin dose adjustments are
recommended to achieve optimal glycaemic control.
The individual insulin requirement in adults and children is usually between 0.5 and 1.0
U/kg/day. In a basal-bolus treatment regimen 50-70% of this requirement may be provided
by NovoRapid and the remainder by intermediate-acting or long-acting insulin. Adjustment
of dosage may be necessary if patients undertake increased physical activity, change their
usual diet or during concomitant illness.
Special population
As with all insulin products, in elderly patients and patients with renal or hepatic impairment,
glucose monitoring should be intensified and insulin aspart dosage adjusted on an
individual basis.
Paediatric use
No studies have been performed in children below the age of 2 years. NovoRapid should
only be used in this age group under careful medical supervision.
NovoRapid can be used in children in preference to soluble human insulin when a rapid
onset of action might be beneficial (see section 5.1 and 5.2). For example, in the timing of
the injections in relation to meals.
Transfer from other insulin products
NovoRapid has a faster onset and a shorter duration of action than soluble human insulin.
When injected subcutaneously into the abdominal wall, the onset of action will occur within
10-20 minutes of injection. The maximum effect is exerted between 1 and 3 hours after the
injection. The duration of action is 3 to 5 hours.
Due to the faster onset of action, NovoRapid should generally be given immediately before
a meal. When necessary NovoRapid can be given soon after a meal. The faster onset of
action compared to soluble human insulin is maintained regardless of injection site. When
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transferring from other insulin products, adjustment of the NovoRapid dose and the dose of
the basal insulin may be necessary.
Method of administration
Administration with a syringe:
NovoRapid is administered subcutaneously by injection in the abdominal wall, the thigh, the
upper arm, the deltoid region or the gluteal region. Injection sites should therefore always
be rotated within the same region. As with all insulin products, subcutaneous injection in the
abdominal wall ensures a faster absorption than other injection sites. The duration of action
will vary according to the dose, injection site, blood flow, temperature and level of physical
activity.
Administration with an insulin delivery system:
NovoRapid Penfill is designed to be used with Novo Nordisk insulin delivery systems and
NovoFine needles.
NovoRapid Penfill is accompanied by a package leaflet with detailed instruction for use to
be followed.
Administration with FlexPen:
NovoRapid FlexPen are pre-filled pens designed to be used with NovoFine or NovoTwist
needles. FlexPen delivers 1-60 units in increments of 1 unit.
NovoRapid FlexPen is colour coded and accompanied by a package leaflet with detailed
instruction for use to be followed.
Continuous Subcutaneous Insulin Infusion (CSII):
NovoRapid may be used for Continuous Subcutaneous Insulin Infusion (CSII) in pump
systems suitable for insulin infusion. CSII should be administered in the abdominal wall.
Infusion sites should be rotated.
When used with an insulin infusion pump, NovoRapid should not be mixed with any other
insulin products.
Patients using CSII should be comprehensively instructed in the use of the pump system
and use the correct reservoir and tubing for the pump (see section 6.6). The infusion set
(tubing and cannula) should be changed in accordance with the instructions in the product
information supplied with the infusion set.
Patients administering NovoRapid by CSII must have alternative insulin available in case of
pump system failure.
Intravenous use:
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If necessary, NovoRapid can be administered intravenously which should be carried out by
health care professionals.
For intravenous use, infusion systems with NovoRapid 100 U/ml at concentrations from
0.05 U/ml to 1.0 U/ml insulin aspart in the infusion fluids 0.9% sodium chloride, 5%
dextrose or 10% dextrose inclusive 40 mmol/l potassium chloride using polypropylene
infusion bags are stable at room temperature for 24 hours.
Although stable over time, a certain amount of insulin will be initially adsorbed to the
material of the infusion bag. Monitoring of blood glucose is necessary during insulin
infusion.
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4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Go to top of the page
4.4 Special warnings and precautions for use
Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes mellitus
(T1DM), may lead to hyperglycaemia and diabetic ketoacidosis.
Usually the first symptoms of hyperglycaemia develop gradually over a period of hours or
days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness,
flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In T1DM,
untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is
potentially lethal.
Before travelling between different time zones the patient should seek the doctor's advice
since this may mean that the patient has to take the insulin and meals at different times.
Hypoglycaemia
Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia.
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin
requirement (see sections 4.8 and 4.9).
Patients whose blood glucose control is greatly improved, e.g. by intensified insulin therapy,
may experience a change in their usual warning symptoms of hypoglycaemia, and should
be advised accordingly. Usual warning symptoms may disappear in patients with
longstanding diabetes.
A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if
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hypoglycaemia occurs, it may occur earlier after an injection when compared with soluble
human insulin.
Since NovoRapid should be administered in immediate relation to a meal the rapid onset of
action should be considered in patients with concomitant diseases or medication where a
delayed absorption of food might be expected.
Concomitant illness, especially infections and feverish conditions, usually increases the
patient's insulin requirements.
When patients are transferred between different types of insulin products, the early warning
symptoms of hypoglycaemia may change or become less pronounced than those
experienced with their previous insulin.
Transfer from other insulin products
Transferring a patient to another type or brand of insulin should be done under strict
medical supervision. Changes in strength, brand (manufacturer), type, origin (animal,
human, human insulin analogue) and/or method of manufacture (recombinant DNA versus
animal source insulin) may result in the need for a change in dosage. Patients transferred
to NovoRapid from another type of insulin may require an increased number of daily
injections or a change in dosage from that used with their usual insulins. If an adjustment is
needed, it may occur with the first dose or during the first few weeks or months.
Injection site reactions
As with any insulin therapy, injection site reactions may occur and include pain, redness,
hives, inflammation, swelling and itching. Continuous rotation of the injection site within a
given area may help to reduce or prevent these reactions. Reactions usually resolve in a
few days to a few weeks. On rare occasions, injection site reactions may require
discontinuation of NovoRapid.
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4.5 Interaction with other medicinal products and other forms of interaction
A number of medicinal products are known to interact with the glucose metabolism.
The following substances may reduce the patient's insulin requirements:
Oral antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers,
angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and
sulphonamides.
The following substances may increase the patient's insulin requirements:
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics,
growth hormone and danazol.
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Beta-blocking agents may mask the symptoms of hypoglycaemia.
Octreotide/lanreotide may both increase or decrease insulin requirement.
Alcohol may intensify or reduce the hypoglycaemic effect of insulin.
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4.6 Pregnancy and lactation
Pregnancy
NovoRapid (insulin aspart) can be used in pregnancy. Data from two randomised controlled
clinical trials (322 and 27 exposed pregnancies) do not indicate any adverse effect of
insulin aspart on pregnancy or on the health of the foetus/newborn when compared to
human insulin (see section 5.1).
Intensified blood glucose control and monitoring of pregnant women with diabetes (type 1
diabetes, type 2 diabetes or gestational diabetes) are recommended throughout pregnancy
and when contemplating pregnancy. Insulin requirements usually fall in the first trimester
and increase subsequently during the second and third trimester. After delivery, insulin
requirements normally return rapidly to pre-pregnancy values.
Breast-feeding
There are no restrictions on treatment with NovoRapid during breast-feeding. Insulin
treatment of the nursing mother presents no risk to the baby. However, the NovoRapid
dosage may need to be adjusted.
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4.7 Effects on ability to drive and use machines
The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia.
This may constitute a risk in situations where these abilities are of special importance (e.g.
driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia while driving. This
is particularly important in those who have reduced or absent awareness of the warning
signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of
driving should be considered in these circumstances.
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4.8 Undesirable effects
Adverse reactions observed in patients using NovoRapid are mainly dose-dependent and
due to the pharmacologic effect of insulin.
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Hypoglycaemia is a common undesirable effect. It may occur if the insulin dose is too high
in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness
and/or convulsions and may result in temporary or permanent impairment of brain function
or even death.
In clinical trials and during marketed use the frequency varies with patient population and
dose regimens therefore no specific frequency can be presented. During clinical trials the
overall rates of hypoglycaemia did not differ between patients treated with insulin aspart
compared to human insulin.
Adverse reactions listed below are classified according to frequency and System Organ
Class. Frequency categories are defined according to the following convention: Very
common ( 1/10); common ( 1/100 to <1/10); uncommon ( 1/1,000 to 1/100); rare
( 1/10,000 to 1/1,000); very rare ( 1/10,000), not known (cannot be estimated fromthe
available data).
Nervous system disorders Rare - Peripheral neuropathy
Fast improvement in blood glucose control may be associated
with a condition termed “acute painful neuropathy”, which is
usually reversible.
Eye disorders
Uncommon - Refraction disorders
Refraction anomalies may occur upon initiation of insulin
therapy. These symptoms are usually of transitory nature.
Uncommon - Diabetic retinopathy
Long-term improved glycaemic control decreases the risk of
progression of diabetic retinopathy. However, intensification of
insulin therapy with abrupt improvement in glycaemic control
may be associated with temporary worsening of diabetic
retinopathy.
Skin and subcutaneous
tissue disorders
Uncommon – Lipodystrophy
Lipodystrophy may occur at the injection site as a
consequence of failure to rotate injection sites within an area.
Uncommon - Local hypersensitivity
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Local hypersensitivity reactions (pain, redness, hives,
inflammation, swelling and itching at the injection site) may
occur during treatment with insulin. These reactions are
usually transitory and normally they disappear during
continued treatment.
General disorders and
administration site
conditions
Uncommon – Oedema
Oedema may occur upon initiation of insulin therapy. These
symptoms are usually of transitory nature.
Immune system disorders Uncommon - Urticaria, rash, eruptions
Very rare - Anaphylactic reactions
Symptoms of generalised hypersensitivity may include
generalised skin rash, itching, sweating, gastrointestinal
upset, angioneurotic oedema, difficulties in breathing,
palpitation and reduction in blood pressure. Generalised
hypersensitivity reactions are potentially life threatening.
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4.9 Overdose
A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop
over sequential stages if too high doses relative to the patient's requirement are
administered:
• Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary
products. It is therefore recommended that the diabetic patient always carries sugar
containing products
• Severe hypoglycaemic episodes, where the patient has become unconscious, can be
treated by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained
person, or by glucose given intravenously by a health care professional. Glucose must also
be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes.
Upon regaining consciousness, administration of oral carbohydrates is recommended for
the patient in order to prevent a relapse.
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5. PHARMACOLOGICAL PROPERTIES
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5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Insulins and analogues for injection, fast-acting: ATC code
A10AB05.
Mechanism of action
The blood glucose lowering effect of insulin aspart is due to the facilitated uptake of glucose
following binding of insulin to receptors on muscle and fat cells and to the simultaneous
inhibition of glucose output from the liver.
NovoRapid produces a more rapid onset of action compared to soluble human insulin,
together with a lower glucose concentration, as assessed within the first four hours after a
meal. NovoRapid has a shorter duration of action compared to soluble human insulin after
subcutaneous injection.
Fig. I. Blood glucose concentrations following a single pre-meal dose of NovoRapid injected
immediately before a meal (solid curve) or soluble human insulin administered 30 minutes
before a meal (hatched curve) in patients with type 1 diabetes mellitus.
When NovoRapid is injected subcutaneously, the onset of action will occur within 10 to 20
minutes of injection. The maximum effect is exerted between 1 and 3 hours after injection.
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The duration of action is 3 to 5 hours.
Adults
Clinical trials in patients with type 1 diabetes have demonstrated a lower postprandial blood
glucose with NovoRapid compared to soluble human insulin (Fig. I). In two long-term open
label trials in patients with type 1 diabetes comprising 1070 and 884 patients, respectively,
NovoRapid reduced glycosylated haemoglobin by 0.12 [95% C.I. 0.03; 0.22] percentage
points and by 0.15 [95% C.I. 0.05; 0.26] percentage points compared to human insulin; a
difference of doubtful clinical significance.
Elderly
A randomised, double-blind cross-over PK/PD trial comparing insulin aspart with soluble
human insulin was performed in elderly patients with type 2 diabetes (19 patients aged 6583 years, mean age 70 years). The relative differences in the pharmacodynamic properties
(GIR max ,AUC GIR, 0-120 min ) between insulin aspart and human insulin in elderly were similar to
those seen in healthy subjects and in younger subjects with diabetes.
Children and adolescent
A clinical trial comparing preprandial soluble human insulin with postprandial insulin aspart
was performed in small children (20 patients aged 2 to less than 6 years, studied for 12
weeks, among those four were younger than 4 years old) and a single dose PK/PD trial
was performed in children (6-12 years) and adolescents (13-17 years). The
pharmacodynamic profile of insulin aspart in children was similar to that seen in adults.
Clinical trials in patients with type 1 diabetes have demonstrated a reduced risk of nocturnal
hypoglycaemia with insulin aspart compared with soluble human insulin. The risk of
daytime hypoglycaemia was not significantly increased.
Pregnancy
A clinical trial comparing safety and efficacy of insulin aspart vs. human insulin in the
treatment of pregnant women with type 1 diabetes (322 exposed pregnancies (insulin
aspart: 157; human insulin: 165)) did not indicate any adverse effect of insulin aspart on
pregnancy or on the health of the foetus/newborn.
In addition the data from a clinical trial including 27 women with gestational diabetes
randomised to treatment with insulin aspart vs. human insulin (insulin aspart: 14; human
insulin: 13) showed similar safety profiles between treatments.
Insulin aspart is equipotent to soluble human insulin on a molar basis.
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5.2 Pharmacokinetic properties
In NovoRapid substitution of amino acid proline with aspartic acid at position B28 reduces
the tendency to form hexamers as observed with soluble human insulin. NovoRapid is
therefore more rapidly absorbed from the subcutaneous layer compared to soluble human
insulin.
The time to maximum concentration is, on average, half of that for soluble human insulin. A
mean maximum plasma concentration of 492±256 pmol/l was reached 40 (interquartile
range: 30–40) minutes after a subcutaneous dose of 0.15 U/kg bodyweight in type 1
diabetic patients. The insulin concentrations returned to baseline about 4 to 6 hours after
dose. The absorption rate was somewhat slower in type 2 diabetic patients, resulting in a
lower C max (352±240 pmol/l) and later t max (60 (interquartile range: 50–90) minutes). The
intra-individual variability in time to maximum concentration is significantly less for
NovoRapid than for soluble human insulin, whereas the intra-individual variability in C max for
NovoRapid is larger.
Children and adolescent
The pharmacokinetic and pharmacodynamic properties of NovoRapid were investigated in
children (6–12 years) and adolescents (13–17 years) with type 1 diabetes. Insulin aspart
was rapidly absorbed in both age groups, with similar t max as in adults. However, C max
differed between the age groups, stressing the importance of the individual titration of
NovoRapid.
Elderly
The relative differences in pharmacokinetic properties between insulin aspart and soluble
human insulin in elderly subjects (65-83 years, mean age 70 years) with type 2 diabetes
were similar to those observed in healthy subjects and in younger subjects with diabetes. A
decreased absorption rate was observed in elderly subjects, resulting in a later t max (82
(interquartile range: 60-120) minutes), whereas C max was similar to that observed in
younger subjects with type 2 diabetes and slightly lower than in subjects with type 1
diabetes.
Hepatic impairment
A single dose pharmacokinetic study of insulin aspart was performed in 24 subjects with
hepatic function ranging from normal to severely impaired. In subjects with hepatic
impairment absorption rate was decreased and more variable, resulting in delayed t max from
about 50 min in subjects with normal hepatic function to about 85 min in subjects with
moderate and severe hepatic impairment. AUC, C max and CL/F were similar in subjects with
reduced hepatic function compared with subjects with normal hepatic function.
Renal impairment
A single dose pharmacokinetic study of insulin aspart in 18 subjects with renal function
ranging from normal to severely impaired was performed. No apparent effect of creatinine
clearance values on AUC, C max , CL/F and t max of insulin aspart was found. Data were
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limited in subjects with moderate and severe renal impairment. Subjects with renal failure
necessitating dialysis treatment were not investigated.
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5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction.
In in vitro tests, including binding to insulin and IGF-1 receptor sites and effects on cell
growth, insulin aspart behaved in a manner that closely resembled human insulin. Studies
also demonstrate that the dissociation of binding to the insulin receptor of insulin aspart is
equivalent to human insulin.
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6. PHARMACEUTICAL PARTICULARS
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6.1 List of excipients
Glycerol
Phenol
Metacresol
Zinc chloride
Disodium phosphate dihydrate
Sodium chloride
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections
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6.2 Incompatibilities
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Substances added to NovoRapid may cause degradation of insulin aspart, e.g. if the
medicinal product contains thiols or sulphites.
This medicinal product must not be mixed with other medicinal products. Exceptions are
NPH (Neutral Protamine Hagedorn) insulin and infusion fluids as described in section 4.2.
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6.3 Shelf life
30 months.
After first opening: A maximum of 4 weeks when stored below 30°C.
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6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Keep away from the cooling element. Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Keep the cartridge in the outer carton in order to protect from light.
Keep the cap on FlexPen in order to protect from light.
After first opening or carried as a spare: Do not refrigerate. Store below 30°C.
NovoRapid must be protected from excessive heat and light.
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6.5 Nature and contents of container
10 ml solution in vial (type 1 glass) closed with a disc (bromobutyl/polyisoprene rubber) and
a protective tamper-proof plastic cap.
Pack sizes of 1 and 5 vials and a multipack with 5 x (1 x 10 ml) vials. Not all pack sizes may
be marketed.
3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper
(bromobutyl/polyisoprene) in a carton.
Pack sizes of 5 and 10 cartridges. Not all pack sizes may be marketed.
3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper
(bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of
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polypropylene.
Pack sizes of 1, 5 and 10 pre-filled pens. Not all pack sizes may be marketed.
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6.6 Special precautions for disposal and other handling
NovoRapid vials are for use with insulin syringes with the corresponding unit scale.
NovoRapid Penfill is for use by one person only. The cartridge must not be refilled.
NovoRapid FlexPen is for use by one person only. The cartridge must not be refilled.
The patient should be advised to discard the needle after each injection.
NovoRapid must not be used if it does not appear clear and colourless.
NovoRapid which has been frozen must not be used.
NovoRapid may be used in an infusion pump system (CSII) as described in section 4.2.
Tubings in which the inner surface materials are made of polyethylene or polyolefin have
been evaluated and found compatible with pump use.
In case of emergency in current NovoRapid users (hospitalisation or insulin pen
malfunction), NovoRapid can be withdrawn with an U100 insulin syringe from the cartridge.
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7. MARKETING AUTHORISATION HOLDER
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark
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8. MARKETING AUTHORISATION NUMBER(S)
NovoRapid 10 ml EU/1/99/119/001, 008
NovoRapid Penfill 3 ml EU/1/99/119/003, 006
NovoRapid FlexPen 3ml EU/1/99/119/009, 010, 011
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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 7 September 1999
Date of last renewal: 30 April 2009
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10. DATE OF REVISION OF THE TEXT
07/2009
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LEGAL CATEGORY
Prescription only medicine (POM)
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APPENDIX 7 SmPC for Insulin Glargine
sanofi-aventis
1 Onslow Street, Guildford, Surrey, GU1 4YS, UK
Telephone: +44 (0)1483 505 515
Fax: +44 (0)1483 535 432
Medical Information e-mail: ukmedicalinformation@sanofi-aventis.com
Summary of Product Characteristics last updated on the eMC: 19/12/2008
SPC Lantus 100 Units/ml solution for injection in SoloStar pre-filled pen
Table of Contents
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1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. MARKETING AUTHORISATION HOLDER
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8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
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1. NAME OF THE MEDICINAL PRODUCT
Lantus 100 Units/ml solution for injection in a pre-filled pen
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2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 100 Units insulin glargine (equivalent to 3.64 mg). Each pen contains 3 ml
of solution for injection, equivalent to 300 Units.
Insulin glargine is produced by recombinant DNA technology in Escherichia coli.
For a full list of excipients, see section 6.1.
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3. PHARMACEUTICAL FORM
Solution for injection in a pre-filled pen. SoloStar.
Clear colourless solution.
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4. CLINICAL PARTICULARS
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4.1 Therapeutic indications
For the treatment of adults, adolescents and children of 6 years or above with diabetes
mellitus, where treatment with insulin is required.
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4.2 Posology and method of administration
The potency of this preparation is stated in units. These units are exclusive to Lantus and
are not the same as IU or the units used to express the potency of other insulin analogues.
See section 5.1 (Pharmacodynamics).
Lantus contains insulin glargine an insulin analogue with a prolonged duration of action. It
should be administered once daily at any time but at the same time each day.
The dosage and timing of dose of Lantus should be individually adjusted. In patients with
type 2 diabetes mellitus, Lantus can also be given together with orally active antidiabetic
medicinal products.
Children
In children, efficacy and safety of Lantus have only been demonstrated when given in the
evening.
Due to limited experience, the efficacy and safety of Lantus have not been demonstrated in
children below the age of 6 years.
Transition from other insulins to Lantus
When changing from a treatment regimen with an intermediate or long-acting insulin to a
regimen with Lantus, a change of the dose of the basal insulin may be required and the
concomitant antidiabetic treatment may need to be adjusted (dose and timing of additional
regular insulins or fast-acting insulin analogues or the dose of oral antidiabetic agents).
To reduce the risk of nocturnal and early morning hypoglycaemia, patients who are
changing their basal insulin regimen from a twice daily NPH insulin to a once daily regimen
with Lantus should reduce their daily dose of basal insulin by 20-30% during the first weeks
of treatment
During the first weeks the reduction should, at least partially, be compensated by an
increase in mealtime insulin, after this period the regimen should be adjusted individually.
As with other insulin analogues, patients with high insulin doses because of antibodies to
human insulin may experience an improved insulin response with Lantus.
Close metabolic monitoring is recommended during the transition and in the initial weeks
thereafter.
With improved metabolic control and resulting increase in insulin sensitivity a further
adjustment in dosage regimen may become necessary. Dose adjustment may also be
required, for example, if the patient's weight or life-style changes, change of timing of
insulin dose or other circumstances arise that increase susceptibility to hypo-or
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hyperglycaemia (see section 4.4).
Administration
Lantus is administered subcutaneously.
Lantus should not be administered intravenously. The prolonged duration of action of
Lantus is dependent on its injection into subcutaneous tissue. Intravenous administration of
the usual subcutaneous dose could result in severe hypoglycaemia.
There are no clinically relevant differences in serum insulin or glucose levels after
abdominal, deltoid or thigh administration of Lantus. Injection sites must be rotated within a
given injection area from one injection to the next.
Lantus must not be mixed with any other insulin or diluted. Mixing or diluting can change its
time/action profile and mixing can cause precipitation.
Before using SoloStar, the Instructions for Use included in the Package Leaflet must be
read carefully (see section 6.6).
Due to limited experience the efficacy and safety of Lantus could not be assessed in the
following groups of patients: patients with impaired liver function or patients with
moderate/severe renal impairment (see section 4.4).
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4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
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4.4 Special warnings and precautions for use
Lantus is not the insulin of choice for the treatment of diabetic ketoacidosis. Instead, regular
insulin administered intravenously is recommended in such cases.
Safety and efficacy of Lantus have been established in adolescents and children of 6 years
and above.
Due to limited experience the efficacy and safety of Lantus could not be assessed in
children below 6 years of age, in patients with impaired liver function or in patients with
moderate/severe renal impairment (see section 4.2).
In patients with renal impairment, insulin requirements may be diminished due to reduced
insulin metabolism. In the elderly, progressive deterioration of renal function may lead to a
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steady decrease in insulin requirements.
In patients with severe hepatic impairment, insulin requirements may be diminished due to
reduced capacity for gluconeogenesis and reduced insulin metabolism.
In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes,
the patient's adherence to the prescribed treatment regimen, injection sites and proper
injection technique and all other relevant factors must be reviewed before dose adjustment
is considered.
Switching a patient to another type or brand of insulin should be done under strict medical
supervision and may require change in dose.
Insulin administration may cause insulin antibodies to form. In rare cases, the presence of
such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a
tendency to hyper- or hypoglycaemia. (See section 4.8)
Hypoglycaemia
The time of occurrence of hypoglycaemia depends on the action profile of the insulins used
and may, therefore, change when the treatment regimen is changed. Due to more
sustained basal insulin supply with Lantus, less nocturnal but more early morning
hypoglycaemia can be expected.
Particular caution should be exercised, and intensified blood glucose monitoring is
advisable in patients in whom hypoglycaemic episodes might be of particular clinical
relevance, such as in patients with significant stenoses of the coronary arteries or of the
blood vessels supplying the brain (risk of cardiac or cerebral complications of
hypoglycaemia) as well as in patients with proliferative retinopathy, particularly if not treated
with photocoagulation (risk of transient amaurosis following hypoglycaemia).
Patients should be aware of circumstances where warning symptoms of hypoglycaemia are
diminished. The warning symptoms of hypoglycaemia may be changed, be less
pronounced or be absent in certain risk groups. These include patients:
- in whom glycaemic control is markedly improved,
- in whom hypoglycaemia develops gradually,
- who are elderly,
- after transfer from animal insulin to human insulin,
- in whom an autonomic neuropathy is present,
- with a long history of diabetes,
- suffering from a psychiatric illness,
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- receiving concurrent treatment with certain other medicinal products (see section 4.5).
Such situations may result in severe hypoglycaemia (and possibly loss of consciousness)
prior to the patient's awareness of hypoglycaemia.
The prolonged effect of subcutaneous insulin glargine may delay recovery from
hypoglycaemia.
If normal or decreased values for glycated haemoglobin are noted, the possibility of
recurrent, unrecognised (especially nocturnal) episodes of hypoglycaemia must be
considered.
Adherence of the patient to the dosage and dietary regimen, correct insulin administration
and awareness of hypoglycaemia symptoms are essential to reduce the risk of
hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly
close monitoring and may necessitate dose adjustment. These include:
- change in the injection area,
- improved insulin sensitivity (by, e.g., removal of stress factors),
- unaccustomed, increased or prolonged physical activity,
- intercurrent illness (e.g. vomiting, diarrhoea),
- inadequate food intake,
- missed meals,
- alcohol consumption,
- certain uncompensated endocrine disorders, (e.g. in hypothyroidism and in anterior
pituitary or adrenocortical insufficiency),
- concomitant treatment with certain other medicinal products.
Intercurrent illness
Intercurrent illness requires intensified metabolic monitoring. In many cases urine tests for
ketones are indicated, and often it is necessary to adjust the insulin dose. The insulin
requirement is often increased. Patients with type 1 diabetes must continue to consume at
least a small amount of carbohydrates on a regular basis, even if they are able to eat only
little or no food, or are vomiting etc. and they must never omit insulin entirely.
Handling of the pen
Before using SoloStar, the Instructions for Use included in the Package Leaflet must be
read carefully. SoloStar has to be used as recommended in these Instructions for Use (see
section 6.6).
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4.5 Interaction with other medicinal products and other forms of interaction
A number of substances affect glucose metabolism and may require dose adjustment of
insulin glargine.
Substances that may enhance the blood-glucose-lowering effect and increase susceptibility
to hypoglycaemia include oral antidiabetic agents, angiotensin converting enzyme (ACE)
inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors,
pentoxifylline, propoxyphene, salicylates and sulfonamide antibiotics.
Substances that may reduce the blood-glucose-lowering effect include corticosteroids,
danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens,
phenothiazine derivatives, somatropin, sympathomimetic agents (e.g. epinephrine
[adrenaline], salbutamol, terbutaline), thyroid hormones, atypical antipsychotic medicinal
products (e.g. clozapine and olanzapine) and protease inhibitors.
Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the bloodglucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia, which may
sometimes be followed by hyperglycaemia.
In addition, under the influence of sympatholytic medicinal products such as beta-blockers,
clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation may be
reduced or absent.
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4.6 Pregnancy and lactation
Pregnancy
For insulin glargin no clinical data on exposed pregnancies from controlled clinical trials are
available. A limited number of exposed pregnancies from Post Marketing Surveillance
indicate no adverse effects of insulin glargine on pregnancy or on the health of the foetus
and newborn child. To date, no other relevant epidemiological data are available.
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal
/foetal development, parturition or postnatal development (see section 5.3).
The available clinical data is insufficient to exclude a risk. The use of Lantus may be
considered in pregnancy, if necessary.
It is essential for patients with pre-existing or gestational diabetes to maintain good
metabolic control throughout pregnancy. Insulin requirements may decrease during the first
trimester and generally increase during the second and third trimesters. Immediately after
delivery, insulin requirements decline rapidly (increased risk of hypoglycaemia). Careful
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monitoring of glucose control is essential.
Lactation
Lactating women may require adjustments in insulin dose and diet.
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4.7 Effects on ability to drive and use machines
The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia
or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a
risk in situations where these abilities are of special importance (e.g. driving a car or
operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This
is particularly important in those who have reduced or absent awareness of the warning
symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be
considered whether it is advisable to drive or operate machinery in these circumstances.
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4.8 Undesirable effects
Hypoglycaemia, in general the most frequent undesirable effect of insulin therapy, may
occur if the insulin dose is too high in relation to the insulin requirement.
The following related adverse reactions from clinical investigations were listed below by
system organ class and in order of decreasing incidence (very common: 1/10; common:
1/100 to <1/10; uncommon: 1/1,000 to < 1/100; rare: 1/10,000 to <1/1,000; very rare: <
1/10,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Metabolism and nutrition disorders
Very common: Hypoglycaemia
Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage.
Prolonged or severe hypoglycaemic episodes may be life-threatening.
In many patients, the signs and symptoms of neuroglycopenia are preceded by signs of
adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood
glucose, the more marked is the phenomenon of counter-regulation and its symptoms.
Immune system disorders
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Rare: Allergic reaction
Immediate-type allergic reactions to insulin are rare. Such reactions to insulin (including
insulin glargine) or the excipients may, for example, be associated with generalised skin
reactions, angio-oedema, bronchospasm, hypotension and shock, and may be lifethreatening.
Insulin administration may cause insulin antibodies to form. In clinical studies, antibodies
that cross-react with human insulin and insulin glargine were observed with the same
frequency in both NPH-insulin and insulin glargine treatment groups. In rare cases, the
presence of such insulin antibodies may necessitate adjustment of the insulin dose in order
to correct a tendency to hyper- or hypoglycaemia.
Nervous system disorders:
Very rare: Dysgeusia
Eyes disorders
Rare: Visual impairment
A marked change in glycaemic control may cause temporary visual impairment, due to
temporary alteration in the turgidity and refractive index of the lens.
Rare: Retinopathy
Long-term improved glycaemic control decreases the risk of progression of diabetic
retinopathy. However, intensification of insulin therapy with abrupt improvement in
glycaemic control may be associated with temporary worsening of diabetic retinopathy. In
patients with proliferative retinopathy, particularly if not treated with photocoagulation,
severe hypoglycaemic episodes may result in transient amaurosis.
Skin and subcutaneous tissue disorders
As with any insulin therapy, lipodystrophy may occur at the injection site and delay local
insulin absorption. Continuous rotation of the injection site within the given injection area
may help to reduce or prevent these reactions.
Common: Lipohypertrophy
Uncommon: Lipoatrophy
Musculoskeletal and connective tissue disorders
Very rare: Myalgia
General disorders and administration site conditions
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Common: Injection site reactions
Such reactions include redness, pain, itching, hives, swelling, or inflammation. Most minor
reactions to insulins at the injection site usually resolve in a few days to a few weeks.
Rare: Oedema
Rarely, insulin may cause sodium retention and oedema particularly if previously poor
metabolic control is improved by intensified insulin therapy.
Paediatric population
In general, the safety profile for patients
patients > 18 years.
18 years of age is similar to the safety profile for
The adverse event reports received from Post Marketing Surveillance included relatively
more frequent injection site reactions (injection site pain, injection site reaction) and skin
reactions (rash, urticaria) in patients 18 years of age than in patients > 18 years.
No clinical study safety data are available in patients below 6 years of age.
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4.9 Overdose
Symptoms
Insulin overdose may lead to severe and sometimes long-term and life-threatening
hypoglycaemia.
Management
Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates.
Adjustments in dosage of the medicinal product, meal patterns, or physical activity may be
needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycaemia may recur
after apparent clinical recovery.
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5. PHARMACOLOGICAL PROPERTIES
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5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antidiabetic agent. Insulins and analogues for injection, longacting. ATC Code: A10A E04.
Insulin glargine is a human insulin analogue designed to have a low solubility at neutral pH.
It is completely soluble at the acidic pH of the Lantus injection solution (pH 4). After
injection into the subcutaneous tissue, the acidic solution is neutralised leading to formation
of micro-precipitates from which small amounts of insulin glargine are continuously
released, providing a smooth, peakless, predictable concentration/time profile with a
prolonged duration of action.
Insulin receptor binding: Insulin glargine is very similar to human insulin with respect to
insulin receptor binding kinetics. It can, therefore, be considered to mediate the same type
of effect via the insulin receptor as insulin.
The primary activity of insulin, including insulin glargine, is regulation of glucose
metabolism. Insulin and its analogues lower blood glucose levels by stimulating peripheral
glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose
production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances
protein synthesis.
In clinical pharmacology studies, intravenous insulin glargine and human insulin have been
shown to be equipotent when given at the same doses. As with all insulins, the time course
of action of insulin glargine may be affected by physical activity and other variables.
In euglycaemic clamp studies in healthy subjects or in patients with type 1 diabetes, the
onset of action of subcutaneous insulin glargine was slower than with human NPH insulin,
its effect profile was smooth and peakless, and the duration of its effect was prolonged.
The following graph shows the results from a study in patients:
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*determined as amount of glucose infused to maintain constant plasma glucose levels
(hourly mean values)
The longer duration of action of insulin glargine is directly related to its slower rate of
absorption and supports once daily administration. The time course of action of insulin and
insulin analogues such as insulin glargine may vary considerably in different individuals or
within the same individual.
In a clinical study, symptoms of hypoglycaemia or counter-regulatory hormone responses
were similar after intravenous insulin glargine and human insulin both in healthy volunteers
and patients with type 1 diabetes.
Effects of Lantus (once daily) on diabetic retinopathy were evaluated in an open-label 5year NPH-controlled study (NPH given bid) in 1024 type 2 diabetic patients in which
progression of retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy
Study (ETDRS) scale was investigated by fundus photography. No significant difference
was seen in the progression of diabetic retinopathy when Lantus was compared to NPH
insulin.
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5.2 Pharmacokinetic properties
In healthy subjects and diabetic patients, insulin serum concentrations indicated a slower
and much more prolonged absorption and showed a lack of a peak after subcutaneous
injection of insulin glargine in comparison to human NPH insulin. Concentrations were thus
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consistent with the time profile of the pharmacodynamic activity of insulin glargine. The
graph above shows the activity profiles over time of insulin glargine and NPH insulin.
Insulin glargine injected once daily will reach steady state levels in 2-4 days after the first
dose.
When given intravenously the elimination half-life of insulin glargine and human insulin
were comparable.
In man, insulin glargine is partly degraded in the subcutaneous tissue at the carboxyl
terminus of the Beta chain with formation of the active metabolites 21A Gly-insulin and
21A Gly-des-30B Thr-insulin. Unchanged insulin glargine and degradation products are
also present in the plasma.
In clinical studies, subgroup analyses based on age and gender did not indicate any
difference in safety and efficacy in insulin glargine-treated patients compared to the entire
study population.
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5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.
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6. PHARMACEUTICAL PARTICULARS
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6.1 List of excipients
Zinc chloride
m cresol
glycerol
hydrochloric acid
sodium hydroxide
water for injections.
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6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products.
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6.3 Shelf life
3 years.
Shelf life after first use of the pen
The product may be stored for a maximum of 4 weeks not above 25°C away from direct
heat or direct light. Pens in use must not be stored in the refrigerator. The pen cap must be
put back on the pen after each injection in order to protect from light.
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6.4 Special precautions for storage
Not in-use pens
Store in a refrigerator (2°C-8°C).
Do not freeze. Do not put Lantus next to the freezer compartment or a freezer pack.
Keep the pre-filled pen in the outer carton in order to protect from light.
In use pens
For storage precautions, see section 6.3.
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6.5 Nature and contents of container
3 ml solution in a cartridge (type 1 colourless glass) with a black plunger (bromobutyl
rubber) and a flanged cap (aluminium) with a stopper (bromobutyl or laminate of
polyisoprene and bromobutyl rubber).The cartridge is sealed in a disposable pen injector.
Needles are not included in the pack.
Packs of 5 pens are available.
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6.6 Special precautions for disposal and other handling
Before first use, the pen must be stored at room temperature for 1 to 2 hours.
Inspect the cartridge before use. It must only be used if the solution is clear, colourless,
with no solid particles visible, and if it is of water-like consistency. Since Lantus is a
solution, it does not require resuspension before use.
Empty pens must never be reused and must be properly discarded.
To prevent the possible transmission of disease, each pen must be used by one patient
only.
Handling of the pen
The Instructions for Use included in the Package Leaflet must be read carefully
before using SoloStar.
Schematic diagram of the pen
Important information for use of SoloStar:
• Before each use, a new needle must always be carefully attached and a safety test must
be performed. Only use needles that are compatible for use with SoloStar.
• Special caution must be taken to avoid accidental needle injury and transmission of
infection.
• Never use SoloStar if it is damaged or if you are not sure that it is working properly.
• Always have a spare SoloStar in case your SoloStar is lost or damaged.
Storage Instructions
Please check section 6.4 of this leaflet for instructions on how to store SoloStar.
If SoloStar is in cool storage, it should be taken out 1 to 2 hours before injection to allow it
to warm up. Cold insulin is more painful to inject.
The used SoloStar must be discarded as required by your local authorities.
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Maintenance
SoloStar has to be protected from dust and dirt.
You can clean the outside of your SoloStar by wiping it with a damp cloth.
Do not soak, wash or lubricate the pen as this may damage it.
SoloStar is designed to work accurately and safely. It should be handled with care. Avoid
situations where SoloStar might be damaged. If you are concerned that your SoloStar may
be damaged, use a new one.
Step 1. Check the Insulin
The label on the pen should be checked to make sure it contains the correct insulin. The
Lantus SoloStar is grey with a purple injection button. After removing the pen cap, the
appearance of insulin should also be checked: the insulin solution must be clear, colorless,
with no solid particles visible, and must have a water-like consistency.
Step 2. Attach the needle
Only needles that are compatible for use with SoloStar should be used.
A new sterile needle will be always used for each injection. After removing the cap, the
needle should be carefully attached straight onto the pen.
Step 3. Perform a safety test
Prior to each injection a safety test has to be performed to ensure that pen and needle work
properly and to remove air bubbles.
Select a dose of 2.
The outer and inner needle caps should be removed.
While holding the pen with the needle pointing upwards, the insulin reservoir should be
tapped gently with the finger so that any air bubbles rise up towards the needle
Then the injection button should be pressed in completely.
If insulin has been expelled through the needle tip, then the pen and the needle are working
properly.
If no insulin appears at the needle tip, step 3 should be repeated until insulin appears at the
needle tip.
Step 4. Select the dose
The dose can be set in steps of 1 unit, from a minimum of 1 unit to a maximum of 80 units.
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If a dose greater than 80 units is required, it should be given as two or more injections.
The dose window must show “0” following the safety test. The dose can then be selected.
Step 5. Inject the dose
The patient should be informed on the injection technique by his health care professional.
The needle should be inserted into the skin.
The injection button should be pressed in completely. Then the injection button should be
held down 10 seconds before withdrawing the needle. This ensures that the full dose of
insulin has been injected.
Step 6. Remove and discard the needle
The needle should always be removed after each injection and discarded. This helps
prevent contamination and/or infection, entry of air into the insulin reservoir and leakage of
insulin. Needles must not be reused.
Special caution must be taken when removing and disposing the needle. Follow
recommended safety measures for removal and disposal of needles (e.g. a one handed
capping technique) in order to reduce the risk of accidental needle injury and transmission
of infectious diseases.
The pen cap should be replaced on the pen.
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7. MARKETING AUTHORISATION HOLDER
Sanofi-Aventis Deutschland GmbH, D 65926 Frankfurt am Main, Germany
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8. MARKETING AUTHORISATION NUMBER(S)
EU/1/00/134/033
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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 9 June 2000
Date of latest renewal: 9 June 2005
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10. DATE OF REVISION OF THE TEXT
17th September 2008
Legal category: POM
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APPENDIX 8 SmPC For insulin Lispro
Eli Lilly and Company Limited
Lilly House, Priestley Road, Basingstoke,
Hampshire, RG24 9NL
Telephone: +44 (0)1256 315 000
Fax: +44 (0)1256 775 858
WWW: http://www.lilly.co.uk
Medical Information e-mail: ukmedinfo@lilly.com
Customer Care direct line: +44 (0)1256 315 999
Medical Information Fax: +44 (0)1256 775 569
Summary of Product Characteristics last updated on the eMC: 14/07/2009
Table of Contents
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1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
LEGAL CATEGORY
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1. NAME OF THE MEDICINAL PRODUCT
HUMALOG* 100U/ml, solution for injection in vial.
HUMALOG 100U/ml, solution for injection in cartridge.
HUMALOG Pen 100U/ml, solution for injection.
HUMALOG 100U/ml KwikPen, solution for injection.
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2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml contains 100U (equivalent to 3.5mg) insulin lispro (recombinant DNA origin
produced in E. coli).
Vial: Each container includes 10ml equivalent to 1000U insulin lispro.
3 ml cartridge: Each container includes 3ml equivalent to 300U insulin lispro.
HUMALOG Pen 3ml/KwikPen: Each container includes 3ml equivalent to 300U insulin
lispro.
For a full list of excipients, see section 6.1.
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3. PHARMACEUTICAL FORM
Solution for injection.
HUMALOG, HUMALOG Pen and HUMALOG KwikPen are sterile, clear, colourless,
aqueous solutions.
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4. CLINICAL PARTICULARS
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4.1 Therapeutic indications
For the treatment of adults and children with diabetes mellitus who require insulin for the
maintenance of normal glucose homeostasis. HUMALOG, HUMALOG Pen or HUMALOG
KwikPen is also indicated for the initial stabilisation of diabetes mellitus.
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4.2 Posology and method of administration
The dosage should be determined by the physician, according to the requirement of the
patient.
HUMALOG may be given shortly before meals. When necessary, HUMALOG can be given
soon after meals.
HUMALOG preparations should be given by subcutaneous injection or by continuous
subcutaneous infusion pump (see section 4.2) and may, although not recommended, also
be given by intramuscular injection. If necessary, HUMALOG may also be administered
intravenously, for example, for the control of blood glucose levels during ketoacidosis,
acute illnesses, or during intraoperative and postoperative periods.
Subcutaneous administration should be in the upper arms, thighs, buttocks, or abdomen.
Use of injection sites should be rotated so that the same site is not used more than
approximately once a month.
When administered subcutaneously, care should be taken when injecting HUMALOG,
HUMALOG Pen or HUMALOG KwikPen to ensure that a blood vessel has not been
entered. After injection, the site of injection should not be massaged. Patients must be
educated to use the proper injection techniques.
HUMALOG, HUMALOG Pen or HUMALOG KwikPen takes effect rapidly and has a shorter
duration of activity (2 to 5 hours) given subcutaneously as compared with soluble insulin.
This rapid onset of activity allows a HUMALOG injection (or, in the case of administration by
continuous subcutaneous infusion, a HUMALOG bolus) to be given very close to mealtime.
The time course of action of any insulin may vary considerably in different individuals or at
different times in the same individual. The faster onset of action compared to soluble
human insulin is maintained regardless of injection site. As with all insulin preparations, the
duration of action of HUMALOG, HUMALOG Pen or HUMALOG KwikPen is dependent on
dose, site of injection, blood supply, temperature, and physical activity.
HUMALOG can be used in conjunction with a longer-acting human insulin or oral
sulphonylurea agents, on the advice of a physician.
Use of HUMALOG in an insulin infusion pump:
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Only certain CE-marked insulin infusion pumps may be used to infuse insulin lispro. Before
infusing insulin lispro, the manufacturer's instructions should be studied to ascertain the
suitability or otherwise for the particular pump. Read and follow the instructions that
accompany the infusion pump. Use the correct reservoir and catheter for the pump.
Change the infusion set every 48 hours. Use aseptic technique when inserting the infusion
set. In the event of a hypoglycaemic episode, the infusion should be stopped until the
episode is resolved. If repeated or severe low blood glucose levels occur, notify your health
care professional and consider the need to reduce or stop your insulin infusion. A pump
malfunction or obstruction of the infusion set can result in a rapid rise in glucose levels. If
an interruption to insulin flow is suspected, follow the instructions in the product literature
and if appropriate, notify your health care professional. When used with an insulin infusion
pump, HUMALOG should not be mixed with any other insulin.
Intravenous administration of insulin:
Intravenous injection of insulin lispro should be carried out following normal clinical practise
for intravenous injections, for example by an intravenous bolus or by an infusion system.
Frequent monitoring of the blood glucose levels is required.
Infusion systems at concentrations from 0.1U/ml to 1.0U/ml insulin lispro in 0.9% sodium
chloride or 5% dextrose are stable at room temperature for 48 hours. It is recommended
that the system is primed before starting the infusion to the patient.
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4.3 Contraindications
Hypersensitivity to insulin lispro or to any of the excipients.
Hypoglycaemia.
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4.4 Special warnings and precautions for use
Transferring a patient to another type or brand of insulin should be done under strict
medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane,
lente, etc), species (animal, human, human insulin analogue), and/or method of
manufacture (recombinant DNA versus animal-source insulin) may result in the need for a
change in dosage. For fast-acting insulins, any patient also on basal insulin must optimise
dosage of both insulins to obtain glucose control across the whole day, particularly
nocturnal/fasting glucose control.
Vials: The shorter-acting HUMALOG should be drawn into the syringe first, to prevent
contamination of the vial by the longer-acting insulin. Mixing of the insulins ahead of time or
just before the injection should be on advice of the physician. However, a consistent routine
must be followed.
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Conditions which may make the early warning symptoms of hypoglycaemia different or less
pronounced include long duration of diabetes, intensified insulin therapy, diabetic nerve
disease, or medications such as beta-blockers.
A few patients who have experienced hypoglycaemic reactions after transfer from animalsource insulin to human insulin have reported that the early warning symptoms of
hypoglycaemia were less pronounced or different from those experienced with their
previous insulin. Uncorrected hypoglycaemic or hyperglycaemic reactions can cause loss of
consciousness, coma, or death.
The use of dosages which are inadequate or discontinuation of treatment, especially in
insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis;
conditions which are potentially lethal.
Insulin requirements may be reduced in the presence of renal impairment. Insulin
requirements may be reduced in patients with hepatic impairment due to reduced capacity
for gluconeogenesis and reduced insulin breakdown; however, in patients with chronic
hepatic impairment, an increase in insulin resistance may lead to increased insulin
requirements.
Insulin requirements may be increased during illness or emotional disturbances.
Adjustment of dosage may also be necessary if patients undertake increased physical
activity or change their usual diet. Exercise taken immediately after a meal may increase
the risk of hypoglycaemia. A consequence of the pharmacodynamics of rapid-acting insulin
analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when
compared with soluble human insulin.
If the 40U/ml vial is the product normally prescribed, do not take insulin from a 100U/ml
cartridge using a 40U/ml syringe.
HUMALOG should only be used in children in preference to soluble insulin when a fast
action of insulin might be beneficial. For example, in the timing of the injection in relation to
meals.
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4.5 Interaction with other medicinal products and other forms of interaction
Insulin requirements may be increased by medicinal products with hyperglycaemic activity,
such as oral contraceptives, corticosteroids, or thyroid replacement therapy, danazol, beta 2
stimulants (such as ritodrine, salbutamol, terbutaline).
Insulin requirements may be reduced in the presence of medicinal products with
hypoglycaemic activity, such as oral hypoglycaemics, salicylates (for example,
acetylsalicylic acid), sulpha antibiotics, certain antidepressants (monoamine oxidase
inhibitors, selective serotonin reuptake inhibitors), certain angiotensin converting enzyme
inhibitors (captopril, enalapril), angiotensin II receptor blockers, beta-blockers, octreotide, or
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alcohol.
The physician should be consulted when using other medications in addition to HUMALOG,
HUMALOG Pen or HUMALOG KwikPen.
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4.6 Pregnancy and lactation
Data on a large number of exposed pregnancies do not indicate any adverse effect of
insulin lispro on pregnancy or on the health of the foetus/newborn.
It is essential to maintain good control of the insulin-treated (insulin-dependent or
gestational diabetes) patient throughout pregnancy. Insulin requirements usually fall during
the first trimester and increase during the second and third trimesters. Patients with
diabetes should be advised to inform their doctor if they are pregnant or are contemplating
pregnancy. Careful monitoring of glucose control, as well as general health, is essential in
pregnant patients with diabetes.
Patients with diabetes who are breast-feeding may require adjustments in insulin dose, diet
or both.
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4.7 Effects on ability to drive and use machines
The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia.
This may constitute a risk in situations where these abilities are of special importance (e.g.,
driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is
particularly important in those who have reduced or absent awareness of the warning signs
of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving
should be considered in these circumstances.
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4.8 Undesirable effects
Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with
diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness and in
extreme cases, death. No specific frequency for hypoglycaemia is presented, since
hypoglycaemia is a result of both the insulin dose and other factors, e.g., a patient's level of
diet and exercise.
Local allergy in patients is common (1/100 to <1/10). Redness, swelling, and itching can
occur at the site of insulin injection. This condition usually resolves in a few days to a few
weeks. In some instances, this condition may be related to factors other than insulin, such
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as irritants in the skin cleansing agent or poor injection technique. Systemic allergy, which
is rare (1/10,000 to <1/1,000) but potentially more serious, is a generalised allergy to
insulin. It may cause a rash over the whole body, shortness of breath, wheezing, reduction
in blood pressure, fast pulse, or sweating. Severe cases of generalised allergy may be lifethreatening.
Lipodystrophy at the injection site is uncommon (1/1,000 to <1/100).
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4.9 Overdose
Insulins have no specific overdose definitions because serum glucose concentrations are a
result of complex interactions between insulin levels, glucose availability and other
metabolic processes. Hypoglycaemia may occur as a result of an excess of insulin activity
relative to food intake and energy expenditure.
Hypoglycaemia may be associated with listlessness, confusion, palpitations, headache,
sweating and vomiting.
Mild hypoglycaemic episodes will respond to oral administration of glucose or other sugar
or saccharated products.
Correction of moderately severe hypoglycaemia can be accomplished by intramuscular or
subcutaneous administration of glucagon, followed by oral carbohydrate when the patient
recovers sufficiently. Patients who fail to respond to glucagon must be given glucose
solution intravenously.
If the patient is comatose, glucagon should be administered intramuscularly or
subcutaneously. However, glucose solution must be given intravenously if glucagon is not
available or if the patient fails to respond to glucagon. The patient should be given a meal
as soon as consciousness is recovered.
Sustained carbohydrate intake and observation may be necessary because hypoglycaemia
may recur after apparent clinical recovery.
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5. PHARMACOLOGICAL PROPERTIES
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5.1 Pharmacodynamic properties
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Pharmacotherapeutic group: Fast-acting human insulin analogue. ATC code: A10A B04.
The primary activity of insulin lispro is the regulation of glucose metabolism.
In addition, insulins have several anabolic and anti-catabolic actions on a variety of different
tissues. Within muscle tissue this includes increasing glycogen, fatty acid, glycerol and
protein synthesis and amino acid uptake, while decreasing glycogenolysis,
gluconeogenesis, ketogenesis, lipolysis, protein catabolism and amino acid output.
Insulin lispro has a rapid onset of action (approximately 15 minutes), thus allowing it to be
given closer to a meal (within zero to 15 minutes of the meal) when compared to soluble
insulin (30 to 45 minutes before). Insulin lispro takes effect rapidly and has a shorter
duration of activity (2 to 5 hours) when compared to soluble insulin.
Clinical trials in patients with Type 1 and Type 2 diabetes have demonstrated reduced
postprandial hyperglycaemia with insulin lispro compared to soluble human insulin.
As with all insulin preparations, the time course of insulin lispro action may vary in different
individuals or at different times in the same individual and is dependent on dose, site of
injection, blood supply, temperature, and physical activity. The typical activity profile
following subcutaneous injection is illustrated below.
The above representation reflects the relative amount of glucose over time required to
maintain the subject's whole blood glucose concentrations near fasting levels and is an
indicator of the effect of these insulins on glucose metabolism over time.
Clinical trials have been performed in children (61 patients aged 2 to 11) and children and
adolescents (481 patients aged 9 to 19 years), comparing insulin lispro to human soluble
insulin. The pharmacodynamic profile of insulin lispro in children is similar to that seen in
adults.
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When used in subcutaneous infusion pumps, treatment with insulin lispro has been shown
to result in lower glycosylated haemoglobin levels compared to soluble insulin. In a doubleblind, crossover study, the reduction in glycosylated haemoglobin levels after 12 weeks
dosing was 0.37 percentage points with insulin lispro compared to 0.03 percentage points
for soluble insulin (P = 0.004).
In patients with Type 2 diabetes on maximum doses of sulphonylurea agents, studies have
shown that the addition of insulin lispro significantly reduces HbA 1c compared to
sulphonylurea alone. The reduction of HbA 1c would also be expected with other insulin
products, e.g., soluble or isophane insulins.
Clinical trials in patients with Type 1 and Type 2 diabetes have demonstrated a reduced
number of episodes of nocturnal hypoglycaemia with insulin lispro compared to soluble
human insulin. In some studies, reduction of nocturnal hypoglycaemia was associated with
increased episodes of daytime hypoglycaemia.
The glucodynamic response to insulin lispro is not affected by renal or hepatic function
impairment. Glucodynamic differences between insulin lispro and soluble human insulin, as
measured during a glucose clamp procedure, were maintained over a wide range of renal
function.
Insulin lispro has been shown to be equipotent to human insulin on a molar basis but its
effect is more rapid and of a shorter duration.
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5.2 Pharmacokinetic properties
The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed and
achieves peak blood levels 30 to 70 minutes following subcutaneous injection. When
considering the clinical relevance of these kinetics, it is more appropriate to examine the
glucose utilisation curves (as discussed in section 5.1).
Insulin lispro maintains more rapid absorption when compared to soluble human insulin in
patients with renal impairment. In patients with Type 2 diabetes, over a wide range of renal
function, the pharmacokinetic differences between insulin lispro and soluble human insulin
were generally maintained and shown to be independent of renal function. Insulin lispro
maintains more rapid absorption and elimination when compared to soluble human insulin
in patients with hepatic impairment.
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5.3 Preclinical safety data
In in vitro tests, including binding to insulin receptor sites and effects on growing cells,
insulin lispro behaved in a manner that closely resembled human insulin. Studies also
demonstrate that the dissociation of binding to the insulin receptor of insulin lispro is
equivalent to human insulin. Acute, one-month and twelve-month toxicology studies
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produced no significant toxicity findings.
Insulin lispro did not induce fertility impairment, embryotoxicity, or teratogenicity in animal
studies.
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6. PHARMACEUTICAL PARTICULARS
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6.1 List of excipients
m-cresol (3.15mg/ml), glycerol, dibasic sodium phosphate.7H 2 O, zinc oxide, water for
injections. Hydrochloric acid and sodium hydroxide may be used to adjust pH to 7.0-7.8.
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6.2 Incompatibilities
HUMALOG, HUMALOG Pen or HUMALOG KwikPen preparations should not be mixed with
insulin produced by other manufacturers or with animal insulin preparations. This medicinal
product must not be mixed with other medicinal products except those mentioned in section
6.6.
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6.3 Shelf life
Unopened vials,
2 years
Unused cartridges and unused pre-filled pens
3 years
After cartridge insertion, or after first use (vial and prefilled pen)
28 days
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6.4 Special precautions for storage
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Unused cartridge and unused pre-filled pens
Store in a refrigerator (2°C-8°C). Do not freeze. Do not expose to excessive heat or direct
sunlight.
After cartridge insertion or first use (pre-filled pen)
Store below 30°C. Do not refrigerate. The pen with the inserted cartridge and the pre-filled
pen should not be stored with the needle attached.
Vials
Do not freeze. Do not expose to excessive heat or direct sunlight.
Unopened vials
Store in a refrigerator (2°C - 8°C).
After first use (vials only)
Store in a refrigerator (2°C - 8°C) or below 30°C.
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6.5 Nature and contents of container
Vials: The solution is contained in Type I flint glass vials, sealed with butyl or halobutyl
stoppers, and secured with aluminium seals. Dimeticone or silicone emulsion may be used
to treat the vial stoppers.
Cartridges/HUMALOG Pens: The solution is contained in Type I flint glass cartridges,
sealed with butyl or halobutyl disc seals and plunger heads, and are secured with
aluminium seals. Dimeticone or silicone emulsion may be used to treat the cartridge
plunger and/or the glass cartridge.
HUMALOG Pens: The 3ml cartridges are sealed in a disposable pen injector. Needles are
not included.
HUMALOG KwikPen: The 3ml cartridges are sealed in a disposable pen injector, called the
'KwikPen'. Needles are not included.
Not all packs may be marketed.
1 x 10ml HUMALOG vial.
2 x 10ml HUMALOG vials.
5 x (1 x 10ml) HUMALOG vials.
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5 x 3ml HUMALOG cartridges for a 3ml pen.
2 x (5 x 3ml) HUMALOG cartridges for a 3ml pen.
5 x 3ml HUMALOG Pens.
2 x (5 x 3ml) HUMALOG Pens.
5 x 3ml HUMALOG 100 U/ml KwikPens.
2 x (5 x 3ml) HUMALOG 100 U/ml KwikPens.
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6.6 Special precautions for disposal and other handling
Instructions for use and handling
Any unused product or waste material should be disposed of in accordance with local
requirements.
HUMALOG Vials
The vial is to be used in conjunction with an appropriate syringe (100 U markings).
a) Preparing a dose
Inspect the HUMALOG solution. It should be clear and colourless. Do not use HUMALOG if
it appears cloudy, thickened, or slightly coloured or if solid particles are visible.
i) HUMALOG
1. Wash your hands.
2. If using a new vial, flip off the plastic protective cap, but do not remove the stopper.
3. If the therapeutic regimen requires the injection of basal insulin and HUMALOG at the
same time, the two can be mixed in the syringe. If mixing insulins, refer to the instructions
for mixing that follow in section (ii) and section 6.2.
4. Draw air into the syringe equal to the prescribed HUMALOG dose. Wipe the top of the
vial with an alcohol swab. Put the needle through the rubber top of the HUMALOG vial and
inject the air into the vial.
5. Turn the vial and syringe upside down. Hold the vial and syringe firmly in one hand.
6. Making sure the tip of the needle is in the HUMALOG, withdraw the correct dose into the
syringe.
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7. Before removing the needle from the vial, check the syringe for air bubbles that reduce
the amount of HUMALOG in it. If bubbles are present, hold the syringe straight up and tap
its side until the bubbles float to the top. Push them out with the plunger and withdraw the
correct dose.
8. Remove the needle from the vial and lay the syringe down so that the needle does not
touch anything.
ii) Mixing HUMALOG with longer-acting Human Insulins (see section 6.2)
1. HUMALOG should be mixed with longer-acting human insulins only on the advice of a
doctor.
2. Draw air into the syringe equal to the amount of longer-acting insulin being taken. Insert
the needle into the longer-acting insulin vial and inject the air. Withdraw the needle.
3. Now inject air into the HUMALOG vial in the same manner, but do not withdraw the
needle.
4. Turn the vial and syringe upside down.
5. Making sure the tip of the needle is in the HUMALOG, withdraw the correct dose of
HUMALOG into the syringe.
6. Before removing the needle from the vial, check the syringe for air bubbles that reduce
the amount of HUMALOG in it. If bubbles are present, hold the syringe straight up and tap
its side until the bubbles float to the top. Push them out with the plunger and withdraw the
correct dose.
7. Remove the needle from the vial of HUMALOG and insert it into the vial of the longeracting insulin. Turn the vial and syringe upside down. Hold the vial and syringe firmly in one
hand and shake gently. Making sure the tip of the needle is in the insulin, withdraw the
dose of longer-acting insulin.
8. Withdraw the needle and lay the syringe down so that the needle does not touch
anything.
b) Injecting a dose
1. Choose a site for injection.
2. Clean the skin as instructed.
3. Stabilise the skin by spreading it or pinching up a large area. Insert the needle and inject
as instructed.
4. Pull the needle out and apply gentle pressure over the injection site for several seconds.
Do not rub the area.
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5. Dispose of the syringe and needle safely.
6. Use of the injection sites should be rotated so that the same is not used more than
approximately once a month.
c) Mixing insulins
Do not mix insulin in vials with insulin in cartridges. See section 6.2.
HUMALOG cartridges
HUMALOG cartridges are to be used with a CE marked pen as recommended in the
information provided by the device manufacturer.
a) Preparing a dose
Inspect the HUMALOG solution. It should be clear and colourless. Do not use HUMALOG if
it appears cloudy, thickened, or slightly coloured, or if solid particles are visible.
The following is a general description. The manufacturer's instructions with each individual
pen must be followed for loading the cartridge, attaching the needle, and administering the
insulin injection.
b) Injecting a dose
1. Wash your hands.
2. Choose a site for injection.
3. Clean the skin as instructed.
4. Remove outer needle cap.
5. Stabilise the skin by spreading it or pinching up a large area. Insert the needle as
instructed.
6. Press the knob.
7. Pull the needle out and apply gentle pressure over the injection site for several seconds.
Do not rub the area.
8. Using the outer needle cap, unscrew the needle and dispose of it safely.
9. Use of injection sites should be rotated so that the same site is not used more than
approximately once a month.
c) Mixing insulins
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Do not mix insulin in vials with insulin in cartridges. See section 6.2.
HUMALOG Pens (excluding Kwikpen)
a) Preparing a dose
1. Inspect the HUMALOG Pen solution.
It should be clear and colourless. Do not use HUMALOG Pen if it appears cloudy,
thickened, or slightly coloured, or if solid particles are visible.
2. Put on the needle.
Wipe the rubber seal with alcohol. Remove the paper tab from the capped needle. Screw
the capped needle clockwise onto the pen until it is tight. Hold the pen with needle pointing
up and remove the outer needle cap and inner needle cover.
3. Priming the pen (check insulin flow).
(a) The arrow should be visible in the dose window. If the arrow is not present, turn the
dose knob clockwise until the arrow appears and notch is felt or visually aligned.
(b) Pull dose knob out (in direction of the arrow) until a '0' appears in the dose window. A
dose cannot be dialled until the dose knob is pulled out.
(c) Turn dose knob clockwise until a '2' appears in the dose window.
(d) Hold the pen with needle pointing up and tap the clear cartridge holder gently with your
finger so any air bubbles collect near the top. Depress the injection button fully until you feel
or hear a click. You should see a drop of insulin at the tip of the needle. If insulin does not
appear, repeat the procedure until insulin appears.
(e) Always prime the pen (check the insulin flow) before each injection. Failure to prime the
pen may result in an inaccurate dose.
4. Setting the dose.
(a) Turn the dose knob clockwise until the arrow appears in the dose window and a notch is
felt or visually aligned.
(b) Pull the dose knob out (in the direction of the arrow) until a '0' appears in the dose
window. A dose cannot be dialled until the dose knob is pulled out.
(c) Turn the dose knob clockwise until the dose appears in the dose window. If too high a
dose is dialled, turn the dose knob backward (anti-clockwise) until the correct dose appears
in the window. A dose greater than the number of units remaining in the cartridge cannot be
dialled.
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b) Injecting a dose
1. Wash your hands.
2. Choose a site for injection.
3. Clean the skin as instructed.
4. Remove outer needle cap.
5. Stabilise the skin by spreading it or pinching up a large area. Insert the needle as
instructed.
6. Press the injection button down with the thumb (until you hear or feel a click); wait 5
seconds.
7. Pull the needle out and apply gentle pressure over the injection site for several seconds.
Do not rub the area.
8. Immediately after an injection, use the outer needle cap to unscrew the needle. Remove
the needle from the pen. This will ensure sterility, and prevent leakage, re-entry of air, and
potential needle clogs. Do not reuse the needle. Dispose of the needle in a responsible
manner. Needles and pens must not be shared.
The prefilled pen can be used until it is empty. Please properly discard or recycle.
9. Replace the cap on the pen.
10. Use of injection sites should be rotated so that the same site is not used more than
approximately once a month.
11. The injection button should be fully depressed before using the pen again.
c) Mixing insulins
Do not mix insulin in vials with insulin in cartridges. See section 6.2.
HUMALOG KwikPen
Inspect the HUMALOG solution. It should be clear and colourless. Do not use HUMALOG if
it appears cloudy, thickened, or slightly coloured or if solid particles are visible.
a) Handling of the pre-filled pen
Before using the KwikPen the user manual included in the package leaflet must be read
carefully. The KwikPen has to be used as recommended in the user manual.
b) Mixing insulins
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Do not mix insulin in vials with insulin in cartridges. See section 6.2.
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7. MARKETING AUTHORISATION HOLDER
Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA Houten, The Netherlands.
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8. MARKETING AUTHORISATION NUMBER(S)
HUMALOG vials
1 x 10ml HUMALOG vial: EU/1/96/007/002
2 x 10ml HUMALOG vials: EU/1/96/007/020
5 x (1 x 10ml) HUMALOG vials: EU/1/96/007/021
HUMALOG cartridges
5 x 3ml HUMALOG cartridges for a 3ml pen: EU/1/96/007/004
2 x (5 x 3ml) HUMALOG cartridges for a 3ml pen: EU/1/96/007/023
HUMALOG Pens
5 x 3ml HUMALOG Pens: EU/1/96/007/015
2 x (5 x 3ml) HUMALOG Pens: EU/1/96/007/026
HUMALOG KwikPen
5 x 3ml HUMALOG 100 U/ml KwikPen: EU/1/96/007/031
2 x (5 x 3ml) HUMALOG 100 U/ml KwikPen: EU/1/96/007/032
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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 30 April 1996
Date of last renewal: 30 April 2006
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10. DATE OF REVISION OF THE TEXT
01 July 2009
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LEGAL CATEGORY
POM (United Kingdom)
For further information in the United Kingdom contact:
Eli Lilly and Company Limited
Lilly House, Priestley Road
Basingstoke, Hampshire, RG24 9NL
Telephone: Basingstoke (01256) 315 999
For further information in the Republic of Ireland contact:
Eli Lilly and Company (Ireland) Limited
Hyde House, 65 Adelaide Road
Dublin 2, Republic of Ireland
Telephone: Dublin (01) 661 4377
*HUMALOG (insulin lispro) and KWIKPEN are trademarks of Eli Lilly and Company.
HLG33M
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APPENDIX 9 Schedule of Events
(On next page)
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study period
4 week wash in period
visit number
informed consent
eligibility criteria
given information sheet on clamp study
hypoglycaemia screening questionnaire
HbA1c
C-peptide and plasma glucose
retinal photographs
urine albumin:creatinine ratio
demographic info
concomitant medication
full physical examination
history of glycaemic control
LFTs, U&Es, lipids
full medical history including glycaemic control
vital signs
height
weight
TFTs
Coeliac antibody
short synacthen test
detailed SH history
Modified Clarke/Edinburgh
QoL questionnaires
week 4 short questionnaire pack
4 week Blood Glucose / hypo diary
7 day CGMS placement
Autonomic function tests
clamp study
education programme
Insulin administration education session
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