Clinical trial NCT02197416
Conditions: Venous Thromboembolism Secondary Prevention
Sponsor: Boehringer Ingelheim
Start date: 2014-09-29; Completion date: 2019-11-19
Enrollment: 214 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This open-label, single arm prospective cohort study will assess the safety of dabigatran etexilate in secondary prevention of venous thromboembolism in paediatric patients. Children from 0 to less than 18 years of age will be eligible to participate.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: dabigatran etexilate
Intervention descriptions: intervention 1: Age and weight appropriate capsule dose (combination of 50 mg, 75 mg and 110 mg capsules) or pellets or oral liquid formulation

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02154816-11
EudraCT No.:
BI Trial No.:
2014-000583-18
1160.108
BI Investigational
Product:
Dabigatran etexilate, BIBR 1048 MS
Title:
Open label, single arm safety prospective cohort study of dabigatran
etexilate for secondary prevention of venous thromboembolism in 
children from 0 to less than 18 years
Clinical Phase:
III
Trial Clinical 
Monitor:
Telephone:   
Fax:              
Co-ordinating 
Investigator:
Telephone:
Fax:
Status:
Final Protocol (Revised protocol (based on Global Amendment 8))
Version and Date:
Version: 9.0
Date: 07 Feb 2019
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Pradaxa
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
07 Feb 2019
08 Apr 2014
1160.108
Title of trial:
Open label, single arm safety prospective cohort study of dabigatran etexilate for  
secondary prevention of venous thromboembolism in children from 0 to less than 18 
years
Co-ordinating 
Investigator:
Telephone:
Fax:
Trial sites:
Multi-centre trial
Clinical phase:
III
Objective:
To assess the safety of dabigatran etexilate for secondary prevention of venous 
thromboembolism
Methodology:
An open label, single arm prospective cohort study designed to assess the safety of 
dabigatran etexilate for secondary prevention of paediatric venous thromboembolism.
No. of patients: 
total entered:
A minimum of 100 patients. Thereafter, the Data Monitoring Committee (DMC) or 
Sponsor may decide to keep recruitment open in case additional safety data needs to 
be generated.
Patients from the 1160.106 trial who completed study treatment and require 
anticoagulation for secondary VTE prevention may be rolled-over into this study.
each treatment:
Not applicable
Diagnosis :
Completed course of initial treatment for confirmed venous thromboembolism (for at 
least 3 months) and requirement for further anticoagulation due to the presence of a 
clinical risk factor
Main criteria
for inclusion:
Patients diagnosed with acute venous thromboembolism who either
-
completed initial course of anticoagulation therapy (for at least 3 months), or 
-
completed the 1160.106 study treatment ,
and require anticoagulation therapy for secondary prevention of venous 
thromboembolism due to presence of a persistent (unresolved) clinical risk factor.
Test product:
Dabigatran etexilate


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Pradaxa
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
07 Feb 2019
08 Apr 2014
1160.108
dose:
Patients aged ≥ 8 years: Age and weight adjusted dabigatran etexilate capsules using 
50 mg, 75 mg, 110 mg and 150 mg doses.
Patients aged < 8 years and for patients who cannot take capsules even if older than 8
years (but below 12 years of age): Age and weight adjusted dabigatran etexilate 
pellets.
Patients aged < 12 months: Age and weight adjusted dabigatran etexilate oral liquid 
formulation (OLF) or any other alternative age-appropriate formulation.
Recruitment will be initiated in adolescent group first (12 to <18 years.) and 
consecutively opened to the second age group (2 to<12 years.) and then to youngest 
age group (0 to <2 years.) based on Data Monitoring Committee (DMC) 
recommendations that take into account information from all ongoing dabigatran 
etexilate paediatric studies; safety aspects, data analyses of PK, PD, exposure-
response model updated with relevant paediatric and adult data as well as the 
appropriateness of dosing algorithm for consecutive age group. 
mode of admin.:
Oral
Comparator products:
None
dose:
Not applicable
mode of admin.:
Not applicable
Duration of treatment: Patients will be treated with dabigatran etexilate until the clinical risk factor has
resolved, or up to a maximum of 12 months. At the end of the study all patients need 
to discontinue dabigatran etexilate, or switch to standard of care, if there is continued 
need for anticoagulant treatment.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Pradaxa
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
07 Feb 2019
08 Apr 2014
1160.108
Criteria for 
 and 
pharmacodynamics:

 

 

Pharmacodynamic parameters: Central measurement of aPTT and ECT
Criteria for efficacy:
All criteria in this study will be considered as safety endpoints.
Criteria for safety:
Primary endpoints:

Recurrence of venous thromboembolism (VTE) at 6 and 12 months 

Major and minor (including clinically relevant non-major (CRNM)) bleeding 
events at 6 and 12 months

Mortality overall and related to thrombotic or thromboembolic events at 6 
and 12 months
Secondary endpoints:

Occurrence of post-thrombotic syndrome (PTS) at 6 and 12 months

Pharmacodynamic assessments (central measurement of dTT (Anti-Factor IIa 
activity), aPTT and ECT) at Visit 3 (after at least six consecutive dabigatran
etexilate doses) and after at least 3 days following any dabigatran etexilate
dose adjustment

Number of dabigatran etexilate dose adjustments during treatment period (i.e. 
Number of patients with dabigatran dose adjustments during treatment 
period)
Other safety assessments:

Incidence of adverse events, protocol-specified AESI and serious adverse 
events

 
 
 
Statistical methods:
Overall assessment of safety will be based on descriptive statistics.


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FLOW CHART
Trial Period
Screening
Treatment Period (open-label) with Dabigatran Etexilate
Follow-up
Visit (V) #:
1 1,2
2 2
3 3
4
5
6
7
8
9
10
11
Titration Visit 
(if needed) 3
Unscheduled Visit 
(if needed) 4
eEOT 5
12
Study week 
-1
1
1
3
6
12
18
26
34
42
52
If medication is 
discontinued 
before Visit 11 
V11 or eEOT
+ 28 days
+7
Day
visit window
-14 to 1
1
4
+3
22
±7
43
±7
85
±7
127
±7
183
±7
239
±7
295
±7
365
±7
Informed consent / assent6
X
Inclusion / exclusion criteria
X
X
Medical history / demographics
X
Physical examination7
X
X
X
X
X
Assessment of Index VTE and clinical risk factor
X
Vital signs (BP and HR) and weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
12-lead resting-ECG (5 min supine)8
X
X
X
X
Evaluate signs / symptoms of recurrent VTE and clinical risk factor
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Evaluation of PTS
X
X
Evaluation of bleeding events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Objective diagnosis of recurrent VTE or bleeding
In case of suspected recurrent VTE, PTS or bleeding
Pregnancy test9
X
X
X
X
Laboratory tests (blood)10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PD sample (aPTT and ECT)11
X
X
X
X
X
X
X
X
X
X
X
X
dTT (or alternative method) sample11
X
X
X
X
X
X
X
X
X
X
X
First administration of dabigatran etexilate12
X
Dispense dabigatran etexilate
X
X
X
X
X
X
X
X
X
X
Adverse events and Concomitant Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medication compliance
X
X
X
X
X
X
X
X
X
X
X
X
Patient treatment assessment13
X
X
X
X
X
X
Investigator treatment evaluation
X
X
X
X
X
X
Termination of trial medication
X
X
Conclusion of Patient Participation
X


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1.
Screening Visit and Visit 8 of 1160.106 trial may be combined for patients who have completed the treatment period of 1160.106 trial (tests will be done only once)
2.
Visit 1 and Visit 2 may occur on the same day provided that results of the local lab are available to confirm eligibility and INR is < 2.3 (for patients who have been treated with 
VKA). Local lab results will be recorded under Visit 1, central lab results will be recorded under Visit 2 in the eCRF.
3.
Visit 3 is not applicable for patients who have previously completed the treatment period in the dabigatran etexilate arm of the 1160.106 study and who continue taking the same 
dose of dabigatran etexilate in this trial. For all other patients, during Visit 3 the trough dabigatran concentration will be determined 
 
 The first concentration assessment 
will be done at Visit 3 (after at least 6 consecutive dabigatran etexilate doses are taken). If target trough exposure of 50 to < 250 ng/mL is not achieved, an Unscheduled Visit 
must be performed in order to adjust the dabigatran etexilate dose (refer to Appendix 10.4.2). A Titration Visit must be scheduled preferably after at least 3 days have elapsed (or 
at least 6 new doses have been taken) since a dose adjustment to reassess if the new trough dabigatran concentration is within the target range. Trough is achieved 10 to 16 hours 
after the last intake of dabigatran etexilate. Patients must not be dosed at home prior to attending a Titration Visit; dosing will be done after a trough plasma sample is collected.
4.
Unscheduled Visits are to be conducted in all cases of suspected recurrent VTE, paradoxical embolism (PDE), occurrence of post-thrombotic syndrome (PTS), major or clinically-
relevant bleeding events (MBEs/CRBEs) or other AESI or SAE. The Unscheduled Visit should be performed as soon as possible, preferably within 24 hours after the site first 
becomes aware of a suspected event.
Unscheduled Visit is also to be performed in case a dose adjustment is needed.
5.
The early End Of Treatment (eEOT) Visit will be required for all patients who have taken a dose of dabigatran etexilate but the study medication was discontinued early for any 
reason (e.g. the clinical risk factor has resolved) before Visit 11. For transition recommendation from dabigatran etexilate to a non-study antithrombotic treatment see Appendix 
10.3
6.
The informed consent (and if applicable assent) should be obtained per local legislations and guidelines from the patient’s parent(s) or legal guardian and patient (where 
applicable) before any study procedures are performed. Should patients reach legal age during the trial they must personally sign and date the informed consent form as soon as 
possible and, at the latest, at the next visit.
7.
A complete physical examination is required at Visit 1, Visit 8, Visit 11, eEOT Visit and Visit 12. At any point during the trial, a comprehensive physical examination should be 
performed if indicated based on the clinical presentation of the patient (reported symptoms and the findings on the basis of the vital signs). Relevant findings should be recorded 
in source notes and captured in the trial eCRF.
8.
The required ECGs should be performed as noted in the flow chart, additional ECGs should be performed in cases of cardiac symptoms (example: rhythm disorders) or per PI 
judgment when medically required.
9.
A pregnancy test will be done centrally in female adolescents of child bearing potential (subjects who have reached menarche). Menstrual period must be confirmed prior to 
inclusion in the trial. More frequent testing can be done if required by the local regulation and / or authority or per investigator judgment. Alternatively serum or urine pregnancy 
testing may be performed locally at screening, see protocol Section 5.2.3.
10. Laboratory tests will be performed according to protocol Section 5.2.3.


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The approximate blood volumes (in ml) to be collected for planned central safety laboratory assessments and
/PD are outlined in Appendix 10.1.1. An additional blood sample
could be collected at screening for local measurement of INR, serum creatinine, HCT, Hb, Platelet count, ALT and AST in order to facilitate the eligibility assessment.
In case of infants and when medically required per Investigator judgment and / or per local guidelines, reduced blood collection will be implemented after consultation with the 
Sponsor (e.g. omission of exploratory coagulation markers, reduced frequency of safety labs during the treatment period, etc.). The decision for the reduced blood collection in 
those cases will be documented in the ISF.
11. Collection of pre-dose trough 
 PD samples will be done as indicated in the flow chart. Pre-dose trough 
 PD samples should be taken at approximately 10 to 16 hours 
after the last dose. Date and exact time of study drug administration on the three days before the samples are taken are to be captured using patient / parent / legal guardian diary 
(must be distributed during the previous visit). Dabigatran etexilate doses must not be delayed to accommodate a preferred pre-dose collection time point. More frequent plasma 
level evaluations may be warranted per investigator judgment for infants and in cases where the patient’s weight is expected to fluctuate in a short timeframe due to patient age, 
physiology and other factors.
12. The appropriate dabigatran etexilate starting dose must be based on the latest age and weight-based nomogram provided in Appendix 10.4.1. Patients who completed the treatment 
period of the 1160.106 study and who are still being treated with dabigatran etexilate may continue taking the same dose also in this trial.
13. This assessment will be completed by the patient (if old enough per investigator judgment) or by the parent / legal guardian. The aim of this evaluation will be to obtain additional 
information about the experience of taking dabigatran etexilate as capsules, pellets or oral liquid formulation (reconstituted with flavoured or unflavoured solvent). The 
assessment should be preferably completed by the same person at all defined time points.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 21
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................21
2.2
TRIAL OBJECTIVES.......................................................................................21
2.3
BENEFIT - RISK ASSESSMENT ...................................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 25
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................25
3.1.1
Administrative structure of the trial...................................................25
3.1.1.1
Data Monitoring Committee....................................................26
3.1.1.2
Central Independent Adjudication Committee ........................27
3.1.1.3
Central laboratory ....................................................................27
3.1.1.4
Steering Committee .................................................................27
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................27
3.3
SELECTION OF TRIAL POPULATION ......................................................27
3.3.1
Main diagnosis for study entry............................................................28
3.3.2 Inclusion criteria...................................................................................28
3.3.3
Exclusion criteria ..................................................................................29
3.3.4
Removal of patients from therapy or assessments.............................31
3.3.4.1
Removal of individual patients................................................31
3.3.4.2
Discontinuation of the trial by the sponsor..............................32
4.
TREATMENTS........................................................................................ 34
4.1
TREATMENTS TO BE ADMINISTERED....................................................34
4.1.1
Identity of BI investigational product and comparator 
product(s)...............................................................................................34
4.1.2
Method of assigning patients to treatment groups ............................35


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4.1.3
Selection of doses in the trial................................................................35
4.1.4
Drug assignment and administration of doses for each patient .......39
4.1.5
Blinding and procedures for unblinding ............................................41
4.1.5.1
Blinding....................................................................................41
4.1.5.2
Procedures for emergency unblinding .....................................41
4.1.6
Packaging, labelling, and re-supply ....................................................41
4.1.7
Storage conditions.................................................................................41
4.1.8
Drug accountability ..............................................................................42
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................43
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................43
4.2.2
Restrictions............................................................................................47
4.2.2.1
Restrictions regarding concomitant treatment .........................47
4.2.2.2
Restrictions on diet and life style.............................................48
4.3
TREATMENT COMPLIANCE.......................................................................48
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 49
5.1
EFFICACY.........................................................................................................49
5.1.1
Endpoints of efficacy.............................................................................49
5.1.2
Assessment of efficacy...........................................................................49
5.2
SAFETY..............................................................................................................49
5.2.1
Endpoint(s) of safety.............................................................................49
5.2.2
Assessment of adverse events...............................................................51
5.2.2.1
Definitions of adverse events...................................................51
5.2.2.2
Adverse event and serious adverse event reporting.................52
5.2.3
Assessment of safety laboratory parameters......................................54
5.2.4
Electrocardiogram................................................................................54
5.2.5
Assessment of other safety parameters...............................................55
5.2.5.1
Vital signs ................................................................................55
5.2.5.2
Weight assessment...................................................................55
5.3.2
Other assessments .................................................................................55
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................56
5.5
 


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5.6
BIOMARKER(S) ...............................................................................................58
5.7
PHARMACODYNAMICS................................................................................58
5.7.1
Pharmacodynamic endpoints...............................................................58
5.7.2 Methods of sample collection...............................................................58
.....59
6.
INVESTIGATIONAL PLAN.................................................................. 60
6.1
VISIT SCHEDULE............................................................................................60
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................60
6.2.1
Screening period....................................................................................60
6.2.2
Treatment period ..................................................................................60
6.2.3
End of trial and follow-up period........................................................61
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 62
7.1
STATISTICAL DESIGN - MODEL................................................................62
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................62
7.3
PLANNED ANALYSES....................................................................................62
7.3.1
Primary analyses...................................................................................62
7.3.2
Secondary analyses ...............................................................................63
7.3.3
Safety analyses.......................................................................................63
7.3.6
Pharmacodynamic analyses.................................................................64
7.4
HANDLING OF MISSING DATA ..................................................................65
7.5
RANDOMISATION ..........................................................................................65
7.6
DETERMINATION OF SAMPLE SIZE ........................................................65
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 66
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................66
8.2
DATA QUALITY ASSURANCE .....................................................................67
8.3
RECORDS..........................................................................................................67
8.3.1
Source documents .................................................................................67
8.3.2
Direct access to source data and documents.......................................68
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................68
8.4.1
Listedness...............................................................................................68
8.4.2
Expedited reporting to health authorities and IECs/IRBs................68


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8.5
STATEMENT OF CONFIDENTIALITY.......................................................68
8.6
COMPLETION OF TRIAL..............................................................................69
9.
REFERENCES......................................................................................... 70
9.1
PUBLISHED REFERENCES...........................................................................70
9.2
UNPUBLISHED REFERENCES.....................................................................74
10. APPENDICES .......................................................................................... 77
10.1
SAFETY AND OTHER CLINICAL LABORATORY EVALUATIONS....77
10.1.1 Blood volume charts .............................................................................78
10.2
CLINICAL EVALUATION OF LIVER INJURY .........................................79
10.2.1 Introduction...........................................................................................79
10.2.2 Procedures .............................................................................................79
10.3
TRANSITION TO NON-STUDY ANTITHROMBOTIC TREATMENT 
WITH EARLY STUDY DRUG DISCONTINUATION OR AT THE END 
OF THE TRIAL.................................................................................................80
10.4
DOSING OF DABIGATRAN ETEXILATE...................................................81
10.4.1 Dosing nomogram (starting doses)......................................................81
10.4.2 Dose Adjustment nomogram ...............................................................83
10.4.2.1 Up-titration...............................................................................83
10.4.2.2 Down-titration..........................................................................84
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 86


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT 
Alanine-Aminotransferase
AP
Alkaline Phosphatase
AST 
Aspartate-Aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval 0 to infinity
aPTT
Activated partial thromboplastin time
APCC
Activated prothrombin complex concentrates
aVTEt
Acute Venous thromboembolism treatment
BI
Boehringer Ingelheim
BIBR 1048
Dabigatran etexilate
BIBR 1048 MS
Indicates the mesylate salt of dabigatran etexilate. Unless otherwise 
specified BIBR1048 MS has been used interchangeably with BIBR 1048
b.i.d.
Twice daily
BP
Blood Pressure
BUN
Blood Urea Nitrogen
C
Centigrade / Celsius
CA
Competent Authority
CI
Confidence Interval
Cmax
Maximum Measured Concentration 
CML
Clinical Monitor Local
CPMP
Committee for Proprietary Medicinal Products
Cpre,ss
Pre-dose concentration of the analyte in plasma at steady-state immediately 
before administration of the next dose
CRA
Clinical Research Associate
CRF/eCRF
Case Report Form / electronic Case Report Form
CRNM
Clinically relevant non-major
CRO
Contract Research Organisation 
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CT
Computed Tomography
CVL
Central venous Line
DILI
Drug-Induced Liver Injury
DMC
Data Monitoring Committee
dTT
Diluted Thrombin Time
DVT
Deep venous thrombosis
EC
Ethics Committee
ECG
Electrocardiogram
ECT
Ecarin clotting time 
EDTA
Ethylenediaminetetraacetic acid
eGFR
Estimated Glomerular Filtration Rate
EOT
End of Treatment


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eEOT
Early End of Treatment
F
Fahrenheit 
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEIBA
Factor Eight Inhibitor Bypassing Activity
FRAC
Fraction of Adult Dose
GCP
Good Clinical Practice
gMean
Geometric Mean
h
Hour
HCT
Haematocrit
HPLC
High Pressure Liquid Chromatography
HR
Heart Rate
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRT
Interactive Response Technology
IRB
Institutional Review Board
ISF
Investigator Site File
ISTH
International Society on Thrombosis and Haemostasis
LMWH
Low Molecular Weight Heparin
MBE
Major Bleeding Event
MedDRA
Medical Dictionary for Drug Regulatory Activities
mL
Millilitre 
mg
Milligram 
MRI
Magnetic Resonance Imaging
MS
Mass Spectrometry
Na
Sodium
ng
Nanogram 
No.
Number
OLF
Oral Liquid Formulation
OPU
Operative Unit
p.o.
per os (oral)
PE
Pulmonary embolism
PD
Pharmacodynamic
PDCO
Paediatric Committee (of the European Medicines Agency)
PDE
Paradoxical Embolism
PK
Pharmacokinetic
PPI
Proton Pump Inhibitor
PTS
Post-Thrombotic Syndrome
REP
Residual Effect Period
SAE
Serious Adverse Event
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamate Pyruvate Transaminase


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SI
International System of Units
SOC
Standard of Care
SOP
Standard Operating Procedure
SPAF
Stroke Prevention in Atrial Fibrillation
SUSAR
Suspected Unexpected Serious Adverse Reaction
sVTEp
Secondary Venous thromboembolism Prevention 
t1/2
Terminal Half-Life
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
tmax
Time From Dosing to Maximum Measured Concentration
THR
Total hip replacement
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TT
Thrombin Time 
UFH
Unfractionated Heparin
ULN
Upper Limit of Normal
VKA
Vitamin K Antagonist
VTE
Venous thrombotic event / Venous Thromboembolism
W
Weight


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
In contrast to adults, venous thromboembolism (VTE) in children is a rare event with an 
overall annual incidence of approximately 0.07-0.14 events per 10,000 children (R06-2301). 
Nevertheless it represents a significant management challenge that requires therapeutic 
intervention (R06-2301, R06-2150, R07-2959). The most common etiologic factor for VTE 
in children is the presence of a central venous line (CVL) (R06-2305, R06-2150). Immediate 
complications of VTE include death from pulmonary embolism (PE) and non-lethal PE. 
Long-term complications involve recurrent VTE, post-thrombotic syndrome (PTS), and 
bleeding associated with anticoagulation therapy (R07-2959, R07-2954, R07-2962, R06-
2305). 
The recommendations on antithrombotic therapy in children are based on extrapolation of 
adult data from randomized controlled studies or on small randomized or non-controlled 
studies in children (P98-11480, R07-2940). The current standard of care (SOC) for the 
treatment of VTE in children is unfractionated heparin (UFH) or low molecular weight 
heparin (LMWH) administered for generally 5 to 7 days followed by 3 to 6 months of 
LMWH or vitamin K antagonists (VKAs) (R07-2939). 
There are frequent challenges with the use of UFH and oral anticoagulants (OAC) in children 
(P06-06652, R07-2938, R07-2956). For UFH, these include variable pharmacokinetics, need 
for venous access for both administration and monitoring and heparin-induced 
thrombocytopenia. For VKA, problematic issues with dosing include the significant 
influences of age, diet, medications and underlying diseases, which result in a need for 
frequent monitoring (R07-2964). Low molecular weight heparin has several potential 
advantages in children over UFH/VKAs for the treatment of VTE, which has prompted it 
becoming the preferred product in children despite the lack of adequate and well-controlled 
clinical trials. However, the use of LMWH requires subcutaneous administration with a 
needle poke causing pain in the child and anxiety for the parent or guardian which may 
translate into non-compliance. These problems with conventional anticoagulation provide the 
rationale for investigations of novel anticoagulants. 
An open-label multicentre randomized study (the REVIVE study) comparing the efficacy and 
safety of a low molecular weight heparin (reviparin-sodium) to UFH/VKA for the treatment 
of VTE in children, showed that at 3 months post-therapy, 2/36 patients (5.6%) treated with 
reviparin-sodium had recurrent VTE or death compared to 4/40 patients (10.0%) receiving 
UFH/VKA (odds ratio = 0.53; 95% CI=(0.05, 4.00); Fisher’s exact test: 2P= 0.677). There 
were 7 major bleeds reported, 2/36 (5.6%) in the reviparin-sodium group and 5/40 (12.5%) in 
UFH/VKA group (odds ratio = 0.41; 95% confidence interval 0.04, 2.76); Fisher’s exact test: 
P=0.435). There were 5 deaths reported during the study period, 1 (2.8%) in the reviparin-
sodium group and 4 (10.0%) in the UFH/VKA group. All five deaths were considered 
unrelated to VTE but one was due to an intracranial haemorrhage in the UFH/VKA group. 
Due to challenges with patient recruitment, REVIVE was closed prematurely. The REVIVE 
study provides valuable information on the incidence of recurrent VTE, major bleeding and 
problematic issues associated with therapy of VTE in children (R06-2304).


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Paediatric VTE has a significant impact on both immediate and long-term health outcomes 
(R13-4251, P94-81556; R12-5109). There are two major consequences of VTE that could 
affect the long-term health status: recurrence of VTE and post-thrombotic syndrome (PTS). 
The risk of recurrent VTE in children is estimated to be approximately 5-10%. However the 
risk may be even higher in patients with one or more persisting risk factors (e.g. central 
venous line (CVL), chronic disease, thrombophilia, etc.) (R07-2936; P09-03357; P12-03887). 
Data from a recent survey conducted in the USA suggested that approximately 14% of 
children develop recurrent VTE with the likelihood of recurrence being the highest in 
adolescent group (19%) (R13-4251). The incidence of clinically significant childhood PTS is 
estimated to be 10% (P09-03357). Up to date, there are no randomized controlled trials that 
investigate secondary VTE prevention in paediatric patients.
In a prospective cohort study conducted by 
 and colleagues at the Hospital for Sick 
Children (Canada), the use of LMWH for treatment and prevention was evaluated in a cohort 
of 173 patients.  There were 146 courses of LMWH administered for treatment and 30 
courses for prophylaxis of VTE (R14-1031). Of the 30 patients who received prophylactic 
doses of LMWH, 11 (37%) patients received LMWH for the prevention of CVL-related 
thrombosis. Of these 30 patients who received prophylactic doses of LMWH, one (3.3%) 
patients had symptomatic recurrence of VTE, and died due to extension of old VTE and 
coronary heart disease. There were no major bleeds. 
In another long-term safety and efficacy prospective cohort study conducted by Schobess and 
colleagues, 80 children aged > 3 months to < 18 years  diagnosed with DVT were 
consecutively recruited to be treated with a LMWH and stratified to once-daily or twice-daily 
enoxaparin administration, with median treatment duration of 4-5 months (R14-1032). The 
median follow-up time was 24 months, during the follow-up period 6.3% of children 
developed PTS and 5% developed recurrent DVT. 
A Canadian Paediatric Registry followed 137 consecutive paediatric VTE patients from 6 
months to up to 3 years (P94-81556). The registry reported that out of 137 patients, 2.2% 
died as a direct result of thrombotic complications, 18.5% developed recurrent VTE or PE, of 
which 70% occurred on anticoagulation therapy. In addition, 21% had evidence of post-
thrombotic syndrome.
In summary, patients who suffered from VTE may remain at risk for recurrent thrombosis
and thromboembolism after completion of initial anticoagulation treatment course, especially 
those with CVL, prothrombotic risk factors, etc. Long-term DVT consequences (e.g. post-
thrombotic syndrome) are important causes of morbidity and mortality in children and require 
further investigation.
1.2
DRUG PROFILE
Dabigatran etexilate (BIBR 1048) is an oral pro-drug of the active direct thrombin inhibitor
dabigatran (BIBR 953). Dabigatran is a low molecular weight, reversible thrombin inhibitor, 
which binds to thrombin with a high affinity and specificity. Dabigatran inhibits free 
thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation. The pro-drug 
itself has no anticoagulant activity.


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The efficacy and safety of dabigatran etexilate have been evaluated in Phase III trials that 
involved over 38,000 adult patients, thereof more than 23,350 dabigatran patients were 
investigated.
These trials investigated primary VTE prevention after hip and knee surgery, acute VTE 
treatment (aVTEt), secondary VTE prevention (sVTEp) and stroke prevention in atrial 
fibrillation (P09-11669).
The aVTEt adult study program with RE-COVER (1160.53, U09-1400-01) and RE-COVER 
II (1160.46, U11-2298-01) and the two sVTEp studies (RE-MEDY: 1160.47, U10-2533-01
and RE-SONATE: 1160.63, U11-2267-02) have been completed.
Dabigatran etexilate is approved for prevention of VTE following total hip or knee 
replacement surgery and for prevention of stroke and systemic embolism in patients with 
atrial fibrillation. At the time this protocol was written, approval was still pending for aVTEt 
and sVTEp in major markets.
For full details on drug profile, please refer to the latest version of the Investigator’s Brochure 
(IB) (U98-3208).
PK/PD data from adult studies:
Dabigatran is a potent, competitive, reversible direct thrombin inhibitor. It inhibits 
thrombin-dependent conversion of fibrinogen to fibrin, thus preventing the formation of 
thrombi. 
The clinical pharmacology study program of dabigatran etexilate is comprised of more than 
45 individual Phase I studies and the collection of pharmacokinetic and pharmacodynamic 
data from seven Phase II studies and four Phase III studies (RE-LY, RE-NOVATE, RE-
NOVATE-2, and RE-COVER).  
Overall, dabigatran plasma concentration increased proportional to the increasing oral dose of 
the prodrug dabigatran etexilate and there was no time or dose dependency in dabigatran 
distribution and elimination indicating linear pharmacokinetics (U09-2262-01).
The pharmacokinetic profile of dabigatran is characterized by maximum plasma 
concentrations at approximately 2 hours after oral administration, a bi-exponential 
distribution phase and a terminal half-life of 11-17 hours in young (U06-1614-01, U00-1856) 
and 12 - 13 hours in elderly healthy volunteers (U03-1878), respectively.
Steady state is generally attained by the third day of treatment with dabigatran etexilate 
administered b.i.d. 
There is a clear relationship between dabigatran plasma concentrations and its 
pharmacodynamic effects (e.g. changes in ecarin clotting time (ECT), thrombin time (TT), 
diluted thrombin time (dTT), and activated partial thromboplastin time (aPTT)) in all 
populations studied, resulting in reproducible dose-dependent prolongation in clotting times 
with rapid onset and offset of these effects. The PK/PD (i.e. prolongation of coagulation 


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time) was consistent between various patient populations and healthy volunteers and not 
affected by age, sex, or co-medication (U09-1399-02).  
In the RE-LY study (U09-3249-02), a relationship between total dabigatran exposure and 
efficacy (i.e. ischemic stroke) has been established; a total dabigatran trough concentration 
above 50 ng/mL was associated with appropriate efficacy for the prevention of stroke and 
even lower concentrations appeared to provide benefit. In the RE-COVER study, the 
correlation between efficacy and total dabigatran trough concentration was weak. Efficacy 
could be considered as adequate at concentrations above the 10th percentile (26 ng/mL) of the 
trough concentrations observed in RE-COVER. Based on the anticipated similarity of the 
pathophysiology of thrombotic events in the populations of these two trials, a trough 
concentration ≥ 50 ng/mL is expected to provide the most favourable efficacy and is therefore 
proposed for paediatric patients in this trial. Furthermore, based on a low risk of major 
bleeding events with rising total dabigatran trough concentrations even beyond 250 ng/mL, it 
is therefore considered that maintaining a trough concentration between 50 and < 250 ng/mL 
as planned in this study, has a reasonable likelihood to be effective, safe and thus have a 
positive benefit / risk ratio in children of all ages.
A Phase I study (1160.87) was conducted in 30 healthy adult volunteers to investigate the 
relative bioavailability of single doses of two formulations: reconstituted solution from 
powder and pellets sprinkled on food in comparison to the standard adult capsule formulation 
(U09-1839-01). The two test formulations (pellets and solution reconstituted from powder) 
had a significantly higher relative bioavailability compared to the reference capsule 
formulation. The average treatment ratio for the comparison between solution reconstituted 
from powder and capsules were 154.8 % and 166.6 % for AUC0-∞and Cmax, respectively. 
The corresponding 90% confidence intervals for the ratios of AUC0-∞and Cmax were 127.4 
% to 188.2 % and 133.2 % to 208.3 %, respectively. The average treatment ratio for the 
comparison between pellets and capsules were 175.1 % and 186.9 % for AUC0-∞and Cmax, 
respectively. The corresponding 90% confidence intervals for the ratios of AUC0-∞and Cmax 
were 141.9 % to 216.1 % and 147.7 % to 236.7 %, respectively. 
Another larger phase I study (1160.194; 54 healthy subjects) further examined the 
bioavailability of steady-state dabigatran etexilate as pellets on food and dabigatran etexilate 
as granules resolved in reconstitution solution in healthy adult volunteers (c02248557). The 
examined test formulations resulted in a higher average relative bioavailability compared 
with the dabigatran etexilate as hard capsule reference formulation (30% for DE as granules 
resolved in reconstitution solution, and 37% for DE as pellets on food). However, individual 
Cmax,ss and AUCτ,ss values observed for the 3 formulations were within the range of exposure 
seen with previous dabigatran studies using capsules and reconstitution solution. The increase 
in exposure is considered small enough to consider the formulations interchangeable. 
Furthermore, trough levels were similar for the 3 formulations. Based on the results of this 
study, no conversion factor needs to be applied for dosing purposes in children.


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The starting dose may be amended based on further data from phase IIa studies in children. 
It is worth mentioning that the goal of the dosing algorithm is to reach the pre-defined target 
exposure for dabigatran (i.e. a trough plasma concentration of 50-250 ng/mL). This will be 
achieved by dose adjustments based on plasma level measurements in steady state. 
PK/PD in-vitro paediatric data:
Prior to administering dabigatran etexilate to any children, its activity was assessed in the 
plasma of children ex vivo to determine whether there were any age-dependent differences in 
the effects of dabigatran on the haemostatic system of children of different ages (P08-09073). 
Cord blood and blood samples were collected from 9-11 children in each age group (0 to 
<1yr; 1 to <5 yrs.; 5 to <10 yrs. and 10 to 16 years) and compared to pooled adult plasma. 
This study demonstrated that there was no remarkable difference in the response to 
dabigatran concentrations ranging from 50-450 ng/ml between adult and paediatric plasma 
(ages 0-16 years) using standard coagulation assays. The only differences in response were 
seen with cord plasma, which was more sensitively prolonged than children’s plasma of all 
ages and adult plasma. Both the TT and ECT were linearly and sensitively correlated with 
dabigatran plasma concentrations.
Evaluation of dabigatran in patients from 12 to less than 18 years of age (study 1160.88): 
Eight adolescent patients have successfully completed the three day treatment safety and 
tolerability Phase IIa study 1160.88 as required per protocol (U12-3378-01) with dabigatran 
etexilate capsules. No drug-related serious adverse events or bleeds were observed in the 
1160.88 study (U12-3378-01). In this small population of patients, dabigatran etexilate 
capsules were well tolerated with only three mild and transient gastrointestinal adverse events 
reported by two patients. The PK/PD relationship in this population was similar to the 
relationship seen in adult VTE patients; as expected, the PK/PD analysis showed linear 
relationship with ECT and dTT.
From these data it seems justified to apply the adapted adult population pharmacokinetic 
model to simulate total dabigatran plasma concentration-time profiles in paediatric 
populations.
Evaluation of dabigatran in patients from 1 to less than 12 years of age (study 1160.89): 
Eighteen patients with VTE aged from 1 to < 12 years of age were entered in a safety and 
tolerability Phase IIa study (1160.89) with dabigatran etexilate oral liquid formulation 
(c09069268). Six patients received multiple doses (3 days twice daily) and fifteen patients 
received a single dose. The dose was adjusted according to an algorithm based on Hayton’s 
estimation for renal function taking into account age and weight. Dabigatran etexilate oral 
liquid formulation was well tolerated, with no study drug-related serious adverse events, no 
study drug-related adverse events, VTE or bleeds observed. The PK/PD relationships were 
similar to those observed in adult and adolescent patients with VTE. A linear PK/PD 
relationship was observed for ECT and dTT whereas the PK/PD relationship was non-linear 
for aPTT. The projected steady-state dabigatran trough concentrations of this study were 
largely comparable to those observed in adult patients with VTE.


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Evaluation of dabigatran in patients from birth to less than 1 year of age (study 1160.105): 
Eight patients with VTE aged from 0 to < 1 year of age were entered in a single dose safety 
and tolerability Phase IIa study (1160.105) with dabigatran etexilate oral liquid formulation 
(c09085437). The dose was adjusted according to an algorithm based on Hayton’s estimation 
for renal function taking into account age and weight. Dabigatran etexilate oral liquid 
formulation was well tolerated, with no study drug-related serious adverse events, no study 
drug-related adverse events, VTE or bleeds observed. The PK/PD relationships were similar 
to those observed in adult and adolescent patients with VTE. A linear PK/PD relationship 
was observed for ECT and dTT whereas the PK/PD relationship was non-linear for aPTT. 
The projected steady-state dabigatran trough concentrations of this study were largely 
comparable to those observed in adult patients with VTE.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
VTE treatment and secondary prevention using current standard of care therapies such as 
LMWH and VKA continues to present some challenges in clinical practice. With VKA use, 
frequent INR monitoring is required due to a narrow therapeutic range which is often 
complicated by age, changing diet, medication interactions and underlying disease. LMWH 
has several benefits in children over VKA and it is currently considered as the preferred agent 
for paediatric VTE treatment and secondary prevention. However, the anxiety that patients 
and parents often feel, which is sparked by the requirement of subcutaneous administration, 
may lead to compliance issues. As well, the use of LMWH for paediatric VTE treatment and 
secondary prevention is not sufficiently studied and characterised in well-controlled clinical 
trials. Clinical challenges observed with VKA and LMWH usage warrant the development of 
easier to use treatment modalities with a comparable safety and efficacy profile to current 
standard of care treatments. Dabigatran etexilate may provide such an option.
The present study is a safety trial of dabigatran etexilate for secondary prevention of VTE in 
children from 0 to less than 18 years of age. The design of this study has been agreed with the 
European Medicines Agency’s Paediatric Committee. This study is part of the paediatric 
dabigatran clinical development program for VTE treatment. This trial has the potential to 
provide critical information regarding the safety of dabigatran etexilate for secondary 
prevention of VTE and hence help pave the way for validation of dabigatran etexilate as a 
potential novel therapy in this indication.
2.2
TRIAL OBJECTIVES
The main objective of this paediatric prospective cohort study is to assess the safety of 
dabigatran etexilate used for secondary prevention of venous thromboembolism in children 
from 0 to less than 18 years of age.
2.3
BENEFIT - RISK ASSESSMENT
Individuals participating in this trial may benefit from receiving a drug which was evaluated 
in preventing secondary VTE in adult patients and demonstrated to be safe and effective in 
that population. The secondary VTE prevention trials conducted in over 4200 adult patients 
demonstrated that dabigatran etexilate was non-inferior to very well controlled warfarin (RE-
MEDY, U10-2533-01) and superior to placebo in preventing recurrent VTE compared to 
placebo (RE-SONATE, U11-2267-02).
In the RE-MEDY trial, the primary endpoint event (VTE or VTE-related death) occurred in 
26 patients in the dabigatran etexilate treatment group and in 18 patients in the warfarin 
group (HR 1.44 (95% CI 0.78-2.74, p = 0.0137 for non-inferiority)). The frequency of major 
bleeding events was numerically lower for the dabigatran etexilate group (0.9%) than for the 
warfarin group (1.8%). However, this difference did not reach statistical significance (HR 
0.52 (95% CI 0.27-1.02, p = 0.0577)).
The RE-SONATE trial demonstrated that dabigatran etexilate was superior to placebo for the 


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primary endpoint, i.e., the composite of recurrent symptomatic VTE and unexplained death 
(HR 0.08 (95% CI 0.02, 0.25, p <0.0001 for superiority)). There were only two patients 
(0.3%) in the dabigatran etexilate treatment group, and none in the placebo group, who had 
confirmed major bleeding events (HR could not be calculated because of the absence of MBE 
events in the placebo group). The hazard ratios comparing dabigatran etexilate to placebo for 
centrally adjudicated clinically relevant bleeding events, measured 2.92 (95% CI, 1.52, 5.60), 
and any bleed events, measured 1.82 for dabigatran etexilate versus placebo are 2.92 and 1.82 
(1.23, 2.68), with p values for both being <0.003.
Based on the adult VTE treatment trials (RE-COVER and RE-COVER II) conducted in over 
5000 patients, the incidence of major bleeding events was lower in the dabigatran arms 
relative to warfarin (hazard ratio DE/W 0.48; 95% CI 0.29 to 0.78) with similar efficacy; 
primary efficacy endpoint hazard ratio DE/W 1.09; 95% CI 0.77-1.53 (U09-1400-01 and 
U11-2298-01). Therefore, this study may have the potential to provide a real therapeutic
benefit to participating patients at an individual level.
The planned study may also help to bring new and innovative therapy to paediatric patients 
with risk of secondary VTE, providing a general benefit to society and to the paediatric 
patient population.
The tolerability and PK/PD profile of dabigatran has been evaluated in a limited number of 
paediatric patients. Data obtained from 8 adolescent patients in trial 1160.88 (U12-3378-01) 
demonstrated that dabigatran etexilate capsules were apparently safe and well tolerated. Data 
obtained from 18 patients aged 1 to < 12 years in trial 1160.89 (c09069268) and in 8 patients 
aged 0 to < 1 year in trial 1160.105 (c09085437) demonstrated that dabigatran oral liquid 
formulation was apparently safe and well tolerated. According to the PK data from study 
1160.89 in the age group of patients aged 1 to less than 12 years, and from study 1160.105 in 
the age group of patients from 0 to less than 1 year, a dosing algorithm based on Hayton’s 
estimation for renal function seems to be appropriate.
A twice daily (BID) dosing nomogram was developed to achieve the steady state trough 
concentrations of dabigatran etexilate between 50 and < 250 ng/ml. Doses in the nomogram 
were estimated using a scaling method according to Hayton, which is considered applicable 
for drugs, like dabigatran etexilate, with predominantly renal clearance (R06-2299). The 
method scales an adult dose which is expected to result in a therapeutically beneficial 
exposure range down to a child’s expected renal function (which Hayton defines based on 
age and weight). 
At the start of study 1160.108, the maximum daily dose of dabigatran etexilate for patients 
with body weight > 40 kg was capped at 440 mg (given as 220 mg twice daily) instead of 
using actual calculated dosages in order to avoid high peak concentrations predicted with 
higher dosages in comparison to expected peak levels in a typical adult VTE patient. The 
initial experience from 5 adolescents in study 1160.106 using a capped dabigatran dose 
regimen in patients with a body weight > 40 kg, has observed dabigatran trough 
concentrations below or close to the lower target cut-off of 50 ng/ml and well below the 
higher end of the target plasma range (250 ng/ml) as measured by the Hemoclot assay. PK 
modelling has projected that the percentage of patients with trough plasma levels < 50 ng/ml 


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is up to 40% depending on the degree of capping (higher dose reductions compared to the 
actual calculated dose will increase the probability).
With protocol version 3.0, a BID regimen using actual calculated dosages (according to 
Hayton equation) rather than any capped dosages has been implemented. This dosing 
regimen will also include the additional safeguard of dose up- or down-titration to achieve a 
trough plasma level of 50 to < 250 ng/ml. Dose adjustments may occur as early as 
approximately 5 -12 days after first medication intake based on results from Visit 3 plasma 
level measurements. 
According to PK simulations, a BID regimen using actual calculated dosages according to 
Hayton will reduce the probability of trough levels to be below 50 ng/ml to approximately
18%. The probability to have levels < 25 ng/ml with the BID uncapped regimen is projected 
to be as low as 3%, which means that exposure will most likely be sufficient in the vast 
majority of patients, when risk of VTE recurrence is highest (i.e. within the first 30 days after 
the index VTE event). Based on the experience from the adult RE-LY and RE-COVER 
studies dabigatran levels between 25 and 50 ng/mL may still be considered adequate. 
In selected patients receiving single dosages greater than 220 mg BID (i.e. up to 330 mg 
single dose at maximum) in an uncapped regimen, peak levels are projected to be higher than 
those predicted for the typical adult patient in VTE study RE-COVER. Higher peak levels 
correspond to high trough levels, for which a down-titration of the dose will occur early in 
the trial (i.e. after approximately 5-12 days), if the trough level is > 250 ng/ml.
According to the literature, the risk of bleeding tends to be in general lower in children than 
in adults (R12-0738; P10-09826). In paediatric studies, the rate of major bleeding reported 
while receiving anticoagulant medication ranged from 0.5% - 1.7% of patients (R12-0738), 
whereas major bleeding rates in adult patients requiring oral anticoagulant therapy range from 
1.3% to 8.3% per year (P04-10723). The proposed BID dosing regimen for dabigatran also 
appears favourable in comparison to the current standard of treatment with Vitamin K 
antagonists (VKAs). With VKAs, the risk of not being within the therapeutic INR range has 
been reported to be much higher than with this proposed dabigatran dosing regimen: 
published studies describe a mean or median time in therapeutic range between 39% and 
81.7% (R12-0738), which means that patients are under- or overdosed for up to 60% of the 
time with VKA treatment. 
A BID regimen with removal of capping (up to a dose of 330 mg BID) is considered 
favourable. In addition, risks associated with this regimen resulting from low exposure have 
been projected to be uncommon. Potential risks associated with higher trough exposure are 
transient and considered acceptable in a paediatric population in the context of less 
favourable treatment alternatives, specifically when comparing to the large percentage of 
time out of the therapeutic range with the current standard of care treatment (VKAs). 
In summary, the bleeding risk in the paediatric patient population is considered to be lower 
than that in adult populations (e.g. in the adult SPAF and VTE indications). Based on an 
overall benefit-risk assessment including the fact that the risk of thrombotic events is highest 


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in the first 30 days, the predicted exposure in an uncapped BID regimen is considered 
acceptable.
The efficacy and safety profile of dabigatran etexilate in paediatric patients as well as the 
appropriateness of proposed dosing algorithm will be evaluated in the phase IIb/III 1160.106 
trial. The data will be closely monitored by an independent Data Monitoring Committee 
(DMC), which will also be utilized to monitor participants' safety during this trial.
The study recruitment will be done similar to that in the 1160.106 trial.  The recruitment will 
be initiated in adolescent patients first (12 to < 18 yrs.) and consecutively opened to the next 
age group (2 yrs to < 12 yrs.) and then to youngest patients (0 to < 2 yrs.) based on DMC 
recommendations that take into account information from the current age group in this trial 
and the 1160.106 trial, as well as data from other dabigatran etexilate paediatric studies. This 
approach ensures that the younger age groups will only be evaluated after the dosing 
algorithm is confirmed, age-appropriate formulations are available, and preliminary PK, PD, 
efficacy and safety data are obtained from older age group(s) from this trial, the1160.106 trial 
and other phase IIa studies. These measures are expected to provide adequate safety 
protection for all study participants.
A specific reversal agent antagonising the pharmacodynamic effect of dabigatran in children
is not available yet; however, a development program is ongoing (P15-06362).
As protein binding is low, dabigatran is dialyzable, 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 700 
mL/min dialysate flow rate, four hour duration, a blood flow rate of either 200 mL/min or 
350-390 mL/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.
Although dabigatran etexilate treatment was not associated with any increase in drug-induced 
liver injury (DILI) in adults, DILI is under constant surveillance by sponsors and regulators. 
Therefore, as in all Boehringer-Ingelheim sponsored studies, this study requires timely 
detection, evaluation, and follow up of laboratory alterations of selected liver laboratory 
parameters to monitor patient safety.
Overall, dabigatran etexilate may reduce the need for frequent blood samples for therapeutic 
drug monitoring as is the case with currently available oral anticoagulants (VKAs). This 
study has the potential to offer to the participating subjects close medical care and an 
alternative therapy which has been evaluated in adults and demonstrated to be safe and 
effective, hence potentially providing an alternative therapeutic option for secondary VTE 
prevention in the paediatric patient population.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-centre, multinational, open-label, single arm prospective cohort study of 
dabigatran etexilate to evaluate safety in the secondary prevention of venous 
thromboembolism in children from 0 to less than 18 years. This study is planned to be 
conducted in approximately 100 sites located worldwide.
After a signed consent form (and assent, if applicable) has been obtained and if all eligibility 
criteria are met, patients will initiate or continue treatment with dabigatran etexilate (Visit 2).
Detailed guidance on how to switch from standard VTE treatment to dabigatran etexilate is
provided in Section 4.1.4.
Patients will be treated with dabigatran etexilate until the clinical risk factor requiring 
secondary VTE prevention has resolved, or up to a maximum of 12 months. The clinical risk 
factor must be specified at screening and evaluated at every visit. At the end of the study all 
patients need to discontinue dabigatran etexilate, or switch to standard of care, if there is 
continued need for anticoagulant treatment (see Appendix 10.3).
Please refer to Section 4.1.3 for information on dose selection.
Study visits and procedures will be performed as outlined in the Flow Chart. Collection and 
processing of PD samples is described in Section 5.7.2. 
All patients who have taken dabigatran etexilate will have a follow-up period of 28 days after 
termination of trial medication (Visit 11). Subject participation is concluded when the 
Follow-up Visit is completed.
Patients who stop study treatment earlier than 12 months (risk factor resolved or early 
treatment discontinuation) will be asked to perform an eEOT Visit and will be followed up 
according to the remaining visit schedule until the end of the study. Prior to entering the trial, 
patients and their parents / legal guardians will be made aware of this requirement.
The end of the trial is defined as “last subject out”, i.e. last visit completed by the last subject.
3.1.1
Administrative structure of the trial
This trial is sponsored by Boehringer Ingelheim (BI).
BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating the activities 
required in order to manage the trial in accordance with applicable regulations and internal 
standard operating procedures (SOPs), directing the clinical trial team in the preparation, 
conduct, and reporting of the trial, ordering the materials as needed for the trial, ensuring 
appropriate training and information of local clinical monitors (CMLs), clinical research 
associates (CRAs), and investigators.


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Data Management and Statistical evaluation will be performed by BI according to BI SOPs. 
For these activities, a Trial Data Manager and a Trial Statistician have been appointed.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs as appropriate. A list of responsible persons will be given in 
the Clinical Trial Master File (CTMF) document.
The local organisation of the trial will be done by the respective local BI-organisation 
(Operating Unit (OPU)) or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial. In general, a CML has been appointed in each participating country or 
OPU. The CML will be responsible for coordinating the activities required in order to 
manage the trial in accordance with applicable regulations and internal SOPs.
Trial sites consist of specialised referral centres experienced in the management of venous 
thromboembolism in the paediatric population. Documents on the participating (Principal) 
investigator(s) and other important participants, especially their curricula vitae, will be filed 
in the CTMF.
Details on handling of the trial supplies including responsible institutions are given in 
Section 4 of this protocol.
The Investigator Site File (ISF) will be kept at sites as required by local regulation and BI
SOP. A copy of the ISF documents will be kept as an electronic CTMF document according 
to BI SOPs.
3.1.1.1
Data Monitoring Committee
Safety and tolerability will be monitored by the same independent DMC responsible for 
1160.106 trial. A detailed DMC charter will govern the activities of this committee. The 
recommendations of the DMC will be maintained in the CTMF.
The committee will review safety on an ongoing basis and will advise the Sponsor on 
recommendations to continue, modify or terminate the study per the Charter. The DMC will 
review study results as well as monitor the overall paediatric program results to ensure patient 
safety. The DMC will recommend whether (and when) it is appropriate to open the trial to 
younger age groups (from 2 to <12 years of age and then 0 to <2 years of age) based on 
available safety and efficacy data from this trial and the 1160.106 trial including but not 
limited to PK and PD analyses, dose adjustment data; exposure-response model updated with 
all relevant paediatric and adult data and the appropriateness of dosing algorithm for 
consecutive age groups. The DMC may implement a partial release of the youngest age group 
(0 to <2 years of age) depending on the availability of PK/PD data from respective age 
groups studied in the phase IIa studies.
In addition, the DMC will recommend modifications of the target dabigatran plasma 
concentration range, if required, based on available data from 1160.106 trial. The dose 
regimen will be reviewed on an ongoing basis by the committee and can be further revised as 
data on trough dabigatran levels and safety data become available during the course of this


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study or if emerging data from other dabigatran etexilate studies in other populations could 
suggest that wider or narrower total dabigatran trough concentration range is associated with 
a better benefit / risk ratio.
The DMC may also decide to keep recruitment open after 100 patients have been recruited, in 
case additional safety data needs to be generated.
3.1.1.2
Central Independent Adjudication Committee
All elements of the primary endpoints will be evaluated by an independent adjudication 
committee that will confirm or refute outcome events.
3.1.1.3
Central laboratory
All planned safety samples will be analysed at a central laboratory, local safety lab 
assessment is acceptable in emergency cases (e.g. bleeding event or emergency surgery). If 
approved by the Sponsor, a local laboratory may alternatively be used for dTT evaluation, as 
well as for serum or urine pregnancy test, INR, serum creatinine, HCT, Hb, platelet count, 
ALT and AST measurement at screening (to facilitate the eligibility assessment). If other 
assays for the quantitative measurement of dabigatran will become available, they may be 
used after consultation with the Sponsor. 
 pharmacodynamic plasma 
samples may be analysed at contract research laboratories.
3.1.1.4
Steering Committee
A Steering Committee will provide scientific leadership regarding the design and conduct of 
the study. It will be composed of one Coordinating Investigator and other representatives. 
The Sponsor will be represented on this committee.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is an open-label, single arm prospective cohort study of dabigatran etexilate evaluating 
safety and tolerability in secondary prevention of venous thromboembolism in paediatric 
patients. Children from 0 to less than 18 years of age will be eligible to participate.
The design of this study (including the definition of endpoints) has been agreed with the 
European Medicines Agency’s Paediatric Committee. This committee has previously 
endorsed the outline of the design and endpoints of this trial. Several safety primary 
endpoints will be used in this study. For details refer to Section 5.2.1. These primary 
endpoints will be centrally adjudicated.
3.3
SELECTION OF TRIAL POPULATION
The trial population will consist of male and female paediatric patients who require 
anticoagulation for secondary VTE prevention. Patients who have completed the treatment 
period (i.e. have reached Visit 8) in 1160.106 study may be rolled-over into this study.


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The trial recruitment goal is to have at least 100 patients participating in this study.
Recruitment will be initiated in the adolescent group first (12 yrs. to <18 yrs.) and may be 
consecutively opened to younger age group (2 yrs. to <12 yrs.), and then to youngest group (0 
to <2 yrs.) based on the DMC recommendations. Patients in age group 2 yrs. to <12 yrs. will
be included and treated in accordance to the availability of the age appropriate dabigatran 
etexilate formulations.
A log of all patients included into the study (i.e. having given informed consent / assent (if 
applicable)) will be maintained in the ISF at the investigational site irrespective of whether 
they have been treated with investigational drug or not.
3.3.1
Main diagnosis for study entry
Patients from 0 to less than 18 years of age with previously confirmed venous 
thromboembolism who have completed initial anticoagulation therapy (for at least 3 months)
or patients who have completed the 1160.106 treatment period and who require further 
anticoagulation for secondary prevention of venous thromboembolism due to presence of a 
clinical risk factor.
3.3.2 
Inclusion criteria
1. Male or female subjects from 0 to less than 18 years of age at the time of informed 
consent / assent.
2. Previously documented objective diagnosis of VTE (e.g. DVT, PE, central line 
thrombosis, sinus vein thrombosis), followed by completed course of initial VTE 
treatment for at least 3 months1 (in case of VKA - intended INR between 2 and 3) or 
completed study treatment (i.e. reached Visit 8) in the 1160.106 trial. Patients, who 
during the treatment phase of 1160.106 trial were switched from dabigatran etexilate 
to SOC arm for any reason, are not eligible for this study.
3. Presence of an unresolved clinical risk factor requiring further anticoagulation for 
secondary VTE prevention (e.g. central venous line, underlying disease, 
thrombophilia, etc.)
4. Written informed consent provided by the patient’s parent or legal guardian and 
assent provided by the patient (if applicable) at the time of ICF signature according to 
local regulations. 
                                                          
1 A temporary interruption of the anticoagulant therapy for the index VTE event or prior to the start of 
secondary VTE prophylaxis is acceptable, if one of the following pre-requisites is fulfilled and documented:

Interruption of anticoagulant treatment due to surgery or intervention, or other medically justifiable 
reason

A risk factor requiring secondary VTE prevention has been newly identified only after the completion 
of initial VTE treatment

Reappearance of a risk factor


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3.3.3
Exclusion criteria
1. Conditions associated with an increased risk of bleeding:
a.
Any prior intracranial haemorrhage, classified as a macrobleed2. Any intracranial 
anatomical abnormality or intracranial aneurysm. Active meningitis, encephalitis, 
or intracranial abscess at Visit 2.
b. Intracranial or intraspinal surgeries within 6 months of Visit 2 or any other major 
surgery within 4 weeks of Visit 2.  Major surgeries may include an invasive 
operation upon an organ within the cranium, chest, abdomen, pelvic cavity or any 
other procedure regarded as major surgery per investigator judgment. In general, 
major surgery involves the opening of a mesenchymal barrier (pleural cavity, 
peritoneum, meninges). Removal or insertion of a central venous line is not 
considered a major surgery provided haemostasis is achieved after the procedure
c.
Any major planned procedure that might put the patient at an increased risk of a 
bleed per investigator judgment within 5 days prior to taking study medication
d. History of intraocular, spinal, retroperitoneal or atraumatic intra-articular 
bleeding unless the causative factor has been permanently treated (e.g. by 
surgery)
e.
Gastrointestinal haemorrhage within the past year prior to screening unless the 
cause has been permanently eliminated (e.g., by surgery)
f.
History of gastroduodenal ulcer disease
g. History of  haemorrhagic disorder or bleeding diathesis (e.g. von Willebrand 
disease, haemophilia A or B or other hereditary bleeding disorder, history of 
spontaneous intra-articular bleeding, history of prolonged bleeding after surgery /
intervention)
h. Administration of a fibrinolytic agents within 48 hours of dabigatran etexilate 
administration (Please note the following exception: use of tissue plasminogen 
activator (t-PA) e.g. alteplase, or any other thrombolytic agents to re-establish 
patency of an obstructed central venous line are allowed as long as the used dose 
is devoid of relevant systemic effects)
_____________________________
2 Patients with history of asymptomatic petechial or microbleeds may be included into the study as per 
investigator`s judgment. As a general recommendation, an intracranial microbleed is considered to be  ≤0.5 
cm in greatest diameter on gradient recalled echo (GRE), or T2* MRI sequences (criteria may vary 
depending on MRI imaging modalities; R15-2999). Irrespective of size, any cerebral bleed that causes focal 
neurologic symptoms and/or signs does not constitute a microbleed. Further, any blood visualized on a CT 
should be classified as a macrobleed, which is an exclusion criterion for the trial.


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i.
Uncontrolled hypertension on antihypertensive medication (systolic and / or 
diastolic above the upper limit of normal for age and sustained over 24 hours) 
j.
Any other disease, health condition or intervention which in the investigator’s 
opinion exposes the patient to a higher risk for bleeding
2. Renal dysfunction (eGFR < 50 mL/min/1.73m2 using the Schwartz formula, refer to 
Appendix 10.1) or requirement for dialysis. eGFR retesting during the screening 
period is allowed (once).
3. Active infective endocarditis
4. Subjects with a heart valve prosthesis requiring anticoagulation.
5. Hepatic disease:
a.
Active liver disease, including known active hepatitis A, B or C or,
b. Persistent alanine aminotransferase (ALT) or aspartate transaminase (AST) or 
alkaline phosphatase (AP) > 3 × upper limit of normal (ULN) within 3 months of 
screening. Transient increases of these parameters are acceptable, if retesting 
demonstrates results within these limits.
6. Pregnant or breast feeding females. Females who have reached menarche and are not 
using an acceptable method of birth control, or do not plan to continue using this 
method throughout the study and / or do not agree to adhere to pregnancy testing 
required by this protocol . Acceptable methods of birth control are listed below and 
must be used in a correct and consistent manner:
i. Oral or parenteral (patch, injection, implant) hormonal contraception 
which has been used continuously for at least one (1) month prior to the 
first dose of study medication
ii. Intrauterine device (IUD) or intrauterine system (IUS)
iii. Double-Barrier method of contraception: condom and spermicidal agent
iv. Complete sexual abstinence. Note: Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
7. Patients in age group 0 to < 2 years with gestational age at birth < 37 weeks or with 
body weight lower than the 3rd percentile (according to the WHO Child growth 
standards - will be provided in the ISF)
8. Anaemia (haemoglobin < 80g/L) or thrombocytopenia (platelet count < 80 x 109/L) at 
screening. Transfusions during the screening period are allowed, provided that a 
satisfactory haemoglobin or platelet level is attained prior to Visit 2
9. Patients who have taken restricted medication prior to first dose of study medication. 
For trial restrictions please see Section 4.2.2


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10. Patients who have received an investigational drug in the past 30 days prior to 
screening, except patients who have completed the treatment period (up to Visit 8) in 
1160.106 trial
11. Patients who are allergic / sensitive to any component of the study medication 
including solvent
12. Patients or parents / legal guardians considered unreliable to participate in the trial per 
investigator judgment or any condition which would present a safety hazard to the 
patient based on investigator judgment
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be withdrawn from the trial if:

The patient / parent / legal guardian withdraws consent, without the need to justify the 
decision.
An individual patient is to be discontinued from trial treatment, but will remain part of the 
study and analysis population:

If the patient is no longer able to take trial medication for other medical reasons (e.g. 
surgery, AEs, other diseases or concomitant therapies).

If the patient is noncompliant with study drug administration despite all possible 
efforts.

If, in the opinion of the Investigator, continuation on the study drug is not in the 
patient’s best interest, if eligibility criteria are being violated, or if the patient fails to 
comply with the protocol (e.g. non-attendance at trial assessments).

In the event that a recurrent thromboembolic event as assessed by appropriate imaging 
modalities is observed or if the patient experiences a drug-related significant or drug-
related serious AE or if drug toxicity is observed.

If the patient does not reach a total dabigatran plasma trough concentration within the 
pre-specified therapeutic range after one dose adjustment.

If the patient becomes pregnant or a pregnancy is suspected during the trial the patient 
will be discontinued from the dabigatran treatment and will be put on an appropriate 
therapy per investigator judgment. The patient will be followed up until the end of the 
study and until the birth or otherwise termination of the pregnancy. For further 
information, including the process for follow up on the outcome of the pregnancy 
please see Section 5.2.2.2.

If a patient develops an active meningitis, encephalitis, or intracranial abscess.


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
If the patient develops renal dysfunction anytime during the course of the study 
(eGFR < 50 mL/min/1.73m2 using the Schwartz formula, confirmed by one retesting 
within the next 14 calendar days). If a patient develops eGFR < 50 mL/min/1.73m2
using the Schwartz formula for a second time during the course of the study, treatment 
with dabigatran etexilate must be stopped without further retesting

If the patient does not require treatment with anticoagulants any longer due to 
resolution of the underlying clinical risk factor prior to 12 months of planned 
anticoagulation treatment. In such cases, an early EOT Visit is to be performed and 
the patient should still be followed up according to the remaining visit schedule until 
the end of the study.
In order to protect patient safety, measurements of dabigatran trough plasma levels will be 
performed in a central laboratory
 
 
 If a patient 
has a dabigatran plasma level of < 50 ng/mL or ≥250 ng/mL confirmed despite a dose 
adjustment, they will be discontinued from trial treatment and must be switched to an 
appropriate alternative therapy at investigator's discretion.
Dabigatran is predominantly excreted by the kidney; special attention should be given to the 
kidney function of these patients when needed. As stated above, any patient with confirmed
eGFR < 50 mL/min/1.73m2 using the Schwartz formula at any time during the treatment 
period will be discontinued from trial treatment. Any suspected worsening of renal function 
during the study should be investigated by eGFR evaluation.
Patients who discontinue study drug or withdraw from the trial after being entered (Visit 2) 
will be considered as “early discontinuations” and will not be replaced. The reason for 
premature discontinuation must be recorded in the eCRF. The data will be included in the 
trial database and will be reported.
Patients who discontinue study drug prior to 12 months of planned treatment due to 
resolution of the underlying clinical risk factor will not be considered as “early 
discontinuations”.
All patients that prematurely discontinue dabigatran etexilate for various reasons as outlined 
above and in cases where consent / assent is not withdrawn, will be invited to perform an 
eEOT Visit and will be followed up according to the remaining visit schedule until the end of 
the study. Procedures to be followed are outlined in Section 6.2.3.
Patients who drop out during screening (i.e. prior to receiving trial medication) will be 
considered a screening failure. These cases have to be recorded as a screening failure in the 
electronic case report form (eCRF) and no further follow up visit is required.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:


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
Advice of the independent DMC, decision by an independent ethics committee /
institutional review board (IEC/IRB) or Competent Authority (CA)

Failure to meet expected enrolment goals overall or at a particular trial site

Emergence of any efficacy / safety information that could significantly affect 
continuation of the trial and / or invalidate the earlier positive benefit-risk assessment

Violation of GCP, the CTP, or the contract by a trial site or investigator


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product dabigatran etexilate will be supplied by Boehringer Ingelheim.
4.1.1
Identity of BI investigational product and comparator product(s)
All patients will be treated with dabigatran etexilate in this trial; there is no comparator 
product.
The composition of dabigatran etexilate formulations is detailed below:
Dabigatran etexilate capsules:

Substance: Dabigatran etexilate

Pharmaceutical formulation: Capsule

Source: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany

Unit strengths: 50 mg, 75 mg, 110 mg and 150 mg

Total Daily dose: The administered dose (b.i.d.) is based on an age and weight 
adjusted nomogram included in Appendix 10.4.1.This nomogram has been generated 
to estimate a yield and exposure comparable to the exposure observed in previously 
completed adult VTEt/sVTEp and AF populations.  

Route of administration: p.o.

List of excipients: The most up to date list will be provided in the ISF
Dabigatran etexilate pellets:

Substance: Dabigatran etexilate

Pharmaceutical formulation: pellets 

Source: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany

Unit strength: pellets stick packs to be sprinkled on food (for the available strengths 
please refer to the nomogram in Appendix 10.4.1). Detailed preparation and 
administration instructions will be included in the ISF. 

Total Daily dose: The administered dose (b.i.d.) is based on an age and weight 
adjusted nomogram included in Appendix 10.4.1. This nomogram has been generated 
to estimate a yield and exposure comparable to the exposure observed in previously 
completed adult VTEt/sVTEp and AF populations

Route of administration: p.o.

List of excipients: The most up to date list will be provided in the ISF


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Dabigatran etexilate oral liquid formulation:

Substance: Dabigatran etexilate granules (180.4 mg) and flavoured or unflavoured 
solvent for reconstitution (28 ml)

Pharmaceutical formulation: oral liquid formulation

Source: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany

Unit strength: Granules for oral solution (6.25 mg/mL after reconstitution)

Total Daily dose: A specific volume of a 6.25 mg/mL solution after reconstitution is 
administered (b.i.d.) based on an age and weight adjusted nomogram included in 
Appendix 10.4.1. This nomogram has been generated to estimate a yield and exposure 
comparable to the exposure observed in previously completed adult VTEt/sVTEp and 
AF populations, particularly in patients whose observed exposure was generally 
associated with the most favourable balance between efficacy and safety. 

Route of administration: p.o.

List of excipients: The most up to date list will be provided in the ISF.
4.1.2
Method of assigning patients to treatment groups
After obtaining signed informed consent and if applicable assent, patients should complete 
the screening (Visit 1) procedures and laboratory assessments. Inclusion and exclusion 
criteria should be assessed to ensure inclusion of eligible patients. The unresolved clinical 
risk factor requiring longer duration anticoagulation for the secondary prevention of VTE 
must be specified at screening (e.g. central venous line).
All eligible patients who fulfil all inclusion and exclusion criteria will be assigned to receive 
dabigatran etexilate. Patients assigned to OLF will be randomized based on 1:1 ratio to 
receive flavoured or unflavoured solvent for reconstitution. The correct trial medication kit 
assignment will be managed by Interactive Response Technology (IRT) based on the 
estimated dose - see Section 4.1.3. All necessary instructions for using the IRT system will be 
described in a user guide / manual, a copy of which will be available in the ISF. In this trial, 
IRT will be used for medication assignments (including dose adjustments) and to control 
aspects of the medication supply chain.
Recruitment will first be initiated in the adolescent group (12 yrs. to <18 yrs.) and may be 
consecutively opened to younger age groups (2 to <12 years of age); and then to the youngest 
patients (0 to <2 yrs.) based on the DMC recommendations.
4.1.3
Selection of doses in the trial
Estimated doses for paediatric patients assigned to take dabigatran etexilate will be based on 
age and weight according to a nomogram (please refer to Appendix 10.4). Patients able to 
swallow capsules (aged ≥ 8 years) will be assigned to take capsules. If a patient aged ≥ 8 


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years but below 12 years of age is unable to take capsules, they will be assigned to take the 
pellets sprinkled on food. Patients < 8 years of age are scheduled to receive pellets sprinkled 
on food. OLF may be used for patients who are < 12 months of age. For patients < 12 months 
of age OLF is preferred over pellets provided that OLF supplies are available to the site.
Switching between different dabigatran etexilate formulations during the study is not 
recommended, but could be considered in special cases following discussion with the 
Sponsor, provided that the steady state has been reached with the currently assigned 
formulation (i.e. at least 6 consecutive dabigatran etexilate doses have been taken). A titration 
visit should be performed 3 days (6 consecutive dabigatran etexilate doses are taken) after the 
formulation switch.
The dose of dabigatran etexilate must be adjusted throughout the study period to ensure that a 
steady state plasma concentration between 50 and < 250 ng/mL is achieved. Assigned dosing 
in this study will be intended to target plasma dabigatran concentrations that have generally 
been proven to be safe and effective in multiple adult populations. The dose regimen will be 
reviewed on an ongoing basis by the DMC and can be further revised as data on trough 
dabigatran levels and safety and efficacy data are obtained. 
Dose selection is based on dabigatran’s linear PK (U09-2262-01) and renal function 
(glomerular filtration rate (GFR)) being the most important determinants of dabigatran PK.
Allometric models are considered appropriate in determining drug doses in paediatrics (R08-
4306). In order to adjust for the on average lower body weight and hence lower absolute 
glomerular filtration rate in children aged below 1 year, the dose estimation procedure 
according to Hayton (R06-2299) seems appropriate. Hayton’s model characterized the 
maturation and growth of renal function parameters based on data obtained from 63 healthy 
children between the ages of 2 days and 12 years.
For renally eliminated drugs like dabigatran, this model can be used to estimate dosing 
regimens based on the adult dose and adjusted to the age and weight of the child. In this way, 
doses and resulting nomograms can be used in clinical practice without the need for regular 
laboratory measurements.
Compared to the adult VTE study RECOVER (mean age 55.0), the general paediatric
population is characterized by better renal function. To yield total dabigatran exposure at 
trough comparable to the trough exposure observed in the adult VTE program (i.e. 
RECOVER: dose 150 mg BID) and to be able to scale down the doses for the paediatric
population within the confines of Hayton’s model (i.e., GFR predictions up to age of 20 
years, at which normal GFR is assumed to be 136 mL/min), a 20 year old adult reference 
patient weighing 70 kg was chosen. Since this reference patient is younger and has a higher 
dabigatran clearance due to the better renal function, the dose of 150 mg BID would result in 
an average trough exposure lower than the trough exposure seen in RE-COVER.
Therefore, this reference patient would receive higher dabigatran etexilate doses, i.e. 300 mg 
dabigatran etexilate BID or 4.3 mg/kg dabigatran etexilate BID and doses are scaled down to 
paediatric doses accordingly (fractional dose). 


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For the reference patient, the equation giving the fractional dose is derived by taking the 
allometric equation for the GFR (equation 4 in R06-2299):
GFR(age,W) = 2.60 W0.662 e-0.0822*age + 8.14 W0.662 (1 – e-0.0822*age),
and subsequently dividing by weight (W) and by the weight-adjusted GFR of the comparator, 
136mL/min / 70kg=1.94mL/min/kg. After rearranging, this results in the following equation 
for the fraction of the adult comparator mg/kg dose:
FRAC = W-0.338 (4.20 – 2.85 e-0.0822*age)
FRAC = fraction of adult comparator mg/kg dose
W = weight (kg)
Age (months)
The FRAC was further multiplied by 4.3 mg/kg (adult comparator BID mg/kg dose) and by 
the child’s weight to obtain the absolute dose in mg. For weight groups (e.g. 5 and 6 kg) the 
average of the derived doses was used.
The derived dabigatran etexilate target doses based on Hayton calculations are displayed in 
Table 4.1.3: 1. Please note that Table 4.1.3: 1 does not contain information about age-
appropriate formulations and available dose strengths. This information is given in the 
adjusted nomogram provided in Appendix 10.4.1. Dosing of patients should only occur
according to the adjusted nomogram provided in Appendix 10.4.1.


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Table 4.1.3: 1
Target dabigatran etexilate doses (given in mg) based on Hayton 
calculations for paediatric patients
Reference Adult dose:
300 mg/70 kg = 4.3 mg/kg
Single Dose [mg]
2.5
3 to <4
4 to <5
5 to <7 
7 to <9 
9 to <11 11 to <13 13 to <16 16 to <21 21 to <26 26 to <31 31 to <41 41 to <51 51 to <61 61 to <71 71 to <81 81 to <91
>=91
0,02083333
0,25
11,1
12,5
15,2
18,7
0,08333333
1
12,4
14,0
17,0
20,9
0,16666667
2
14,1
15,9
19,2
23,7
0,25
3
15,6
17,6
21,2
26,2
32,2
0,33333333
4
16,9
19,1
23,1
28,5
35,0
0,41666667
5
20,6
24,9
30,7
37,7
44,1
0,500
6
26,5
32,7
40,1
46,9
0,583
7
28,0
34,5
42,4
49,5
0,667
8
29,3
36,2
44,4
52,0
59,0
0,750
9
30,6
37,7
46,3
54,2
61,5
0,833
10
39,1
48,1
56,2
63,8
72,7
0,917
11
40,5
49,7
58,1
66,0
75,1
1
12
41,7
51,2
59,9
67,9
77,4
91,3
1,5
18
47,2
57,9
67,8
76,9
87,6
103,3
121,6
2
24
62,0
72,6
82,4
93,8
110,7
130,2
2,5
30
64,6
75,5
85,7
97,6
115,2
135,5
154,4
180,5
3
36
66,1
77,3
87,7
99,9
117,9
138,8
158,1
184,8
4
48
79,1
89,8
102,2
120,6
141,9
161,7
189,0
222,9
5
60
79,7
90,5
103,1
121,6
143,1
163,1
190,6
224,8
256,4
6
72
80,0
90,8
103,4
122,0
143,6
163,6
191,2
225,5
257,2
287,1
7
84
90,9
103,5
122,1
143,7
163,8
191,4
225,7
257,5
287,4
315,8
8
96
90,9
103,5
122,2
143,8
163,8
191,5
225,8
257,6
287,6
316,0
9
108
103,6
122,2
143,8
163,9
191,5
225,8
257,7
287,6
316,0
10
120
103,6
122,2
143,8
163,9
191,5
225,9
257,7
287,6
316,0
343,2
357,8
11
132
122,2
143,8
163,9
191,5
225,9
257,7
287,6
316,0
343,2
357,8
12
144
122,2
143,8
163,9
191,5
225,9
257,7
287,6
316,0
343,2
357,8
13
156
122,2
143,8
163,9
191,5
225,9
257,7
287,6
316,0
343,2
357,8
14
168
143,8
163,9
191,5
225,9
257,7
287,6
316,0
343,2
357,8
15
180
143,8
163,9
191,5
225,9
257,7
287,6
316,0
343,2
357,8
16
192
163,9
191,5
225,9
257,7
287,6
316,0
343,2
357,8
17
204
163,9
191,5
225,9
257,7
287,6
316,0
343,2
357,8
Age 
[completed 
years]
Age 
[completed 
months]
Weight [kg]
Patients who have a total dabigatran steady state trough concentration between 50 and < 250 
ng/mL will be advised to continue the same dose until the following visit. In case patients 
have trough concentrations at the first measurement (within first week of dosing, after 6 
consecutive doses are taken) below 50 ng/mL the dose must be increased by 10 to 100%
according to the dosing nomogram. Assuming dose proportionality, a doubling of the dose 
would, in the extreme case, not lead to trough concentration > 100 ng/mL and is, hence, 
considered appropriate. The maximal allowed dose in this study is age and weight adjusted 
and will neither exceed a daily dose level of 22.2 mg/kg (dabigatran etexilate limit, based on 
excipient acceptable daily intake) nor a single dose of 330 mg. In the higher age / body 
weight group this results in a maximal daily dose of 660 mg. Whenever a trough 
concentration is greater than or equal to 250 ng/mL, the dose must be reduced by 25 to 50%. 
This dosing decision algorithm is summarized in the Table 4.1.3: 2. For the detailed dosing 
decision algorithm please refer to Appendix 10.4.2.


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Table 4.1.3: 2
Summary of dose adjustments based on trough dabigatran plasma 
concentration
Steady State Dose Range
Corresponding Action
Between 50 and < 250 ng/mL
Continue on same dose
Less than 50 ng/mL
Dose may be increased by 10-100%.
Maximal allowed single dose in this 
study is 330 mg.
Greater than or equal to 250 ng/mL
Dose may be reduced by 25-50%
The reduction of a dose is not expected to result in concentrations < 75 ng/mL, but should be 
sufficient to avoid high concentration of ≥250 ng/mL. Blood sampling to measure trough 
dabigatran concentration (derived from dTT or alternative method) will be repeated at least 3 
days (after at least 6 adjusted consecutive dabigatran etexilate doses have been taken), but no 
later than 6 days after dose adjustment, to confirm the new dose. After dose adjustment, the 
total dabigatran trough concentration should be between 50 and < 250 ng/mL.
If a patient cannot reach trough plasma concentrations between 50 and < 250 ng/mL after one
dose adjustment, they must discontinue the study medication.
Due to the dabigatran etexilate limit of 22.2 mg/kg/day (based on excipient acceptable daily
intake) as well as the maximal dabigatran etexilate single dose of 330 mg, up-titration will not 
be feasible in all instances. Likewise down-titration will not be possible in all cases due to 
unavailability of required dosages, see Appendix 10.4.2. Affected patients have to be 
discontinued from dabigatran etexilate once the defined plasma trough concentration between 
50 and < 250 ng/mL is not reached.
During the course of the study, the DMC can recommend further refinement of the target 
therapeutic trough steady state dabigatran concentrations based on data from ongoing 
paediatric studies or if emerging data from other dabigatran etexilate studies in other 
populations suggest that wider or narrower total dabigatran trough concentration range is 
associated with better benefit / risk ratio.
4.1.4
Drug assignment and administration of doses for each patient
At Visit 2 patients who meet all eligibility criteria will be assigned to receive dabigatran 
etexilate (as capsules or pellets to be sprinkled on food or oral liquid formulation based on 
age and weight and ability to swallow capsules or pellets).
For patients who have been treated with VKA, Visit 2 should take place only if INR is < 2.3 
otherwise it should be postponed. The patient will start the study medication on the day of 
Visit 2 if INR is below 2.0 or on the next day if the INR is between 2.0 and 2.3.


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Patients who have been treated with parenteral anticoagulants should start the study 
medication 0-2 hours prior to the time that the next dose of the alternate therapy (e.g. 
LMWH) would be due, or at the time of discontinuation in case of continuous treatment (e.g. 
UFH).
The estimated dosages of dabigatran etexilate (as capsules, pellets to be sprinkled on food or 
oral liquid formulation) will be based on age and weight according to a nomogram provided 
in Appendix 10.4.1. Patients who completed the treatment period of study 1160.106 receiving
dabigatran etexilate may continue taking the same dose and formulation also in this trial.
Patients aged ≥ 8 years will be assigned to take capsules. In case a patient aged ≥ 8 years but 
below 12 years of age is unable to take capsules (per investigator judgment), they will be 
assigned to take pellets sprinkled on food. Patients < 8 years of age are scheduled to receive 
pellets sprinkled on food. OLF may be used for patients who are < 12 months of age. For 
patients < 12 months of age OLF is preferred over pellets provided that OLF supplies are 
available to the site.
Dabigatran etexilate should be taken in the morning and in the evening, at approximately the 
same time every day. The capsules must not be crushed, not opened and can be taken with or 
without food. Dabigatran etexilate should be taken with a glass of water to facilitate delivery 
to the stomach. If gastrointestinal symptoms develop it is recommended to take dabigatran 
etexilate with a meal and/or a proton pump inhibitor according to the locally approved 
labelling recommendations. For paediatric patients receiving dabigatran and who suffer from 
dyspeptic symptoms, it should be taken into account that the local approval status as specified 
in the Prescribing Information or Product Information may vary between proton pump 
inhibitors and across countries. Therefore, the local standard of care in accordance with local 
labelling recommendations for proton pump inhibitors should be followed when treating 
gastrointestinal symptoms in paediatric patients treated with dabigatran. Alternative 
measures, such as taking dabigatran with a meal, should be considered if the local labelling 
recommendations and standard of care do not allow for the use of proton pump inhibitors in 
certain age groups and/or individual patients.
Pellets should be mixed with food (examples may include baby rice cereal, carrot mush, 
banana mush, strawberry jam, apple juice or apple sauce) and should be taken in its entirety 
(pellets and food) at every dose. The volume of the OLF must be taken in its entirety at every 
dose. The instructions for preparation of the OLF and pellets will be provided in the ISF. 
Younger patients must be assisted by the parent / legal guardian or an appropriate caregiver 
to ensure that the dabigatran etexilate dose is properly taken.
The interval between dabigatran etexilate 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 otherwise the missed dose should be omitted 
and the next dose should be taken as scheduled. A double dose to make up for missed 
individual doses must never be taken. In addition, if a dose has only been taken partially, 
there should be no attempt to administer a second dose at that time-point, and the next dose 
should be taken as scheduled approximately 12 hours later.


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Patients will be treated with dabigatran etexilate until the clinical risk factor that necessitated 
further anticoagulant use has resolved, however for a maximum of 12 months. At the end of 
the study, all patients need to discontinue dabigatran etexilate, or switch to standard of care, if 
there is continued need for anticoagulant treatment (see Appendix 10.3 for recommendations 
for transition to a non-study antithrombotic treatment with early study drug discontinuation or 
at the end of the trial).
In the event that a patient decides to discontinue dabigatran etexilate and has to be switched 
to non-study treatment according to the local practice, the Investigator should plan this
transition taking into consideration the patient’s risk profile and previous experience with
anticoagulants. As patients have different risk profiles, optimal approaches might differ 
between patients and not all possible approaches can be fully outlined.
The transition plan will be up to the Investigator’s judgment based on the patient’s medical 
history and prior therapy experience (see Appendix 10.3 for further guidance). Close 
monitoring of the patient’s coagulation profile during the transition period must be 
implemented to optimize safety. In general, dabigatran etexilate therapy should not overlap 
with other anticoagulation therapy.
Investigators should recognise that the presence of dabigatran etexilate could elevate the INR. 
Once dabigatran etexilate has been stopped for >2 days, the INR will better reflect the effect
of VKA therapy alone.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open-label, single arm prospective cohort study.
4.1.5.2
Procedures for emergency unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Dabigatran etexilate should be kept out of the reach of children and be stored protected from 
moisture and direct sunlight. Dabigatran etexilate capsules should be kept in their supplied 
container and the bottle lid must be kept closed. Dabigatran etexilate capsules must not be 
transferred to other types of containers.
The medication stick packs containing the dabigatran etexilate pellets should be kept sealed 
until just prior to intake. 
The medication stick packs containing the dabigatran etexilate granules should be kept sealed 
until just prior to reconstitution, once reconstituted, the oral solution is stable for two hours at 
room temperature.


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Patients / parents / legal guardians should be instructed to keep medication containers tightly 
closed and not to remove capsules from original package material until immediately prior to 
the time of intake. Dabigatran etexilate may only be dispensed to trial patients (under 
supervision of their parent / legal guardian) fulfilling the inclusion and exclusion criteria by 
authorised study personnel as documented in the ISF. Receipt, usage, and return of the study 
medication must also be documented on the respective forms in the ISF. All unused 
medication including bottles and outer boxes (empty or filled) must be either returned to the 
Sponsor, or, following written authorisation from the Sponsor, may be destroyed at site if 
applicable. Receipt, usage and return must be documented on the respective forms. Reasons 
for any discrepancies must be thoroughly documented.
A temperature log must be maintained at the site to make certain that the drug supplies are 
stored at the correct temperature. For storage conditions refer to the locally approved medication 
label and the STORM document in the ISF. 
Detailed instructions for the preparation and / or reconstitution of dabigatran etexilate (when 
applicable) and for dispensing and intake of dabigatran etexilate formulations (capsules, 
pellets and OLF) will be placed in the ISF.
4.1.8
Drug accountability
Drug supplies, which will be provided by the Sponsor, must be kept in a secure, limited 
access storage area under the storage conditions defined by the Sponsor.
The Investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

approval of the study protocol by the IRB / ethics committee, 

availability of a signed and dated clinical trial contract between the Sponsor and the 
Head of Trial Centre,

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 clinical trial protocol or immediately imminent 
signing of the clinical trial protocol,  

if applicable, availability of the Form 1572.
The investigator / 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 alternative disposition of unused medication. 
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 product received from the Sponsor. At the time of return to the 
Sponsor / appointed CRO, the investigator / pharmacist / investigational drug storage 


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manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the investigator’s possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
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 in this 
protocol and the IB.
Details of concomitant medication administered to the patient during the course of the study 
should be recorded in the eCRF. This includes all concomitant therapies from time of patient 
screening until the patient completes follow up.
Certain concomitant therapies or surgery / intervention may require the temporary 
discontinuation of dabigatran etexilate. Study medication should be restarted as soon as 
safely possible.
At the Screening Visit, the site must document details of the anticoagulant therapy given for 
the treatment of the acute VTE.
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 during the study (also refer to Section 5.2).
Major bleeds for patients on dabigatran:
If a patient experiences a major bleed, dabigatran etexilate should be stopped and the source 
of bleeding investigated and treated. This will generally involve coagulation testing (e.g. 
activated partial thromboplastin time (aPTT), TT, dTT (where available), ecarin clotting time 
(ECT), platelet count), and possibly transfusion, diagnostic procedures and / or surgical 
haemostasis.
There is currently no specific reversal agent commercially available to counteract the 
antithrombotic activity of dabigatran in children, however such is in development (P15-
06362). If a clinical study with specific reversal agent in paediatric patients is approved by 
the local health authority and ethic committees during the course of this study, instructions on 
how to use the specific reversal agent in appropriate cases or conditions and the requirements
of participation in the respective clinical studies may be provided to the investigators. In such 
cases cross reporting of lab results might be applied in order to limit the blood volume 
required for analysis.
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). As protein binding is low, dabigatran is 


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dialyzable, however there is limited clinical experience in this setting. 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 thrombocytopenia is present or long-acting antiplatelet drugs 
have been used. All symptomatic treatment has to be given according to the physician's 
judgment.
A summary of how to manage bleedings on dabigatran etexilate is outlined in Figure 4.2.1: 1.
1 for bleeding definitions see Section 5.2.1
2 when appropriate
3 recommendations based on limited clinical or non-clinical data only, limited or no experience in volunteers or patients
Figure 4.2.1: 1 
Management of bleeding on dabigatran therapy (P10-03790)


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Dabigatran etexilate must be stopped if a major bleeding event is observed. Initiation of any 
other alternative therapy for secondary VTE prevention after complete haemostasis has been 
achieved is at the Investigator discretion.
Clinically relevant non-major bleeds or minor bleeds:
If a patient experiences a clinically relevant non-major bleed or minor bleed, dabigatran 
etexilate may be continued, temporarily interrupted or permanently discontinued, at the 
discretion of the Investigator. It is not a requirement, however, that study drug be stopped in 
these cases.
Management of dabigatran etexilate prior to and after planned surgery:
Dabigatran etexilate Treatment Discontinuation for Elective Surgical Interventions
Patients on dabigatran etexilate who undergo surgery or invasive procedures are at an
increased risk for bleeding. Therefore, surgical interventions may require the temporary
discontinuation of dabigatran etexilate.
Preoperative Phase: Due to an increased risk of bleeding dabigatran etexilate may be stopped 
temporarily, in advance of invasive or surgical procedures (U11-1642-01). If possible, 
dabigatran etexilate should be discontinued at least 24 hours before invasive or surgical 
procedures. In patients at higher risk of bleeding or in major surgery where complete 
haemostasis may be required, stopping dabigatran etexilate 2-4 days before surgery should be 
considered. 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.
In patients, who develop renal insufficiency before the surgery, the recommendations 
summarized in the table below should be considered (Table 4.2.1:1). The decision to re-start 
treatment with dabigatran etexilate after the surgery is at the Investigator’s discretion and can
be started any time as soon as haemostasis has been achieved.


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Table 4.2.1:1
Recommendations on cessation of study drug in relation to the timing 
of surgery – under special consideration of the pharmacokinetics of 
dabigatran
Renal function 
(eGFR, mL/min)
Estimated half-
life in hours 
(for dabigatran)
Stop study drug before surgery
High risk of bleeding1
Standard risk
>80
~13 
2 days before 
24 h before (2 doses)
≥50-80
~15 (12-18)
2-3 days before
1-2 days before
≥30 to <50
~18 (18-24)
4 days
at least 2 days (> 48 
hours)
<30
~27 (>24 )
> 5 days
2-5 days
1 In addition to renal function, high risk determinants of bleeding risk include type of surgery, 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 anesthesia may also require complete hemostatic function.
The decision to use bridging therapy by UFH/LMWH during the peri-procedural period is 
left to the investigator's discretion and would depend on the bleeding and thrombotic risk in 
each patient.
Dabigatran etexilate Treatment discontinuation for Acute Surgical Interventions
If urgent surgery / acute intervention is required dabigatran etexilate should be temporarily 
discontinued. The surgery / intervention should be delayed at least 12 hours if possible after 
the last dabigatran etexilate dose. If surgery cannot be delayed there may be an increased risk 
of bleeding. The risk of bleeding should be weighed together with the urgency of the 
intervention. Local haemostasis and supportive care should be used during and after surgical 
intervention.
An elevated TT or dTT should lead the clinician to consider delaying surgery. If the TT/dTT 
test is not available, an aPTT, though less precise than the TT, can be used.  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.
If a dabigatran specific reversal agent becomes available in a framework of clinical 
investigation during the conduct of this study and the patient fulfils the criteria for inclusion, 
it could be proposed to patients who require urgent reversal of dabigatran effects.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The following treatments should not be taken prior to dabigatran etexilate administration:

Fibrinolytic agents - within 48 hours (Please note the following exception: the use of 
tissue plasminogen activator (t-PA) e.g. alteplase, or any other thrombolytic agents to re-
establish patency of obstructed central venous line are allowed as long as the used dose is 
devoid of relevant systemic effects)

P-glycoprotein inducers including but not limited to: Rifampicin, St. John´s Wort, 
Carbamazepine, Phenytoin - within one week

Asparaginase - within one week (or within 2 weeks in case of PEG-Asparaginase)
The following treatments should not be taken together with dabigatran etexilate:

Any VKAs

Therapeutic unfractionated heparin or LMWH (heparin flushes of indwelling catheters are 
allowed)

Fibrinolytic agents (with the following exception: use of tissue plasminogen activators (t-
PA) e.g. alteplase, or any other thrombolytic agents to re-establish patency of obstructed 
central venous line are allowed as long as the used dose is devoid of relevant systemic 
effects)

P-glycoprotein inhibitors including but not limited to: Amiodarone, Cyclosporine, 
Dronedarone, Itraconazole, Ketoconazole, Nelfinavir, Quinidine, Ritonavir, Saquinavir, 
Tacrolimus, Verapamil

P-glycoprotein inducers including but not limited to: Rifampicin, St. John´s Wort, 
Carbamazepine, Phenytoin

Asparaginase

Any other investigational drug (with the exception of a specific reversal agent to 
counteract the antithrombotic activity of dabigatran etexilate where the patient is eligible 
to participate in a specific trial in a framework of clinical investigation)
Note: Intended extended use of anti-inflammatory agents or agents containing ASA should be 
avoided. Corticosteroids in general should be avoided but may be administered if they are 
part of a chemotherapy regimen given in cycles, or if the benefits of corticosteroid therapy 
clearly outweigh risks.


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4.2.2.2
Restrictions on diet and life style
Dabigatran etexilate may be taken with or without food. Dabigatran etexilate hard capsules 
should preferably be taken with a glass of water, if feasible to facilitate delivery to the 
stomach. If gastrointestinal symptoms develop it is recommended to take dabigatran etexilate 
with a meal and/or a proton pump inhibitor such as pantoprazole.
4.3
TREATMENT COMPLIANCE
Subjects or, if applicable, parents or legal guardians, will be asked to carefully complete a
daily medication intake log for dabigatran. Subjects or, if applicable, parents or legal 
guardians, are requested to bring this completed log and all remaining trial medication to 
every clinic visit which they will attend. Empty dabigatran etexilate capsule containers, 
pellets boxes or solution vials must also be returned to the investigator’s site for compliance 
calculation and disposal. Compliance will be calculated using the below equation preferably 
based on the returned medication (completed logs may also be used):
Compliance (in %)  = (Actual number of dabigatran etexilate doses taken since last count / 
Planned number of dabigatran etexilate doses which should have been taken in the same 
period) X 100 
If an interruption of dabigatran etexilate was medically required this would be considered by 
reducing the number of expected doses that “should have been taken” accordingly in the 
compliance calculation.
Unreliable subjects should not be entered in the study at the discretion of the investigator. 
Compliance during the treatment period should be between 80% and 120%. In cases where 
compliance is not achieved based on the above definition, the parent or legal guardian and 
when applicable the patient should be interviewed and re-informed about the purpose and the 
conduct of the trial and the importance to maintain good compliance. If non-compliance 
persists despite all possible efforts, patients should be removed from the treatment and 
alternative therapy should be proposed in such cases.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY
5.1.1
Endpoints of efficacy
All criteria in this study will be considered as safety endpoints.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoint(s) of safety
Primary endpoints:

Recurrence of venous thromboembolism (VTE) at 6 and 12 months

Major and minor (including clinically relevant non-major (CRNM)) bleeding events 
at 6 and 12 months

Mortality overall and related to thrombotic or thromboembolic events at 6 and 12 
months
All elements of the primary endpoints will be assessed by qualified clinicians using an 
appropriate objective method and will be centrally adjudicated by an independent committee.
Secondary endpoints:

Occurrence of post-thrombotic syndrome (PTS) at 6 and 12 months
An appropriate instrument (e.g. the Manco-Johnson Instrument or Villalta scale or a 
similar instrument; the chosen instrument will be available in the ISF)

Pharmacodynamic assessments (central measurement of dTT (Anti-Factor IIa 
activity), aPTT and ECT) at Visit 3 (after at least six consecutive dabigatran etexilate
doses) and after at least 3 days following any dabigatran etexilate dose adjustment

Number of dabigatran etexilate dose adjustments during treatment period (i.e. Number 
of patients with dabigatran dose adjustments during treatment period)


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Venous thromboembolism assessment
In case of suspected recurrent VTE, the event should be evaluated using appropriate imaging 
modalities per local guidelines or as required per investigator judgment. Example of 
appropriate evaluations methods are listed below.
o
Suspected DVT: Venous compression ultrasonography (CUS) or venography
o
Suspected PE: Ventilation-perfusion (V-Q) lung scan, pulmonary angiography or 
spiral (helical) CT
o
Suspected paradoxical embolism (PDE): CT/MR angiography or other appropriate 
evaluation 
Bleeding assessment
Patients will be carefully assessed for signs and symptoms of bleeding
The following definitions for bleeding are based on recommendations made by the 
Perinatal and Paediatric Haemostasis Subcommittee during the 56th-58th Scientific and 
Standardization Committee (SSC) Meetings of the ISTH (R11-4225).
Major bleeding:
o
Fatal Bleeding
o
Clinically overt bleeding associated with a decrease in haemoglobin of at least 
2 g/dL (20 g/L) in a 24 hour period
o
Bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves 
the central nervous system
o
Bleeding that requires surgical intervention in an operating suite
Clinically relevant non-major (CRNM) bleeding:
o
Overt bleeding for which a blood product is administered and which is not 
directly attributable to the patient’s underlying medical condition
o
Bleeding that requires medical or surgical intervention to restore haemostasis, 
other than in an operating suite.
Minor bleeding:
o
Minor bleeds are any overt or macroscopic evidence of bleeding that does not 
fulfil the criteria for either major bleeding or clinically relevant, non-major 
bleeding.


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5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient or clinical investigation subject who 
received a pharmaceutical product. The event does not necessarily have to have a causal 
relationship with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, 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.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which 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 adverse event
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. Assessment of causal relationship should be recorded in the case report forms.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF.


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Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF , if they are judged clinically relevant by the investigator.
Protocol-specified Adverse Events of Special Interest (AESI)
The following are considered as Protocol-specified AESI:

Hepatic injury defined by the following alterations of liver parameters: An elevation 
of AST and / or ALT >3 fold ULN combined with an elevation of total bilirubin >2 
fold ULN measured in the same blood draw sample.
Patients showing these lab abnormalities need to be followed up according to 
Appendix 10.2 of this clinical trial protocol and the “DILI checklist” provided in 
ISF/RDC.

Creatinine value shows a ≥2 fold increase from baseline and is above the upper limit 
of normal.
Protocol-specified AESI are to be reported in an expedited manner similar to Serious Adverse 
Events, even if they do not meet any of the seriousness criteria – for details please see Section 
5.2.2.2.
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent until end of follow-up period) will be collected, 
documented and reported to the Sponsor by the investigator on the appropriate CRF(s)/ 
eCRFs/SAE reporting forms. The investigator does not need to actively monitor patients for 
adverse events once the clinical trial has ended. However, if the investigator becomes aware 
of an SAE(s) that occurred after the patient has completed the clinical trial (including any 
protocol required residual effect period (REP) and / or follow-up), it should be reported by 
the investigator to the Sponsor if considered relevant by the investigator. Reporting will be 
done according to the specific definitions and instructions detailed in the ‘Adverse Event 
Reporting’ section of the Investigator Site File.
The residual effect period (REP) for dabigatran is 3 days after last drug administration. 
Therefore all AEs reported within 3 days of the last trial medication will be considered on 
treatment. All AEs, including those persisting after trial completion must be followed up until 
they have resolved or have been sufficiently characterized. 
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1.
The investigator must report the following events using paper process SAE form via 
telephone / fax immediately (within 24 hours) to the Sponsor: SAEs, AESIs and non-serious 
AEs relevant to the SAE and / or AESI.


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BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non-serious
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event.  If the event description is correct, the 
item “serious” needs to be ticked and an SAE has to be reported in expedited fashion 
following the same procedure as above.
The list of these adverse events can be found via the RDC-system.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File). This 
immediate report is required irrespective of whether the investigational product has been 
administered or not and irrespective of causal relationship. It also applies if new information 
to existing SAEs or protocol-specified AESI becomes available.


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Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the Sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours) to the defined unique 
entry point for SAE forms of the respective BI operative unit (country-specific contact details 
will be provided in the Investigator Site File). The outcome of the pregnancy associated with 
the drug exposure during pregnancy must be followed up. In the absence of an (S)AE, only 
the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
A central laboratory will be used for the analysis of all laboratory measurements with the 
exception of serum or urine pregnancy test, INR, serum creatinine, HCT, Hb, Platelet count, 
ALT and AST measurement at screening (if applicable) which may be done locally to 
facilitate the eligibility assessment. If needed and when feasible a local laboratory may 
alternatively be used for dTT testing to evaluate dabigatran concentration. Local lab 
assessments are also acceptable in emergency situations (e.g. bleeding event or emergency 
surgery), see Appendix 10.1.
Refer to the Flow Chart and Section 5.7.2 for additional information.
For patients who have completed the treatment period of study 1160.106, the lab results from 
Visit 8 will be taken as Visit 1 or Visit 2 results of this trial, depending on the day Visit 1 and 
Visit 2 take place in correlation to Visit 8 of study 1160.106 (see Flow Chart, Footnotes 1 and 
2).
A centralized serum pregnancy test for females who have reached menarche will be done as 
noted in the Flow Chart.
5.2.4
Electrocardiogram
An ECG will be done at screening and all other time points as noted in the Flow Chart. 
Documentation of, and findings from ECGs, must be part of the source documents available 
at the site. 
Printed paper tracings from 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be 
collected and stored at the site. In the event of any cardiac symptoms or ECG abnormalities 
(i.e. heart rhythm disorders, PR prolongation, QRS enlargement, QT prolongation, etc.),
additional ECGs will be recorded at investigator discretion. All ECGs will be evaluated 
(signed, dated and commented upon) by the treating physician / investigator and stored 
locally. Any clinically relevant changes (according to investigators judgment) in the ECG 
will be reported as AEs and followed up and / or treated locally until a normal or stable 
condition if feasible is achieved.


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All ECGs performed at any time during the conduct of the trial (whether clinically relevant or 
routine) will be stored in the subject source notes.
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs 
Blood pressure (BP) and heart rate (HR) will be performed at the time points noted in the 
Flow Chart. For each patient, all BP recordings shall be made using preferably the same type 
of instrument on the same arm during the entire course of the study. 
5.2.5.2
Weight assessment
Weight measurements should preferably be done on the same age-appropriate scale. In order 
to get comparable body weight values, weight measurements should be performed in the 
following way:

shoes and coats / jackets should be taken off (when applicable) 

pockets should be emptied of heavy objects (i.e. keys, coins etc.) when applicable
5.3.2
Other assessments

Incidence of adverse events, protocol-specified AESI and serious adverse events

 
 
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All safety and clinical assessments are determined using standard methods and procedures.
 
 
 
 
 


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5.6
BIOMARKER(S)
Please refer to Section 5.7.
5.7
PHARMACODYNAMICS
5.7.1
Pharmacodynamic endpoints
Determination of the exploratory pharmacodynamic parameters dTT (Anti-Factor IIa 
activity), aPTT and ECT will be performed in this trial. Diluted thrombin time (dTT) or 
alternative registered method / assay (where available and after consultation of the Sponsor) 
will be employed for the quantitative measurement of dabigatran concentrations for dose 
adjustment. The analysis of dTT will be done by a central laboratory. Diluted TT may also be 
analysed by a local laboratory, if feasible. The dabigatran etexilate dose administered to 
patients may be adjusted upon dabigatran plasma level measurement from Visit 3 or other 
future visits as needed to achieve the target plasma range, based on the assessment of 
dabigatran plasma levels. Further, alternative coagulation assays for dabigatran, e.g. ecarin 
based tests, may be explored.
5.7.2 
Methods of sample collection
About 22.8 mL of blood (approximately 2.4 mL per sampling time point) in total per patient 
assigned to dabigatran etexilate is planned for collection for the PD samples.
The collection time point for aPTT, ECT and dTT (Anti-Factor IIa activity) (or alternative 
method) are indicated in the Flow Chart. The date and exact clock time of when these PD 
samples are taken is to be recorded in the eCRF. Further, the date and the exact clock time of 
dabigatran etexilate administration on the three days before the PD samples are taken is to be 
recorded in the eCRF. The PD samples should be taken immediately after the PK samples 
have been obtained. To ensure correct identification and tracking of the PD samples, all 
sample tubes will be labelled with trial number, patient number and day and exact time of 
sample collection.
 
 
 
 
 
 
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The trial consists of three periods, a screening period, an open-label dabigatran etexilate 
treatment period and a follow-up period.
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 treatment assignment (Visit 2). 
In the event that visits are missed or out of sequence, subsequent visits will be planned 
according to the date of Visit 2.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
No study procedures may be initiated prior to the patient’s parents (or legal guardian) signing 
the informed consent and the patient providing assent (if applicable) in compliance with ICH-
GCP and local legislation.
6.2.1
Screening period
For the schedule of assessments and procedures to be done during screening refer to the 
Flow Chart. In addition:

Document consenting procedure (and assenting if applicable) in the patient’s source file.

Record enrolment (date of patient consent) on the enrolment log (located in the 
Investigator Site File).
For patients participating in study 1160.106 the Screening Visit may be conducted together 
with Visit 8 of 1160.106 trial.
6.2.2
Treatment period
Before giving the first dose of study medication, eligibility must be confirmed.
For the schedule of assessments and procedures during the treatment period refer to the Flow 
Chart. For information on dose selection and drug assignment and administration refer to 
Section 4.1.3 and Section 4.1.4. For details 
 PD sample collection and analyses 
refer to 
and Section 5.7.
Visit 3 is not applicable for patients who have previously completed the treatment period of 
the 1160.106 study being on dabigatran etexilate and continue taking the same dose in this 
trial. For all other patients, during Visit 3 the trough dabigatran concentration will be
determined
 
 ensure maintenance within 
a 50 to < 250 ng/mL window. If target exposure of 50 to < 250 ng/mL is not achieved an 
Unscheduled Visit must be performed in order to adjust the dabigatran etexilate dose (refer to 


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Appendix 10.4.2). A Titration Visit must be scheduled preferably after 3 days have elapsed 
(or 6 new doses have been taken) after a dose adjustment to reassess if the new trough 
dabigatran concentration is within the target range. Patients must not be dosed at home prior 
to attending a Titration Visit; dosing will be done after a trough plasma sample is collected. If 
patients cannot reach trough plasma concentrations between 50 and < 250 ng/mL after one
dose adjustment, they must discontinue the study medication.
Unscheduled Visits are to be conducted in all cases of suspected recurrent VTE, paradoxical 
embolism (PDE), occurrence of post-thrombotic syndrome (PTS), major or clinically-
relevant bleeding events (MBEs/CRBEs) or other suspected AESI or SAE. The Unscheduled 
Visit should be performed as soon as possible, preferably within 24 hours after the site first 
becomes aware of a suspected event.
6.2.3
End of trial and follow-up period
Follow-up Visit should be planned for 28 days after last drug intake. For the assessments and 
procedures to be done during the Follow-up Visit refer to the Flow Chart.
All patients who prematurely discontinue treatment will be invited to perform an eEOT Visit.
Subsequently they will be followed up according to the remaining visit schedule until the end 
of the study. At these visits collection of AEs, outcome events (e.g. occurrence of PTS, VTE, 
bleeding events, etc.) and use of concomitant medication will be made. 
Patients that are not actively taking study drug and their parent/legal guardian may be less 
motivated to adhere to the study visit schedule. Investigator and site staff should work to 
detect early signs of losing interest and readily present such patients (not actively taking 
study drug) and their parent/legal guardian with the following opportunities to encourage 
continued participation:

continue to attend regularly scheduled study visits until the trial ends

conduct only the final visit in person. All other visits would be done over the phone.  

conduct all remaining study visits over the phone 

discontinue participation in remaining trial activities but permit collection of vital status 
and outcome events at the end of the trial.

discontinue participation in remaining trial activities but permit collection of vital status 
at the end of the trial.
The patient / parent / legal guardian will be asked to choose the most rigorous follow-up they 
are willing to comply with.
For patients who completely withdraw consent no more data on their medical information 
will be requested. 
The site must make periodic documented attempts (approximately every three months) to 
locate patients who are lost to follow up (LTFU).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This trial has a single treatment group with no control group. Overall assessment of safety 
will be based on descriptive statistics.
7.2
NULL AND ALTERNATIVE HYPOTHESES
There is no hypothesis testing for this trial.
7.3
PLANNED ANALYSES
The primary analysis will include patients who were dispensed study medication and have 
received at least one dose of study medication (Treated set).
The analysis of the 
/PD parameters will be performed on Pharmacokinetic set (PKS). PKS
will include all treated patients with at least one 
/PD measurement and having no protocol 
violations relevant to the evaluation of 
 PD endpoints.
7.3.1
Primary analyses
The primary analyses will be based on the primary safety endpoints. The recurrence of VTE, 
major bleeding events, minor (including clinically relevant non-major (CRNM)) bleeding 
events, overall mortality and mortality related to thromboembolic events will be analysed as 
time-to-event and will be summarized by Kaplan-Meier estimates. The rate of occurrence of 
events at 6 and 12 months will also be provided by K-M estimation. Patients who do not have 
any of the events or drop out early will be considered as censored for this analysis.  
Additionally, descriptive rate with number of patients with event divided by total treated 
patients will also be provided. Early drop out and lost-to-follow-up will be considered as non-
event.  The components of the composite event will be summarized as below:
Recurrence of venous thromboembolism will be summarized by Kaplan-Meier 
estimate of time to first recurrence of VTE. The rate of recurrence at 6 and 12 months 
will also be provided by K-M estimation. Patients, who do not experience recurrent 
VTE by the time of analyses, drop out from the study, or die from non-VTE related 
cause will be considered as censored. The descriptive rate of number of patients with 
event divided by total treated patients will also be provided. Early drop out and lost-
to-follow-up will be considered as non-event when calculating the descriptive rate.
Major bleeding and minor (including clinically relevant non-major (CRNM)) bleeding
will be analysed by K-M estimate of time to first occurrence as competing events. 
The K-M rate estimate at 6 and 12 month will be provided. The descriptive rate will 
also be calculated by dividing number of patients with major / minor bleeding by the 
number of total treated patients. Early drop out, lost-to-follow-up and non-bleeding 
related death will be considered as non-event and censored.


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Mortality overall and related to thrombotic or thromboembolic event will be 
summarized separately by K-M estimate of time to death. The K-M rate and 
descriptive rate at 6 and 12 month will be calculated. Early drop out and lost-to-
follow-up will be considered as non-event. Non-thrombotic or non-thromboembolic 
related death will be considered as censored case for mortality due to thrombotic or 
thromboembolic events.
7.3.2
Secondary analyses
Secondary analyses are planned for occurrence of post-thrombotic syndrome (PTS), number 
of dabigatran etexilate dose adjustments (i.e. Number of patients with dabigatran dose 
adjustments) and pharmacodynamic assessments at Visit 3 (after at least six consecutive 
dabigatran etexilate doses) and after at least 3 days following any dabigatran etexilate dose
adjustment.

Occurrence of PTS will be summarized by K-M estimate of time to first occurrence. 
The K-M rate and descriptive rate at 6 and 12 month will be calculated. Early drop 
out, lost-to-follow-up and death will be considered as non-event and censored.

Frequency of dabigatran etexilate dose adjustments will be summarized descriptively.
This refers to the number of patients with dabigatran etexilate dose adjustment during 
treatment period because each patient is allowed to have only one dose adjustment.

 pharmacodynamic analyses details can be found in Section 7.3.5
and 7.3.6.
7.3.3
Safety analyses
The safety analyses will be descriptive in nature and will be based on BI standards. 
Parameters to be evaluated for safety are described in Section 5.2.
AEs will be coded using the MedDRA dictionary. All AEs will be classified according to the 
following trial periods: screening, treatment, safety follow-up. All AEs with an onset date /
time after administration of trial medication up to 3 days after the last intake of study 
medication will be assigned to the treatment period for evaluation. In addition, AEs with 
onset date before start of the trial treatment but with worsening in intensity during the 
treatment will also be assigned to the on-treatment period. Other AEs will be assigned to the 
screening or post-treatment period, respectively. All AEs (including bleeding) in the 
treatment period will be tabulated in total and according to seriousness, severity and possible 
relationship to trial medication. AEs in the screening or follow-up period will be listed.
 
 


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7.3.6
Pharmacodynamic analyses
The following descriptive statistics will be calculated for the pharmacodynamic parameters 
aPTT, ECT and any additional PD assay: these include, but are not limited to N, arithmetic 
mean, standard deviation, minimum, median, and maximum. Further, ratios to baseline (i.e. 
Visit 2) for these parameters will be calculated and assessed by descriptive statistics. 
Dabigatran concentrations derived from dTT or alternative methods, e.g. ecarin based tests,
will be compared to dabigatran concentrations determined by HPLC-MS/MS. This
comparison will be reported separately.
 


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7.4
HANDLING OF MISSING DATA
Missing data will not be imputed in general. All patients will be followed to collect necessary 
efficacy and safety information, even if patients discontinue study medication prematurely. 
7.5
RANDOMISATION
Randomisation is in general not applicable to this study. Only patients assigned to OLF will 
be randomized based on 1:1 ratio to receive flavoured or unflavoured solvent for 
reconstitution.
7.6
DETERMINATION OF SAMPLE SIZE
The design of this study (including the definition of endpoints and sample size) has been 
agreed with the European Medicines Agency’s Paediatric Committee. A minimum of 100 
patients will be entered in this trial, including patients rolling over from study 1160.106, who 
require secondary VTE prevention and new patients who should have completed treatment 
for an acute VTE episode. The Data Monitoring Committee (DMC) or Sponsor may decide to 
keep recruitment open after 100 patients have been recruited, in case additional safety data 
needs to be generated.
Under the assumption of 5% of event rate for the composite of recurrent VTE, major bleeds 
and mortality related to thromboembolic event at 12 months, 100 patients will provide more 
than 99% of probability observing at least 1 event,  it will provide higher than 63% of 
probability if the event  rate is 1%. The expected 95% Wilson confidence interval for event 
rates under the assumption of 100 patients are provided in Table 7.6: 1.
Table 7.6:1 Expected 95% Wilson confidence interval based on 100 available patients
Observed rate (%)
95% Wilson CI
1
(0.18 – 5.45)
2
(0.55 – 7.00)
3
(1.03 – 8.45)
4
(1.57 – 9.89)
5
(2.15 – 11.2)
10
(5.52 – 17.4)
20
(13.3 – 28.9)
The sample size is considered adequate to capture any safety signal for the primary safety 
endpoints defined in the study.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator should inform the Sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol / ICH GCP.
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.
Depending upon local requirements:
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(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 
parents or the legal guardian according to ICH GCP and to the regulatory and legal 
requirements of the participating country. In addition and if applicable an informed assent 
must be obtained from the patients. 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, assent and 
any additional patient information must be given to each patient or to the parents or the legal 
guardian. Should patients reach legal age during the trial they must personally sign and date 
the informed consent form as soon as possible and, at the latest, at the next visit.
Parents or the legal guardian and the patient (as appropriate) must be informed that personal 
trial-related data will be used by Boehringer Ingelheim in accordance with the local data 
protection law. The level of disclosure must also be explained to the patient / parent / legal 
guardian.
Parents or the legal guardian and the patient (as appropriate) must be informed that medical 
records may be examined by authorised monitors (CML/CRA) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
The trial will be conducted according to the principles of Good Clinical Practice (GCP) and 
the company standard operating procedures (SOPs).
The following measures will be taken to ensure accurate, consistent, complete and reliable 
data:
All required trial documents will be distributed to every trial site and kept in the Investigator 
Site File (ISF). An investigator meeting will be held (may be held by webcast or similar 
means) before the trial to assure a high quality and standardization across sites.
Trial teams at the sites will be trained on protocol requirements, trial procedures, adverse 
event reporting, and remote data capture during the investigator meeting and / or by Clinical 
Research Associates (CRAs) during the respective monitoring visits.
On-site monitoring: Data captured in the eCRF will be verified against source data and vice 
versa by CRAs. The identity and informed consent of all patients as well as SAE reporting 
will be checked. For the remaining parts of the eCRF source data verification will be 
performed as described in the Monitoring Manual.
Auditing (internal and, if required by any regulatory authorities, external) will be performed 
as necessary.
Coding (e.g., according to MedDRA for adverse events) will be performed according to the 
company’s SOPs as described in the trial data management and analysis plan (TDMAP). The 
data management procedures to ensure the quality of the data are described in detail in the 
(TDMAP) available in the CTMF.
A quality assurance audit / inspection of this trial may be conducted by the Sponsor or 
Sponsor’s designees or by IRBs/IECs 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.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the Sponsor, either on 
paper or via remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. 
For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 


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to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
Copies of source documents necessary for adjudication will be provided to the adjudication 
committee. Before sending or uploading those copies, 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 from any copy of the patients´ source 
documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For dabigatran etexilate this is the current version of the Investigator’s Brochure (U98-
3208).The current versions of these reference documents are to be provided in the ISF. No 
AEs are classified as listed for study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
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 


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need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.
8.6
COMPLETION OF TRIAL
For trials performed in EU member states: The EC / competent authority in each participating 
EU member state needs to be notified about the end of the trial (last patient / patient out, 
unless specified differently in Section 6.2.3 of the CTP) or early termination of the trial.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Israels SJ, Michelson AD.  Antiplatelet therapy in children.  Thromb Res 
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Chan AK, Deveber G, Monagle P, Brooker LA, Massicotte PM. Venous 
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Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral 
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Mitchell LG, Dietrich K, Bajzar L, Bauman M, Massicotte P, Stang L, et al. 
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Price VE, Chan AKC. Venous thrombosis in children. Expert Rev 
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Chalmers E, Ganesen V, Liesner R, Maroo S, Nokes T, Saunders D, 
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Monagle P, Chan AKC, Goldenberg NA, Ichord RN, Journeycake JM, 
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Andrew M, David M, Adams M, Ali K, Anderson R, Barnad D, Bernstein 
M, Brisson L, Cairney B, DeSai D, Grant R, Israels S, Jardine L, Luke B, 
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children: First analyses of the Canadian registry of VTE. Blood 1994. 
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Michelson AD, Bovill E, Monagle P, Andrew M. Antithrombotic therapy in 
children. Chest 1998;114(5):748S-769S. 
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Mitchell LG, Andrew M, Hanna K, Abshire T, Halton J, Anderson R, et al. 
A prospective cohort study determining the prevalence of thrombotic events 
in children with acute lymphoblastic leukemia and a central venous line who 
are treated with L-asparaginase: results of the Prophylactic Antithrombin 
Replacement in Kids with Acute Lymphoblastic Leukemia Treated with 
Asparaginase (PARKAA) Study.  Cancer 2003;97(2):508-516.
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Hayton WL. Maturation and growth of renal function: dosing renally cleared 
drugs in children. AAPS PharmSci 2002;2(1):3.
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van Ommen CH, Heijboer H, Buller HR, Hirasing RA, Heijmans HS, Peters 
M.  Venous thromboembolism in childhood: a prospective two-year registry 
in The Netherlands.  J Pediatr 2001;139(5):676-81.


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R06-2304
REVIVE Study Group, Massicotte P, Julian JA, Gent M, Shields K, 
Marzinotto V, Szechtman B, Andrew M. An open-label randomized 
controlled trial of low molecular weight heparin compared to heparin and 
oumadin for the treatment of venous thromboembolic events in children: the 
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venous line-related thrombosis in children: association with central venous 
line location and insertion technique.  Blood 2003;101(11):4273-4278. 
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Nowak-Goettl U, Junker R, Kreuz W, Eckardstein A von, Kosch A, Nohe N, 
Schobess R, Ehrenforth S, Childhood Thrombophilia Study Group. Risk of 
recurrent venous thrombosis in children with combined prothrombotic risk 
factors. Blood 2001. 97(4):858-862.
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Revel-Vilk S, Sharathkumar A, Massicotte P, Marzinotto V, Daneman A, 
Dix D, Chan A. Natural history of arterial and venous thrombosis in children 
treated with low molecular weight heparin: a longitudinal study by 
ultrasound. J Thromb Haemost 2004;2:42-46.
R07-2938
Kuhle S, Eulmesekian P, Kavanagh B, Massicotte P, Vegh P, Mitchell LG.  
A clinically significant incidence of bleeding in critically ill children 
receiving therapeutic doses of unfractionated heparin: a prospective cohort 
study.  Haematologica 2007;92(2):244-247.
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Bonduel MM.  Oral anticoagulation therapy in children.  Thromb Res 
2006;118(1):85-94.
R07-2940
Young G.  Current and future antithrombotic agents in children.  Expert Rev 
Cardiovasc Ther 2004;2(4):523-534.
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Kahn SR.  The post-thrombotic syndrome: the forgotten morbidity of deep 
venous thrombosis.  J Thromb Thrombolysis 2006;21(1):41-48. 
R07-2956
Balasa VV.  New anticoagulants: a pediatric perspective.  Pediatr Blood 
Cancer 2005;45(6):741-752. 
R07-2959
Goldenberg NA.  Long-term outcomes of venous thrombosis in children.  
Curr Opin Hemato 2005;12(5):370-376. 
R07-2962
Barnes C, Newall F, Monagle P.  Post-thrombotic syndrome.  Arch Dis 
Child 2002;86(3):212-214. 
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Kenet G, Nowak-Gottl U.  Bleeding and thrombosis issues in pediatric 
patients: current approach to diagnosis and treatment.  Acta Haematol 
2006;115(3-4):137-140.


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Anderson BJ, Holford NHG. Mechanism-based concepts of size and 
maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48, 303 - 332 
(2008)
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Newcombe RG. Interval estimation for the difference between independent 
proportions: comparison of eleven methods. Stat Med 1998;17:873-890.
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Greenland S, Robins JM. Estimation of a common effect parameter from 
sparse follow-up data. Biometrics 1985;41:55-68.
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ICH Harmonised Tripartite Guideline: Guidance on Nonclinical Safety 
Studies for the Conduct of Human Clinical Trials and marketing 
authorisation for Pharmaceuticals: M3(R2) (current step 4 version, 11 June
2009)
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Mitchell L, Goldenberg N, Male C, Kenet G, Monagle P, Nowak-Gottl U. 
Definition of clinical efficacy and safety outcomes for clinical trials in deep 
vein thrombosis and pulmonary embolism in children. J Thromb Haemost 
2011;9:1856-1858.
R12-0738
Jones S, Newall F, Manias E, Monagle P. Assessing outcome measures of 
oral anticoagulation management in children. Thromb Res 2011. 127:75-80.
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Settty BA, O'Brien SH, Kerlin BA. Pediatric venous thromboembolism in 
the United States: a tertiary care complication of chronic diseases. Pediatr 
Blood Cancer 2012. 59:258-264.
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Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous 
thromboembolism in children's hospitals in the United States from 2001 to 
2007. Pediatrics 124 (4), 1001 - 1008 (2009)
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Young G, et al. Impact of inherited thrombophilia on venous 
thromboembolism in children: a systematic review and meta-analysis of 
observational studies. Circulation 2008. 118(13):1373-1382.
R14-1031
Dix D, Andrew M, Marzinotto V, Charpentier K, Bridge S, Monagle P, 
DeVeber G, Leaker M, Chan AKC, Massicotte MP. The use of low 
molecular weight heparin in pediatric patients: a prospective cohort study. J 
Pediatr 2000. 136(4):439-445.
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Schobess R, Duering C, Bidlingmaier C, Heinecke A, Merkel N, Nowak-
Goettl U. Long-term safety and efficacy data on childhood venous 
thrombosis treated with a low molecular weight heparin: an open-label pilot 
study of once-daily versus twice-daily enoxaparin administration. 
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Wardlaw JM, et al. Neuroimaging standards for research into small vessel 
disease and its contribution to ageing and neurodegeneration. Lancet Neurol 
2013. 12, 822 - 838.
9.2
UNPUBLISHED REFERENCES
U00-1856
. Safety, 
pharmacodynamics and pharmacokinetics after multiple oral doses of 50, 
100, 200 and 400 mg BIBR 1048 MS solution administered t.i.d. for 7 days 
to healthy volunteer subjects. An open study, placebo-controlled, 
randomized, double blind at each dose level. 1160.2. 22 August 2000.
U03-1878
. Pharmacokinetics of BIBR 953 ZW after 
150 mg of BIBR 1048 (oral pro-drug of BIBR 953) administered as capsule 
twice daily over seven days with our without Pantoprazole co-treatment to 
healthy male and femaile elderly subjects.  1160.10. 08 December 2003.
U06-1614-01
 Safety, pharmacodynamics and 
pharmacokinetics after single oral administration of 600 mg, 750 mg and 
900 mg dabigatran etexilate as capsule in healthy subjects. A randomised, 
placebo-controlled study, double blind at each dose level. 1160.60. 
25 August 2006.
U09-1399-02
.  Combined 
population analysis of dabigatran etexilate.  30 October 2009.
U09-1400-01
.  A 
Phase III, randomised, double blind, parallel-group study of the efficacy and 
safety of oral dabigatran etexilate (150 mg b.i.d.) compared to warfarin 
(INR 2.0-3.0) for 6 month treatment of acute symptomatic venous 
thromboembolism. 1160.53. 21 October 2009.
U09-1839-01
 
  Relative bioavailability of dabigatran after administration of different 
application forms of a single oral dose of 150 mg dabigatran etexilate 
(capsule, powder for reconstitution into solution, pellets on food) in healthy 
male and female volunteers (an open-label, randomised, three-way 
crossover, clinical Phase I study). 1160.87. 20 October 2009.
U09-2262-01
 2.7 Clinical Summary Dabigatran 
etexilate 75 mg, 110 mg and 150 mg hard capsules. 11 November 2009.


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U09-3249-02
. Randomized Evaluation of 
Long term anticoagulant therapy (RE-LY®) comparing the efficacy and 
safety of two blinded doses of dabigatran etexilate with open label warfarin 
for the prevention of stroke and systemic embolism in patients with non-
valvularatrial fibrillation: prospective, multi-centre, parallel-group, non-
inferiority trial (RE-LY® STUDY). 1160.26. 16 October 2009.
U10-2533-01
. A Phase III, 
randomised, multicenter, double-blind, parallel-group, active controlled
study to evaluate the efficacy and safety of oral dabigatran etexilate (150 mg 
b.i.d.) compared to warfarin (INR 2.0 to 3.0) for the secondary prevention of 
venous thromboembolism. RE-MEDY. 1160.47. 12 July 2011.
U11-1642-01
. Amendment to 
Pradaxa ® CCDS after approval of dabigatran etexilate for SPAF in US and 
EU. Amendment to Pradaxa ® CCDS concerning the use of fibrinolytic 
agents for acute ischemic stroke and the simultaneous use of ticagrelor (plus 
ASA), selective serotonin re-uptake inhibitors or dronedarone (Multaq®). 
21 September 2011.
U11-2267-02
 Twice-daily oral direct thrombin inhibitor 
dabigatran etexilate in the long-term prevention of recurrent symptomatic 
venous thromboembolism in patients with symptomatic deep-vein 
thrombosis or pulmonary embolism. RE-SONATE. 1160.63 29 May 2012.
U11-2298-01
. A Phase III randomised, double 
blind, parallel-group study of the efficacy and safety of oral dabigatran 
etexilate (150 mg b.i.d.) compared to warfarin (INR 2.0-3.0) for 6 month 
treatment of acute symptomatic venous thromboembolism, following initial 
treatment for at least 5 days with a parenteral anticoagulant approved for 
this indication.  RE-COVER II. 1160.46. 22 Sep 2011.
U12-3378-01
. Open-label safety and tolerability 
study of dabigatran etexilate given for 3 days at the end of standard 
anticoagulant therapy in children aged 12 years to less than 18 years. 
1160.88. 05 July 2012
U98-3208
. Dabigatran
investigator’s brochure (current version – see ISF).
c02248557
. Relative bioavailability of 
dabigatran after administration of different dosage forms of multiple doses 
of 150 mg dabigatran etexilate (hard capsule, granules resolved in 
reconstitution solution, pellets on food) in healthy male volunteers (an 
openlabel, randomised, multiple-dose, three-way crossover study). 
1160.194. 26 September 2014.


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c09069268
Single dose open-label PK/PD, safety and tolerability study of dabigatran 
etexilate mesilate given at the end of standard anticoagulant therapy in 
successive groups of children aged 2 years to less than 12 years followed by 
1 year to less than 2 years. 1160.89. Clinical Trial Report. 27 July 2016.
c09085437
Open-label, single dose, tolerability, pharmacokinetic/pharmaco-dynamics 
and safety study of dabigatran etexilate given at the end of standard  
anticoagulant therapy in children aged less than 1 year old. 1160.105. 
Clinical Trial Report. 14 July 2016.
c09149467
 Analysis of the PK-PD relationship of dabigatran etexilate in 
paediatric patients based on combined data from multiple studies.


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10.
APPENDICES
10.1
SAFETY AND OTHER CLINICAL LABORATORY EVALUATIONS
Standard Safety Lab Panels will include:
Comprehensive Metabolic Panel (central lab):
Haematology Panel (central lab):
Glucose (fasting or non-fasting)
White Blood Cell Count
Calcium
Red Blood Cell Count
Albumin
Haemoglobin
Total Protein 
Haematocrit
Sodium
Red Blood Cell Indices
Potassium
Differential
Chloride
Platelet Count
BUN
Creatinine
Alkaline Phosphatase
ALT (alanine aminotransaminase, SGPT)
AST (aspartate aminotransaminase, SGOT)
Bilirubin - total or conjugated (direct) / unconjugated 
(indirect)
Other centralized labs tests:
Serum pregnancy test performed on all female patients who have reached menarche 
Activated Partial Thromboplastin Time (aPTT)
Ecarin Clotting Time (ECT)
Diluted Thrombin Time / Anti-Factor IIa activity (dTT)
Diluted Thrombin Time (dTT) to evaluate dabigatran concentration (or an alternative method 
for the quantitative determination of dabigatran plasma concentration)
Other potential locally evaluated labs tests / exploratory biomarkers:
 
Serum or urine pregnancy test, INR (International Normalized Ratio), serum creatinine, HCT, 
Hb, Platelet count, ALT and AST at screening - to facilitate the eligibility assessment
Safety Lab Panel – in case of emergency (e.g. bleeding event or emergency surgery)


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Estimated Glomerular Filtration Rate (eGFR) for children using Schwartz formula. This 
employs serum creatinine (mg/dL), the child's height (cm) and a constant to estimate the 
glomerular filtration rate:

eGFR (Schwartz) = (0.413 x Height in cm) / Serum Creatinine in mg/dL
Conversion from conventional unit to SI unit:  
Conventional unit
Conversion Factor
SI Unit
mg/mL
88.4
µmol/L
10.1.1
Blood volume charts
The blood volumes to be collected during the course of the trial are age adjusted. Patients are 
generally divided in three age groups: 6 to 18 years, 2 to 6 years and 0 to 2 years of age. For 
patients assigned to the dabigatran etexilate arm, approximate blood volumes (in ml) to be 
collected for planned central safety laboratory assessments, 
/PD and exploratory markers 
are outlined in the age specific charts below:

6 to <18 years
Table 10.1.1: 1 
Blood volume chart 6-<18 years
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Chemistry
3,5
3,5
3,5
3,5
3,5
3,5
3,5
3,5
3,5
3,5
3,5
3,5
Haematology
2
2
2
2
2
2
2
2
2
2
2
2
PD (aPTT and ECT)
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
dTT
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
Total
5,5
6,7
9,1
9,1
9,1
9,1
9,1
9,1
9,1
9,1
9,1
5,5
4 weeks interval
9,1
9,1
9,1
9,1
9,1
9,1
9,1
5,5
Total (for trial - 13 months)
30,4
99,6

2 to< 6 years
Table 10.1.1: 2 
Blood volume chart 2-<6 years
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Chemistry
2,6
2,6
2,6
2,6
2,6
2,6
2,6
2,6
2,6
2,6
2,6
2,6
Haematology
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
PD (aPTT and ECT)
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
dTT
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
Total
3,8
5
7,4
7,4
7,4
7,4
7,4
7,4
7,4
7,4
7,4
3,8
4 weeks interval
7,4
7,4
7,4
7,4
7,4
7,4
7,4
3,8
Total (for trial - 13 months)
23,6
79,2


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
0 to ≤2 years
Table 10.1.1: 3 
Blood volume chart 0-<2 years
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Chemistry
2,2
2,2
2,2
2,2
2,2
2,2
2,2
2,2
2,2
2,2
2,2
2,2
Haematology
0,5
0,5
0,5
0,5
0,5
0,5
0,5
0,5
0,5
0,5
0,5
0,5
PD (aPTT and ECT)
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
dTT
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
1,2
Total (per visit)
2,7
3,9
6,1
6,1
6,1
6,1
6,1
6,1
6,1
6,1
6,1
2,7
4 weeks interval
6,1
6,1
6,1
6,1
6,1
6,1
6,1
2,7
Total (for trial - 13 months)
18,8
64,2
In case of infants and when medically required per Investigator judgment and/or per local 
guidelines, reduced blood collection will be implemented after consultation with the Sponsor 
(e.g. omission of exploratory coagulation markers, reduced frequency of safety labs during 
the treatment period, etc.). The decision for the reduced blood collection will be documented 
in the ISF.
10.2
CLINICAL EVALUATION OF LIVER INJURY
10.2.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (refer to Protocol-
Specified AESI), are to be further evaluated using the following procedures:
10.2.2
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 hours and provide additional blood sample to the central laboratory for automatic reflex 
testing of the below listed laboratory parameters. Only in case whereby the central laboratory 
is not immediately available (e.g. if the logistics are such that the patient´s repeat specimen 
would not reach the central laboratory in a reasonable timeframe), ALT, AST, and bilirubin 
(total and direct) will be evaluated by local laboratory and results are made available to the 
investigator and to BI as soon as possible. If in such a case ALT and / or AST >3 fold ULN 
combined with an elevation of total bilirubin >2 fold ULN are confirmed, results of the 
laboratory parameters described below must be made available to the investigator and to BI 
as soon as possible.
Clinical chemistry
alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-
HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody 
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-


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mitochondrial antibody. The need for hepatitis serology to be assessed by the investigator 
based on patient age and clinical presentation.
Hormones, tumormarker
TSH
Haematology
Thrombocytes, eosinophils
In addition,

Obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF

Obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
according to the “DILI checklist” provided in the ISF;

Obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the “DILI checklist” provided in the ISF;

Provide abdominal ultrasound to rule out biliary tract, pancreatic or intra-hepatic 
pathology, e.g. bile de duct stones or neoplasm.

Initiate close observation of patients by repeat testing of ALT, AST, and total bilirubin 
(with fractionation by total and direct) at least weekly until the laboratory ALT and or 
AST abnormalities stabilize or return to normal, then according to the protocol. 
Depending on further laboratory changes, additional parameters identified e.g. by reflex 
testing will be followed up based on medical judgment and Good Clinical Practices 
(GCP).
and report these via the CRF.
10.3
TRANSITION TO NON-STUDY ANTITHROMBOTIC TREATMENT 
WITH EARLY STUDY DRUG DISCONTINUATION OR AT THE END OF 
THE TRIAL
Patients actively taking study drug at their final treatment visit and patients who stop study 
medication early may need to switch to a non-study antithrombotic treatment at the 
Investigator`s discretion. The following recommendations are provided for guidance only:

If the non-study treatment is a Vitamin K antagonist, the starting time of the VKA should 
be adjusted according to the patient´s eGFR as follows:
o
eGFR ≥ 50 mL/min: start VKA 3 days before discontinuing study drug
o
eGFR ≥ 30-< 50 mL/min: start VKA 2 days before discontinuing study drug

If the non-study treatment will be a LMWH, it is recommended to wait 12 hours after the 
last dose of dabigatran etexilate (study medication) before switching to a parenteral 
anticoagulant (e.g. UFH, LMWH).  

If the non-study treatment will be an antiplatelet agent, this medication can be initiated at 
any time-point after last intake of study medication.


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10.4
DOSING OF DABIGATRAN ETEXILATE
Patients aged ≥ 8 years: Age and weight adjusted dabigatran etexilate capsules.
Patients aged < 8 years or for patients who cannot take capsules even if older than 8 (but 
below 12 years of age): Age and weight adjusted dabigatran etexilate pellets.
Patients aged < 12 months: Age and weight adjusted dabigatran etexilate OLF or any other 
alternative age-appropriate formulation. For patients < 12 months of age OLF is preferred 
over pellets provided that OLF supplies are available to the site.
Dabigatran etexilate is taken twice daily (BID). 
Estimated age and weight adjusted doses are outlined in the following nomograms, which 
refer to the total amount of dabigatran etexilate to be taken at a single time-point.
10.4.1
Dosing nomogram (starting doses)

dabigatran etexilate capsules - 50, 75, 110 and 150 mg
9 to <11
11 to <13
13 to <16
16 to <21
21 to <26
26 to <31
31 to <41
41 to <51
51 to <61
61 to <71
71 to <81
81 to <91
≥ 91
8
96
100
100
125
150
150
185
220
260
300
300
9
108
100
125
150
150
185
220
260
300
300
10
120
100
125
150
150
185
220
260
300
300
330
330
11
132
125
150
150
185
220
260
300
300
330
330
12
144
125
150
150
185
220
260
300
300
330
330
13
156
125
150
150
185
220
260
300
300
330
330
14
168
150
150
185
220
260
300
300
330
330
15
180
150
150
185
220
260
300
300
330
330
16
192
150
185
220
260
300
300
330
330
17
204
150
185
220
260
300
300
330
330
Doses > 330 mg BID capped to 330 mg BID
100
2x50mg capsules
150
150mg or 2x75mg capsules
220
2x110mg capsules
300
2x150mg or 4x75mg capsules
125
50mg + 75mg capsules
185
75mg + 110mg capsules
260
110+150mg or 110+2x75mg capsules
330
3x110mg capsules
Weight [kg]
Initial Dose
Single Dose [mg]
Age 
[completed 
years]
Age 
[completed 
months]
Figure 10.4.1: 1 
Age and weight adjusted starting doses using capsules


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
dabigatran etexilate pellets
Weight [kg]
2.5 to < 3 3 to < 4
4 to < 5
5 to < 7
7 to < 9
9 to < 11
11 to < 13 13 to < 16 16 to < 21 21 to < 26 26 to < 31 31 to < 41 41 to < 51 51 to < 61 61 to < 71 71 to < 81 81 to < 91
>= 91
<0.08
<1
20
0,08
1
20
20
0,17
2
20
20
0,25
3
20
20
30
30
0,33
4
20
20
20
30
40
0,42
5
20
20
30
40
40
0,50
6
30
30
40
50
0,58
7
30
30
40
50
0,67
8
30
40
40
50
60
0,75
9
30
40
50
50
60
0,83
10
40
50
50
70
70
0,92
11
40
50
60
70
80
1
12
40
50
60
70
80
90
1,5
18
50
50
70
80
90
90
110
2
24
60
70
80
100
100
140
2,5
30
60
70
90
100
110
140
150
160
3
36
60
70
90
100
110
140
150
160
4
48
80
90
100
110
140
150
160
220
5
60
80
90
100
110
140
150
160
220
260
6
72
80
90
100
110
140
150
160
220
260
300
7
84
90
100
110
150
150
160
220
260
300
300
8
96
90
100
110
150
150
160
220
260
300
300
9
108
100
110
150
150
160
220
260
300
300
10
120
100
110
150
150
160
220
260
300
300
330
330
11
132
110
150
150
160
220
260
300
300
330
330
Doses > 330 mg BID capped to 330 mg BID
20
20 mg stick pack
80
2x 40 mg stick packs
160
110 +50 mg stick pack
30
30 mg stick pack
90
40+50 mg stick packs
220
2x 110 mg stick packs
40
40 mg stick pack
100
2x 50 mg stick pack
260
110 + 150 mg stick pack
50
50 mg stick pack
110
110 mg stick pack
300
150 + 150 mg stick pack
60
2x 30 mg stick packs
140
30+110 mg stick packs
330
3 x 110 mg stick pack
70
30+40 mg stick packs
150
150 mg stick packs
Initial Dose
Age
[completed
 months]
Age
[completed
 years]
Single Dose [mg]
Figure 10.4.1: 2 
Age and weight adjusted starting doses using pellets

dabigatran etexilate OLF - 6.25 mg per mL
2.5 <3
3 to <4
4 to <5
5 to <7
7 to <9
9 to <11
11 to <13
13 to <16
16 to <21
21 to <26
26 to <31
<0.08
<1
12,50
12,50
12,50
18,75
0,08
1
12,50
12,50
18,75
18,75
0,17
2
12,50
18,75
18,75
25,00
0,25
3
12,50
18,75
25,00
25,00
31,25
0,33
4
18,75
18,75
25,00
31,25
37,50
0,42
5
18,75
25,00
31,25
37,50
43,75
0,50
6
25,00
31,25
43,75
43,75
0,58
7
25,00
31,25
43,75
50,00
0,67
8
31,25
37,50
43,75
50,00
62,50
0,75
9
31,25
37,50
43,75
56,25
62,50
0,83
10
37,50
50,00
56,25
62,50
75,00
0,92
11
43,75
50,00
56,25
68,75
75,00
12,50
2 mL
31,25
5 mL
50,00
8 mL
68,75
11 mL
18,75
3 mL
37,50
6 mL
56,25
9 mL
75,00
12 mL
25,00
4 mL
43,75
7 mL
62,50
10 mL
Initial Dose
Single Dose [mg]
Age 
[completed 
years]
Age 
[completed 
months]
Weight [kg]
Figure 10.4.1: 3
Age and weight adjusted starting doses using OLF


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10.4.2 Dose Adjustment nomogram
10.4.2.1 Up-titration
In case patients have trough concentrations below 50 ng/mL, the dose may be increased by 15 
to 100% as outlined in the following nomograms:

dabigatran etexilate capsules - 50, 75, 110 and 150 mg
9 to <11
11 to <13
13 to <16
16 to <21
21 to <26
26 to <31
31 to <41
41 to <51
51 to <61
61 to <71
71 to <81
81 to <91
≥ 91
8
96
125
150
220
260
300
330
330
330
330
9
108
125
150
220
260
300
330
330
330
330
10
120
125
150
220
260
300
330
330
330
330
11
132
150
220
260
300
330
330
330
330
12
144
150
220
260
300
330
330
330
330
13
156
150
220
260
300
330
330
330
330
14
168
220
260
300
330
330
330
330
15
180
220
260
300
330
330
330
330
16
192
260
300
330
330
330
330
17
204
260
300
330
330
330
330
Doses > 330 mg BID capped to 330 mg BID
125
50mg + 75mg capsules
260
110+150mg or 110+2x75mg capsules
discontinue due to 330mg BID capping
150
150mg or 2x75mg capsules
300
2x150mg or 4x75mg capsules
220
2x110mg capsules
330
3x110mg capsules
discontinue due to dabigatran etexilate limit of 22.2 mg/kg/day, 
based on excipient acceptable daily intake limit
Weight [kg]
Up-titration
Single Dose [mg]
Age 
[completed 
years]
Age 
[completed 
months]
Figure 10.4.2.1: 1 
Up-titration doses using capsules

dabigatran etexilate pellets
Weight [kg]
2.5 to < 3 3 to < 4
4 to < 5
5 to < 7
7 to < 9
9 to < 11
11 to < 13 13 to < 16 16 to < 21 21 to < 26 26 to < 31 31 to < 41 41 to < 51 51 to < 61 61 to < 71 71 to < 81 81 to < 91
>= 91
<0.08
<1
40
0,08
1
40
40
0,17
2
40
40
0,25
3
30
40
50
60
0,33
4
30
40
50
70
0,42
5
30
40
50
70
80
0,50
6
40
50
70
90
0,58
7
40
50
70
90
0,67
8
40
50
70
90
110
0,75
9
40
50
70
90
110
0,83
10
50
70
90
110
140
0,92
11
50
70
90
110
140
1
12
50
70
90
110
140
160
1,5
18
70
90
110
140
160
220
2
24
70
90
110
140
160
220
2,5
30
70
90
110
140
160
220
260
300
3
36
70
90
110
140
160
220
260
300
4
48
90
110
140
160
220
260
300
330
5
60
90
110
140
160
220
260
300
330
330
6
72
90
110
140
160
220
260
300
330
330
330
7
84
110
140
160
220
260
300
330
330
330
330
8
96
110
140
160
220
260
300
330
330
330
330
9
108
140
160
220
260
300
330
330
330
330
10
120
140
160
220
260
300
330
330
330
330
11
132
160
220
260
300
330
330
330
330
Doses > 330 mg BID capped to 330 mg BID
30
30 mg stick pack
80
2x 40 mg stick packs
40
40 mg stick pack
90
40+50 mg stick packs
220
2x 110 mg stick packs
discontinue due to 330 mg BID capping
50
50 mg stick pack
110
110 mg stick pack
260
110 + 150 mg stick pack
discontinue due to dabigatran etexilate
60
2x 30 mg stick packs
140
30+110 mg stick packs
300
150 + 150 mg stick pack
limit of 22.2 mg/kg/day, based on
70
30+40 mg stick packs
160
110 +50 mg stick pack
330
3 x 110 mg stick pack
excipient acceptable daily intake limit.
Up-titration
Single Dose [mg]
Age
[completed
 years]
Age
[completed
 months]
Figure 10.4.2.1: 2 
Up-titration doses using pellets


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
dabigatran etexilate OLF - 6.25 mg per mL
2.5 <3
3 to <4
4 to <5
5 to <7
7 to <9
9 to <11
11 to <13
13 to <16
16 to <21
21 to <26
26 to <31
<0.08
<1
25,00
25,00
25,00
37,50
0,08
1
25,00
25,00
37,50
37,50
0,17
2
25,00
31,25
37,50
50,00
0,25
3
25,00
31,25
43,75
50,00
62,50
0,33
4
25,00
31,25
43,75
50,00
75,00
0,42
5
31,25
43,75
50,00
75,00
87,50
0,50
6
43,75
50,00
75,00
87,50
0,58
7
43,75
50,00
75,00
93,75
0,67
8
43,75
50,00
75,00
93,75
118,75
0,75
9
43,75
50,00
75,00
93,75
118,75
0,83
10
50,00
75,00
93,75
118,75
143,75
0,92
11
50,00
75,00
93,75
118,75
143,75
25,00
4 mL
43,75
7 mL
75,00
12 mL
118,75
19 mL
31,25
5 mL
50,00
8 mL
87,50
14 mL
143,75
23 mL
37,50
6 mL
62,50
10 mL
93,75
15 mL
Up-titration
Single Dose [mg]
Age 
[completed 
years]
Age 
[completed 
months]
Weight [kg]
Figure 10.4.2.1: 3
Up-titration doses using OLF
10.4.2.2 Down-titration
Whenever a trough concentration is greater than or equal to 250 ng/mL, the dose may be 
reduced by 40 to 50% as outlined in the following nomograms:

dabigatran etexilate capsules - 50, 75, 110 and 150 mg
9 to <11
11 to <13
13 to <16
16 to <21
21 to <26
26 to <31
31 to <41
41 to <51
51 to <61
61 to <71
71 to <81
81 to <91
≥ 91
8
96
50
50
75
75
75
110
110
150
150
150
9
108
50
75
75
75
110
110
150
150
150
10
120
50
75
75
75
110
110
150
150
150
185
185
11
132
75
75
75
110
110
150
150
150
185
185
12
144
75
75
75
110
110
150
150
150
185
185
13
156
75
75
75
110
110
150
150
150
185
185
14
168
75
75
110
110
150
150
150
185
185
15
180
75
75
110
110
150
150
150
185
185
16
192
75
110
110
150
150
150
185
185
17
204
75
110
110
150
150
150
185
185
Doses > 330 mg BID capped to 330 mg BID
50
50mg capsules
110
110mg capsules
185
75mg + 110mg capsules
75
75mg capsules
150
150mg or 2x75mg capsules
Down-titration
Single Dose [mg]
Age 
[completed 
years]
Age 
[completed 
months]
Weight [kg]
Figure 10.4.2.2: 1 
Down-titration doses using capsules


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
dabigatran etexilate pellets
Weight [kg]
2.5 to < 3 3 to < 4
4 to < 5
5 to < 7
7 to < 9
9 to < 11
11 to < 13 13 to < 16 16 to < 21 21 to < 26 26 to < 31 31 to < 41 41 to < 51 51 to < 61 61 to < 71 71 to < 81 81 to < 91
>= 91
<0.08
<1
0,08
1
0,17
2
0,25
3
20
20
0,33
4
20
20
0,42
5
20
20
20
0,50
6
20
20
20
30
0,58
7
20
20
20
30
0,67
8
20
20
20
30
30
0,75
9
20
20
30
30
30
0,83
10
20
30
30
40
40
0,92
11
20
30
30
40
40
1
12
20
30
30
40
40
50
1,5
18
30
30
40
40
50
50
50
2
24
30
40
40
50
50
80
2,5
30
30
40
50
50
60
80
80
80
3
36
30
40
50
50
60
80
80
80
4
48
40
50
50
60
80
80
80
110
5
60
40
50
50
60
80
80
80
110
150
6
72
40
50
50
60
80
80
80
110
150
150
7
84
50
50
60
80
80
80
110
150
150
150
8
96
50
50
60
80
80
80
110
150
150
150
9
108
50
60
80
80
80
110
150
150
150
10
120
50
60
80
80
80
110
150
150
150
170
170
11
132
60
80
80
80
110
150
150
150
170
170
Doses > 330 mg BID capped to 330 mg BID
20
20 mg stick pack
50
50 mg stick pack
110
110 mg stick pack
30
30 mg stick pack
60
2x 30 mg stick packs
150
150 mg stick pack
40
40 mg stick pack
80
2x 40 mg stick packs
170
110 + 2x30 mg stick packs
Down-titration
Single Dose [mg]
Age
[completed
 years]
Age
[completed
 months]
Figure 10.4.2.2: 2
Down-titration doses using pellets

dabigatran etexilate OLF - 6.25 mg per mL
2.5 <3
3 to <4
4 to <5
5 to <7
7 to <9
9 to <11
11 to <13
13 to <16
16 to <21
21 to <26
26 to <31
<0.08
<1
6,25
6,25
6,25
12,50
0,08
1
6,25
6,25
12,50
12,50
0,17
2
6,25
12,50
12,50
12,50
0,25
3
6,25
12,50
12,50
12,50
18,75
0,33
4
12,50
12,50
12,50
18,75
18,75
0,42
5
12,50
12,50
18,75
18,75
25,00
0,50
6
12,50
18,75
25,00
25,00
0,58
7
12,50
18,75
25,00
25,00
0,67
8
18,75
18,75
25,00
25,00
31,25
0,75
9
18,75
18,75
25,00
31,25
31,25
0,83
10
18,75
25,00
31,25
31,25
37,50
0,92
11
25,00
25,00
31,25
37,50
37,50
6,25
1 mL
18,75
3 mL
31,25
5 mL
12,50
2 mL
25,00
4 mL
37,50
6 mL
Down-titration
Single Dose [mg]
Age 
[completed 
years]
Age 
[completed 
months]
Weight [kg]
Figure 10.4.2.2: 3 
Down-titration doses using OLF


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
01
Date of CTP revision
02 Oct 2014
EudraCT number
2014-000583-18
BI Trial number
1160.108
BI Investigational Product(s)
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open label, single arm safety prospective cohort 
study of dabigatran etexilate for secondary 
prevention of venous thromboembolism in 
children from 0 to less than 18 years
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
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
2.3 BENEFIT - RISK ASSESSMENT
Description of change
Detailed information about the dosing regimen 
was provided, as well as the current status of 
1160.106 study.
Decision to temporarily suspend the recruitment 
of patients with a body weight greater than 40kg.
Announcement of the upcoming TID dosing 
regimen.
Rationale for change
To provide background for the decision to 
temporarily suspend the recruitment of patients 
with a body weight greater than 40kg until TID 
dosing regimen is implemented


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Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criterion 1 was modified as follows:
Male or female subjects  0 to less than 18 years of age at the 
time of informed consent / assent and body weight ≤ 40kg
Rationale for change
To temporarily suspend the recruitment of 
patients with a body weight greater than 40kg 
until TID dosing regimen is implemented


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Number of global amendment
02
Date of CTP revision
28 Jan 2015
EudraCT number
2014-000583-18
BI Trial number
1160.108
BI Investigational Product(s)
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open label, single arm safety prospective cohort 
study of dabigatran etexilate for secondary 
prevention of venous thromboembolism in 
children from 0 to less than 18 years
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
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
2.3 BENEFIT - RISK ASSESSMENT and 
4.1.3 Selection of doses in the trial
Description of change
Rationale for dosing regimen has been provided
Rationale for change
Justification of dose regimen
Section to be changed
All relevant sections of the CTP have been 
updated to implement BID regimen using actual 
calculated dosages (according to Hayton) rather 
than capped dosages
Description of change
The maximal single dose was defined to be 330 
mg. It was clarified that the maximal daily dose 
level will neither exceed a daily dose level of 22.2 
mg/kg nor a single dose of 330 mg. In the higher 


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age / body weight group this results in a maximal 
daily dose of 660 mg.
Only one up-titration will be acceptable. The dose 
may be increased by 15-100% depending on the 
age and weight of the patient.
Patients who cannot reach the target trough 
plasma concentrations after one dose adjustment
must discontinue dabigatran treatment and be 
treated at the investigator’s discretion on SOC. 
The extent of up-titration has been modified from 
initially 85-100% to now 15-100% in order to not 
exceed maximum daily dosages based on 
acceptable toxicology limits.
Dosing and dose adjustment nomograms were 
incorporated as Appendix 10.4
Rationale for change
The bleeding risk in the paediatric patient 
population is considered to be lower than that in 
adult populations (e.g. in the adult SPAF and 
VTE indications). Based on an overall benefit-risk 
assessment including the fact that the risk of 
thrombotic events is highest in the first 30 days, 
the predicted exposure in an uncapped BID 
regimen (up to a dose of 330 mg BID) is 
considered favourable
Section to be changed
All relevant sections of the CTP
Description of change
The dabigatran etexilate formulations assignment 
was clarified as follows:
Patients aged ≥ 8 years: Age and weight adjusted 
dabigatran etexilate capsules using 50 mg, 75 mg 
and 110 mg doses.
Patients aged 6 months to < 8 years or for patients 
who cannot take capsules even if older than 8 (but 
below 12 years of age): Age and weight adjusted 
dabigatran etexilate pellets.
Patients aged 0 to < 6 months or for patients who 
cannot take pellets at an age of 6 to 12 months: 
Age and weight adjusted dabigatran etexilate oral 
liquid formulation
Rationale for change
Clarification on the use of age-appropriate 
formulations


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Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
More detailed and current information about the 
status of the phase IIa studies 1160.89 and 
11.60.145 has been provided
Rationale for change
To update the status of the phase IIa studies as 
they are prerequisite for opening the second age 
group (2 to <12 years)
Section to be changed
3.1.1.1 Data Monitoring Committee
Description of change
The following text was added:
The DMC may implement a partial release of the 
youngest age group (0 to <2 years of age) 
depending on the availability of PK/PD data from 
respective age groups studied in the phase IIa 
studies.
Rationale for change
To allow partial release of the youngest age 
group (0 to <2 years of age) depending on 
completion of phase IIa studies and DMC 
decision
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criterion 1 was modified as follows:
Male or female subjects  0 to less than 18 years of age at the 
time of informed consent / assent and body weight ≤ 40kg
Rationale for change
To terminate the temporarily suspension of  
recruitment of patients with a body weight greater 
than 40kg
Section to be changed
3.3.2 Inclusion criteria
Description of change
The following was added to Inclusion criterion 2:
In case of the initial VKA treatment the intended INR 
should be between 2 and 3.
Patients, who during the treatment phase of 1160.106 trial 
were switched from dabigatran etexilate to SOC arm for any 
reason, are not eligible for this study.
Rationale for change
Clarification


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Section to be changed
3.3.3 Exclusion criteria
Description of change
Additional exclusion criterion was introduced:
7)
Patients in age group 0 to < 2 years with 
gestational age at birth < 37 weeks or with body 
weight lower than the 3rd percentile (according 
to the WHO Child growth standards)
Rationale for change
To exclude very vulnerable population
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criterion 5.b. was modified as follows:
Persistent alanine aminotransferase (ALT) or 
aspartate transaminase (AST) or alkaline 
phosphatase (AP) > 3 × upper limit of normal 
(ULN) within 3 months of screening
Rationale for change
Less restrictive exclusion criterion was 
considered based on vast post-marketing 
experience with no signs of hepatotoxicity so far 
and in order to make criterion consistent across 
dabigatran etexilate paediatric trials
Section to be changed
5.7.2 Methods of sample collection (PD)
Description of change
It was specified that the date and the exact clock 
time of dabigatran administration on the three 
days before the 
/PD samples are taken is to be 
recorded in the eCRF
Rationale for change
To ensure precise assessment of the 
-pharmacodynamic relationship
Section to be changed
Flow Chart footnote 10 and
Appendix 10.1.1 Blood volume charts
Description of change
The blood volume table was removed from the 
Flow Chart and more detailed, age specific charts 
were provided in Appendix 10.1.1


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Rationale for change
To provide detailed and age specific description 
of the blood sample volumes collected during the 
trial
Section to be changed
Flow Chart footnote 3,
3.3.4 Removal of patients from therapy or 
assessments and
Description of change
HPLC-MS/MS assay could be used to assess the 
need of dabigatran etexilate dose adjustment
Rationale for change
To provide alternative to dTT (if needed)
Section to be changed
All relevant sections of the CTP
Description of change
The target dabigatran steady state trough 
concentration was precisely defined to be ≥50 to 
<250 ng/mL
Rationale for change
Clarification
Section to be changed
4.2.2 Restrictions
Description of change
The following exception was clarified: use of a 
specific reversal agent to counteract the 
antithrombotic activity of dabigatran etexilate is 
allowed if available in a framework of clinical 
investigation
Rationale for change
To allow use of a specific reversal agent in case 
available in a framework of clinical investigation


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Number of global amendment
03
Date of CTP revision
27 Nov 2015
EudraCT number
2014-000583-18
BI Trial number
1160.108
BI Investigational Product(s)
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open label, single arm safety prospective cohort 
study of dabigatran etexilate for secondary 
prevention of venous thromboembolism in 
children from 0 to less than 18 years
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
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
10.4.2 Dose Adjustment nomogram
10.4.2.1 Up-titration 
Description of change
Up-titration dosing nomograms for capsules and 
pellets have been updated 
Rationale for change
To correct calculation errors identified to ensure 
the acceptable daily intake of tartaric acid for 
patients with body weight up to 31kg who would 
need up-titration would not be exceeded
Section to be changed
10.4.1 Dosing nomogram (starting doses)
10.4.2 Dose Adjustment nomogram
Description of change
Dosing nomograms for dabigatran etexilate OLF 
have been temporarily removed from the protocol


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Rationale for change
The dosing nomograms for dabigatran etexilate 
OLF need to be revised in light of the errors 
identified for the capsule and pellet nomograms. 
These will be updated to reflect  the acceptable 
daily intake of tartaric acid and will be re-
introduced into the protocol, by a subsequent 
protocol amendment, in advance of opening the 
youngest age group (0 to <2 years.)


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Number of global amendment
04
Date of CTP revision
16 Mar 2016
EudraCT number
2014-000583-18
BI Trial number
1160.108
BI Investigational Product(s)
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open label, single arm safety prospective cohort 
study of dabigatran etexilate for secondary 
prevention of venous thromboembolism in 
children from 0 to less than 18 years
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
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
All relevant sections of the CTP
Description of change
Flavoured and unflavoured solvent will be used 
for reconstitution of OLF
Patients assigned to OLF will be randomized 
based on 1:1 ratio to receive flavoured or 
unflavoured solvent for reconstitution 
Assessment of acceptability of all age-appropriate 
formulations, including OLF reconstituted with 
flavoured or unflavoured solvent, at days 4(V3)
(for patients starting DE for the first time), 
22(V4), 85(V6), 183(V8) and 365 (V11)(or eEOT, 
whichever comes first) was introduced as other 
safety assessment


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Rationale for change
To assess acceptability of all age-appropriate 
formulations (capsules, pellets, OLF). To evaluate 
the acceptability of flavoured and unflavoured 
solvent types in a comparable number of patients. 
Section to be changed
1.2 DRUG PROFILE
Description of change
Summary of phase I bioavailability study 
1160.194 was provided
Rationale for change
To provide background for considering 
dabigatran etexilate formulations to be used 
interchangeable (no need for conversion factor).
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
More detailed and current information about the 
status of the phase IIa study 1160.89 has been 
provided
Rationale for change
To update the status of the phase IIa study
Section to be changed
All relevant sections of the CTP
Description of change
It was clarified that a specific reversal agent for 
dabigatran is not yet available in children
Rationale for change
The specific reversal agent for dabigatran was 
recently approved for adults but is not approved 
for children.
Section to be changed
3.3.2 Inclusion criteria
Description of change
A temporary interruption of the anticoagulant 
therapy for the index VTE event will be
acceptable
Rationale for change
To allow including of patients who had medically 
justifiable interruptions of the anticoagulant 
therapy for the index VTE event or after treatment 
of index VTE and prior to inclusion into this trial
if certain pre-requisites are fulfilled and 
documented.


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Section to be changed
3.3.3 Exclusion criteria
Description of change
Insertion of a central venous line is not 
considered a major surgery provided haemostasis 
is achieved after the procedure
Rationale for change
Clarification that central venous line insertion is 
not considered a major surgery
Section to be changed
3.3.3 Exclusion criteria
Description of change
It was clarified that patients with history of 
asymptomatic petechial or microbleeds are 
eligible for the study. Definition of microbleeds 
was provided in a footnote.
Rationale for change
Asymptomatic petechial or microbleeds are 
incidental findings that are not considered to 
increase the risk of bleeding. Therefore, they do 
not constitute an exclusion criterion. It was 
clarified in the footnote how microbleeds are 
defined in order to distinguish them from 
macrobleeds, which represent an exclusion 
criterion for this trial.
Section to be changed
3.3.3 Exclusion criteria
3.3.4 Removal of patients from therapy or 
assessments
Description of change
eGFR retesting during the screening period was
allowed
Patients will have to discontinue dabigatran 
treatment anytime during the course of the study 
if eGFR drops < 50 mL/min/1.73m2 using the 
Schwartz formula and this is confirmed by one 
retesting within the next 14 calendar days
Rationale for change
This safeguard regarding renal function during 
the trial is considered overly conservative. It led 
to an unnecessary stop of dabigatran etexilate 
treatment in of some initial patients in this trial, 
where eGFR was measured to be just below 80 
mL/min/1.73m2. Beyond renal function, this trial 
will use PK measurements of dabigatran and a 
target plasma level range as safeguard. In 


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addition, only patients with good renal function 
(eGFR of >80 mL/min/1.73m2 are allowed to 
enter this trial. Thus, it is considered safe to 
lower the removal criterion of eGFR during the 
trial to 50 mL/min/1.73m2.
Section to be changed
3.3.3 Exclusion criteria
4.2.2 Restrictions
Description of change
P-glycoprotein inhibitors intake up until first dose 
of study medication will not be restricted or 
considered as exclusion criterion
Rationale for change
The interaction of P-gp inhibitors and dabigatran 
occurs on the gut level during the absorption of 
dabigatran. Peak plasma levels of dabigatran are 
reached within a few hours after intake of 
dabigatran. Therefore, the initially proposed 
washout period of one week is considered not 
necessary for P-gp inhibitors. As an additional 
safeguard, plasma level measurements of 
dabigatran will be performed
Section to be changed
4.1 Treatments to be administered
10.4 Dosing of Dabigatran etexilate
Description of change
150 mg capsule was introduced
Rationale for change
150 mg dabigatran etexilate capsule was 
introduced to the trial in order to reduce the 
number of capsules taken by patient at a single 
time point
Section to be changed
4.1.3 Selection of doses in the trial
Description of change
Table 4.1.3: 1 Target dabigatran etexilate doses 
(in mg) based on Hayton calculations for 
paediatric patients was updated
Rationale for change
To display the derived dabigatran etexilate target 
doses based on Hayton calculations for newborns 
aged < 1 month and with body weight < 3 kg


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Section to be changed
4.1.3 Selection of doses in the trial
Description of change
Dose adjustment step ranges for up- and down-
titration were corrected to reflect the respective 
dosing nomograms 
Rationale for change
Correction
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
4.2.2.2 Restrictions on diet and life style
Description of change
If gastrointestinal symptoms develop it is 
recommended to take dabigatran etexilate with a 
meal and/or a proton pump inhibitor such as 
pantoprazole.
Rationale for change
To provide guidance to the Investigator in 
analogy to recommendations for adults.
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatment
Description of change
Cross reporting of lab results might be applied in 
case a patient receives specific reversal agent of 
dabigatran in frame of clinical study
Rationale for change
To limit the blood volume required for analysis
and to make most effective use of blood drawn
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatment
Description of change
Treatment with dabigatran etexilate after the 
surgery can be re-started any time as soon as 
haemostasis has been achieved
Rationale for change
To provide guidance to the Investigator in 
analogy to recommendations for adults.


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Section to be changed
5.2.3 Assessment of safety laboratory parameters
10.1 Safety and other clinical laboratory 
evaluations
Description of change
Local safety lab assessment will be acceptable in 
emergency cases only (e.g. bleeding event or 
emergency surgery)
Rationale for change
To ensure timely safety lab assessment in 
emergency cases
Section to be changed
10.1
Safety and other clinical laboratory 
evaluations
Description of change
eGFR Schwarz formula has been precisely 
defined
Rationale for change
Clarification
Section to be changed
10.4.1 Dosing nomogram (starting doses)
10.4.2 Dose Adjustment nomogram
Description of change
Dosing nomograms for dabigatran etexilate OLF 
have been restored into the protocol
Rationale for change
Calculation errors have been corrected to ensure 
the acceptable daily intake of tartaric acid for 
patients with body weight up to 31kg who would 
need up-titration would not be exceeded
Section to be changed
10.4.1 Dosing nomogram (starting doses)
10.4.2 Dose Adjustment nomogram
Description of change
Dosing nomograms for dabigatran etexilate 
capsules and pellets have been re-formatted
Rationale for change
To clearly display the age and weight ranges.
There are no changes to the doses. This change is 
for clarification only.


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Number of global amendment
05
Date of CTP revision
30 Nov 2016
EudraCT number
2014-000583-18
BI Trial number
1160.108
BI Investigational Product(s)
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open label, single arm safety prospective cohort 
study of dabigatran etexilate for secondary 
prevention of venous thromboembolism in 
children from 0 to less than 18 years
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
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
7.6 DETERMINATION OF SAMPLE SIZE
Description of change
It was clarified that Sponsor may decide to keep 
recruitment open after 100 patients have been 
recruited, in case additional safety data needs to 
be generated.
Rationale for change
To allow inclusion of additional patients in case 
further scientific data is required
Section to be changed
1.2 DRUG PROFILE
2.3 BENEFIT - RISK ASSESSMENT
Description of change
Summary of phase IIa studies 1160.89 and 
1160.105 was provided.


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Rationale for change
To provide the final results of the completed
phase IIa PK/PD studies relevant for the patients 
to be included in second age group (2 to<12 
years) and in youngest age group (0 to <2 years)
Section to be changed
3.3
SELECTION OF TRIAL POPULATION
Description of change
It was clarified that patients in in age group 2 yrs. 
to <12 yrs. will be included and treated in 
accordance to the availability of the age 
appropriate dabigatran etexilate formulations
Rationale for change
To reflect the sequential introduction of 
dabigatran age appropriate formulations and 
OLF in particular
Section to be changed
3.3.3
Exclusion criteria
Description of change
eGFR level for exclusion criterion 2) relative to 
patients aged 12 to < 18 years was set at < 60 
mL/min/1.73m2. 
For patients aged 0 to < 12 years the eGFR level 
for exclusion remains < 80 mL/min/1.73m2
Rationale for change
An interim analysis of 27 patients treated with 
dabigatran etexilate in the 1160.106 and 
1160.108 has shown a good safety and 
tolerability profile in adolescent patients aged 12 
to <18 years. Also, the currently used dosing 
algorithm with uncapped starting dose resulted 
into approximately 95% of PK trough plasma 
concentrations within the dabigatran target 
plasma range (50 to <250 ng/ml). After one dose 
adjustment more than 98% or measurement were 
within the target range. No measurement was 
above the target range. The previous exclusion 
criterion of eGFR <80 mL/min/1.73m2 seems to 
be too restrictive in patients 12 to <18 years; 
therefore, a cut-off of 60 mL/min/1.73m2 is 
considered acceptable for this age group and will 
allow inclusion of more patients who could 
benefit from the participation of the study.


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Section to be changed
3.3.3
Exclusion criteria
Description of change
Exclusion criterion 4) was modified to clarify that 
patients with be excluded if they have heart valve 
prosthesis requiring anticoagulation treatment.
Rationale for change
To comply with dabigatran etexilate IB, allowing 
patients with heart valve prosthesis not requiring 
anticoagulation treatment to be included in the 
study if they would benefit from their
participation.
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
The recommendation to use “a proton pump 
inhibitor such as pantoprazole” in case of 
development of gastrointestinal symptoms was 
replaced by recommendation to use a proton 
pump inhibitor according to “the local standard 
of care in accordance with local labelling 
recommendations”.
Rationale for change
The locally approved labelling information, e.g. 
the Prescribing Information or Product 
Information of different proton pump inhibitors 
(PPIs) may vary between products and countries. 
Importantly, certain PPIs may only be approved 
for certain age groups according to local 
labelling information.
The wording has been adapted accordingly.
 
 
 
 
 


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Section to be changed
7.3.2
Secondary analyses 
Description of change
It was clarified that all cases of death will be 
considered as non-event for occurrence of PTS 
and therefore censored 
Rationale for change
Clarification. PTS itself could not be a direct 
cause of death
 
 
 
 
 
 
 
 
Section to be changed
10.4
Dosing of Dabigatran Etexilate
Description of change
Dosing nomograms for Dabigatran Etexilate 
pellets have been updated to remove 60 mg and 
70 mg strengths
Rationale for change
Dabigatran Etexilate pellets 60 mg and 70 mg 
strengths will not be used in this trial


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Number of global amendment
06
Date of CTP revision
19 Jan 2018
EudraCT number
2014-000583-18
BI Trial number
1160.108
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open label, single arm safety prospective cohort 
study of dabigatran etexilate for secondary 
prevention of venous thromboembolism in 
children from 0 to less than 18 years
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
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
3.3.3
Exclusion criteria
Description of change
Exclusion criterion 1 a) was modified adding: 
Active meningitis, encephalitis, or intracranial 
abscess at Visit 2.
Rationale for change
On 13 January 2018, the DMC recommended to 
exclude patients with active meningitis, 
encephalitis, or intracranial abscess from the 
study because of an increased risk of intracranial 
bleeding with these conditions.
Section to be changed
3.3.4       Removal of patients from therapy or 
assessments
3.3.4.1    Removal of individual patients
Description of change
Additional criterion to discontinue a patient from 
the trial was added: If a patient develops an 
active meningitis, encephalitis, or intracranial 
abscess.


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Rationale for change
On 13 January 2018, the DMC recommended to 
exclude patients with active meningitis, 
encephalitis, or intracranial abscess from the 
study because of an increased risk of intracranial 
bleeding with these conditions.
Also, patients who develop any of these conditions 
during the trial are to be discontinued from trial 
treatment due to the increased risk of bleeding. 


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Number of global amendment
07
Date of CTP revision
10 Sep 2018
EudraCT number
2014-000583-18
BI Trial number
1160.108
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open label, single arm safety prospective cohort 
study of dabigatran etexilate for secondary 
prevention of venous thromboembolism in 
children from 0 to less than 18 years
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
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
CTP Synopsis
Section 4.1.3 Selection of the doses in the trial
Section 4.1.4 Drug assignment and administration 
of the doses for each patient
Section 10.4 Dosing of Dabigatran etexilate
Section 10.4.1 Dosing nomogram (starting doses)
Section 10.4.2 Dose Adjustment nomogram
Description of change
The option to administer pellets was expanded to 
patients < 6 months of age. A preference for 
usage of OLF over pellets in patients <12 months 
of age was implemented, provided that OLF 
supplies are available to the site.
Rationale for change
To allow pellet treatment of patients < 6 months 
of age. To facilitate both, recruitment of patients 
below 6 months of age and collection of 
information on OLF treatment respectively.


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Section to be changed
Flow Chart
Description of change
The time window from visit 1 (screening) to visit 2 
(start of study medication) was expanded to 14 
days. 
Rationale for change
To facilitate screening procedures.
Section to be changed
Flow Chart
Section 3.3.4.1 Removal of individual patients
Description of change
The preferred way of follow-up of patients who 
have discontinued study medication prematurely 
(eEOT, Follow-up Visit 12 after 28 days, further 
follow-up according remaining visit schedule) 
was implemented consistently throughout the 
protocol.
Rationale for change
To clarify the preferred way of follow-up of 
patients who have discontinued study medication
prematurely.
Section to be changed
Flow Chart, Footnotes 9 and 10
Section 3.1.1.3 Central laboratory
Section 5.2.3 Assessment of safety laboratory 
parameters
Description of change
The exceptions from the generally central 
laboratory assessments were implemented 
consistently throughout the protocol.
Rationale for change
To align the wording related to exceptions from 
central laboratory assessments between relevant 
protocol sections.
Section to be changed
Section 3.3.4.1 Removal of individual patients
Description of change
A Patient is to be discontinued from study 
medication if he experiences a drug-related 
significant or serious AE. This was changed to “a 
drug-related significant or drug- related serious 
AE”.
Rationale for change
To clarify that the discontinuation from study 
medication is required in case of drug-related 
serious AEs, but not required in case of serious 
AEs that are not drug-related.


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Section to be changed
Section 4.1.3 Selection of doses in the trial
Description of change
It was added that the steady state of the currently 
assigned dabigatran etexilate formulation (i.e. at 
least 6 consecutive dabigatran etexilate doses 
have been taken) has to be achieved before a
formulation switch could be considered.
It was added that dabigatran etexilate up- or 
down-titration is not possible in some instances 
(limit of 22.2 mg/kg/day based on excipient 
acceptable daily intake, maximal single dose of 
330 mg, unavailability of dosages) and affected 
patients have to be discontinued from dabigatran 
etexilate prematurely.
Rationale for change
To clarify the prerequisites for a potential 
dabigatran etexilate formulation switch.
To clarify how to handle patients in case that up-
or down-titration is not possible due to certain 
circumstances.
Section to be changed
Section 4.1.4 Drug assignment and administration 
of doses for each patient
Description of change
Banana mush, strawberry jam and apple juice 
were added to the list of foods that are allowed to 
be mixed with dabigatran etexilate pellets.
It was added that if a dabigatran etexilate dose 
has only been taken partially, there should be no 
attempt to administer a second dose at that time-
point, and the next dose should be taken as 
scheduled approximately 12 hours later.
Rationale for change
To reflect the latest list of foods that are allowed 
to be mixed with dabigatran etexilate pellets.
To give guidance how to proceed in case a 
dabigatran etexilate dose has been taken only 
partially.
Section to be changed
Section 4.2.1 Rescue medication, emergency 
procedures, and additional treatment(s)
Description of change
The option to re-start dabigatran etexilate after a 
major bleeding event has occurred was deleted.


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Rationale for change
To align with Section 3.3.4.1 Removal of 
individual patients which states that patients have
to be discontinued from study medication
prematurely if they experience a drug-related 
serious AE.
Section to be changed
Section 4.3 Treatment Compliance
Description of change
It was added that subjects or, if applicable,
parents or legal guardians, will be asked to 
carefully complete a daily medication intake log 
for dabigatran and are requested to bring this 
completed log to every clinic visit.
It was added that the compliance calculation
should preferably be based on the returned 
medication however completed logs may also be 
used.
It was added that if an interruption of dabigatran 
etexilate was medically required this would be 
considered in the compliance calculation by 
reducing the number of expected doses that 
“should have been taken” accordingly.
Rationale for change
To reflect the process related to the medication 
intake log implemented in the trial.
To clarify how to calculate the compliance in case 
of dabigatran etexliate interruptions.
Section to be changed
CTP Synopsis
Section 5.2.1 Endpoint(s) of safety
Section 5.7.1 Pharmacodynamic endpoints
Section 5.7.2 Methods of sample collection
Section 7.3.2 Secondary analyses
Appendix 10.1 Safety and other Clinical 
Laboratory Evaluations
Description of change
The term dTT was supplemented with its synonym 
Anti-Factor IIa activity in connection with the 
secondary endpoint of “Pharmacodynamic 
assessments”.
For the secondary endpoint “Pharmacodynamic 
assessments” evaluations at Visit 3 (after at least
six consecutive dabigatran etexilate doses) and 
after at least 3 days following any dabigatran
etexilate dose adjustment will be considered. The 
reference to Visit 4 was deleted.


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Rationale for change
To clarify and distinguish between dTT (Anti-
Factor IIa activity) and dTT utilized for the 
evaluation of dabigatran etexilate plasma 
concentrations.
To correct the secondary endpoint 
“Pharmacodynamic assessments”.
Section to be changed
Section 5.7.2 Methods of sample collection
Description of change
It was added that if Aliquot 1 is not required for 
dabigatran concentration measurements guiding 
dose adjustment, Aliquot 1 may be sent to the 
central laboratory 
, 
Germany for analysis of pharmacodynamics and 
pharmacokinetics based on dTT (Anti-Factor IIa 
activity), aPTT and/or ECT.
Rationale for change
To clarify the handling of the pharmacodynamic 
sample Aliquot 1 in case it is not required for
dabigatran concentration measurements guiding 
dose adjustment.
Section to be changed
CTP Synopsis
Section 5.2.1 Endpoint(s) of safety
Section 7.3.2 Secondary analyses
Description of change
The secondary endpoint of “Number of
dabigatran etexilate dose adjustments during 
treatment period” was supplemented with the 
explanation “i.e. Number of patients with 
dabigatran dose adjustments during treatment 
period”.
 
Rationale for change
To clarify the meaning of the secondary endpoint 
of “Number of dabigatran etexilate dose 
adjustments during treatment period”.
 
 


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Section to be changed
Section 7.3 Planned Analyses
Description of change
The wording that the primary analysis will be 
conducted after all patients completed the 12-
months evaluation or otherwise dropped out from 
the study was deleted. 
Rationale for change
To introduce flexibility in order to adapt for 
different regulatory requirements.
 
 
 
Section to be changed
Section 8. Informed Consent, Data Protection, 
Trial records 
Description of change
The requirement not to publish any trial data 
prior finalisation of the Clinical Trial Report was 
deleted. 
Rationale for change
To clarify the current publishing process.
Section to be changed
Flow Chart, Footnote 6
Section 8.1 Study approval, Patient Information, 
and Informed Consent 
Description of change
It was added that in case patients reach legal age 
during the trial they must personally sign and 
date the informed consent form as soon as 
possible and, at the latest, at the next visit.
Rationale for change
To clarify the consenting process in patients 
reaching legal age in the course of the trial.
Section to be changed
Section 8.3.1 Source documents
Description of change
It was added that copies of source documents 
necessary for adjudication will be provided to the 
adjudication committee. Before sending or 
uploading those copies, 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 from any copy of the patients´ source 
documents. 


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Rationale for change
To clarify source data handling in the course of 
the adjudication process.
Section to be changed
Section 10.4 Dosing of Dabigatran Etexliate
Description of change
The reference to the dosing nomogram and 
titration guide document located the ISF for 
nomogram clarifications and dose calculation 
examples was deleted.
Rationale for change
To clarify that the process of dose calculation by 
the investigator is not applicable any longer. 
Required dabigatran etexilate dose is calculated 
by the IRT System only. 


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Number of global amendment
08
Date of CTP revision
07 Feb 2019
EudraCT number
2014-000583-18
BI Trial number
1160.108
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open label, single arm safety prospective cohort 
study of dabigatran etexilate for secondary 
prevention of venous thromboembolism in 
children from 0 to less than 18 years
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
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
Section 3.3.3 Exclusion criteria
Description of change
The eGFR level for exclusion criterion no. 2 was 
lowered to < 50 mL/min/1.73m2 for all patients, 
irrespective of their age.
Rationale for change
The previous exclusion criteria regarding eGFR 
were set up when limited data of patients exposed 
to dabigatran were available. As currently, the 
available data show a favorable benefit/risk 
relationship for dabigatran and no excess of 
dabigatran plasma levels (≥250ng/ml) in patients 
below 12 years of age, these criteria seem to be 
too restrictive as they do not take into account the 
physiological maturation of renal function with 
age. A cut-off of 50 mL/min/1.73m2 takes into 
account the physiologically lower eGFR at 
younger age, and would allow for the inclusion of 


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Number of global amendment
08
patients who may benefit from participation in the 
study. As an additional safeguard, the protocol 
eGFR criterion for stopping dabigatran 
treatment, i.e. if eGFR drops below 50 
mL/min/1.73m2 would remain unchanged.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02154816
11.0
clinical-trial-protocol-version-09
Open label, single arm safety prospective cohort study of dabigatran etexilate for
secondary prevention of venous thromboembolism in children from 0 to less than 18
years
Approval-Team Member Medicine
08 Feb 2019 09:11 CET
Author-Trial Clinical
Pharmacokineticist
08 Feb 2019 10:28 CET
Author-Clinical Trial Leader
08 Feb 2019 11:11 CET
Author-Trial Statistician
08 Feb 2019 23:13 CET
Approval-Therapeutic Area 
09 Feb 2019 21:27 CET
Verification-Paper Signature
Completion
13 Feb 2019 10:40 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02154816
11.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c09412381-02
BI Trial No.:
1160.108
Title:
Open label, single arm safety prospective cohort study of 
dabigatran etexilate for secondary prevention of venous 
thromboembolism in children from 0 to less than 18 years
Including Global Protocol Amendment 6 [c02154816-08],  7 
[c02154816-09], and 8 [c02154816-11]
Investigational
Product:
Dabigatran etexilate, BIBR 1048 MS
Responsible trial 
statistician:
Tel.: 
Responsible 
trial clinical 
pharmacokineticist
Tel.: 
Fax: 
Date of statistical 
analysis plan:
25 MAR 2019 REVISED
Version:
Revised
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINTS.....................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoint .......................................................................................8
5.2.2
Other secondary endpoints ..................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENT.....................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................10
6.3
PATIENT SETS AND ANALYSED .................................................................13
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........15
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................15
7.3
TREATMENT COMPLIANCE........................................................................15
7.4
PRIMARY ENDPOINTS...................................................................................16
7.5
SECONDARY ENDPOINTS.............................................................................17
7.5.1
Key secondary endpoint .....................................................................................17
7.5.2
Other secondary endpoints ................................................................................17
7.7
EXTENT OF EXPOSURE.................................................................................19
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse events.....................................................................................................19
8.
REFERENCES....................................................................................................22


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10.
HISTORY TABLE..............................................................................................25


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LIST OF TABLES
Table 6.2: 1
Important protocol deviations ..........................................................................11
Table 6.3: 1
Patient sets analysed.........................................................................................13
Table 10: 1
History table .....................................................................................................25


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse Event of Special Interest
aPTT
Activated partial thromboplastin time
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BRPM
Blinded report planning meeting
BSA
Body surface area
CRNM
Clinically Relevant Non-Major
CTP
Clinical Trial Protocol
DMC
Data Monitoring Committee 
dTT
Diluted Thrombin Time
eCRF
electronic Case Report Form
ECT
Ecarin clotting time
eGFR
estimated Glomerular Filtration Rate
EOT
End of Treatment
HPLC
High Pressure Liquid Chromatography
ICH
International Conference on Harmonisation
IPD
Important Protocol Deviation
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
MS
Mass Spectrometry
PD
Pharmacodynamics 
PKS
Pharmacokinetic Set
PK
Pharmacokinetics
PTS
Post-Thrombotic Syndrome
REP
Residual Effect Period
SAE
Serious adverse event
SD
Standard Deviation
TSAP
Trial Statistical Analysis Plan
VTE
Venous Thromboembolism
WHO
World Health Organization


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (1), 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 of the primary and secondary variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), 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.”
SAS® Version 9.4 or higher will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The changes to the statistical analyses are described in protocol amendments.  Please refer to 
latest protocol amendment (Amendment 8, dated 07 Feb 2019).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
There are no efficacy endpoints. All criteria in this study will be considered as safety 
endpoints. There are three primary endpoints. 

Recurrence of venous thromboembolism (VTE) at 6 and 12 months

Major and minor (including clinically relevant non-major (CRNM)) bleeding events 
(as defined in CTP Section 5.2.1) at 6 and 12 months

Mortality overall and related to thrombotic or thromboembolic events at 6 and 
12 months
All primary endpoints will be assessed by qualified clinicians using an appropriate objective 
method and will be centrally adjudicated by an independent committee.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint is defined.
5.2.2
Other secondary endpoints
The following secondary endpoints are defined:

Occurrence of post-thrombotic syndrome (PTS) at 6 and 12 months

Pharmacodynamic assessments (central measurement of of dTT (Anti-Factor IIa 
activity), aPTT and ECT) at Visit 3 (after at least six consecutive dabigatran etexilate 
doses) and after at least 3 days following any dabigatran etexilate dose adjustment

Number of dabigatran etexilate dose adjustments during treatment period (refers to 
number of patients with dabigatran etexilate dose adjustments during treatment 
period) 

Incidence of adverse events (AEs), protocol-specified adverse events of special 
interest (AESI) and serious adverse events


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
This is an open-label single arm prospective cohort study of dabigatran etexilate to evaluate 
safety in the secondary prevention of venous thromboembolism in paediatric patients. A 
minimum of 100 paediatric patients are planned to be entered into the trial and be assigned to 
dabigatran etexilate at a dose (twice daily) based on patient’s age and weight according to a 
nomogram. This includes patients rolling over from study 1160.106, who require secondary 
VTE prevention and new patients who should have completed treatment for an acute VTE 
episode. The Data Monitoring Committee (DMC) or Sponsor may decide to keep recruitment 
open after 100 patients have been recruited, in case additional safety data need to be 
generated.
The residual effect period (REP) is 3 days after the last trial medication administration. 
The following periods will be defined:

Screening: day of informed consent to time of first dabigatran etexilate administration 
in trial 1160.108. 

On-treatment: time of first administration of dabigatran etexilate in trial 1160.108 to 3
days (REP) after day of last administration of dabigatran etexilate in trial 1160.108. 

Post-treatment: end of on-treatment period + 1 day up to day of the last follow-up visit, 
lost to follow-up, death, or consent withdrawn regarding participation in the trial. 

Post-study: last follow-up visit + 1 day up to end of the trial, i.e.  the last contact/last 
information received during the trial.

Full follow-up: time of first administration of dabigatran etexilate in trial 1160.108 until 
day of the last follow-up visit, lost to follow-up, death, or consent withdrawn regarding 
participation in the trial. This treatment period was defined for sensitivity analyses only.
Please note: for patients who had not reached the end of treatment period as defined above at 
EMA interim data cut-off date, the respective treatment period ends at the cut-off date.
The screening, on-treatment, post-treatment, and post-study periods will be used for the 
summary and listings of adverse events. The on-treatment and full follow-up periods will be 
used for descriptive and statistical analysis of primary/secondary/further endpoints. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
No per protocol set will be defined for this study, however patients with potentially important 
protocol deviations (IPDs) will be documented. The following list of potentially IPDs will be 
used.


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Table 6.2: 1
Important protocol deviations
Category / 
Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1.1
Age >=18 years at the time of 
informed consent / assent
Inclusion criterion 1 not met
None
A1.2
Previously documented objective 
diagnosis of VTE, not complete the 
course of initial VTE treatment for 
at least 3 months, or not complete 
study treatment in the 1160.106
Inclusion criterion 2 not met.  
None
A1.3
No presence of an unresolved 
clinical risk factor requiring further 
anticoagulation for secondary VTE 
prevention 
Inclusion criterion 3 not met 
None
A2.1
Patients had conditions associated 
with an increased risk of bleeding
Exclusion criterion 1 met.  Details are 
specified in the protocol Section 3.3.3.
None
A2.2
Renal dysfunction or requirement 
for dialysis
Exclusion criterion 2 met. Estimated 
glomerular filtration rate (eGFR) < 60 
mL/min/1.73m2 for patients aged 12 to < 18 
years or eGFR < 80 mL/min/1.73m2 for 
patients aged 0 to < 12 years using the 
Schwartz formula, or requirement for dialysis
None
A2.3
Active infective endocarditis
Exclusion criterion 3 met.
None
A2.4
Heart valve prosthesis requiring 
anticoagulation
Exclusion criterion 4 met.
None
A2.5
Patients with hepatic disease
Exclusion criterion 5 met.
None
A2.6
Pregnant or breast feeding females
Exclusion criterion 6 met.
None
A2.7
Age group 0 to < 2 years with 
gestational age at birth < 37 weeks 
or with body weight < 3rd 
percentile
Exclusion criterion 7 met.
None
A2.8
Anaemia or thrombocytopenia at 
screening
Exclusion criterion 8 met.
None
A2.9
Restricted medication use prior to 
first dose of study medication
Exclusion criterion 9 met.
A2.10
Patients received an investigational 
drug in the past 30 days prior to 
screening
Exclusion criterion 10 met (except patients 
who have completed the treatment period in 
1160.106 trial)
None
A2.11
Allergic / sensitive to any 
component of the study medication 
including solvent
Exclusion criterion 11 met. f
None
A2.12
Patients or parents / legal guardians 
considered unreliable to participate 
in the trial per investigator 
judgment or any condition which 
would present a safety hazard to the 
patient based on investigator 
judgment
Exclusion criterion 12 met. 
None
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing
All
B2
Informed consent too late
Informed consent date <actual consent date> 
was after Visit 1 date <Visit 1 date>
None


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Table 6.2: 1 (continued)
Important protocol violations
Category /
Code
Description
Example/Comment
Excluded 
from
C
Trial medication and 
randomisation
C1.1
Incorrect trial medication taken
Medication kit assigned not matching 
interactive voice response system (IVRS) 
assignment, not leading to a change in the 
assigned treatment. (e.g. wrong dose or 
formulation of dabigatran etexilate was 
administered). Wrong dose assigned by 
investigator.
None
C2
Non-compliance
Medication compliance of <80% or >120%. 
Temporary interruption following protocol 
specified procedures will not be considered as 
violation.
None
C3.1
Incorrect dabigatran titration
A second dabigatran titration was performed 
after one titration attempt failed, or 
dabigatran titration was performed when it 
was not required according to protocol.
None
C3.2 
Dabigatran titration not done when 
required
DE could have been titrated when the trough 
DE concentration is outside the 50 to <250 
ng/mL range.
None
C3.3
Dabigatran not stopped when 
plasma trough concentration did 
not reach therapeutic range after 
one dose adjustment
Dabigatran not stopped after two confirmed 
trough concentrations outside 50 to < 250 
ng/mL range
None
D
Concomitant medication
D1
Prohibited concomitant medication 
use
Restricted concomitant treatments are listed 
in protocol Section 4.2.2.1 with appropriate 
exceptions.  
None
Z
Other
Z1
Patients treated with dabigatran 
etexilate developed renal 
dysfunction and were not 
discontinued from DE
Patients with eGFR < 50 mL/min/1.73m2
twice on dabigatran and trial treatment 
continued
None
Z2
Patients with observed recurrent 
thromboembolic event by 
appropriate imaging modalities and 
were not discontinued from DE
Patients with recurrent VTE and not stopped 
from dabigatran etexilate. Details in protocol 
Section 3.3.4.1.
None
Z3
Patients with drug related 
significant/serious AE or drug
toxicity and were not discontinued 
from DE
Patients with drug related significant/serious
AE or drug toxicity and not stopped from 
dabigatran etexilate. Details in protocol 
Section 3.3.4.1.
None
Z4
Patients became pregnant and were 
not discontinued from DE
Patients become pregnant and not stopped 
from dabigatran etexilate. Details in protocol 
Section 3.3.4.1.
None
Z5
Patients developed active 
meningitis, encephalitis, or 
intracranial abscess and were not 
discontinued from DE
Patients developing active meningitis, 
encephalitis or intracranial abscess and NOT 
stopped from dabigatran etexilate. Details in 
protocol Section 3.3.4.1.
None
Z6
Use of DE outside the clinical trial
None


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This table includes IPDs checked by both automated SAS program and manual reporting. All manual findings 
should be reported in manual protocol deviation log for team review during medical quality review meeting 
(MQRM) and blinded report planning meeting (BRPM).
6.3
PATIENT SETS AND ANALYSED
The following analysis sets are defined for the data analysis in this trial:

Enrolled set: This patient set includes all patients with signed informed consent. The 
enrolled set will be used for disposition summaries.  

Entered set: This patient set includes all patients with signed informed consent and 
were eligible to enter the trial, whether treated or not. The entered set will be used for 
sensitivity analysis of the primary endpoints.  

Treated set: This patient set includes all patients who were dispensed study 
medication and were documented to have taken at least one dose of investigational 
treatment.  The treated set will be used to assess safety endpoints, demographics and 
baseline characteristics, and concomitant diagnosis/therapy and medical history.  
 
 

Pharmacodynamic set (PDS): This patient set includes all treated patients who 
provide at least one evaluable PD observation and had no protocol deviations relevant 
to the evaluation of PD endpoints. The PDS will be used for the PD analyses.
 
 
.
A summary of the patient sets analysed is provided in the following table:
Table 6.3: 1
Patient sets analysed
Class of endpoint
Treated set
Entered set
PDS
Primary endpoints
X, Primary 
analysis
X, 
Sensitivity 
analysis
Secondary endpoints except PD
X
Demographic/baseline 
characteristics
X
X
PK/PD 
X
Other variables except PK/PD  
X


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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
Missing data will not be imputed in general. All patients will be followed to collect necessary 
efficacy and safety information, even if patients discontinue study medication prematurely.
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (2). 
Missing data and outliers of PK data are handled according to (3).
The repeated measurements are handled according to BI standards (see “Handling, display 
and analysis of laboratory data”) (5).  
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Unless otherwise specified, baseline value will be the last available measurement taken prior 
to first administration of dabigatran etexilate in this trial.  If baseline measurements are 
missing for a patient who has completed the treatment period of 1160.106, the measurements 
from Visit 8 of 1160.106 will be taken as baseline for this trial.


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7.
PLANNED ANALYSIS
Descriptive statistics for continuous variables will generally be N (number of patients with 
non-missing values), mean, standard deviation (SD), minimum, median, and maximum. In 
general, means, medians and SDs will be presented by one more decimal place than the raw 
data. Minimums and maximums will be presented by the same number of decimal places as 
the raw data. Geometric means and geometric coefficients of variation will be used in 
summaries of PK values.
Tabulations of frequencies for categorical data will include all possible categories unless 
otherwise specified (e.g. adverse event terms) 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. The category “Missing” will be displayed 
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.
There is no hypothesis testing for this trial. Analyses and summaries will be performed by 
age groups (birth to <2 year, 2 to <12 years, 12 to <18 years) and overall.  
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.  Demographic data 
(including age, sex, ethnicity, and race) and baseline characteristics (including the following 
measurements at baseline: height, weight, body mass index, body surface area, blood 
pressure, and pulse rate) will be summarized for the treated set. Baseline disease 
characteristics, including the previous VTE diagnosis (deep vein embolism, pulmonary 
embolism, etc.), days since previous diagnosis, and previous VTE treatments, will be 
summarized for the treated set. The demographic data and baseline characteristics, and 
baseline disease characteristics will also be listed by patient. 
Additional demographic data and baseline disease characteristics tables will be provided for 
the entered set if the entered set substantially differs from the treated set.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be summarised descriptively.  The concomitant medications taken 
at baseline and those taken while on treatment will be coded using the WHO Drug coding 
dictionary. These will then be summarized by WHO Drug ATC coding and listed by patient 
with each medication taken for the treated set.  
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. Compliance since last 
visit at individual visits collected in the eCRF will be listed, and average overall compliance 
will be summarized for the treated set. Number and percentage of patients with compliance 
categories <80%, 80%-120%, and >120% will also be presented.   


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7.4
PRIMARY ENDPOINTS
There are no primary efficacy endpoints. 
The primary analysis for the primary safety endpoints will be performed with the treated set 
during the on-treatment period.
 
Frequency and percentage of patients with recurrence of VTE, major and minor (including 
CRNM) bleeding, and mortality overall and related to thrombotic or thromboembolic events 
at 3, 6 and 12 months will be summarized descriptively for each age group and overall. 
The survival/event-free probability of primary safety endpoints will be provided by Kaplan-
Meier estimation with its 95% confidence intervals at above planned time points. The 
primary safety endpoints will also be analyzed as time-to-event data and summarized by
Kaplan-Meier estimates for quartiles of the time to first occurrence of events, given sufficient 
number of observed events. 
Recurrence of VTE at 6 and 12 months
Time to first recurrence of VTE will be analysed using Kaplan-Meier method. Patients, who 
do not experience recurrent VTE, drop out from the study early, are lost to follow-up, or die 
from non-VTE related cause will be considered as non-events and censored.
Major and minor (including CRNM) bleeding events at 6 and 12 months
Time to first occurrence of major bleeding event or minor (including CRNM) will be 
analysed using Kaplan-Meier method. Patients free from major or minor (including CRNM) 
bleeding event, early drop-outs, lost to follow-ups, and non-bleeding related deaths will be 
considered as non-events and censored.
Mortality overall and related to thrombotic or thromboembolic events at 6 and 12 months
Time to mortality overall and time to mortality related to thrombotic or thromboembolic 
event will be summarized separately by Kaplan-Meier method. Early drop outs and lost to
follow-ups will be considered as non-events and censored. Non-thrombotic or non-
thromboembolic related death will be considered as censored case for mortality due to 
thrombotic or thromboembolic events. 
 
All primary endpoints will be evaluated by an independent adjudication committee that will 
confirm or refute outcome events. Adjudicated assessments for the primary endpoints will be 
used in the primary and subgroup analyses.
Concordance between adjudicated events and investigator-reported events will also be 
summarized. 


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Other secondary endpoints
Secondary analyses are planned for occurrence of PTS at 3, 6 and 12 months, 
pharmacodynamic assessments at Visit 3 and protocol specified time points after each dose 
adjustment, and number of patients with dabigatran etexilate dose adjustments during 
treatment period. 

Time to first occurrence of PTS will be analysed using the Kaplan-Meier estimation if 
number of observed events is sufficient. Descriptive frequency and percentage of 
patients with PTS at 3, 6 and 12 month will be presented. Patients free from PTS, 
early drop-outs, lost to follow-ups and deaths will be considered as non-event and 
censored.  The PTS event-free probability will be estimated by Kaplan-Meier curve 
with its 95% confidence intervals at such time points. Analysis will be performed with 
the treated set during the on-treatment period
 

Pharmacodynamic assessments (central measurement of dTT, aPTT and ECT) at Visit 
3 (after at least six consecutive dabigatran etexilate doses) and after at least 3 days 
following any dabigatran etexilate dose adjustment will be summarized using 
descriptive statistics. 

Frequency of dabigatran etexilate dose adjustments during on-treatment period will be 
summarized descriptively. This refers to number of patients with dabigatran etexilate 
dose adjustment during treatment period because each patient is allowed to have only 
one dabigatran etexilate dose adjustment.
 


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7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the report. Summaries will be 
provided for treated set. Total treatment time (in days) is defined as date of last 
administration of dabigatran etexilate – date of first administration of dabigatran etexilate + 1.
For rollover patients who received dabigatran treatment in 1160.106, their exposure clock 
starts from first administration of dabigatran etexilate in 1160.108. Number of patients with 
dose adjustment is analysed as a secondary endpoint and specified in Section 7.5. Descriptive 
statistics for the dabigatran etexilate dose assigned will be provided for each age group.
7.8
SAFETY ANALYSIS
The analyses for the primary safety endpoints are described in Section 7.4. Safety analyses 
will be performed on the treated set.  Safety analysis will also be performed on the entered set
if the entered set substantially differs from the treated set. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
7.8.1
Adverse events
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.
AEs will be coded with the most recent available version of MedDRA referred to in the 
footnote of tables and listings.
AE data will be combined in a 2-step procedure into AEs records. In a first step, AE 
occurrences, i.e. AE entries on the eCRF, 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 (the second occurrence 
started at the end date of first occurrence)


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
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
In a second step, AE episodes will be condensed into AE records provided that episodes are 
reported with the same term on the respective MedDRA level and that the episodes are 
assigned to the same treatment.
For further details on summarization of AE data, please refer (2, 6).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all adverse events occurring between first drug intake till 3 days after last drug intake 
will be assigned to the administered treatment. All adverse events occurring outside the on-
treatment period will be summarized in listings only and assigned to ‘screening’, ‘post-
treatment’, or ‘post-study’ see Section 6.1. In addition, AEs occurring before first drug intake
but worsening in intensity during the treatment period will also be assigned to the 
administered treatment. For details on the treatment definition, see Section 6.1. Death 
information will be provided as listings and will include all treatment periods (i.e. also the 
post-study period).
According to ICH E3 (6), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant AEs with 
(i) ‘action taken = discontinued’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Trial Leader/Investigator at a Medical Quality Review 
Meeting.
An overall summary of AEs will be presented. 
Frequency of patients with AEs will be summarised by age group, treatment, primary system 
organ class and preferred term. Separate tables will be provided for patients with other 
significant AEs according to ICH E3 (7), for patients with serious adverse events (SAEs), 
protocol-specified adverse events of special interest (AESIs), for patients with drug related 
AEs, as well as patients with AEs leading to treatment discontinuation and death. The system 
organ classes and preferred terms will be sorted by descending order of frequency. 
The following are considered as AESI for this trial:

Hepatic injury defined by the following alterations of liver parameters: An elevation 
of AST and/or ALT ≥ 3 fold ULN combined with an elevation of total bilirubin ≥ 2 
fold ULN measured in the same blood draw sample. 

Creatinine value shows a ≥ 2 fold increase from baseline and is above the upper limit 
of normal.
The system organ classes and preferred terms will be sorted by frequency in a descending 
order.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
3
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
4
c09149501-01: “Population pharmacokinetic analysis of dabigatran etexilate using 
combined data from paediatric and adult studies”; BIRDS.
5
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
6
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical Trials
", current version; IDEA for CON.
7
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.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
26-JAN-17
 
None
This is the final TSAP without any modification 
based on the protocol Version 6.0 dated 
30 Nov 2016.  
Revised
25-MAR-19
4
Update changes in planned analysis in accordance 
with the latest protocol amendment.
5.2.2
Update description of other secondary endpoint 
regarding PD assessments to be aligned with CTP 
version 8, dated 10 Sep, 2018.
6.1
Update definitions of different periods. 
 
 
6.2
Update IPD sub-categories according to team 
discussion. 
6.3
Add definition of enrolled set, 
, PDS, and 
PK/PD set.
7.3
Update calculation of compliance in terms of 
overall average.
7.4
Clarify analysis periods for primary and
 
analyses.
Update analysis plan of primary endpoints based 
on BRPM in Dec 2018.
7.5.2
Update description of other secondary endpoint 
regarding PD assessments to be aligned with CTP 
version 8, dated 10 Sep, 2018.
Update analysis plan of PTS based on BRPM in 
Dec 2018.
Add description of subgroup analysis.
7.7
Clarify the exposure clock for rollover patients 
from 1160.106.
7.8.1
Complete the second step of AE data processing 
from AE occurrences to AE records.
Update the order of AE display in summary tables.
8
Update references table.