<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
<<Notes on using this template:






It is recommended that as far as possible you should create all of the headings
first, before entering the relevant text, to avoid problems with numbering
Headings in blue indicate sections which may be omitted if they are not applicable;
please delete as appropriate. If you retain the heading please delete ‘<<’ and ‘>>’
symbols and change to black text.
Blue text must either be replaced with black text specific to your trial or provides
guidance notes regarding what should be written and must therefore be deleted
from the final draft. Please use the ‘Find’ function in Word to search for a double
less-than symbol (<<) which should identify any blue text you may have missed
Under headings in black which are not applicable should you should state “Not
applicable” or “document will not be used”, as appropriate; please do not delete
the heading
Text in black must in general be retained as this is expected standard text; any
deletions of or amendments to the standard text must be discussed with the trial
management team
Once you are happy that the draft is complete, please click at the top of the
contents page to update it automatically (choose the ‘update entire table’ option)
Notes on formatting:

This document has been formatted so that text is
o Calibri font; main text is 12pt
o Justified
o Placed with 0pt spacing before a paragraph and 6pt spacing after
o Spaced at 1.15 lines
If you wish to change any of these properties please ensure consistent formatting
is applied throughout the document.
Please ensure headings are formatted as headings rather than normal text under
‘Styles’ on the Home tab in Word. This will ensure they are added automatically to
the contents page.
PLEASE DELETE THIS ENTIRE PAGE FROM THE FINALISED PROTOCOL>>
Page 1 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
<<Main Research Unit Name>>
Research Protocol
<<Version Number and Date>>
Study Short Title: <<summary of full title>>
Study Full Title: <<including summary study design, product/treatment(s), nature of the
treatment, comparators (and/or any placebo), indication, patient population and
setting>>
Sponsor Name:
Sponsor Number:
Protocol status:
Details of previous amendments
1. <<Version number and date, date of amendment>>
2. <<Version number and date, date of amendment>>
Page 2 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
Key contacts
Chief Investigator
<<Name>>
<<Title>>
<<Clinical Address>>
<<Contact telephone number>>
<<Contact email address>>
Principal Investigator
<<Name>>
<<Title>>
<<Address>>
<<Contact telephone number>>
<<Fax number>>
<<Contact email address>>
Trial Co-ordinator
<<Name>>
<<Title>>
<<Clinical Address>>
<<Contact telephone number>>
<<Contact email address>>
Page 3 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
INVESTIGATOR DECLARATION AND SIGNATURE(S)
<<Trial Acronym>> <<Protocol Version number and date>>
DECLARATION OF PROTOCOL ACCEPTANCE
I confirm that I am fully informed and aware of the requirements of the protocol and agree
to conduct the study as set out in this protocol.
Chief Investigator
Date
<<title of other relevant individual>>
Date
<<Insert additional signature tables as appropriate>>
Page 4 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
<<This Table of Contents will update automatically to accommodate changes made to the
body of the document. When you have finished making changes to the text, click within
the Table of Contents to bring up the ‘Update table’ tab and select ‘Update entire table’
then click OK.>>
Table of Contents
INVESTIGATOR DECLARATION AND SIGNATURE(S) ............................................................. 4
ABBREVIATIONS ................................................................................................................. 10
PROTOCOL SYNOPSIS ......................................................................................................... 11
SCHEMATIC DIAGRAM ....................................................................................................... 13
1. INTRODUCTION .............................................................................................................. 14
1.1. Background.............................................................................................................. 14
1.2. Rationale for the proposed study ........................................................................... 14
2. STUDY AIM AND OBJECTIVES ......................................................................................... 14
2.1. Study aim ................................................................................................................. 14
2.2. Primary objective .................................................................................................... 14
2.3. Secondary objective(s) ............................................................................................ 15
3. STUDY ENDPOINTS ......................................................................................................... 15
3.1. Primary endpoint..................................................................................................... 15
3.2. Secondary endpoint(s) ............................................................................................ 15
3.3. <<Other endpoint(s)>> ............................................................................................ 15
4. STUDY VARIABLES .......................................................................................................... 15
4.1. Standard variables ................................................................................................... 15
4.2. Efficacy variables (if appropriate) ........................................................................... 15
4.3. Safety variables ....................................................................................................... 15
4.4. Routine laboratory assessments ............................................................................. 15
5. STUDY DESIGN................................................................................................................ 15
5.1. Study description..................................................................................................... 15
5.2. Study duration ......................................................................................................... 15
5.3. Rationale for study design ....................................................................................... 15
6. SELECTION AND WITHDRAWAL OF SUBJECTS ............................................................... 15
6.1. Target population .................................................................................................... 15
6.2. Estimated number of eligible participants .............................................................. 15
6.3. Eligibility criteria ...................................................................................................... 16
6.3.1. Inclusion criteria ..................................................................................................... 16
Page 5 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
6.3.2. Exclusion criteria..................................................................................................... 16
6.3.3. Exclusions for general safety .................................................................................. 16
6.3.4. <<Laboratory exclusion (including imaging) at screening>> .................................. 16
6.4. Withdrawal criteria ................................................................................................. 16
6.5. Recruitment, consent and randomisation processes ............................................. 16
6.5.1. Recruitment ............................................................................................................ 16
6.5.2. Consent ................................................................................................................... 16
6.5.3. <<Randomisation process>> .................................................................................. 17
6.5.4. STUDY BLINDING .................................................................................................... 17
6.5.5. Patients who withdraw consent ............................................................................. 17
6.5.6. Managing/replacing patients who withdraw early ................................................ 18
6.5.7. Definition for the end of the trial ........................................................................... 18
7. STUDY TREATMENTS ...................................................................................................... 18
7.1. General information on the products or interventions to be used ........................ 18
7.2. Use within the trial .................................................................................................. 18
7.3. Prior and concomitant illnesses .............................................................................. 18
7.4. Prior and concomitant medications and procedures ............................................. 19
7.4.1. Permitted prior medications and procedures ........................................................ 19
7.4.2. Prohibited prior medications and procedures ....................................................... 19
7.4.3. Permitted concomitant medications and procedures ........................................... 19
7.4.4. Prohibited concomitant medications and procedures ........................................... 19
7.4.5. Surgical procedures ................................................................................................ 19
7.5. Special warnings and precautions for use............................................................... 19
7.6. Treatment modifications ......................................................................................... 19
7.7. Assessing subject compliance with study treatment(s) .......................................... 19
7.8. Withdrawal of treatment ........................................................................................ 19
7.8.1. Subject compliance ................................................................................................. 19
7.8.2. <<Lack of efficacy>> ............................................................................................... 19
8. METHODS OF ASSESSMENT ........................................................................................... 19
8.1. Standard assessment variables ............................................................................... 20
8.1.1. <<Please use subheadings for each variable>> ...................................................... 20
8.2. <<Efficacy assessment variable(s)>> ....................................................................... 20
Page 6 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
8.2.1. <<Primary efficacy assessment variable(s)>>......................................................... 20
8.2.2. <<Secondary efficacy assessment variables>> ....................................................... 20
8.2.3. <<Please use subheadings for each variable>> ...................................................... 20
8.3. Safety assessment variables .................................................................................... 20
8.3.1. <<Please use subheadings for each variable>> ...................................................... 20
8.4. Routine laboratory assessments ............................................................................. 20
8.4.1. <<Please use subheadings for each variable>> ...................................................... 20
8.5. <<Imaging – delete subheadings if not applicable>>.............................................. 20
8.5.1. MSK imaging ........................................................................................................... 20
8.5.2. Cardiovascular imaging........................................................................................... 20
8.5.3. Gait laboratory........................................................................................................ 21
9. STUDY PROCEDURES BY VISIT ........................................................................................ 21
9.1. Summary schedule of study assessments ............................................................... 21
9.2. <<Screening visit>>.................................................................................................. 21
9.3. Baseline <<or Cross-sectional single visit>> ............................................................ 21
9.4. <<Follow-up visits (weeks x, x, x… make new subheadings as needed)>> ............. 21
9.5. <<Early withdrawal visit (± x days)>> ...................................................................... 21
9.6. <<Completion visit (week xx)>> .............................................................................. 21
9.7. <<Safety follow-up visit (<<xx>> weeks after last visit)>> ...................................... 21
9.8. <<Unscheduled visits>> ........................................................................................... 21
10. SAFETY ISSUES .............................................................................................................. 21
10.1. Defining serious adverse events (SAEs) ................................................................ 21
10.2. AEs of special interest .......................................................................................... 22
10.2.1. Pregnancy ............................................................................................................. 22
10.2.2. <<Other AEs of special interest (specify)>>.......................................................... 22
10.3. Defining related and unexpected serious adverse events (RUSAEs) .................... 22
10.4. Exemptions from safety reporting ........................................................................ 22
10.5. Recording and reporting of (RU)SAEs ................................................................... 22
10.5.1. Recording and reporting of (RU)SAEs ................................................................... 22
10.5.2. RUSAE reporting requirements ............................................................................ 23
10.6. Urgent safety measures ........................................................................................ 23
Page 7 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
10.7. Serious breaches of protocol ................................................................................ 24
10.8. Laboratory measurements .................................................................................... 24
10.9. Other safety measurements ................................................................................. 24
10.10. Annual reports..................................................................................................... 24
10.11. End of trial report ................................................................................................ 25
11. STUDY MANAGEMENT AND ADMINISTRATION .......................................................... 25
11.1. Good clinical practice (GCP) .................................................................................. 25
11.2. Adherence to protocol .......................................................................................... 25
11.3. Monitoring and audit ............................................................................................ 25
11.4. Study management ............................................................................................... 25
11.4.1. Definition of source data ...................................................................................... 25
11.4.2. Source data verification........................................................................................ 26
11.4.3. Trial oversight ....................................................................................................... 26
11.5. Data handling ........................................................................................................ 26
11.5.1. CRF completion ..................................................................................................... 26
11.5.2. Database entry and reconciliation ....................................................................... 26
11.5.3. <<Screening and enrolment logs [if applicable]>> ............................................... 27
11.6. Archiving and data retention ................................................................................ 27
11.7. Study suspension, termination and completion ................................................... 28
12. DATA EVALUATION ...................................................................................................... 28
12.1. Responsibilities ...................................................................................................... 28
12.2. Hypotheses ............................................................................................................ 28
12.3. General statistical considerations ......................................................................... 28
12.4. Planned analyses ................................................................................................... 28
12.5. Safety analyses ...................................................................................................... 28
12.6. <<Definition of ‘per protocol’ set>> ...................................................................... 29
12.7. Handling of dropouts and missing data ................................................................ 29
12.8. Planned interim analysis ....................................................................................... 29
12.9. Determination of sample size <<and randomization method>> .......................... 29
12.10. <<Procedure for unblinding the study prior to analysis>> <<if appropriate>> .. 29
13. ETHICS AND REGULATORY REQUIREMENTS ................................................................ 29
Page 8 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
13.1. Good Clinical Practice ............................................................................................ 29
13.2. Delegation of Investigator duties .......................................................................... 30
13.3. Subject information and informed consent .......................................................... 30
13.4. Subject confidentiality........................................................................................... 31
13.5. Approval of clinical study protocol and amendments .......................................... 31
13.6. Protocol amendments ........................................................................................... 31
13.7. Ongoing information for Research Ethics Committee .......................................... 32
14. FINANCE AND INSURANCE ........................................................................................... 32
14.1. Indemnity and insurance....................................................................................... 32
14.2. Financial disclosure ............................................................................................... 32
15. PUBLICATION ............................................................................................................... 32
16. REFERENCES ................................................................................................................. 34
17. APPENDICES ................................................................................................................. 35
Page 9 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
ABBREVIATIONS
Abbreviation
Term
AE
Adverse Event
CI
Chief Investigator
CRF
Case Report Form
DMEC
Data Monitoring and Ethics Committee
DSUR
Developmental Safety Update Report
ECG
Electrocardiogram
GCP
Good Clinical Practice
GP
General Practitioner
IB
Investigator Brochure
ICH
International Conference On Harmonisation
IMP
Investigational Medicinal Product
LIRMM
Leeds Institute of Rheumatic and Musculoskeletal Medicine
MHRA
Medicines And Healthcare Products Regulatory Agency
MRI
Magnetic Resonance Imaging
NIMP
Non-Investigational Medicinal Product
QA
Quality Assurance
REC
Research Ethics Committee
SAE
Serious Adverse Event
SD
Standard Deviation
SPC
Summary Of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
Page 10 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
PROTOCOL SYNOPSIS
GENERAL INFORMATION
Short Title
Full Title
Sponsor
Sponsor ID
MREC No.
Chief Investigator
Co-ordinating Centre
National / International
STUDY INFORMATION
Phase
<<Proof-of-concept,
I/II/III/IV>>
feasibility,
confirmatory
phase
sequential,
cluster
Indication
Design
<<e.g. Parallel group/crossover,
randomised, equivalence>>
Number of sites
<<If up to 3 please list, otherwise give total number>>
Primary Objective
<<Some proof-of-concept and feasibility studies may not
have clearly defined primary and secondary objectives; in this
situation please change to ‘Study Objective(s)’>>
Secondary Objective(s)
<<Some proof-of-concept and feasibility studies may not
have clearly defined primary and secondary objectives; in this
situation please delete this row>>
Primary Endpoint
<<Some proof-of-concept and feasibility studies may not
have clearly defined primary and secondary endpoints; in this
situation please change to ‘Study Endpoint(s)’>>
Secondary Endpoint(s)
<<Some proof-of-concept and feasibility studies may not
have clearly defined primary and secondary endpoints; in this
situation please delete this row>>
STUDY TIMELINES
Expected start date
Subject enrolment phase
Follow-up duration
End of Study Definition
Expected completion date
STUDY SUBJECT INFORMATION
Number of study subjects
Page 11 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
Age group of study subjects
Inclusion criteria
Exclusion criteria
Page 12 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
SCHEMATIC DIAGRAM
<<Please provide flow diagram to demonstrate study visit structure and procedures>>
Page 13 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
1. INTRODUCTION
1.1. Background
<<A general introduction to the study backed up by literature review, referencing relevant
papers, previous clinical experience and any pilot work. This section should include:

Description of the indication, its diagnosis, incidence, current or theoretical
treatments and their limitations

Comparative studies>>
1.2. Rationale for the proposed study
<<Please add a brief summary of the study rationale:

Explanation of why the study is appropriate (potential benefits to patients/health
service). If applicable, include a description of, and justification for, the proposed
intervention, the route of administration of drugs, dosage, dosing regimen,
intervention periods, or behavioural intervention methods and selection of study
population.

A summary of the hypothesis to be tested including a statement of what would be a
worthwhile study outcome>>
2. STUDY AIM AND OBJECTIVES
<<A detailed description of the primary and secondary objectives of the study is included in
this section. An objective is the reason for performing the study in terms of the scientific
question to be answered by the analysis of data collected during the study. These typically
include:

Statement of purpose, e.g. to assess, to determine, to compare, to evaluate

General purpose, e.g. feasibility, reliability, efficacy, safety, immunogenicity,
pharmacokinetics

Specific purpose, e.g. variability estimation, superiority to control

If applicable the name(s) of intervention (e.g. procedure, drug, behavioural
intervention) being evaluated, specification of doses or dose ranges to be studied,
dose regimens
Some proof-of-concept and feasibility studies may not have clearly defined primary and
secondary objectives; in this situation, headings 2.2 and 2.3 may be combined under ‘2.2.
Study Objective(s)’>>
2.1. Study aim
2.2. Primary objective
Page 14 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
2.3. Secondary objective(s)
3. STUDY ENDPOINTS
<<Some proof-of-concept and feasibility studies may not have clearly defined primary and
secondary endpoints; in this situation, headings 3.1 and 3.2 may be combined under ‘3.1.
Study Endpoint(s)’>>
3.1. Primary endpoint
3.2. Secondary endpoint(s)
3.3. <<Other endpoint(s)>>
4. STUDY VARIABLES
<<List the variables to be recorded during the study (detailed descriptions will be provided
in the ‘methods of assessment’ section)>>
4.1. Standard variables
4.2. <<Efficacy variables (if appropriate)>>
4.3. Safety variables
4.4. <<Routine laboratory assessments>>
5. STUDY DESIGN
5.1. Study description
5.2. Study duration
5.3. Rationale for study design
6. SELECTION AND WITHDRAWAL OF SUBJECTS
6.1. Target population
6.2. Estimated number of eligible participants
<<Provide an estimate of the number of eligible patients per year and the proportion
expected to consent to participate>>
Page 15 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
6.3. Eligibility criteria
6.3.1. Inclusion criteria
(a)
(b)
(c)
6.3.2. Exclusion criteria
(a)
(b)
(c)
6.3.3. Exclusions for general safety
6.3.4. <<Laboratory exclusion (including imaging) at screening>>
6.4. Withdrawal criteria
6.5. Recruitment, consent and randomisation processes
6.5.1. Recruitment
<<Suggested text: A verbal explanation of the trial and Patient Information Sheet will be
provided by the authorised trial clinician for the patient to consider. This will include
detailed information about the rationale, design and personal implications of the study.>>
Following information provision, patients will have at least <<24 hours [note that shorter
periods are permissible provided they can be justified to the REC e.g. in emergency
medicine]>> to consider participation and will be given the opportunity to discuss the trial
with their family and healthcare professionals before they are asked whether they would be
willing to take part in the trial. This process will be clearly documented into the patient’s
medical notes.
6.5.2. Consent
<<How will consent be obtained? Who will gain consent? Will a witness be present? What
are the arrangements for special groups (e.g. patients who have dementia)?
Suggested text: Assenting patients will then be formally assessed for eligibility and invited
to provide informed, written consent.>>
Page 16 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
Where English is not the patient’s first language every effort will be made to provide a Trust
interpreter according to normal Trust procedures. The right of the patient to refuse consent
without giving reasons will be respected. Further, the patient will remain free to withdraw
from the study at any time without giving reasons and without prejudicing any further
treatment. A copy of the consent will be given to the patient, one filed in the Study Files,
and one filed in the hospital notes. The written consent will be taken by a clinician, who has
signed / dated the staff authorisation / delegation log. The process of obtaining written
consent will be clearly documented in the patient’s medical notes.
6.5.3. <<Randomisation process>>
<<If applicable include detail and justification for each of the following:

Information regarding how the randomisation schedule will be generated (including
who will generate the schedule)

Information regarding how randomisation will be implemented (including who,
where, how, and procedure for out of hours)

Approach to be used to conceal allocation (e.g. sealed envelopes, telephone central
allocation office, computerised randomisation etc)>>
6.5.4. <<STUDY BLINDING>>
<<If the trial is not to be blinded please state ‘The trial will not be blinded’>>
6.5.4.1. <<Type of blinding>>
<<double-blind, single blind, open>>
6.5.4.2. <<Procedure for production and maintenance of blind>>

<<Discuss with pharmacy if appropriate>>
6.5.4.3. <<Breaking the blind in an emergency>>
6.5.5. Patients who withdraw consent
<< Subject withdrawal criteria and procedures identifying:

When and how to withdraw subjects.

If appropriate describe circumstances under which randomisation codes may need to
be broken and the procedure for this (you may need to refer to pharmacy decoding
procedures)

The type and timing of any data to be collected for withdrawn subjects.>>

Unless the patient specifically withdraws consent for their data to be stored all data
and samples collected from them will continue to be stored as per the original
patient consent.
Page 17 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
6.5.6. Managing/replacing patients who withdraw early
<<Include details of:

The follow up procedures for withdrawn subjects (n.b. to comply with intention-totreat principles it is strongly recommended that you make every attempt to continue
the follow-up schedule as originally planned for patients who are withdrawn from
study treatment).>>

Patients who withdraw from the study early will not be replaced.
6.5.7. Definition for the end of the trial
7. <<STUDY INTERVENTIONS>>
<<This refers to an intervention which is under investigation and any non placebo control.
Detail in this section may be referenced to other documents, such as the Investigators
Brochure. Some study designs may not feature any interventions in which case this section
can be deleted.>>
7.1. <<General information on the products or interventions to be used>>
<<Provide general information about the intervention/control treatment including detail of
any previous use and current evidence of risks/benefits. For medicinal products, procedures
or devices in particular include full name, generic name/trade name and licence information
and summary of Product Characteristics.>>
7.2. <<Use within the trial>>
<<Please include:

Detailed description of the interventions/treatments that will be provided in the
trial, including how they will be administered/provided in the trial and by whom (e.g.
patient, nurse, doctor, therapist, surgeon).

Arrangements for continuation of intervention/treatment for study patients after
the end of the trial

For medicinal interventions include (if appropriate):
-
Description and justification for the proposed route of administration,
dosage, and treatment period
-
Description of dosage form, dispensing records, accountability and disposal
procedures during the trial
-
Details of who will supply the products, shelf life, arrangements for storage
etc>>
7.3. <<Prior and concomitant illnesses>>
Page 18 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
7.4. <<Prior and concomitant medications and procedures>>
7.4.1. <<Permitted prior medications and procedures>>
7.4.2. <<Prohibited prior medications and procedures>>
7.4.3. <<Permitted concomitant medications and procedures>>
7.4.4. <<Prohibited concomitant medications and procedures>>
7.4.5. <<Surgical procedures>>
7.5. <<Special warnings and precautions for use>>
<<Present a general summary and indicate where further details can be found –
please avoid copying and pasting. If there are none or if this section does not apply to your
study please state ‘none’ or ‘not applicable’>>
7.6. <<Intervention modifications>>
<<Clearly set out the details of the circumstances that will lead to a treatment modification.
If there are none please state ‘none’>>
7.7. <<Assessing subject compliance with study intervention(s)>>
<<Describe method of assessing study intervention compliance, if applicable.
Procedures for monitoring study treatment compliance of subjects (e.g. patient diaries to
record daily treatment or exercise)
Recording of patient compliance information (what will be recorded, when and where, use
of study treatment compliance form)>>
7.8. <<Withdrawal of treatment>>
7.8.1. <<Subject compliance>>
<<Define the acceptable and unacceptable level of compliance for the patients to remain in
the study>>
7.8.2. <<Lack of efficacy>>
<<Give details of how lack of efficacy leading to withdrawal is to be defined>>
8. METHODS OF ASSESSMENT
Page 19 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
<<In this section give detailed descriptions of all assessments; for some assessment
methods there are standard text descriptions available. If you wish to use a non-standard
tool please give detail on reliability and validity>>
8.1. Standard assessment variables
<<For some proof-of-concept or feasibility studies there may not be clearly defined primary
and secondary efficacy variables; if this is the case combine these two headings under
‘Efficacy assessment variables’>>
8.1.1. <<Please use subheadings for each variable>>
8.2. <<Efficacy assessment variable(s)>>
8.2.1. <<Primary efficacy assessment variable(s)>>
8.2.2. <<Secondary efficacy assessment variables>>
8.2.3. <<Please use subheadings for each variable>>
8.3. Safety assessment variables
8.3.1. <<Please use subheadings for each variable>>
8.4. Routine laboratory assessments
8.4.1. <<Please use subheadings for each variable>>
8.5. <<Imaging – delete subheadings if not applicable>>
8.5.1. MSK imaging
8.5.1.1. MRI details
8.5.1.2. Information wanted from scan
8.5.1.3. Image safety reporting
8.5.1.4. Image analysis
8.5.2. Cardiovascular imaging
8.5.2.1. MRI details
8.5.2.2. Information wanted from scan
8.5.2.3. Image safety reporting
Page 20 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>
8.5.2.4. Image analysis
8.5.3. Gait laboratory
8.5.3.1. Gait analysis details
8.5.3.2. Duration of gait analysis
8.5.3.3. Data capture
8.5.3.4. Data analysis
9. STUDY PROCEDURES BY VISIT
9.1. Summary schedule of study assessments
<<Can be provided in tabular form>>
9.2. <<Screening visit>>
9.3. Baseline <<or Cross-sectional single visit>>
9.4. <<Follow-up visits (weeks x, x, x… make new subheadings as needed)>>
9.5. <<Early withdrawal visit (± x days)>>
9.6. <<Completion visit (week xx)>>
9.7. <<Safety follow-up visit (<<xx>> weeks after last visit)>>
9.8. <<Unscheduled visits>>
10. SAFETY ISSUES
10.1. Defining serious adverse events (SAEs)
A serious adverse event (SAE) is an adverse event which is defined as serious, i.e. that it:

Results in death. Death may occur as a result of the basic disease process.
Nevertheless, all deaths occurring within <<30 days>> of the patient’s final research
clinic appointment must be treated as an SAE and reported as such. All deaths which
may be considered as related to the trial, regardless of the interval, must be treated
as a SAE and reported as such.

Is life-threatening.
Page 21 of 35
<<Protocol version>>
<<Short title>><< R&D number[IRAS code if available]>>

Requires inpatient (overnight) hospitalization or prolongation of an existing
hospitalization.

Results in a persistent or significant disability or incapacity.

Results in a congenital anomaly or birth defect.

Additionally, important medical events that may not result in death, be lifethreatening, or require hospitalization may be considered SAEs when, based on
appropriate medical judgment, they may jeopardize the subject and may require
medical or surgical intervention to prevent one of the outcomes listed in this
definition.

Any other significant clinical event, not falling into any of the criteria above, but
which in the opinion of the Investigator requires reporting.
10.2. AEs of special interest
10.2.1. Pregnancy
If a trial subject falls pregnant, the patient will be withdrawn from the trial unless pregnancy
is an inclusion criterion. All pregnancies will be followed up until birth. Should there be a
congenital anomaly or birth defect, then this will be reported as an SAE to the main REC and
Sponsor if in the opinion of the chief investigator the congenital anomaly or birth defect is
related to the research treatment or procedure.
10.2.2. <<Other AEs of special interest (specify)>>
10.3. Defining related and unexpected serious adverse events (RUSAEs)
A serious adverse event suspected to have a reasonable causal relationship to the study
treatment or procedure which is unexpected i.e. where the nature or severity is inconsistent
with the available information relating to the treatment or procedure, or is not listed in this
protocol as an expected occurrence is subject to expedited reporting.
10.4. Exemptions from safety reporting
The following events are expected and will not be reported:
<<please list, or state ‘none’. Note that events not listed will be subject to reporting to the
REC>>
10.5. Recording and reporting of (RU)SAEs
10.5.1. Recording and reporting of (RU)SAEs
Determination of SAEs should be based on the signs or symptoms detected during the
physical examination and on clinical evaluation of the subject, and should be assessed and
recorded at every visit. Signs and symptoms must be recorded using standard medical
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terminology. Subjects considered incapable of giving consent would not be considered for
this study.
SAEs will be collected from <<the signing of the informed consent form/randomisation/first
dose of protocol treatment>> to <<30 days>> after the final study appointment. The
Investigator must instruct the subject to report all SAEs during this time period.
During the time period specified above, the investigator will:

Record all SAEs on source documents.

Record all SAEs in the CRF for subjects who are not screen failures.

Report all RUSAEs on a ‘Serious Adverse Event report form for non-CTIMPs’,
available from the NRES website. This form should be sent to the main REC for the
trial.
The Investigator must follow up on all SAEs until the events have subsided, returned to
baseline, or, in case of permanent impairment, until the condition has stabilized. The
Sponsor will maintain detailed records of the SAEs reported by an investigator in accordance
with good clinical practice and applicable local regulations.
10.5.2. RUSAE reporting requirements
All SAEs identified by the local Investigator as both likely to be related to protocol-treatment
and unexpected will be reviewed by the Chief Investigator (CI). The CI, local PI or other
qualified and delegated individual may declare an SAE a RUSAE. This may be downgraded in
discussion with the CI but if no agreement can be made or in the absence of the CI the event
should be reported as a RUSAE. A RUSAE once reported can be downgraded at a later date
upon the receipt of new information. All investigators should refer to the <<Investigators
Brochure/protocol>> when determining whether a SAE is expected.
Identifiable patient data, other than linked anonymised data required by the NRES nonCTIMP SAE form, must not be included when reporting RUSAEs.
The CI will then inform the Research Ethics Committee (REC) that gave the favourable
opinion for the study of RUSAEs within the required expedited reporting timescales. RUSAEs
must be reported to the REC within 15 calendar days of the CI (or their research team) being
informed of the event.
RUSAEs will be reported in accordance with the principles of ICH GCP and the Research
Governance Framework 2005. They will all be signed off by the Principle Investigator or, in
their absence, by a delegated individual.
10.6. Urgent safety measures
If the research team becomes aware of information affecting the risk/benefit balance of the
trial they may take immediate action to ensure patient safety. Urgent safety measures
deemed necessary must be reported immediately by telephone to the main REC for the trial
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and must be followed within three days by notice in writing setting out the reasons for the
urgent safety measures and the plan for further action. The REC co-ordinator will
acknowledge within 30 days.
10.7. Serious breaches of protocol
A serious breach is a breach which is likely to effect to a significant degree either:

The safety or physical or mental integrity of the subjects of the trial; or

The scientific value of the trial
Serious breaches of GCP, the trial protocol and the Clinical Trial Authorisation will be
reported to the Sponsor QA office within 24 hours (1 working day) from the time the
research team becomes aware of the incident.
10.8. <<Laboratory measurements>>
<<The contents of this section will vary from study to study. Avoid providing too much detail
but give sufficient information on the extent and timing of sampling.
Example:
[Each centre will be provided with a/The laboratory staff will have access to a] laboratory
manual which will provide detailed descriptions of collection, preparation and labelling
[/shipping] requirements for all laboratory samples for the study.
A maximum of xxml of blood will be collected at [specify time-points]. The blood will be
drawn into a combination of EDTA, Li Hep, red clotted, paxgene […] tubes, according to the
planned experiments at each time-point. Additional samples are required for [specify substudy (if any)], see section [xxx]. After collection blood samples will be processed for serum,
plasma, or used fresh for flow cytometry and other functional studies, or stored as whole
blood for future DNA, RNA extraction depending on biomarker types to be evaluated and
methods/techniques applicable to the study (see Section 9.5).
Sample labels containing appropriate identification information will be provided [to the
site].
The laboratory measurements to be collected in this study include [haematology, clinical
chemistry, pregnancy testing (for females of childbearing potential), urinalysis, CRP,
CV/metabolic measurements, immunological measurements, inflammation biomarkers, and
other measurements] as presented in Table xxx.>>
10.9. Other safety measurements
10.10. Annual reports
An annual report describing the general progress and any relevant safety data related to the
trial must be submitted to the main REC and the Sponsor on the anniversary of the REC
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approval being granted. The appropriate form for non-CTIMPs is available from the NRES
website.
The CI must review and sign / date the report.
10.11. End of trial report
Upon completing the trial, as defined in section <<enter section number for ‘Definition for
the end of the trial’>>, an end of trial report must be submitted to the REC within one year
of the end of the trial. A copy of this end of trial report should also be submitted to the
Sponsors office and supplied to all support departments involved in the study, for example
pharmacy and or radiology.
The CI must review and sign / date the report.
11. STUDY MANAGEMENT AND ADMINISTRATION
11.1. Good clinical practice (GCP)
This clinical trial will be run in accordance with the Principles of ICH GCP and the Research
Governance Framework 2005.
11.2. Adherence to protocol
The Investigator should not deviate from the protocol. In medical emergencies, the
Investigator may use his/her medical judgment and may remove a study participant from
immediate hazard before notifying the Sponsor and the REC in writing regarding the type of
emergency and the course of action taken.
11.3. Monitoring and audit
The Sponsor reserves the right to audit any site involved in the trial and authorisation for
this is given via the study contract or agreement. A site may be audited by LIRMM or an
independent contractor working for LIRMM, and the Investigator should allow direct access
to trial documentation.
11.4. Study management
11.4.1. Definition of source data
Source documents are original records in which raw data are first recorded. These may
include, e.g. hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory
results, printouts, pharmacy records, care records, ECG or other printouts, completed
scales, or Quality of Life Questionnaires. Source documents should be kept in a secure,
limited access area.
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Some data will be recorded directly in the CRF and will not appear in a source document as
defined in the Source Data Verification form.
11.4.2. Source data verification
Source data verification ensures accuracy and credibility of the data obtained. The
Investigator will review the reported data to ensure they are accurate, complete, and
verifiable from source documents (e.g. subject files, recordings from automated
instruments, ECG tracings, x-ray films, laboratory notes). All data reported on the CRF
should be supported by source documents, unless otherwise specified in section <<enter
the section number for ‘Definition of source data’>>. Data Verification and will be carried
out by the Investigator(s) and members of the study team who will check the case report
forms for completeness and clarity, and crosscheck them with source documents.
11.4.3. Trial oversight
11.4.3.1. Trial steering committee
<<Example: Independent oversight of the study will be conducted by the Trial Steering
Committee. Amongst its members will be an independent chair, a lay individual (from the
Leeds Musculoskeletal Biomedical Research Unit Public and Patient Advocacy Group), a
clinician who is independent of the study research team, and a representative of the LIRMM
study management team. They are expected to meet at least quarterly. For its terms of
reference see appendix <<xxx>>.>>
11.4.3.2. <<Data Monitoring and Ethics Committee (DMEC)>>
<<If a multi-centre study a DMEC may be required; give details of its structure>>
11.5. Data handling
11.5.1. CRF completion
The research team is responsible for prompt reporting of accurate, complete, and legible
data in the CRFs and in all required reports. Any change or correction to the CRF should be
dated, initialled, and explained (if necessary) and should not obscure the original entry. Use
of correction fluid is not permitted. The Investigator should maintain a list of personnel
authorized to enter data into the <<(e)>>CRF. Detailed instructions will be provided in the
<<(e)>>CRF Instructions.
11.5.2. Database entry and reconciliation
Case report forms/external electronic data will be entered/loaded in a <<describe database
in consultation with LIRMM Business Systems Analyst>>. Regular backups of the electronic
data will be performed.
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11.5.3. <<Screening and enrolment logs [if applicable]>>
<<Subject’s Screening will be recorded in the Subject Screening Log.
The Investigator will keep a list containing all subjects enrolled into the study. This list
remains with the Investigator and is used for unambiguous identification of each subject.
The list contains the subject identification number, full name, date informed consent signed,
date of screening, and the hospital number or National Health Security number, if
applicable.
The subject’s consent and enrolment in the study must be recorded in the subject’s medical
record. These data should identify the study and document the dates of the subject’s
participation.>>
11.6. Archiving and data retention
Although not required by law for non-CTIMPs, in line with the principles of ICH GCP essential
study documents will be retained for a minimum of 5 years following the completion of the
study. Arrangements for confidential destruction will then be made. If a patient withdraws
consent for their data to be used, it will be confidentially destroyed immediately. No
records/study documentation/data may be destroyed without first obtaining written
permission from the Sponsor.
Essential documents include (this list is not exhaustive):

Signed informed consent documents for all subjects.

Subject identification code list, screening log (if applicable) and enrolment log.

Record of all communications between the Investigator, the REC and the Sponsor.

Composition of the REC, and the Sponsor (or other applicable statement as
described in section <<enter the section number for ‘Approval of clinical study
protocol and amendments’>>).

List of sub-investigators and other appropriately qualified persons to whom the
Investigator has delegated significant trial-related duties, together with their roles in
the study and their signatures.

Copies of case report forms and documentation of corrections for all subjects.

Investigational product accountability records.

Record of any body fluids or tissue samples retained.

All other source documents (subject medical records, hospital records, laboratory
records, etc.).

All other documents as listed in section 8 of the ICH E6 Guideline for Good Clinical
Practice (Essential Documents for the Conduct of a Clinical Trial).
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Normally, these records will be held in the Investigator's archives. If the Investigator is
unable to meet this obligation, he or she must ask the Sponsor for permission to make
alternative arrangements. Details of these arrangements should be documented.
11.7. Study suspension, termination and completion
Suspension or termination of the study may occur at any time for any reason, following
discussion between the Investigator and the Sponsor. Upon study completion, the
Investigator will provide the Sponsor with final reports and summaries as required by
regulations, and will be responsible for completing a premature end of study report to the
Research Ethics Committee (REC) within 15 days.
12. DATA EVALUATION
12.1. Responsibilities
<<Who will perform the analysis and write the report(s)?>>
12.2. Hypotheses
12.3. General statistical considerations
<<TO BE COMPLETED BY STATISTICIAN: Mention accommodation for randomisation
stratification factors if appropriate, one- or two-tailed tests, the level of significance to be
used, corrections for multiple comparisons.>>
In general, summary statistics [n (number of available measurements), arithmetic mean,
standard deviation, median, minimum, and maximum] for quantitative variables and
absolute and relative frequency tables for qualitative data will be presented.
<<If a randomised, controlled trial include the following: Wherever possible the trial will be
reported in accordance with the recommendations of the CONSORT (Consolidated
Standards of Reporting Trials) statement.>>
12.4. Planned analyses
<< TO BE COMPLETED BY STATISTICIAN: …>>
12.5. Safety analyses
Line listings of all SAEs will be provided in the end of trial report. The frequency of all SAEs
recorded during the study period will be presented. The data will be displayed as number of
subjects experiencing the SAEs, percentage of subjects, and number of SAEs. Data will also
be corrected for exposure by 100 patient-years.
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<<Include if appropriate: Laboratory evaluations and vital signs will be analyzed over time
for observed cases and at the end of treatment.>>
12.6. <<Definition of ‘per protocol’ set>>
<<Example: In addition to an intention-to-treat analysis including all patients, a
supplemental ‘per protocol’ analysis (including only those who adhered to the treatment
regimen of the programme they were allocated, provided sufficient assessment of primary
and secondary outcomes, and did not violate the trial protocol in any substantial way) may
be performed. Prior to analysis, patients will be allocated to or excluded from the ‘per
protocol’ set by a panel including the clinical project manager, trial statistician, and other
appropriate clinical study team members.>>
12.7. Handling of dropouts and missing data
<< TO BE COMPLETED BY STATISTICIAN: …>>
12.8. Planned interim analysis
<< TO BE COMPLETED BY STATISTICIAN: …>>
12.9. Determination of sample size <<and randomization method>>
<< TO BE COMPLETED BY STATISTICIAN: …>>
12.10. <<Procedure for unblinding the study prior to analysis>> <<if
appropriate>>
<< TO BE COMPLETED BY STATISTICIAN: …>>
13. ETHICS AND REGULATORY REQUIREMENTS
13.1. Good Clinical Practice
This study will be conducted in accordance with applicable laws and regulations including,
but not limited to, the International Conference on Harmonisation (ICH) Guideline for Good
Clinical Practice (GCP) and the recommendations guiding ethical research involving human
subjects adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, amended at
the 48th General Assembly, Somerset West Republic of South Africa, October 1996. The
Research Ethics Committee (REC) must review and approve the protocol and informed
consent form before any subjects are enrolled. Before any protocol-required procedures are
performed, the subject must sign and date the REC-approved informed consent form. The
right of a patient to refuse participation without giving reasons must be respected. The
patient must remain free to withdraw at any time from the study without giving reasons and
without prejudicing his/her further treatment. The study will be submitted to and approved
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by a main Research Ethics Committee (REC) and the appropriate regulatory authorities prior
to entering patients into the study.
13.2. Delegation of Investigator duties
The Investigator should ensure that all persons assisting with the trial are adequately
qualified and informed about the protocol, any amendments to the protocol, the study
treatments, and their trial-related duties and functions.
The Investigator should maintain a delegation log of co-investigators and other
appropriately qualified persons to whom he or she has delegated significant trial-related
duties.
13.3. Subject information and informed consent
Before being enrolled in the study, subjects must consent to participate after the nature,
scope, and possible consequences of the study have been explained in a form
understandable to them.
An informed consent document (Patient Information Leaflet) that includes both information
about the study and the consent form will be prepared and given to the subject at least
<<24 hours>> prior to the screening visit. This document will contain all the elements
required by the ICH E6 Guideline for Good Clinical Practice and any additional elements
required by local regulations. The document must be translated (by an independent
interpreter) into a language understandable to the subject and must specify who informed
the subject. Where required by local law, the person who informs the subject must be a
physician.
At the screening visit, patients will be given the opportunity to ask questions and the nature
and objectives of the study will be explained. A research nurse may help in this process but
the study doctor is responsible for the informed consent discussions.
After reading the informed consent document, the subject must give consent in writing. The
subject's consent must be confirmed at the time of consent by the personally dated
signature of the subject and by the personally dated signature of the person conducting the
informed consent discussions, the study doctor.
The original signed consent document will be retained in the study files. Other copies of the
consent form are required:

One copy of the informed consent document will be kept in the patient’s clinical
notes.

One copy will be given to the patient.
Consent is an ongoing process and will be reassessed at each study visit.
The Investigator will not undertake any measures specifically required only for the clinical
study until valid consent has been obtained.
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The Investigator must inform the subject’s primary physician about the subject’s
participation in the trial if the subject has a primary physician and if the subject agrees to
the primary physician being informed.
13.4. Subject confidentiality
Only the subject number will be recorded in the case report form, and if the subject name
appears on any other document (e.g. laboratory report), it must be obliterated on the copy
of the document to be supplied to anyone outside the clinical care team. The subjects will
be informed that representatives of the Sponsor, Research Ethics Committee (REC) or
regulatory authorities may inspect their medical records to verify the information collected,
and that all personal information made available for inspection will be handled in strictest
confidence.
All information collected during the course of the trial will be kept strictly confidential.
Information will be held securely on paper and electronically.
The <<Specify Department/Research Organisation/Laboratory>> will comply with all aspects
of the Data Protection Act 1998.
The Principle Investigator at each site will maintain a personal subject identification list
(subject numbers with the corresponding subject names) to enable records to be identified.
13.5. Approval of clinical study protocol and amendments
Before the start of the study, the clinical study protocol, informed consent document, and
any other appropriate documents will be submitted to the REC and the Sponsor with a cover
letter or a form listing the documents submitted, their dates of issue, and the site (or region
or area of jurisdiction, as applicable) for which approval is sought.
Before the first subject is enrolled in the study, all ethical and legal requirements must be
met, including approval of the study by the NHS, the Sponsor Research and Development
department and the REC.
Amendments must be evaluated to determine whether formal approval must be sought and
whether the informed consent document should be revised, thus all protocol amendments
and administrative changes must first be discussed with and approved by the Sponsor
before being submitted to the REC, in accordance with legal requirements. Amendments
must be evaluated to determine whether formal approval must be sought and whether the
informed consent document should be revised.
The Investigator must keep a record of all communication with the REC and the Sponsor.
13.6. Protocol amendments
Requests for any amendments to the study must be sent to the Sponsor by the Chief
Investigator. The Sponsor will determine whether said amendments are substantial or
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non-substantial prior to their submission to the appropriate bodies for approval. Patients
should be re-consented to the study if the amendments affect the information they have
received, patient safety, or if the change alters the type or quality of the data collected for
the study. Patients should only be re-consented AFTER an amendment has been fully
approved.
13.7. Ongoing information for Research Ethics Committee
Unless otherwise instructed by the REC and the Sponsor, the Investigator must submit to
the REC and the Sponsor:

Information on serious adverse events that are unexpected and related to study
procedures (RUSAEs) from the Investigator’s site, within 15 calendar days of the
research team becoming aware of them.

Expedited safety reports, as soon as possible.

Annual reports on the progress of the study.

The NRES Declaration of End of Study form.
14. FINANCE AND INSURANCE
14.1. Indemnity and insurance
<<(LTHT sponsored study:)Clinical negligence indemnification will rest with the participating
NHS Trust or Trusts under standard NHS arrangements. As Sponsor, the Trust does not
provide indemnification against claims arising from non-negligent harm. >>
<<(UoL sponsored study:)The University of Leeds is able to provide insurance to cover for
liabilities and prospective liabilities arising from negligent harm. In certain circumstances we
provide insurance cover for claims arising from non-negligent harm. Clinical negligence
indemnification will rest with the participating NHS Trust or Trusts under standard NHS
arrangements. >>
<<Further details of liability and insurance provisions for this study are given in separate
agreements.>>
14.2. Financial disclosure
None of the Investigators or members of the research team have any financial involvement
with the sponsorship or funding bodies or will receive personal benefits, incentives or
payment over and above normal salary.
15. PUBLICATION
<<A statement on the ownership of the data and results should be made, explaining the
data restrictions and the process, if any, for obtaining publication rights.>>
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16. REFERENCES
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17. APPENDICES
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