RAPS Protocol
Version 5.0
22 September 2014
GENERAL INFORMATION
This document was constructed using the University College London (UCL) Clinical Trials Unit (CTU)
Protocol Template Version 1.0. It describes the RAPS trial, coordinated by the UCL CTU, and provides
information about procedures for entering patients into it. The protocol should not be used as an
aide-memoire or guide for the treatment of other patients. Every care has been taken in drafting this
protocol, but corrections or amendments may be necessary. These will be circulated to the
registered investigators in the trial, but sites entering patients for the first time are advised to
contact the UCL CTU, London, UK, to confirm they have the most up-to-date version.
COMPLIANCE
The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki
(version 2008), the principles of Good Clinical Practice (GCP) as laid down by Commission Directive
2005/28/EC with the implementation in national legislation in the UK by Statutory Instrument
2004/1031 and subsequent amendments, the UK Data Protection Act (DPA number: Z5886415), and
the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF).
SPONSOR
UCL is the trial sponsor and has delegated responsibility for the overall management of the RAPS
trial to the UCL CTU. Queries relating to UCL sponsorship of this trial should be addressed to the
Director, UCL CTU or via the trial team.
FUNDING
Arthritis Research UK
Arthritis Research UK is supporting this trial with regard to staff salaries and trial expenses, which
are reduced as the UCL CTU is undertaking RAPS as a CTU development project.
Bayer
Bayer is supporting this trial by supplying without charge rivaroxaban for clinical trial use and
financial support for specific pharmacovigilance functions.
Local Clinical Research Network (LCRN)
Funding for the Research Nurse input will be obtained from the LCRN.
AUTHORISATIONS AND APPROVALS
This trial was approved by NIHR Coordinated System for gaining NHS Permission (NIHR CSP) and is,
therefore, part of the NIHR clinical research network portfolio.
TRIAL REGISTRATION
This trial will be registered with the International Standard Randomised Controlled Trial Number
Register and the registration number will be added when provided.
UCL CTU
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TRIAL ADMINISTRATION
Please direct all queries to the Trial Manager at the coordinating site in the first instance; clinical
queries will be passed to the Chief Investigator via the Trial Manager.
COORDINATING SITE
UCL Clinical Trials Unit
Switchboard:
020 7679 1975
Email:
rapstrial@ucl.ac.uk
Gower Street
London
WC1 6BT
UCL CTU STAFF
Trial Manager:
Simon Clawson
Tel:
020 7679 5669
Statistical
oversight:
Caroline Doré
Tel:
020 7679 1824
Trial Statistician:
Yvonne Sylvestre
Tel:
020 3108 3939
Project Leader:
Nicola Muirhead
Tel:
020 3108 3263
Tel:
020 3447 7368 / 9456 (PA)
CHIEF INVESTIGATOR
Dr Hannah Cohen
Consultant Haematologist and Honorary
Email:
Reader
Dept of Haematology, University College
London (UCL) Hospitals NHS Foundation Trust
and Haemostasis Research Unit, UCL
1st Floor Central
250 Euston Road, London
NW1 2PG
UCL CTU
hannah.cohen@uclh.nhs.uk
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CO-INVESTIGATORS
Professor Munther Khamashta
Kings College London and Guy’s and St Thomas’ NHS
Foundation Trust
Lupus Research Unit,
Kings College London and
Consultant Physician
Guys and St Thomas’ NHS Foundation Trust
Westminster Bridge Road
London, SE1 7EH
Professor Beverley Hunt
Professor of Thrombosis & Haemostasis
Kings College London and
Consultant Haematologist
Guys and St Thomas’ NHS Foundation Trust
4th Floor, North Wing
Westminster Bridge Road
London, SE1 7EH
Professor Samuel Machin
Professor of Haematology
Haemostasis Research Unit
Haematology Dept
University College London
1st Floor, 51 Chenies Mews
London, WC1E 6HX
UCL CTU
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COLLABORATORS
Dr Ian Mackie
Haemostasis Research Unit
Haematology Dept
University College London
1st Floor, 51 Chenies Mews
London, WC1E 6HX
Dr Andrew Lawrie
Haemostasis Research Unit
Haematology Dept
University College London
1st Floor, 51 Chenies Mews
London, WC1E 6HX
Professor David Isenberg
University College London Hospitals NHS Foundation
Trust and University College London
Centre for Rheumatology
UCL Division of Medicine
4th Floor, Rayne Building
5 University Street
London WC1E 46F
Professor Anisur Rahman
University College London Hospitals NHS Foundation
Trust and University College London
Centre for Rheumatology
UCL Division of Medicine
4th Floor, Rayne Building
5 University Street
London WC1E 46F
Dr Ian Giles
University College London Hospitals NHS Foundation
Trust and University College London
Centre for Rheumatology
UCL Division of Medicine
4th Floor, Rayne Building
5 University Street
London WC1E 46F
Dr John Ioannou
University College London Hospitals NHS Foundation
Trust and University College London
Centre for Rheumatology
UCL Division of Medicine
4th Floor, Rayne Building
5 University Street
UCL CTU
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London WC1E 46F
Professor David D’Cruz
Lupus Research Unit
Guys and St Thomas’ NHS Foundation Trust and
Kings College London
Westminster Bridge Road
London, SE1 7EH
Dr Maria Cuadrado
Lupus Research Unit
Guys and St Thomas’ NHS Foundation Trust
Westminster Bridge Road
London, SE1 7EH
Dr Maria Efthymiou
RAPS trial post-doc Haemostasis Research Unit
Haematology Dept
University College London
1st Floor, 51 Chenies Mews
London, WC1E 6HX
Dr Deepa Arachchillage
Haemostasis Research Unit
Haematology Dept
University College London
1st Floor, 51 Chenies Mews
London, WC1E 6HX
UCL CTU
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CONTRACT RESEARCH ORGANISATION (CRO) – PRODUCTLIFE LTD
ProductLife Ltd
The Jeffreys Building
St John’s Innovation Park
Cowley Road
Cambridge
CB4 0WS
UCL CTU
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SUMMARY OF TRIAL
SUMMARY INFORMATION TYPE
SUMMARY DETAILS
ACRONYM (or Short Title of
Trial)
Rivaroxaban in Antiphospholipid Syndrome (RAPS)
Long Title of Trial
A prospective randomised controlled phase II/III clinical trial of
rivaroxaban versus warfarin in patients with thrombotic
antiphospholipid syndrome, with or without SLE
Version
5.0
Date
22 September 2014
UCL CTU ID
12/0033/CTU/IMM/001
ISRCTN #
ISRCTN68222801
EudraCT #
2012-002345-38
CTA #
20363
REC #
12.SC.0566
Study Design
Phase II/III randomised controlled non-inferiority clinical trial
Type of Participants to be
Studied
Patients with thrombotic antiphospholipid syndrome (APS)
Interventions to be Compared
Study Hypothesis
Primary Outcome Measure(s)
Secondary Outcome
Measure(s)
UCL CTU
Rivaroxaban versus warfarin, target International Normalised
Ratio (INR) 2.5 (range 2.0-3.0)
The study hypothesis is that the intensity of anticoagulation
achieved in patients on rivaroxaban is not inferior to that
obtained on warfarin. Intensity of anticoagulation will be
assessed by the Endogenous Thrombin Potential (ETP) which is
the area under the thrombin generation curve, a key parameter of
the Thrombin Generation Test (TGT). The TGT is a global measure
of anticoagulation which can assess the anticoagulant effects of
both rivaroxaban and warfarin (drugs with very different modes of
action on the coagulation mechanisms). Clinically, our hypothesis
is that in patients with thrombotic APS, rivaroxaban could induce
more predictable anticoagulation and therefore a greater
sustained reduction in thrombin generation than would warfarin,
with additional benefits to patients because there is no
requirement for regular laboratory monitoring of anticoagulation.
The primary outcome measure is the percentage change in ETP
from randomisation to day 42.
a) Efficacy:
i) recurrent venous thromboembolism (VTE) alone;
ii) a composite of recurrent VTE and other thrombotic events.
iii) The thrombin generation curve will also be quantified in terms
of: the lag-time; the time to peak; and peak thrombin
concentration.
iv) markers of in vivo coagulation activation: prothrombin
fragment 1.2, thrombin-antithrombin complex and D-dimer
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b) Safety:
i) serious adverse events;
ii) all bleeding events.
c) Quality of life (QoL):
EQ5D 5L.
d) Laboratory assessment of compliance:
i) anti-Xa assay in patients on rivaroxaban;
ii) factor X amidolytic assay as an antiphospholipid antibodyindependent assessment of anticoagulation, in addition to an
International Normalised Ratio (INR) in patients on warfarin,
iii) percentage time in therapeutic range (TTR) between baseline
and day 180 (ideally ±14 days) in patients on warfarin.
Randomisation
Patients will be randomised to either remain on warfarin or switch
to rivaroxaban.
Number of Participants to be
Studied
116 patients will be randomised (Ratio 1:1)
Duration
Ancillary Studies/Substudies
Each patient will have a six month treatment period and a final
visit 30 days after the end of treatment for the trial. The planned
recruitment period is 18 months and overall planned duration of
the study is 44 months.
Optional blood sample storage for translational laboratory
research.
Sponsor
University College London
Funders
Arthritis Research UK and Bayer Plc.
Trial Manager
Simon Clawson
Chief Investigator
Dr Hannah Cohen
UCL CTU Project Manager
Nicola Muirhead
UCL CTU
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TRIAL SCHEMA
Trial Entry, Randomisation and Treatment
UCL CTU
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TRIAL ASSESSMENT SCHEDULE
Assessment
(Procedure/activity)
Screening
Consent
Medical History
Demographics
Patient review
Height
Weight
BMI
Blood pressure
FBC
U&E, CrCl
LFTs
Anti-DNA
aPL
20 mL citrated blood
sample for trial
assessments (all
patients)
20 mL blood sample for
the translational
research (optional)
Pregnancy tests
Current medication
Document INRs
Dispensation
rivaroxaban
Drug accountability of
rivaroxaban
Enquiry for bleeding
symptoms
Enquiry for recurrent
thrombosis
QoL questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Baseline
Visit 1 Day
42
(ideally 12days+14
days)
Visit 2
Day 90
(ideally
±14days)
Visit 3
Day 180
(ideally
±14days)
Visit 4
Day 210
(ideally
±14days)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
For full details on the screening and baseline procedures refer to section 3.5.
For full details on the trial assessment schedule (visits) refer to section 6.
Full details on collection and processing the trial assessment blood samples and the blood samples
for translational research are found in Appendix C.
UCL CTU
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CONTENTS
GENERAL INFORMATION ......................................................................................... 2
COMPLIANCE ................................................................................................................................... 2
SPONSOR ........................................................................................................................................ 2
FUNDING ........................................................................................................................................ 2
AUTHORISATIONS AND APPROVALS ....................................................................................................... 2
TRIAL REGISTRATION.......................................................................................................................... 2
TRIAL ADMINISTRATION ..................................................................................................................... 3
Coordinating Site ..................................................................................................................................................... 3
UCL CTU Staff ........................................................................................................................................................... 3
Chief Investigator..................................................................................................................................................... 3
Co-investigators ....................................................................................................................................................... 4
Collaborators ........................................................................................................................................................... 5
Contract Research Organisation (CRO) – ProductLife Ltd ....................................................................................... 7
SUMMARY OF TRIAL ................................................................................................ 8
TRIAL SCHEMA ....................................................................................................... 10
Trial Entry, Randomisation and Treatment ........................................................................................................... 10
TRIAL ASSESSMENT SCHEDULE ............................................................................... 11
CONTENTS ............................................................................................................. 12
ABBREVIATIONS .................................................................................................... 15
1
BACKGROUND........................................................................................... 21
1.1
1.2
1.3
1.4
1.5
DISEASE SETTING & CONTEXT OF STUDY ................................................................................ 22
WHAT EVIDENCE IS ALREADY AVAILABLE TO SUPPORT THE INTERVENTION ..................................... 23
RESEARCH LEADING TO THE PROPOSED TRIAL .......................................................................... 24
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ....................................................................... 25
RATIONALE & OBJECTIVES OF THE STUDY ............................................................................... 25
Rationale ................................................................................................................................................................ 25
Objectives .............................................................................................................................................................. 26
1.6
1.7
HYPOTHESIS TO BE TESTED.................................................................................................. 27
RISKS AND BENEFITS ......................................................................................................... 28
2
SELECTION OF SITES/CLINICIANS ............................................................... 31
2.1
SITE/INVESTIGATOR ELIGIBILITY CRITERIA ............................................................................... 31
2.1.1
2.1.2
2.1.3
PI's Qualifications & Agreements ......................................................................................................... 31
Adequate Resources ............................................................................................................................ 31
Site Assessment.................................................................................................................................... 32
2.2
APPROVAL AND ACTIVATION ............................................................................................... 32
3
SELECTION OF PATIENTS ........................................................................... 33
3.1
3.2
3.3
3.4
3.5
PATIENT INCLUSION CRITERIA .............................................................................................. 33
PATIENT EXCLUSION CRITERIA ............................................................................................. 33
NUMBER OF PATIENTS ....................................................................................................... 34
CO-ENROLMENT GUIDELINES ............................................................................................... 34
SCREENING PROCEDURES & PRE-RANDOMISATION INVESTIGATIONS............................................. 34
Screening ............................................................................................................................................................... 34
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4
REGULATION & RANDOMISATION............................................................. 36
4.1
4.2
4.3
RANDOMISATION PRACTICALITIES ........................................................................................ 36
RANDOMISATION CODES & UNBLINDING ............................................................................... 36
CO-ENROLMENT GUIDELINES ............................................................................................... 36
5
TREATMENT OF PATIENTS ......................................................................... 37
5.1
5.2
INTRODUCTION ................................................................................................................ 37
ARM A .......................................................................................................................... 37
5.2.1
5.2.2
Products ............................................................................................................................................... 37
Compliance & Adherence..................................................................................................................... 37
5.3
ARM B........................................................................................................................... 37
5.3.1
5.3.2
5.3.3
5.3.4
5.3.5
5.3.6
5.3.7
Products ............................................................................................................................................... 37
Treatment Schedule ............................................................................................................................. 37
Dispensing ............................................................................................................................................ 37
Dose Modifications, Interruptions & Discontinuations ........................................................................ 38
Stopping Drug Early .............................................................................................................................. 38
Accountability & Unused Drugs/Devices ............................................................................................. 38
Compliance & Adherence..................................................................................................................... 39
5.4
5.5
5.6
5.7
5.8
5.9
5.10
OVERDOSE OF TRIAL MEDICATION ........................................................................................ 39
UNBLINDING ................................................................................................................... 39
PROTOCOL TREATMENT DISCONTINUATION ............................................................................ 39
ACCOUNTABILITY & UNUSED DRUGS/DEVICES ........................................................................ 40
COMPLIANCE & ADHERENCE ............................................................................................... 40
TREATMENT DATA COLLECTION ........................................................................................... 40
NON-TRIAL TREATMENT ..................................................................................................... 40
5.10.1
5.10.2
5.10.3
5.10.4
Medications Permitted ........................................................................................................................ 40
Medications Not Permitted .................................................................................................................. 40
Medications to be Used With Caution ................................................................................................. 41
Treatment After Trial Event ................................................................................................................. 41
5.11
CO-ENROLMENT GUIDELINES ............................................................................................... 41
6
ASSESSMENTS & FOLLOW-UP .................................................................... 42
6.1
6.2
6.3
6.4
6.5
6.6
6.7
6.8
TRIAL ASSESSMENT SCHEDULE ............................................................................................. 42
PROCEDURES FOR ASSESSING EFFICACY .................................................................................. 44
PROCEDURES FOR ASSESSING SAFETY .................................................................................... 45
PROCEDURES FOR ASSESSING QUALITY OF LIFE ........................................................................ 45
OTHER ASSESSMENTS ........................................................................................................ 45
EARLY STOPPING OF FOLLOW-UP ......................................................................................... 45
PATIENT TRANSFERS.......................................................................................................... 46
LOSS TO FOLLOW-UP ......................................................................................................... 46
7
SAFETY REPORTING ................................................................................... 47
7.1
DEFINITIONS ................................................................................................................... 47
Table 7.1: Definitions ............................................................................................................................................. 47
Adverse Reactions ................................................................................................................................................. 48
Guidance for Adverse Event Inclusions & Exclusions ............................................................................................ 48
Disease-related Events .......................................................................................................................................... 48
7.2
INVESTIGATOR RESPONSIBILITIES .......................................................................................... 48
7.2.1
Investigator assessment ....................................................................................................................... 48
Seriousness
48
Severity or Grading of Adverse Events
49
Causality
49
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Table 7.2: Assigning Type of SAE Through Causality ............................................................................................. 49
Expectedness
49
Notification
50
7.2.2
Notification Procedure ......................................................................................................................... 50
7.3
7.4
Pregnancy
UCL CTU RESPONSIBILITIES ................................................................................................ 50
OTHER NOTIFIABLE EVENTS ................................................................................................ 51
51
8
QUALITY ASSURANCE & CONTROL ............................................................ 52
8.1
8.2
8.3
RISK ASSESSMENT ............................................................................................................ 52
CENTRAL MONITORING AT UCL CTU .................................................................................... 52
ON-SITE MONITORING....................................................................................................... 52
8.3.1
8.3.2
Direct Access to Patient Records.......................................................................................................... 52
Confidentiality ...................................................................................................................................... 52
9
STATISTICAL CONSIDERATIONS ................................................................. 53
9.1
9.2
9.3
9.4
9.5
METHOD OF RANDOMISATION ............................................................................................ 53
OUTCOME MEASURES ....................................................................................................... 53
SAMPLE SIZE ................................................................................................................... 53
INTERIM MONITORING & ANALYSES ..................................................................................... 54
ANALYSIS PLAN (BRIEF) ..................................................................................................... 54
10
11
ANCILLARY STUDIES .................................................................................. 57
REGULATORY & ETHICAL ISSUES ................................................................ 58
11.1
COMPLIANCE ................................................................................................................... 58
11.1.1
11.1.2
11.1.3
Regulatory Compliance ........................................................................................................................ 58
Site Compliance .................................................................................................................................... 58
Data Collection & Retention ................................................................................................................ 58
11.2
ETHICAL CONDUCT OF THE STUDY ......................................................................................... 58
11.2.1
11.2.2
Ethical Considerations .......................................................................................................................... 58
Ethical Approvals .................................................................................................................................. 59
11.3
11.4
COMPETENT AUTHORITY APPROVALS .................................................................................... 59
OTHER APPROVALS ........................................................................................................... 59
12
13
14
INDEMNITY ............................................................................................... 60
FINANCE ................................................................................................... 61
OVERSIGHT & TRIAL COMMITTEES ............................................................ 62
14.1
14.2
14.3
14.4
TRIAL MANAGEMENT GROUP (TMG) ................................................................................... 62
TRIAL STEERING COMMITTEE (TSC) ...................................................................................... 62
INDEPENDENT DATA MONITORING COMMITTEE [IDMC] ........................................................... 62
ROLE OF STUDY SPONSOR .................................................................................................. 62
15
16
17
18
PUBLICATION ............................................................................................ 63
PROTOCOL AMENDMENTS ........................................................................ 64
REFERENCES .............................................................................................. 66
APPENDICES .............................................................................................. 72
UCL CTU
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ABBREVIATIONS
A&E
Accident and Emergency
ABPI
Association of the British Pharmaceutical Industry
AE
Adverse event
ALT
Alanine transaminase
ANA
Antinuclear antibodies
APS
Antiphospholipid syndrome
aPL
Antiphospholipid antibodies
AR
Adverse reaction
Bid
Bis in die (twice a day)
BCSH
British Committee for Standards in Haematology
BMI
Body Mass Index
BNF
British National Formulary
CF
Consent Form
CI
Chief Investigator
CI
Confidence interval
COM
Clinical Operations Manager
CPM
Clinical Project Manager
CrCl
Creatinine Clearance
CRF
Case Report Form
CRN
Clinical Research Network
CRO
Contract Research Organisation
CTA
Clinical Trials Authorisation
CTAAC
Clinical Trials Awards and Advisory Committee
CTIMP
Clinical trial of an investigational medicinal product
CTU
Clinical Trials Unit
DCF
Data Clarification Form
DH
Department of Health
DM
Data Manager
DNA
Deoxyribonucleic acid
DPA
(UK) Data Protection Act
DVT
Deep vein thrombosis
ECRIN
European Clinical Research Infrastructure Network
EFGCP
European Forum for Good Clinical Practice
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ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
ETP
Endogenous Thrombin Potential
EU
European Union
EudraCT
European Union Drug Regulatory Agency Clinical Trial
FBC
Full blood count
GCP
Good Clinical Practice
GP
General Practitioner
GPL
IgG phospholipid units
GSA
Group-specific appendix
HE
Health economics
HES
Hospital Episodes Statistics
HIV
Human Immunodeficiency Virus
IB
Investigator Brochure
IBW
Ideal body weight
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IMP
Investigational medicinal product
INR
International Normalised Ratio
IRAS
Integrated Research Application System
IRB
Institutional Review Board
ISRCTN
International Standard Randomised Controlled Trial Number
ITT
Intention-to-treat
LA
Lupus anticoagulant
LCRN
Local Clinical Research Network
LFTs
Liver Function Tests
LLN
Lower Limit of Normal
LMWH
Low molecular weight heparin
MPL
IgM phospholipid units
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MoU
Memorandum of Understanding
NHS
National Health Service
NHSCR
National Health Service Central Register
NHS-IC
National Health Service Information Centre
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NICE
National Institute for Health and Clinical Excellence
NIHR
National Institute for Health Research
NIHR CSP
National Institute for Health Research Co-ordinated System for
gaining NHS Permission
NIMP
Non-investigational-medicinal product
NPSA
National Patient Safety Agency
OD
Once daily
PE
Pulmonary Embolism
PI
Principal Investigator
PIS
Patient Information Sheet
PK
Pharmacokinetics
PT
Prothrombin time
QMG
Quality Management Group
QoL
Quality of life
QP
Qualified Person
R&D
Research and Development
RCT
Randomised controlled trial
REC
Research Ethics Committee
RGF
Research Governance Framework (for Health and Social Care)
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAR
Serious adverse reaction
SD
Standard deviation
SLE
Systemic lupus erythematosus
SMT
Senior Management Team
SOP
Standard operating procedure
SPC
Summary of Product Characteristics
SSA
Site-specific approval
SSI
Site-specific information
SUSAR
Suspected unexpected serious adverse reaction
TGT
Thrombin Generation Test
TM
Trial Manager
TMF
Trial Master File
TMG
Trial Management Group
TMT
Trial Management Team
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ToR
Terms of Reference
TTR
Time in Therapeutic Range
TSC
Trial Steering Committee
UAR
Unexpected adverse reaction
UCL
University College London
UCL CTU
University College London Clinical Trials Unit
U&E
Urea and electrolytes
ULN
Upper limit of normal
VKA
Vitamin K antagonist
VTE
Venous thromboembolism
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GLOSSARY
Adequate contraception
Adequate contraception is defined as hormonal contraception or barrier method contraception.
Sub-therapeutic anticoagulant therapy
Patients who develop a new venous thromboembolic event while on warfarin with an INR
(International Normalised ratio) of <2.0 (target INR 2.5, i.e. range 2.0-3.0) will be considered to have
had the event when sub-therapeutically anticoagulated. The same would apply if the patient was on
a dose of another anticoagulant (e.g. low molecular weight heparin) administered at less than the
manufacturer’s recommended therapeutic dose for VTE at the time of the event.
Thrombotic APS
Thrombotic APS is defined as venous thromboembolism (VTE) associated with persistent positivity of
one or more antiphospholipid antibodies (aPL; i.e. lupus anticoagulant, IgG and/or IgM
anticardiolipin and/or anti beta 2 glycoprotein 1 antibodies at >40 GPL or MPL units or > the 99th
percentile of normal). Persistent aPL positivity is defined as aPL present on at least two consecutive
occasions at least 12 weeks apart as defined in the International (Sydney) Consensus Statement
criteria.
Clinical outcome events
All thrombotic events, defined below, will be classified by the PI at the trial site.
1. Venous thromboembolism
The diagnosis of symptomatic recurrent venous thromboembolism (VTE), i.e. deep-vein thrombosis
(DVT) or non-fatal or fatal pulmonary embolism (PE) is based on the following:
DVT is diagnosed objectively on venous doppler or duplex scanning or venography.
PE is diagnosed objectively on computed tomography pulmonary angiogram (CTPA) or
ventilation/perfusion (V/Q) lung scanning.
Fatal PE: the diagnosis of fatal PE is based on objective diagnostic testing, autopsy, or death which
cannot be attributed to a documented cause and for which PE cannot be ruled out (unexplained
death).
2. Other thrombotic events
a) Arterial thrombosis/thromboembolism
Stroke is defined as a sudden focal neurologic deficit of presumed cerebrovascular etiology that
persists beyond 24 hours and is not due to another identifiable cause. An event matching this
definition but lasting less than 24 hours is considered to be a transient ischemic attack. The diagnosis
of stroke is based on brain imaging (computed tomography or magnetic resonance imaging).
Systemic embolism is defined as abrupt vascular insufficiency associated with clinical or radiological
evidence of arterial occlusion in the absence of another likely mechanism (e.g. atherosclerosis,
instrumentation, or trauma).
Myocardial infarction (MI) is defined by typical symptoms, cardiac biomarker elevation and
electrocardiogram changes, or confirmation at autopsy.
Deaths are classified as either vascular (e.g. due to stroke, embolism, myocardial infarction, or
arrhythmia) or non-vascular (e.g. malignancy or infection).
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b) Microvascular thrombosis
Thrombosis in the microvasculature, generally associated with evidence of organ dysfunction in
patients with thrombotic APS, is diagnosed on histological examination of a tissue biopsy.
Categorisation of bleeds:
Major bleeding
Major bleeding is defined as clinically overt bleeding associated with any of the following: fatal
outcome, involvement of a critical anatomic site (intracranial, spinal, ocular, pericardial, articular,
retroperitoneal, or intramuscular with compartment syndrome), fall in hemoglobin concentration of
at least 20 g/L, transfusion of 2 or more units of red blood cells, or permanent disability.
Clinically relevant non-major bleeding
Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major
bleeding but associated with medical intervention, unscheduled contact (visit or telephone) with a
physician, temporary interruption of study drug (i.e. delayed dosing), or associated with any other
discomfort such as pain or impairment of activities of daily life.
Minor bleeding
Bleeding events that do not meet the criteria of major or clinically relevant non-major bleeding are
defined as minor.
Lack of Drug Effect (LODE)
Non-serious adverse events (AE) will be considered due to LODE if the investigator explicitly states
that the non-serious adverse event occurred due to the drug not working. A non-serious AE would
not be considered to be due to LODE if e.g. there has been a medication error (insufficient dose was
used, prescribed dosing regimen was not followed), handling error (instructions for use not followed,
product stored incorrectly or used after expiry date) or there was a misuse or abuse of the product.
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1
BACKGROUND
Thrombotic antiphospholipid syndrome (APS) is a potentially fatal and devastating clinical disorder
with the cardinal features being venous and/or arterial thromboembolism associated with persistent
antiphospholipid antibodies (aPL). It constitutes a unique form of autoantibody mediated
thrombophilia.1,2,3
aPL is detected in 20% of patients who have had a stroke aged below 50 years4 and in 24% of
approximately 4500 patients with venous thromboembolism (VTE) (deep venous thrombosis (DVT)
and/or pulmonary embolism (PE)) in whom thrombophilia testing was done.5 APS may occur alone,
however, approximately 40% of patients with systemic lupus erythematosus (SLE) have aPL6 and
40% of these patients will develop thrombotic APS,7,8 which is considered to be a major adverse
prognostic factor in patients with SLE.7 Particularly in patients with SLE, appropriate management of
thrombotic APS is of key importance to minimise its deleterious clinical impact.
The current mainstay of the treatment of venous and/or arterial thromboembolism in patients with
APS is long-term anticoagulation with oral vitamin K antagonists (VKAs) such as warfarin.
Prospective, randomised controlled trials suggest that high-intensity warfarin (target International
Normalised Ratio (INR) 3.5, range 3.0 – 4.0, INR being the test used to monitor the anticoagulant
effect of VKAs) is not superior to moderate-intensity warfarin (target INR 2.5, range 2.0 – 3.0) in the
management of these patients,9,10 and the current recommendations based on these data are
indefinite anticoagulation at a target INR of 2.5 for patients with APS, with or without SLE,
presenting with a first VTE event, or a recurrent VTE event which occurred whilst off
anticoagulation11,12. However, patients with recurrent thrombosis on VKAs were excluded from
studies investigating anticoagulation intensity in patients with APS9,10 and those with APS and
previous arterial events were poorly represented, and so the optimal intensity of anticoagulation
with VKAs in these patient groups with APS is not established, although the consensus view is that
they should be maintained at a target INR of >3.0.12
Unfortunately, treatment with VKAs is problematic. Warfarin, the most widely used VKA in the UK,
has a slow onset of action of 3-5 days and a narrow therapeutic window. This, as well as its
numerous drug and dietary interactions, and potential for variation of action with alcohol,
intercurrent illness, exercise and smoking necessitates frequent monitoring of the INR, which is
inconvenient and costly. Over-anticoagulation with warfarin is associated with a risk of bleeding (12% of patients suffer major bleeds and 0.25% die from bleeding) and under-anticoagulation is
associated with recurrent thrombosis. As around 1 million people in the UK receive oral
anticoagulant therapy, with the numbers increasing by approximately 10% each year,13 warfarinassociated bleeding represents a significant healthcare problem.
VKAs present particular problems in patients with APS. First, VKA monitoring in patients with aPL can
be complicated by the variable responsiveness of thromboplastin reagents (thromboplastin being
the main reagent used in the INR test) to lupus anticoagulants (LA; one of the family of aPL) which
may in turn potentially influence the validity of the prothrombin time–INR in monitoring oral VKA
treatment in patients with APS. A multisite study of laboratory INR testing in patients with APS
concluded that LA interference with the PT-INR measured with the majority of commercial
thromboplastins is not enough to cause concern if insensitive thromboplastins, properly calibrated
to assign them an instrument-specific International Sensitivity Index (ISI) are used. The investigators
also suggested that new thromboplastins, especially those made of relipidated recombinant human
tissue factor (rTF), should be checked to ensure that they are insensitive to the effects of aPL before
they are used to monitor oral anticoagulant treatment in patients with APS.14 Whilst these
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procedures are generally routine in specialist centres, they may not be as easily undertaken in other
institutions, and thus as a result the INR may not accurately reflect the true level of anticoagulation.
The variable responsiveness of aPL to LA can result in instability of the INR, which necessitates
frequent anticoagulant monitoring with the attendant inconvenience to the patient, adverse impact
on quality of life and increased costs. It may also be associated with thrombotic or bleeding
complications. A systematic review reported that approximately 2.8% of APS patients on VKA had
recurrent thrombotic events, and bleeding rates of up to 10% per year.15 Secondly, LA detection in
patients on warfarin may be problematic because of the prolonged basal clotting time.16 This limits
the ability to diagnose APS in patients on VKA and also monitoring of aPL status in those with an
established diagnosis. The limitations of warfarin and other existing anticoagulants have driven a
search for new agents.
1.1
DISEASE SETTING & CONTEXT OF STUDY
The lives of patients with thrombotic APS, with or without SLE, are often blighted by the
requirement to take warfarin with all its complications and need for frequent, often weekly, INR
monitoring. It is often very difficult to establish the correct dose leading to major concern about
excessive bleeding and/or recurrent thrombosis. Furthermore, warfarin interacts with many other
drugs and dietary constituents, making the treatment of concomitant diseases, including SLE,
problematic.
The new oral anticoagulants are fixed-dose, and, unlike warfarin, have a predictable anticoagulant
effect and do not require routine monitoring with coagulation tests. They offer a potential
opportunity to revolutionize the lives of those patients on warfarin. Dabigatran etexilate (Pradaxa®;
Boehringer Ingelheim), a direct thrombin inhibitor,17 and rivaroxaban (Xarelto®; Bayer HealthCare), a
direct anti-Xa inhibitor and the first in a new class of drugs,18 are licensed in the UK and many other
countries for the prevention of VTE following high risk lower limb orthopaedic surgery,19-25 and
endorsed for these indications by the National Institute of Health and Clinical Excellence (NICE).26,27
In 2011 rivaroxaban was licensed for the treatment of deep vein thrombosis (DVT), prevention of
recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults and prevention of
stroke and systemic embolism in adult patients with non-valvular atrial fibrillation, and in the same
year dabigatran was licenced for the prevention of stroke and systemic embolism in adult patients
with non-valvular atrial fibrillation.28-31 This could lead to dabigatran and rivaroxaban being
established as therapeutic alternatives to warfarin and becoming the new standard of care for a
wide range of indications, but without data being available on patients with thrombotic APS.
The RAPS trial will include patients who have thrombotic APS, with or without SLE, currently on
warfarin with a target INR 2.5 (range 2.0 - 3.0), who will be randomised to either continue on
warfarin or switch to rivaroxaban. Inclusion of patients with and without SLE is appropriate for the
following reasons:
a) Many patients with ‘primary’ thrombotic APS have clinical features such as joint pain which in
effect makes some of these patients ‘lupus like’.
b) Our findings in ‘primary’ thrombotic APS will be applicable to all APS patients, i.e. with or without
SLE. Of note here, we have previously established that there is no difference in the risk of recurrent
thrombosis between patients with SLE- and non-SLE associated thrombotic APS.32
c) No difference in the effect of rivaroxaban would be expected between patients with SLEassociated thrombotic APS or thrombotic APS alone. The randomisation will be stratified by site and
also by patient type (SLE/non-SLE), to ensure a balance of patients in each arm for each site and
patient type.
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1.2
WHAT EVIDENCE IS ALREADY AVAILABLE TO SUPPORT THE INTERVENTION
Rivaroxaban and dabigatran etexilate are both fixed-dose orally administered agents which exert
their anticoagulant effects within hours rather than days and, due to their predictable
pharmacokinetics, do not require routine laboratory monitoring with coagulation tests. Following
phase III international multisite trials in a total of about 21,500 patients, they were licensed in the
UK and Europe for the prevention of VTE in adults undergoing elective total hip replacement or knee
replacement;19-25 and in 2011, following phase III trials in over 44,000 patients, they were licenced as
detailed in section 1.1.28-31
The phase III clinical trials using therapeutic fixed-dose rivaroxaban or dabigatran for medium and
long-term indications suggest that they could offer an attractive alternative to warfarin in patients
with thrombotic APS. The EINSTEIN-DVT international multisite randomised trial in 3,449 patients,
which was open label, assigned patients with acute symptomatic DVT to either around 5 days of
subcutaneous (SC) low molecular weight heparin (LMWH) followed by a VKA (warfarin or
acenocoumarol) to maintain an INR of 2.0-3.0, or rivaroxaban given as 15 mg twice daily for the first
three weeks followed by 20 mg daily. The primary efficacy outcome, the rate of first symptomatic
VTE events, was similar in both groups, occurring in 2.1% of those on rivaroxaban compared with 3%
of those on VKA. The safety profiles with the two regimens were also similar, a composite of major
and other clinically relevant bleeding events being 8.1% in both treatment groups. In a parallel
randomised double-blind, placebo-controlled, superiority trial (the EINSTEIN-Extension study
published together with the Einstein-DVT trial in December 2010) in 1,196 patients, rivaroxaban
20mg daily for a duration of 6-12 months after completion of 6-12 months treatment with VKAs
following acute VTE, was associated with a significantly lower rate of recurrent events (1.3% vs.
7.1%). Major bleeds were not significantly different between the rivaroxaban and placebo arms
although there were more minor bleeds with rivaroxaban (5.4% vs. 1.2%).29 In a randomized, openlabel, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic PE with
or DVT, rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) was compared
with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6,
or 12 months. Rivaroxaban was noninferior to standard therapy for the primary efficacy outcome of
symptomatic recurrent VTE, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the
standard-therapy group (1.8%). The principal safety outcome, major or clinically relevant nonmajor
bleeding, occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standardtherapy group. Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52
patients (2.2%) in the standard-therapy group (P=0.003). Rates of other adverse events were similar
in the two groups.33
In an international multisite randomised, double blind, non-inferiority trial in 1,274 patients with
acute VTE (the RE-COVER trial) initially given parenteral anticoagulation with subcutaneous (SC)
LMWH for 9 days, and oral dabigatran 150 mg twice daily versus warfarin to achieve a target INR of
2.5, the primary efficacy outcome, the six month incidence rate of recurrent symptomatic,
objectively confirmed VTE and related deaths, was similar (2.4% and 2.1% respectively).28 The safety
profile of dabigatran, including with regard to bleeding events, was similar to that of warfarin, with
major bleeding episodes in 1.6% of patients assigned to dabigatran and 1.9% of patients assigned to
warfarin. Other adverse effects, including acute coronary events, elevation of the alanine or
aspartate transaminase exceeding three times the upper limit of normal, did not differ significantly
in patients on dabigatran versus those on VKA. Patients on dabigatran in the RE-COVER trial had a
significantly higher incidence of dyspepsia, 3.1%, compared with 0.7% in patients on warfarin.28 This
may be explained by the increased acidity as a result of the tartaric acid core within dabigatran
capsules. The findings in the RE-COVER trial were confirmed in RECOVER II which included a larger
number of patients and more ethnic variability (with approximately 20% Asian patients).34
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In the international multisite RE-LY (Randomised Evaluation of Long-term Anticoagulation Therapy)
non-inferiority trial of the efficacy and safety of dabigatran versus warfarin, 18,113 patients with
atrial fibrillation were assigned to warfarin or dabigatran 110 or 150 mg twice daily. Dabigatran at
both doses was as efficacious as warfarin, however in patients on the higher dose of 150 mg twice
daily, dabigatran was associated with lower rates of stroke and systemic embolism but similar rates
of major haemorrhage, although the incidence of intracranial haemorrhage was significantly lower in
the dabigatran groups.30 A recent analysis of the efficacy and safety of dabigatran compared with
warfarin at different levels of INR control in this study showed that for all vascular events, nonhaemorrhagic events and mortality, the advantages of dabigatran were greater at sites with poor
INR control than those with good INR control35. These advantages of dabigatran therapy could be
particularly beneficial in patients with thrombotic APS. In the ROCKET AF trial, rivaroxaban was
demonstrated to be as efficacious as warfarin in the prevention of stroke and systemic embolisation
in patients with atrial fibrillation and was also associated with similar rates of major haemorrhage
but, as with dabigatran, significantly lower rates of intracranial haemorrhage compared with
warfarin.31
1.3
RESEARCH LEADING TO THE PROPOSED TRIAL
Systematic review of the literature has not identified any published studies of any of the new oral
anticoagulants in patients with thrombotic APS, with or without SLE; there are no trials in this area
registered on clinicaltrials.gov; and there are no other studies on-going, or, to the best of our
knowledge, planned. The new generation of oral anticoagulants are a major advance as, unlike
warfarin, they do not require regular monitoring, have no interactions with dietary constituents or
alcohol, and have few reported drug interactions which affect anticoagulant intensity. These agents
therefore would be expected to result in a major improvement in quality of life for patients. Among
patients with acute VTE, approximately 10% have APS, and therefore it is likely that patients with
APS were included in the study populations in the phase III clinical trials of rivaroxaban or dabigatran
versus VKA in patients with VTE. However, aPL status was not documented in these trials.28,29
The question arises as to whether specific clinical trials are required in patients with thrombotic APS.
Patients with APS inherently differ from other patients with VTE by virtue of their aPL, particularly LA
and anti-prothrombin antibodies, which are known to interfere with a number of haemostatic
mechanisms, and which could therefore modulate the actions of anticoagulants. VKAs exert their
anticoagulant action by inhibition of the vitamin K dependent post-translational gammacarboxylation of procoagulant factors II, VII, IX and X. However, VKAs also reduce the activity of the
major naturally occurring anticoagulant protein C/S system (both protein C and S are vitamin K
dependent), which counterbalances the anticoagulant effects of VKAs. aPL not infrequently induce
reduced protein C and S activity ex vivo36,37 which could increase this counterbalancing effect, and
thus potentially shift the equilibrium further away from anticoagulation. An activated protein C
(APC) resistant phenotype in the absence of factor V Leiden, demonstrated in a thrombin
generation-based test, is seen in individuals with APS exhibiting LA, with a history of thrombotic
events in these patients associated with a stronger resistance to the anticoagulant effects of APC.38
Rivaroxaban and dabigatran have very specific targets (factor Xa and the active site of thrombin
respectively)17,18 and would not be expected to directly influence protein C and S activity. As a result,
these new oral anticoagulants may have greater anticoagulant efficacy than warfarin in patients with
APS. It is possible that aPL could directly interfere with the anticoagulant action of rivaroxaban or
dabigatran, although this is unlikely as rivaroxaban and dabigatran are both small molecules with
high affinity for their specific targets. The available phase III clinical trials of rivaroxaban or
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dabigatran compared with VKA in the treatment of acute VTE may therefore not be applicable to
patients with thrombotic APS where there remains an unmet need.28,29,34,39 Clinical trials are
therefore needed to establish whether or not the new oral anticoagulants should become the
standard of care for the treatment of these patients.
Thrombin is a pivotal component of the haemostatic mechanism, with increased ex vivo thrombin
generation a key marker of thrombogenic potential with predictive value for the development of
recurrent VTE.40,41 Generation of thrombin via the tissue factor (TF) pathway is integral to the blood
coagulation process, and thus, assessment of TF-triggered thrombin generation provides a useful
means of studying the inhibitory actions of antithrombotic agents.42,43 The Thrombin Generation
Test (TGT) provides information about the dynamics of ex vivo thrombin generation, with the
thrombin generation curve described in terms of: the lag-time; the time to peak; peak thrombin
concentration; and the area under the thrombin generation curve, known also as the Endogenous
Thrombin Potential (ETP).43 Markers of in vivo coagulation activation, prothrombin fragment 1.2
(F1.2), thrombin-antithrombin complex (TAT) and D-dimer (a marker of activation of fibrinolysis
secondary to coagulation activation), also provide information about an individual's thrombogenic
potential,41,44-49 and anticoagulation reduces the levels of these markers.44 F1.2, as the activation
peptide originating from the factor Xa-mediated activation of prothrombin, is a sensitive marker of
anticoagulation intensity.50,51 Warfarin (in non-APS patients) at a target INR of 2.5 (range 2-3) has
been shown to reduce the ETP by 30%-50% compared with the pre-warfarin result52 or normal
controls.53 After activation of the TF pathway in healthy subjects, nanomolar concentrations of
rivaroxaban significantly prolonged the initiation phase of thrombin generation and significantly
reduced the rate of propagation of the thrombin phase. These effects led to a reduction in the total
amount of thrombin generated and to a decrease in ETP.54 LMWHs have an indirect inhibitory effect
on thrombin generation via the physiological anticoagulant antithrombin.55 In hip/knee replacement
surgery, where there is an increase in thrombin generation, we have demonstrated that rivaroxaban
inhibits thrombin generation more than does the LMWH dalteparin at 24 hours after surgery.56 The
TGT, as a global measure of anticoagulation, can assess the anticoagulant effects of both rivaroxaban
and warfarin (drugs with very different modes of action on the coagulation mechanisms). We and
others have established that the ETP, a key parameter of the TGT, is an appropriate measure of the
intensity of the anticoagulant effect in individuals on rivaroxaban.56,57
1.4
INVESTIGATIONAL MEDICINAL PRODUCT (IMP)
Warfarin (generic) used as per standard care – the comparator
Rivaroxaban as 20mg and 15mg film-coated tablets
1.5
RATIONALE & OBJECTIVES OF THE STUDY
RATIONALE
Approximately 10% of patients with acute VTE have APS, however, the presence of APS was not
documented in the phase III trials of the new oral anticoagulants in patients with acute VTE. We are
therefore keen to take advantage of what we strongly believe is a limited time-window to study the
effects of these new drugs in patients with thrombotic APS in a controlled and optimal fashion. If we
do not do the appropriate trial now, these drugs will be introduced piecemeal, and the situation is
very likely to end up unsatisfactory both from a clinical and scientific viewpoint.
Utilization of the window of opportunity that we now have to demonstrate a) non-inferiority in the
intensity of the anticoagulant effect of rivaroxaban compared with that of warfarin in the TGT; and
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b) absence of safety signals, c) improved quality of life, would provide sufficient supporting data to
change practice for our patients, i.e. for rivaroxaban to become the standard of care for the
treatment of patients with thrombotic APS, with or without SLE.
OBJECTIVES
We plan to compare the anticoagulant effect of the new fixed-dose anticoagulant drug rivaroxaban
with that of warfarin in patients with thrombotic APS, with or without SLE. We will do this by
assessment of the TGT, which as a global measure of anticoagulation can assess the anticoagulant
effects of both rivaroxaban and warfarin (drugs with very different modes of action on the
coagulation mechanisms). We and others have established that the ETP which is the area under the
thrombin generation curve, a key parameter of the TGT, is an appropriate measure in individuals on
rivaroxaban.56,57 We will also compare rates of bleeding and recurrent thrombosis, and compare
quality of life in patients on rivaroxaban with those on warfarin.
Primary aim
The primary aim is to demonstrate that the intensity of anticoagulation achieved with rivaroxaban is
not inferior to that of warfarin, by measurement of the dynamics of ex vivo thrombin generation
using the TGT with the ETP as the key parameter, in patients with thrombotic APS with or without
SLE.
Secondary aims
a) To compare efficacy outcomes defined as:
i) recurrent VTE alone, and
ii) a composite of recurrent VTE and other thrombotic events in patients on
rivaroxaban versus those on warfarin;
iii) The thrombin generation curve will also be quantified in terms of: the lag-time;
the time to peak; and peak thrombin concentration;
iv) markers of in vivo coagulation activation: prothrombin fragment 1.2, thrombinantithrombin complex and D-dimer.
b) To compare serious adverse events and all bleeding events in patients on rivaroxaban
versus those on warfarin;
c) To compare quality of life (QoL) outcomes in patients on rivaroxaban versus those on
warfarin.
d) To assess compliance, concurrent with the TGT, an anti-Xa assay for rivaroxaban will be
performed in patients on rivaroxaban and a factor X amidolytic assay will be performed in
patients on warfarin as an antiphospholipid antibody-independent assessment of
anticoagulation.58,59 Percentage time in therapeutic range (TTR) between baseline and day
180 will be calculated in patients on warfarin.60
aPL status at baseline
aPL (lupus anticoagulant, IgG and IgM anticardiolipin and anti beta 2 glycoprotein 1 antibodies) will
be assessed at baseline in all patients using established methods16,61-65, to define the aPL status of
the patient population at the time of trial entry.
The primary outcome measure will be assessed after six weeks, but the total treatment duration will
be six months for the following reasons:
a) It will take a number of weeks to re-establish patients on warfarin, and during this period they
would require even more frequent INR monitoring, which we feel would be clinically unreasonable if
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they had only received treatment for a brief period of six weeks.
b) Six months of treatment should be long enough to identify any impact on the quality of life of
patients randomised to rivaroxaban, as routine anticoagulation clinic visits for INR monitoring will no
longer be required.
c) A six month treatment duration will provide more opportunity to identify any clinical safety signals
of rivaroxaban treatment.
1.6
HYPOTHESIS TO BE TESTED
The RAPS trial is designed as a non-inferiority trial, to demonstrate that the intensity of
anticoagulation in patients on rivaroxaban is not inferior to that obtained with warfarin as assessed
by the ETP, with the non-inferiority margin based on the inter site assay variability of test
performance and on clinical relevance.
Clinically, our hypothesis is that in patients with thrombotic APS, with or without SLE, rivaroxaban
can induce more predictable anticoagulation and therefore a greater sustained reduction in
thrombin generation than would warfarin, with additional benefits to patients because of the lack of
requirement for frequent laboratory monitoring of anticoagulation. The TGT is a global measure of
anticoagulation which can assess the anticoagulant effects of both rivaroxaban and warfarin (drugs
with very different modes of action on the coagulation mechanisms). The ETP is a key parameter of
the TGT which we and others have established to be an appropriate measure in individuals on
rivaroxaban.56,57
The primary outcome measure is the percentage change in ETP from randomisation to Day 42. The
time point of Day 42 (first trial visit post-randomisation), was chosen as the therapeutic effect of
rivaroxaban would be expected to be stable after 30 days of rivaroxaban therapy and would not be
influenced by any residual warfarin, based on the biological half-lives of the vitamin K-dependent
coagulation factors which range from 2-5 hours (factor VII) up to 72 hours (factor II).66
We also hypothesize that the percentage change from baseline in ETP could be lower (i.e. a greater
anticoagulant effect) in the rivaroxaban group compared with the warfarin group in patients with
thrombotic APS because:
i) Rivaroxaban will be prescribed as a fixed-dose with a predictable anticoagulant effect, which does
not require monitoring; conversely, warfarin displays an inherent variability of anticoagulant effect;
ii) Rivaroxaban has a specific target (factor Xa) and, unlike warfarin, should not directly influence
protein C and S activity and therefore may have greater anticoagulant efficacy in patients with
thrombotic APS than warfarin; and
iii) It is unlikely that aPL would interfere with the anticoagulant action of rivaroxaban as it is a small
molecule with a high affinity for its specific target; conversely, in patients on warfarin, because aPL
can induce reduced protein C and S activity, the equilibrium can be shifted further away from
anticoagulation.
If we can demonstrate i) that the anticoagulant effect of rivaroxaban is not inferior to that of
warfarin using the TGT; and ii) absence of any adverse effects that cause concern with regard to the
use of rivaroxaban, we believe that this would provide sufficient supporting information to change
practice for our patients, i.e. to make rivaroxaban the standard of care for the treatment of patients
with thrombotic APS, with or without SLE.
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1.7
RISKS AND BENEFITS
Rivaroxaban was licensed in the UK and Europe for VTE thromboprophylaxis in major lower limb
orthopaedic surgery in 2008, and was subsequently approved by NICE for this indication.27 The Phase
III trials of rivaroxaban in patients with VTE and atrial fibrillation showed an acceptable side effect
profile for rivaroxaban.29,31,33 In an orthopaedic study of 26 patients at UCLH/UCL receiving extended
duration prophylactic dose rivaroxaban (10 mg daily) for up to six weeks, no patient experienced any
problems with rivaroxaban.67
Benefits
1) Warfarin has an erratic anticoagulant effect in patients with APS who therefore require frequent
blood tests for INR monitoring. These blood tests are inconvenient for patients and reduce their
quality of life. Rivaroxaban is given as fixed-dose tablets once daily and, unlike warfarin, does not
require monitoring because it has a predictable anticoagulant effect.
2) Warfarin has numerous interactions with other drugs and dietary constituents and interacts with
alcohol, which interferes with the anticoagulant effect of warfarin and can result in over- or
under-anticoagulation with the potential for bleeding or thrombotic events respectively. These
interactions also necessitate more frequent INR monitoring. In contrast to warfarin, rivaroxaban
has no reported interactions with food or alcohol and has few drug interactions, and is therefore
potentially safer and also more convenient for the patient, which would be expected to improve
quality of life.
3) Although the new oral anticoagulants have not been specifically trialled in thrombotic APS
patients, they have been widely used in large multinational Phase III trials for the prophylaxis
and treatment of DVT and PE, the prevention of stroke in patients with atrial fibrillation, and for
acute coronary syndrome. To date we estimate that over 100,000 patients with these conditions
have been assessed and no major safety issues have emerged.
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Risks of rivaroxaban and actions to be taken to minimise and manage these risks
1) All patients randomised to rivaroxaban will be given a Patient Information Sheet (PIS) about
rivaroxaban and will be given opportunities at trial visits to discuss any specific issues pertaining
to this.
2) All patients randomised will be given a Patient Card with contact details for the Research Nurse
and the investigators for advice both in and out of hours and when the Research Nurse is on
leave.
3) The trial visit schedule (detailed in section 6.1) will enable face-to-face contact with patients to
discuss any concerns. Patients will be advised to contact the Research Nurse to report any
concerns about the treatment between trial visits.
4) The management of warfarin reversal for routine or emergency procedures will be according to
the hospital’s local guidelines based on national guidelines11 for bridging
anticoagulation/emergency reversal. Patients on rivaroxaban will be supplied with the contact
telephone number for a healthcare professional to use to gain information about what to do
about rivaroxaban in the event of routine or emergency procedures. Clinical advice, based on a
mutually agreed guideline, will also be available from the trial investigators.
5) All patients who experience bleeding should seek medical attention as per advice given by their
local anticoagulation clinic. Patients should report to hospital immediately in the event of severe
or persistent bleeding, and contact their trial site immediately.
6) Patients randomised to warfarin who experience bleeding will be managed according to the
hospital’s local guidelines based on national guidelines11.
7) Patients randomised to rivaroxaban will be supplied with the contact telephone number for a
healthcare professional to use to gain information on what to do about rivaroxaban in the event
of bleeding, based on the site and severity of the bleed. They should be managed according to
the hospital’s local guidelines in line with the manufacturer’s Summary of Product
Characteristics (SPC). Clinical advice, based on local practice, will also be available from the trial
investigators.
8) Patients who experience symptoms suggestive of recurrent thrombosis, VTE or arterial, will be
asked to attend hospital and also to contact their trial site immediately. In patients on
rivaroxaban, the rivaroxaban may be stopped based on clinical judgement. If the rivaroxaban is
stopped the patient will be commenced initially on therapeutic dose subcutaneous LMWH with
warfarin restarted to achieve a higher target INR range of 3.5 (3.0-4.0)11, and with overlap
between LMWH and warfarin until the INR is in the target range. A similar approach will be
undertaken in patients on warfarin. Recommencement of rivaroxaban will be considered if
clinically appropriate.
9) Patients will be asked to contact their trial site immediately about any serious adverse events
(SAEs).
10) We will undertake pregnancy tests in all women of childbearing age (pre-menopausal) prior to
entry to the trial and at three and six months for both treatment arms and women will be
strongly advised to avoid pregnancy in the PIS. Warfarin is teratogenic, particularly if
administered between weeks six and 12 of gestation, and therefore all women of childbearing
age are routinely counselled and given advice on obtaining effective contraception when
warfarin is commenced, and also advised to contact their trial site staff as soon as possible in the
event of pregnancy so that the warfarin can be switched to LMWH (which does not cross the
placenta). Although there are no adequate data on the risks of rivaroxaban in pregnant women,
studies in animals have shown that rivaroxaban crosses the placenta and is linked with
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reproductive toxicity. It is also secreted into animal milk.18 Therefore, the use of rivaroxaban in
pregnancy and breast feeding is contraindicated. Women of childbearing age randomised to
rivaroxaban will also be given advice on obtaining effective contraception when rivaroxaban is
commenced, and advised, should they unexpectedly conceive on rivaroxaban, to contact their
trial site staff as soon as possible so that early review by a haematologist and obstetrician, to
discuss the potential implications in pregnancy, can be organised.
11) As the patients will be self-dosing it is only possible to reduce the risk of overdose. Patients will
be informed of the correct dose of the drug at trial entry and their GP will be informed, in all
cases, that they are on the trial. The correct dose is also stated on the patient information
sheet, which the patient keeps, and the patient card. In the event of an overdose the use of
activated charcoal to reduce absorption may be considered, for both warfarin and rivaroxaban.
Bleeding in patients on warfarin as a result of overdose will be managed according to the
hospital’s local guidelines based on national guidelines.11 Bleeding in patients on rivaroxaban as
a result of overdose will be managed according to the hospital’s local practice in line with the
manufacturer’s SPC. Clinical advice, based on local practice, will also be available from the trial
investigators.
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2
SELECTION OF SITES/CLINICIANS
The trial sponsor has overall responsibility for site and investigator selection and has delegated this
activity to UCL CTU.
2.1
SITE/INVESTIGATOR ELIGIBILITY CRITERIA
Once a site has been identified as satisfying the eligibility criteria, the trial team will provide the site
with a copy of this protocol, a trial summary and the SPC.
To participate in the RAPS trial, investigators and clinical trial sites must fulfil a set of basic criteria
that have been agreed by the RAPS Trial Management Group (TMG) and are defined below.
Sites where a previous serious protocol breach has occurred will be visited, thoroughly reviewed,
and staff retrained before allowing further participants to enter the trial.
Those sites that meet the criteria will be issued with the RAPS master file documentation for their
Site-specific assessment (SSA) and UCL CTU site assessment documents. Sites must complete the
RAPS site assessment documents (Section 2.1.3) at the same time as applying for their SSA.
2.1.1 PI'S QUALIFICATIONS & AGREEMENTS
1. The investigators should be qualified by education, training, and experience to assume
responsibility for the proper conduct of the trial at their site and should provide evidence of
such qualifications through an up-to-date curriculum vitae and/or other relevant
documentation requested by the Sponsor, the REC and/or the regulatory authority.
2. The investigator should be thoroughly familiar with the appropriate use of the
investigational product, as described in the protocol, in the current SPC, in the product
information and in other information sources provided by the Sponsor.
3. The investigator should be aware of, and should comply with, the principles of GCP as given
in the protocol compliance statement and the applicable regulatory requirements. A record
of GCP training should be accessible for all investigators.
4. The investigator/site should permit monitoring and auditing by the Sponsor, and inspection
by the appropriate regulatory authority.
5. The investigator should maintain a delegation log of appropriately-qualified persons to
whom the investigator has delegated significant trial-related duties.
6. The investigator should sign a site agreement, which verifies that the site is willing and able
to comply with the requirements of the trial.
2.1.2 ADEQUATE RESOURCES
1. The investigator should be able to demonstrate the potential for recruiting the required
number of suitable patients within the agreed recruitment period (that is, the investigator
regularly treats the target population).
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2. The investigator should have sufficient time to properly conduct and complete the trial
within the agreed trial period.
3. The investigator should have available an adequate number of qualified staff and adequate
facilities for the foreseen duration of the trial to conduct the trial properly and safely.
4. The investigator should ensure that all persons assisting with the trial are adequately
informed about the protocol, the investigational product, and their trial-related duties and
functions.
5. The site should have sufficient data management resources to allow prompt data return to
the UCL CTU. Sites that have previously participated in UCL CTU-coordinated trials should
have a proven track record of good data return.
2.1.3 SITE ASSESSMENT
Each selected clinical trial site must complete the RAPS site assessment process which includes
completing the Site agreement, Signature and Delegation of Responsibilities Log, and staff contact
details. The Site agreement confirms that the site is willing, and able to comply with the
requirements of the trial. This will be signed by the Principal Investigator (PI) at the site. In addition
and in compliance with the principles of GCP, all site staff participating in the trial must complete the
Signature and Delegation of Responsibilities Log and forward this to the UCL CTU. The UCL CTU must
be notified of any changes to trial personnel and/or their responsibilities. An up-to-date copy of this
log must be stored in the Investigator Site File (ISF) at the site and Trial Master File (TMF) at the UCL
CTU.
2.2
APPROVAL AND ACTIVATION
The Clinical Trial Authorisation (CTA) for the trial requires that the Medicines and Healthcare
products Regulatory Agency (MHRA) is supplied with the names and addresses of all participating
site Principal Investigators. Trial staff at the UCL CTU will perform this task; hence it is vital to receive
full contact details for all investigators prior to their entering patients.
On receipt of the above documents, UCL CTU will send written confirmation to the PI. The trial
manager or delegate will notify the PI in writing of the plans for site initiation.
1. The site should conduct the trial in compliance with the protocol as agreed by the Sponsor
and by the regulatory authority and which was given favourable opinion by the REC.
2. The PI or delegate should document and explain any deviation from the approved protocol,
and communicate this with the trial team at the UCL CTU.
A list of activated sites may be obtained from the Trial Manager.
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3
SELECTION OF PATIENTS
There will be NO EXCEPTIONS (waivers) to eligibility requirements at the time of randomisation.
Questions about eligibility criteria should be addressed PRIOR to attempting to randomise the
participant.
The eligibility criteria for this trial have been carefully considered and are the standards used to
ensure that only medically appropriate patients are entered. Patients not meeting the criteria
should not join the study for their safety and to ensure that the study results can be used to make
treatment decisions for other patients with similar diseases. It is therefore important that no
exceptions be made to these eligibility criteria.
Participants will be considered eligible for enrolment in this trial if they fulfil all the inclusion criteria
and none of the exclusion criteria as defined below.
3.1
PATIENT INCLUSION CRITERIA
1) Patients with thrombotic APS68, with or without SLE, who have had either a single episode of VTE
whilst not on anticoagulation or recurrent episode(s) which occurred whilst off anticoagulation or on
sub-therapeutic anticoagulant therapy
2) Patients with a target INR of 2.5 (range 2.0 – 3.0)
3) Treated with warfarin for a minimum period of three months since last VTE
4) Female patients must be using adequate contraception with the exception of postmenopausal or
sterilised women
3.2
PATIENT EXCLUSION CRITERIA
1) Previous arterial thrombotic events due to APS
2) Recurrent venous thromboembolic events whilst on warfarin at a therapeutic INR of 2.0 – 3.0
3) Pregnant or lactating women
4) Severe renal impairment (creatinine clearance (calculated using the Cockcroft & Gault formula
(Appendix A)) < 30 mL/min (i.e. 29 mL/min or less)
5) Liver function tests ALT > 2 x ULN
6) Cirrhotic patients with Child Pugh B or C
7) Thrombocytopenia (platelets < 75 x 109/L)
8) Non-compliance on warfarin (based on clinical assessment)
9) Patients on azole antifungals (e.g. ketoconazole, itraconazole, voriconazole and posaconazole)
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10) Patients on Human Immunodeficiency Virus (HIV) protease inhibitors (e.g. ritonavir)
11) Patients on strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or
St. John's Wort)
12) Patients on dronedarone
13) Patients less than 18 years of age
14) Refusal to consent to the site informing GP and healthcare professional responsible for
anticoagulation care, of participation
3.3
NUMBER OF PATIENTS
A total of 116 patients will be randomised using random permuted blocks for treatment allocation
and to maintain balanced numbers in the two groups.
3.4
CO-ENROLMENT GUIDELINES
Co-enrolment in previous or future trials is considered in Section 4.3.
3.5
SCREENING PROCEDURES & PRE-RANDOMISATION INVESTIGATIONS
Written informed consent to enter the trial and be randomised must be obtained from each patient,
after explanation of the aims, methods, benefits and potential hazards of the trial and BEFORE any
trial-specific procedures are performed or any blood is taken for the trial.
It must be made completely and unambiguously clear that the patient is free to refuse to participate
in all or any aspect of the trial, at any time and for any reason, without incurring any penalty or
affecting their treatment.
Signed consent forms must be kept by the investigator and documented in the CRF and a copy given
to the patient. Upon consent, a letter should be sent to the general practitioner informing him/her
of the trial and the participant's involvement in it.
SCREENING
The patient must have the following pre-randomisation assessments. These must be done no more
than 30 days prior to randomisation (with exceptions: anti-DNA and aPL):
Consent
Medical history
Demographics
Patient review
Height
Weight
Body mass index (BMI)
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Blood pressure (BP)
Full blood count (FBC)
Urea and electrolytes (U&E) and creatinine clearance (CrCl) (to be calculated using the Cockcroft &
Gault formula (Appendix A))
Liver function tests (LFTs) to include ALT
+
Anti-DNA
++
aPL
International Normalised Ratio (INR)
Current medication
Enquiry for bleeding
Enquiry for recurrent thrombosis
The patient will also attend a routine specialist clinic visit at the time of screening.
+
Results of anti-DNA done routinely at the trial sites within three months of (prior to or at the time
of) the screening visit, with the date of testing, to be documented in the CRF (i.e. testing for antiDNA is not required within 30 days prior to randomisation).
++
All patients will have been diagnosed with thrombotic antiphospholipid syndrome (APS), prior to
trial entry. Results of antiphospholipid antibodies (aPL) establishing a diagnosis of thrombotic APS,
with the dates when the tests were performed routinely at the trial sites, to be documented in the
CRF (i.e. testing for aPL is not required within 30 days prior to randomisation). aPL will also be
assessed at baseline in all patients to define the aPL status of the patient population at the time of
trial entry.
Pre-randomisation (baseline) assessments – post patient consent
Pregnancy test
INR
Current medication documentation
Document INRs for the three month period prior to randomisation
Enquiry for bleeding
Enquiry for recurrent thrombosis
QoL assessment
Note: Repeat the following tests if the screening was more than 14 days prior to randomisation:
Full blood count (FBC)
Urea and electrolytes (U&E) and creatinine clearance (CrCl) (to be calculated using the Cockcroft &
Gault formula (Appendix A))
Liver function tests (LFTs) to include ALT
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4
4.1
REGULATION & RANDOMISATION
RANDOMISATION PRACTICALITIES
Randomisations should be done via the CTU randomisation website (details below). If there are any
difficulties in accessing this website they should call the number below. Further details on the
process of randomisation can be found in Section 9.1.
RANDOMISATIONS
To randomise access website: https://www.sealedenvelope.com/uclctu/
In case of difficulties call UCL CTU, Monday to Friday 09:00 to 17:00hrs:
Tel: 07823536715
A manual randomisation process will be set up to cover any instances when the main electronic
system is not working. This will be detailed in the trial Working Instructions.
4.2
RANDOMISATION CODES & UNBLINDING
Randomisation codes and unblinding are considered in Section 5.5.
4.3
CO-ENROLMENT GUIDELINES
No co-enrolment into interventional clinical trials is allowed in the RAPS trial during the period of
intervention. However, co-enrolment in another interventional trial is permissible two days (2 x
maximum half-life) after the last administration of the rivaroxaban.
There is no prohibition on co-enrolment into observational studies.
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5
TREATMENT OF PATIENTSINTRODUCTION
This is a pragmatic trial comparing the standard care for patients with thrombotic APS, which is
warfarin anticoagulation, with rivaroxaban, a new fixed-dose anticoagulant drug.
5.2
ARM A
This is the control arm where the treatment of patients with warfarin will remain unchanged.
Warfarin will be prescribed and dispensed in accordance with national guidance (NPSA Safer Practice
Notice 1869 and BCSH11) and warfarin anticoagulant monitoring will be undertaken by the patient’s
usual anticoagulation clinic, which may be based at one of the trial sites or locally to the patient,
either within a hospital or primary care anticoagulation clinic setting, or by patient self-monitoring
under medical supervision.
5.2.1 PRODUCTS
Warfarin
5.2.2 COMPLIANCE & ADHERENCE
Compliance with warfarin treatment schedule is assessed by a laboratory assay for the INR and
amidolytic factor X, which measure the anticoagulant effect of warfarin with the latter providing an
aPL-independent assessment of anticoagulation. Percentage time in therapeutic range (TTR)
between baseline and day 180 will also be calculated in patients on warfarin.
5.3
ARM B
Patients randomised to rivaroxaban may have an INR above the upper limit of the target therapeutic
range of 2.0 – 3.0 at the time of randomisation. These patients need to have an INR of ≤3 before
starting rivaroxaban (please see below for details).
5.3.1 PRODUCTS
Rivaroxaban 20mg and 15mg film-coated tablets
5.3.2 TREATMENT SCHEDULE
Patients without renal impairment (creatinine clearance ≥ 50 mL/min) should take one 20mg tablet
orally once daily in the morning, with food to maximise absorption, for six months18.
Patients with moderate renal impairment (creatinine clearance of 30 – 49 mL/min) will be prescribed
either one 20mg tablet or one 15mg tablet to be taken orally once daily in the morning, with food,
for six months depending on local clinical care and following the SPC. If the patient is prescribed
15mg and subsequent testing shows that the patient’s creatinine clearance is ≥50 mL/min, the
patient’s dose of rivaroxaban should generally be increased to one 20mg tablet once daily in the
morning depending on local clinical care and following the SPC.
5.3.3 DISPENSING
Dispensing will be in blister packs, with each pack containing 28 tablets. Sufficient packs of
rivaroxaban will be dispensed to the patient to ensure that they have sufficient tablets between the
scheduled assessment visits. For pragmatic reasons, as some patients live remote from the trial sites,
it may be necessary for the rivaroxaban to be dispensed to the patient with instructions to not start
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taking the tablets until their INR is ≤3 (please see below for details). This will mean that they will be
monitored by their local anticoagulant clinic until their INR is ≤3. In such cases the patient will
remain in daily telephone contact with the trial Research Nurse who will inform the patient when to
start taking the study drug.
Regimen for patients converting from warfarin to rivaroxaban:
 For patients randomised to rivaroxaban, the warfarin should be stopped on the day of
conversion from warfarin to rivaroxaban
 If the INR is ≤2.5, the rivaroxaban should be started the following morning
 If the INR is 2.6 to ≤3, the rivaroxaban should be started 2 days later in the morning
 If the INR is >3, the INR should be rechecked as required and the rivaroxaban should be
started, as a morning dose:
o when the INR is 2.6 to ≤3, the rivaroxaban should be started 2 days later in the
morning
o when the INR is ≤2.5, the rivaroxaban should be started the following morning
Note: when converting a patient from warfarin to rivaroxaban, the INR will be falsely elevated after
dosing. Therefore, the INR should not be used as a measure of anticoagulant activity of rivaroxaban.
5.3.4 DOSE MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS
Dose modifications are required for patients on rivaroxaban with renal impairment. With changes in
the creatinine clearance the following dose modification should be made:
 Creatinine clearance 30 – 49 mL/min, if the patient is on 20mg rivaroxaban once daily the
clinician should consider changing to 15mg as per local clinical care and following the SPC
 Creatinine clearance ≥50 mL/min, if the patient is on 15mg rivaroxaban once daily they
should be changed to 20mg rivaroxaban once daily
 Creatinine clearance of ≤29 mL/min, if the patient is on rivaroxaban they should be
converted to warfarin
It may be necessary to temporarily stop or interrupt treatment with rivaroxaban for patients who
have bleeding events or bridging anticoagulation for procedures (routine or emergency).
Supplementary information documents have been produced for these procedures. Copies of these
documents should be present in the trial site file.
Any bleeding event should be reported on the appropriate CRF and serious bleeding events should
also be reported on a SAE report, see section 7 for details.
If it is necessary to switch a patient from rivaroxaban to warfarin, this should be carried out
according to local clinical care and following the SPC.
Situations where the rivaroxaban should be discontinued are stated in section 5.6.
5.3.5 STOPPING DRUG EARLY
If a patient requires treatment with one of the drugs specified as not being permitted in section
5.10.2 it is recommended that the patient is taken off rivaroxaban and reverts back to warfarin
treatment.
5.3.6 ACCOUNTABILITY & UNUSED DRUGS/DEVICES
The dispensing pharmacist at the site will keep accountability logs of the number of tablets
prescribed and returned, and for the destruction of any returned rivaroxaban. At the end of the
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trial, unused rivaroxaban will either be destroyed or taken into general hospital stock, as agreed by
the drug provider and the MHRA.
5.3.7 COMPLIANCE & ADHERENCE
Compliance will be tested by a laboratory assay for anti-factor Xa, which measures the anticoagulant
effect of rivaroxaban.
5.4
OVERDOSE OF TRIAL MEDICATION
Full details on the effects of an overdose of rivaroxaban and the management of such an overdose
can be found under section 4.9 of the SPC for rivaroxaban.
5.5
UNBLINDING
This trial will not be blinded or masked. We believe that it would be potentially unsafe to do so for
the following reasons:
1) Uncertainty about the intensity of the anticoagulant effect of warfarin and increased instability of
the INR in patients with thrombotic APS on warfarin necessitates frequent anticoagulant monitoring
at variable time intervals which cannot be predetermined, therefore a regular trial schedule for
anticoagulant monitoring would not be expected to be effective.
2) In patients on warfarin, the INR result has to be acted upon promptly (within a few hours), with
computerized assisted dosing by an experienced individual who has access to the patient's previous
warfarin dosing history and thus, knowledge of the individual patient's sensitivity to changes in
warfarin dose. Dosing in a blinded fashion would be likely to result in suboptimal dosing
management decisions.
3) Should patients experience bleeding, it is important to know immediately whether they are on
warfarin or rivaroxaban as the management of bleeding differs.
5.6
PROTOCOL TREATMENT DISCONTINUATION
In consenting to the trial, patients are consenting to trial treatment, trial follow-up and data
collection. However, an individual patient may stop treatment early or be stopped early for any of
the following reasons:




Serious adverse events (SAE)
Thrombotic event*
Any change in the patient’s condition that justifies the discontinuation of treatment in
the clinician’s opinion
Withdrawal of consent for treatment by the patient
* Patients who experience symptoms suggestive of recurrent thrombosis, VTE or arterial, should be
managed as detailed in Section 1.7.
An individual must be stopped early for the following reasons:
 Unacceptable toxicity
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

Unacceptable SAE
Pregnancy
As the patient’s participation in the trial is entirely voluntary, they may choose to discontinue the
trial treatment at any time without penalty or loss of benefits to which they are otherwise entitled.
Although the patient is not required to give a reason for discontinuing their trial treatment, a
reasonable effort should be made to establish this reason while fully respecting the patient's rights.
Patients should remain in the trial for the purpose of follow-up and data analysis (unless the patient
withdraws their consent from all stages of the trial). If a patient is withdrawn from follow-up, refer
to Section 6.6.
Data will be kept and included for patients who stop follow-up early.
5.7
ACCOUNTABILITY & UNUSED DRUGS/DEVICES
Refer to section 5.3.5 for accountability of rivaroxaban.
5.8
COMPLIANCE & ADHERENCE
Refer to sections 5.2.2 for warfarin and 5.3.7 for rivaroxaban, for the respective processes for
assessing compliance and adherence.
5.9
TREATMENT DATA COLLECTION
Refer to the follow-up assessment schedule in section 6 assessments & follow-up.
5.10 NON-TRIAL TREATMENT
5.10.1 MEDICATIONS PERMITTED
All non-contraindicated medications that the investigator responsible for the patients care feels are
appropriate are permitted in the trial. Refer to sections 5.10.2 for medications not permitted and to
5.10.3 for medications to be used with caution.
5.10.2 MEDICATIONS NOT PERMITTED
The use of azole antifungals (such as ketoconazole, itraconazole, voriconazole and posaconazole)
and HIV protease inhibitors (such as ritonavir), which increase rivaroxaban levels, are not permitted,
while the patient is on the rivaroxaban. This is because these agents are all strong inhibitors of both
CYP3A4 and P-gp and concurrent use with rivaroxaban is not recommended due to the increased risk
of bleeding.18
The use of strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital or St.
John's Wort) may lead to reduced rivaroxaban plasma concentrations and are not permitted, while
the patient is on rivaroxaban.18
Avoid co-administration with dronedarone for patients on rivaroxaban.
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If it is in the interest of patient’s best care that these are prescribed, it is recommended that the
patient is taken off rivaroxaban and reverts to appropriate anticoagulation.
5.10.3 MEDICATIONS TO BE USED WITH CAUTION
Caution should be taken prescribing antiplatelet agents e.g. aspirin, clopidogrel and dipyridamole,
and also fluconazole, although their use during the trial is not prohibited. If fluconazole is required in
trial patients, which is unlikely, these patients are likely to be in hospital and will be closely
monitored.
Rivaroxaban should be used with caution in patients with renal impairment who are concomitantly
receiving other medicinal products, which increase rivaroxaban plasma concentrations (e.g.
clarithromycin, erythromycin, fluconazole. Refer to the SPC for further information and discuss with
the CI).
5.10.4 TREATMENT AFTER TRIAL EVENT
Treatment will be at the discretion of the responsible physician.
5.11 CO-ENROLMENT GUIDELINES
Co-enrolment in previous or future trials is considered in Section 4.3.
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6
ASSESSMENTS & FOLLOW-UP
All patients entered into this trial are under routine specialist long-term follow up and clinical
surveillance by the clinical co-applicants and collaborators at the trial sites, and this will continue
long-term after the trial has been completed
6.1
TRIAL ASSESSMENT SCHEDULE
The trial visit schedule will enable face-to-face contact with patients to discuss any concerns.
Patients will be advised to contact the Research Nurse to report any concerns about the treatment
between trial visits.
Routinely, patients with thrombotic APS and with thrombotic SLE are seen in clinic on average every
three months. Where possible, trial visits will be scheduled to coincide with routine follow up and
trial participation will entail approximately three additional hospital visits for each patient in this
trial.
Patients on warfarin require additional visits, which may be weekly, for monitoring of
anticoagulation (managed at either the trial site or locally). Unlike patients on warfarin, patients on
the new fixed-dose oral anticoagulants do not need routine anticoagulant monitoring because of the
predictable anticoagulant effect of these agents, and so patients on rivaroxaban will not need to
attend anticoagulation clinics during the trial period.
At each routine specialist clinic visit, routine clinical assessment will include assessment with regard
to potential effects relating to the efficacy and safety of anticoagulation: bleeding, recurrent
thrombosis (VTE or arterial) and SAEs. Samples for research laboratory investigations will be
obtained from routine blood draws at these routine specialist clinic visits where possible.
At each routine specialist clinic visit, patients will have routine laboratory assessment as clinically
indicated: full blood count (FBC), U&E, LFTs and INR/coagulation screen. aPL and anti-DNA are
checked every six to 12 months. Additional laboratory or other tests will be performed as clinically
indicated.
At the end of the trial treatment period of six months patients will be offered appropriate
anticoagulant care.
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Visit 0 (Baseline) - Post randomisation procedure
Blood collection
20 mL citrated blood for TGT, INR, amidolytic factor X and aPL
20 mL blood for the translational research (see section 10); this is optional and only
applicable to patients who have consented to this part of the trial. This sample will be
collected at the same time as the trial sample.
Visit 1 – Day 42 after randomisation (ideally -12 days +14 days). The patient must have been on
rivaroxaban for a minimum of 30 days before this visit.
Blood collection
20 mL of citrated blood for TGT and anti-Xa (rivaroxaban patients)/INR, amidolytic factor X
(warfarin patients). For patients on rivaroxaban the blood samples should preferably be
collected 2–4 hours after tablet intake when the maximum concentration (Cmax) of
rivaroxaban will be present.
20 mL blood for the translational research (section 10), this is optional and only applicable to
patients who have consented to this part of the trial. This sample will be collected at the
same time as the trial sample.
Documentation of medication
Document INRs since last trial visit
Drug accountability of rivaroxaban
Enquiry for bleeding
Enquiry for recurrent thrombosis
Visit 2 – Day 90 after randomisation (ideally ±14 days)*
Full blood count
U&E, LFTs
Pregnancy test
Documentation of medication
Document INRs since last trial visit
Drug accountability of rivaroxaban
Enquiry for bleeding
Enquiry for recurrent thrombosis
Visit 3 – Day 180 after randomisation (ideally ±14 days)* – end of trial treatment
Weight
Body mass index
Blood pressure
Full blood count - as clinically indicated
U&E, LFTs - as clinically indicated
Pregnancy test
Documentation of medication
Document INRs since last trial visit
Drug accountability of rivaroxaban
Enquiry for bleeding
Enquiry for recurrent thrombosis
Quality of life assessment
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Visit 4 – Day 210 after randomisation (ideally ±14 days) – 30 days after end of trial treatment
Documentation of medication
Enquiry for bleeding
Enquiry for recurrent thrombosis
*Note: Trial visits should be scheduled to coincide with routine specialist clinic visits where possible.
6.2
PROCEDURES FOR ASSESSING EFFICACY
The primary aim is to compare the thrombogenic potential, by measurement of the dynamics of ex
vivo thrombin generation using the TGT with the key parameter the ETP, the area under the
thrombin generation curve, which we and others have established to be an appropriate measure in
individuals on rivaroxaban.56,57 The primary outcome measure is the percentage change in the ETP
from randomisation to Day 42. The time point of Day 42 (first trial visit following randomisation),
was chosen as the therapeutic effect of rivaroxaban would be expected to be stable after 30 days of
treatment, and rivaroxaban treatment must begin within a maximum of 10 days from
randomisation. The ETP at Day 42 would not be influenced by any residual warfarin effect, based on
the biological half-lives of the vitamin K-dependent coagulation factors which range from two to five
hours (factor VII) up to 72 hours (factor II).66
The TGT will be performed using the Calibrated Automated Thrombogram (CAT) system
(Thrombinoscope BV, Maastricht, The Netherlands) as described by Hemker43. In order to reduce
intra-assay variation, paired samples for each patient will be tested at the same time. Despite the
wide application of TGT in thrombotic disorders, literature searches of peer-reviewed journals failed
to produce data relating to the assessment of thrombin generation in patients with APS on warfarin
or rivaroxaban. We and others have previously assessed thrombin generation in warfarinised
patients using a trigger reagent that gives a reaction concentration of 5 pmol/L tissue factor and 4
µmol/L phospholipids.70,71
Secondary laboratory outcome measures of efficacy are also being determined to provide a
comprehensive assessment of ex vivo thrombin generation and in vivo coagulation activation. The
thrombin generation curve will therefore also be quantified in terms of: the lag-time; the time to
peak; and peak thrombin concentration.43 In addition, markers of in vivo coagulation activation, F1.2,
TAT and D-dimer (a marker of activation of fibrinolysis secondary to coagulation activation), will
provide supplementary information about thrombogenic potential;41,44-49 and F1.2 will also provide
supplementary information about anticoagulation intensity.50,51
Symptoms suggestive of recurrent VTE will be evaluated according to the usual diagnostic methods
(see Glossary). All recurrent thrombotic events (VTE or arterial) should be reported immediately to
the trial site, and the trial investigators will advise on anticoagulant management as detailed in 1.7
(risks: point 7). Patients who present with symptoms suggestive of stroke, myocardial infarction or
arterial thrombosis at other sites, generally present as a clinical emergency and clinical and
diagnostic information will be obtained retrospectively from the site at which they have been
managed.
Clinical efficacy outcomes will be defined as:
(i)
recurrent VTE alone; and
(ii)
a composite of recurrent VTE and other thrombotic events.
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6.3
PROCEDURES FOR ASSESSING SAFETY
Results of liver function tests at 90 days and as clinically indicated and any other SAEs since the
previous visit will be routinely assessed at each follow up visit.
A bleeding event will be classified using established criteria as major if it is associated with a fall in
the haemoglobin level of at least 20 g/L, results in the need for a transfusion of two or more units of
red cells, involves a critical site, or is fatal.29,72 Less severe bleeding will be classified as clinically
relevant non-major bleeding29 and bleeds not falling in these categories will be classed as minor
bleeding.
6.4
PROCEDURES FOR ASSESSING QUALITY OF LIFE
QoL will be evaluated via the EQ 5D 5L questionnaire73 in all patients at baseline (time of
randomisation) and at visit three (180 days post randomisation after completion of the six months
trial treatment period). Patients with thrombotic APS on warfarin require frequent INR monitoring
blood tests, which may be weekly, to monitor the anticoagulant effect of warfarin. In contrast,
patients on the new fixed-dose oral anticoagulant rivaroxaban do not need anticoagulant monitoring
because of its predictable anticoagulant effect, and so patients randomised to switch to rivaroxaban
will not need to attend anticoagulation clinics during the trial period. We anticipate that the
reduction in the need for frequent anticoagulant monitoring will have a major impact on the quality
of life of patients randomised to rivaroxaban. We recognise that the EQ 5D 5L with five dimensions
each with five levels and visual analogue score is not an ideal instrument to assess QoL in patients on
this trial. However, there is no other validated questionnaire for this situation, and we believe that
the EQ 5D 5L might pick up differences, particularly in the question on ‘usual activities’ and the visual
analogue score.
6.5
OTHER ASSESSMENTS
An anti-Xa assay (to assess compliance) in patients on rivaroxaban at Day 42 , and an INR and factor
X amidolytic assay as an antiphospholipid antibody-independent assessment of anticoagulation in
patients on warfarin at baseline and at Day 42, will be performed by established methods.58,59 The
percentage time in therapeutic range (TTR) in patients on warfarin will be calculated using the
method described by Rosendaal et al.60
6.6
EARLY STOPPING OF FOLLOW-UP
If a patient chooses to discontinue their trial treatment, they should be encouraged not to leave the
whole trial and to continue with their visit schedule as planned. Where possible the patient should
be encouraged to attend all their visits, but if that is not possible they should be encouraged to
attend at least the 42 day and 180 day visits as these are the most important. If they do not wish to
remain on trial follow-up, however, their decision must be respected and the patient may ask to be
withdrawn from the trial completely. The UCL CTU should be informed of this in writing using the
appropriate documentation. Patients stopping early have a negative impact on a trial's conclusions.
If the medical data collected during the patient’s participation in the trial are kept for research and
analysis purposes, they can be anonymised if necessary. Consent for future use of stored samples
already collected can be refused when leaving the trial early (but this should be discouraged and
should follow a discussion).
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Patients may change their minds about stopping trial follow-up at any time and re-consent to
participation in the trial.
Patients who stop trial follow-up early will not be replaced.
6.7
PATIENT TRANSFERS
If a patient moves from the area, every effort should be made for the patient to be seen at another
participating trial site. With the patient’s consent a copy of the patient’s CRFs should be provided to
the new site and the patient will need to sign a new consent form. Once this has been done, the new
site will take over responsibility for the patient; until this has been done, responsibility for the
patient lies with the original site.
6.8
LOSS TO FOLLOW-UP
In the EINSTEIN Phase III open-label, randomised, non-inferiority study that compared oral
rivaroxaban with warfarin in patients with acute DVT, premature discontinuation of treatment
occurred in 11.3% of patients in the rivaroxaban arm and 14.2% in the warfarin arm. The reasons for
this were: adverse events 4.3% and 3.9%; consent withdrawn 2.0% and 3.9%; and 0.9% and 1.0% of
patients were lost to follow up in the rivaroxaban and warfarin arms respectively. In patients who
were continued on rivaroxaban, versus placebo, beyond the initial treatment period, premature
discontinuation of rivaroxaban occurred in 12.6%, with the reasons: adverse events in 6.5%, consent
withdrawn in 3.7% and 1.0% were lost to follow up29. Based on our experience with the first 84
patients recruited, 2 patients have been lost to follow-up or withdrawn before the first trial visit post
randomisation and a pair of ETP values has not been obtained in 5 patients, we conservatively allow
for 12% non evaluable patients.
It is expected that the loss to follow-up in RAPS trial, due to patients withdrawing consent, will be
less than in the EINSTEIN trial. In the EINSTEIN trial patients were recruited post thrombotic event
and were not routinely being followed up at the sites, whereas the RAPS patient population are
routinely seen by the sites on a regular basis and therefore know the clinicians and nurses who will
care for them in the trial.
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7
SAFETY REPORTING
Investigators and sponsors are required to follow specific procedures when notifying and reporting
adverse events or reactions in clinical trials. These procedures are described in this section of the
protocol. Section 7.1 lists definitions, Section 7.2 gives details of the investigator responsibilities and
Section 7.3 provides information on ProductLife Ltd responsibilities who have been contracted by
the UCL CTU to undertake the clinical safety and pharmacovigilance aspect of the RAPS trial.
7.1
DEFINITIONS
The definitions of the EU Directive 2001/20/EC Article 2 based on ICH GCP apply to this trial
protocol. These definitions are given in Table 7.1.
TABLE 7.1: DEFINITIONS
TABLE
DEFINITION
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical trial
subject to whom a medicinal product has been administered
including occurrences that are not necessarily caused by or
related to that product.
Adverse Reaction (AR)
Any untoward and unintended response to an investigational
medicinal product related to any dose administered.
Unexpected Adverse Reaction (UAR)
An adverse reaction, the nature or severity of which is not
consistent with the information about the medicinal product
in question set out in the Summary of Product Characteristics
(SPC) or Investigator Brochure (IB) for that product.
Serious Adverse Event (SAE) or Serious
Adverse Reaction (SAR) or Suspected
Unexpected Serious Adverse Reaction
(SUSAR)
Respectively any adverse event, adverse reaction or
unexpected adverse reaction that:
 Results in death
 Is life-threatening*
 Requires hospitalisation or prolongation of existing
 hospitalisation**
 Results in persistent or significant disability or
incapacity
 Consists of a congenital anomaly or birth defect
 Is another important medical condition***
*The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient is at risk of
death at the time of the event; it does not refer to an event that hypothetically might cause death if it
were more severe, for example, a silent myocardial infarction.
**Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the
hospitalisation is a precautionary measure for continued observation. Hospitalisations for a pre-existing
condition (including elective procedures that have not worsened) do not constitute an SAE.
*** Medical judgement should be exercised in deciding whether an AE or AR is serious in other situations.
The following should also be considered serious: important AEs or ARs that are not immediately lifethreatening or do not result in death or hospitalisation but may jeopardise the subject or may require
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intervention to prevent one of the other outcomes listed in the definition above; for example, a
secondary malignancy, an allergic bronchospasm requiring intensive emergency treatment, seizures or
blood dyscrasias that do not result in hospitalisation or development of drug dependency.
An investigational medicinal product is defined as the tested investigational medicinal product and
the comparators used in the study. (EU guidance ENTR/CT 3, April 2006 revision).
ADVERSE REACTIONS
Adverse reactions include any untoward and unintended response to drugs.
GUIDANCE FOR ADVERSE EVENT INCLUSIONS & EXCLUSIONS
Adverse Events Include:
 An exacerbation of a pre-existing illness
 An increase in frequency or intensity of a pre-existing episodic event or condition
 A condition (even though it may have been present prior to the start of the trial) detected
after trial drug administration
 Continuous persistent disease or a symptom present at baseline that worsens following
administration of the study treatment
Adverse Events Do Not Include:
 Medical or surgical procedures; the condition that leads to the procedure is the adverse
event
 Pre-existing disease or a condition present before treatment that does not worsen
 Hospitalisations where no untoward or unintended response has occurred, e.g. elective
cosmetic surgery, social admissions
 Overdose of medication without signs or symptoms
DISEASE-RELATED EVENTS
Due to the systemic nature of SLE, events can occur in any system. Events related to SLE can range
from a skin rash to joint pain, headaches, fever etc. APS in the absence of SLE is also associated with
a variety of clinical manifestations affecting various systems.
Adverse events (with the exception of bleeding, thrombotic events and adverse events due to lack of
drug effect) and adverse reactions do not need to be recorded for the RAPS trial.
7.2
INVESTIGATOR RESPONSIBILITIES
All SAEs and SARs should be notified to ProductLife Ltd within 24 hours of the investigator becoming
aware of the event.
7.2.1
INVESTIGATOR ASSESSMENT
Seriousness
When an AE or AR occurs, the investigator responsible for the care of the patient must first assess
whether or not the event is serious using the definition given in Table 7.1. If the event is serious,
then an SAE Form must be completed and ProductLife Ltd notified within 24 hours.
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Severity or Grading of Adverse Events
The severity of all SAEs and SARs in this trial should be graded using the CTCAE toxicity gradings
version 4.0. A copy of this grading system should be located in the ISF.
Causality
The investigator must assess the causality of all serious events or reactions in relation to the trial
therapy using the definitions in Table 7.2. There are five categories: unrelated, unlikely, possible,
probable, and definitely related. If the causality assessment is unrelated or unlikely to be related, the
event is classified as an SAE. If the causality is assessed as possible, probable or definitely related,
then the event is classified as an SAR.
TABLE 7.2: ASSIGNING TYPE OF SAE THROUGH CAUSALITY
RELATIONSHIP
DESCRIPTION
Event Type
Unrelated
There is no evidence of any causal relationship
Unrelated SAE
Unlikely
There is little evidence to suggest that there is a causal
Unrelated SAE
relationship (for example, the event did not occur within a
reasonable time after administration of the trial
medication). There is another reasonable explanation for
the event (for example, the patient’s clinical condition, other
concomitant treatment).
Possible
There is some evidence to suggest a causal relationship (for SAR
example, 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
(for example, the patient’s clinical condition, other
concomitant treatments).
Probable
There is evidence to suggest a causal relationship and the
influence of other factors is unlikely.
SAR
Definitely
There is clear evidence to suggest a causal relationship and
other possible contributing factors can be ruled out.
SAR
If an SAE is considered to be related to trial treatment and drug is stopped or the dose modified,
refer to Section 5.2.4.
Expectedness
If there is at least a possible involvement of the trial treatment (or comparator), the investigator
must assess the expectedness of the event. An unexpected serious adverse reaction is one not
previously reported in the current SPC or one that is more frequent or more severe than previously
reported. The definition of an unexpected adverse reaction (UAR) is given in Table 7.1. Please see
Appendix B for a list of expected toxicities associated with the drugs being used in this trial. If a SAR
is assessed as being unexpected, it becomes a SUSAR.
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Notification
ProductLife Ltd should be notified of all SAEs within 24 hours of the investigator becoming aware of
the event.
Investigators should notify ProductLife Ltd of all SAEs occurring from the time of randomisation until
30 days after the last protocol treatment administration. SARs and SUSARs must be notified to
ProductLife Ltd until trial closure. Any subsequent events that may be attributed to treatment
should be reported to the MHRA using the yellow card system.
7.2.2 NOTIFICATION PROCEDURE
1. The SAE Form must be completed by the investigator (the consultant named on the
Signature List and Delegation of Responsibilities Log who is responsible for the patient’s
care), with due care being paid to the grading, causality and expectedness of the event as
outlined above. In the absence of the responsible investigator, the form should be
completed and signed by a member of the site trial team and faxed or emailed as
appropriate. The responsible investigator should subsequently check the SAE Form, make
changes as appropriate, sign and then re-fax to ProductLife Ltd as soon as possible. The
initial report must be followed by detailed, written reports as appropriate.
The minimum criteria required for reporting an SAE are the trial number and date of birth, name of
investigator reporting and why the event is considered serious.
SAE REPORTING
Within 24 hours of becoming aware of an SAE, please fax a
completed SAE form to ProductLife Ltd on:
Fax: +44 (0) 1223 413 689 or email to
safety@verius.co.uk
2. Follow-up: patients must be followed up until clinical recovery is complete and laboratory
results have returned to normal or baseline, or until the event has stabilised. Follow-up
should continue after completion of protocol treatment if necessary. A further SAE Form,
indicated as ‘Follow-up’ should be completed and faxed to ProductLife as information
becomes available. Extra, annotated information and/or copies of test results may be
provided separately. The patient must be identified by trial number, date of birth and initials
only. The patient’s name should not be used on any correspondence and should be deleted
from any test results.
3. Staff should follow their institution’s procedure for local notification requirements.
7.3
UCL CTU RESPONSIBILITIES
Medically-qualified staff at ProductLife Ltd will review all SAE reports received. The causality
assessment given by the local investigator at the hospital cannot be overruled; in the case of
disagreement, both opinions will be provided in any subsequent reports.
On behalf of the UCL CTU, ProductLife Ltd will review the assessment of expectedness and if, based
on the wider knowledge of the reference material for the rivaroxaban or comparator and after
discussion with the Chief Investigator (CI) may overrule the Investigator assessment of expectedness
for the purposes of onward reporting.
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ProductLife Ltd as a CRO is undertaking the clinical safety and pharmacovigilance duties for the RAPS
trial on behalf of the sponsor. ProductLife Ltd is responsible for the reporting of SUSARs and other
SARs to the regulatory authorities and the research ethics committees, as appropriate. Fatal and
life-threatening SUSARs must be reported to the competent authorities within seven days of
ProductLife Ltd becoming aware of the event; other SUSARs must be reported within 15 days. The
responsibility of producing the Development Safety Update Report (DSUR) remains with UCL CTU.
Bayer plc will keep UCL CTU informed of any safety issues associated with rivaroxaban that arise
during the course of the trial and UCL CTU will report these issues to the trial sites and investigators.
ProductLife Ltd, will submit line listing of SARs and SUSARs to Competent Authorities (Regulatory
Authority and Ethics Committee), on behalf of the sponsor.
Bayer plc will also be notified of all reportable (serious and unexpected and drug-related/unknown
relationship) events. UCL CTU will also provide Bayer with a copy of the DSURs (line-listing of SARs
and SUSARs).
7.4
OTHER NOTIFIABLE EVENTS
Pregnancy
Female patients who are not postmenopausal or sterilised should be on adequate contraception for
inclusion into the trial. However, if pregnancies do occur during the trial they should be reported on
a RAPS SAE report to ProductLife within 24 hours of the investigator becoming aware of the
pregnancy.
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8
8.1
QUALITY ASSURANCE & CONTROL
RISK ASSESSMENT
The Quality Assurance (QA) and Quality Control (QC) considerations have been based on a formal
Risk Assessment, which acknowledges the risks associated with the conduct of the trial and
proposals of how to mitigate them with QA and QC processes. QA includes all the planned and
systematic actions established to ensure the trial is performed and data generated, documented
and/or recorded and reported in compliance with the principles of GCP and applicable regulatory
requirements. QC includes the operational techniques and activities done within the QA system to
verify that the requirements for quality of the trial-related activities are fulfilled. This Risk
Assessment has been reviewed by the Quality Management Group (QMG) and has led to the
development of a Quality Management Plan (QMP), which will be kept in the TMF.
8.2
CENTRAL MONITORING AT UCL CTU
UCL CTU staff will review CRFs for errors and missing values. The clinical database will be used to
monitor the validity of the data with validation checks and data compliance reports.
Other essential trial issues, events and outputs will be detailed in the Monitoring and Quality
Management Plan that is based on the trial-specific Risk Assessment.
8.3
ON-SITE MONITORING
The frequency, type and intensity of routine monitoring and the requirements for triggered
monitoring will be detailed in the Monitoring and Quality Management Plan. This plan will also detail
the procedures for review and sign-off of monitoring reports.
8.3.1 DIRECT ACCESS TO PATIENT RECORDS
Participating investigators should agree to allow trial-related monitoring, including audits, ethics
committee review and regulatory inspections by providing direct access to source data and
documents as required. Patients’ consent for this must be obtained.
8.3.2 CONFIDENTIALITY
UK DPA will be followed in this trial.
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9
9.1
STATISTICAL CONSIDERATIONS
METHOD OF RANDOMISATION
1) Patients will be prospectively randomised to either remain on warfarin or switch to rivaroxaban.
2) Randomisation will be stratified by site and patient type (SLE/non-SLE), to ensure a balance of
patients in each arm in each site and patient type.
3) Random permuted blocks will be used to randomly allocate patients to treatment groups within
each stratum.
4) Blocked randomisation with randomly varying block length will be used to ensure that the
numbers in each group are balanced throughout the trial.
5) Randomisation will be carried out using the SealedEnvelope randomisation system with manual
back up being supplied by the UCL CTU.
9.2
OUTCOME MEASURES
Primary outcome measure
The primary outcome measure is the percentage change in the ETP from randomisation to Day 42.
Secondary outcome measures
a) Efficacy outcomes
Efficacy outcomes will be defined as (i) recurrent VTE alone; and ii) a composite of recurrent VTE and
other thrombotic events.
The thrombin generation curve will be quantified in terms of: the lag-time; the time to peak; peak
thrombin concentration.
Markers of in vivo coagulation activation: prothrombin fragment 1.2, thrombin-antithrombin
complex and D-dimer
b) SAEs and bleeding events
Results of liver function tests will be assessed at baseline, day 90 and as clinically indicated. SAEs
since the previous visit will be routinely assessed at each follow up visit.
Bleeding will be categorised as: major, clinically relevant non-major, minor.
c) Quality of life
QoL will be evaluated via the EQ 5D 5L questionnaire in all patients at baseline and after completion
of the six months trial treatment period.
d) Laboratory measures of compliance
An anti-Xa assay, in patients on rivaroxaban at Day 42, and an INR and factor X amidolytic assay, in
patients on warfarin at baseline and at Day 42, will be performed by established methods.
Percentage time in therapeutic range (TTR) between baseline and day 180 will be calculated in
patients on warfarin.
9.3
SAMPLE SIZE
Primary outcome
RAPS is designed as a non-inferiority trial, to demonstrate that the intensity of anticoagulation in
patients on rivaroxaban is not inferior to that obtained with warfarin as assessed by the ETP, with
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the non-inferiority margin based on the inter site assay variability of test performance and on clinical
relevance. The primary outcome measure is the percentage change in ETP from randomisation to
Day 42. The time point of Day 42 (first trial visit post-randomisation), was chosen as the therapeutic
effect of rivaroxaban would be expected to be stable after a minimum of 30 days of rivaroxaban
therapy and would not be influenced by any residual warfarin, based on the biological half-lives of
the vitamin K-dependent coagulation factors. Rivaroxaban would be regarded as non-inferior to
warfarin if the percentage change in ETP is not more than 20% higher (i.e. less anticoagulant effect)
than that for warfarin. This non-inferiority limit of 20% is based on the inter site assay variability of
test performance74 and on clinical relevance.
The null hypothesis (H0) is that rivaroxaban is inferior to warfarin with respect to the mean
percentage change in ETP at six weeks:
H0: μR - μW ≥ 20%
The alternative hypothesis (H1) is that rivaroxaban is not inferior to warfarin with respect to the
mean percentage change in ETP at six weeks:
H1: μR - μW < 20%
Where: μR = mean percentage change in ETP in the rivaroxaban group
μW = mean percentage change in ETP in the warfarin group
In order to conclude non-inferiority, we need to reject the null hypothesis.
Using information on the ETP in patients on warfarin at a comparable INR range the standard
deviation of % change in ETP was 36% six weeks after starting warfarin treatment.52 Using a onesided 2.5% significance level and 80% power it is calculated that 51 patients per group are required
for the study. Based on our experience with the first 84 patients recruited, 2 patients have been lost
to follow-up or withdrawn before the first trial visit post randomisation, and 5 patients have not
provided paired ETP values. If we conservatively allow for 12% non evaluable patients, it is
anticipated that a total of 116 patients will be required. The sample size has not been adjusted for
non-compliance since, unlike in a superiority trial, it does not necessarily reduce the power for a
non-inferiority design.75
Secondary outcomes: efficacy and safety
The trial is not powered to detect differences between the two randomised groups for efficacy
(recurrent thrombosis) or safety endpoints (i.e. SAEs and bleeding events). Therefore, for secondary
outcomes the two groups will be compared using estimates and confidence intervals.
9.4
INTERIM MONITORING & ANALYSES
The Independent Data Monitoring Committee (IDMC) is the only group who will see the confidential,
accumulating data split by trial arm (see Section 14.3). Reports to the IDMC will be produced by the
UCL CTU statisticians. The IDMC will meet within six months of the trial opening. The timing and
frequency of subsequent meetings and any interim analyses will be stated in the IDMC ToR.
9.5
ANALYSIS PLAN (BRIEF)
The analyses will be described in detail in the Statistical Analysis Plan located in the Statistics Master
File. This section summarises the main issues.
Summary statistics will be calculated for all baseline patient characteristics and study outcomes in
each arm. Numbers and percentages will be used for categorical variables, whilst means/standard
deviations or medians/inter-quartile ranges will be used for continuous variables, as appropriate. All
analyses will be performed on an intention to treat basis. No subgroup analyses are planned.
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Primary outcome
Regression modelling will be used to estimate the difference in ETP between the two treatments
(rivaroxaban - warfarin) at day 42 together with a two-sided 95% confidence interval, adjusting for
the stratification variables. Baseline ETP will be included as a covariate. ETP will be log transformed
for the statistical analysis. Estimates and 95% confidence intervals on the log scale will be back
transformed to percentage changes for presentation, as the difference between two logarithms is
the log of their ratio. If the upper end of the 95% confidence interval does not cross the noninferiority limit of 20%, then rivaroxaban will be regarded as non-inferior (see B and C in the figure
below76). If the mean difference is negative and the 95% CI does not include a difference of zero
then we can conclude that rivaroxaban is superior to warfarin (see A in the figure below76).
Treatment Difference for Adverse Outcome
(New Treatment minus Reference Treatment)
Sensitivity analysis will be performed for the primary outcome measure using tobit regression which
can include censored values, below the limit of detection of the assay77. In addition, a per protocol
analysis will be performed for the primary outcome measure.
Efficacy and safety secondary outcomes
The differences between the two arms for the efficacy and safety secondary outcomes, efficacy
(recurrent thrombosis alone as well as a composite of VTE and other thrombotic events) and safety
(the rates of SAEs and all bleeding events), will be presented as estimates and confidence intervals.
The trial is not powered to perform hypothesis tests for these outcomes.
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Quality of Life
Quality of life, as measured by EQ-5D-5L, will be measured at baseline and at six months. The scores
at six months will be compared between treatment groups, adjusting for baseline values and
stratifying variables. Estimates of treatment difference with 95% CI will be presented.
Laboratory measures of compliance
The anti-factor Xa assays in the patients on rivaroxaban (at Day 42) and the INRs and factor X
amidolytic assays in patients on warfarin (at baseline and Day 42), done concurrently with the TGTs,
will be correlated with log transformed ETP to assess whether there are any relationships.
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10 ANCILLARY STUDIES
Future translational research
Patients are given the opportunity to consent for extra blood (20 mL extra) to be taken at baseline
and the 42 day time point for storage at the UCL Haemostasis Research Unit for translational
research purposes. This is an optional part of the trial and patients not wanting to enter this part of
the trial are not excluded from the main trial.
The transport, processing and storage of these samples are covered in Appendix C.
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11 REGULATORY & ETHICAL ISSUES
11.1 COMPLIANCE
11.1.1 REGULATORY COMPLIANCE
The trial will be conducted in accordance with the principles of the Declaration of Helsinki (version
2008).
It will also be conducted in compliance with the approved protocol, the principles of GCP as laid
down by the Commission Directive 2005/28/EC with the implementation in national legislation
in the UK by Statutory Instrument 2004/1031 (The Medicines for Human Use (Clinical Trials)
Regulations 2004) and subsequent amendments, the UK Data Protection Act (DPA number:
Z5886415), and the National Health Service (NHS) Research Governance Framework for Health and
Social Care (RGF).
11.1.2 SITE COMPLIANCE
The site will comply with the approved protocol, unless it is in the patients’ best interest to treat
them otherwise, and with the above regulations and will comply with the principles of GCP as laid
down by the ICH topic E6 (Note for Guidance on GCP), Commission Directive 2005/28/EC, the
European Directive 2001/20/EC (where applicable) and applicable National regulations. An
agreement will be in place between each site and UCL CTU, setting out respective roles and
responsibilities (see Section 13).
The site must inform UCL CTU as soon as they become aware of a possible protocol violation or
serious breach of compliance, so that the CTU can report the breach if necessary within seven days
as per the UK regulatory requirements. For the purposes of this regulation, a 'serious breach' is one
that is likely to affect to a significant degree:
 The safety or physical or mental integrity of the patients in the trial, or
 The scientific value of the trial
11.1.3 DATA COLLECTION & RETENTION
CRFs, clinical notes and administrative documentation should be kept in a secure location (for
example, locked filing cabinets in a room with restricted access) and held for five years after the end
of the trial. During this period, all data should be accessible to the competent or equivalent
authorities and the Sponsor, with suitable notice. The data may be subject to an audit by the
competent authorities.
11.2 ETHICAL CONDUCT OF THE STUDY
11.2.1 ETHICAL CONSIDERATIONS
Patients will have to attend approximately three extra visits for the trial, but they will be reimbursed
for the extra travelling expenses incurred for these visits.
To assess the primary end point and to assess compliance, patients will have to give 20 mL of blood
at baseline and at day 42 (ideally -12 days +14days). These are not standard tests and samples will
be transported to the Haemostasis Research Unit at UCL, where the tests will be performed. Patients
will also be given the opportunity to give a further 20 mL of blood for storage for future translational
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research. This is optional and there is a separate patient information sheet and consent form for
this.
There are specific instructions for the management of bleeds and for elective surgical procedures for
patient on rivaroxaban. The TMG have produced information sheets for both events which are
available 24 hours of the day at each site. Patients are asked to carry patient cards, which have the
number that the healthcare professional should call to gain this information.
If a patient is allocated to rivaroxaban, after the study period of six months they may have to change
back to warfarin, if this is considered to be best care at that time.
These issues are covered in the Patient Information Sheet.
11.2.2 ETHICAL APPROVALS
Before initiation of the trial at each clinical site, the protocol, all informed consent forms, and
information materials to be given to the prospective participant will be submitted to the ethics
committee for approval. Any further amendments will be submitted and approved by the ethics
committee.
The rights of the patient to refuse to participate in the trial without giving a reason must be
respected. After the patient has entered into the trial, the clinician must remain free to give
alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the
best interest of the patient. The reason for doing so, however, should be recorded; the patient will
remain within the trial for the purpose of follow-up and will be included in the statistical analysis
according to the treatment to which they were randomly allocated. Similarly, the patient must
remain free to change their mind at any time about the protocol treatment and trial follow-up
without giving a reason and without prejudicing his/her further treatment.
11.3 COMPETENT AUTHORITY APPROVALS
This protocol will be submitted to the national competent authority (MHRA).
This is a Clinical Trial of an Investigational Medicinal Product (IMP) as defined by the EU Directive
2001/20/EC. Therefore, a CTA is required in the UK.
The EUdraCT number for the trial is 2012-002345-38.
The progress of the trial and safety issues will be reported to the competent authority, regulatory
agency or equivalent in accordance with local requirements and practices in a timely manner.
Safety reports, including expedited reporting and SUSARS will be submitted to the competent
authority in accordance with each authority’s requirements in a timely manner.
11.4 OTHER APPROVALS
The protocol will be submitted to the relevant R&D department of each participating site by those
delegated to do so. A copy of the local R&D approval (or other relevant approval as above) and of
the PIS and Consent Form (CF) on local headed paper should be forwarded to the UCL CTU before
any patients are entered.
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12 INDEMNITY
UCL holds insurance against claims from participants for injury caused by their participation in the
clinical trial. Participants may be able to claim compensation if they can prove that UCL has been
negligent. However, as this clinical trial is being carried out in a hospital, the hospital continues to
have a duty of care to participants. UCL does not accept liability for any breach in the hospital’s duty
of care, or any negligence on the part of hospital employees. This applies whether the hospital is a
NHS Trust or otherwise.
Participants may also be able to claim compensation for injury caused by participation in this clinical
trial without the need to prove negligence on the part of UCL or another party. Participants who
sustain injury and wish to make a claim for compensation should do so in writing in the first instance
to the Chief Investigator, who will pass the claim to the Sponsor’s Insurers, via the Sponsor’s office.
Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance cover
for harm caused by their employees and a copy of the relevant insurance policy or summary shall be
provided to UCL, upon request.
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13 FINANCE
Funding for staff salaries and trial expenses is provided by Arthritis Research UK Clinical Studies
funding stream (Grant reference number: 19708), which have been reduced as the UCL CTU is
undertaking RAPS as a CTU development project.
The supply of rivaroxaban is being provided by Bayer Healthcare AG free of charge. The company is
also providing financial support for a specified amount of pharmacovigilance work.
Research Nurse support at the sites is supported by the LCRN.
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14 OVERSIGHT & TRIAL COMMITTEES
There are a number of committees responsible for the oversight of the trial, which are detailed
below.
14.1 TRIAL MANAGEMENT GROUP (TMG)
A Trial Management Group (TMG) will be formed comprising the Chief Investigator, other lead
investigators (clinical and non-clinical) and members of the UCL CTU. The TMG will be responsible for
the day-to-day running and management of the trial. It will meet at least three times a year at least
one of which will be in-person. The full details can be found in the TMG Terms of Reference (ToR).
14.2 TRIAL STEERING COMMITTEE (TSC)
The Trial Steering Committee (TSC) has independent membership, including the Chair plus members
from the TMG. The role of the TSC is to provide overall supervision for the trial and provide advice
through its independent Chair. The ultimate decision for the continuation of the trial lies with the
TSC. Further details of TSC functioning are presented in the TSC ToR.
14.3 INDEPENDENT DATA MONITORING COMMITTEE [IDMC]
An Independent Data Monitoring Committee (IDMC) is the only group who will see the confidential,
accumulating data for the trial split by trial arm. Reports to the IDMC will be produced by the UCL
CTU statisticians. The IDMC will meet within six months of the trial opening. The timing and
frequency of subsequent meetings and any interim analyses and will be stated in the IDMC ToR. The
IDMC can recommend premature closure or reporting of the trial to the TSC. Further details of IDMC
processes are provided in the IDMC ToR.
14.4 ROLE OF STUDY SPONSOR
The sponsor is responsible for securing the arrangements to initiate, manage and finance a study.
UCL is the trial sponsor and has delegated the duties as sponsor to UCL CTU with a memorandum of
understanding (MoU).
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15 PUBLICATION
After completion of all data entry, the final analysis for the RAPS trial will be discussed by the TMG.
Results of the analysis will be presented at an investigators’ meeting to provide an opportunity for
them to discuss and comment on the results. Following the investigators’ meeting a paper will be
written by the TMG. The TMG will determine the scientific meetings to present the work and the
journal(s) to submit the publication(s).
Drafts of any publications resulting from the analysis will be reviewed by the IDMC and TSC. Bayer
plc will be given the proposed abstract for presentation at scientific meetings or proposed
manuscript for publication(s) of the results at least 15 days prior to submission or at least 15 days
prior to presentation to allow them the opportunity for comments.
Bayer will be acknowledged for their support in any publications. Arthritis Research UK will be
acknowledged for their financial support of the trial.
The RAPS trial will have an ISRCTN; this will be included in any presentations and publications for
provenance.
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16 PROTOCOL AMENDMENTS
Additions/amendments from protocol version 4.0 – 02 July 2013
The section, sub-section and where applicable paragraph and sentence are stated to give the
location of the amendment.
Substantial amendments:
Summary of trial, Secondary outcome measures
Markers of in vivo coagulation activation (point iv) have been added to the outcome measures.
Summary of trial, Number of participants to be studied
The number of participants to be studied has been reduced from 156 to 116.
Summary of trial, Duration
The planned recruitment period has been increased from 10 to 18 months, and the overall planned
duration of the study has been increased from 24 to 44 months.
Trial assessment schedule
The requirement to measure the patient’s abdominal circumference at screening and Visit 3 has
been removed.
Glossary, Clinical outcome events
The reference to the Independent Adjudication Committee has been removed. Classification of
thrombotic events will be done by the PI at the trial site.
Section 1.5 Rationale and objectives of the study, Objectives, Secondary aims
Additional markers of coagulation activation (point iv) have been added to the secondary outcome
measures.
Section 3.2 Patient exclusion criteria
An additional exclusion criterion has been added to exclude patients on dronedarone.
Section 3.3 Number of patients
The number of participants to be studied has been reduced from 156 to 116.
Section 3.5 Screening procedures and pre-randomisation investigations, Screening
The requirement to measure the patient’s abdominal circumference at screening has been removed.
Section 5.3.6 Accountability and unused drugs/devices
Additional wording has been added to state that unused rivaroxaban will either be destroyed or
taken into general hospital stock.
Section 5.10.2 Medications not permitted
Additional wording has been added regarding the co-administration of dronedarone for patients on
rivaroxaban.
Section 5.10.3 Medications to be used with caution
Additional wording has been added regarding prescribing rivaroxaban in patients with renal
impairment who are concomitantly receiving other medicinal products that increase rivaroxaban
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concentrations and that rivaroxaban should be used with caution in patients who require
dronedarone.
Section 6.1 Trial Assessment Schedule, Visit 3
The requirement to measure the patient’s abdominal circumference at Visit 3 has been removed.
Section 6.2 Procedure for assessing efficacy
A paragraph has been inserted describing the secondary laboratory in vivo markers of coagulation
activation measures of efficacy.
Section 6.8 Loss to follow-up
Additional wording has been added regarding the rate of non evaluable patients in the first 84
patients.
Section 9.2 Outcome measures, Secondary outcome measures, a) Efficacy outcomes
Additional markers of coagulation activation have been added to the outcome measures.
Section 9.3 Sample size, Primary outcome
The sample size has been recalculated, the power has been reduced from 90% to 80% and the total
sample size been reduced from 156 to 116.
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77. StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP.
Acknowledgements:
UCL CTU acknowledges the kind support and the provision of the MRC Clinical Trials Unit Protocol
Template that has been used as a basis for that of the UCL CTU.
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18 APPENDICES
APPENDIX A - FORMULA
Cockcroft and Gault FORMULA (C&G) in μmol/L
Estimated CrCl (mL/min) = (140 – age) x weight*(kg) [x 1.23 if male] or [x 1.04 if female]
serum creatinine (µmol/L)
CrCl is creatinine clearance (mL/min) corrected for body weight
*Calculate weight as follows (steps 1 and 2)
1. Estimate ideal body weight (IBW) kg
 Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
 Females:
IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.
2. Compare IBW to patient’s total body weight (TBW) kg (as measured using weighing scales).
a.
If TBW is 120% or less of the IBW then use TBW in the C&G formula
b.
If TBW is more than 120% of the IBW, then calculate the adjusted body
weight (ABW) kg, and use ABW in the C&G formula
Adjusted body weight (ABW) = IBW + 0.4 x (TBW-IBW)
REFERENCES
1.
2.
Cockcroft DW and Gault H. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:
31-41.
Basic Clinical Pharmacokinetics 4th edition; 2004. Michael Winter. Editor: DB Troy. Lippincott Williams&
Wilkins, Philadelphia
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APPENDIX B – EXPECTED TOXICITIES
WARFARIN
Expected warfarin toxicities taken from the warfarin SPC Mercury Pharma Group Limited (date of
last revision 18 Sep 2012), obtained from the Medicines Compendium (www.medicines.org.uk).
MedDRA system organ
class
Adverse Reaction
Infections and
infestations
Fever
Immune system
disorders
Hypersensitivity
Nervous system
disorders
Cerebral haemorrhage; Cerebral subdural haematoma
Vascular disorders
Haemorrhage
Respiratory, thoracic and Haemothorax, epistaxis
mediastinal disorders
Gastrointestinal
disorders
Gastrointestinal haemorrhage, rectal haemorrhage,
haematemesis; pancreatitis; diarrhoea; nausea; vomiting;
melaena
Hepatobiliary disorders
Jaundice; hepatic dysfunction
Skin and subcutaneous
disorders
Rash; alopecia; purpura; 'purple toes' syndrome;
erythematous swollen skin patches leading to ecchymosis,
infarction and skin necrosis
Renal and Urinary
disorders
Haematuria
Investigations
Unexplained drop in haematocrit; haemoglobin decreased
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RIVAROXABAN
Expected rivaroxaban toxicities taken from the 15mg and 20mg rivaroxaban (Xarelto) SPC Bayer plc
(Date of last revision November 2013), obtained from the Medicines Compendium
(www.medicines.org.uk), for the following therapeutic indications:
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with
one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes
mellitus, prior stroke or transient ischaemic attack.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of
recurrent DVT and PE in adults.
Common
Uncommon
Blood and lymphatic system disorders
Anaemia (incl. respective
laboratory parameter)
Rare
Not known*
Thrombocythaemia (incl.
platelet count increased)A
Immune system disorders
Allergic reactions,
dermatitis allergic
Nervous system disorders
Dizziness, headache
Cerebral and intracranial
haemorrhage, syncope
Eye Disorders
Eye haemorrhage (incl.
conjunctival
haemorrhage)
Cardiac disorders
Tachycardia
Vascular disorders
Hypotension, haematoma
Respiratory, thoracic and mediastinal disorders
Epistaxis, haemoptysis
Gastrointestinal disorders
Gingival bleeding,
gastrointestinal tract
haemorrhage (incl.
rectal haemorrhage),
gastrointestinal and
abdominal pains,
dyspepsia, nausea,
constipationA, diarrhoea,
vomitingA
Dry mouth
Hepatobiliary disorders
Hepatic function
abnormal
Jaundice
Skin and subcutaneous tissue disorders
Pruritus (incl. uncommon
cases of
generalised pruritus),
rash, ecchymosis,
cutaneous and
subcutaneous
haemorrhage
Urticaria
Musculoskeletal and connective tissue disorders
Pain in extremityA
Haemarthrosis
Muscle haemorrhage
Compartment syndrome
secondary to a bleeding
Renal and urinary disorders
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Urogenital tract
haemorrhage (incl.
haematuria and
menorrhagiaB) renal
impairment (incl.
blood creatinine
increased,
blood urea increased)A
Renal failure/acute renal
failure secondary to a
bleeding sufficient to
cause hypoperfusion
General disorders and administration site conditions
FeverA, peripheral
oedema, decreased
general strength and
energy (incl. fatigue and
asthenia)
Feeling unwell (incl.
malaise)
Localized oedemaA
Increased bilirubin,
increased blood alkaline
phosphataseA, increased
LDHA, increased lipaseA,
increased amylaseA,
increased GGTA
Bilirubin conjugated
increased (with or
without
concomitant increase of
ALT)
Investigations
Increase in
transaminases
Injury, poisoning and procedural complications
Postprocedural
haemorrhage (incl.
postoperative anaemia,
and wound
haemorrhage), contusion,
wound secretionA
Vascular
pseudoaneurysmC
Frequencies are defined as:
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 from the available data)
A: observed in prevention of venous thromboembolism (VTE) in adult patients undergoing elective
hip or knee replacement surgery
B: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55
years
C: observed as uncommon in prevention of cardiovascular death and MI in patients after an ACS
(following percutaneous coronary intervention)
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APPENDIX C – BLOOD SAMPLES
1. Introduction
Blood samples for trial assessments
A 20 mL blood sample for the TGT, anti-Xa, INR, amidolytic factor X, and aPL should be collected in
0.105M sodium citrate tubes. These should then be processed preferably within one hour to
separate the plasma for storage, ready for testing.
Blood samples for translational research (optional)
A further 20 mL blood sample is collected from patients giving consent to the storage of their blood
for translational research. These samples will undergo the same processing and storage as the trial
samples. The samples will be stored for the duration of the RAPS trial plus a further maximum of
five years, after which they will be destroyed.
2. Equipment
Trial samples: Citrate Tubes - Tubes containing 0.105M tri-sodium citrate, to give a ratio of 9:1,
blood: anticoagulant (preferably: Vacutainers, Becton Dickinson). The same type of tube must be
used by the site throughout the study.
3. Blood collection
The blood collection tubes should be labelled with the labels provided by CTU and the following
information entered on the label. The sample collection form should be completed to document
that the sample was taken, transported and stored.
Note: For patients on the rivaroxaban arm, blood samples should preferably be collected 2-4 hour
after taking the rivaroxaban tablet (when the maximum concentrations (Cmax) appear in the blood).
Label data fields
Trial number:
Arm: Warfarin/Rivaroxaban
Site:
Patient initials:
Collection date:
Sample type: trial assessment/translational research
4. Sample transportation
Transportation of samples from UCLH
Blood samples from UCLH, will be transported to the Haemostasis Research Unit by hand, to the
following address. These samples need to be processed preferably within one hour of collection as
specified in section 5.
UCL Haemostasis Research Unit
Department of Haematology
University College London
1st Floor, 51 Chenies Mews
London
WC1E 6HX
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Transportation of samples from other sites
Blood samples from other sites will be processed at the site preferably within one hour of collection
as specified in section 5 and stored as specified in section 6. The Haemostasis Research Unit will
arrange for the bulk collection of these samples and their transportation on dry ice using a UCL
approved courier.
5. Centrifugation and separation of plasma – trial samples
Centrifuge the citrate tube at 2000g (approximately 3800 rpm in a typical laboratory bench-top
centrifuge), at room temperature (18-20°C), for 15 minutes, preferably within one hour of collection.
Carefully remove the supernatant plasma, avoiding disturbance of the buffy coat, with a
polypropylene transfer pipette, and deliver into polypropylene tubes, which are then capped.
Repeat the centrifugation step above, to remove any residual platelets. Ensure that the tubes are
labelled throughout the separation process.
6. Storage of plasma – trial samples
The aliquots of plasma must be frozen rapidly and stored at a minimum temperature of –40oC but
preferably –70°C, where they should be maintained until required. When placed in the freezer, the
samples must be allowed to freeze rapidly, preferably in a metal rack, they should not be placed in
polystyrene racks as this can delay freezing.
For any questions regarding the above, please direct your questions to the RAPS Trial Manager.
UCL CTU
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