Clinical trial NCT02913326
Conditions: Thromboembolism
Sponsor: Boehringer Ingelheim
Start date: 2016-12-13; Completion date: 2018-06-22
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, prospective, international, randomized (1:1), open-label study with two parallel groups. This phase III study is planned to investigate the efficacy and safety of dabigatran etexilate versus dose-adjusted warfarin on a net clinical benefit endpoint of major bleeding (ISTH criteria) and new venous thrombotic event (VTE) (primary endpoint) with blinded endpoint adjudication.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Dabigatran etexilate intervention 2: Warfarin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03714648-02
EudraCT No.:
2015-004412-38
BI Trial No.:
1160.248
BI Investigational 
Product:
Pradaxa®, dabigatran etexilate
Title:
RE-SPECT CVT: a randomised, open-label, exploratory trial 
with blinded endpoint adjudication (PROBE), comparing 
efficacy and safety of oral dabigatran etexilate versus oral 
warfarin in patients with cerebral venous and dural sinus 
thrombosis over a 24-week period
Brief Title:
A clinical trial comparing efficacy and safety of dabigatran 
etexilate with warfarin in patients with cerebral venous and 
dural sinus thrombosis (RE-SPECT CVT)
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final
Version and Date:
Version: 2.0
Date: 10 February 2017
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Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Pradaxa®
Name of active ingredient:
Dabigatran etexilate
Protocol date:
07 July 2016
Trial number:
1160.248
Revision date:
10 February 2017
Title of trial:
RE-SPECT CVT: a randomised, open-label, exploratory trial with 
blinded endpoint adjudication (PROBE), comparing efficacy and 
safety of oral dabigatran etexilate versus oral warfarin in patients 
with cerebral venous and dural sinus thrombosis over a 24-week
period
Principal Investigator
< for single-centre trial
or > Coordinating
Investigator< for multi-
centre trial if 
applicable >:
Trial site(s):
Multi-centre trial
Clinical phase:
III
Objective(s):
This is an exploratory trial to investigate the efficacy and safety of 
dabigatran etexilate versus dose-adjusted warfarin in patients with 
cerebral venous and dural sinus thrombosis (CVT).
Methodology:
This is a phase III randomised, open label, exploratory trial with 
two parallel groups over 24 weeks, with blinded endpoint 
adjudication (PROBE design, i.e. prospective, randomised, open-
label, blinded endpoint).
No. of patients: 
total entered:
120 planned
each treatment:
60 planned in each treatment arm
Diagnosis :
CVT diagnosed using one or more of the following techniques:


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Pradaxa®
Name of active ingredient:
Dabigatran etexilate
Protocol date:
07 July 2016
Trial number:
1160.248
Revision date:
10 February 2017

Magnetic Resonance Imaging (MRI)+MR venography 
(preferred) and/or

Computed tomography (CT)+CT venography and/or

MRI or CT in combination with catheter angiography (DSA)
Main criteria
for inclusion:

Patients aged ≥ 18 years and < 79 years with confirmed 
diagnosis of CVT, with or without intracranial 
haemorrhage (ICH), excluding patients whose CVT is 
associated with central nervous system infection or is due 
to head trauma

Patient has achieved clinical stability after having received
standard acute CVT treatment as required, including 
anticoagulation therapy for 5-15 days which has been 
administered until randomisation; anticoagulation must 
include full-dose low molecular weight heparin (LMWH) 
or unfractionated heparin (UFH) and may be followed by 
oral vitamin K antagonist (VKA) treatment. 

Eligible for treatment with an oral anticoagulant for CVT

Exclusion criteria include conditions associated with 
increased risk of bleeding, severe renal impairment, active 
liver disease and current or recent malignancies
Test product(s):
Dabigatran etexilate
dose:
150 mg b.i.d.
mode of 
administration:
p.o
Comparator products:
Warfarin
dose:
1, 3 and 5 mg (dose adjusted to INR 2.0 – 3.0)
mode of 
administration:
p.o.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Pradaxa®
Name of active ingredient:
Dabigatran etexilate
Protocol date:
07 July 2016
Trial number:
1160.248
Revision date:
10 February 2017
Duration of treatment:
24 weeks
Endpoints:
Primary endpoint (based on adjudicated data):

Composite endpoint: number of patients with major bleeding 
according to ISTH (International Society on Thrombosis and 
Haemostasis) criteria and venous thrombotic event (VTE)
(recurring CVT; deep vein thrombosis (DVT) of any limb, 
pulmonary embolism (PE), splanchnic vein thrombosis) after 
up to 24 weeks
Secondary efficacy endpoints (based on adjudicated data):

Number of patients with recurring CVT; DVT of any limb, 
PE or splanchnic vein thrombosis after up to 24 weeks

Cerebral venous recanalisation as measured by the change in
number of occluded cerebral veins and sinuses after up to 24 
weeks
Secondary safety endpoints (based on adjudicated data):

Number of patients with major bleeding according to ISTH 
criteria after up to 24 weeks

Composite endpoint of number of patients with new ICH or 
worsening of the haemorrhagic component of a previous 
lesion after up to 24 weeks

Number of patients with clinically relevant non-major 
bleeding events (CRNMBE) after up to 24 weeks

Number of patients with major bleeding according to ISTH 
criteria or CRNMBE after up to 24 weeks

Number of patients with any bleeding event after up to 24 
weeks (not based on adjudicated data)
Safety criteria:
In addition to the above mentioned safety endpoints the following 
safety parameters are assessed: laboratory parameters and adverse 
events.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Pradaxa®
Name of active ingredient:
Dabigatran etexilate
Protocol date:
07 July 2016
Trial number:
1160.248
Revision date:
10 February 2017
Statistical methods:
The study is an exploratory trial and not intended for registration. 
No formal hypothesis will be tested. All analyses are descriptive in 
nature and confidence intervals and p-values from statistical models 
are used for exploratory purposes only


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FLOW CHART
Trial Periods
Screening 
Period
Randomised Treatment Period
Follow
-up 
period
Extended 
follow-up for 
early discon-
tinuations
Visit
11
22
3
4
5
End of 
treat-
ment3
63
74
Study Day
-1
Day 1
Day 29
Day 85
Day 169
Day 7
after 
Visit 5
Day 176
Time window for visits
Up to
-15 days
none
±7 days
±7 days
±7 days
+7 
days
+7 days
Informed consent1, 5
X
Demographics
X
Medical history
X
CVT risk score
X
Physical examination
X
X
X
NIHSS6
X
Vital signs
X
X
X
X
X
Weight and height7
X
X
X
X
Safety laboratory tests
X
X
X
X
Pregnancy test8
X
X
X
X
12 lead-ECG
X
Assessment of venous occlusion / 
recanalisation by imaging
X9
X10
Assessment of intracranial 
haemorrhage by CT or MRI11
X9
X
Review of in-/exclusion criteria
X
X
Randomisation
X
Dispense trial drugs
X
X
X
First administration of trial 
medication
X
INR / warfarin dose adjustment12
X
X
Adverse events
X
X
X
X
X
X
X
Assessment of bleeding
X
X
X
X
X
X
X
Collection of data of new venous 
thrombotic events (CVT, DVT, 
PE, splanchnic vein thrombosis)11
X13
X
X
X
X
X
Compliance check
X
X
X
Termination of trial medication
X
Concomitant therapy
X
X
X
X
X
X
 
Collection of post-study anti-
coagulation information
X
Completion of patient 
participation15
X
X


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1)
Signing of informed consent and subsequent screening should be done after the diagnosis of CVT has been 
established, treatment with parenteral anticoagulation has started and the patient is considered to be stable. A fictitious 
Day number (Day -1) has been assigned to the Screening Visit (Visit 1). See Footnote 2 and Sections 6.1, 6.2.1 and 
6.2.2 on the performance of Visit 1 and Visit 2, including instructions on the use of existing pre-trial data (from 
moment of diagnosis of CVT) for the purpose of this trial.
2)
Day of Randomisation. May be performed on the same day as Visit 1. In that case Visit 2 procedures that are 
performed as part of Visit 1 do not need to be repeated.
3)
End of Treatment (EOT) and follow-up procedures (Visits 5 and 6) are performed for all patients at the time of 
discontinuation of trial medication. This includes patients who discontinue trial medication prior to Day 169 (the Day 
number does not apply in that case). See also footnotes 4 and 15.
4)
Extended follow-up applies only to patients who discontinue trial medication early (see Section 3.3.4).
5)
Re-consenting may become necessary when new relevant information becomes available and should be conducted 
according to the sponsor’s (Boehringer Ingelheim’s) instructions.
6)
National Institutes of Health Stroke Scale (NIHSS) is a tool used to evaluate impairment after a stroke. See Section 
5.6.2. This neurological assessment is to be completed for the qualifying CVT.
7)
Height is measured at screening only.
8)
Pregnancy tests required for all women of childbearing potential. See Section 3.3.2 for definition of women of 
childbearing potential. A urine test is acceptable, unless local regulations demand a serum test to be performed. If a 
pregnancy test is not routinely performed in female CVT patients, the test at the Screening visit should be performed 
after informed consent has been obtained.
In addition to the tests performed at the visits, women of child bearing potential will be supplied with pregnancy tests 
and instructed to perform pregnancy testing every 4 weeks when visits are more than 4 weeks apart.
9)
At screening imaging should not be performed specifically for the trial. The imaging that was done for diagnosis of the 
cerebral venous or dural sinus thrombosis (CVT) will be used and should be submitted for review by the trial’s 
Adjudication Committee (AC). It is expected that CVT is diagnosed and venous occlusion assessed by any of the 
following techniques: MRI+MR venography, CT+CT venography or MRI or CT in combination with catheter 
angiography (DSA).
10)
At EOT the assessment of recanalisation must be done by MRI+MR venography. A separate MRI protocol will be 
provided as part of the ISF and should be followed for the EOT imaging. The EOT images should be submitted for 
review by the Adjudication Committee.
11)
Throughout the trial, whenever routine imaging is performed due to worsening of the patient’s condition, a suspected 
new intracranial haemorrhage or a new venous thrombotic event (VTE), those images are to be made available to the 
trial’s AC for independent blinded review.
EOT assessment of intracranial haemorrhage is to be done by MRI (see also Footnote 10).
12)
Assessment of International Normalised Ratio (INR) for:
Patients who are on a vitamin K antagonist (VKA) prior to randomisation. At least one measurement prior to start 
of trial treatment in order to determine when to stop initial parenteral therapy and when to start trial treatment (see 
Section 4.1.4); further measurements until start of trial treatment as outlined in Section 4.1.4;
Patients randomised to warfarin. Daily measurements from just prior to start of treatment until concomitant heparin 
treatment is stopped. At least two-weekly INR measurements for the first three months and monthly subsequently.
13)
At Visit 2 information on any new venous thrombotic events since signing of consent is collected.
 
 
15)
Completion of patient participation
Patients who complete the full treatment period of 169 days complete their participation at the follow-up visit 
(Visit 6);
Patients who discontinue trial medication early (see Section 3.3.4): after the follow-up visit they should be 
followed 
, for major bleeding events, VTE events and any other adverse events until Day 176 (25 
weeks) after randomisation. They complete participation at that moment.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................14
MEDICAL BACKGROUND.............................................................................14
1.1
DRUG PROFILE................................................................................................16
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....19
RATIONALE FOR PERFORMING THE TRIAL.........................................19
2.1
TRIAL OBJECTIVES........................................................................................19
2.2
BENEFIT - RISK ASSESSMENT.....................................................................20
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................23
OVERALL TRIAL DESIGN AND PLAN .......................................................23
3.1
3.1.1
Administrative structure of the trial .................................................................24
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................25
SELECTION OF TRIAL POPULATION .......................................................26
3.3
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Removal of patients from therapy or assessments...........................................29
Removal of individual patients .............................................................................29
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................31
3.3.4.2
4.
TREATMENTS...................................................................................................32
TREATMENTS TO BE ADMINISTERED.....................................................32
4.1
4.1.1
Identity of BI investigational product and comparator product....................32
4.1.2
Method of assigning patients to treatment groups...........................................33
4.1.3
Selection of doses in the trial..............................................................................33
4.1.4
Drug assignment and administration of doses for each patient......................33
Completion of trial treatment................................................................................36
4.1.4.1
4.1.5
Blinding and procedures for unblinding...........................................................36
Blinding.................................................................................................................36
4.1.5.1
Unblinding and breaking the code ........................................................................36
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................36
4.1.7
Storage conditions...............................................................................................37
4.1.8
Drug accountability.............................................................................................37


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CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT.....................................................................................................38
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....38
Major Bleeds.........................................................................................................38
4.2.1.1
Minor Bleeds.........................................................................................................40
4.2.1.2
Emergency and Elective Surgery..........................................................................41
4.2.1.3
Spinal Anaesthesia/Epidural Anaesthesia/Lumbar Puncture................................43
4.2.1.4
Stroke of non-CVT origin.....................................................................................43
4.2.1.5
Venous thrombotic event (VTE)...........................................................................44
4.2.1.6
Renal failure..........................................................................................................45
4.2.1.7
Other Medical Intervention...................................................................................45
4.2.1.8
Overdose ...............................................................................................................45
4.2.1.9
4.2.2
Restrictions ..........................................................................................................46
Restrictions regarding concomitant treatment ......................................................46
4.2.2.1
Precautions regarding concomitant treatment.......................................................46
4.2.2.2
Restrictions on diet and life style..........................................................................48
4.2.2.3
Restrictions regarding women of childbearing potential......................................48
4.2.2.4
TREATMENT COMPLIANCE........................................................................49
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................50
TRIAL ENDPOINTS..........................................................................................50
5.1
5.1.1
Primary Endpoint(s)...........................................................................................50
5.1.2
Secondary Endpoint(s) .......................................................................................50
5.1.4
Classification of endpoints for trial disclosure purposes.................................51
ASSESSMENT OF EFFICACY........................................................................51
5.2
5.2.1
Venous thrombotic events ..................................................................................51
5.2.6
Cerebral venous recanalisation..........................................................................54
ASSESSMENT OF SAFETY.............................................................................57
5.3
5.3.1
Physical examination ..........................................................................................57
5.3.2
Vital Signs, body weight and height ..................................................................57
5.3.3
Safety laboratory parameters ............................................................................57
5.3.4
Electrocardiogram ..............................................................................................58
5.3.5
Other safety parameters (safety endpoints)......................................................58
Composite endpoint of new haemorrhagic brain lesion or worsening of the 
5.3.5.1
haemorrhagic component of a previous lesion .....................................................58
Bleeding ................................................................................................................59
5.3.5.2
5.3.6
Assessment of adverse events.............................................................................61
Definitions of AEs ................................................................................................61
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................63


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DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................65
5.4.1
Assessment of Pharmacokinetics.......................................................................65
5.4.2
Methods of sample collection .............................................................................65
5.4.3
Analytical determinations ..................................................................................65
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................65
OTHER ASSESSMENTS...................................................................................66
5.6
5.6.1
CVT risk score.....................................................................................................66
5.6.2
National Institutes of Health Stroke Scale........................................................67
APPROPRIATENESS OF MEASUREMENTS..............................................67
5.7
6.
INVESTIGATIONAL PLAN.............................................................................68
VISIT SCHEDULE.............................................................................................68
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................69
6.2
6.2.1
Screening period..................................................................................................69
6.2.2
Treatment period(s)............................................................................................69
6.2.3
Follow Up Period and Trial Completion...........................................................70
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................72
STATISTICAL DESIGN - MODEL.................................................................72
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................72
7.2
PLANNED ANALYSES.....................................................................................72
7.3
7.3.1
Primary endpoint analyses.................................................................................73
7.3.2
Secondary endpoint analyses .............................................................................73
7.3.4
Safety analyses.....................................................................................................74
7.3.5
Pharmacokinetic analyses ..................................................................................75
INTERIM ANALYSES ......................................................................................75
7.4
HANDLING OF MISSING DATA ...................................................................75
7.5
RANDOMISATION ...........................................................................................76
7.6
DETERMINATION OF SAMPLE SIZE .........................................................76
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................77
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................77
DATA QUALITY ASSURANCE ......................................................................78
8.2
RECORDS...........................................................................................................78
8.3
8.3.1
Source documents ...............................................................................................78
8.3.2
Direct access to source data and documents.....................................................79
8.3.3
Storage period of records ...................................................................................80
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................80
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........80
8.5


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TRIAL MILESTONES.......................................................................................80
8.6
9.
REFERENCES....................................................................................................82
PUBLISHED REFERENCES............................................................................82
9.1
10.
APPENDICES.....................................................................................................88
TRIAL MEDICATION START AND BRIDGING RULES..........................88
10.1
10.1.1
When to start dabigatran etexilate following treatment by other 
anticoagulants......................................................................................................88
10.1.2
When to start warfarin following treatment by other anticoagulants or 
VKAs ....................................................................................................................88
10.1.3
Bridging Therapy (e.g. for temporary interruptions of trial medication due 
to interventions)...................................................................................................88
SWITCHING FROM TRIAL TREATMENT AT EOT.................................89
10.2
NATIONAL INSTITUTES OF HEALTH STROKE SCALE .......................91
10.3
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................93
GLOBAL AMENDMENT 1 ..............................................................................93
11.1


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ABBREVIATIONS
AC
Adjudication Committee
AE
Adverse Event
AESI
Adverse Event of Special Interest
AHA/ASA
American Heart Association/American Stroke Association
ALT (SGPT)
Alanine aminotransferase
APCC
Activated prothrombin complex concentrates
aPTT
Activated partial thromboplastin time
ASA
Acetylsalicylic acid
AST (SGOT)
Aspartate aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
b.i.d.
bis in die (twice daily dosing)
BP
Blood Pressure
CCDS
Company Core Data Sheet
CI
Confidence Interval
CRA
Clinical Research Associate
CrCl
Creatinine Clearance
CRF
Case Report Form
CRNMBE
Clinically Relevant Non-Major Bleeding Event
CT
Computed Tomography
cTn
Cardiac troponin
CTP
Clinical Trial Protocol
CVT
Cerebral venous and dural sinus thrombosis
DEDP
Drug exposure during pregnancy
DMC
Data Monitoring Committee
DSA
Digital Subtraction Angiography
dTT
Diluted thrombin time
DVT
Deep Venous Thrombosis
ECG
Electrocardiogram
ECT
Ecarin clotting time
EFNS
European Federation of Neurological Societies
EOT
End of treatment
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HI
Haemorrhagic infarction
HR
Hazard Ratio
IB
Investigator’s Brochure
ICH
Intracranial haemorrhage
IEC
Independent Ethics Committee
INR
International normalised ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology


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ISF
Investigator Site File
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intent to treat
i.v.
intravenous
LBBB
Left bundle branch block
LMWH
Low molecular weight heparin
LPDD
Last Patient Drug Discontinuation
MBE
Major Bleeding Event
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Myocardial infarction
MRI
Magnetic Resonance Imaging
NIHSS
National Institutes of Health Stroke Scale
NSAID
Non-steroidal anti-inflammatory drug
PD
Pharmacodynamics
PE
Pulmonary Embolism
P-gp
P-glycoprotein
PH
Parenchymatous haematoma
PK
Pharmacokinetics
p.o.
per os (oral)
PPS
Per Protocol Set
PROBE
Prospective, Randomised, Open label, Blinded Endpoint
q.d.
quaque die (once a day)
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SC
Steering Committee
s.c.
subcutaneous
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SNRI
Serotonin norepinephrine re-uptake inhibitor
SOP
Standard Operating Procedure
SPAF
Stroke prevention in atrial fibrillation
SSRI
Selective serotonin re-uptake inhibitor
TCM
Trial Clinical Monitor
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
TT
Thrombin clotting time
TTR
Time in therapeutic range
UFH
Unfractionated heparin
ULN
Upper limit of normal
VKA
Vitamin K antagonist(s)
VTE
Venous thromboembolic event / venous thrombotic event
WBC
White blood cell
WOCBP
Women of childbearing potential


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
According to the American Heart Association/American Stroke Association (AHA/ASA)
Scientific Statement on Diagnosis and Management of Cerebral Venous Thrombosis, 
published 2011 [R15-5005], cerebral venous and dural sinus thrombosis (CVT) is a 
thrombosis of the dural sinus and/or cerebral veins considered to be an uncommon form of 
stroke. It is estimated that approximately 5 persons per million experience it annually and that 
it may account for 0.5% to 1% of all strokes. Even large medical centres only admit 5-10 
cases in a given year [R15-5879]. At the same time, CVT can be life-threatening and can 
have a sustained negative impact on a patient´s health status. Approximately 5 percent of 
patients die in the acute phase of the disorder [R15-5857, R15-5861]. In addition, the 
International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) [R15-4849]
found that acute CVT was associated with a 15 percent overall death or dependency rate at 
the end of follow-up, which varied from 3 to 78 months. 
Although the pathophysiology of CVT is not yet completely understood, there are at least two 
different mechanisms that may contribute to the clinical features of CVT [R15-5879]:

Thrombosis of cerebral veins or dural sinus leading to cerebral parenchymal lesions 
or dysfunction

Occlusion of dural sinus resulting in decreased cerebrospinal fluid absorption and 
elevated intracranial pressure
Risk factors for CVT are diverse (e.g. coagulopathies, pregnancy, oral contraception, 
puerperium, head injury, etc.). It is noteworthy that 75% of all patients suffering CVT are 
female. The mean age of patients in ISCVT was 39 years [R15-4849] and only a few CVT 
patients (less than 10%) are older than 65 years of age.
CVT have a highly variable clinical presentation [R15-5858] and many of the symptoms are 
non-specific, making it difficult to diagnose. The onset of symptoms can be acute, sub-acute, 
or chronic. Symptoms and signs can be grouped in three major syndromes:

Isolated intracranial hypertension syndrome (headache with or without vomiting in 
close to 90% of patients, papilledema, and visual problems) [R15-5851]

Focal syndrome (focal deficits, seizures, or both)

Encephalopathy (multifocal signs, mental status changes, stupor, or coma)
[R15-5878]
In patients with CVT, 30-40% present with intracerebral haemorrhage [R15-5859, 
R15-5863]. The haemorrhage in CVT is believed to be caused by venous outflow blockage 
and very high intradural and intravenous pressure, leading to both rupture of venules and to 
haemorrhagic transformation of venous infarctions. This difference in aetiology compared 
to arterial haemorrhagic stroke is why anticoagulation is not contraindicated in this setting.


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Clinical trial results support this approach, as reflected in the AHA/ASA guidelines 
[R15-5005].
Magnetic resonance imaging (MRI) in combination with magnetic resonance (MR)
venography is the most sensitive examination technique for demonstrating the thrombus and 
the occluded dural sinus or vein (absence of flow and intraluminal venous thrombus). 
Computed tomography (CT) venography is a useful alternative to MR venography. Although 
a head CT scan alone is normal in up to 30 percent of CVT cases and most of the findings 
with CVT are nonspecific; the overall accuracy of head CT combined with CT venography is 
90 to 100 percent. Cerebral intra-arterial angiography is recommended when the diagnosis of 
CVT is uncertain, such as in the rare suspected cases of isolated cortical vein thrombosis, or 
when the clinical suspicion for CVT is high but CT venography or MR venography are 
inconclusive [R15-5005]. Regarding relevant lab values, an elevated plasma D-dimer level 
supports the diagnosis of CVT, but a normal D-dimer does not exclude CVT in patients with 
suggestive symptoms and predisposing factors [R15-5005]. In contrast, a recent meta-
analysis concluded that in low-risk patients with isolated headache the absence of increased 
D-dimer levels does have a high predictive value for excluding CVT. In these patients 
D-dimer is as sensitive for diagnosing CVT as it is in Pulmonary Embolism (PE) and deep 
venous thrombosis (DVT) [R15-6315].
Initial therapy, as recommended by the AHA/ASA Scientific Statement, is intravenous (i.v.)
heparin or subcutaneous (s.c.) low molecular weight heparin (LMWH). Upon stabilisation, 
the patient is switched to oral anticoagulation, until now, vitamin K antagonists (VKA). The 
duration of the oral anticoagulant therapy depends upon the suspected cause of the CVT. In 
patients with transient causes, 3-6 months; in patients with other factors, 6-12 months; in 
patients with recurrent CVT or venous thrombotic event (VTE) after CVT or first CVT in 
presence of severe thrombophilia, permanent anticoagulation is considered.
The immediate goals of antithrombotic treatment are:

To recanalise the occluded sinus/vein

To prevent the propagation of the thrombus to the bridging cerebral veins

To treat, if applicable, an underlying prothrombotic state, in order to prevent venous 
thrombosis in other parts of the body, particularly PE [R15-5864], and to prevent the 
recurrence of CVT
Where available, endovascular treatment is another option, but its use is typically restricted to 
patients with a poor prognosis who have not responded to anticoagulation with heparin or 
LMWH [R15-5865]. Available data suggest that cerebral vein and sinus recanalisation occurs 
in 40 to 90 percent of patients after CVT, mostly within the first four months [R15-5239].
Randomised controlled studies with non-VKA oral anticoagulants have not been conducted 
in patients with CVT to date. Therefore information on their use in this indication is limited 
to publications of individual case studies and case series. The largest case series of patients 
with CVT administered dabigatran etexilate included 15 patients and there were no recurrent 
events detected over 6 months [P15-10422]. In order to evaluate their efficacy and safety in 
the treatment of CVT, clinical trials with non-VKA oral anticoagulants are needed.


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DRUG PROFILE
1.2
Dabigatran etexilate is the orally bioavailable prodrug of the anticoagulant dabigatran, 
a synthetic, direct thrombin inhibitor. Following oral administration dabigatran etexilate is 
rapidly converted to the active moiety dabigatran, which is a potent, competitive, and 
reversible inhibitor of thrombin. 
In vivo and ex vivo animal studies have demonstrated anti-aggregatory efficacy and 
anticoagulant activity of dabigatran after both i.v. and oral administration in various animal 
models of arterial and venous thrombosis. 
Dabigatran etexilate was well tolerated in more than 47 Phase I studies at all doses evaluated 
(up to 400 mg three times a day) with no evidence of major bleeding. These studies have 
established the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of 
dabigatran etexilate, and included testing selected populations (Japanese, elderly, those with 
renal and hepatic impairment), testing for food-drug and drug-drug interactions and for 
QT prolongation.
The PK profile is characterized by peak plasma concentrations of dabigatran etexilate that 
occur approximately two hours after oral administration of the prodrug and a half-life 
depending on renal function (see Table 4.2.1.3: 1
for prolongation of half-life 
with decline in renal function). Dabigatran maximum plasma concentrations and area under 
curve increase in a dose proportional manner. Pharmacokinetic steady state is reached in 
three days with twice daily (b.i.d.) dosing; PD (anticoagulant) activity is closely correlated 
with dabigatran plasma concentrations. Dabigatran is eliminated primarily by the kidneys 
with urinary excretion accounting for approximately 80% of the dose administered 
intravenously. The absolute bioavailability of the current capsule formulation of dabigatran 
etexilate is approximately 6.5%.
Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P450 system and 
had no effects in vitro on human cytochrome P450 enzymes 
. Dabigatran etexilate
is a substrate for the efflux transporter P-glycoprotein (P-gp). In Phase I drug-drug interaction 
studies with other P-gp substrates, no significant influence of dabigatran etexilate on the PK 
of atorvastatin, diclofenac or digoxin was found, and the exposure of dabigatran was not 
significantly altered by these drugs. There was, however, an effect on dabigatran etexilate
bioavailability after co-administration with some P-gp inhibitors or inducers. The 
concomitant use with P-gp inducers (e.g. rifampicin) reduces exposure to dabigatran and 
should be avoided 
 Concomitant administration of P-gp 
inhibitors (such as amiodarone, verapamil, quinidine, systemic ketoconazole 
(contraindicated), dronedarone (not recommended) 
, ticagrelor 
 
and clarithromycin) results in increased dabigatran plasma concentrations which increases 
bleeding risk.
The concomitant use of dabigatran etexilate with treatments that act on haemostasis or 
coagulation including VKA can markedly increase the risk of bleeding. Antiplatelet agents 
(acetylsalicylic acid (ASA) or clopidogrel) are also known to increase bleeding; in the 
phase III RE-LY study in patients with atrial fibrillation 
 bleeding risk was 


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about twice as high in patients receiving additional ASA or clopidogrel both in patients 
treated with dabigatran etexilate and warfarin [P13-00071].
The concomitant use of dabigatran etexilate with the following treatments has not been 
studied and may increase the risk of bleeding: unfractionated heparins (UFH) (except at doses 
necessary to maintain patency of central venous or arterial catheter) and heparin derivatives, 
LMWH, fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, 
ticlopidine, dextran, sulfinpyrazone, non-VKA-anticoagulants, prasugrel, VKA, and the P-gp 
inhibitors itraconazole, tacrolimus, cyclosporine, ritonavir, tipranavir, nelfinavir and 
saquinavir. 
In addition, bleeding risk may be increased in patients concomitantly treated with selective 
serotonin re-uptake inhibitors (SSRI) 
 or selective serotonin norepinephrine 
re-uptake inhibitors (SNRIs) 
. 
The PK and PD of dabigatran in subjects with normal renal function in comparison to 
patients with varying degrees of renal impairment have been studied in an open, group-
comparison design trial of 36 subjects. In otherwise healthy volunteers with mild (creatinine 
clearance (CrCl) ≥50 and <80mL/min), moderate (CrCl ≥30 and <50mL/min), and severe 
(CrCl <30mL/min) renal impairment, the area under the curves (AUCs) of dabigatran were 
increased 1.8, 2.7 and 6.8 fold respectively, compared to healthy volunteers with normal renal 
function (CrCl >80mL/min) 
. This is in accordance with the fact that dabigatran is 
mainly renally excreted. Dabigatran etexilate is contraindicated in cases of severe renal 
impairment (CrCl < 30 mL/min), and patients who develop acute renal failure should 
discontinue dabigatran etexilate 
. Factors such as decreased renal function 
(CrCl 30-50 mL/min) and age ≥ 75 years are associated with increased dabigatran plasma 
levels. The presence of one, or more than one factor may increase the risk of bleeding. 
Dabigatran etexilate is currently authorised for marketing in over 100 countries worldwide. 
There are 4 authorised indications for dabigatran etexilate:

Prevention of venous thromboembolic events (VTEs) in patients who have undergone 
major orthopaedic surgery

Prevention of stroke, systemic embolism and reduction of vascular mortality in 
patients with atrial fibrillation

Treatment of acute DVT and/or PE and prevention of related death 

Prevention of recurrent DVT and/or PE and related death
Results of pivotal clinical trials for the authorised indications
:

In the studies in which primary prevention of DVT after major orthopaedic surgery 
was investigated (total knee replacement RE-MODEL, total hip replacement RE-
NOVATE and RE-NOVATE II) dabigatran etexilate was non-inferior to enoxaparin 
40 mg daily. In one study on elective total knee surgery (RE-MOBILIZE), non-
inferiority as compared to enoxaparin was not established.

The study on stroke prevention in atrial fibrillation (SPAF) (RE-LY) demonstrated 
superior efficacy of dabigatran etexilate 150 mg b.i.d. over warfarin (international 
normalised ratio (INR) 2-3) regarding prevention of stroke and systemic embolism in 
patients with non-valvular atrial fibrillation. Dabigatran etexilate 110 mg b.i.d. was 


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non-inferior to warfarin. Intracranial bleeding and total bleeding were reduced with 
both doses. Vascular mortality was reduced with dabigatran etexilate 150 mg b.i.d.
Overall, lower plasma concentrations were associated with a higher risk of ischemic 
stroke, whereas the risk of major bleeding increased with higher plasma 
concentrations [P13-12662].

In treatment of acute DVT and PE, RE-COVER and RE-COVER II demonstrated that 
150 mg b.i.d. was non-inferior to treatment with warfarin with respect to efficacy, and 
any bleeding was significantly lower in patients receiving dabigatran etexilate 150 mg 
b.i.d.

In the clinical trials investigating prevention of recurrent DVT and/or PE, RE-MEDY 
demonstrated that treatment with dabigatran etexilate 150 mg b.i.d. was non-inferior 
to warfarin (p=0.0135 for non-inferiority). Bleeding events (major bleeding events 
(MBEs)/clinically relevant non-major bleeding events (CRNMBEs); any bleeding) 
were significantly lower in patients receiving dabigatran etexilate compared to those 
receiving warfarin.
For a more detailed description of the dabigatran etexilate drug profile please refer to the 
current Investigator’s Brochure (IB)
, which will be included in the Investigator 
Site File (ISF).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
As in other conditions where anticoagulation is required, warfarin has many challenges and 
risks associated with its use. These include among others numerous drug-drug interactions, 
drug-food interactions, risk of bleeding and the need of regular INR monitoring.
Thus, an alternative method of anticoagulation which can be taken orally, has fewer 
interactions and no regular monitoring requirement would be beneficial for the post-acute 
care of CVT patients. Dabigatran etexilate has a marketing authorisation for treatment of 
DVT and PE in many countries. The aetiology of CVT can be considered sufficiently similar 
to other VTE [P10-00396, R15-5862] to consider treatment with the same dose of dabigatran 
etexilate as an alternative to standard treatment with VKA. Therefore, the selected dose of 
150 mg b.i.d. is expected to be as efficacious as warfarin without the burden/disadvantages 
associated with that drug. It can be expected that the overall bleeding risk under dabigatran 
etexilate will be similar to that of warfarin or potentially better.
There is currently limited but promising clinical data on the use of dabigatran in this 
indication. Since the incidence of CVT is very low and the occurrence of clinical endpoints is 
infrequent, a large confirmatory phase III trial including clinical endpoints in this indication 
is not feasible. Although considered a phase III trial, this trial is not designed to show 
statistically significant differences in clinical endpoints and is not conducted for registration 
purposes. The trial is designed as an exploratory trial that could provide numerical 
reassurance regarding net clinical benefit of dabigatran etexilate compared to warfarin. 
A largely comparable percentage of clinical endpoints (VTE + MBEs according to 
International Society on Thrombosis and Haemostasis (ISTH) definition) for both treatment 
arms would provide clinicians with important new information.
TRIAL OBJECTIVES
2.2
This is an exploratory trial to investigate the efficacy and safety of dabigatran etexilate versus 
dose-adjusted warfarin in patients with CVT after initial acute treatment.
The primary objective is to compare the net clinical benefit of the treatment arms, as 
measured by the composite of VTE (recurring CVT; DVT of any limb, PE, or splanchnic 
vein thrombosis) + major bleeding according to ISTH criteria after up to 24 weeks.
Secondary objectives include a comparison of additional efficacy and safety parameters.
 
 


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BENEFIT - RISK ASSESSMENT
2.3
At the time this protocol was prepared, the safety and efficacy of dabigatran etexilate had 
been evaluated in more than 27,000 patients in over 47 Phase I studies, nine completed 
Phase II studies, and 11 completed Phase III studies within multiple populations including:

Venous thromboembolism (i.e. DVT and/or PE) prevention in patients who have 
undergone major orthopaedic surgery

prevention of stroke and systemic embolism in patients with non-valvular AF

acute treatment and secondary prevention of VTE (DVT and PE)
The most commonly reported adverse reactions of dabigatran etexilate are bleedings events. 
Although rare in frequency in clinical trials, major or severe bleeding may occur and, 
regardless of location, may lead to disabling, life-threatening or even fatal outcomes. 
Standard management for bleeding (such as transfusion of blood products, etc.) needs to be 
applied as described in Section 4.2.1 and in Figure 4.2.1.1: 1. A specific reversal agent 
(idarucizumab) for dabigatran has been developed and is currently available in many 
countries and being reviewed for registration in various other countries. When clinically 
indicated and available, it can be given to a patient from commercial supply if it becomes 
locally approved. See Section 4.2.1.1 (Major Bleeds) for more information regarding the 
specific reversal agent for dabigatran.
The risk of major bleeding correlates with dabigatran plasma concentrations [P13-12662], but 
also depends on individual patient characteristics, such as age and renal function. Bleeding 
risk may also be higher in patients concomitantly treated with an antiplatelet agent, such as 
ASA or clopidogrel. Factors, such as decreased renal function (CrCl 30-50 mL/min), age 
≥75 years, low body weight (< 50 kg), or mild to moderate P-gp inhibitor co-medication (e.g. 
amiodarone, quinidine or verapamil) are associated with increased dabigatran plasma levels, 
thereby contributing to the overall risk of bleeding in an individual patient.
Major advantages of treatment with dabigatran etexilate lie in the greater convenience for the 
patient. Dabigatran etexilate does not require regular monitoring of the anticoagulant effect, 
and it has no food interactions, and few clinically relevant drug-drug interactions compared to 
VKA. 
In addition, dabigatran etexilate has been shown to be associated with significantly less
intracranial haemorrhage (ICH) compared to warfarin (relative risk reduction of 60-70%), 
which is seen irrespective of age and dosing
.
In the CVT indication, the recommended warfarin dosing is identical to the warfarin dosing 
recommended for the SPAF indication and the acute treatment/secondary prevention of 
DVT/PE indications in which dabigatran etexilate was tested against warfarin. The
recommended dosing of dabigatran etexilate for these indications (300 mg total daily dose) 
has therefore been chosen as the best equivalent for the CVT indication (see Section 4.1.3).


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Apart from the general considerations above, patient safety will be protected by 
recommendations provided in this clinical trial protocol. Patients may only be enrolled after 
stabilisation of the acute phase of the CVT. Patients participating in this clinical trial will be 
monitored throughout the course of the study for recovery from CVT and for any adverse 
effects of the trial medication.
Further safeguards that will be implemented to protect patient safety include:

For both trial medications, the protocol includes guidance on handling haemorrhages 
which may occur in either treatment arm.

In patients in the comparator arm (standard VKA treatment) plasma INR will be 
monitored and should be maintained between 2 and 3 to optimize efficacy and 
minimize risk of haemorrhage with VKA.

Concerning the dabigatran etexilate treatment arm, similar efficacy to VKA is 
expected based on the mode of action of the drug and previous clinical trial 
experience in other indications.

Medications which interact with dabigatran etexilate or warfarin are forbidden during
the trial. 

Patients will undergo CrCl measurements at screening and patients with CrCl 
<30mL/min (at screening) will be excluded from participation to reduce the risk of 
bleeding when randomised to dabigatran etexilate; see Section 3.3.3 exclusion 
criteria.

If a patient randomised to dabigatran etexilate experiences severe renal impairment 
(CrCl <30mL/min) during the study, study drug will be withheld or stopped (see 
Section 3.3.4.1 and Section 5.3.3).

Patients with a large volume of ICH will be excluded from this trial, by excluding 
patients that are planned for surgical treatment for CVT (e.g. decompressive surgery, 
ear-nose-throat surgery)

Based on the findings on the nonclinical studies with dabigatran etexilate conducted 
to date and the available information for warfarin, and in accordance with 
international regulatory guidelines, the inclusion of women of childbearing potential 
(WOCBP) in this study is justified. To minimize the risk of unintentional exposure of 
an embryo or foetus to the investigational drug, WOCBP must agree to the 
requirements for pregnancy testing and contraceptive methods described in this 
protocol.

Female patients are required to immediately contact the investigator if they 
experience signs and/or symptoms suggesting a potential pregnancy, or know that 
they are pregnant.

A Data Monitoring Committee (DMC) will be established to monitor safety data of 
the study throughout the trial, and will recommend to the Sponsor (BI) whether to 
continue, modify or terminate the study (refer to Section 3.1.1 for details).
It is expected that this study will provide data that support the assumption that the net clinical 
benefit (composite of recurrent CVT/VTE and major ISTH bleeding) of dabigatran etexilate 
in CVT is similar to warfarin, with an overall lower risk of haemorrhage.


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Thus, the risk benefit assessment is considered favourable for the initiation and conduct of 
this trial.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a phase III randomised, open label, exploratory trial with two parallel groups, with 
blinded endpoint adjudication (PROBE design, i.e. prospective, randomised, open-label, 
blinded endpoint).
Patients may be enrolled into the trial (i.e. sign informed consent) once they have a confirmed 
diagnosis of CVT and have received any required treatment for the acute phase of the illness
as recommended by the AHA/ASA [R15-5005] and the European Federation of Neurological 
Societies (EFNS) [P10-11802]. This should include any treatment required for causal 
pathology or secondary symptoms, such as intracranial hypertension and must also include
standard treatment with initial parenteral anticoagulation (UFH or LMWH) according to local 
treatment practice. Patients may have started oral anticoagulation with a VKA. After a short 
screening period patients should be randomised 5 to 15 days after start of UFH / LMWH (see 
Section 4.1.4 for details).
Patients will be randomised in a 1:1 ratio to receive either dabigatran etexilate (150 mg b.i.d.) 
or warfarin (dose adjusted to maintain an INR between 2.0 and 3.0). 
Figure 3.1: 1 Study Design


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3.1.1
Administrative structure of the trial
A Coordinating Investigator will be nominated and will be responsible to coordinate 
investigators at different centres participating in this multicentre trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in the Trial Master File (TMF).
A Steering Committee (SC) consisting of external (non-BI) experts and BI representatives
has been established to support the Coordinating Investigator who will be the chair of the SC. 
The composition of the SC will be documented in the TMF. The tasks and responsibilities 
will be agreed in a SC-charter, which will be filed in the TMF.
A DMC, independent of the sponsor (BI) and of the SC, will be established to assess the 
progress of the clinical trial (including safety and efficacy assessment at specified intervals)
and to recommend to the SC/sponsor whether to continue, modify, or stop the trial. The tasks 
and responsibilities of the DMC will be specified in a charter. The DMC will maintain 
written records of all its meetings.
An endpoint Adjudication Committee (AC), independent of the study sites and the SC, will 
be established for blinded adjudication of the following:

VTEs

MBE and CRNMBE

Composite endpoint of new ICH or worsening of the haemorrhagic component of 
a previous lesion

Cerebral venous recanalisation
The tasks and responsibilities of the AC will be specified in a charter.
BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating all required
activities, in order to:

manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedures (SOPs),

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

order the materials as needed for the trial, 

ensure appropriate training and information of local clinical monitors, Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical evaluation, including programming, will be done according 
to BI SOPs.


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Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of relevant responsible persons and relevant local 
contact information can be found in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
Since VKAs are the standard of care for CVT, a controlled trial versus one such drug, 
warfarin, is considered appropriate. Dabigatran etexilate has been proven to be at least non-
inferior in efficacy vs. warfarin in several trials of other indications, with fewer bleeding 
events as compared to warfarin, specifically less ICH
.
Double-blind, double-dummy trials in anticoagulation have limitations due to potential 
unavoidable deviations from routine clinical procedures [R08-4453]. This exploratory trial 
will use the PROBE design (Prospective Randomised Open-label with Blinded Endpoint 
assessment). The PROBE approach has been used in several trials of anticoagulation 
comparing against VKA, e.g. in patients with atrial fibrillation.
In accordance with the applicable BI-SOP the trial database will be handled in a blinded way 
as appropriate until database lock; see also Section 4.1.5.1.
An independent DMC will ensure patient safety in case of a highly relevant difference in the 
efficacy or safety between the trial treatments. The trial duration is in line with current CVT 
treatment guidelines from AHA/ASA [R15-5005] and EFNS [P10-11802] and with the 
duration of anticoagulation trials conducted in DVT/PE.
The following procedures will be implemented to reduce the potential for bias in the
reporting and assessment of primary and secondary events.

Clearly defined objective outcomes:
The primary and secondary outcomes of the study are clinically relevant events for 
which objective documentation will be obtained. Standard, widely accepted 
definitions are to be used that rely on objective documentation.

Blinded AC:
The events that make up the primary endpoint and the most relevant secondary 
endpoints will be adjudicated by blinded adjudication experts independent of the 
study sites and the SC. Blinding of all event documentation will be performed by 
trained specialists. The committee will report to the SC and the DMC.

Review of Data for Clinical Events:
Any Adverse Event (AE) indicative for a focal neurological deficit, such as limb 
weakness, loss of vision or sensory disturbance will trigger a request for more 
information from the centre for event adjudication if potentially consistent with a trial 
endpoint. Any decrease in haemoglobin of >2g/dL and any new VTE will be similarly 
investigated.


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
Data Handling:
Patients will be randomly allocated to the treatment arms via Interactive Response 
Technology (IRT). Wherever feasible, data review and data handling will be 
undertaken without knowledge of patient treatment allocation. By treatment data 
tabulations will not be reviewed during the course of the trial.
By implementing these appropriate measures to avoid bias, the PROBE design is an 
acceptable and preferred approach for this study.
SELECTION OF TRIAL POPULATION
3.3
This study will randomise approximately 120 patients at approximately 50 trial sites. This 
means that each site should randomise 2-3 patients.
Trial sites are anticipated to mainly be stroke units or neurology wards.
Enrolment will be competitive and will be terminated when the required number of patients 
have been included into the trial, regardless of enrolment at individual centres. If enrolment is 
delayed, additional study centres may be recruited.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
If a patient is deemed ineligible for a reason which later resolves and all eligibility criteria 
can be met (e.g. requirement to take specific restricted medication), patients can be re-
screened up to one time provided they can still be randomised within 5 to 15 days after start 
of initial parenteral therapy. Patients cannot be re-screened if any of the following exclusions 
were met during the initial screening: # 2, 3, 4, 7, 11, 12 and 13.
3.3.1
Main diagnosis for trial entry
Patients with CVT who are eligible to receive treatment with oral anticoagulation and who 
meet all other eligibility criteria can enter the trial. CVT should be diagnosed per local 
practice, using the following techniques:

MRI+MR venography (preferred) and/or

CT+CT venography and/or

MRI or CT in combination with catheter angiography (DSA)
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Written informed consent in accordance with International Conference on Harmonization  
Good Clinical Practice (GCP) guidelines and local legislation and/or regulations.


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2. Male or female patients. WOCBP1 must be ready and able to use highly effective 
methods of birth control per International Conference on Harmonization M3(R2) 
[R09-1400] that result in a low failure rate of less than 1% per year when used 
consistently and correctly. A list of contraception methods meeting these criteria is 
provided Section 4.2.2.4 and in the patient information.
3. Age ≥ 18 years and < 79 years at Visit 1.
4. Confirmed diagnosis of CVT2, with or without ICH.
5. Patient has achieved clinical stability after having received standard acute CVT treatment 
as required, including anticoagulation therapy for 5-15 days which has been administered
until randomisation; anticoagulation must include full-dose LMWH or UFH and may be 
followed by oral VKA treatment.
6. Eligible for treatment with an oral anticoagulant for their CVT, based on Investigator 
judgment. Based on risk assessment and clinical condition, patient should be a candidate 
for at least 24 weeks of oral anticoagulation.
7. Availability of the imaging that was used to diagnose the CVT for the purpose of external 
review.
3.3.3
Exclusion criteria
1. Inability to swallow medications.
2. CVT associated with central nervous system infection.
3. CVT due to head trauma.
4. Planned for surgical treatment for CVT (e.g. decompressive surgery, ear-nose-throat
surgery).
5. Conditions associated with increased risk of bleeding3 such as:
o
Major3 surgery in the month prior to Visit 1
o
Planned major3 surgery or intervention in the next 6 months
o
History of intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding 
unless the causative factor has been permanently eliminated or repaired per 
Investigator judgment (e.g. by surgery)
o
Gastrointestinal haemorrhage within the past six months (prior to Visit 1) unless 
the cause has been permanently eliminated or repaired per Investigator judgment 
(e.g. by surgery), or endoscopically documented gastroduodenal ulcer disease in 
the previous 30 days prior to Visit 1
                                                
1 WOCBP are defined as:
Any female who has experienced menarche and does not meet the criteria for "women not of childbearing 
potential" as described below.
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an alternative medical cause) or who are 
permanently sterilized (e.g., hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
2 Diagnosis of CVT will need to be confirmed by means of any (combination) of the following techniques: 
MRI+MR venography, CT+CT venography and/or MRI or CT in combination with catheter angiography 
(DSA).
3 Definition of “increased bleeding risk” and “major” is per Investigator judgment.


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o
Haemorrhagic disorder or bleeding diathesis, e.g. history of thrombocytopenia or 
platelet count <100,000/ml at screening, von Willebrand disease, haemophilia A 
or B or other hereditary bleeding disorder, history of prolonged bleeding after 
surgery/intervention
o
Fibrinolytic agents within 48 hours of starting trial medication
o
Uncontrolled hypertension (Systolic Blood Pressure (BP) >180mmHg and/or 
Diastolic BP >100 mmHg)
o
Any history of intracranial aneurysm (unless it was permanently resolved with 
either clipping or coiling at least one year prior to the study entry)
6. Life-threatening or major bleeding (per ISTH criteria, see Section 5.3.5.2) other than ICH
due to the index CVT, during the 6 months prior to randomisation or while on 
anticoagulants during the acute phase of CVT.
7. History of symptomatic non-traumatic ICH with risk of recurrence according to 
Investigator judgment (including haemorrhagic stroke within 6 months prior to screening, 
but other than ICH during the acute phase of CVT).
8. Severe renal impairment defined as CrCl (calculated by Cockcroft-Gault equation) 
<30mL/min at screening, or if the Investigator expects CrCl is likely to drop below 
30mL/min during the course of the study.
9. Patients who require taking any of the drugs listed as restricted in Section 4.2.2.1 while on 
active treatment with study drug.
10. Patients receiving treatment with warfarin, dabigatran etexilate or other antithrombotic 
regimen (i.e. anticoagulants or anti-platelet medication) for an indication other than CVT 
and requiring continuation of that treatment for the original diagnosis without change in 
the regimen.
11. Patients with prosthetic heart valves.
12. Known hypersensitivity to dabigatran etexilate or warfarin or to any of the excipients of 
either product.
13. Any current or recent malignancy (≤ 6 months prior to Visit 1) unless the malignancy was 
a basal cell carcinoma that was completely removed.
14. Concomitant disease that increases the risk of an adverse reaction to study interventions 
or with life expectancy < 6 months (for any reason) as per Investigator’s judgment.
15. Pre-menopausal women (last menstruation ≤ 1 year prior to Visit 1) who are pregnant, 
nursing, or who plan to become pregnant while in the trial.
16. Patients who have participated in another trial with an investigational drug or device 
within the past 14 days preceding Visit 1 or who currently are participating in another 
trial1. Patients who are still experiencing a clinical effect from an investigational drug or 
device.
17. Patients considered unreliable by the Investigator concerning the requirements for 
follow-up during the study or at the end of the study.
18. Any condition the Investigator believes would not allow safe participation in the study.
19. Active liver disease, as indicated by at least one of the following:
o
Prior and persistent Alanine aminotransferase (ALT (SGPT)) or Aspartate 
transaminase (AST (SGOT)) or Alkaline Phosphatase >3 x upper limit of normal 
(ULN)
                                                
1 Patients participating in a purely observational study will not be excluded.


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and/or
o
Known Active hepatitis C (as evidenced by positive hepatitis C virus ribonucleic
acid assay by sensitive polymerase chain reaction (PCR) based assay, such as
Roche Monitor or Bayer TMA assay)
and/or
o
Known Active hepatitis B (HBs antigen positive or anti HBc IgM positive)1
and/or
o
Known Active hepatitis A
20. Previous randomisation in this trial.
Note to the eligibility criteria: Pre-randomisation interventional treatment (i.v. r-tPA or 
urokinase and/or stenting) is neither required nor excluded provided that the start of trial 
medication is at least 48 hours after the application of any fibrinolytic agent.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
It is important to distinguish between premature study drug discontinuation and premature
study discontinuation.
Patients can stop study drug for various reasons as described below however they should be
encouraged to re-start study medication at the Investigator’s discretion and when he/she
considers it safe to do so.
Regardless of whether or not study drug continues to be taken, patients will continue to
participate in regularly scheduled follow-up visits and assessments until 25 weeks after 
randomisation, unless they withdraw their consent to do so. Patients not actively taking study 
drug are strongly encouraged to continue trial participation, 
 
 and report events that comprise the primary endpoint at minimum.
Data collected for all randomised patients will be used in the analysis. This includes
randomised patients who never take study medications and patients that prematurely
discontinue study drug. Procedures to be followed for patients prematurely terminating the
trial are detailed in Section 6.2.3. Patients that withdraw from trial participation or study drug 
will not be replaced.
If study drug is permanently stopped, patients should attend two follow-up visits. Refer to 
Section 6.2.3 for further details.
An individual patient is to be withdrawn from trial treatment if:
                                                
1 Patients having received recent hepatitis B vaccination and thus testing positive for these antibodies will not be 
excluded.


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
The patient withdraws consent for trial treatment or trial participation, without the need to 
justify the decision.

The patient becomes pregnant.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication (see Section 4.2.2).

Patients randomised to receive dabigatran who are found to have a CrCl <30mL/min 
during the course of the trial should have trial medication temporarily discontinued (see 
Section 5.3.3 for calculation of CrCl). Labs can be repeated before stopping trial 
medication if Investigator wishes to confirm initial lab result. The patient will be 
permanently discontinued from trial medication, unless CrCl recovers to ≥30mL/min 
within seven days. 
A patient should also be permanently discontinued from trial medication if CrCl drops 
<30mL/min on two different occasions during the trial. During period of interruption, 
a patient can be treated per standard of care according to Investigator’s discretion. 

The patient can no longer be treated with trial medication for other medical reasons
(such as surgery, AEs, other diseases).

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future.
Guidelines for transitioning to non-study antithrombotic medications are provided in 
Appendix 10.2.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart and Section 6.2.3.
For all patients the reason for withdrawal (e.g. AEs) must be recorded in the Case Report 
Form (CRF). These data will be included in the trial database and reported.
If a trial patient becomes pregnant, the trial medication will be discontinued permanently. 
All end of treatment (EOT) procedures should be performed and the patient should be 
followed in the trial as outlined in the Flow Chart and below for patients who discontinue 
trial medication early.
In addition the patient will be followed up until birth or otherwise termination of the 
pregnancy. See also Section 5.3.7.
The data of the patient until last patient last visit (for the total trial) will be collected and 
reported in the clinical trial report. Any events thereafter will be reported in the BI drug 
safety database only.
Patients who discontinue trial treatment before completing 24 weeks of treatment will be 
followed-up for the collection of further data on 
, MBEs, VTEs, any other AEs and 
post-study anti-coagulation therapy (until 25 weeks after the date of randomisation), unless 
they withdraw their consent for any further participation. Data will be collected during
a contact at 25 weeks after randomisation and from existing medical records. Every effort 
should be made to obtain this information. Patients who discontinue trial medication and who 
do not agree to be contacted themselves should be asked if they agree to another person being 
contacted to obtain this information. Contact details of that person should then be obtained.


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Discontinuation of the trial by the sponsor
3.3.4.2
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract disturbing the 
appropriate conduct of the trial
4. Advice of the independent DMC, decision by an independent ethics committee 
(IEC)/institutional review board (IRB) or Competent Authority
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
The trial medication will be provided by Boehringer Ingelheim Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator product
The investigational product dabigatran etexilate and the comparator warfarin will be supplied 
by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. For details see Table 4.1.1: 1 
and Table 4.1.1: 2.
Table 4.1.1: 1
Dabigatran etexilate (Investigational drug)
Substance
Brand name
Dabigatran etexilate
Pradaxa®
Pharmaceutical formulation
Capsule
Source
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength
150 mg
Posology
1 capsule 150 mg b.i.d. (total daily dose 300 mg)
Route of administration
p.o.
The main excipients of the dabigatran capsule include tartaric acid, acacia, hypromellose,
dimeticone, talc, and hydroxylpropyl cellulose, HPMC (hydoxylpropylmethylcellulose) 
capsule shell consisting of titanium dioxide (E171) FD&C Yellow 6/Sunset Yellow (E110), 
FD&C Blue 2 /Indigo Carmine (E132) hypromellose, carrageenan and potassium chloride.
Table 4.1.1: 2
Warfarin (active comparator)
Substance
Warfarin
Pharmaceutical formulation
Tablet
Source
Teva UK Limited, UK
Unit strength
1 mg; 3 mg; 5 mg
Posology
As needed to maintain a target INR of 2.0- 3.0
Route of administration:
p.o.
For easy identification warfarin tablet strengths will have a different colour label.


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Patients will in general take warfarin once daily (q.d.). The individual doses will be titrated as 
needed, without splitting of any tablet, to maintain a target INR of 2.0 - 3.0. INR controls in 
patients randomised to receive warfarin will be performed as described in Section 4.1.4 and
the Flow Chart.
Warfarin and dabigatran etexilate supplies will be managed using an IRT system.
4.1.2
Method of assigning patients to treatment groups
During Visit 2 and after the patient’s eligibility has been confirmed, the treatment will be 
assigned via IRT. Note that the medication number is different from the patient number (the 
latter is assigned at trial entry). Site personnel will enter the medication number in the CRF. 
To facilitate the use of the IRT system, all necessary instructions for using the system will be 
described in a user guide/manual, a copy of which will be available in the ISF.
4.1.3
Selection of doses in the trial
Many experts with specific knowledge regarding CVT are of the opinion that CVT should be 
regarded as a thrombosis at a specific site and is more similar than dissimilar to DVT / PE
[P10-00396], [R15-5862]. It was therefore decided to use the approved dosage of dabigatran 
for treatment of acute DVT/PE, i.e. 150 mg b.i.d. This dose was also used in a 15-patient case 
series [P15-10422] published on dabigatran use in CVT which resulted in favourable efficacy 
and safety outcomes for all patients.
The comparator warfarin will be administered according to an accepted standard regimen
recommended for treatment of CVT (titration to maintain an INR of 2.0-3.0) [P10-11802], 
[R15-5005].
The IRT will assign the correct kit number for dabigatran etexilate for the patients at each
time point, but for the warfarin patients, individual management will be by the Investigator.
4.1.4
Drug assignment and administration of doses for each patient
Each patient will be randomised at Visit 2 to receive either dabigatran etexilate 150 mg b.i.d. 
or warfarin. Randomisation should take place within the timeframe provided below as soon
as the patient is stable and is considered eligible to receive oral anticoagulation therapy:

Ideally patients are randomised 5 days (120 hours) after start of UFH / LMWH;

Randomisation should not take place before 5 days of initial treatment with UFH or 
LMWH have been given;

Randomisation should occur no later than 15 days after start of initial UFH / LMWH.
If there is no need for wash-out (see below), the first dose of trial medication will be taken at 
the study centre. Patients who need a wash-out period will take the first dose after completion 
of that wash-out. This may be done at home as instructed by their investigator.


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Patient randomised to receive dabigatran etexilate
Patients randomised to dabigatran etexilate will start the trial medication on the day of 
randomisation if they are not on oral anticoagulation (VKA) or if the INR is <2.0. If a patient 
is still receiving parenteral therapy, the first dose (capsule) of dabigatran etexilate should be 
given 0-2 hours prior to the time that the next dose of the initial parenteral therapy would be 
due, or at the time of discontinuation in case of continuous treatment (e.g. i.v. UFH). 
If the patient is on oral anticoagulation with a VKA for their CVT and the INR is ≥2.0, trial
medication can be dispensed but the patient will be instructed not to start it until notified. 
The initial parenteral anticoagulation and VKA will be discontinued. Follow-up INRs will 
be performed in 1-3 day intervals until it falls below 2.0, at which time the patient will be 
instructed by telephone to start taking the trial medication.
Actual date and time of administration of the first dose of trial medication and in case of 
interruptions are to be recorded in the CRF.
Patients will take their dabigatran etexilate dose as scheduled for a period of 24 weeks.
Dabigatran etexilate capsules should be taken in the morning and in the evening (one at each 
time point), at approximately the same time every day with a full glass of water. The capsules 
must not be crushed, nor opened and can be taken with or without food. If dyspeptic 
symptoms occur, the Investigator should instruct the patient to take the medication together 
with food and/or should consider adding a proton pump-inhibitor to the concomitant therapy 
of the patients. 
The interval between doses should be as close to 12 hours as possible. If a dose of dabigatran 
etexilate is missed for any reason, the forgotten dose may still be taken up to six hours prior 
to the next scheduled dose. From six hours prior to the next scheduled dose on, the “missed” 
dose should be omitted. A double dose to make up for missed individual doses must not be 
taken.
Any patient who decides to discontinue trial medication should be considered for a switch to 
an appropriate (non-study) anticoagulant according to local practice. For patients receiving 
dabigatran etexilate, continuation of trial medication for 2-3 days to assist bridging may be 
appropriate. For recommendations on how to switch from dabigatran etexilate to other 
anticoagulants see Appendix 10.2.
Patient randomised to receive warfarin
Patients randomised to warfarin will start the trial medication on the day of randomisation. 
If they are on oral anticoagulation (VKA) at the moment of randomisation, it needs to be 
confirmed that INR is <3.0 before trial medication is started. If the INR is ≥3.0, warfarin 
must not be started until the INR is in the therapeutic range. Actual date and time of 
administration of the first dose of warfarin are to be recorded in the CRF.
Initial parenteral anticoagulation should be continued together with study warfarin if INR 
is <2.0. Initial parenteral therapy should be discontinued as soon as INR is ≥ 2.0 (one
measurement). Randomisation should occur no later than 15 days after start of UFH / 


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LMWH. For patients randomised to receive warfarin, UFH / LMWH may continue beyond 
day 15 until the requirement of INR ≥ 2.0 has been met.
INR monitoring should continue and warfarin doses adjusted to maintain an INR between 
2.0 and 3.0.
Warfarin tablets are to be taken with water, preferably at the same time each day.
Warfarin patients will usually be managed by their Investigator. However, Investigators will 
also be able to assign INR monitoring to a local anticoagulation clinic. All dose adjustments
will be done according to usual clinical practice, taking into account that tablets may not be 
split (i.e. only whole tablets to be taken by the patient). The Investigator will be responsible 
for reporting INR results and the dose of warfarin prescribed.
For patients randomised to warfarin, the INR measurements should be performed as 
necessary for dose adjustment and maintenance until the EOT visit in order to obtain the 
target INR as soon as possible and to avoid over- or under-dosing. INR measurements should 
be performed daily from the start of treatment until concomitant heparin treatment is stopped
(if applicable), at least once every two weeks for the first three months thereafter and monthly 
subsequently. More frequent INR measurements will be done as necessary at the discretion of 
each Investigator or anticoagulation clinic.
To aid investigators, a validated nomogram will be provided which will indicate 
recommended dose changes and INR re-testing times for different INR values. This 
nomogram requires more frequent INR monitoring after out-of-range INR values have 
occurred. 
Patients with protein C deficiency are at risk of developing skin necrosis when starting 
warfarin treatment. Therefore, for patients with known protein C deficiency, therapy should 
be introduced slowly without a loading dose of warfarin even if heparin is given. Patients 
with protein S deficiency may also be at risk and it is advisable to also introduce warfarin
therapy slowly in such patients.
Numerous factors, alone or in combination, may influence the patient’s response to 
anticoagulants. Thus to ensure adequate control it is recommended that additional INR 
measures are performed when other medications are initiated, discontinued or taken 
irregularly and/or in case of diet changes. All patients should be educated about potential 
interactions with other medications, herbal preparations and foods and about the importance 
of monitoring. INR measurements can be performed independently from the scheduled study 
visits (see Flow Chart), however all available INR values should be entered into the CRF. 
It is critical to obtain the best possible level of INR control.
Heparin and LMWH
In accordance with current treatment guidelines (AHA/ASA scientific statement on diagnosis 
and management of CVT [R15-5005] and EFNS guideline [P10-11802]), patients must be 
treated with parenteral anticoagulation during the acute stage of illness until they are 
medically stable and can be switched to oral anticoagulation. Patients must be randomised 


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into this trial within 5-15 days after start of parenteral anticoagulation. This parenteral 
treatment will not be provided as part of the clinical trial supplies, unless required by local 
laws or regulations.
Completion of trial treatment
4.1.4.1
Regular trial treatment will be completed with the last dose of trial medication being taken on 
the evening before or the morning of the EOT visit. Decisions regarding the continuation of 
anticoagulation agents after the completion of the treatment period (EOT) should be based on 
the recommendations and guidelines of the AHA/ASA [R15-5005] and the EFNS
[P10-11802] or alternative local treatment practice.
For recommendations on how to switch from trial treatment to other anticoagulants see 
Appendix 10.2.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
This is an open-label trial; treatment allocation to the Investigators and patients will not be 
concealed throughout the study. Trial medication will be identified by a medication code 
number. This code number will be entered into the CRF. Despite the trial being open label, 
the activities conducted by the trial team will be performed in a blinded manner as much as 
possible until database lock. Specifically, medical and quality review and review of protocol 
violations will be performed without knowledge of or reference to the treatment that the 
patient was assigned to, or any other unblinding information.
For further justification of the PROBE design chosen for this study see Section 3.2.
The randomisation code will be kept secret by Clinical Trial Support up to database lock.
Unblinding and breaking the code
4.1.5.2
Not applicable.
4.1.6
Packaging, labelling, and re-supply
Dabigatran etexilate will be provided in bottles. Each bottle will contain 60 capsules of 
150 mg dabigatran etexilate. The number of bottles provided to the patient will vary 
depending on the time between visits.
Patients on warfarin will receive the required combination of 1 mg, 3 mg and 5 mg tablets in 
blister strips placed into wallet cards according to their actual needs as defined by the 
measured INR value. Each warfarin wallet will contain 70 tablets. The number of wallets
provided to the patient will vary depending on the time between visits.
For details of packaging and the description of the label, refer to the ISF.


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Supply and re-supply will be managed by the IRT system.
4.1.7
Storage conditions
Patients randomised to dabigatran should be instructed to keep medication bottles tightly 
closed. It is not allowed to use medication from more than one dabigatran etexilate bottle at 
the same time.
Patients should be instructed not to remove tablets/capsules from original package material 
until immediately prior to time of intake.
Trial medication must be stored under the recommended storage conditions indicated on the 
label. A temperature log must be maintained by the investigator / pharmacist / investigational 
drug storage manager to make certain that the drug supplies are stored at the correct 
temperature. If the storage conditions are found to be outside the specified range, the process 
outlined in the ISF should be followed.
Trial medication must be stored securely at the study sites, out of reach of children and be 
protected from moisture and direct sunlight, e.g. in a locked cupboard or at a pharmacy.
4.1.8
Drug accountability
The Investigator and/or Pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:

Approval of the trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated CTP,

Availability of the proof of a medical license for the principal Investigator, if applicable.
Trial medication may only be dispensed to trial patients fulfilling the inclusion and none of 
the exclusion criteria by authorised study personnel as documented in the ISF.
The Investigator and/or Pharmacist/investigational drug storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each
patient, and the return to the sponsor or warehouse/drug distribution centre or alternative 
disposal of unused products. If applicable, the sponsor or warehouse/drug distribution centre 
will maintain records of the disposal. Account must be given for any discrepancies.
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor or appointed contract research organisation, the Investigator / Pharmacist / 
investigational drug storage manager must verify that all unused or partially used drug 


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supplies have been returned by the clinical trial patient and that no remaining supplies are in
the Investigator’s possession.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
Any additional drugs considered necessary for the patient’s welfare may be given at the
discretion of the Investigator and with due consideration of the information provided below.
Certain concomitant therapies (e.g. fibrinolytics, anticoagulants other than warfarin/
dabigatran etexilate) or surgery/intervention may require the temporary discontinuation of
warfarin or dabigatran etexilate. Study medication should be restarted as soon as safely
possible. In case of a temporary interruption, bridging therapy with a parenteral anticoagulant
is allowed at the discretion of the Investigator (see Appendix 10.1 for guidance on bridging
therapy). Following study drug discontinuation due to AEs (e.g. bleeds) the patient should be
treated according to local clinical practice. After resolution of an AE, consideration should be
given to resuming study medication at the assigned dose.
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
The Investigator is responsible for ensuring that procedures and expertise are available to 
cope with medical emergencies that may occur during the study.
Major Bleeds
4.2.1.1
Dabigatran Etexilate Treated Group
If a patient experiences major bleeding, the trial medication should be temporarily stopped 
and the source of bleeding investigated and treated. This will generally involve coagulation 
testing (e.g. activated partial thromboplastin time (aPTT), thrombin clotting time (TT), ecarin 
clotting time (ECT)), platelet count, and possibly transfusion, diagnostic procedures and/or 
surgical haemostasis. Renal function should be assessed.
Since dabigatran is excreted predominantly by the renal route adequate diuresis must be 
maintained. Appropriate standard treatment, e.g. surgical haemostasis as indicated and 
volume replacement should be undertaken as appropriate. In addition, consideration may be 
given to the use of fresh frozen plasma [P10-03790, P13-06400]. As protein binding is low, 
dabigatran is dialysable; however there is limited clinical experience in using dialysis in this 
setting. Clearance of dabigatran by haemodialysis was investigated in patients with end-stage 
renal disease. Dialysis was conducted with 700mL/min dialysate flow rate, four hour 
duration, a blood flow rate of either 200mL/min or 350 - 390mL/min. This resulted in a 
removal of 50% or 60% of free or total dabigatran concentrations, respectively. The amount 
of drug cleared by dialysis is proportional to the blood flow rate. There is some experimental 
evidence to support the role of agents such as activated prothrombin complex concentrates 
(APCC, e.g. FEIBA), recombinant Factor VIIa and three- or four-factor concentrates (Factors 
II, IX and X with or without Factor VII) in reversing the anticoagulant activity of dabigatran. 
The usefulness in clinical settings has not yet been systematically demonstrated. 
Consideration should also be given to administration of platelet concentrates in cases where 


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thrombocytopenia is present or long acting antiplatelet drugs have been used. All 
symptomatic treatment will be given according to the treating physician's judgement.
For situations of life-threatening or uncontrolled bleeding when rapid reversal of the 
anticoagulation effects of dabigatran is required, the specific reversal agent (idarucizumab) 
may be available from commercial supply depending on the status of national authorization.
Idarucizumab is indicated for use in selected patients treated with dabigatran when reversal of 
the anticoagulant effects of dabigatran is urgently needed (i.e., for emergency surgery/urgent 
procedures or if there is life-threatening or uncontrolled bleeding). Idarucizumab is 
a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant 
effect of dabigatran as evidenced by reduced unbound dabigatran concentrations and 
normalized coagulation tests. Preliminary Phase 3 results from the RE-VERSE-AD trial 
(Pollack et al. 2015, P15-06362) demonstrated a median maximum reversal of 100%, 
a median time to bleeding cessation of 11.4 hours, and normal intraoperative haemostasis in 
92% of patients requiring an urgent procedure. Current evidence suggests that idarucizumab 
functions as a safe, effective, and specific “off-switch” to dabigatran-based anticoagulation in 
selected cases of life-threatening or uncontrolled bleeding or when in need for emergency 
surgery.
Idarucizumab should be used according the locally approved labelling information.
If the specific reversal agent for dabigatran is given, information surrounding the clinical 
circumstances, treatment and clinical outcome will be collected on the CRF of the appropriate 
trial(s).
It is at the discretion of the Investigator whether trial medication should be re-administered 
after the bleeding has resolved and haemostasis has been achieved. In the case of a temporary 
stop of dabigatran etexilate bridging therapy with a parenteral anticoagulant with e.g. UFH or 
LMWH (according to local practice) is at the discretion of the Investigator. See Appendix 
10.1 for additional information related to bridging.
A summary of how to manage bleeding events on dabigatran etexilate is presented in 
Figure 4.2.1.1: 1.


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1
For bleeding definitions see Section 5.3.5.2
2 
When appropriate
3 
Recommendations based on limited clinical or 
non-clinical data only, limited or no experience 
in volunteers or patients
4
Consider haemodialysis especially if there also 
is acute renal failure
Figure 4.2.1.1: 1 
Management of bleeding on dabigatran etexilate therapy [P10-03790]
Warfarin Treated Group
If a patient experiences a major bleed warfarin should be temporarily stopped. The 
anticoagulant effect of VKAs can be reversed with vitamin K, prothrombin complex 
concentrates and/or fresh frozen plasma. Re-administration of warfarin after the bleeding has 
resolved and haemostasis has been achieved is at the discretion of the Investigator. Bridging 
therapy, e.g. UFH until the INR has returned back to the target range, is at the discretion of 
the Investigator (see Appendix 10.1).
Minor Bleeds
4.2.1.2
If a patient experiences a minor bleed, trial medication may be continued, interrupted 
temporarily or permanently discontinued, at the discretion of the Investigator. It is not 
a requirement, however, that trial medication be stopped in these cases.
Minor bleeding1
Continue treatment, delay 
next dose, temporarily or 
permanently discontinue
treatment, as appropriate

Symptomatic treatment

Maintain adequate diuresis

Mechanical compression2

Surgical intervention2

Fluid replacement and haemodynamic 
support2

Blood product /platelet concentrate 
transfusion2

Oral charcoal application2,3 (if dabigatran 
etexilate ingestion <2hr before)

Haemodialysis2, 3, 4

Consideration of 

rFVIIa or APCC2, 3

Delay next dose, temporarily or permanently 
discontinue treatment2

If available and clinically indicated, apply 
reversal agent (idarucizumab)
Patient with bleeding on dabigatran etexilate 
therapy
Major or Life-threatening 
Bleeding1


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Emergency and Elective Surgery
4.2.1.3
Dabigatran Etexilate Treated Group
Preoperative phase, Emergency Surgery:
In the case of emergency surgery, trial medication should be discontinued. If possible, 
surgery should be postponed until 12 hours, or longer in case of renal failure, after the last 
oral intake of trial medication.
In an emergency event, a measure of anticoagulation may become necessary to manage the 
situation. A physician may consider using the TT or diluted thrombin time (dTT) (where 
available), aPTT or ECT. For an adequate interpretation of the results the time of last intake 
of dabigatran etexilate needs to be known. For further details on results of coagulation times 
expected with dabigatran etexilate, see Section on elective surgery below.
If the condition is considered life threatening and surgery cannot be postponed, consider 
measures to reduce anticoagulation as described under major bleeds. See Section 4.2.1.1.
In case of emergency surgery or urgent procedures when rapid reversal of the anticoagulation
effect is required the specific reversal agent (idarucizumab) to dabigatran may be available in
the context of a clinical trial, or from commercial supply depending on status of national
authorization.
Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying
disease. Dabigatran treatment can be re-initiated 24 hours after administration of
idarucizumab, if the patient is clinically stable and adequate haemostasis has been achieved.
Preoperative phase, Elective Surgery:
Physicians may consider the following information regarding dabigatran etexilate when 
patients need to undergo surgery or elective procedures. Provided that the patient has normal 
renal function, the onset of effect of dabigatran etexilate is within 1 hour of dosing and 
dabigatran has peak concentrations 2-3 hours after an oral dose. Steady state is reached 
within 2-3 days. Plasma levels of dabigatran at steady state will vary across the population 
and are particularly affected by renal function. Patients with renal dysfunction may have 
elevated concentrations of dabigatran due to longer half-lives of active drug (see Table 
4.2.1.3: 1). Serum creatinine should normally be checked 1-2 weeks before surgery and the 
CrCl should be calculated using the Cockcroft-Gault formula (Section 5.3.3). Patients with 
a CrCl <30mL/min during the course of this study should not be receiving trial medication 
(see Section 3.3.4.1). 
The following is a guide to the discontinuation of dabigatran etexilate (under special 
consideration of the half-life of dabigatran etexilate depending on renal function) before 
surgery taking renal function and additional risk factors into account. In patients with normal 
renal function, discontinuation of two doses of dabigatran etexilate will decrease plasma 
levels to approximately 25% of steady state trough levels and discontinuation of four doses 
will decrease dabigatran plasma levels to approximately 5-10% of steady-state trough levels.


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Table 4.2.1.3: 1
Recommendations on cessation of trial medication in relation to the 
timing of major surgery
Renal function 
(CrCl, 
mL/min)1
Estimated half-
life if on 
dabigatran 
etexilate
Stop study dabigatran etexilate before surgery
High Risk of 
bleeding2
Standard Risk
80
~ 13 hours
2 days before
24h prior (2 doses)
50 to <80
~ 15 (12-18) hours
2-3 days before
1-2 days before
30 to <50
~18 (18-24) hours
4 days before
At least 2 days (>48 hours)
<30
~ 27 (>24) hours
>5 days before
2-5 days
1
CrCl can be estimated using serum creatinine by the Cockcroft-Gault formula (see Section 5.3.3). Patients who develop 
CrCl <30mL/min during the course of the trial should have trial medication stopped (see Section 3.3.4.1). 
2
In addition to renal function, high risk determinants of bleeding risk include type of surgery, advancing age, 
comorbidities (e.g. major cardiac, respiratory or liver disease) and concomitant use of antiplatelet therapy. The type of 
surgery associated with a high risk of bleeding includes but is not limited to cardiac surgery, neurosurgery, abdominal 
surgery or those involving a major organ. Other procedures such as spinal anaesthesia may also require complete 
haemostatic function.  
The clinician should consider delaying surgery in patients at high risk of bleeding, including 
those in whom severe renal dysfunction may occur in the course of the trial (<30mL/min 
CrCl), an elevated TT or dTT (dTT only in countries where this assay is approved). If the 
TT/dTT test is not available, an aPTT, though less precise than the TT, can be used. 
A TT/dTT should be performed 6-12 hours before elective surgery and a normal result as 
defined by the local lab should be obtained before a patient undergoes surgery. A persistently 
prolonged thrombin time (TT or dTT) in the absence of heparin, fibrin/fibrinogen degradation 
products (e.g. with disseminated coagulation activation, sepsis, severe inflammation and 
other conditions) or high concentrations of serum proteins (e.g. myeloma) suggests 
persistently elevated levels of dabigatran in the blood.
In patients receiving chronic therapy with dabigatran etexilate 150 mg b.i.d., the median peak 
aPTT is approximately 63 sec 
. Assuming the baseline range of normal is 
between 22 to 40 sec (aPTT assay as used in RE-LY) this peak aPTT prolongation 
corresponds to approximately 1.5 times the upper limit of normal 
. Twelve 
hours after the last dose, the median aPTT is approx. 1.3 times upper limit of normal (median 
trough aPTT prolongation for patients receiving 150 mg b.i.d. in RE-LY: 51.9 sec), with less 
than 10% of patients exceeding 2 times upper limit of normal (90th percentile trough aPTT 
prolongation for patients receiving 150 mg b.i.d. in RE-LY: 76.4 sec) 
 
 
ECT shows a linear correlation with the plasma concentrations of direct thrombin inhibitors, 
including dabigatran. Median ECT ratios over baseline (median baseline: 30.3 sec) of approx. 
2.1 at trough (median trough ECT prolongation for patients receiving 150 mg b.i.d. in 
RE-LY: 62.9 sec) and 3.0 at peak (median peak ECT prolongation for patients receiving 
150 mg b.i.d. in RE-LY: 92.9 sec) have been observed after intake of dabigatran etexilate 150 
mg b.i.d 
. Twelve hours after the last dose, less than 10% exceed a ratio of 3.5 
from baseline (90th percentile of trough ECT for patients receiving 150 mg b.i.d. as observed 


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in RE-LY: 103 s) 
 Coagulation times should always be 
interpreted in relation to the timing of last drug intake of trial medication (peak versus trough 
dabigatran levels). The current version of the IB should be referenced for further information 
about dabigatran etexilate.
Post-procedural Period:
With the exception of cardiac surgery, dabigatran etexilate will be initiated as soon as the 
patient is haemodynamically stable and haemostasis is achieved. If oral medication is not 
feasible, bridging therapy with i.v. or s.c. UFH or s.c. LMWH should be considered at the 
discretion of the Investigator (see Appendix 10.1).
Note: In patients where renal function is impaired or procedures undertaken which may 
temporarily compromise renal function, a serum creatinine should be performed and CrCl 
calculated based on the Cockcroft-Gault formula. See Section 3.3.4.1 for how to handle 
patients receiving dabigatran etexilate and for whom CrCl drops to <30 mL/min during the 
course of the study.
Warfarin Treated Group
Preoperative Phase
Bridging therapy with a parenteral anticoagulant should be considered depending on the 
length of trial medication interruption. Bridging therapy is at the discretion of the Investigator 
and can be performed according to local practice (see Appendix 10.1 for guidance). 
Post-procedural Period
Anticoagulation can be started as soon as clinically feasible with i.v. (unfractionated) heparin
or s.c. LMWH and simultaneously with study warfarin until the INR is ≥2.0. Parenteral 
bridging therapy should be stopped when target INR is achieved (see Appendix 10.1 for 
guidance). 
Spinal Anaesthesia/Epidural Anaesthesia/Lumbar Puncture
4.2.1.4
Dabigatran etexilate and Warfarin Treated Group
Procedures such as spinal anaesthesia may require complete haemostatic function. See Table 
4.2.1.3: 1 for recommendations on when to stop dabigatran before spinal/epidural 
anaesthesia. For patients randomised to Warfarin, INR measurements should be performed to 
ensure that coagulation is under control.
The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated 
puncture and by the prolonged use of epidural catheters. After removal of a catheter, resume 
treatment with trial medication after complete haemostasis is achieved, but at minimum an 
interval of one hour should elapse for all patients. These patients require frequent observation 
for neurological signs and symptoms of spinal or epidural haematoma.
Stroke of non-CVT origin
4.2.1.5
Patients with documented or suspected stroke of non-CVT origin should be managed 
according to usual clinical practice. It is anticipated that in most cases trial medication will be 


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withheld until a CT or MRI scan has been obtained and diagnosis has been made. For 
recommendations regarding a new CVT or worsening of symptoms of the index CVT, refer 
to Section 4.2.1.6.
Ischaemic stroke 
For ischaemic stroke usual clinical practice may be followed, which may include 
administration of ASA and/or clopidogrel, or ASA/dipyridamole (the latter in lieu of 
clopidogrel). The decision whether or not to continue administration of the trial medication is 
at the discretion of the local Investigator, also taking into account the possible presence of
bleeding [P13-06400].
Fibrinolytics may be considered for ischaemic stroke, if the patient presents with a TT, dTT, 
ECT, or (if TT, dTT or ECT are not available) an aPTT lab result not exceeding the upper 
limit of normal (ULN) according to the local reference range for patients receiving dabigatran 
etexilate, or if the INR is ≤ 1.7 in patients receiving warfarin.
Haemorrhagic stroke 
For haemorrhagic stroke (not directly related to CVT) or other intracranial bleeding, 
consultation with a coagulation expert and a neurosurgeon is recommended. 
See Section 4.2.1.1 and Figure 4.2.1.1: 1 for details relating to how to manage bleeding on 
dabigatran etexilate or warfarin.
Reintroduction of trial treatment following a stroke
Dabigatran Etexilate Treated Group
The decision for restarting dabigatran etexilate following a stroke is at the discretion of the 
Investigator. For the timing of restarting anticoagulation after stroke event clinical 
recommendations should be consulted [P12-02400]. The following recommendations on 
when to restart dabigatran etexilate are provided for guidance only: In general, dabigatran 
etexilate can be restarted after a TIA as soon as imaging has excluded a cerebral 
haemorrhage. For mild, moderate and severe stroke, expert recommendations [P12-02400] 
suggest restarting dabigatran etexilate 3-5 days, 5-7 days, and 2 weeks after stroke onset, 
respectively.
Warfarin Treated Group
The decision for restarting study warfarin following a stroke and its exact timing is at the 
discretion of the Investigator.
Venous thrombotic event (VTE)
4.2.1.6
CVT
A new event of CVT occurring during the trial treatment period, as well as worsening 
symptoms such as an ischaemic stroke as a result of the index CVT, should be treated 
according to current AHA/ASA and EFNS guidelines [R15-5005; P10-11802]. Trial 
treatment should be interrupted while the patient is being treated with other antithrombotic
therapy or with other medication that is restricted per Section 4.2.2.1. The decision for
restarting trial treatment is at the discretion of the Investigator.


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DVT, PE or splanchnic vein thrombosis
An event of DVT, PE or splanchnic vein thrombosis occurring during the trial treatment 
period should be treated according to local clinical practice. Trial treatment should be 
interrupted if the patient is being treated with other anticoagulation therapy or with other 
medication that is restricted per Section 4.2.2.1. The decision for restarting trial treatment is 
at the discretion of the Investigator. 
Renal failure
4.2.1.7
See Section 3.3.4.1 for instructions in case CrCl drops to below 30mL/min in a patient 
randomised to receive dabigatran etexilate.
Other Medical Intervention
4.2.1.8
Other Minor Procedures:
Dabigatran Etexilate Treated Group
In the case of other elective procedures or minor surgery, dabigatran etexilate can be 
continued until 24 hours before the procedure. For the timing of treatment interruption before 
the procedure see also Table 4.2.1.3: 1.
Warfarin Treated Group
For patients randomised to Warfarin, refer to Section 4.2.1.3.
Reintroduction following medical intervention
Dabigatran Etexilate Treated Group
Dabigatran etexilate can be re-commenced at the cessation of parenteral anticoagulant 
treatment according to the same regimen as at randomisation, provided clinically indicated 
and in accordance with the recommendations in Appendix 10.1. 
Warfarin Treated Group
For patients randomised to Warfarin, refer to Section 4.2.1.3.
Overdose
4.2.1.9
Overdose following administration of dabigatran etexilate may lead to haemorrhagic 
complications due to its pharmacodynamic properties. In cases of suspected overdose it may 
be advisable to assess the anticoagulation status of a patient. A TT measure with the 
calibrated Hemoclot® thrombin inhibitor assay indicating a dabigatran plasma concentration 
of >200ng/mL (approximately >65 seconds) prior to the next drug intake after 150 mg twice-
daily dosing (trough measure, i.e. 10-16 hours after the last drug intake) may be associated 
with an increased risk of bleeding. An aPTT test may be useful to assist in determining an 
excess of anticoagulant activity, despite its limited sensitivity. An aPTT > 2-fold ULN at 
trough, i.e. when the next dose is due, may be associated with a higher risk of bleeding.
For a summary how to manage bleeding events on dabigatran etexilate see also Section 
4.2.1.1 and corresponding Figure 4.2.1.1: 1.


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If an overdose is associated with bleeding, see the advice given in Section 4.2.1.1. and 
4.2.1.2.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
The following treatments should not be taken during the active treatment phase of the trial:

Fibrinolytic agents (see Section 4.2.1.5 for exceptions)

GPIIb/IIIa antagonists (e.g. abciximab, tirofiban)

Rivaroxaban, apixaban and edoxaban, or other oral anticoagulants (e.g. VKAs)

Treatment with systemic ketoconazole, itraconazole, posaconazole, cyclosporine, 
tacrolimus and dronedarone, and rifampicin, carbamazepine, phenytoin and St. John’s 
Wort

Any type of dual antiplatelet therapy
Patients suffering from seizures

Patients with CVT often have seizures, requiring anticonvulsive treatment. Due to 
(a potential for) interactions with dabigatran etexilate and warfarin, phenytoin and 
carbamazepine should not be used in those cases. It is possible to use levetiracetam 
instead, if available.
Precautions regarding concomitant treatment
4.2.2.2
General precautions
ASA, dipyridamole, clopidogrel, ticagrelor, prasugrel, corticosteroids, or non-steroidal anti-
inflammatory drugs (NSAIDs) may be used if clinically indicated according to current 
treatment guidelines but it is strongly recommended to avoid these if possible. The patients 
should be advised to not use ASA-containing over-the-counter medications on a regular 
basis. In case of the need for pain relief, the use of acetaminophen, diclofenac or ibuprofen 
instead of ASA should be considered where appropriate. The use of these medications should 
be limited to the absolute minimum possible time period.
Co-administration of oral anti-platelet (including ASA) and NSAID therapies increase the 
risk of bleeding 
.
For any drug potentially increasing the risk of bleeding the factor age needs to be considered 
as the effect may be more pronounced in elderly patients (≥75 years). If bleeding is clinically 
suspected, appropriate measures such as testing for occult blood in stool, or testing for a drop 
in haemoglobin is suggested 
. Investigators should assess the benefit-risk of 
the concomitant use of drugs that can promote bleeding, e.g., NSAIDs, corticosteroids and 
ASA, other anticoagulants and use them only when the benefits are thought to outweigh the 
risks.


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Dabigatran Etexilate Treated Group
The Investigator is alerted to the use of concomitant administration of moderate to strong 
P-gp inhibitors in patients receiving dabigatran etexilate (e.g. such as amiodarone, verapamil, 
quinidine, nelfinavir, ritonavir, saquinavir and tipranavir+ritonavir or lopinavir+ritonavir) or 
P-gp inducers due to a potential risk of higher or lower plasma levels of dabigatran and 
consequent exaggerated or reduced pharmacodynamic effect of dabigatran etexilate (notably 
bleeding or thromboembolic risk). Concomitant use of such drugs is not prohibited in this 
study per se (except for treatment with ketoconazole, itraconazole, posaconazole, 
cyclosporine, tacrolimus, dronedarone, rifampicin, phenytoin, carbamazepine or St. John’s 
Wort), but should be used with caution or, at Investigator discretion, switched to a suitable 
alternative. 
For patients in the RE-LY study who were concomitantly treated with verapamil, average 
dabigatran plasma concentrations increased by only 16% at trough and 20% two hours post-
dose. Accordingly, the annualised bleeding rates in patients who had used verapamil at least 
once together with warfarin, dabigatran etexilate 110 mg b.i.d. or 150 mg b.i.d. were 3.33%, 
3.09% and 3.92%, respectively. If verapamil is initiated during the course of this trial, it 
should be considered to separate the timing of administration of dabigatran etexilate and 
verapamil. 
If dabigatran etexilate is given at least two hours before verapamil particularly in the first 
three days, the increase of dabigatran exposure will be reduced compared to taking verapamil 
and dabigatran etexilate at the same time-point.
In the RE-LY study, concomitant administration of amiodarone or quinidine and dabigatran 
etexilate did not increase the relative risk of bleeding compared to patients on warfarin and 
amiodarone or quinidine. As with verapamil separation of administration (dabigatran 
etexilate given at least two hours before any P-gp inhibitor) will mitigate any potential risk of 
drug interaction.
A list of common P-gp inhibitors will be provided in the ISF.
The concomitant use of dabigatran etexilate with the following treatments has not been 
studied and may increase the risk of bleeding: UFHs (except at doses necessary to maintain 
patency of central venous or arterial catheter) and heparin derivatives, LMWHs, 
fondaparinux, desirudin, ticlopidine, dextran, sulfinpyrazone, prasugrel, direct thrombin 
inhibitors, VKAs.
Bleeding risk may be increased in patients concomitantly treated with selective serotonin re-
uptake inhibitors 
 or selective serotonin norepinephrine re-uptake inhibitors 
.


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Warfarin Treated Group
Patients randomised to receive warfarin must be aware of the potential risk of over- or under 
dosing with changes of co-medications (e.g. use of antibiotics), including over the counter 
medicines, herbal remedies or vitamin preparations.
For more specific advice on potential interactions with warfarin and on how to handle those, 
please refer to the summary of product characteristics that will be provided in the ISF.
Restrictions on diet and life style
4.2.2.3
Dabigatran etexilate can be taken with or without food. There are no specific dietary 
restrictions with dabigatran etexilate, whereas patients randomised to warfarin need to follow 
dietary instructions regarding their vitamin K intake. They must also be aware of the potential 
risk of over- or under dosing with concomitant diseases (e.g. diarrhoea).
Restrictions regarding women of childbearing potential
4.2.2.4
WOCBP must be ready and able to use highly effective methods of birth control per 
International Conference on Harmonization M3(R2) [R09-1400] that result in a low failure 
rate of less than 1% per year when used consistently and correctly. This includes:

Placement of intrauterine device (IUD) or intrauterine system (IUS; e.g. Mirena
(IUS with low dose progesterone))

Bilateral tubal occlusion

Male sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate)

Complete sexual abstinence
Periodic abstinence, e.g. calendar, ovulation, symptothermal, post-ovulation methods, and 
withdrawal are not considered acceptable methods of contraception based on the above 
criterion of low failure rate of less than 1% per year.
Highly effective methods of contraception should be applied from signing of informed 
consent until the follow-up visit (Visit 6).
WOCBP are defined as:
Any female who has experienced menarche and does not meet the criteria for "women not of 
childbearing potential" as described below.
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an alternative medical 
cause) or who are permanently sterilized (e.g., hysterectomy, bilateral oophorectomy or 
bilateral salpingectomy).
Please also refer to the inclusion and exclusion criteria for this study (see Sections 3.3.2
and 3.3.3)


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In the case of male patients participating in the trial, since there is no documented evidence to 
suggest a risk to sperm quality (for either dabigatran etexilate or warfarin), no special 
consideration is required.
TREATMENT COMPLIANCE
4.3
Principles regarding the evaluability of non-compliant patients will be outlined in the Trial 
Statistical Analysis Plan (TSAP). Decisions about evaluability of patients will be made at the 
Blinded1 Report Planning Meeting and at the latest prior to database lock.
Patient randomised to receive dabigatran etexilate
Based on capsule counts, treatment compliance will be calculated as the number of capsules 
taken, divided by the number of capsules which should have been taken according to the 
scheduled period, multiplied by 100.
Doses taken on the current visit day will be excluded from the count and doses taken on the 
previous visit day will be included in the count.
Treatment compliance (%) =
Number of tablets actually taken 100
Number of tablets which should have been taken2
A patient will be considered as non-compliant if the number of doses taken is not between 
80-120% of the expected number of doses. If compliance does not meet this range the patient 
should be asked to provide an explanation and be re-informed about the purpose and conduct 
of the trial. Non-compliance should be discussed with BI.
Patient randomised to receive warfarin
Warfarin compliance will be monitored by means of the INR rather than by pill counts as it is 
a more accurate and biologic measure of pharmacodynamic effect. 
The quality of warfarin therapy for each patient will be assessed by reporting the number of 
INR values within the indicated therapeutic target range (2.0 – 3.0) as well as those above 
and below this range. The Rosendaal method [R08-1695] will be used to evaluate the 
percentage of time that a patient’s INR is in range (i.e. time in therapeutic range (TTR)). For 
each calendar month, the mean of all INR values will be reported. This will be calculated for 
each patient, for each centre, for each country and for the whole study. The mean percentage 
of time of INR in range will be calculated for each centre and each country during the trial 
conduct to monitor the INR control. The percentage of time of INR in range for each country 
and for the trial will be reported at study end.
                                                
1 Despite the trial being open label, medical and quality review will be performed without reference to the trial treatment that 
the patient receives.
2 The number of tablets which should have been taken should take into account any temporary interruptions in trial 
medication


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint(s)
The primary endpoint for this trial is the composite of the number of patients with major 
bleeding according to ISTH criteria and VTE (recurring CVT; DVT of any limb, PE,
splanchnic vein thrombosis) after up to 24 weeks. All components are adjudicated in a 
blinded manner by an AC.
5.1.2
Secondary Endpoint(s)
All secondary endpoints will be based on adjudicated data (except for any bleeding event).
The secondary efficacy endpoints are:

Number of patients with recurring CVT; DVT of any limb, PE or splanchnic vein 
thrombosis after up to 24 weeks

Cerebral venous recanalisation as measured by the change in number of occluded 
cerebral veins and sinuses after up to 24 weeks
The secondary safety endpoints are:

Number of patients with major bleeding according to ISTH criteria after up to 24 
weeks

Composite endpoint of number of patients with new ICH or worsening of the 
haemorrhagic component of a previous lesion after up to 24 weeks

Number of patients with CRNMBE after up to 24 weeks

Number of patients with major bleeding according to ISTH criteria or CRNMBE after 
up to 24 weeks

Number of patients with any bleeding event after up to 24 weeks


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5.1.4
Classification of endpoints for trial disclosure purposes
This trial and its results will be publicly disclosed. Disclosure of trial endpoints should 
include information as to whether or not the endpoint pertains to a known safety issue. For 
that purpose the primary endpoint (major bleeding according to ISTH criteria and VTE) and 
all secondary safety endpoints (major bleeding according to ISTH criteria, composite 
endpoint of new ICH or worsening of the haemorrhagic component of a previous lesion, 
CRNMBE, the composite of major bleeding according to ISTH criteria or CRNMBE, and the 
endpoint of any bleeding events) are considered to pertain to a known safety issue. The other 
endpoints are not.
ASSESSMENT OF EFFICACY
5.2
5.2.1
Venous thrombotic events
VTE should meet the following criteria:
CVT
New neurological signs / symptoms or worsening of previous signs / symptoms with new 
CVT on neuroimaging.
New CVT must be confirmed by the AC by review of appropriate imaging as mentioned in 
Section 3.3.1 for the qualifying CVT.
DVT (of any limb)
DVT is generally documented by one of the following:

Abnormal compression ultrasonography

An intraluminal filling defect on venography

At autopsy
Any suspected DVT must be confirmed by the AC by review of images and/or reports of 
venous compression ultrasonography or of venography.
Splanchnic vein thrombosis
The presence of endoluminal material or absence of flow in the extrahepatic portal veins or 
mesenteric veins as shown by duplex-Doppler ultrasound, or contrast-enhanced CT scan or 
MRI.
Any suspected splanchnic vein thrombosis must be confirmed by the AC by review of images 
and/or reports of above mentioned imaging techniques.
PE
Pulmonary embolism is generally documented by one of the following:

An intraluminal filling defect in segmental or more proximal branches on spiral CT 
scan


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
An intraluminal filling defect or an extension of an existing defect or a sudden cut-off 
of vessels more than 2.5 mm in diameter on the pulmonary angiogram

Perfusion defect of at least 75% of a segment with a local normal ventilation result 
(high-probability) on ventilation/perfusion lung scan

Inconclusive spiral CT, pulmonary angiography or lung scintigraphy with 
demonstration of DVT in the lower extremities by compression ultrasonography or 
venography

At autopsy
Any suspected PE must be confirmed by the AC by review of images and/or reports of any of 
the above in order to be considered a PE.
These events will be assessed based on clinical information and supporting imaging. No 
specific imaging will be required to be performed, but events will only be considered as 
confirmed if images as indicated above (from routine medical practice) that support the 
diagnosis are available.
Note: the endpoint of new VTE does NOT include retinal thrombosis
 
 


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5.2.6
Cerebral venous recanalisation
Cerebral venous recanalisation will be assessed by imaging and will be adjudicated by the
AC. Due to the specific skills that are required to assess recanalisation, an investigator 
assessment of this endpoint will not be requested.
 Recanalisation as a secondary 
efficacy endpoint will be assessed as described below, analogues to the calculations made by 
Miranda et al [R16-2716].
1. At baseline and at the end of treatment, occlusion of cerebral veins and sinuses will be 
scored as follows:
1 = full occlusion
0 = no occlusion or partial occlusion
2. This score will be applied to each of the veins and sinuses using the below 
conventions:

Superior sagittal sinus, straight sinus, cavernous sinus, left jugular vein, right 
jugular vein will each be scored individually (i.e. each will be scored as either 
0 or 1)


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
Right lateral transverse and sigmoid sinus will be scored together (i.e. 0 points if 
neither is fully occluded; 1 point if at least one of them is fully occluded)

Left lateral transverse and sigmoid sinus will be scored together (i.e. 0 points if 
neither is fully occluded; 1 point if at least one of them is fully occluded)

Superior petrous sinus and inferior petrous sinus will be scored together (i.e. 0 
points if neither is fully occluded; 1 point if at least one of them is fully occluded)

Deep venous system will be scored as system, irrespective of the number of 
occluded veins (i.e. 0 points if none is fully occluded; 1 point if at least one is 
fully occluded)

Superficial cortical veins will be scored as system, irrespective of the number of 
occluded veins (i.e. 0 points if none is fully occluded; 1 point if at least one is 
fully occluded)

Cerebellar veins will be scored as system, irrespective of the number of occluded 
veins (i.e. 0 points if none is fully occluded; 1 point if at least one is fully 
occluded)
3. For each individual patient a total score will be calculated at baseline and at the end of 
treatment.
4. A recanalisation score will subsequently be calculated for each patient as the 
difference between the baseline total score and the end of treatment total score.
 
 
 
Patients who died during the trial before an EOT scan is made and patients for whom for 
other reasons no EOT scan is available or analyzable will not be included in the analysis of 
recanalisation (this applies to change in number of occluded cerebral veins and sinuses 
 


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Diagnosis of CVT and assessment of venous occlusion is expected to be performed by any of 
the following techniques or a combination of them:

MRI + MR venography

CT + CT venography

MRI or CT in combination with angiography (DSA)
Patients are diagnosed prior to trial entry. The imaging that was performed for diagnosis of 
CVT (as part of the clinical routine) will be used as baseline assessment.
At EOT the assessment of recanalisation must be done by MRI+MR venography. These 
techniques are expected to provide a better view of any remaining venous occlusion than CT 
would. Furthermore, for WOCBP it is desirable to refrain from CT scans in the non-acute 
setting due to radiation exposure of CT scans.
A separate MRI protocol will be provided as part of the ISF and should be followed for the 
EOT imaging.
All scans (both baseline and EOT) will be sent in for central review by the AC. Review 
criteria will be outlined in the AC charter governing the adjudication process. Details on how
to provide the images will be provided in the ISF. Central review will focus on assessment of 
endpoints (grade of cerebral venous recanalisation / recurrence of CVT).
 
 
 
 
 


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ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A complete physical examination will be performed by the Investigator at the visits indicated 
in the Flow Chart. Documentation of the physical examination and any findings must be part 
of the source documents available at the site.
5.3.2
Vital Signs, body weight and height
Systolic and diastolic BP and Pulse Rate should be performed at the visits indicated in the 
Flow Chart. The testing should be performed after resting for at least five minutes. For each 
patient, all BP recordings should be made using the same type of instrument (i.e. manual BP 
recording vs. automatic digital vital signs monitor) on the same arm if possible. Weight 
should be measured at the visits indicated in the Flow Chart in order to calculate CrCl 
according to Cockcroft-Gault (see Section 5.3.3). Height should be measured at the screening 
visit.
5.3.3
Safety laboratory parameters
All blood samples can be taken in a fasting or non-fasting condition.
Blood samples for safety testing will be analysed at the local laboratory and results will be 
recorded in the CRF. Testing should be done at visits as specified in the Flow Chart. The tests 
to be performed are listed in Table 5.3.3: 1.
If medically indicated, laboratory parameters may be retested or followed-up on as 
unscheduled tests.
Table 5.3.3: 1
Safety laboratory parameters
Chemistry
Haematology 
ALT (SGPT)
Erythrocytes
AST (SGOT)
Haemoglobin
Alkaline Phosphatase
Haematocrit
Bilirubin total, fractionated if increased
Platelet Count
GGT
WBC count
Creatinine
CrCl**
**
According to Cockcroft-Gault formula
Pregnancy Testing
A pregnancy test will be performed locally on all women of child bearing potential at the 
visits as specified in the Flow Chart. A urine test is acceptable, unless local regulations 


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demand a serum test to be performed.
In addition, women of child bearing potential will be supplied with pregnancy tests and will 
be instructed to perform pregnancy testing every 4 weeks when visits are more than 4 weeks 
apart.
Renal Function Measurements
Renal function must be measured before enrolling a patient in the trial, and at visits as 
indicated in the Flow Chart (safety laboratory tests). CrCl will be calculated using the 
Cockcroft-Gault formula, as follows:

For creatinine in Mol/L:
(140-age [years]) weight [kg] x 1.23 (0.85 if female)
serum creatinine [Mol/L]

For creatinine in mg/dL:
(140-age [years]) weight [kg] (0.85 if female)
72 serum creatinine [mg/dL]
5.3.4
Electrocardiogram
12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be performed using the site’s own 
devices at the visits indicated in the Flow Chart. The ECGs must be evaluated by the 
Investigator or a designee immediately, for investigation or treatment if necessary.
5.3.5
Other safety parameters (safety endpoints)
Composite endpoint of new haemorrhagic brain lesion or worsening of the 
5.3.5.1
haemorrhagic component of a previous lesion
The neuroimaging which established the diagnosis of CVT will be used as baseline value. 
The safety endpoint “new haemorrhagic brain lesion or worsening of the haemorrhagic 
component of a previous lesion” will be assessed by comparing repeated neuroimaging that is 
routinely performed if the patient has a neurological worsening during the trial, or at the EOT 
visit, to the baseline image. The comparing of images and the categorisation of the lesions
(see below) will be done by the AC.
A separate MRI protocol will be provided as part of the ISF and should be followed for the 
EOT imaging.
In order to assess any worsening of previous lesions, haemorrhagic brain lesions at baseline 
and during treatment / at EOT will be categorised as indicated in Table 5.3.5.1: 1 below, 
according the definitions as recommended by Von Kummer et al [P15-09432]:


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Table 5.3.5.1: 1
Categorisation of haemorrhagic brain lesions
Class
Type
Description
1
Haemorrhagic transformation of infarcted brain tissue
1a
HI-1*
Scattered small petechiae, no mass effect
1b
HI-2
Confluent petechiae, no mass effect
1c
PH-1*
Haematoma within infarcted tissue, occupying <30%,
no substantive mass effect
2
Intracerebral haemorrhage within and beyond infarcted brain tissue
PH-2
Haematoma occupying 30% or more of the infarcted tissue,
with obvious mass effect
3
Intracerebral haemorrhage outside the infarcted brain tissue
or intracranial-extracerebral haemorrhage
3a
Parenchymal haematoma remote from infarcted brain tissue
3b
Intraventricular haemorrhage
3c
Subarachnoid haemorrhage
3d
Subdural haemorrhage
*
HI: haemorrhagic infarction; PH: parenchymatous haematoma
Any new haemorrhagic brain lesion will be categorised as Class 3 (Intracerebral haemorrhage 
outside the infarcted brain tissue or intracranial-extracerebral haemorrhage).
If there is more than one haemorrhagic lesion present on imaging, the category of the most 
severe lesion is assigned.
Bleeding
5.3.5.2
All bleeding events that occur after signing of informed consent will be collected. Depending 
on the specific endpoint, events that occur after randomisation to trial medication or events 
that occur after first intake of trial medication will be part of the analysis of the bleeding 
events. See Section 7.3 for more details.
Patients should be carefully assessed for signs and symptoms of bleeding. Bleeding will be 
classified as major or minor. Major bleeds will be further sub-classified as fatal and other 
major bleeds. The location of the bleeding including the specific critical area or organ into 
which the bleeding occurred and whether or not it prolongs hospitalisation will be recorded. 
MBEs and CRNMBEs will be reviewed by the AC.


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The following definitions are specified for bleeds:
Definition of a major bleed
Major bleeds will be defined according to the ISTH definition of a major bleed, as follows 
[R05-0344]:

Symptomatic bleeding in a critical area or organ, such as intracranial1, intraspinal, 
intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with 
compartment syndrome 
and/or

Bleeding associated with a reduction in haemoglobin of at least 2g/dL (1.24mmol/L)
within 24 hours, or leading to transfusion of two or more units of blood or packed 
cells2
and/or

Fatal bleed
Definition of a life-threatening bleed
For the purpose of exclusion criterion 5, life-threatening bleeds are defined as follows:

Symptomatic intracranial bleed
and/or

reduction in haemoglobin of at least 5g/dL
and/or

transfusion of at least four units of blood or packed cells, associated with hypotension 
requiring the use of i.v. inotropic agents
and/or

necessitates surgical intervention.
Definition of intracranial haemorrhage (ICH)
ICH comprises the subtypes of intracerebral bleeds, subdural bleeds, epidural bleeds and 
subarachnoid bleeds and will be recorded.
Definition of a fatal bleeding
Fatal bleeding is defined as a bleeding event that the AC determines as the primary cause of 
death or contributing directly to death.
                                                
1 A seizure associated with a new intracranial bleed will be considered a symptomatic bleeding in a critical organ.
2 Bleeding should be overt and the haemoglobin drop should be considered to be due to and temporally related to the 
bleeding event.


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Definition of a CRNMBE
A CRNMBE is a clinically overt bleed that does not meet the criteria for a major bleed but 
prompts a clinical response, in that it leads to at least one of the following:

A hospital admission (i.e. overnight stay in the hospital) for bleeding
or

A physician guided medical or surgical treatment for bleeding
or

A physician guided change, interruption1 or discontinuation of trial medication
Any bleed
This is the sum of all major and non-major bleeds.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event (AE)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have 
a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility. Adverse reactions may arise from use 
of the product within or outside the terms of the marketing authorisation or from occupational 
exposure. Conditions of use outside the marketing authorization include off-label use, 
overdose, misuse, abuse and medication errors.
Serious adverse event (SAE)
An SAE is defined as any AE which:

results in death

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have
caused death if more severe

requires inpatient hospitalisation or

prolongation of existing hospitalisation
                                                
1 Interruption of trial medication (more than omitting one dose) due to the bleeding event.


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
results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect
or

is to be deemed serious for any other reason if it is an important medical event when
based upon appropriate medical judgment which may jeopardise the patient and may
require medical or surgical intervention to prevent one of the other outcomes listed in
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalisation or development of dependency or
abuse. 
Any suspected transmission via a medicinal product of an infectious agent is 
considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence 
of the cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of further AEs, which by their nature, can always be considered to be 
“serious” even though they may not have met the criteria of an SAE as given above.
The latest list of “Always Serious AEs” can be found in the RDC system. These events 
should always be reported as SAEs as described in Section 5.3.7.
Adverse events of special interest (AESIs)
No AESIs have been defined for this trial.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.


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Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. 
pre-existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial medication treatment continues or 
remains unchanged.
5.3.7
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files. The 
following must be collected and documented on the appropriate CRF by the Investigator:

From signing the informed consent onwards through the follow-up period (which 
includes the Residual Effect Period (REP)), until individual patient’s end of trial (for 
patients who discontinue trial medication early, this includes the extended follow-up 
period):
o
All AEs (serious and non-serious)

After the individual patient’s end of trial:
o
The Investigator does not need to actively monitor the patient for AEs but 
should only report relevant SAEs which the Investigator may become aware of
The AE reporting requirements are displayed in Figure 5.3.7: 1.


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Figure 5.3.7: 1AE reporting requirements
The REP is defined as 6 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment (see Section 7.3.4). Events which occurred after the REP will be considered 
as post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, and non-serious AEs which are relevant for the reported 
SAE, on the BI SAE form via fax immediately (within 24 hours) to the sponsor’s unique 
entry point (country specific contact details will be provided in the ISF). The same timeline 
applies if follow-up information becomes available. In specific occasions the Investigator 
could inform the sponsor upfront via telephone. This does not replace the requirement to 
complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication.
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions.
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.


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Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the sponsor’s unique entry point (country-
specific contact details will be provided in the ISF). The Pregnancy Monitoring Form for 
Clinical Trials (Part A) should be used. 
The outcome of the pregnancy associated with the DEDP must be followed up and reported 
to the sponsor’s unique entry point on the Pregnancy Monitoring Form for Clinical Trials 
(Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Not applicable
5.4.2
Methods of sample collection
Not applicable
5.4.3
Analytical determinations
Not applicable
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Not applicable
 


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OTHER ASSESSMENTS
5.6
5.6.1
CVT risk score
The CVT risk score is assessed for each patient at baseline for characterisation of the patient 
population. The score is applied as described by Ferro et al [R15-5237].
Prognostic variable
Risk points
Malignancy
2
Coma
2
Thrombosis of the deep venous system
2
Mental status disturbance
1
Male gender
1
ICH
1
The scores for the individual variables are summed up to arrive at the CVT risk score.
The following definitions apply:
Coma
Persistent disturbance of consciousness, patient being non-alert and non-arousable, with 
a Glasgow Coma Scale score measured at admission of < 9 points.
Mental status disturbance
Includes executive deficits (frontal lobe syndromes), delirium and personality or other acute 
behavioural changes, but not disturbances of the instrumental cognitive domains, such as 
aphasia, apraxia, agnosia, amnesia or visuospatial disturbances, present from onset of 
symptoms to the day of the diagnosis.
Intracranial haemorrhage
Any ICH, including haemorrhagic transformation of a venous infarct, detected on the 
admission neuroimaging (CT or MR).
Thrombosis of the deep venous system
Thrombosis of any of the veins of the deep cerebral venous system (Rosenthal’s basal vein, 
inferior longitudinal sinus, thalamo-striate vein), isolated or in combination with thrombosis 
of other veins or sinus.
Malignancy
Any malignant tumour in any location of the body or any haematological malignancy 
(leukaemia or lymphoma), diagnosed before CVT or during hospitalisation for acute CVT.


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5.6.2
National Institutes of Health Stroke Scale
The National Institutes of Health Stroke Scale (NIHSS) will be recorded, if it had been 
collected at the time of qualifying (index) CVT. In patients, where NIHSS has not been done 
at the time of index CVT, it will be performed at study entry (at Visit 1). It is a tool used by 
healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is 
composed of 11 items, and for each item a score of 0 typically indicates normal function in 
that specific ability, while a higher score is indicative of some level of impairment. The 
individual scores from each item are summed in order to calculate a patient's total NIHSS 
score. The maximum possible score is 42, with the minimum score being a 0 [R13-4008, 
R13-4023, P13-10973].
Score
Stroke Severity
0
No Stroke Symptoms
1-4
Minor Stroke
5-15
Moderate Stroke
16-20
Moderate to Severe Stroke
21-42
Severe Stroke
The NIHSS is located in Appendix 10.3.
 
 
 
 
 
 
 
 
 
APPROPRIATENESS OF MEASUREMENTS
5.7
All used methods are standard and generally recognized.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
Informed consent of all study patients (or their legally acceptable representative) will be 
obtained in compliance with the International Conference on Harmonization and GCP 
guidelines and the principles stipulated in the Declaration of Helsinki prior to any study 
related procedure.
The study will consist of three sequential periods, a Screening Period of up to 15 days, 
a Treatment Period of 24 weeks and a Follow-up Period of one week. If a patient 
discontinues trial medication prior to completing 24 weeks of treatment, he/she will be 
followed up until 25 weeks after randomisation. Their trial participation will then end.
The schedule for trial visits is summarised in the study Flow Chart including time windows 
for study visits. All visit dates are calculated from the date of randomisation. In the event that 
visits are missed or performed late, subsequent visits will be planned according to the date of 
randomisation.
There is no requirement for clinic visits to take place at a specific time of day.
Visits 1 and 2 may take place on the same day (see also Flow Chart and Section 6.2.2). In that 
case Visit 2 procedures that are performed as part of Visit 1 do not need to be repeated.
It is anticipated that most patients are still hospitalised for their CVT at the time of 
randomisation. Investigators should ensure that all required procedures of trial visits are 
performed at the scheduled time points, even if the patient is still hospitalised. The allowed 
visit windows (see Flow Chart) can be used in order to avoid having patients return to the 
trial centre for a trial visit within a few days from hospital discharge.
No protocol waivers will be given (e.g. sponsor will not grant permission to include a known 
ineligible patient). In the case of medical emergencies, prior approval from the sponsor for 
protocol deviations (e.g. visit schedule) will not be required, but BI should be notified as soon 
as possible. The relevance of any such protocol deviation will be assessed prior to analysing 
the data.
The procedures to be conducted at each visit are provided in the Flow Chart and further 
described in Section 6.2.


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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening period
Screening Period
Patients may be enrolled into the trial (i.e. sign informed consent) once they have a confirmed 
diagnosis of CVT and have received any required treatment for the acute phase of the illness
as recommended by the AHA/ASA [R15-5005] and EFNS [P10-11802]. See Sections 3.1 and 
4.1.4. Written informed consent must be obtained prior to any study specific procedures.
It is anticipated that the majority of Screening procedures (see Flow Chart) will already have 
been performed as part of the routine care during hospitalisation and diagnosis. Trial related
data from these procedures will be used for the trial and the procedures should not be 
repeated for the purpose of the trial. Any trial procedures that were not performed as part of 
routine care yet, should only be performed after informed consent has been obtained.
Brain images (i.e. CT, CT venography, MRI, MRI venography, or other) related to the 
qualifying CVT and any imaging performed during the trial (both those required by the Flow 
Chart as well as those performed as part of medical care) plus their corresponding reports 
must be provided to sponsor’s designee where possible.
Baseline Conditions
The individual components of the CVT risk score and of the NIHSS will also serve as 
documentation of baseline conditions. In addition conditions relevant to the current CVT and 
symptoms of CVT not captured by the two scores mentioned above will be collected.
Medical History:
Data on any history of thromboembolic events and haemorrhagic events, including detailed 
history of the qualifying CVT, data on cardiovascular disease, known coagulopathies, other 
risk factors for VTE (including CVT) and any other relevant medical and surgical history will 
be collected.
6.2.2
Treatment period(s)
All assessments for the visits in the treatment phase are detailed in the Flow Chart.
After eligibility has been confirmed and all Visit 1 procedures completed, Visit 2 can be
conducted including randomisation via IRT. IRT should not be called in advance of Visit 2,
as randomisation of a patient cannot be reversed.
At the start of Visit 2, it should be ensured that all Visit 1 procedures have been successfully
completed. Visit 2 procedures are outlined in the Flow Chart. Restricted medications as 
outlined in Section 4.2.2 will be stopped if applicable.
Randomisation should occur as soon as the patient is stable and patient eligibility is 
confirmed, at 5 days (120 hours) and up to a maximum of 15 days (360 hours) after start of 
initial parenteral therapy (LMWH or UFH) (see Sections 3.1 and 4.1.4). 


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Trial medication will be dispensed and should be initiated as outlined in Section 4.1.4. 
In short, patients randomised to receive warfarin will start trial medication on the day of 
randomisation. They must continue to receive LMWH / UFH until the patient’s INR ≥2.0 
(one measurement). At that moment LMWH / UFH will be discontinued. If they are on oral 
anticoagulation (VKA) at the moment of randomisation, it needs to be confirmed that INR is 
<3.0 before trial medication is started. If the INR is ≥3.0, warfarin must not be started until 
the INR is <3.0.
Patients randomised to receive dabigatran etexilate will also start trial medication on the day 
of randomisation if they are not on oral anticoagulation (VKA) or if the INR is <2.0. The first 
dose (capsule) of dabigatran etexilate should be given 0-2 hours prior to the time that the next 
dose of the initial parenteral therapy would be due, or at the time of discontinuation in case of 
continuous treatment (e.g. i.v. UFH).
If the patient is on oral anticoagulation with a VKA for their CVT and the INR is ≥2.0, trial
medication can be dispensed but the patient will be instructed not to start it until notified. 
No further parenteral anticoagulation or VKA should be given. Follow-up INRs will be 
performed in 1-3 day intervals until it falls below 2.0, at which time the patient will be 
instructed by telephone to start taking the trial medication.
Patients will take trial medication until 24 weeks after randomisation.
AEs and SAEs, including specified endpoints, will be collected as described in Section 5.1, 
Section 5.2 and Section 5.3.
Treatment visits will take place as indicated in the Flow Chart.
Unscheduled visits will be possible at any time, specifically in the first 3 months after
treatment initiation, in order to check the safety of the patient including a potential worsening
of renal function (CrCl). It is at the discretion of the investigator to perform an unscheduled
visit including safety laboratory assessments, if deemed necessary.
6.2.3
Follow Up Period and Trial Completion
For any patient who discontinues trial medication (both patients who complete the full 
24-week treatment period as well as patients who discontinue early) the EOT (Visit 5)
procedures as specified in the Flow Chart should be performed at that moment.
All patients should be followed for another 7 days after the EOT visit and a Follow-up Visit 
be performed 7 to 14 days after the EOT visit. If the patient needs to continue with dabigatran 
etexilate trial medication for bridging to VKA (see Appendix 10.2), the follow-up visit 
should be performed 7 days after the last trial medication intake. In that case used and unused 
trial medication should be collected at that visit.
Patients who discontinue trial medication early (see Section 3.3.4) should be followed (after 
the follow-up visit) 
 for MBEs, VTE and any other AEs until Day 176


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(25 weeks) after randomisation, unless they withdraw their informed consent completely.
In addition, data on post-study anti-coagulation therapy will be collected. Those patients
complete trial participation at that contact moment (Day 176).
This follow-up may be done in any way that is acceptable to the patient, i.e. it does not need 
to consist of clinic visits. The minimum requirement is a contact at 25 weeks after 
randomisation. It is anticipated that the majority of data (such as data on bleeding events and 
VTE, if any) will be collected from existing medical records. Patients should be made aware 
of this. See Flow Chart and Section 3.3.4 for further details.
After discontinuation of trial medication, further treatment is up to the discretion of the 
treating physician, in accordance with relevant treatment guidelines. For recommendations 
on how to switch from dabigatran etexilate to other anticoagulants see Appendix 10.2.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This study is a PROBE (Prospective, Randomised, Open label, Blinded Endpoint), 
multicentre, international, parallel group study with an active control and equal treatment 
allocation. This phase III study is planned to investigate the efficacy and safety of dabigatran 
etexilate versus dose-adjusted warfarin in patients with CVT over a 24-week period. The 
primary endpoint is a composite of the number of patients with new VTE (CVT, DVT, PE, 
splanchnic vein thrombosis) or major bleeding according to ISTH criteria after up to 
24 weeks.
The study is an exploratory trial and not intended for registration. No formal statistical
hypothesis will be tested. All analyses are descriptive in nature and confidence intervals and 
p-values from statistical models are used for exploratory purposes only.
NULL AND ALTERNATIVE HYPOTHESES
7.2
This trial is conducted as an exploratory trial; no hypotheses testing will be performed.
PLANNED ANALYSES
7.3
The following analysis sets will be defined for this trial:

Screened Set (SCR)
All patients who sign informed consent and complete at least some screening 
procedures.

Treated set:
The set includes patients who receive at least one dose of study medication and will be 
analysed according to the treatment they have received.

Full analysis set (FAS):
All patients randomised will be analysed in the treatment group to which they are 
randomised regardless of whether they took study medication. The start date of the 
observation period for this analysis set is the date of randomisation. This follows the 
intent-to-treat (ITT) principle.

Per protocol set (PPS):
This is a subset of the Treated set, restricted to patients without important protocol 
violations. Important protocol violations will be defined in the TSAP. If the number of 
patients excluded from PPS is small, (e.g. <10% of the Treated set), then analyses on 
this set may not be conducted.
The efficacy analysis based on FAS will follow the ITT principle. Patients will be allocated
to the randomised treatment groups regardless of actual medication taken.
Two observation periods are defined:


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
Full observation period: from date of randomisation until the end of the trial, 
including all observed time on and off trial medication until the last known alive date 
(or date of death).

On-treatment: from date of first intake of trial medication until discontinuation of trial 
medication + 6 days.
7.3.1
Primary endpoint analyses
The primary analysis will be based on the FAS and will use the full observation period for 
each patient. Patients will be analysed according to the treatment as randomised to follow the 
ITT principle.
The primary endpoint is defined as the number of patients with composite of VTE or major 
bleeding according to ISTH criteria after up to 24 weeks. 
The number and frequency of patients by treatment as well as by subgroup will be displayed
along with the 95% confidence intervals. No difference between the treatments dabigatran 
etexilate versus warfarin will be tested. Hazard ratios (HR) and 95% CI will be displayed, 
only if data is sufficient to do so.
The primary endpoint will also be analysed by subgroup, i.e. by stratification factor (see 
Section 7.6). The following subgroups are of interest: 

Patients with or without ICH at baseline as assessed by the investigator. It is 
estimated that 30-40% of patients would present with intracerebral haemorrhage 
(which is a subtype of ICH) at baseline.
Further specification of analyses and further subgroups may be defined in the TSAP.
7.3.2
Secondary endpoint analyses
Secondary analyses will be based on the FAS for the following endpoints: number of patients 
with CVT, DVT, PE, splanchnic vein thrombosis and the endpoint on cerebral venous 
recanalisation as measured by the change in number of occluded cerebral veins and sinuses 
after up to 24 weeks.
The following analyses will be based on the treated set: number of patients with major 
bleeding according to ISTH, number of patients with clinically relevant non-major bleeding, 
as well as the composite of the two mentioned above, number of patients with any bleeding, 
number of patients with composite endpoint of new ICH or worsening of the haemorrhagic
component of a previous lesion.
The analyses for the secondary endpoints as described in Section 5.1.2 will be mainly based 
on frequency counts and percentages along with 95% confidence intervals.
Means and standard deviations will be displayed by treatment arm for the endpoint on 
cerebral venous recanalisation as measured by the change in number of occluded cerebral 


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veins and sinuses after up to 24 weeks. Means and standard deviations will be displayed by 
stratification factor of presence or absence of ICH at baseline. Patients with missing or not 
analysable MRI scans at EOT would need to be excluded from this analysis.
The composite endpoint of new ICH or worsening of the haemorrhagic component of 
a previous lesion will be categorized as described in Section 5.3.5.1. This ordinal endpoint 
will be analysed with Cochrane-Mantel-Haenszel test.
Further specification of analyses can be found in the TSAP.
7.3.4
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 
coding dictionary available at database lock. Standard BI summary tables and listings will be 
produced. All AEs with an onset between start of trial medication and end of the REP, 
a period of 6 days after the last dose of trial medication, will be assigned to the treatment 
period for evaluation.


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All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment and end of the residual effect period will be 
considered ‘treatment-emergent’. The residual effect period is defined as 6 days. AEs that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of MedDRA.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic analyses
Not applicable.
INTERIM ANALYSES
7.4
No interim analysis is planned but the conduct of the trial will be monitored by a DMC (see 
Section 3.1.1). Formal efficacy or safety stopping rules, if any, will be defined in the DMC
charter. The DMC will review the trial data at pre-defined intervals. The number of patients 
in each treatment group is small and only a limited number of outcome events is expected to 
occur. It is therefore not expected that DMC review will result in statistically significant 
differences between the treatment groups. In order for the trial to provide relevant data, the 
full sample size and follow-up period are likely to be necessary. Only under exceptional 
circumstances, in case of highly relevant difference in the efficacy or safety between the trial 
treatments, should the DMC consider early termination of the trial.
HANDLING OF MISSING DATA
7.5
For the primary and secondary endpoints no general imputations are planned. In case of early 
discontinuation of patients with no follow-up and no events, those will be handled as imputed 
no event.


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In case of no available or no analysable MRI scans at EOT, those patients will be graded as 0 
for a sensitivity analysis for grading of recanalisation.
RANDOMISATION
7.6
Patients will be randomised in blocks to open-label treatment with stratification by presence 
or absence of ICH at baseline. Presence of ICH prior to randomisation will be assessed by the 
investigator from the scans made at the moment of diagnosis. Approximately equal numbers 
of patients will be randomised to each treatment group. BI will arrange for the randomisation
and the packaging and labelling of trial medication. The randomisation list will be generated 
using a validated system, which involves a pseudo-random number generator so that the 
resulting treatment will be both reproducible and non-predictable. The block size will be 
documented in the Clinical Trial Report. Access to the codes will be controlled and 
documented.
DETERMINATION OF SAMPLE SIZE
7.7
It is planned to randomise 60 patients per arm, resulting in 120 patients randomised in total. 
Assuming a drop-out rate of 10%, this should result in 108 evaluable patients (54 per 
treatment arm).
Due to the rare nature of the disease (CVT incidence of around 2 per 100.000 per year), and 
with limited availability of patients in this indication, the planned sample size in this trial is 
not based on any statistical considerations. No hypotheses will be tested or confirmed. 
Data about recurrence rates for CVT patients are limited; Martinelli et al. [R15-5570] report 
a 5% recurrence rate after discontinuation of anticoagulation within the first year. We assume 
a 2-3% event rate for the composite primary endpoint with 6 months of treatment.
The trial is designed as exploratory; a comparable frequency for the primary endpoint 
between dabigatran and warfarin would provide clinicians with important new information.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the International Conference on 
Harmonization Harmonized Tripartite Guideline for GCP, relevant BI SOPs, the EU 
regulation 536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of International Conference on Harmonization GCP.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor with regard 
to publication of the results of this trial are described in the Investigator contract. As a rule, 
no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF where required.
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / IEC and competent authority (CA) according to national 
and international regulations. The same applies for the implementation of changes introduced 
by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to International 
Conference on Harmonization / GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional patient-information form retained by the Investigator as 
part of the trial records. A signed copy of the informed consent and any additional patient 
information must be given to each patient or the patient’s legally accepted representative.
Due to the nature of the disease under study, it is anticipated that patients may be enrolled 
who cannot personally consent to trial participation. In such cases consent should be obtained 
from a legally acceptable representative, if acceptable per the regulatory and legal 
requirements of the participating country. A document will be provided in the ISF to specify 
the procedures to be followed for those patients, or to clarify that consent by a legally 
acceptable representative is not accepted at the specific trial site or in the country.


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DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
Electronic CRFs for individual patients will be provided by the sponsor.
For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
For this trial source documents are expected to include:

Originals or copies of imaging diagnostics

ECG results (original or copies of printouts)

Medical chart including all documentation about the hospital admission for and 
diagnosis of the qualifying CVT

All proceedings / medical notes from the moment of diagnosis of CVT until the 
completion of the patient participation in the trial

Documentation of the results of local laboratory tests, including INR results

Notes of telephone contact with patients, 
It is anticipated that the majority of screening procedures will already have been performed as 
part of the routine procedures for hospitalisation and diagnosis before enrolment of the 
patient into the trial. These data (that will be generated before informed consent will have 
been obtained) will be used for the trial. The original hospital records for these data will be 
the source documents.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. 
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must put every effort into retrieving previous 
medical records prior to randomisation of the patient. If this fails a verbal history from the 
patient, documented in their medical records, would be acceptable.


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Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure patient confidentiality.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient 
was informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

NIHSS  

AEs and outcome events (onset date (mandatory), and end date (if available))

SAEs (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

Documentation of all INR measurements both from prior to start of trial medication 
(patients on a VKA prior to randomisation) and during the 24-week treatment period 
(patients randomised to receive warfarin) (e.g. sponsor-provided INR logs; this may 
be a (paper or electronic) copy of original data in case INR management is done by 
another facility)

Termination of trial medication (last date of intake and the reason for termination in 
case of premature discontinuation)

Completion of Patient’s Participation in the trial (end date; in case of premature 
discontinuation document the reason for it)

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial 
participant meets all inclusion criteria and does not meet any exclusion criteria. The 
absence of records (either medical records, verbal documented feedback of the patient 
or testing conducted specific for a protocol) to support inclusion/exclusion criteria 
does not make the patient eligible for the clinical trial.
For adjudication purposes, supporting documentation and imaging (as needed and available) 
must be provided.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 


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assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g. 
FDA). The CRA and auditor may review all CRFs and informed consents. The accuracy of 
the data will be verified by direct comparison with the source documents described in 
Section 8.3.1. The sponsor will also monitor compliance with the protocol and International 
Conference on Harmonization GCP.
8.3.3
Storage period of records
Trial site(s)
The trial site(s) must retain the source and essential documents (including ISF) according to 
the national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor
The sponsor must retain the essential documents according to the sponsor’s SOPs.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”).The “Last Patient Drug Discontinuation” (LPDD) date is defined as 
the date on which the last patient at an individual trial site ends trial medication (as scheduled 
per protocol or prematurely). Individual Investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LPDD at their site.


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Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P10-00396
Filippidis Aristotelis et al.: Cerebral venous sinus thrombosis: Review of 
demographics, pathophysiology, current diagnosis and treatment; Neurosurg 
Focus 27 (5): E3, 2009
P10-03790
Ryn J van, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, 
Clemens A. Dabigatran etexilate - a novel, reversible, oral direct thrombin 
inhibitor: interpretation of coagulation assays and reversal of anticoagulant 
activity. Thromb Haemost 2010; 103 (6): 1116-1127
P10-11802
Einhaeupl K, Stam J, Bousser MG, Bruijn SFTM de, Ferro JM, Martinelli I, 
Masuhr F. EFNS guideline on the treatment of cerebral venous and sinus 
thrombosis in adult patients. Eur J Neurol 2010; 17(10): 1229-1235
P12-02400
Huisman MV, Lip GYH, Diener HC, Brueckmann M, Ryn J van, Clemens A.
Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: 
resolving uncertainties in routine practice. Thromb Haemost 2012; 10: 838-
847
P13-00071
Dans AL, Connolly SJ, Wallentin L, Yang S, Nakamya J, Brueckmann M, 
Ezekowitz M, Oldgren J, Eikelboom JW, Reilly PA, Yusuf S. Concomitant 
use of antiplatelet therapy with dabigatran or warfarin in the Randomized 
Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial. Circulation 
2012; 127 (5): 634-640 
P13-06400
Heidbuchel H, Verhamme P, Alings M, Antz M, et al. European Heart Rhythm 
Association Practical Guide on the use of new oral anticoagulants in patients 
with non-valvular atrial fibrillation. Europace 2013; 15 (5): 625-651
P13-10973
Hage AV. The NIH Stroke Scale: A Window into Neurological Status. 
https://ce.nurse.com/PrintTopic.aspx?TopicId=5975. Access date: 5 September 
2013.
P13-12662
Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, 
Ezekowitz MD, Nehmiz G, Wang S, Wallentin L, RE-LY Investigators.
The effect of dabigatran plasma concentrations and patient characteristics 
on the frequency of ischemic stroke and major bleeding in atrial fibrillation 
patients in the RE-LY trial. J Am Coll Cardiol 2014; 63 (4): 321-328
P15-06362
Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, 
Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, 
Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI. Idarucizumab 
for dabigatran reversal. N Engl J Med 2015; 373 (6), 511 - 520


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P15-09432
Kummer R von, Broderick JP, Campbell BCV, Demchuk A, Goyal M, Hill 
MD, Treurniet KM, Majoie CBLM, Marquering HA, Mazya MV, San Roman 
L, Saver JL, Strbian D, Whiteley W, Hacke W. The Heidelberg Bleeding 
Classification: classification of bleeding events after ischemic stroke and 
reperfusion therapy. Stroke 2015; 46:00-00, DOI: 
10.1161/STROKEAHA.115.010049
P15-10422
Mendonca MD, Barbosa R, Cruz-e-Silva V, Calado S, Viana-Baptista M. 
Oral direct thrombin inhibitor as an alternative in the management of cerebral 
venous thrombosis: a series of 15 patients. Int J Stroke 2015; 10 (7): 1115-
1118
 
R05-0344
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the 
Scientific and Standardization Committee of the International Society on 
Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medicinal products in non-surgical patients. 
J Thromb Haemost 2005; 3: 692-694
R08-1695
Rosendaal FR, Cannegieter SC, Meer FJM van der, Briet E. A method to 
determine the optimal intensity of oral anticoagulant therapy. Thromb 
Haemost 1993; 69: 236-239
R08-4453
Bueller HR, Halperin JL, Bounameaux H, Prins M. Double-blind studies are 
not always optimum for evaluation of a novel therapy: the case of new 
anticoagulants. J Thromb Haemost. 2008; 6: 227-229
R09-1400
European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical safety 
studies for the conduct of human clinical trials and marketing authorization for 
pharmaceuticals: step 4: note for guidance on non-clinical safety studies for 
the conduct of human clinical trials and marketing authorization for 
pharmaceuticals (June 2009, CPMP/ICH/286/95). http://www.emea.europa.eu 
2009
R13-4008
NIH Stroke Scale. NIH. Rev 10/1/2003. 
http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf. Access date: 
6 September 2013
R13-4023
Know Stroke: Know the Signs. Act in Time. NIH Stroke Scale. National 
Institute of Neurological Disorders and Stroke. 2013. 
http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale_Booklet.pdf. Access 
date: 6 September 2013
 
 


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R15-4849
Ferro JM, Canhao P, Stam J, Bousser MG, Barinagerrementeria F, ISCVT 
Investigators. Prognosis of cerebral vein and dural sinus thrombosis: results of 
the International Study on Cerebral Vein and Dural Sinus Thrombosis 
(ISCVT). Stroke 2004; 35: 664-670
 
 
R15-5005
Saposnik G, Barinagerrementeria F, Brown RD, Bushnell CD, Cucchiara B, 
Cushman M, DeVeber G, Ferro JM, Tsai FY, American Heart Association 
Stroke Council and the Council on Epidemiology and Prevention. Diagnosis 
and management of cerebral venous thrombosis: a statement for healthcare 
professionals from the American Heart Association/American Stroke 
Association. Stroke 2011; 42(4): 1158-1192
R15-5237
Ferro JM, Bacelar-Nicolau H, Rodrigues T, Bacelar-Nicolau L, Canhao P, 
Crassard I, Bousser MG, Dutra AP, Massaro A, Mackowiack-Cordiolani MA, 
Leys D, Fontes J, Stam J, Barinagarrementeria F, ISCVT and VENOPORT 
Investigators. Risk score to predict the outcome of patients with cerebral vein 
and dural sinus thrombosis. Cerebrovasc Dis 2009; 28: 39-44
R15-5239
Baumgartner RW, Studer A, Arnold M, Georgiadis D. Recanalisation of 
cerebral venous thrombosis. J Neurol Neurochir Psychiatr 2003; 74: 459-461
R15-5570
Martinelli I, Bucciarelli P, Passamonti SM, Battaglioli T, Previtali E, 
Mannucci PM. Long-term evaluation of the risk of recurrence after cerebral 
sinus-venous thrombosis. Circulation 2010; 121(25): 2740-2746
R15-5851
Biousse V, Ameri A, Bousser MG. Isolatedintracranial hypertension as the 
only sign of cerebral venous thrombosis. Neurology 1999; 53: 1537-1542
R15-5857
Canhao P, Ferro JM, Lindgren AG, Bousser MG, Stam J, Barinagerrementeria 
F, ISCVT Investigators. Causesand predictors of death in cerebral venous 
thrombosis. Stroke 2005; 36 (8): 1720-1725


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R15-5858
Bousser MG, Chiras J, Bories J, Castaigne P. Cerebralvenous thrombosis - a 
review of 38 cases. Stroke 1985; 16 (2): 199-213
R15-5859
Wasay M, Bakshi R, Bobustuc G, Kojan S, Sheikh Z, Dai A, Cheema Z. 
Cerebralvenous thrombosis: analysis of a multicenter cohort from the United 
States. J Stroke Cerebrovasc Dis 17 (2), 49 - 54 (2008)
R15-5861
Haghighi AB, Edgell RC, Cruz-Flores S, Feen E, Piriyawat P, Vora N, 
Callison RC, Alshekhlee A. Mortality of cerebral venous-sinus thrombosis 
in a large national sample. Stroke 2012; 43: 262-264
R15-5862
Villringer A: Pathophysiological aspects of cerebral sinus venous thrombosis 
(SVT); Journal of Neuroradiology 1994; 21 (2): 72-80
R15-5863
Girot M, Ferro JM, Canhao P, Stam J, Bousser MG, Barinagerrementeria F, 
Leys D, ISCVT Investigators. Predictors of outcome in patients with cerebral 
venous thrombosis and intracerebral hemorrhage. Stroke 2007; 38 (2): 337-
342
R15-5864
Diaz JM, Schiffman JS, Urban ES, Maccario M. Superiorsagittal sinus 
thrombosis and pulmonary embolism: a syndrome rediscovered. Acta Neurol 
Scand 1992; 86: 390-396
R15-5865
Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med 2005; 352 
(17): 1791-1798
R15-5878
Ferro JM, Correia M, Pontes C, Baptista MV, Pita F, Cerebral Venous 
Thrombosis Protugese Collaborative Study Group (Venoport). Cerebralvein 
and dural sinus thrombosis in Portugal: 1980 - 1998. Cerebrovasc Dis 2001; 
11, 177-182
R15-5879
Ferro JM, Canhao P. Etiology, clinical features, and diagnosis of cerebral 
venous thrombosis (last updated: Jan 30, 2015).
http://www.uptodate.com/contents/etiology-clinical-features-and-diagnosis-of-
cerebral-venous-thrombosis (access date: 24 November 2015); UpToDate 
(2015)
R15-6315
Alons IME, Jellema K, Wermer MJH, Algra A. D-dimer for the exclusion of 
cerebral venous thrombosis: a meta-analysis of low risk patients with isolated 
headache. BMC Neurol 2015; 15: 118
 
 
 
 


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R16-2716
Miranda B, Ferro JM, Canhao P, Stam J, Bousser MG, Barinagarrementeria F, 
et al, ISCVT Investigators. Venous thromboembolic events after cerebral vein 
thrombosis. Stroke 2010; 41: 1901-1906.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.
APPENDICES
TRIAL MEDICATION START AND BRIDGING RULES
10.1
10.1.1
When to start dabigatran etexilate following treatment by other anticoagulants
Heparins
UFH or LMWH (if given) should be stopped prior to the first dose of dabigatran etexilate. 
Dabigatran etexilate should be initiated with the following suggested time windows:

UFH: initiate dabigatran etexilate at the time the UFH is stopped 

LMWH: initiate dabigatran etexilate 0-2 hours prior to the time that the next dose of 
the LMWH would be due.
Vitamin K antagonists
Patients already on VKA, should start dabigatran etexilate once the INR is <2.0. If the INR is 
≥2.0, study medication can be dispensed but the patient will be instructed not to start it until 
notified. Follow-up INR testing will be performed in 1-2 day intervals until INR falls below 
2.0, at which time the patient will be instructed to start taking the study medication.
10.1.2
When to start warfarin following treatment by other anticoagulants or VKAs 
Parenteral anticoagulants
Warfarin can be initiated at the same time as the patient is taking parenteral anticoagulants 
(for recommendations on how to dose warfarin see the nomogram provided in the ISF). 
Parenteral bridging therapy (e.g. UFH, LMWH) should be stopped when target INR is 
achieved.
Vitamin K antagonists
For recommendations on how to switch a patient from another VKA to warfarin and for 
maintenance of warfarin therapy see the nomogram provided in the ISF.
10.1.3
Bridging Therapy (e.g. for temporary interruptions of trial medication due to 
interventions)
The use of bridging therapy depends on the thromboembolic risk status of the patient and the 
length of the planned interruption. It is at the discretion of the investigator whether to use 
a parenteral anticoagulant for bridging purposes or not. 
Due to the short off- and onset of action, the majority of interventions in patients receiving 
dabigatran etexilate may not require the use of bridging therapy. If bridging therapy is 
deemed necessary for patients in the dabigatran etexilate arm, it is recommended to wait 
12 hours after the last dose before switching from dabigatran etexilate to a parenteral 
anticoagulant.
Patients in the warfarin arm should be treated at the discretion of the investigator. In general, 
a parenteral anticoagulant may be considered when the INR is below the target INR.


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SWITCHING FROM TRIAL TREATMENT AT EOT
10.2
Any patient that decides to discontinue trial medication should be considered for a switch to 
an appropriate (non-study) anticoagulant according to local practice. For patients receiving 
dabigatran etexilate in the trial, continuation of trial medication for 2-3 days to assist bridging 
may be appropriate in case patients are switched to a VKA.
Decisions regarding the continuation of the systemic anticoagulation agents after the 
completion of the treatment period (EOT) should be based on the recommendations and 
guidelines of the AHA/ASA [R15-5005] and EFNS [P10-11802] or alternative local 
treatment practice.
Investigators should plan for each subject’s transition to standard of care taking into 
consideration the individual patient’s risk profile and previous experience with non-study 
VKA, if any. 
As patients have different risk profiles, optimal approaches might differ between patients and 
not all possible approaches are described below. 
OPTION 1:
STARTING VKA PRIOR TO DABIGATRAN ETEXILATE 
DISCONTINUATION 
Start VKA at the EOT Visit and continue on dabigatran etexilate for 2-3 days after the EOT 
Visit1. 

In patients with CrCl >50mL/min who discontinue dabigatran etexilate but still 
require anticoagulation, dabigatran etexilate should be continued for three days
together with VKA.

For patients with moderate renal dysfunction (CrCl ≥30 to <50mL/min), as measured 
in the visit before EOT, dabigatran can be stopped after two days of concomitant 
VKA.
Many physicians will want to see VKA naïve patients before starting VKA. There is no 
special need to measure the INR before starting a VKA. If the INR is checked on the day of 
the EOT visit, Investigators should recognise that the presence of dabigatran etexilate could 
elevate the INR. Because dabigatran etexilate can increase the INR, the INR will better 
reflect warfarin’s effect only after dabigatran etexilate has been stopped for at least 24 hours.
OPTION 2:
BRIDGING WITH LMWH
A patient comes in on the day of the EOT Visit, dabigatran etexilate is stopped and non-study 
VKA is started. LMWH can be used to bridge the patient until the INR becomes therapeutic. 
The LMWH can be started 12 hours after the last dose of dabigatran etexilate. This approach 
is an alternative to Option 1 described above. 
                                                
1 The date of final intake of dabigatran etexilate must be documented in the CRF.


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The decision to use bridging therapy is at the discretion of the investigator.
Please consult local guidelines for the starting dose of the respective VKA. 
Although there are large differences in the plasma half-lives of the various VKAs in clinical 
use, apart from the selection of the starting dose, the half-life of the VKA will have no impact 
on the transition from dabigatran etexilate.


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NATIONAL INSTITUTES OF HEALTH STROKE SCALE
10.3
1a.Level of consciousness
0
Alert
1
Not alert, but arousable with minimal stimulation
2
Not alert, requires repeated stimulation to attend
3
Coma
1b. Ask patient the month and 
their age
0
Answers both correctly
1
Answers one correctly
2
Both incorrect
1c.Ask patient to open/close 
eyes and form/release fist
0
Obeys both correctly
1
Obeys one correctly
2
Both incorrect
2.Best gaze (only 
horizontal eye movements)
0
Normal
1
Partial gaze palsy
2
Forced gaze deviation
3. Visual field testing
0
No visual field loss
1
Partial hemianopsia
2
Complete hemianopsia
3
Bilateral hemianopsia (blind, incl. Cortical blindness)
4. Facial paresis (Ask 
patient to show teeth or raise 
eyebrows and close eyes 
tightly)
0
Normal symmetrical movement
1
Minor paralysis (flattened nasolabial fold, asymmetry on
2
Partial paralysis (total or near total paralysis of lower face)
3
Complete paralysis of one or both sides (absence of facial movement in the 
upper and lower face)
5a.Motor Function 
- right arm
0
Normal (extends arm 90º or 45º for 10 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
5b. Motor 
Function - left arm
0
Normal (extends arm 90º or 45º for 10 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
6a. Motor Function 
-right leg
0
Normal (holds leg in 30º position for 5 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
6b. Motor 
Function -left leg
0
Normal (holds leg in 30º position for 5 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
7. Limb ataxia
0
No ataxia
1
Present in one limb
2
Present in two limbs
8. Sensory (use pinprick to test 
arms, legs trunk and face, 
compare side to side)
0
Normal
1
Mild to moderate decrease in sensation
2
Severe to total sensory loss


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9. Best language (describe 
picture, name items)
0
No aphasia
1
Mild to moderate aphasia
2
Severe aphasia
3
Mute
10. Dysarthria (read several 
words)
0
Normal articulation
1
Mild to moderate slurring of words
2
Near unintelligible or unable to speak
9
Intubated or other physical barrier
11. Extinction and inattention
(use visual double stimulation
or sensory double stimulation)
0
Normal
1
Inattention or extinction to bilateral simultaneous stimulation in one of the 
sensory modalities
2
Severe hemi-inattention or hemi-inattention to more than one modality


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
GLOBAL AMENDMENT 1
11.1
Number of global amendment
1
Date of CTP revision
10 February 2017
EudraCT number
2015-004412-38
BI Trial number
1160.248
BI Investigational Product(s)
Pradaxa®, dabigatran etexilate
Title of protocol
RE-SPECT CVT: a randomised, open-label, 
exploratory trial with blinded endpoint adjudication 
(PROBE), comparing efficacy and safety of oral 
dabigatran etexilate versus oral warfarin in patients 
with cerebral venous and dural sinus thrombosis 
over a 24-week period
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Clinical Trial Protocol Synopsis
3.3 SELECTION OF TRIAL POPULATION
7.7 DETERMINATION OF SAMPLE SIZE
Description of change
No. of patients was changed from total 180 planned 
to total 120 planned and from 90 to 60 planned in 
each treatment arm
The anticipated drop-out rate was changed from 
15-20% to 10%, resulting in 108 evaluable patients 
(54 per treatment arm)
Rationale for change
Due to the exploratory nature of the trial the total 
number of required patients is difficult to 
determine. During trial preparation it became clear 
that the trial may be conducted with fewer patients 
than originally assumed. Since it would be 


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considered unethical to put more patients at risk 
than is required, the number was reduced.
The drop-out rate was updated based on experience 
of the trial’s Steering Committee members
Section to be changed
Flow Chart, footnote 8
5.3.3 Safety laboratory parameters
Description of change
Text about pregnancy testing was changed to 
clarify that all WOCBP should perform a 
pregnancy test every 4 weeks (instead of only 
women randomised to warfarin)
Rationale for change
Request from authorities and simplification of 
instructions for trial sites
Section to be changed
3.3.2 Inclusion criteria
4.2.2.4 Restrictions regarding women of 
childbearing potential
Description of change
Addition of a list of acceptable contraception 
methods to section 4.2.2.4 and Inclusion criterion 2 
was updated to include a reference to that list;
Removal of tubal ligation from the list of 
procedures to render a woman not of childbearing 
potential;
Addition of text (section 4.2.2.4) to specify that 
WOCBP should use effective methods of birth 
control from the moment of signing informed 
consent for the trial until completion of the follow-
up visit (Visit 6)
Rationale for change
Request from the authorities and adaptation to 
recently updated recommendations from the 
European Union Heads of Medicines Agency 
related to contraception and pregnancy testing in 
clinical trials (CTFG, 2014)
Section to be changed
2.2 TRIAL OBJECTIVES
Description of change
Clarification that the primary objective does not 
require 24 weeks of treatment
Rationale for change
To be consistent with the description of the trial’s 
endpoints: the primary endpoint will be assessed up 
to 24 weeks after randomisation irrespective of 
whether or not treatment was taken for 24 weeks.
Section to be changed
3.1.1 Administrative structure of the trial
3.2 DISCUSSION OF TRIAL DESIGN, 
INCLUDING THE CHOICE OF CONTROL 
GROUP(S)
Description of change
Change in set-up of the adjudication committee
Rationale for change
For this exploratory trial the adjudication 
committee (AC) for central assessment of 
endpoints will be set-up by the sponsor, hiring 


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external experts. By not using a third party vendor 
for AC coordination, the AC may not be 
considered completely independent of the sponsor 
by all stakeholders, although all decisions made by 
AC members will not be influenced by the sponsor. 
Therefore the description of the AC is changed.
Section to be changed
4.1.4 Drug assignment and administration of doses 
for each patient
Description of change
Addition of caution statement about treatment with 
warfarin in patients with known protein C or
protein S deficiency
Rationale for change
Request from authorities
Section to be changed
5.2.1 Venous thrombotic events
Description of change
The requirements for confirmation of DVT, PE and 
splanchnic vein thrombosis were changed to 
require images and/or reports (instead of both) to 
be provided to the AC
Rationale for change
In order to be in line with what was done in prior 
trials with the same IMP, and in order to limit the 
source data transfer to the necessary elements 
required for adjudication
Section to be changed
7.3 PLANNED ANALYSES
Description of change
An additional patient population, Screened Set 
(SCR), was defined, i.e. All patients who sign 
informed consent and complete at least some 
screening procedures.
Rationale for change
This patients set will be used for display of 
disposition tables etc.
Section to be changed
8.3.1 Source documents
Description of change
Deletion of the list of documents and images that 
will be made available for adjudication purposes
Rationale for change
This will be defined in the adjudication charter 
instead of the trial protocol


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03714648
2.0
clinical-trial-protocol
RE-SPECT CVT: a randomised, open-label, exploratory trial with blinded endpoint
adjudication (PROBE), comparing efficacy and safety of oral dabigatran etexilate
versus oral warfarin in patients with cerebral venous and dural sinus thrombosis over
a 24-week period
Author-Trial Clinical Monitor
14 Feb 2017 10:12 CET
Author-Statistician
14 Feb 2017 10:45 CET
Approval-Team Member Medicine
14 Feb 2017 17:06 CET
Approval-Therapeutic Area 
14 Feb 2017 19:14 CET
Verification-Paper Signature
Completion
15 Feb 2017 10:58 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03714648
2.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c09087498-01
BI Trial No.:
1160.248
Title:
RE-SPECT CVT: a randomised, open-label, exploratory trial with 
blinded endpoint adjudication (PROBE), comparing efficacy and 
safety of oral dabigatran etexilate versus oral warfarin in patients 
with cerebral venous and dural sinus thrombosis over a 24-week 
period
(Including protocol amendment 1 [c03714648-02])
Investigational
Product(s):
Pradaxa®, dabigatran etexilate
Responsible trial 
statistician(s):
Tel.: 
Date of statistical 
analysis plan:
05 MAR 2018 SIGNED
Version:
Final
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINT(S).......................................................................................................8
5.1
PRIMARY ENDPOINT(S) ..................................................................................8
5.2
SECONDARY ENDPOINT(S) ............................................................................8
5.2.1
Key secondary endpoint(s)...................................................................................8
5.2.2
(Other) Secondary endpoint(s) ............................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENT(S)................................................................................................13
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................13
6.3
PATIENT SETS ANALYSED...........................................................................17
6.5
POOLING OF CENTRES .................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................19
7.
PLANNED ANALYSIS......................................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........21
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................22
7.3
TREATMENT COMPLIANCE........................................................................22
7.3.1
Dabigatran Compliance......................................................................................22
7.3.2
Warfarin Compliance.........................................................................................23
7.4
PRIMARY ENDPOINT(S) ................................................................................23
7.5
SECONDARY ENDPOINT(S) ..........................................................................24
7.5.1
Key secondary endpoint(s).................................................................................24
7.5.2
(Other) Secondary endpoint(s) ..........................................................................24
7.7
EXTENT OF EXPOSURE.................................................................................25
7.8
SAFETY ANALYSIS..........................................................................................25
7.8.1
Adverse events.....................................................................................................25
7.8.2
Laboratory data ..................................................................................................26
7.8.3
Vital signs.............................................................................................................26
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................27
8.
REFERENCES....................................................................................................28
10.
HISTORY TABLE..............................................................................................30


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LIST OF TABLES
Table 5.2.2: 1 Categorisation of haemorrhagic brain lesions (Von Kummer et al [13]).........10
Table 6.2: 1
Important protocol violations ...........................................................................14
Table 6.3: 1
Patient sets analyzed.........................................................................................18
Table 7.1: 1
NIHSS score .....................................................................................................22
Table 10: 1
History table .....................................................................................................30


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AC
Adjudication committee
ADS
Analysis Datasets
AE
Adverse event
BRPM
Blinded report planning meeting
CI
Confidence interval
CrCl
Creatinine clearance
CRNMBE
Clinically relevant non-major bleeding event
CTP
Clinical trial protocol
CTR
Clinical trial report
CVT
Cerebral venous or dural sinus thrombosis
DBL
Database lock
DMC
Data Monitoring Committee
DVT
Deep vein thrombosis
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
EOT
End of treatment
FAS
Full analysis set
HI
Haemorrhagic infarction
HR
Hazard ratio
ICH
International Conference on Harmonisation
“ICH”
Intracranial haemorrhage
INR
International normalised ratio
IPV
Important protocol violation
IRT
Interactive response technology
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intent-to-treat
LMWH
Low molecular weight heparin
MBE
Major bleeding event
MedDRA
Medical Dictionary for Regulatory Activities


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Term
Definition / description
MRI
Magnet resonance imaging
NIHSS
National Institutes of Health Stroke Scale
PE
Pulmonary embolism
PH
Parenchymatous haematoma
PN
Preferred name
PPS
Per protocol set
PROBE
Prospective, randomised, open label, blinded endpoint
PSTAT
Project statistician
PT
Preferred term
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
REP
Residual effect period
SA
Statistical analysis
SCR
Screened set
SD
Standard deviation
SMQ
Standardised MedDRA query
SOC
System organ class
TCM
Trial clinical monitor
TSAP
Trial statistical analysis plan
TTR
Time in therapeutic range
UFH
Unfractionated heparin
VKA
Vitamin K antagonist(s)
VTE
Venous thrombotic event
WHO-DD
World Health Organisation – Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 [2], the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis (SA) of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the clinical trial protocol 
(CTP) [11], including protocol amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomization.
This TSAP does not cover the planned data review by the Data Monitoring Committee 
(DMC). A separate DMC SAP was produced for this purpose.
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
In the CTP version 1 only three analysis populations have been defined: treated set (TS), full 
analysis set (FAS) and per protocol set (PPS). A screened set (SCR) as described in CTP 
version 2 (01FEB2017) will also be created for display of disposition tables, etc., see Section 
6.3.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint for this trial is the number of patients with the composite of major
bleeding event (MBE) according to International Society on Thrombosis and Haemostasis 
(ISTH) criteria or venous thrombotic event (VTE: recurring cerebral venous or dural sinus 
thrombosis (CVT), deep vein thrombosis (DVT) of any limb, pulmonary embolism (PE),
splanchnic vein thrombosis) up to 24 weeks.
All components of the primary endpoint will be adjudicated by an independent adjudication 
committee (AC). Details of the adjudication criteria can be found in the adjudication charter. 
All endpoints are either explicitly collected in the electronic case report form (eCRF) or 
captured in the database following adjudication. Adjudicated data takes precedence over 
eCRF data where both are available.
ISTH definition of an MBE: 

Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with 
compartment syndrome or other critical location
and/or

Bleeding associated with a reduction in haemoglobin of at least 2g/dL (1.24mmol/L) 
within 24 hours, or leading to transfusion of two or more units of blood or packed 
cells
and/or

Fatal bleed
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not defined.
5.2.2
(Other) Secondary endpoint(s)
All secondary endpoints will be based on adjudicated data (except for any bleeding event).
The secondary efficacy endpoints are:

Number of patients with recurring VTE (CVT, DVT of any limb, PE or splanchnic 
vein thrombosis) up to 24 weeks

Cerebral venous recanalisation as measured by the change in number of occluded
cerebral veins and sinuses up to 24 weeks
The secondary safety endpoints are:

Number of patients with MBE according to ISTH criteria up to 24 weeks

Composite endpoint of number of patients with new intracranial haemorrhage (also 
abbreviated as “ICH”) or worsening of the haemorrhagic component of a previous 
lesion up to 24 weeks (categorisation see Table 5.2.2: 1)


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
Number of patients with clinically relevant non-major bleeding event (CRNMBE) up 
to 24 weeks

Number of patients with MBE according to ISTH criteria or CRNMBE up to 24 weeks

Number of patients with any bleeding event up to 24 weeks
Recanalisation will be assessed as described below, analogous to the calculations made by 
Miranda et al [12].
1. At baseline and at the end of treatment EOT, occlusion of cerebral veins and sinuses 
will be scored as follows:
1 = full occlusion
0 = no occlusion or partial occlusion
2. This score will be applied to each of the veins and sinuses using the below 
conventions:

Superior sagittal sinus, straight sinus, cavernous sinus, left jugular vein, right 
jugular vein will each be scored individually (i.e. each will be scored as either 
0 or 1)

Right lateral transverse and sigmoid sinus will be scored together (i.e. 0 points if 
neither is fully occluded; 1 point if at least one of them is fully occluded)

Left lateral transverse and sigmoid sinus will be scored together (i.e. 0 points if 
neither is fully occluded; 1 point if at least one of them is fully occluded)

Superior petrous sinus and inferior petrous sinus will be scored together 
(i.e. 0 points if neither is fully occluded; 1 point if at least one of them is fully 
occluded)

Deep venous system will be scored as system, irrespective of the number of 
occluded veins (i.e. 0 points if none is fully occluded; 1 point if at least one is 
fully occluded)

Superficial cortical veins will be scored as system, irrespective of the number of 
occluded veins (i.e. 0 points if none is fully occluded; 1 point if at least one is 
fully occluded)

Cerebellar veins will be scored as system, irrespective of the number of occluded 
veins (i.e. 0 points if none is fully occluded; 1 point if at least one is fully 
occluded)
3. For each individual patient a total score will be calculated at baseline and at the EOT.
4. A recanalisation score will subsequently be calculated for each patient as the 
difference between the baseline total score and the EOT total score.


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Table 5.2.2: 1
Categorisation of haemorrhagic brain lesions (Von Kummer et al [13])
Class
Type
Description
1
Haemorrhagic transformation of infarcted brain tissue
1a
HI-1*
Scattered small petechiae, no mass effect
1b
HI-2
Confluent petechiae, no mass effect
1c
PH-1*
Haematoma within infarcted tissue, occupying <30%,
no substantive mass effect
2
Intracerebral haemorrhage within and beyond infarcted brain tissue
PH-2
Haematoma occupying 30% or more of the infarcted tissue,
with obvious mass effect
3
Intracerebral haemorrhage outside the infarcted brain tissue
or intracranial-extracerebral haemorrhage
3a
Parenchymal haematoma remote from infarcted brain tissue
3b
Intraventricular haemorrhage
3c
Subarachnoid haemorrhage
3d
Subdural haemorrhage
*
HI: haemorrhagic infarction; PH: parenchymatous haematoma
Any new haemorrhagic brain lesion will be categorised as Class 3 (Intracerebral haemorrhage 
outside the infarcted brain tissue or intracranial-extracerebral haemorrhage). If there is more 
than one haemorrhagic lesion present on imaging, the category of the most severe lesion is 
assigned.
For each patient, intracranial haemorrhage will be classified at baseline and EOT (in case 
there is no EOT visit, the classification based on the last on-treatment images up to 6 days 
after last study drug intake will be taken for the determination of worsening).
Worsening is defined as follows:

Class 3 is worse than class 2, which is worse than class 1.

Within class 1, type PH-1 (1c) is worse than type HI-2 (1b), which is worse than type 
HI-1 (1a).

Within class 3 (a, b, c, d), an increase of at least 25% in volume is considered a 
worsening.
Patients who died during the trial before an EOT scan is made and patients for whom for other 
reasons no EOT or on-treatment scan is available or analysable will not be included in the 
analysis of number of patients with new intracranial haemorrhage or worsening of the
haemorrhagic component of a previous lesion.


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ISTH definition of a CRNMBE: 
A CRNMBE is a clinically overt bleed that does not meet the criteria for an MBE but prompts 
a clinical response, in that it leads to at least one of the following:

A hospital admission (i.e overnight stay in the hospital) for bleeding
or

A physician guided medical or surgical treatment for bleeding
or

A physician guided change, interruption or discontinuation of trial medication


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
The following treatment periods based on actual start and stop dates/times of randomised 
study drug administration are defined:

Screening: date of informed consent (time “0:00:00”) to date of randomisation (time 
“0:01:00”)

Post-randomisation: date of randomisation (time “0:01:00”) to time-point of first intake 
(date and time, “0:02:00” if time is missing) of randomised study drug.

On-treatment: first intake (date and time)/date restarted of randomised study drug to date 
stopped/last intake (date and time) of randomised study drug.  The residual effect period 
(REP) of 6 days will be added to this period.  

Off-treatment: date randomised study drug stopped + REP to date randomised study drug 
restarted

Post-treatment: last intake (date/time) of randomised study drug + REP until date of trial 
completion.  This is the date given on the termination page (trial completion page) of the 
eCRF. If date of trial completion is before last intake + REP, REP will be cut accordingly.

Post-study: day after date of trial completion to database lock (DBL) + 1 day (time 
“0:00:00”).
The REP is the time period after the last administration of trial medication when measurable 
drug levels or pharmacodynamic effects are still likely to be present. Events occurring in the 
REP are handled as occurring on-treatment. Data from the post-study period will only be 
listed.
For the analysis two observation periods are defined:

Full observation period: from date of randomisation until the end of the trial, 
including all observed time on and off trial medication until the last known alive date 
(or date of death)
This observation period will be used for the efficacy analysis.

On-treatment: from date of first intake of trial medication until discontinuation of trial 
medication + REP
This observation period will be used for the safety analysis.
Despite the trial being open label, all activities conducted by the trial team will be performed 
in a blinded manner (as much as possible) until DBL.  For example, data tabulations and 
listings will be presented using dummy treatment group information instead of actual 
treatment group allocations.  The planned data review will be handled by the DMC in an 
unblinded manner (refer to the DMC SAP for more information).
6.2
IMPORTANT PROTOCOL VIOLATIONS
The following table defines the different categories of important protocol violations (IPVs).
The final column describes which IPVs will be used to exclude patients from the different 
patient analysis sets. In this study, patients are either excluded from “All” analysis sets, the 


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PPS, the FAS or “None” of the analysis sets. Refer to Section 6.3 for more details.  IPVs will 
be identified by the trial team prior to DBL in a blinded manner [4].
Table 6.2: 1
Important protocol violations
Category /
Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1.1
Male or female patients. Women of 
childbearing potential must be ready and 
able to use highly effective methods of 
birth control
Inclusion criterion 2 not met as 
specified in the protocol.
None
A1.2
Age ≥ 18 years and < 79 years at Visit 1
Inclusion criterion 3 not met as 
specified in the protocol.
PPS
A1.3
Confirmed diagnosis of CVT, with or 
without ICH
Inclusion criterion 4 not met as 
specified in the protocol.
PPS
A1.4
Patient has achieved clinical stability 
after having received standard acute 
CVT treatment as required, including 
anticoagulation therapy for 5-15 days 
which has been administered until 
randomisation.
Inclusion criterion 5 not met as 
specified in the protocol.
PPS
A1.5
Eligibility for treatment with an oral 
anticoagulant for their CVT, based on 
Investigator judgment. Based on risk 
assessment and clinical condition, patient 
should be a candidate
for at least 24 weeks of oral 
anticoagulation
Inclusion criterion 6 not met as 
specified in the protocol.
PPS
A1.6
Availability for external review of the 
imaging that was used to diagnose the 
CVT
Inclusion criterion 7 not met as 
specified in the protocol.
None
A2.1
Inability to swallow trial medications
Exclusion criterion 1 met as specified in 
the protocol
PPS
A2.2
CVT associated with central nervous 
system infection 
Exclusion criterion 2 met as specified in 
the protocol
PPS
A2.3
CVT due to head trauma
Exclusion criterion 3 met as specified in 
the protocol
PPS
A2.4
Planned for surgical treatment for CVT
Exclusion criterion 4 met as specified in 
the protocol
PPS
A2.5
Patient with conditions associated with 
increased risk of bleeding
Exclusion criterion 5 met as specified in 
the protocol
PPS
A2.6
Life-threatening or major bleeding (per 
ISTH criteria) other than intracranial 
bleeding due to inclusion CVT, during 
the 6 months prior to randomisation or 
while on anticoagulants during the acute 
phase of CVT
Exclusion criterion 6 met as specified in 
the protocol
PPS
A2.7
History of symptomatic non-traumatic 
ICH with risk of recurrence (including 
haemorrhagic stroke within 6 months 
prior to Visit 1)
Exclusion criterion 7 met as specified in 
the protocol
PPS


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Requirements
Excluded 
from
A2.8
Severe renal impairment defined as CrCl 
(calculated by Cockcroft-Gault equation) 
<30mL/min at screening, or if the 
Investigator expects CrCl is likely to 
drop below 30mL/min during the course 
of the trial
Exclusion criterion 8 met as specified in 
the protocol
PPS
A2.9
Patients who are taking any of the drugs 
listed as restricted in CTP section 4.2.2.1 
while on active treatment with study 
drug
Exclusion criterion 9 met as specified in 
the protocol
PPS
A2.10
Patients receiving treatment with 
warfarin, dabigatran etexilate or other 
antithrombotic regimen (i.e. 
anticoagulants or anti-platelet 
medication) for an indication other than 
CVT and requiring continuation of that 
treatment for the original diagnosis 
without change in the regimen
Exclusion criterion 10 met as specified 
in the protocol
None
A2.11
Patients with prosthetic heart valves
Exclusion criterion 11 met as specified 
in the protocol
PPS
A2.12
Known hypersensitivity to dabigatran 
etexilate or warfarin or to any of the 
excipients of either product
Exclusion criterion 12 met as specified 
in the protocol
None
A2.13
Any current or recent malignancy (≤ 6 
months prior to Visit 1) unless the 
malignancy was a basal cell carcinoma 
that was completely removed
Exclusion criterion 13 met as specified 
in the protocol
PPS
A2.14
Concomitant disease that increases the 
risk of an adverse reaction to trial 
interventions or with life expectancy < 6 
months (for any reason) per Investigator 
judgment
Exclusion criterion 14 met as specified 
in the protocol
PPS
A2.15
Pre-menopausal women (last 
menstruation ≤ 1 year prior to Visit 1) 
who are pregnant, nursing, or who plan 
to become pregnant while in the trial.
Exclusion criterion 15 met as specified 
in the protocol
None
A2.16
Patients who have participated in another
trial with an investigational drug or 
device within the past 14 days preceding 
Visit 1 or who currently are participating 
in another trial. Patients who are still 
experiencing a clinical effect from an 
investigational drug or device.
Exclusion criterion 16 met as specified 
in the protocol
None
A2.17
Patients considered unreliable by the 
Investigator concerning the requirements 
for follow-up during the trial or at the 
end of the trial.
Exclusion criterion 17 met as specified 
in the protocol
None
A2.18
Any condition the Investigator believes 
would not allow safe participation in the 
trial.
Exclusion criterion 18 met as specified 
in the protocol
None
A2.19
Active liver disease
Exclusion criterion 19 met as specified 
in the protocol
None


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Requirements
Excluded 
from
A2.20
Previous randomisation in this trial
Exclusion criterion 20 met as specified 
in the protocol
PPS
B
Informed consent
B1
Informed consent not available/not done
Inclusion criterion 1 not met as 
specified in the protocol.
All
B2
Informed consent too late
Informed consent date was after Visit 2 
date 
None
C
Trial medication and randomisation
C1
Incorrect trial medication taken
Medication kit assigned not matching 
treatment patient was randomised to 
(cross-treatment) and/or not matching 
IRT assignment
PPS
C2
Randomisation order not followed, e.g. 
forced randomization, misstratification
Cases will be identified from IRT 
reports and read in via the manual PV 
spreadsheet
PPS
C3
Non-Compliance
Compliance <80% or >120% over the 
course of the study for dabigatran 
patients, or time in therapeutic target 
range for warfarin patients <45%. See 
Section 7.3 for details on compliance 
calculation.
Non-compliance caused by temporary 
interruption of the treatment due to a 
procedure or a drop in CrCl to less than 
30 mL/min should not be classified as a 
protocol violation.
PPS
D
Concomitant medication
D1
Prohibited medication use
See CTP section 4.2.2.1
Those treatments should not be taken 
during the active treatment phase of the 
trial:
-
Fibrinolytic agents (refer to 
CTP section 4.2.1.5 for 
exceptions)
-
GPIIb/IIIa antagonists (e.g. 
abciximab, tirofiban)
-
Rivaroxaban, apixaban and 
edoxaban, or other oral 
anticoagulants (e.g. VKAs)
-
Treatment with systemic 
ketoconazole, itraconazole, 
posaconazole, cyclosporine, 
tacrolimus and dronedarone, 
and rifampicin, carbamazepine, 
phenytoin and St. John’s Wort
Medications will be identified through 
medical review and details will be 
provided in the technical TSAP.
PPS


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Requirements
Excluded 
from
G
Trial Specific Protocol Violations
G1
Patient randomized to dabigatran 
etexilate not withdrawn from trial 
treatment if CrCl drops to <30mL/min at 
two different occasions during the trial or 
drops to <30mL/min and does not 
recover to above 30 within 7 days
PPS
G2
Creatinine clearance not measured / not 
reviewed prior to start of treatment 
PPS
G3
Woman of child bearing potential and 
pregnancy test not confirmed to be 
negative prior to start of trial treatment
None
G4
Woman become pregnant during the trial
None
G5
Patient on VKA prior to randomization, 
randomized to dabigatran etexilate and 
treated although INR not confirmed to be 
<2.0
PPS
G6
Patient on VKA prior to randomization, 
randomized to warfarin and treated 
although INR not confirmed to be <3.0
PPS
G7
Patient randomized to warfarin and 
treated and UFH / LMWH stopped 
although INR not confirmed to be >= 2.0
PPS
The following IPV are programmed automatically: all from A and B, C3, D1, G1, G3-G7.
The remaining IPV are manual IPVs and need to be identified at a site level on the manual PV 
log.
The frequency of patients with IPVs will be presented. Those which lead to a patient being 
excluded from the PPS will be presented separately to those which do not.
6.3
PATIENT SETS ANALYSED
The following analysis sets will be defined for this trial:

Screened set (SCR)
All patients who signed informed consent; these patients will have completed routine 
procedures to establish the diagnosis of CVT.

Treated set (TS):
The set includes patients who received at least one dose of study medication.

Full analysis set (FAS):
This set includes all patients randomised.

Per protocol set (PPS):
This is a subset of the TS, restricted to patients without relevant important protocol 
violations as defined in Table 6.2: 1.


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The efficacy analysis (i.e. analysis of primary and secondary efficacy endpoints, as well as 
further endpoints 
based on the FAS will follow the 
intent-to-treat (ITT) principle. Patients will be allocated to the randomised treatment groups 
regardless of actual medication taken.
The safety analysis (including analysis of secondary safety endpoints 
 
as well as adverse event analysis) will be based on the TS, and patients will be analyzed
according to the treatment they have received.
Secondary efficacy analysis on the PPS may not be conducted if the number of patients 
excluded from the patient set is small (i.e. <10% of the TS).
Disposition data on the SCR will be presented according to the randomized treatment groups.
For patients not entered/randomised on the total number will be presented.
Table 6.3: 1
Patient sets analyzed
Patient set
Class of endpoint/data
SCR
TS
FAS
PPS
Primary endpoint (Section 5.1)
primary 
analysis
secondary 
analysis
Secondary and further efficacy 
endpoints (Section 5.2.2 and 
5.3)
X
Safety endpoints (Section 7.8)
X
Demographic/baseline data
(Section 7.1)
X
(X)
Disposition
X
(X) An additional FAS presentation of the demographic/baseline data may be provided in the End of Text
section of the clinical trial report (CTR) if patient numbers for FAS and TS are clearly different, i.e. if ≥10% of 
the TS are excluded from the FAS.
Note that the number of patients with available data for an endpoint may differ. For details, 
see Section 6.6 “Handling of missing data and outliers”.


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
A major goal of the trial is to obtain virtually complete follow-up of vital status and full 
collection of outcome event data. For the primary and secondary endpoints no general 
imputations are planned. In case of early discontinuation of patients with no follow-up and no 
events, those will be handled as imputed no event.
 
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates” [5]). The same philosophy will be applied to missing or 
incomplete outcome event and concomitant medication dates/times. 
Other missing data will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline assessment is the last measurement made (or sample taken) prior to first study 
drug administration. The first study drug administration should occur at Visit 2. Any
assessments made on this day, where time is not collected, are assumed to be prior to study 


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drug administration. This does not apply to adverse events (AEs) and outcome events where it 
will be assumed that events occurred on-treatment.
Actual dates will be used for assigning AEs and outcome events to the appropriate treatment 
period as defined in Section 6.1.  Windowing with regard to visits will not be applied as the 
main objective of this trial is the collection of outcome events, which are not necessarily 
associated with clinic visits.


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7.
PLANNED ANALYSIS
Patient disposition (number of patients screened, randomised, treated, discontinued, etc...) 
will be presented for all patients.
Disposition as well as demographic and baseline data will be displayed by treatment group 
and overall. Primary, secondary and further as well as safety endpoints will be displayed by 
treatment group.
Descriptive statistics for continuous variables will generally be N (number of patients with 
non-missing values), mean, standard deviation (SD), minimum, Q1 (lower quartile), median,
Q3 (upper quartile), maximum. In general, means, medians, Q1 and Q3 will be presented to 
one more decimal place than the raw data and SDs will be presented to two more decimal 
places. Minima and maxima will be presented to the same number of decimal places as the 
raw data.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage relative to the 
respective treatment group. Percentages will be rounded to one decimal place. A missing 
category will be displayed if and only if there are actually missing values. Percentages will be 
based on all patients in the respective patient set whether they have non-missing values or not.
For calculations, 7 days will be considered 1 week, 30 days will be considered 1 month.
Generally, displays will follow [1], [3] and [6].
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Data from the 
demographic, as well as medical and surgical history eCRF pages will be presented, including 
details on CVT history.
With regard to demographic data the following categorisations will be considered, in addition 
to the continuous data:

Age class (years): <30, ≥30-<40, ≥40-<50, ≥50-<60, ≥60-<70, ≥70-<80, ≥80

Weight class (kg): <30, ≥30 - <60, ≥60 - <90, ≥90

Body mass index (BMI) class (kg/m2): < 18.5, ≥18.5-<25, ≥25-<30, ≥30
The National Institutes of Health Stroke Scale (NIHSS) will be recorded, if it had been
collected at the time of qualifying (index) CVT. In patients, where NIHSS has not been done
at the time of index CVT, it will be performed at study entry (at Visit 1). It is a tool used by
healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is
composed of 11 items, and for each item a score of 0 typically indicates normal function in
that specific ability, while a higher score is indicative of some level of impairment. The
individual scores from each item are summed in order to calculate a patient's total NIHSS
score. The maximum possible score is 42, with the minimum score being a 0 ([16], [17]).


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Table 7.1: 1
NIHSS score
Score
Stroke Severity
0
No Stroke Symptoms
1-4
Minor Stroke
5-15
Moderate Stroke
16-20
Moderate to Severe Stroke
21-42
Severe Stroke
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Baseline conditions will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA), and summarized by ATC class 3 and 
preferred name (PN). The frequency of patients with different baseline conditions will be 
presented. 
Therapies will be classified using the most recent version of the World Health Organisation –
Drug Dictionary (WHO-DD), and the frequency of patients with therapies will be presented 
according to whether these were concomitantly taken during the on-treatment period defined 
in Section 6.1, or whether these are prior or post therapy.
Details on administration of commercially available idarucizumab – including indication, 
information on surgery / invasive procedures and bleeding – will additionally be listed.
7.3
TREATMENT COMPLIANCE
Cumulative days of temporary treatment interruptions will be summarized in classes (0, 1 -
<5, 5 - <10, 10 - <20, 20 - <30, ≥30). Frequency of patients with treatment interruptions for 
AEs as well as for other reasons will be presented. Additionally, time to first temporary 
treatment interruption will be analyzed. For this purpose, patients who permanently 
discontinue from treatment before having had a temporary treatment interruption will be 
censored at time of treatment discontinuation.
Treatment compliance will be calculated as follows: 
7.3.1
Dabigatran Compliance
Based on capsule counts, treatment compliance (%) will be calculated as:
Dabigatran compliance (%) =
Number of tablets actually taken × 100
Number of tablets which should have been taken
This value will be entered directly into the eCRF.


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Only treatment interruptions not due to AE will be considered as a compliance issue and will 
be taken into account in the calculation (duration of interruptions due to AE will be subtracted 
from the duration of the study period).
Dabigatran compliance will be summarised continuously and in classes (<80%; 80-120%; 
>120%).
A patient will be considered as non-compliant if the number of doses taken is not between 80-
120% of the expected number of doses.
7.3.2
Warfarin Compliance
Warfarin compliance will be monitored by means of the international normalised ratio (INR) 
rather than by pill counts as it is a more accurate and biologic measure of pharmacodynamic 
effect. The quality of warfarin therapy for each patient will be assessed by reporting the 
number of INR values within the indicated therapeutic target range (2.0 – 3.0) as well as those 
above and below this range. The Rosendaal method [10] will be used to evaluate the 
percentage of time that a patient’s INR is in range (i.e. time in therapeutic range [TTR]). For 
each calendar month, the mean of all INR values will be reported. This will be calculated for 
each patient, for each centre, for each country and for the whole study. The mean percentage 
of time of INR in range will be calculated for each centre and each country during the trial 
conduct to monitor the INR control. The percentage of time of INR in range for each country 
and for the trial will be reported at study end. 
For patients who had a temporary discontinuation of study warfarin, INR values taken in the 
time interval between the day after the temporary discontinuation and restart of medication 
will not be counted.
If INR is evaluated during the first week after randomisation, those INR 
values will not be used in calculating TTR.
The Rosendaal method: assume the INR value between two measurements will vary linearly 
from the value of the first to the value of the second measurement, divide the time between 
two measurements in days, fit a linear equation using the two measured INR values, and then 
calculate the INR for each day in the interval.  The percentage of time when INR is in target 
range is calculated for each patient.
Furthermore, the number and frequency of patients with percentage of time in INR target 
range by cutpoints 45, 55 and 65%, as well as 60 and 75% will be presented for the trial.
Descriptive statistics will be provided for the number of INR measurements per months.
7.4
PRIMARY ENDPOINT(S)
This is a prospective, randomised, open label, blinded endpoint (PROBE), active comparator 
trial and the clinical endpoints are being adjudicated by an AC in a blinded fashion. All 
analyses are exploratory, no statistical hypothesis will be tested.
The number and frequency of patients by treatment as well as by subgroup will be displayed
along with the 95% confidence intervals (CIs). No difference between the treatments 
dabigatran etexilate versus warfarin will be tested. 


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Hazard ratios (HR) and 95% CI will be calculated as well; however the result will only be 
considered interpretable if the CI is not too wide, i.e. (lower limit of CI ) ≥ (estimate of HR /
4) and (upper limit of CI) ≤ (4 * estimate of HR). A Cox proportional hazard model stratified 
by ICH at baseline will be applied. 
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
The analyses for the secondary endpoints as described in Section 5.2.2 will be mainly based 
on frequency counts and percentages along with 95% CIs. 
Means and standard deviations will be displayed for the endpoint on cerebral venous 
recanalisation as measured by the change in number of occluded cerebral veins and sinuses 
after up to 24 weeks. Patients with missing or not analyzable MRI scans at EOT will be 
excluded from this analysis.
The frequency of patients with new intracranial haemorrhage (“ICH”) or worsening of the 
haemorrhagic component of a previous lesion will be presented, along with 95% CIs. The 
single components of this composite endpoint will be presented in the same way.


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7.7
EXTENT OF EXPOSURE
The date of first administration is recorded at visit 2. 
Days on treatment = date of last administration – date of first administration + 1 day
There will be one summary of duration of exposure [weeks] including treatment interruptions 
(i.e. they will not be substracted from days on treatment), and one excluding treatment 
interruptions (i.e. they will be substracted from days on treatment).
Duration of exposure class [weeks]: ≤8 weeks (56 days), >8 weeks (56 days) to ≤16 weeks 
(112 days), >16 weeks (112 days) to ≤24 weeks (168 days), >24 weeks (168 days) 
Additionally, time to permanent discontinuation of trial medication will be analyzed.
7.8
SAFETY ANALYSIS
7.8.1
Adverse events
Adverse events (AEs) will be coded with the most recent version of MedDRA.
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and NOT on the number of AEs.
For analysis of AE attributes such as duration, severity, etc. multiple AE occurrence data on 
the CRF will be collapsed into AE episodes provided that all of the following applies:
•
The same MedDRA lowest level term was reported for the occurrences
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)
•
Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
For further details on summarization of AE data, please refer to [5], [7].
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs occurring between first drug intake till 6 days after last drug intake will be assigned to 
the randomised treatment. For details on the treatment definition, see Section 6.1.
According to ICH E3 [8], AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical and Quality Review
Meeting.


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An overall summary of AEs will be presented.
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for patients with serious 
AEs, AEs leading to treatment discontinuation, AEs leading to death, other significant AEs 
according to ICH E3 and AEs considered to be drug-related by the investigator (any, as well 
as serious). Furthermore, AEs will be summarised by intensity. For data disclosure purposes, 
non-serious AEs will also be provided in separate tables.
The system organ classes will be sorted according to the standard sort order specified by the 
European Medicines Agency (EMA), preferred terms will be sorted by descending frequency 
(within SOC).
The overall summary, as well as the frequency table of patients with any AEs by SOC and 
PT, will also be presented by stratification factor intracranial haemorrhage (“ICH”) at baseline 
as assessed by investigator.
For the listings AEs will be presented per the period in which they occurred, for details see 
Section 6.1.
7.8.2
Laboratory data
The following safety laboratory parameters will be tested / collected: 

Chemistry: ALT (SGPT), AST (SGOT), Alkaline Phosphatase, Bilirubin total 
(fractionated if increased), GGT, Creatinine and Creatinine Clearance (CrCl, 
according to Cockcroft-Gault formula)

Haematology: Erythrocytes, Haemoglobin, Haematocrit, Platelet count, WBC count
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[9].
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will be 
done via comparison of laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.
Additionally, potential Hy’s Law cases will be presented graphically.
Thrombophilia testing is not a required trial procedure, but the results will be collected if it 
was performed as part of routine care at any time after randomisation. These data will only be 
listed.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


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Vital signs data – systolic and diastolic blood pressure, as well as pulse rate - observed at 
Visit 3 and 4, and at the end-of-trial evaluation will be assessed with regard to possible 
changes compared to findings before start of treatment.
Weight (collected to calculate CrCl) will only be listed.
7.8.4
ECG
Frequency of patients with any clinically relevant ECG finding during screening period will 
be presented.
7.8.5
Others
Pregnancy test results will only be listed.


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8.
REFERENCES
1
2
CPMP/ICH/363/96: “Statistical Principles for Clinical Trials”, ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
3
 
4
5
 
6
 
7
 
8
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version
9
 
10
Rosendaal FR, Cannegieter SC, Meer FJM van der, Briet E. A method to determine the 
optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239 
[R08-1695]
11
1160.248 Clinical Trial Protocol incl. Amendment 1 
12
Miranda B, Ferro JM, Canhao P, Stam J, Bousser MG, Barinagarrementeria F, et al, 
ISCVT Investigators. Venous thromboembolic events after cerebral vein thrombosis. 
Stroke 2010; 41: 1901-1906.
13
Kummer R von, Broderick JP, Campbell BCV, Demchuk A, Goyal M, Hill MD, 
Treurniet KM, Majoie CBLM, Marquering HA, Mazya MV, San Roman L, Saver JL, 
Strbian D, Whiteley W, Hacke W. The Heidelberg Bleeding Classification: 
classification of bleeding events after ischemic stroke and reperfusion therapy. Stroke 
2015; 46:00-00, DOI: 10.1161/STROKEAHA.115.010049
 
 
16
NIH Stroke Scale. NIH. Rev 10/1/2003.
http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf. Access date: 6 September 
2013
17
Know Stroke: Know the Signs. Act in Time. NIH Stroke Scale. National Institute of 
Neurological Disorders and Stroke. 2013.
http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale_Booklet.pdf. Access date: 6 
September 2013
18
Hage AV. The NIH Stroke Scale: A Window into Neurological Status.
https://ce.nurse.com/PrintTopic.aspx?TopicId=5975. Access date: 5 September 2013.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
16-NOV-16
None
This is the initial TSAP with necessary 
information for trial conduct.
Final
05-MAR-18
 
All
This is the final TSAP, based on the 
initial one, with necessary information 
for the analysis for the CTR.