Clinical trial NCT01895777
Conditions: Venous Thromboembolism
Sponsor: Boehringer Ingelheim
Start date: 2013-09-25; Completion date: 2019-11-14
Enrollment: 267 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objectives of this large phase IIb/III paediatric study are to assess the efficacy and safety of dabigatran etexilate relative to standard of care and to document the appropriateness of the proposed dabigatran etexilate dosing algorithm for use in patients from birth to less than 18 years of age.

Detailed description:

Arms: arm 1: Dabigatran etexilate capsules, pellets or liquid formulation given BID in an open label fashion for 3 months arm 2: Low molecular weight heparin, vitamin K antagonist or fondaparinux prescribed in an open label fashion for 3 months (these medications will not supplied in this study as IMP)
Interventions: intervention 1: dabigatran etexilate intervention 2: standard of care
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 intervention 2: Low molecular weight heparin, vitamin K antagonist or fondaparinux prescribed in an open label fashion for 3 months (these medications will not supplied in this study as IMP)

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02102933-16
EudraCT No.:
BI Trial No.:
2013-002114-12
1160.106
BI Investigational
Product:
   Dabigatran etexilate, BIBR 1048 MS
Title:
Open-label, randomized, parallel-group, active-controlled, multi-centre,
non-inferiority study of dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children from birth to less than 
18 years of age: The DIVERSITY study
Clinical Phase:
IIb/III
Trial Clinical 
Monitor:
Telephone:  
Fax:             
Co-ordinating 
Investigators:
Phone:
Fax: 
Phone:
Fax:
Status:
Final Protocol (Revised protocol (based on Global Amendment 9))
Version and Date:
Version: 10.0
         
Date:    06 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:
Not applicable
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
06 Feb 2019
05 June 2013
1160.106
Title of trial:
Open-label, randomized, parallel-group, active-controlled, multi-centre, non-
inferiority study of dabigatran etexilate versus standard of care for venous 
thromboembolism treatment in children from birth to less than 18 years of age: The 
DIVERSITY study
Co-ordinating 
Investigator:
Phone: 
Fax:  
Phone: 
Fax:
Trial sites:
Multi-centre trial
Clinical phase:
IIb/III
Objectives:
Main objectives:

To assess the efficacy and safety of dabigatran etexilate relative to standard 
of care.  

To document the appropriateness of the proposed dabigatran etexilate dosing 
algorithm.   
Methodology:
An active-controlled, open-label, randomized, parallel-group study designed to 
confirm a proposed dabigatran etexilate dosing algorithm and to assess the safety and 
effectiveness of dabigatran etexilate compared to standard of care (SOC) for 
treatment of paediatric venous thromboembolism.
No. of patients: 


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BI Trial No.: 1160.106
Doc. No.: c02102933-16
Trial Protocol
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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
06 Feb 2019
05 June 2013
1160.106
total entered:
A minimum of 141 evaluable patients for the primary efficacy endpoint including a
target of: 60 patients in age stratum 1 (from 12 to < 18 years of age), 18 patients in age
stratum 2 (from 2 to < 12 years of age) and 15 patients in age stratum 3 (from birth to
< 2 years of age). 8 patients in stratum 3 are targeted to be below one year of age. The
recruitment of patients could continue after achieving the minimum total number of
patients and the minimum number of patients per age strata if required by Regulatory
Authorities. Recruitment will be initiated in stratum 1 and consecutively opened to age
stratum 2 and then 3 based on Data Monitoring Committee (DMC) recommendations
that take into account information from the current stratum (from this trial and the
secondary VTE prevention trial 1160.108); data analyses of PK, PD, dose adjustments
from current stratum, exposure-response model updated with relevant paediatric and
adult data as well as the appropriateness of dosing algorithm for consecutive stratum.
each treatment:
A 2:1 randomization scheme is planned (dabigatran etexilate : standard of care 
comprised of low molecular weight heparins (LMWH) or vitamin K antagonists 
(VKA) or fondaparinux). Therefore approximately 94 evaluable patients on 
dabigatran etexilate and 47 evaluable patients on SOC are expected. The intended 
SOC treatment must be specified at randomization. 
Diagnosis:
Confirmed acute venous thromboembolism with an anticipated requirement for at 
least 3 months of treatment with anticoagulants, including an initial parenteral 
treatment of a minimum of 5 to 7 days (but not longer than 21 days) with an 
unfractionated heparin (UFH) or a low molecular weight heparin (LMWH).
Main criteria
for inclusion:
Clinically stable patients diagnosed with acute venous thromboembolism (VTE) who 
have completed an initial parenteral treatment with an unfractionated or a low 
molecular weight heparin for a minimum of 5 to 7 days (but not longer than 21 days) 
and who have an anticipated need for continued anticoagulation therapy for at least 3 
months (including the initial parenteral therapy).
Test product:
Dabigatran etexilate 
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 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 oral liquid
formulation or any other alternative age-appropriate formulation.
mode of admin.:
Oral 
Comparator products:
A comparator product is not provided for this study


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Doc. No.: c02102933-16
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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
06 Feb 2019
05 June 2013
1160.106
dose:
This is not applicable per above
mode of admin.:
This is not applicable per above
Duration of treatment:
Patients assigned to take dabigatran etexilate or standard of care will be treated for a 
planned duration of 3 months which includes the initial parenteral therapy. 
Criteria for 
pharmacokinetics:
and pharmacodynamics:

Pharmacokinetic parameters:  Plasma concentrations of total dabigatran

Pharmacodynamic parameters: Central measurement of aPTT, ECT and dTT


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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
06 Feb 2019
05 June 2013
1160.106
Criteria for efficacy:
Primary endpoint: 
Efficacy combined endpoint. Proportion of patients with:
o
Complete thrombus resolution and;
o
Freedom from recurrent venous thromboembolic event  (including symptomatic and 
asymptomatic, contiguous progression or non-contiguous new thrombus, deep vein 
thrombosis, pulmonary and paradoxical embolism, thrombus progression) and;
o
Freedom from mortality related to venous thromboembolic event.
The events outlined in the above combined endpoint will be assessed by radiologists or other 
such qualified clinicians using an appropriate method such as ultrasound, echocardiography, 
venography or computed tomography (CT scan) based on the location of the thrombus and the 
test used to perform the baseline assessment.
All components of the primary efficacy endpoint as well as all bleeding and all fatal events will be 
centrally adjudicated by an independent blinded committee.
Secondary endpoints: 

Freedom from major bleeding events (MBEs), defined as either fatal bleeding, clinically overt
bleeding associated with a decrease in haemoglobin of at least 20 g/L in a 24-hour period, 
bleeding that is retroperitoneal, pulmonary, intracranial or otherwise involves the central 
nervous system, or bleeding that requires intervention in an operating suite.

Pharmacokinetic 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 

Frequency of dose adjustments (i.e. Number of subjects with dose adjustment), temporary and 
permanent discontinuation from therapy and number of subjects with laboratory monitoring 
requirements for dose adjustment during the treatment phase

Frequency of switch of type of anti-coaguation therapy (including from dabigatran etexilate to 
standard of care) (Frequency of subjects switching the type of anti-coagulation therapy including 
dabigatran etexilate to standard of care and switching from an intended standard of care treatment 
to another)

Freedom from thrombus progression at end of therapy (day 84 after randomisation or eEOT, 
whichever comes first) compared to baseline

Assessment of the acceptability of an age-appropriate formulations at end of therapy

All bleeding events

All-cause mortality

All components of the primary efficacy endpoints


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
06 Feb 2019
05 June 2013
1160.106
Criteria for safety:

Incidence of bleeding events including:
o
Major bleeding events, clinically relevant non-major (CRNM)
bleeding events, minor bleeding events and any bleeding events
o
Combined endpoint of major and CRNM bleeding events 

Incidence of adverse events, protocol-specified AESIs and serious adverse 
events 

Treatment discontinuation due to an adverse event

Change from baseline in safety laboratory values, vital signs and physical 
examination 

Global assessment of tolerability (measured as treatment discontinuation and 
adherence) to study medication
Statistical methods:
The primary efficacy endpoint will be tested for non-inferiority using non-
inferiority margin of 20% at one-sided level of 0.05. Upon showing non-inferiority 
for the primary endpoint, superiority test for the primary endpoint will be 
performed subsequently at one-sided level of 0.05 without multiplicity correction.
Mantel-Haenszel type weighted average of proportion difference, Kaplan-Meier 
method, Cox proportional hazard model, Logistic regression and descriptive 
statistics will be used in the planned analyses.


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FLOW CHART
Trial Period
Screeni
ng
Treatment Period (open-label) with 
Dabigatran Etexilate (Dabi) or Standard Of Care (SOC)
Follow-up A
Visit (V) #:
1X
2
3B
4
5 Y
6
7
8C
Dabi Titration
Visit if neededB
INR/anti-Xa Visit if neededB
Unscheduled Visit if 
neededD
eEOTE
9
Study week 
-2
1
1
2
3
6
9
12
Only for early 
discontinued patients 
(before V8)
V8 or eEOT 
+ 28 days
Days from Visit 2
preferred visit window
-21
-1
0
3
+2
7
-1
to
+7
21
±7
42
±7
63
±7
84
±7
+14
In-person clinic visits
X
X
X
X
X
X
X  
X
X
X
X
X
X
Informed consent / assent F
X
Inclusion / exclusion criteria G
X
X
Medical history / demographics
X
Physical examination H
X
X
X
X
Baseline assessment of VTE
X
Vital signs (BP and HR)
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
Weight
X
X
X
X
X
X
X
X
X
12-lead resting-ECG (5 min supine) I
X
X
X
Evaluate thrombosis or symptoms J
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of thrombus extension J
X
X
X
Pregnancy test K 
X
X
X
Laboratory tests (blood) L
XZ
X
X
X
X
X
X
X
X
X
X
X
X
aPTT and ECT (only for Dabi)
X
X
X
XT
X
X
X
X
X
X
Diluted thrombin time (only for Dabi)
X
X
XT
X
X
X
X
X
INR or Anti-Factor Xa (only for 
SOC)M
X
X
X
X
X
X
X
X
PK sample (only for Dabi) O
XZ
X
XT
X
X
X
X
X
X
Select Dabi dose per age and weight p
X
Medication intake evaluation Q
X
X
Dispense Dabi or prescribe SOCW
X
X
X
X
X
X
X
Possible titration of Dabi dose 
X
X
X
X
X
X
Possible titration of SOC dose 
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy  R
X
X
X
X
X
X
X
X
X
X
X
X
X
Medication compliance U
X
X
X
X
X
X
X
X
X
Patient treatment assessment V
X
X
X
X
Investigator treatment evaluation  
X
X
X
X
Termination of trial medication
X
X
Conclusion of patient participation 
X S


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A.
Visits 9 should occur at least 28 days after Visit 8 or the early End Of Treatment (eEOT) visit which is planned for 
early discontinued patients. 
B.
Patients are randomised at visit 2 to dabigatran etexilate or standard therapy (LMWH or VKA or fondaparinux) in a 2 
to 1 ratio. Visit 3 will only be required for patients assigned to dabigatran etexilate. During this visit the trough 
dabigatran concentration will be determined by high performance liquid chromatography – tandem mass spectrometry 
(HPLC-MS/MS) assay at the central lab or assessed by central lab measurement of diluted thrombin time (dTT) (or 
alternatively by local lab if needed and when feasible) to ensure maintenance within a 50 to < 250 ng/mL window. In 
case the use of the HPLC-MS/MS or dTT assays is not feasible, an alternative method may be used. The first 
concentration assessment will be done at Visit 3 (after at least 6 consecutive dabigatran etexilate doses are taken), a 
dose adjustment must occur if a target dose exposure of 50 to < 250 ng/mL is not achieved (refer to Appendix 10.3.2). 
A titration visit must be scheduled preferably after 3 days have elapsed (or 6 new doses have been taken) since 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. Also,
additional INR/anti-Xa visits (prothrombin time (PT) / INR: international normalized ratio and/or anti-factor Xa 
activity) to adjust standard of care therapy may be scheduled at any time point during the treatment phase outside of 
scheduled titration measurements as outlined in the Flow Chart. Refer to footnote M for additional information related 
to SOC. Refer to footnote Z for patients less than 2 months of age.
C.
Eligible patients requiring secondary VTE prevention due to unresolved clinical risk factor may roll over into 1160.108
trial. For such patients, the 1160.106 trial follow-up visit is no longer required as they will be followed in the secondary 
VTE prevention study.
D.
Unscheduled clinic visits are to be conducted in all cases of suspected symptomatic and asymptomatic VTE,
progression/recurrence of VTE, paradoxical embolism (PDE), occurrence of post-thrombotic syndrome (PTS), major or
clinically relevant bleeding events (MBEs / CRBEs) or other suspected significant AE 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. This visit should include all appropriate diagnostic procedures. If VTE progression/recurrence, PDE, PTS, 
MBEs, CRBEs are confirmed, the patient taking dabigatran etexilate is to be discontinued from the dabigatran etexilate
treatment arm (eEOT visit to be performed as soon as possible), and an appropriate standard of care VTE treatment
should be initiated per the investigator’s discretion and/or local guidelines and the patient should be followed for the
remainder of the study. If it is decided that a patient is to be discontinued from treatment due to an event, an eEOT visit 
should be conducted.
An unscheduled Visit is also to be performed in case a dabigatran etexilate dose adjustment is needed.
E.
The early End Of Treatment (eEOT) visit will be required for all patients who have taken a dose of dabigatran etexilate
but failed to complete the full planned treatment observation period (completion of Visit 8). If feasible, this visit is also 
required for patients randomized to SOC should they decide to discontinue the trial or permanently stop SOC treatment
for any reason. eEOT visit is not required if the SOC treatment is changed during the course of the trial.
F.
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
G.
Prior to start of therapy, all study inclusion and exclusion criteria must be checked to confirm patient eligibility.
H.
A complete physical examination is required at Visit 1, Visit 8, eEOT Visit and Visit 9. 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 eCRFs.
I.
The required ECGs 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.
J.
Based on physical examination and in case of suspected 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.
- Suspected DVT: Venous compression ultrasonography (CUS) or venography
- Suspected PE: Ventilation-perfusion (V-Q) lung scan, pulmonary angiography or spiral (helical) CT
- Suspected PTS: 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)


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- Suspected PDE: CT / MR angiography or other appropriate evaluation 
The final assessment (at end of therapy) of the resolution status of the thrombus must be done using the same method as
the baseline evaluation when appropriate. Note: If clinical evaluations warrant imaging (e.g. suspected thrombus 
extension), then per investigator judgment, appropriate imaging may be performed. During the screening period, when
feasible, a baseline radiological assessment (e.g. CT) may be supplemented with an acceptable non-radiological 
assessment (e.g. MRI) at baseline which could then be repeated at study day 84 (Visit 8) or at eEOT visit (whichever
comes first) hence alleviating any potential unwarranted radiation exposure.  
Patients who have worsening of their VTE any time during the study must be discontinued from dabigatran etexilate
and should be treated with SOC per the investigator’s judgment. If feasible, such early discontinued patients should 
continue the trial period on SOC. Early discontinued patients will be followed using the intent-to-treat principle and 
should preferably complete the remaining visit schedule until the end of the study (at minimum complete follow-up 
Visit 9 and scheduled Visit 8).
K.
A pregnancy test will be done in female adolescents of child bearing potential (subjects who have reached menarche). 
More frequent testing can be done if required by the local regulation and/or authority or per investigator judgment.
L.
Laboratory tests will be performed according to protocol Section 5.2.3.
For patients assigned to the dabigatran etexilate arm, approximate blood volumes (in ml) to be collected for planned 
central safety laboratory assessments, PK/PD
are outlined in Appendix 10.1.1. 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.
M.
Patients on standard of care treated with LMWH or VKA or fondaparinux, may be monitored respectively with anti-
factor Xa activity (anti-Xa) or prothrombin time (PT) / INR (international normalized ratio) when applicable. Related 
analyses will be performed at the central lab. Alternatively local lab testing for anti-factor Xa activity, prothrombin time 
(PT) / INR (international normalized ratio) or aPTT (activated partial thromboplastin time) is also acceptable, see Section 
5.2.3
O.
Collection of pre-dose trough PK samples will be done as indicated in the Flow Chart for patients assigned to 
dabigatran etexilate. Pre-dose trough PK samples should be taken at approximately 10 to 16 hours after the last dose. 
Dabigatran etexilate doses must not be delayed to accommodate a preferred pre-dose collection time point.
P.
The appropriate dabigatran etexilate starting dose must be based on the latest age and weight-based nomogram provided 
in Appendix 10.3.1. More frequent 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.
Q.
If the patient aged 8 to < 12 years is randomized to the dabigatran etexilate arm, the investigator may assign capsules or
pellets formulation depending on the patient's ability to swallow capsules. The decision will be done in the clinic at
Visit 2 prior to dispensing dabigatran etexilate. The choice of the formulation to be used as treatment will be recorded in 
the eCRF. The patient and parent / legal guardian should be reminded about the proper procedures for administration of 
dabigatran etexilate (dabigatran etexilate capsules for patients aged ≥8 years, dabigatran etexilate pellets for patients
aged < 8 years or for patients who cannot take capsules even if older than 8 (but below 12 years of age) and dabigatran 
etexilate oral liquid formulation (OLF) for patients less than 12 months of age). More frequent training can take place as 
needed. Similarly, the procedures to take standard of care (LWMH or VKA or fondaparinux) will also be explained to 
patients and parents / legal guardians based on local requirements.
R.
Concomitant therapies, which were stopped within 14 days prior to informed consent, are to be recorded on specific 
eCRF pages.
S.
For patients completing study medication per protocol at Visit 8, the Follow-up Visit 9, which corresponds to 
approximately 4 months after start of trial drug, represents the end of trial.


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T.
Pre-dose and post-dose sampling will be performed for PK, dTT, and aPTT/ECT only for patients on the dabigatran
etexilate arm. Pre-dose sampling should occur immediately before intake of dabigatran etexilate, post-dose sampling 
should be performed at 2 hours post-dabigatran etexilate dose (this time point corresponds to the approximately peak 
dabigatran plasma concentration). Pre-dose sampling is mandatory for all dabigatran etexilate assigned patients. The 
post-dose sample is optional for dabigatran etexilate patients.
U.
Compliance for dabigatran etexilate and SOC will be calculated by the investigator or designee preferably based on 
actual medication count (or alternatively based on daily medication intake logs which will be completed by the patient 
or if appropriate by the parent/legal guardian). Counting the returned medication is the preferred calculation method to 
assess compliance.
V.
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).
W.
Dabigatran etexilate or SOC (not supplied in the study) may be re-dispensed as needed in appropriate cases (e.g. 
dabigatran etexilate at Visit 3 and Visit 4).
X.
Screening procedures may begin as soon as informed consent is obtained and after the patient is diagnosed with a VTE 
requiring at least 3 months of treatment with anticoagulants including an initial parenteral treatment course of at 
minimum 5 to 7 days (but not longer than 21 days). Screening procedures may take place at different time points during 
the screening window. Screening laboratory tests are to be collected early enough during the screening window to 
ensure that results are received and reviewed by Visit 2 and that there is enough time for retesting, if needed.
In case pre-treatment with VKAs has been initiated during the screening period, a local INR measurement should be 
performed at Visit 2 to confirm eligibility (INR < 2.0)
Y.
Visit 5 should be performed at least 3 days (6 consecutive dabigatran etexilate doses are taken) after Visit 4.
Z.
Patients below 2 months must have a baseline aPTT measurement available (before any anticoagulant treatment is
started). For these patients who are randomized to dabigatran etexilate, the first trough dabigatran concentration 
assessment (at Visit 3) must be supplemented by a local aPTT measurement. If the aPTT level at Visit 3 is ≥2-fold over 
aPTT at baseline or exceeds 100 seconds, the dabigatran etexilate dose must be down-titrated. In order to ensure 
maintenance of trough dabigatran concentration within a 50 to < 250 ng/mL window, all further assessments for these 
patients will be based on HPLC-MS/MS assay or dTT assay performed at the central lab. See Section 5.2.3. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................7
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS.......................................................................................... 15
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE...............................................................................................19
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 25
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................25
2.2
TRIAL OBJECTIVES.......................................................................................25
2.3
BENEFIT - RISK ASSESSMENT ...................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.1.1
Administrative structure of the trial...................................................30
3.1.1.1
Data Monitoring Committee....................................................31
3.1.1.2
Central Independent Blinded Adjudication Committee...........31
3.1.1.3
Central laboratory ....................................................................31
3.1.1.4
Steering Committee .................................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................32
3.3.1
Main diagnosis for study entry............................................................32
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................33
3.3.4
Removal of patients from therapy or assessments.............................35
3.3.4.1
Removal of individual patients................................................35
3.3.4.2
Discontinuation of the trial by the sponsor..............................38
4.
TREATMENTS........................................................................................ 39
4.1
TREATMENTS TO BE ADMINISTERED....................................................39
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................39
4.1.2
Method of assigning patients to treatment groups ............................40
4.1.3
Selection of doses in the trial................................................................41
4.1.4
Drug assignment and administration of doses for each patient .......45
4.1.5
Blinding and procedures for unblinding ............................................46
4.1.5.1
Blinding....................................................................................46


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4.1.5.2
Procedures for emergency unblinding .....................................47
4.1.6
Packaging, labelling, and re-supply ....................................................47
4.1.7
Storage conditions.................................................................................47
4.1.8
Drug accountability ..............................................................................47
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................48
4.2.1
Rescue medication, emergency procedures, and additional 
treatment................................................................................................49
4.2.2
Restrictions............................................................................................51
4.2.2.1
Restrictions regarding concomitant treatment .........................51
4.2.2.2
Restrictions on diet and life style.............................................52
4.3
TREATMENT COMPLIANCE.......................................................................52
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 54
5.1
EFFICACY - PHARMACODYNAMICS........................................................54
5.1.1
Endpoints of efficacy.............................................................................54
5.1.2
Assessment of efficacy...........................................................................55
5.1.2.1
Physical examination ...............................................................55
5.1.2.2
Venous thromboembolism assessment ....................................55
5.1.2.3
Bleeding assessment ................................................................56
5.2
SAFETY..............................................................................................................56
5.2.1
Endpoints of safety................................................................................56
5.2.2
Assessment of adverse events...............................................................57
5.2.2.1
Definitions of adverse events...................................................57
5.2.2.2
Adverse event and serious adverse event reporting.................58
5.2.3
Assessment of safety laboratory parameters......................................60
5.2.4
Electrocardiogram................................................................................60
5.2.5
Assessment of other safety parameters...............................................60
5.2.5.1
Vital signs ................................................................................60
5.2.5.2
Weight assessment...................................................................61
5.3
OTHER...............................................................................................................61
5.3.2
Other assessments .................................................................................61
5.3.2.1
Acceptability and tolerability of age appropriate formulations61
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................61
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................62
5.5.1
Pharmacokinetic endpoints..................................................................62
5.5.2
Methods of sample collection...............................................................62
5.5.2.1
Plasma sampling for pharmacokinetic analysis......................62
5.5.3
Analytical determinations ....................................................................63
5.6
BIOMARKERS..................................................................................................63


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5.6.1
Endpoints based on biomarkers ..........................................................63
5.6.2
Methods of sample collection...............................................................63
5.6.3
Analytical determinations ....................................................................63
5.7
PHARMACODYNAMICS................................................................................63
5.7.1
Pharmacodynamic endpoints...............................................................63
5.7.2 Methods of sample collection...............................................................63
6.
INVESTIGATIONAL PLAN.................................................................. 66
6.1
VISIT SCHEDULE............................................................................................66
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................66
6.2.1
Screening period....................................................................................66
6.2.2
Treatment period ..................................................................................66
6.2.3
End of trial and follow-up period........................................................66
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 68
7.1
STATISTICAL DESIGN - MODEL................................................................68
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................68
7.3
PLANNED ANALYSES....................................................................................68
7.3.1
Primary analyses...................................................................................69
7.3.2
Secondary analyses ...............................................................................69
7.3.3
Safety analyses.......................................................................................71
7.3.5
Pharmacokinetic analyses ....................................................................73
7.3.6
Pharmacodynamic analyses.................................................................73
7.3.7
Pharmacogenomic analyses..................................................................73
7.4
HANDLING OF MISSING DATA ..................................................................73
7.5
RANDOMISATION ..........................................................................................73
7.6
DETERMINATION OF SAMPLE SIZE ........................................................74
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 77
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................77
8.2
DATA QUALITY ASSURANCE .....................................................................78
8.3
RECORDS..........................................................................................................78
8.3.1
Source documents .................................................................................78
8.3.2
Direct access to source data and documents.......................................79
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................79
8.4.1
Listedness...............................................................................................79
8.4.2
Expedited reporting to health authorities and IECs/IRBs................79
8.5
STATEMENT OF CONFIDENTIALITY.......................................................79


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8.6
COMPLETION OF TRIAL..............................................................................80
9.
REFERENCES......................................................................................... 81
9.1
PUBLISHED REFERENCES...........................................................................81
9.2
UNPUBLISHED REFERENCES.....................................................................84
10. APPENDICES .......................................................................................... 88
10.1
SAFETY AND OTHER CLINICAL LABORATORY EVALUATIONS....88
10.1.1 Blood volume charts .............................................................................89
10.2
CLINICAL EVALUATION OF LIVER INJURY .........................................90
10.2.1 Introduction...........................................................................................90
10.2.2 Procedures .............................................................................................90
10.3
DOSING OF DABIGATRAN ETEXILATE...................................................91
10.3.1 Dosing nomogram (starting doses)......................................................92
10.3.2 Dose Adjustment nomogram ...............................................................94
10.3.2.1 Up-titration...............................................................................94
10.3.2.2 Down-titration..........................................................................96
11. DESCRIPTION OF GLOBAL AMENDMENTS................................... 98


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT 
Alanine-Aminotransferase
AP
Alkaline Phosphatase
AST 
Aspartate-Aminotransferase
AUC
Area Under the Curve 
aPTT
Activated partial thromboplastin time
aVTEt
Acute Venous thromboembolism treatment
BI
Boehringer Ingelheim
BIBR 1048 MS
Indicates the mesylate salt. Unless otherwise specified BIBR 1048 MS has 
been used interchangeably with BIBR 1048
BID, b.i.d.
Twice daily
BUN
Blood Urea Nitrogen
C
Centigrade/Celsius
CA
Competent Authority
Cmax
Maximum Measured Concentration 
CML
Local Clinical Monitor
CPMP
Committee for Proprietary Medicinal Products
CRA
Clinical Research Associate
CRF/eCRF
Case Report Form / electronic Case Report Form
CRNM
Clinically relevant non-major (bleeding)
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
EU SPC
European Union Summary of Product Characteristics
EOT
End of Treatment
eEOT
Early End of Treatment
F
Fahrenheit 
FIIA
Factor IIA (synonym for thrombin)
FAS
Full Analysis Set
FDA
Food and Drug Administration


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FEIBA
Factor Eight Inhibitor Bypassing Activity
FRAC
Fraction of Adult Dose
GCP
Good Clinical Practice
h
Hour
HPLC
High Pressure Liquid Chromatography
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRT
Interactive Response Technology
ISF
Investigator Site File
ISTH
International Society on Thrombosis and Haemostasis
IRB
Institutional Review Board
IUD
Intra-Uterine Device
IVRS / IWRS
Interactive Voice Response System / Interactive Web Response System
LMWH
Low Molecular Weight Heparin
MedDRA
Medical Dictionary for Regulatory Activities
mL
Millilitre 
mg
Milligram 
MRI
Magnetic Resonance Imaging
MS
Mass Spectrometry
Na
Sodium
ng
Nanogram 
No.
Number
OAC
Oral anticoagulant
OLF
Oral Liquid Formulation
OPU
Operative Unit (of BI)
PE
Pulmonary embolism
PD
Pharmacodynamic
PDCO
Paediatric Committee (of the European Medicines Agency)
PK
Pharmacokinetic
PKS
Pharmacokinetic Set
PPI
PT
Proton Pump Inhibitor
Prothrombin Time
PTS
Post Thrombotic Syndrome
SAE
Serious Adverse Event
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamate Pyruvate Transaminase
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
TDMAP
Trial Data Management and Analysis Plan


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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 dilemma 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 (VKA) (R07-2939).  
There are frequent challenges with the use of UFH and 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 slow patient accrual, REVIVE was closed prematurely. The REVIVE study provides


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valuable information on the incidence of recurrent VTE, major bleeding and problematic 
issues associated with therapy of VTE in children (R06-2304).
1.2
DRUG PROFILE
Dabigatran inhibits free thrombin, fibrin-bound thrombin, clot-bound thrombin and 
thrombin-induced platelet aggregation. Dabigatran is not absorbed via the oral route. 
However, dabigatran etexilate, a small molecule prodrug which does not exhibit any 
anticoagulant activity, is orally bioavailable. 
Overall, the efficacy and safety of dabigatran etexilate (also referred to in this document as 
dabigatran) have been evaluated in Phase III trials that involved over 38,000 adult patients. 
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 study program with RE-COVER (1160.53, U09-1400-01) and RE-COVER II 
(1160.46, U11-2298-01) and the two secondary prevention studies (RE-MEDY: 1160.47, 
U10-2533-01) and RE-SONATE: 1160.63, U11-2267-01) have been recently completed. 
The clinical program investigating the efficacy and safety of dabigatran etexilate for 
treatment of acute VTE consists of two studies: 1160.53 (RE-COVER) and 1160.46 (RE-
COVER II). RE-COVER I and RE-COVER II were almost identical in design. Both of these 
studies were randomized, double-blind, active-controlled trials comparing dabigatran 
etexilate 150 mg b.i.d. to warfarin in a 1 to 1 ratio, with all patients starting VTE treatment 
with an initial period of at least 5 days of a parenteral anticoagulant. The primary endpoint 
was recurrent symptomatic VTE and deaths related to VTE. The secondary endpoint was 
DVT, PE, all deaths. The primary safety endpoint was major bleeding.
The RE-COVER study, conducted in 2,539 patients diagnosed with acute VTE, demonstrated 
that the rate of recurrent symptomatic VTE and VTE related death was similar in the 
dabigatran etexilate and warfarin treatment group and the pre-specified criteria for declaring 
non-inferiority was met. At 6 months, the primary endpoint occurred in 30 out of 1274 
patients (2.4%) randomized to dabigatran etexilate group vs. 27 out of 1265 patients (2.1%) 
randomized to warfarin (risk difference 0.4; 95% CI. -0.8 to 1.5; p<0.001 for the prespecified 
noninferiority margin). The rate of major bleeding events was also similar between the two 
treatment groups. Major bleeding occurred in 20 out of 1274 patients (1.6%) randomized to 
dabigatran and 24 out of 1265 patients (1.9%) randomized to warfarin (hazard ratio 0.82; 
95% CI, 0.45 to 1.48). The rates of clinically relevant bleeding events and of any bleeding 
events were significantly lower in the group treated with dabigatran vs. warfarin (1160.53, 
U09-1400-01). 
The RE-COVER II study, conducted in 2,559 patients diagnosed with acute VTE,
demonstrated that dabigatran etexilate was non-inferior to warfarin for the primary efficacy 
endpoint and the pre-specified criteria for declaring non-inferiority was met. At 6 months, the 
primary endpoint occurred in 30 out of 1270 patients (2.4%) randomized to the dabigatran 
etexilate group vs. 28 out of 1289 patients (2.2%) randomized to warfarin (risk difference 


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0.2; 95% CI. -1.0 to 1.3; p<0.0001 for the prespecified noninferiority margin). Major
bleeding occurred in 15 out of 1270 patients (1.2%) randomized to dabigatran and 22 out of
1289 patients (1.7%) randomized to warfarin (hazard ratio 0.69; 95% CI, 0.36 to 1.32); 
(1160.46, U11-2298-01).
RE-COVER and RE-COVER II’s pooled results showed similar outcomes for the 
components of the primary efficacy endpoint (hazard ratio DE/W 1.09; 95% CI. 0.77-1.53), 
and lower incidence of major bleeding events (hazard ratio DE/W 0.48; 95% CI 0.29 to 0.78).
The RE-MEDY study assessed the safety and efficacy of oral dabigatran etexilate (150 mg 
b.i.d.) compared to warfarin in the secondary prevention of VTE in patients with a prior 
history of DVT or PE. This trial demonstrated that dabigatran etexilate was non-inferior to 
very well controlled warfarin for the primary endpoint (the composite of recurrent 
symptomatic VTE and VTE-related death). In the active-control study, recurrent venous 
thromboembolism occurred in 26 out of the 1430 patients (1.8%) in the dabigatran group and 
18 out of 1426 patients (1.3%) in the warfarin group (hazard ratio with dabigatran, 1.44; 95% 
95% CI,  0.78 to 2.64; p=0.01 for non-inferiority). The frequency of major bleedings was 
numerically lower but not statistically significant for the dabigatran etexilate group.  Major 
bleeding occurred in 13 out of 1430 patients (0.9%) in the dabigatran group and 25 out of
1426 patients (1.8%) in the warfarin group (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). The 
incidence of patients with any bleeding events was, statistically, significantly lower in the 
dabigatran etexilate group than in the warfarin group.  Fewer patients in the dabigatran 
etexilate group than in the warfarin group reported multiple bleeding events.
The long term secondary VTE prevention RE-SONATE trial established that dabigatran 
etexilate was superior to placebo with at least a 75% reduction in the occurrence of VTE. The 
frequency of patients with major bleeding was low (0.3%); however, the incidence of patients 
with any bleeding events was greater in the dabigatran etexilate group (95/684 treated 
patients) than in the placebo group (50/684 treated patients).  
The efficacy and safety of dabigatran etexilate for stroke prevention in patients with atrial 
fibrillation was evaluated in the “Randomized Evaluation of Long term anticoagulation 
therapy (RE-LY) study” (U09-3249-02). In total, 18,113 patients with non-valvular atrial 
fibrillation and, at least, one additional risk factor for stroke were randomized to dabigatran 
etexilate 110 mg b.i.d., dabigatran etexilate 150 mg b.i.d. or warfarin, titrated to a target INR 
of 2 to 3. The RE-LY study results demonstrate that 150 mg dabigatran etexilate is superior 
to warfarin for the prevention of stroke/SEE and similar to warfarin with respect to the rate of 
major bleeding. The 110 mg dose of dabigatran etexilate was non-inferior to warfarin in the 
prevention of stroke/SEE and superior with respect to the rate of major bleeding. In addition, 
for both doses of dabigatran etexilate, there is a reduced risk of intracranial haemorrhage and 
total bleeding compared to warfarin. The risk of myocardial infarction was low for all 
treatment groups but numerically higher in the dabigatran groups. In conclusion, in atrial 
fibrillation patients with moderate to high risk of stroke, dabigatran etexilate has similar or 
superior efficacy compared to standard treatment with clinically meaningful reductions in the 
bleeding risks associated with standard anticoagulation regimen.


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Two investigational phase II trials examined dabigatran etexilate and warfarin in patients 
with recent mechanical heart valve surgery (i.e. within the current hospital stay) and in
patients who received a mechanical heart valve replacement more than three months prior to 
screening in these studies. In these two phase II studies, 252 patients were entered and 
dabigatran etexilate doses between 150 mg b.i.d. and 300 mg b.i.d. were tested. During the 
conduct of these studies, an imbalance in thromboembolic events (primarily stroke) in 
disfavour of dabigatran in comparison to warfarin was observed. Furthermore, the frequency 
of total bleeding events was higher in patients treated with dabigatran etexilate in comparison 
with warfarin. This imbalance in total bleeding events was mainly driven by a higher number 
of minor bleeding events with dabigatran etexilate. In the early post-operative patients, major 
bleeding manifested predominantly as post-operative haemorrhagic pericardial effusion, 
specifically in patients starting dabigatran etexilate early after surgery (i.e. on day 3).  Based 
on the above data, dabigatran etexilate treatment was stopped and all patients were switched 
to warfarin. Dabigatran etexilate is contraindicated in patients with prosthetic heart valve 
replacement.
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 
41 individual Phase I studies and the collection of pharmacokinetic and pharmacodynamic 
data from seven Phase II studies and three Phase III studies (RE-LY, RE-NOVATE 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 close correlation between dabigatran plasma concentrations and its 
pharmacodynamic effects (e.g. changes in ecarin clotting time (ECT), thrombin time (TT), 
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. aPTT prolongation) was consistent between various patient 
populations and healthy volunteers and not affected by age, sex, or co-medication 
(U09-1399-02).  


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In the RE-LY study (U09-3249-02) a relationship between total dabigatran exposure and 
efficacy (i.e. ischemic stroke) has been established. 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 
physiopathology of thrombotic events in the two populations, 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. 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.
However, it is worth mentioning that the goals of the dosing algorithm for initial dabigatran 
etexilate dosing and for dose-titrations are to reach the pre-defined target exposure for 
dabigatran. This target will be amended based on further data from phase I and IIa studies as 
well as data from this study population.
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 


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<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.
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.


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The projected steady-state dabigatran trough concentrations of this study were largely 
comparable to those observed in adult patients with VTE.
Combined PK-PD analysis of studies 1160.88, 1160.89, and 1160.105):
A combined PK-PD analysis conducted on data from three paediatric studies (1160.88, 
1160.89 and 1160.105) covering the full age spectrum of paediatric patients has shown that 
the concentration-coagulation time relationships observed in paediatric patients of all age 
groups, including the age range 0 to <2 years, were similar to those observed in adult  
populations when considering ratios over baseline (c09149467). When considering absolute 
clotting times, the relationships are similar across age groups for dTT. For ECT and aPTT, 
PK-PD relationships are similar for all age groups, except for the ages <2 months. PK-PD 
relationships for aPTT and ECT in infants <2 months old are shifted upward by on average 
10-15% (ECT) and 10-20% (aPTT) relative to the most sensitive predicted PK-PD profiles in 
the adult volunteer population. These results indicate that very young children at an age of < 
2 months who have higher baseline aPTT and ECT values may show an increased sensitivity 
to dabigatran exposure.
Pharmacokinetic evaluation in juvenile rats:
The pharmacokinetic evaluation of juvenile toxicity studies in rats has shown higher 
dabigatran exposures (up to 5-fold) in neonate rats (7 days of age) than in child rats (28 days 
of age) or adolescent rats (8 weeks of age) (n00249900, n00251085) . The exposures, profiles 
and linear kinetics found in child rats (28 days of age) and adolescent rats (8 weeks of age) 
were completely in line with the respective observations in adult rats. The most probable 
explanation for the pharmacokinetic differences in neonate rats in comparison to child rats 
and adolescent rats may be a reduced activity of P-glycoprotein, a lower activity of carboxyl 
esterase 2 in the intestines, and a pH-dependent saturation of absorption due to higher gastric 
pH in neonate rats (c01632884).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
VTE treatment 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 regards as the preferred agent for paediatric VTE treatment.
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 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 may provide such an option.
The present study is a non-inferiority trial of dabigatran etexilate versus standard of care in 
children from birth to less than 18 years of age. This study is an agreed upon design based on 
the recommendations of the European Medicines Agency’s Paediatric Committee. This study
is part of the paediatric dabigatran clinical development program for VTE treatment and has 
the potential to provide critical information regarding the safety and efficacy of dabigatran 
etexilate for VTE treatment 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 objectives of this large phase IIb/III paediatric study are to assess the efficacy and 
safety of dabigatran etexilate relative to standard of care and to document the appropriateness 
of the proposed dabigatran etexilate dosing algorithm for use in patients from birth to less 
than 18 years of age.
2.3
BENEFIT - RISK ASSESSMENT
Individuals participating in this trial will benefit from the close medical care which will be 
provided within the framework of this study. Patients assigned to dabigatran etexilate 
treatment may also benefit from receiving an extensively evaluated drug which was shown to 
be safe and effective in adult patients with VTE.  In fact, 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. Moreover this study may help to bring a new and innovative therapy to 
paediatric patients with VTE, therefore providing a general benefit to society and to the entire 
paediatric patient population with VTE.


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The tolerability and PK/PD profile of dabigatran has also been evaluated in paediatric 
patients. Data obtained from 8 adolescent patients in trial 1160.88 (U12-3378-01) 
demonstrated that dabigatran capsules were apparently safe and well tolerated in this small 
study. 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.
The PK findings of the juvenile toxicity studies (n00249900, n00251085) as well as the 
results from the combined PK-PD analysis of studies 1160.88, 1160.89, and 1160.105 
(c09149467), could be potentially relevant for dabigatran exposure in patients aged from 
birth to less than 2 months old.
Dabigatran plasma concentrations will be evaluated at all treatment study visits and the 
dabigatran dose will be up or down titrated to maintain dabigatran plasma concentrations
within the proposed therapeutic range. This is expected to enhance efficacy and also 
minimize the risk of bleeding.
In addition, the potential risk of bleeding in patients below 2 months randomized to 
dabigatran etexilate will be assessed in an expedited manner after at least six doses of study 
medication (at steady state, Visit 3), based on aPTT ratio over baseline and the absolute aPTT 
value measured locally. Down-titration of the dose will occur if the aPTT level at Visit 3 is ≥ 
2-fold over aPTT at baseline or exceeds 100 seconds. In order to ensure maintenance of 
trough dabigatran concentration within a 50 to < 250 ng/mL window, all further assessments 
for these patients will be based on HPLC-MS/MS assay or dTT assay performed at the 
central lab.
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 1160.106, 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 (250ng/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) rather than 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 or as 
early as possible after Visit 3 in case of patients < 2 months based on aPTT ratio over 
baseline and the absolute aPTT value obtained locally.
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 > 250ng/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. 
To further minimize risk, individual patient risk will be carefully monitored by close 
observation during the treatment and follow-up periods.  A Data Monitoring Committee 
(DMC) will also be utilized during the study to further insure the participants’ safety. A 
separate charter specifies their roles and responsibilities. The planned tiered-approach of only 
evaluating younger age groups (stratum-2 and then 3) after a DMC-evaluation of a relevant 
number of older patients will provide added safety. This approach ensures that the younger 
age groups will only be evaluated after the dosing algorithm is confirmed and preliminary 
efficacy and safety data are obtained from older age group(s), and preliminary PK, PD and 
safety data are available from other phase IIa studies. These measures are expected to provide 
adequate safety protection for all study participants.
A specific reversal agent for dabigatran in children is not available yet, however, a 
development program in children is ongoing (P15-06362).
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 ensure patient safety.
Overall, dabigatran etexilate, as an oral treatment, may offer an alternative to LMWHs, 
without any need for daily injections for VTE treatment.  It may also reduce the need for 
frequent blood samples for therapeutic drug monitoring as is the case with currently available 
VKAs. This study has the potential to offer to the participating subjects close medical care 
and an alternative therapy which was shown to be safe and effective in adults, hence 
potentially providing a real therapeutic benefit to individual subjects as well as benefit the 
entire paediatric patient population with VTE by developing an alternative therapeutic option 
for this disease.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-centre, open-label, randomized, parallel-group, active-controlled, non-
inferiority study of dabigatran etexilate versus standard of care (SOC) in children from birth 
to less than 18 years of age. This study will be conducted at approximately 100 sites located 
in approximately 30 countries.
After a signed consent form (and assent, if applicable) has been obtained, the patients will
enter a screening period while they are completing their initial phase of their VTE treatment
by parenteral therapy. A 2:1 randomization scheme is planned (dabigatran to standard of care).
The intended SOC (LMWH or VKA or fondaparinux) must be specified at randomization.
Once eligibility has been confirmed, patients will receive either daily dabigatran etexilate or
SOC for up to 3 months (inclusive of the initial parenteral therapy). Guidance on how to 
switch from parenteral therapy to dabigatran etexilate is provided in Section 4.1.4. Refer to
Section 4.1.3 for information on dose selection. Patient experiencing an event requiring
discontinuation of dabigatran per protocol will be switched to an appropriate SOC therapy and
will be followed until the end of the study based on an intent-to-treat principle. Patients
requiring VTE therapy beyond 3 months have to be switched at Visit 8 (day 84) to SOC
treatment (if randomized to dabigatran etexilate) or continue SOC treatment (if randomized to
the SOC arm) and could be maintained on SOC during the follow-up period. Patients requiring
further anticoagulation for secondary VTE prevention due to an unresolved clinical risk factor
may be enrolled in an open-label secondary prevention trial and their follow-up visits will be
performed within this separate study
Figure 3.1: 1
Diagram representing the major study periods
Study visits and procedures will be performed as outlined in the Flow Chart.  Collection and 
processing of PK samples is described in Section 5.5.2 and for the PD samples, in Section 
5.7.2.  
All patients who have taken dabigatran or SOC will have a follow-up visit at least 28 days
after Visit 8 (end of planned treatment) or after early EOT. Study participation of a subject, 
who did not prematurely discontinue study medication, is concluded when the last planned


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study visit (Visit 9) has been completed. For information about study procedures for patients who 
prematurely discontinued from study medication see Section 3.3.4. Patients who will require
secondary VTE prevention due to unresolved clinical risk factor may continue in a long-term 
secondary VTE prevention study and their follow-up visit will be performed within this
separate study.
The residual effect period for which AEs will still be considered on-treatment following the 
last intake of trial medication (dabigatran and SOC) is 6 days. In case of an ongoing AE at 
the end of the planned follow-up period, the patient will be evaluated until resolution of the 
AE or until the investigator and sponsor agree that no further follow-up is necessary. If a 
patient develops a VTE or a MBE, they should be followed until the resolution of the event.
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.
Boehringer Ingelheim (BI) will appoint 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.
Data Management and Statistical evaluation will be performed by BI according to BI SOPs. 
For these activities, a Trial Data Manager, a Trial Programmer and a Trial Statistician will be 
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 organisation of the trial will be done by the respective local BI organisation (Operating 
Unit (OPU)) or a 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 will be 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.
Documents on the participating principal investigators 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.


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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 an independent Data Monitoring Committee 
(DMC). A detailed DMC charter will govern the activities of this committee. The 
recommendations of the DMC will be maintained in the clinical trial master file.
The members of the DMC will be external experts in the fields of VTE treatment and 
anticoagulation; members with statistical expertise will also be included in the committee as 
outlined in the DMC charter. The committee will review efficacy and 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 relevant dabigatran adult and paediatric study 
results as well as monitor the overall paediatric program to ensure patient safety. The DMC 
will also have access to information collected in ongoing and previously completed paediatric 
phase IIa trials. The DMC may open the trial to age stratum 2 and then 3 based on available 
safety and efficacy data 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 stratum. The DMC may implement a 
partial release of stratum 3 depending on the availability of PK/PD data from respective age 
groups studied in the phase IIa studies.
Specifically, the DMC will have the ability to recommend to the sponsor modifications with 
respect to the target dabigatran plasma concentration range based on available data. The dose 
regimen will be reviewed on an ongoing basis by the committee and can be further revised as 
data on dabigatran levels and safety and efficacy data become available during the course of 
the 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.
3.1.1.2
Central Independent Blinded Adjudication Committee
All components of the primary efficacy endpoint as well as all bleeding and all fatal events 
will be centrally adjudicated by an independent adjudication committee that will be blinded 
to all treatment assignments and will confirm or refute outcome events.
3.1.1.3
Central laboratory
All planned safety samples will be analysed at a central laboratory. If approved by the 
sponsor, a local laboratory may be used in certain circumstances where centralized 
assessments are not feasible. Pharmacokinetic and pharmacodynamic plasma samples may be 
analysed at contract research laboratories.


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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 or more Coordinating Investigators (CIs) and other 
representatives. The sponsor will be represented on this committee.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This is an open-label, randomized, parallel-group, active-controlled, multi-centre non-
inferiority study of dabigatran etexilate versus standard of care for the treatment of VTE in 
paediatric patients. Children from birth to less than 18 years of age will be eligible to 
participate and will be stratified based on three age groups; refer to Section 3.3 for details. 
The design of this study (including the definition of endpoints and SOC comparators) is 
based upon the European Medicines Agency’s Paediatric Committee’s recommendations. 
This committee has previously reviewed and approved the principal design elements and 
endpoints of this trial. For details on the primary efficacy endpoint, refer to Section 5.1.1. The
components of the primary efficacy endpoint as well as all bleeding and all fatal events will 
be centrally adjudicated in a blinded fashion.
3.3
SELECTION OF TRIAL POPULATION
Subjects will be stratified in 3 separate age groups: Age stratum 1 (from 12 to < 18 years of
age), age stratum 2 (from 2 to < 12 years of age) and age stratum 3 (from birth to < 2 years of
age). A minimum of 141 randomized evaluable patients will be needed to evaluate the
primary endpoint including a target of 60 patients in age stratum 1, 18 patients in age stratum 
2 and 15 patients in age stratum 3. 8 patients in stratum 3 are targeted to be below one year of 
age. The recruitment of patients could continue after achieving the minimum total number of 
patients and the targeted number of patients per age strata if required by Regulatory
Authorities. All patients who received at least one dose of study medication will be 
considered evaluable. Recruitment will be initiated in stratum 1 and may be opened to age
stratum 2 and then 3 based on Data Monitoring Committee (DMC) recommendations.
Patients in stratum 3 will be included and treated in accordance to the availability of the age
appropriate dabigatran etexilate formulations
Patient eligibility will be assessed based upon a complete medical history including a 
physical examination and laboratory testing. A log of all patients screened and included in the 
study (i.e. having given informed consent) 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 between 0 to less than 18 years of age with a confirmed acute venous 
thromboembolism diagnosis and an anticipated requirement for at least 3 months of anti-
thrombotic treatment; patient screening may start as soon as the patient has been diagnosed 
with a VTE. It is expected that parenteral therapy would be administered for a minimum of 5 


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to 7 days using an unfractionated heparin (UFH) or a low molecular weight heparin (LMWH) 
in all study participants, although for some patients a longer period of initial therapy may be 
given (but not exceeding 21 days).
3.3.2
Inclusion criteria
1) Male or female subjects 0 to less than 18 years of age at the time of informed consent / 
assent.
2) Documented diagnosis of clinically stable VTE (e.g. DVT, PE, central line thrombosis, 
sinus vein thrombosis) per investigator judgment, initially treated (minimum of 5 to 7 
days, but not longer than 21 days) with parenteral anticoagulation therapy, such as 
unfractionated heparin (UFH) or a low molecular weight heparin (LMWH)2.
3) Anticipated treatment duration with anticoagulants for the VTE episode (under inclusion 
2) for at least 3 month period, inclusive of the initial parenteral therapy.
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.
3.3.3
Exclusion criteria
1) Conditions associated with an increased risk of bleeding:
a) Any prior intracranial haemorrhage, classified as a macrobleed1. Any intracranial 
anatomical abnormality or intracranial aneurysm. Active meningitis, encephalitis, 
or intracranial abscess at randomisation.
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, 
in major surgery, a mesenchymal barrier is opened (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.
_____________________________
1 Patients with 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 


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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.
2 Short-term pre-treatment with VKAs is permitted if the INR has not yet reached a therapeutic level (i.e. the
INR is still < 2.0). The duration of the initial parenteral therapy inclusive VKA treatment if applicable must 
not exceed 21 days.
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) Fibrinolytic agents within 48 hours of dabigatran administration (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).
i)
Uncontrolled hypertension on antihypertensive medication (systolic and/or 
diastolic blood pressure (BP) 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) > 3x 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 a medically accepted contraceptive method per local guidelines. 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


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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 stratum 3 (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 < 80x109/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 prohibited or restricted medication within one week of the first 
dose of study medication other than medication for prior VTE treatment and P-
glycoprotein inhibitors. For trial restrictions please see Section 4.2.2.
10) Patients who have received an investigational drug in the past 30 days prior to screening.
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.
13) Patients or parents/legal guardians who are unwilling or unable to undergo or permit  
repeat of the baseline imaging tests required to confirm thrombus resolution at study day 
84 (or at eEOT, whichever comes first) or in whom repeating such imaging tests at these 
pre-specified time points may not be medically in the patient’s best interest. Examples 
may include unwarranted radiation exposure as a result of a repeat CT scan at study day 
84 (or eEOT, whichever comes first) for a patient with an isolated case of pulmonary 
embolism evaluated at baseline solely by a CT scan. In such cases, the baseline 
radiological assessment (e.g. CT) may be supplemented with an acceptable non-
radiological assessment at baseline (e.g. MRI) which could then be repeated at day 84 (or 
eEOT, whichever comes first) hence alleviating any potential unwarranted radiation 
exposure.  
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
The parent(s) / legal guardian(s) and/or their child may decide to be removed from the study 
as follows:

The patient/parent/legal guardian may decide to discontinue from treatment and wish 
to switch to another treatment prior to end of trial and be willing to be followed up 
within the clinical trial until the time at which study completion would have occurred.


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
The patient/parent/legal guardian may decide to discontinue study treatment or not 
participate in any further trial related activities, but be willing to be contacted once at 
a time point at which the patient would have completed the study to determine the 
patient’s vital status.

In very rare cases, the patient/parent/legal guardian may withdraw consent/assent to 
continue in the study for any reason; in doing so they refuse to participate in any 
further trial related activities and decline any contact or data to be collected for trial 
purposes. If this occurs, this decision must be clearly documented.
An individual patient is to be discontinued from trial treatment, but will remain part of the 
analysis population:

If the patient is no longer able to participate for other medical reasons (e.g. surgery, 
AEs, other diseases or concomitant therapies).

In the event that a new thromboembolic event or a clear clinical progression of the
baseline VTE (e.g. based on ISTH guidelines) are observed as assessed by the
Investigator and using appropriate imaging modalities or if the patient experiences a
drug-related significant or drug-related serious AE or if drug toxicity is observed, then 
the patient is to be removed from the dabigatran treatment arm and be put on standard 
of care per investigator judgment and be followed until the end of the study. Subjects 
in the SOC arm may also require changes in their therapy.

Patients who do not reach a total dabigatran plasma trough concentration within the 
pre-specified therapeutic range after one dose adjustment.

In the opinion of the Investigator, continuation in the trial is not in the patient’s best 
interest. If treatment non-compliance persists despite all possible efforts, patients 
should be removed from the allocated treatment and alternative therapy should be 
proposed in such cases.

If a patient becomes pregnant or a pregnancy is suspected during the trial the 
investigational drug (dabigatran) will be stopped, the patient will be discontinued 
from the dabigatran treatment arm and will be put on an appropriate SOC 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.

If a 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 
14 calendar days), treatment with dabigatran must be stopped and the patient must be 
switched to an appropriate SOC regimen.
If a patient develops eGFR < 50 mL/min/1.73m2 using the Schwartz formula for 


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second time during the course of the study, treatment with dabigatran etexilate (when 
applicable) must be stopped without further retesting and the patient must be switched 
to an appropriate SOC regimen.

The patient does not require treatment with anticoagulants any longer due to a
complete thrombus resolution as confirmed by appropriate imaging modalities prior to
12 weeks 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.
A patient can be discontinued from treatment after discussion between patient/parent/legal
guardian, sponsor and Investigator if eligibility criteria are being violated, or if the patient
and/or parent/legal guardian fail to comply with the protocol (e.g. non-attendance at trial
assessments, improper drug intake, etc.). In such cases and when feasible, the patient is to be
followed until the end of study preferably according to the remaining visit schedule.
In addition, in order to protect patient safety, measurements of dabigatran trough plasma
levels will be performed in a central laboratory using HPLC-MS/MS or dTT assay or an
alternative assay from blood samples taken at steady state (initially after a minimum of three
to five days on study treatment, i.e. at minimum after six consecutive dabigatran doses are
taken). If a patient has a dabigatran plasma level of < 50ng/mL or ≥250ng/mL confirmed
despite a dose adjustment, they will stop taking dabigatran and will be switched to SOC for 
the remainder of the study. 
Dabigatran is predominantly excreted by the kidney; special attention should be given to the
kidney function of these patients when needed. As stated above, patients with an eGFR < 50
mL/min/1.73m2 using the Schwartz formula at the screening visit (Visit 1) or any patient with
confirmed eGFR < 50 mL/min/1.73m2 at any time during the treatment period will be
excluded from the dabigatran arm and will be switched to SOC for the remainder of the study. 
Any suspected worsening of renal function during the study should be investigated by eGFR
evaluation.
Patients who drop out during screening (i.e. prior to randomisation at Visit 2) 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 is required.
Patients who discontinue study drug or withdraw from the trial after randomisation (Visit 2) 
will be considered as “early discontinuations” and the reason for premature discontinuation 
must be recorded in the eCRF. The data will be included in the trial database and will be 
reported.
All patients that prematurely discontinue dabigatran for various reasons as outlined above and 
who do not withdraw consent/assent will be switched to SOC after a dabigatran eEOT visit 
and then followed for the remainder of the study preferably according to the remaining visit 
schedule. In cases where the patient/parent/legal guardian does not allow for a follow-up 
according to the remaining schedule and where consent/assent is not withdrawn, the 
patient/parent/legal guardian will be contacted by the Investigator to perform a dabigatran 


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eEOT visit (i.e. before 12 weeks of treatment) and subsequently be contacted at 4 months in 
order to gather information for study endpoints (e.g. bleeding events, survival, occurrence of 
VTE, etc.). If an outcome event is reported to the site (e.g. bleeding events, occurrence of 
VTE, etc.) then, to ensure patient safety, the patient/parent/legal guardian will be asked to 
come to clinic for an unplanned visit as soon as possible.
Procedures to be followed for patients prematurely terminating the trial are detailed in
Section 6.2.3.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the entire trial, or terminate the 
conduct of the trial at all sites within a particular country or at any individual site.
The following reasons are examples that may lead to discontinuation of some or all of the 
trial sites:

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
4.1.1
Identity of BI investigational product and comparator products
The investigational product dabigatran etexilate will be supplied by Boehringer Ingelheim. 
The composition of planned formulations is detailed below.
Dabigatran etexilate capsules:

Substance: Dabigatran etexilate

Pharmaceutical formulation: Capsule

Source: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany

Unit strength: 50 mg, 75 mg, 110 mg and 150 mg

Total Daily dose: The administered dose (BID) is based on an age and weight 
adjusted nomogram included in Appendix 10.3.1. 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 10.3.1). Detailed preparation and 
administration instructions will be included in the ISF. 

Total Daily dose: The administered dose (BID) is based on an age and weight 
adjusted nomogram included in Appendix 10.3.1. 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 (BID) based on an age and weight adjusted nomogram included in 
Appendix 10.3.1. 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
The active comparator (e.g. LMWHs or VKAs or fondaparinux used as SOC) will not be 
supplied as part of the investigational medicinal product. 
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. 
Eligible patients who meet all inclusion and exclusion criteria will be randomly assigned to 
receive either dabigatran or standard of care (LMWH or VKA or fondaparinux) in an open-
label fashion based on a 2:1 ratio (dabigatran:SOC). In addition, patients assigned to 
dabigatran etexilate OLF will be randomized based on 1:1 ratio to receive flavoured or 
unflavoured solvent for reconstitution. The intended SOC treatment must be specified at
randomization.  Patient assignment to the treatment groups will be managed by IRT. Access 
to the randomisation code will be controlled and documented. 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 randomization, to track medication 
assignments, to monitor the appropriate age stratification according to strata 1, 2 and 3 and 
the minimum number of patients required in each age group. The IRT will also be used to 
control aspects of the medication supply chain. 
Randomization will be initiated in stratum 1 and progressively open to stratum 2 and then 3 
once the DMC authorizes the start of recruitment in strata 2 and 3 following the review of 
ongoing data in stratum 1 (considering patients from this trial and from the secondary VTE 


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prevention trial 1160.108), data from previously completed phase IIa studies and any other 
relevant information as described in the DMC charter. 
4.1.3
Selection of doses in the trial
Estimated doses for paediatric patients assigned to take dabigatran will be based on age and
weight according to a nomogram (please refer to Appendix 10.3). Provided that a dabigatran
assignment is confirmed, patients aged ≥8 years who are able to swallow capsules will be
assigned to take capsules. If a patient aged ≥8 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, however, 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 SOC (including LMWH or VKA or fondaparinux) will be monitored regularly and dose 
adjusted throughout the treatment period as needed based on investigator recommendations 
and local guidelines. In case of VKA use, the patient will be adjusted to ensure the INR for 
the patient is maintained at a level appropriate for the individual thromboembolic risk factors 
as recommended by local guidelines and investigator. In case of LMWH use, monitoring may 
be done (although it is not required) using anti-factor Xa activity and the LMWH dose may 
be adjusted when needed according to local guidelines and investigator recommendations to 
ensure maintenance within an acceptable therapeutic range.
The dose of dabigatran etexilate may 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 most extensive data 
set comes from over 12,000 patients exposed to dabigatran for a median of 2 years in the 
completed atrial fibrillation program. Dabigatran etexilate 150 mg BID was shown to be 
more effective at preventing strokes than well-controlled warfarin (median time in therapeutic 
range of the INR between 2.0 and 3.0 was 67%) with comparable or less bleeding. A large 
dataset is also available from adult VTE patients treated with 150 mg bid (1160.53, U09-
1400-01) where dabigatran had about half the bleeding of well controlled warfarin while 
being non-inferior for VTE prevention, albeit with a hazard ratio slightly greater than 1.0. 
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 developed.
In the RE-LY study, 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 clearly associated with efficacy for the prevention of stroke and even lower 


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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 physiopathology of 
thrombotic events in the two populations, a trough concentration ≥ 50 ng/mL is expected to 
provide a satisfactory benefit risk ratio for paediatric patients. Furthermore, based on a low 
risk of major bleeding events with rising total dabigatran trough concentrations even beyond 
250 ng/mL, it is considered that trough concentrations between 50 and < 250 ng/mL have the 
potential to have a positive benefit/risk ratio in children of all ages. 
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 RE-COVER (mean age 55.0), the general paediatric 
population is characterised 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).
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 W 0.662 (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)


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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 10.3.1. Dosing of patients should only occur
according to the adjusted nomogram provided in Appendix 10.3.1.
Table 4.1.3: 1
Target dabigatran etexilate doses (in mg) based on Hayton 
calculations for paediatric patients
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 may be increased by 10 to 100%.
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 safe. 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 
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]


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may 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 10.3.2. 
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%
For patients below 2 months at Visit 3 the dabigatran etexilate dose will be down-titrated if 
the locally measured aPTT level is > 2-fold over aPTT at baseline or exceeds 100 seconds.
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 will be repeated at about 3 days after dose adjustment (after at least 
6 adjusted consecutive dabigatran doses have been taken) to confirm the new dose. After 
dose adjustment, the total dabigatran trough concentration should be ≥50 ng/mL and < 250 
ng/mL.
If patients cannot reach trough plasma concentrations between 50 and < 250 ng/mL after one
dose adjustment, they must discontinue dabigatran treatment and be treated at the
investigator’s discretion on SOC but will remain in the study according to the visit schedule
until the end of the trial.
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 10.3.2. 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 could suggest that wider or narrower total dabigatran trough concentration range 
is associated with better benefit/risk ratio. 


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4.1.4
Drug assignment and administration of doses for each patient
Treatment will be randomly assigned in this trial and then dispensed in an open-label fashion.
Patients will either take dabigatran (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) or they
will be assigned to take SOC (LMWH or VKA or fondaparinux). The intended SOC 
treatment must be specified prior to randomization. If deemed necessary the type of SOC 
may be changed during the treatment period. Concerned patients will not be considered as 
having discontinued study medication early, will remain to be on study medication and will be 
followed per the visit schedule until the end of the study (see Flow Chart and Section 6.2.3).
Eligible patients, who meet all inclusion and exclusion criteria at visit 2, will be randomised
to receive either dabigatran or SOC (LMWH or VKA or fondaparinux) in a ratio of 2:1
(dabigatran:SOC). Patients assigned to take SOC are to follow the investigator’s
recommendation for adequate dosing and administration based on the product’s locally
approved label and in consideration of local treatment guidelines. Patients assigned to take 
dabigatran and 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). In case pre-treatment with VKAs has been initiated during the screening period, a 
local INR measurement should be performed at Visit 2 to confirm eligibility (INR < 2.0) (see 
Flow Chart).
The estimated dosages for paediatric patients assigned to take dabigatran as capsules, pellets
to be sprinkled on food or the oral liquid formulation will be based on age and weight
according to a nomogram provided in Appendix 10.3.1. Provided that a dabigatran
assignment is confirmed, patients aged ≥8 years who are able to swallow capsules (per
investigator judgment) will be assigned to take capsules. In case a patient aged ≥8 years but
below 12 years of age is unable to take capsules, 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 up to < 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 capsules 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 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 


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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 dose (or the recommended SOC dose) is properly taken.
The interval between dabigatran 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.
In the event that a patient has to be switched from dabigatran therapy to SOC, the investigator 
should plan for each subject’s transition to SOC taking into consideration the patient’s risk 
profile and previous experience with a VKA or a LMWH or fondaparinux. 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. Close monitoring of the patient’s coagulation profile 
during the transition period must be implemented to optimize safety. In general, dabigatran 
therapy should not be overlapped with LMWH, VKA or fondaparinux therapy.
Investigators should recognise that the presence of dabigatran could elevate the INR. Once 
dabigatran has been stopped for >2 days, the INR will better reflect the effect of VKA 
therapy alone. Investigators should also be mindful that the use of LMWH needs to be 
monitored closely in patients with an extreme weight for their age and height or in patients 
with potential renal dysfunction due to the renal-based clearance of LMWHs. Anti-factor Xa 
activity may be useful for monitoring anticoagulation with LMWH therapy. 
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open-label study. Due to the safety obligation in this paediatric setting, the trial will 
be conducted in an unblinded fashion to ensure a rigorous supervision of the study.
Investigators, patients, and trial members will be unblinded. The only party blinded to 
treatment assignment are members of the adjudication committee.


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4.1.5.2
Procedures for emergency unblinding
Not applicable as this is an open-label study.
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
Patients/parents/legal guardians should be reminded to store and use LMWHs or VKAs or 
fondaparinux according to investigator instructions in consideration of local product labels.
Dabigatran should be kept out of the reach of children and be stored protected from moisture 
and direct sunlight. Dabigatran capsules should be kept in their supplied container and the 
bottle lid must be kept closed. Dabigatran capsules must not be transferred to other types of 
containers. The medication stick packs containing the dabigatran etexilate granules should be 
kept sealed until just prior to reconstitution. The medication stick packs containing the 
dabigatran etexilate pellets should be kept sealed until just prior to intake.
Patients/parents/legal guardians should be instructed to keep medication containers tightly 
closed and not to remove capsules from the original packaging material until immediately 
prior to the time of intake. Dabigatran may only be dispensed to trial patients 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.
For storage conditions refer to the locally approved medication label and the STORM 
(Storage conditions for Trial Medications) document in the ISF.
Detailed instructions for the preparation and/or reconstitution of the dabigatran (when 
applicable) and for dispensing and intake for dabigatran formulations (capsules, pellets and 
oral liquid formulation) will be placed in the ISF.
If the storage conditions are found to be outside the specified range, the local Clinical 
Monitor (CML) for the study should be contacted immediately and the medication should be 
quarantined in the IRT until further notice.
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. A temperature log 


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must be maintained to make certain that the drug supplies are stored at the correct 
temperature.
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 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 
randomisation until the patient completes follow up. In addition, at the randomisation visit, 
information regarding specific drugs (e.g. antithrombotic medication, medications with a 
potential drug-drug interaction with dabigatran etexilate (P-glycoprotein inhibitors and 
inducers)), administered in the 14 days prior to informed consent until time of randomisation 
and any medication given to directly treat an adverse event during the screening period will 
be recorded.
Certain concomitant therapies or surgery/intervention may require the temporary 
discontinuation of SOC or dabigatran etexilate. Study medication should be restarted as soon 
as safely possible. 


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At the screening visit, the site must document details of the initial parenteral anticoagulant 
therapy given for the treatment of the VTE.
4.2.1
Rescue medication, emergency procedures, and additional treatment
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 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, 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 there is one 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 
dialyzable, however there is limited clinical experience 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. 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.


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1 for bleeding definitions see Section 5.1.2.3
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)
Dabigatran must be stopped if a major bleeding event is observed. The patient must be treated 
and stabilized. Thereafter, the patient should be given SOC per investigator judgment and 
followed until the end of the trial based on the Flow Chart visit schedule.
Major bleeds for patients on SOC:
The local product label and local treatment guidelines should be followed in case a major 
bleed is observed with a LMWH or a VKA or fondaparinux. For major bleeding under 
LMWH therapy, protamine sulphate will reverse about 75% of the effects of LMWH. With 
VKA, treatment should be temporarily stopped and the anticoagulant effect reversed with 
vitamin K, prothrombin complex concentrates and/or fresh frozen plasma. Readministration 
of SOC, after the bleeding has been resolved and haemostasis has been achieved, is at the 
discretion of the investigator.
Clinically relevant non-major bleeds or minor bleeds:
If a patient experiences a clinically relevant non-major bleed or minor bleed, dabigatran or 
SOC may be continued, temporarily interrupted or permanently discontinued, at the 
discretion of the investigator. It is not a requirement; however, that study drug is stopped in 
these cases.


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Management of dabigatran and SOC prior to and after planned surgery:
Dabigatran Treatment Discontinuation for Elective Surgical Interventions
For minor surgery or interventions with a low risk for bleeding per investigator judgment, 
elective procedures could take place 36 hours after the last dabigatran intake (two missed
doses). Treatment can restart at investigator’s discretion but not earlier than 2 days after 
minor surgical interventions.
For major surgery with high risk for bleeding per investigator judgment, interventions could 
take place at least 72 hours after the last dabigatran intake (5 missed doses). The decision to 
re-start treatment with dabigatran is at the investigator’s discretion but should not occur prior 
to 7 days after major surgery. Patients should not re-start treatment with dabigatran after 
major surgery if there is a persistent increased risk of bleeding. The choice of alternative 
treatment is at the investigator’s discretion. For minor procedures involving a critical organ 
such as lumbar or epidural punctures, interventions could only take place at least 72 hours 
after the last dabigatran intake (5 missed doses). The decision to re-start treatment with 
dabigatran is at the investigator’s discretion but should not occur prior to 3 days after 
intervention.
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 risk and the thrombotic 
risk in each patient.
Dabigatran 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 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. 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.
SOC Treatment discontinuation for Elective and Acute Surgical Interventions
Local treatment guidelines should be followed for discontinuation and reintroduction of SOC
in cases of planned or emergency surgery.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The following treatments should not be taken with dabigatran:


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
All VKAs

Therapeutic unfractionated heparin or LMWH (heparin flushes of indwelling catheters is 
allowed) or fondaparinux

Fibrinolytic agents (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)
Note: Additionally fibrinolytic agents should not be taken within 48 hours prior to 
dabigatran administration.

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
Note: Additionally P-glycoprotein inducers should not be taken within one week prior 
to dabigatran administration.

Asparaginase - one week wash-out period to be considered (two weeks in case of 
PEG- Asparaginase)

Any other investigational drug (with the exception of the 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 excluded but may be included if they are part of
a chemotherapy regimen given in cycles, or if the benefits of corticosteroid therapy clearly 
outweigh risks.
4.2.2.2
Restrictions on diet and life style
Dabigatran etexilate may be taken with or without food. For more details please refer to 
Section 4.1.4.
SOC restrictions should be followed based on locally approved product labels.
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 or SOC. Subjects / parents / legal guardians will be 
asked to bring this completed log to every clinic visit which they will attend. Empty 
dabigatran capsule containers or solution vials or any unused drug should also be returned to
the investigator’s site for disposal and compliance calculation. Compliance should be 
calculated using the below equation preferably based on the returned medication (completed 
logs may also be used):
Compliance (in %)  =  (Actual number of dabigatran doses taken since last count / Planned 
number of dabigatran doses which should have been taken in the same period) x 100 


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If an interruption of SOC or 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 allocated treatment 
and alternative therapy should be proposed in such cases.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - PHARMACODYNAMICS
5.1.1
Endpoints of efficacy
Primary endpoint: 
Efficacy combined endpoint Proportion of patients with:

Complete thrombus resolution and;

Freedom from recurrent VTE  (including symptomatic and asymptomatic, 
contiguous progression or non-contiguous new thrombus, deep vein thrombosis, 
pulmonary and paradoxical embolism, thrombus progression) and;

Freedom from mortality related to VTE.
The events outlined in the above combined primary endpoint will be assessed by 
radiologists or other such qualified clinicians using an appropriate method such as 
ultrasound, echocardiography, venography or computed tomography (CT scan) based 
on the location of the thrombus and the test used to perform the baseline assessment.
All components of the primary efficacy endpoint as well as all bleeding and all fatal events 
will be centrally adjudicated by an independent blinded committee.
Secondary endpoints: 

Freedom from major bleeding events (MBEs), defined as either fatal bleeding;
clinically overt bleeding associated with a decrease in haemoglobin of at least 
20 g/L in a 24-hour period; bleeding that is retroperitoneal, pulmonary,
intracranial or otherwise involves the central nervous system; or bleeding that
requires intervention in an operating suite.

Pharmacokinetic and pharmacodynamic assessments at visit 3 (after at least six 
consecutive dabigatran doses) and after at least 3 days following any 
dabigatran dose adjustment 

Frequency of dose adjustments (i.e. Number of subjects with dose adjustment), 
temporary and permanent discontinuation from therapy and number of subjects 
with laboratory monitoring requirements for dose adjustment during the 
treatment phase

Frequency of switch of type of anti-coagulation therapy (including dabigatran
to SOC) (Frequency of subjects switching the type of anti-coagulation therapy 
including dabigatran etexilate to standard of care and switching from an 
intended standard of care treatment to another)

Freedom from thrombus progression at end of therapy (day 84 after
randomisation (Visit 8) or eEOT whichever comes first) compared to baseline

Assessment of the acceptability of an age-appropriate formulation at end of
therapy

All bleeding events


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
All-cause mortality

All components of the primary efficacy endpoints
5.1.2
Assessment of efficacy
5.1.2.1
Physical examination
A complete physical examination will be completed for all patients at the time points noted in 
the Flow Chart. All abnormal findings at the screening visit will be recorded on the Medical 
History/Baseline Conditions eCRF page. New abnormal findings or worsening of baseline 
conditions detected at follow-up physical examinations will be recorded as AEs on the 
appropriate eCRF page, if judged clinically relevant by the investigator. A complete physical 
examination should be done when a patient discontinues the trial prematurely. In the event 
that clinically relevant findings are observed during the physical examination at the end of the 
study (or at early withdrawal from the trial), the patient should be followed by the 
investigator until resolution of the event, or an agreement has been made with the sponsor 
that follow-up is sufficient on that patient.
5.1.2.2
Venous thromboembolism assessment
In case of suspected 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.

Suspected DVT: Venous compression ultrasonography (CUS) or venography

Suspected PE: Ventilation-perfusion (V-Q) lung scan, pulmonary angiography or 
spiral (helical) CT

Suspected PTS: 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)

Suspected paradoxical embolism (PDE): CT / MR angiography or other appropriate 
evaluation 
The final assessment (at end of therapy) of the resolution status of the thrombus must be done 
using the same method as the baseline evaluation when appropriate.


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Note: If clinical evaluations warrant imaging (e.g. suspected thrombus extension), then per 
investigator judgment, appropriate imaging may be performed. When feasible, a baseline 
radiological assessment (e.g. CT) may be supplemented with an acceptable non-radiological
assessment (e.g. MRI) at baseline which could then be repeated at the end of therapy (study
day 84 (visit 8) or eEOT, whichever comes first) hence alleviating any potential unwarranted 
radiation exposure.
5.1.2.3
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:

Fatal Bleeding

Clinically overt bleeding associated with a decrease in haemoglobin of at least 2 g/dL 
(20 g/L) in a 24 hour period

Bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the 
central nervous system

Bleeding that requires surgical intervention in an operating suite
Clinically relevant non-major (CRNM) bleeding:

Overt bleeding for which a blood product is administered and which is not directly 
attributable to the patient’s underlying medical condition

Bleeding that requires medical or surgical intervention to restore haemostasis, other 
than in an operating suite
Minor bleeding:

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
5.2
SAFETY
5.2.1
Endpoints of safety
The main safety endpoint, freedom from major bleeding events (MBEs), is defined as either 
fatal bleeding; clinically overt bleeding associated with a decrease in haemoglobin of at least 
20 g/L in a 24-hour period; bleeding that is retroperitoneal, pulmonary, intracranial or 
otherwise involves the central nervous system; or bleeding that requires intervention in an 
operating suite.
Other safety endpoints:


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
Incidence of bleeding events including:
o
Major bleeding events; clinically relevant non-major bleeding events 
(CRNM), minor bleeding events and any bleeding events
o
Combined endpoint of major and CRNM bleeding events 

Incidence of adverse events, protocol-specified AESI and serious adverse events 

Treatment discontinuation due to an adverse event

Change from baseline in safety laboratory values, vital signs and physical 
examination 

Global assessment of tolerability (measured as treatment discontinuation and 
adherence) to study medication
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 in a clinical investigation 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


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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.
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.

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 chapter 
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 onwards through the follow-up period) will be 
collected, documented and reported to the sponsor by the investigator on the appropriate 
CRF(s) / eCRFs / SAE reporting forms. Reporting will be done according to the specific 


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definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the 
Investigator Site File. 
The end of residual effect period (REP) for dabigatran etexilate and SOC is set at 6 days after 
last drug administration. Therefore all events reported within 6 days of the last trial 
medication will be considered on treatment. All adverse events will be reported up until the 
end of the follow-up period, which is approximately 16 weeks after randomization.
Post Study:
The investigator may report SAEs which occurred in a subject after the end of the follow-up 
period, if the investigator becomes aware of them.
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 or the next business day whichever is shorter) to
the sponsor: SAEs, AESIs and non-serious AEs relevant to the SAE and/or AESI.    
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 RDC.
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. 
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 of awareness) to the 
defined unique entry point for SAE forms of the respective BI OPU (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 


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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 lab will be used for the analysis of the standard safety laboratory panel, see 
Appendix 10.1. If needed and when feasible a local laboratory may alternatively be used for 
dTT testing to evaluate dabigatran concentration. Local safety lab assessment is acceptable in 
emergency cases (e.g. bleeding event or emergency surgery). Furthermore local lab 
assessment of PT (prothrombin time)/ INR (international normalized ratio), aPTT (activated 
partial thromboplastin time) or Anti-Factor Xa activity for coagulation monitoring in SOC 
patients is an acceptable alternative to central lab testing. Refer to the Flow Chart and Section 
5.7.2 for additional information.
If a patient has already begun treatment with VKA, a local lab will be used for INR
measurement at Visit 2 to confirm eligibility.
An aPTT assessment at Visit 3 (taken locally) will be performed for all patients < 2 months of 
age. Patients < 2 months must have a locally performed baseline (i.e. before start of any
anticoagulant therapy) aPTT measurement available.
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 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. 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.
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. 


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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)

if applicable, pockets should be emptied of heavy objects (i.e. keys, coins, etc.)
5.3.2
Other assessments
5.3.2.1
Acceptability and tolerability of age appropriate formulations
Acceptability is defined as the overall ability and willingness of the patient and/or parent 
(legal guardian) to use the medicinal product as intended.
The global clinical assessment of acceptability will be performed by the patient (if old 
enough per investigator judgment) or by the parent / legal guardian.
In between study visits, the parent /legal guardian will be asked to document any failed or 
missed intake of medication (e.g. the patient did not swallow the medication, or doses missed, 
etc.) and provide this documentation to the investigator at the next study visit. The parent / 
legal guardian will be instructed to inform the investigator immediately if two or more 
consecutive doses of study medication are missed or not taken correctly.
In addition, for patients taking OLF, the acceptability will be described by the parent / legal 
guardian’s ability to administer the medicine as intended (under consideration of total volume 
to be administered and swallowed by the patient). It is determined by the caregiver based on 
his assessment of medication intake by the patient, and may depend on palatability of the 
study medication. 
5.4
APPROPRIATENESS OF MEASUREMENTS
All safety and clinical assessments are determined using standard methods and procedures.  


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.5.1
Pharmacokinetic endpoints
Exposure of dabigatran as assessed by measurement of the following plasma concentrations 
for total (after alkaline cleavage of glucuronide conjugates) dabigatran.

Cpre,ss (pre-dose concentration of the analyte in plasma at steady state immediately 
before administration of the next dose) taken at 10 to 16 hours after the last dose
(trough)

C2,ss (concentration of the analyte in plasma at steady state at 2 hours after 
administration of the last dose) taken at 1 to 3 hours after the last dose (peak)
The dabigatran dose administered to patients may be adjusted based on the determined pre-
dose dabigatran plasma concentration (Cpre,ss) at Visit 3 or at other future visits as needed. 
5.5.2
Methods of sample collection
Approximately 28.8 mL blood will be taken per subject during the whole course of the study 
for pharmacokinetic/pharmacodynamic purposes.
5.5.2.1
Plasma sampling for pharmacokinetic analysis
The visits where the pharmacokinetic (PK) samples are taken are noted in the Flow Chart. 
The date and exact clock time a PK sample is 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 PK sample collection should be recorded in the eCRF. About 8.4 mL of blood 
(approximately 1.2 mL per sampling time point) in total per patient is planned for collection 
for the PK samples.


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5.5.3
Analytical determinations
Analytical determination of total dabigatran will be performed by a validated high 
performance liquid chromatography – tandem mass spectrometry (HPLC-MS/MS) assay at a 
central laboratory. The procedure and specification of the analytical method are available at 
the analytical laboratory.
5.6
BIOMARKERS
Refer to section 5.7
5.6.1
Endpoints based on biomarkers
Refer to section 5.7
5.6.2
Methods of sample collection
Refer to section 5.7
5.6.3
Analytical determinations
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) will be 
employed for the quantitative measurement of dabigatran concentrations. The analysis of 
dTT will be done by a central laboratory. If centralized dTT testing is not possible, dTT may
also be analysed by a local laboratory. In case the use of the dTT assay is not feasible, an 
alternative method may be used. The dabigatran dose administered to patients may be 
adjusted at Visit 3 or other future visits as needed, based on the assessment of dabigatran 
plasma levels.
5.7.2 
Methods of sample collection
The collection time point for aPTT + ECT + dTT (Anti-Factor IIa activity) (for dabigatran-
assigned patients) and potentially other exploratory coagulation markers (for all patients) 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 are to be recorded


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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 treatment period and a 
follow-up period.
During the treatment period, patients will receive open-label dabigatran etexilate or SOC.  
Dabigatran dose selection and titration instructions are described in Section 4.1.3; detailed 
instructions are also located in the ISF.
All required assessments and procedures are listed in the Flow Chart and are further 
described in Section 5.
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).
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).
6.2.2
Treatment period
Before giving the first dose of study medication, eligibility must be confirmed. Throughout 
the treatment period, unscheduled visits and titration visits can be scheduled at any time to 
optimize dabigatran or SOC VTE treatment. 
For the schedule of assessments and procedures during the treatment period refer to the Flow 
Chart.  For information on dose selection refer to Section 4.1.3.  For details on PK and PD 
sample collection and analyses refer to Section 5.5 and Section 5.7.
6.2.3
End of trial and follow-up period
Patients who complete the treatment period and are not enrolled into the secondary VTE 
prevention study (BI trial 1160.108) are to be followed at Visit 9. For the schedule of 
assessments and procedures to be done at the follow-up visit refer to the Flow Chart.
All patients who prematurely discontinue study medication will be invited to perform an 
eEOT Visit and the follow-up Visit 9, taking place 28 days thereafter. Subsequently they will 
be followed-up preferably according to the remaining visit schedule until the end of the 


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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 done.
Patients having switched from dabigatran etexilate to SOC are considered as having early 
discontinuation of dabigatran etexilate treatment. However, such patients will still remain in 
the trial and will be followed as per the visit schedule till the end of the study. Patients having 
switched from one SOC to another during the treatment period, are not considered as having 
early discontinuation of treatment and should remain in the treatment period and be followed 
as per the visit schedule till the end of the study.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The study is designed to assess the efficacy and safety of dabigatran etexilate using a dosing 
algorithm to SOC for treatment and/or secondary prevention of paediatric VTE in patients 
from birth to less than 18 years of age. This trial is a prospective, multicentre, international, 
open-label, randomized, parallel-group, non-inferiority study comparing dabigatran etexilate 
to SOC. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
This trial is designed to provide evidence of efficacy and safety in paediatric patients by 
showing non-inferiority of dabigatran compared with SOC for paediatric VTE treatment. For 
the primary endpoint, proportion of patients with complete thrombus resolution, with no 
recurrent VTE and no VTE-related death, the non-inferiority hypothesis is: 
H01: p1C – p1D ≥ δ1 vs. H11: p1C – p1D < δ1 for the primary endpoint (δ1 = 20%) 
The selection of non-inferiority margin (δ1 = 20%) is summarized in Section 7.6.
Upon showing significance of non-inferiority for the primary endpoint using 90% confidence 
interval, test of superiority will be performed subsequently at one-sided level of 0.05 in the 
following order without multiplicity correction.
H03: p1C – p1D ≥ 0 vs. H13: p1C – p1D < 0 for the primary endpoint
The efficacy and safety of dabigatran for VTE treatment have been established in adult 
studies (U09-1400-01 and U11-2298-01). The objective of this paediatric trial is to confirm 
the dosing algorithm for paediatric patients and to provide evidence of efficacy and safety of 
dabigatran treatment in paediatric population. Therefore the one-side statistical significance 
level of 0.05 is considered adequate. The sample size and power calculations are detailed in 
Section 7.6.
7.3
PLANNED ANALYSES
The following analysis populations will be defined:
The randomized set (RS) will include all randomized patients in the treatment groups to 
which they are randomized. The intent-to-treat (ITT) principle will be applied to the 
randomized set including events from the time of randomization to the time point of interest 
(e.g. visit 8 for the primary efficacy endpoint). Patients who terminate the study medication 
prematurely will be followed and the events which occur after premature discontinuation of 
medication and before the time point of interest will be included in the analysis using the 
randomized set.


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The treated set (TS) will include all patients who are dispensed study medication and are
documented to have taken at least one dose of study medication in the treatment groups 
according to their initial treatment. The analyses using the treated set will include the efficacy 
and safety endpoint events which occur from the date of first drug administration to visit 8 or 
date of last drug administration + 6 days if discontinued prematurely.
The pharmacokinetic set (PKS) will include all treated patients with at least one PK/PD 
measurement and having no protocol violations relevant to the evaluation of PK or PD 
endpoints. 
More details will be specified in the TSAP.
7.3.1
Primary analyses
The primary efficacy endpoint, proportion of patients with complete thrombus resolution and 
freedom from recurrent VTE or mortality related to VTE, will be analysed following the ITT 
principle on the randomized set. Age group will be used as stratification factor using a 
Mantel-Haenszel type weighted average of differences with weights as proposed by 
Greenland and Robins (R09-1299).
The primary analyses for primary endpoints will include only adjudicated events. 
 
The planned analyses are summarized in Table 7.3.1: 1 for each population set. More details 
and additional analyses will be specified in TSAP if deemed necessary. 
Table 7.3.1: 1
Summary of planned analyses
Population / 
analysis
Intent-to-treat analysis (from 
randomization to the time point of 
interest)
On-treatment analysis (from 
treatment start to drug stop date + 6 
days)
Randomized 
set
1. Primary efficacy endpoint:
primary and secondary analysis
2. Secondary efficacy endpoints
4. All cause mortality
Treated set
1. Major bleeding events analysis
 
4. All cause mortality
7.3.2
Secondary analyses
Secondary analyses of primary endpoint


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Secondary analysis of the proportion of patients with complete thrombus resolution, with no 
recurrent VTE and no VTE-related death will consider age group as covariate and the 
treatment and age group interaction in a logistic regression model using ITT as the primary 
analysis. 
Analyses of secondary endpoints
Major bleeding events will be analysed as time-to-event endpoint using Kaplan-Meier 
method. The proportion of patients free from major bleeding events at the end of planned 
treatment period (84 days (Visit 8) or eEOT) will be provided by Kaplan-Meier estimates for 
the two treatment arms pooling all age groups. Due to the low event rate of major bleeding, 
age group stratification will not be considered in the primary model for this endpoint. The 
confidence interval of proportion difference will be calculated based on Kaplan-Meier 
estimates and its variances. This safety analysis will be based on the treated set which will 
include events that occur between the date of first dose of study medication to the date of last 
dose of medication plus six-days (on treatment analysis). Patients who do not have major 
bleeding events during the treatment period and patients who discontinue from the trial 
prematurely without having major bleeding events will be censored. For patients who have 
more than one event during the trial, the time to the first occurrence of the event will be 
considered for the analysis. 
 
Pharmacokinetic and pharmacodynamic analyses will be summarized in Section 7.3.5 and 
Section 7.3.6. 
Frequency of dose adjustments, temporary and permanent discontinuation from therapy, 
number of laboratory monitoring requirements for dose adjustment during the treatment 
phase and frequency of switch of type of anti-coagulation therapy (including dabigatran to 
SOC) will be summarized descriptively for each treatment arm.
Freedom from thrombus progression at baseline will be summarized descriptively and for 
each treatment arm. Frequency of patients free from thrombus progression at day 84 after 
randomization (or eEOT, whichever comes first) will be analysed descriptively.
The assessment of the acceptability of an age-appropriate formulation at the end of therapy 
will be provided descriptively.


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All bleeding events and all-cause mortality will be analysed as time-to-event endpoint using 
stratified Cox proportional hazard model with treatment being a factor in the model and age 
group as stratification factor. A pooling of age groups might be necessary if no event is 
observed in certain age group.
The components of the primary efficacy endpoint will be analysed as proportions using the 
same model as the primary analysis.
7.3.3
Safety analyses
Major bleeding events will be analysed as a secondary endpoint. All bleeding events and 
combined endpoint of major and clinical-relevant bleeding events will be analysed by the 
Cox proportional hazards model with treatment being the factor and stratified by age group if 
appropriate. Pooling of age groups or non-stratified analysis might be performed if the event 
rate is low. All safety analyses as well as all bleeding events and all-cause mortality analysed
as efficacy endpoints will be performed on the treated set.
The safety analysis set will include all randomized patients who take at least one dose of 
study medication. Patients in the safety population will be analysed according to the study 
treatment they have received. The safety analyses will be descriptive in nature and will be 
based on BI standards. The safety analyses will include the following parameters:
o
All AEs
o
protocol-specified AESI
o
serious AEs
o
AEs leading to treatment discontinuation
AEs will be coded using the MedDRA dictionary. All AEs will be classified according to the 
following trial periods: screening, on-treatment, post treatment. All AEs with an onset 
date/time after the 1st dose of trial medication up to 6 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. 
Other lab data, vital signs, physical examinations data and ECG data will be reported 
descriptively.


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7.3.5
Pharmacokinetic analyses
The analysis of the PK/PD parameters will be performed on PKS.
All concentrations will be listed and summarized descriptively. The concentrations will be 
compared descriptively with the exposure observed in adult patients or healthy subjects 
previously.
PK data from this study along with data from other trials in the dabigatran program will be 
used to further refine the adult population pharmacokinetic model, allowing it to be used for 
the generation of predictions optimized for paediatric populations. The results of this model 
refinement will be reported separately. 
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. 
7.3.7
Pharmacogenomic analyses
Not applicable.
7.4
HANDLING OF MISSING DATA
Missing data will not be imputed in general. For complete thrombus resolution assessment, if 
the assessment at Visit 8 (84 days) is missing, then the last observation at eEOT visit will be 
carried forward providing there is no VTE related events occurred between the two visits.  
All patients will be followed to collect necessary efficacy and safety information, even if 
patients discontinue study medication prematurely. 
 
 
7.5
RANDOMISATION
Interactive response technology (IRT) will be used to randomize patients to treatment groups.  
The randomization will be performed in blocks and stratified by age groups, and the 
allocation ratio will be 2:1 for dabigatran to SOC. The randomization list will be generated 
using a validated system, which involves a pseudo-random number generator to guarantee the 
reproducibility of the assignments. In addition, patients assigned to dabigatran OLF will be 


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randomized based on 1:1 ratio to receive flavoured or unflavoured solvent for reconstitution.
This randomization list will be checked by an independent statistician and will be used by a
third-party IRT to assign randomization numbers to eligible patients.
7.6
DETERMINATION OF SAMPLE SIZE
After an extensive literature search, 11 articles which were relevant to thrombus resolution in 
paediatric patients with VTE (R07-2937, P16-07690, P08-12132, P11-06995, P14-05231, 
R16-2873, R16-2876, R16-2877, R16-2878, R16-2879, P16-03657) were included in a meta-
analysis of the complete thrombus resolution rate using SOC anticoagulants (predominantly 
low-molecular weight heparins or vitamin K antagonists) after a careful screening. Most of 
the studies are not randomized controlled clinical trials. However, a Bayesian meta-analysis 
concluded a stable mean complete thrombus resolution rate of 72% using data from the 11 
studies. This rate was used as the assumption which both dabigatran etexilate and SOC would 
have achieved in this trial.
A complete thrombus resolution rate without treatment cannot be established from recent 
publications. It is uncommon to see patient completely without treatment, and the rate of 
complete thrombus resolution is believed to be low. This is specifically true for cases not 
involving a central line, such as DVT/PE, which will represent the majority of case in this 
trial. Central line thrombosis, which has a potentially better resolution rate due to catheter 
removal, is predominantly expected to occur in younger children (below the age of 
approximately 2 years). However, the number patients in stratum 3 is approximately 15 only, 
therefore, the number of central line thrombosis in this trial is expected to be low overall. 
Thus, the clot resolution rate under no treatment in this trial is predominantly resulting from 
the DVT/ PE cases included.
In the absence of solid evidence of spontaneous thrombus resolution, a precise effect size is 
difficult to be determined. As an alternative, a wide range of plausible complete thrombus 
resolution rate without treatment (5% to 20%) have been considered, and it has been 
demonstrated that the proposed 20% non-inferiority margin can preserve at least 62% and up 
to 70% of the effect size under SOC treatment.
Table 7.6: 1
Effect size preserved by 20% NI margin 
Complete thrombus resolution rate of SOC 
(based on meta-analysis result)
72%
Complete thrombus resolution rate without 
treatment (plausible assumptions)
5%
10%
15%
20%
Effect size preserved by 20% NI margin
70%
68%
65%
62%
With a total sample size of 141 patients and a 2:1 randomization to dabigatran and SOC, 
respectively, approximately 94 patients will be randomized to receive dabigatran and 
approximately 47 patients to receive SOC. The following simulation has been performed to 
consider the variability in the estimate of the complete thrombus resolution rate. Assuming 
the number of complete thrombus resolution follows binomial distribution with unknown 
probability of success, the estimates of the complete thrombus resolution rate are subject to 
the variability of this distribution. One hundred thousand binomial samples were generated 


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for dabigatran arm and SOC arm, with 94 and 47 patients respectively. The lower bound of 
the 90% confidence interval was calculated for each simulation using:
̂	 −̂ −1.64 × ̂	(1 −̂	)
94
+ ̂(1 −̂)
47
where, ̂	 and ̂ are point estimates of the complete thrombus resolution rates of 
dabigatran arm and stand of care arm from each simulation.  Samples are generated from 
binomial distribution assuming the true complete thrombus resolution rates are 	 and , 
respectively. The proportions of the lower bound above the non-inferiority margin among the 
100,000 simulations are provided in the table below, under various assumptions of binomial 
distributions.
Table 7.6: 2
Summary of power estimates for primary efficacy endpoint with a 
sample size of 141
Assumptions used in generating simulated samples
Power of 90% CI lower bound above 
the non-inferiority margin -20%
Superior assumption: (	, ) = (0.77, 0.72)
95%
Non-inferior assumption: (	, ) = (0.72, 0.72)
82%
Suboptimal assumption: (	, ) = (0.68, 0.72)
63%
Extremely conservative but non-inferior assumption: 
(	, ) = (0.62, 0.72)
33%
Inferior assumption: (	, ) = (0.52, 0.72)
5% (false positive)
Under the assumption that the true unknown complete thrombus resolution rate is 72% of 
both dabigatran and SOC, the proposed sample size of 141 is sufficient to demonstrate non-
inferiority with adequate power (82%).
If the complete thrombus resolution rate in dabigatran is truly lower than the SOC, the chance 
of showing non-inferiority drops to 33% when the difference is 10% (complete thrombus 
resolution rate 62% vs 72% for dabigatran and SOC, respectively), and to below 5% when 
the non-inferiority margin of 20% is reached (complete thrombus resolution rate 52% vs 72%
for dabigatran and SOC, respectively). 
However, the most likely scenario for the paediatric population is to assume similar thrombus 
resolution rates with both dabigatran and SOC, based on the following considerations: 
primary efficacy results obtained from adult VTE RE-COVER-trials (P13-16985) 
demonstrated robust non-inferiority. In addition, it is the expectation that the gMean trough 
concentration in the paediatric trials will exceed the average trough exposure of RE-COVER 
due to the option of up-titration of the dose if initial exposure is < 50 ng/ml compared to fixed 
dosing in the adult trials. Therefore the Sponsor considers the sample size and 20% margin 
are reasonably sensitive to evaluate non-inferiority in the paediatric population. See Table 
7.6: 3 for summary.


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Table 7.6: 3
Summary of power estimates for the primary endpoint with a sample 
size of 141
One-sided 
confidence level
Primary 
endpoints (non-
event rate)
True rate 
difference
Margin for rate 
difference
Power#
90%
72%
0.0%
20%
82%
95%
72%
0.0%
20%
71%
# Power for the non-inferiority approach is computed as the proportion of 100,000 simulations in 
which the observed upper bound of one-sided confidence intervals for p1C – p1D and p2C – p2D 
(assuming 94 and 47 evaluable patients in dabigatran arm and control arm, respectively) are below the 
specified equivalence margin. The confidence interval for the VTE endpoint is estimated by 
Newcombe-Wilson method (R08-4386). 
A discontinuation rate of up to 15% before the completion of at least 3 months treatment with 
dabigatran has been estimated for both 1160.106 and 1160.108 trials. 94 patients will be 
randomized to receive dabigatran in 1160.106 trial. It is estimated that there will be 120 
patients entering 1160.108 by end of recruitment. Assuming that 20% of 1160.106 dabigatran 
patients will be rolled over to 1160.108, this would result in roughly 101 of the 120 total 
patients receiving dabigatran treatment in 1160.108 trial to be unique patients. Across both 
trials, this would result in 94 + 101 = 195 unique patients treated with dabigatran. With a 
discontinuation rate of 15% (i.e. stop of treatment earlier than 3 months), a total of 166
unique patients are expected to complete at least 3 months of dabigatran treatment in both 
trials together.


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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 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 each
patient (or the patient’s legally accepted representative) according to ICH GCP and to the
regulatory and legal requirements of the participating country. Each signature must be
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the
informed consent and any additional patient information must be given to each patient or the
patient’s legally accepted representative. 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.
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 the dabigatran this is the current version of the Investigator’s Brochure (c01632884). For
Standard of Care this is the EU sPC. No AEs are classified as listed for 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
P98-11480
Michelson AD, Bovill E, Monagle P, Andrew M. Antithrombotic therapy in 
children. Chest 1998;114(5):748S-769S. 
P04-10723
Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S. Hemorrhagic 
Complications of Anticoagulant Treatment. Chest 2004;126(3 suppl):287S–310S.
P06-06652
Israels SJ, Michelson AD.  Antiplatelet therapy in children.  Thromb Res 
2006;118(1):75-83.
P08-05411
Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral 
direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 
2008;47(5):285-295.
P08-08706
Ryn J van, Ruehl D, Priepke H, Hauel N, Wienen W. Reversibility of the 
anticoagulant effect of high doses of the direct thrombin inhibitor 
dabigatran, by recombinant factor VIIa or activated prothrombin complex 
concentrate. 13th Cong of the European Hematology Association, 
Copenhagen, 12 - 15 Jun 2008 Haematologica 2008;93(Suppl 1):148 
Abstr 0370.
P08-09073
Mitchell LG, Dietrich K, Bajzar L, Bauman M, Massicotte P, Stang L, et al. 
A direct thrombin inhibitor (dabigatran) in pediatric patients: an in vitro 
study determining optimum dose and monitoring tests in plasma from 
healthy children. Pathophysiol Haemost Thromb 2008;36(Suppl 1):A41 
Abstr P065.
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Biss TT, Brandao LR, Kahr WH, Chan AK, Williams S. Clinical features 
and outcome of pulmonary embolism in children. Br J Haematol 142 (5), 
808 - 818 (2008)
P09-11669
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et 
al. Dabigatran versus warfarin in patients with atrial fibrillation.  N Engl J 
Med 2009;361(12):1139-1151.
P10-09826
Payne JH. Aspects of anticoagulation in children. Br J Haematol 2010. 
150(3):259-277.
P11-06995
Wright JM, Watts RG. Venous thromboembolism in pediatric patients: 
epidemiologic data from a pediatric tertiary care center in Alabama. 23rd 
Ann Mtg of the American Society of Pediatric Hematology-Oncolgy, 
Montreal, 8 Apr 2010. J Pediatr Hematol Oncol 33 (4), 261 - 264 (2011)
P13-05131
Schiele F, Ryn J van, Canada K, Newsome C, Sepulveda E, Park J, et. al. A 
specific antidote for dabigatran: functional and structural characterization. 


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P13-16985
Blood. 2013. 121(18): 3554-3562.
Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti 
P, Vedel Christiansen A, Friedman J, Maulf F le, Peter N, Kearon C, RE-
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Treatment of acute venous thromboembolism with dabigatran or warfarin 
and pooled analysis.
Circulation 129 (7), 764 - 772 (2014)
P14-05231
Gasior AC, Knott EM, Peter SDS. Management of peripherally inserted 
central catheter associated deep vein thrombosis in children. Pediatr Surg Int 
29 (5), 445 - 449 (2013)
P15-06362
Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, 
Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, 
Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI Idarucizumab 
for dabigatran reversal. N Engl J Med 373 (6), 511 - 520 (2015)
P16-03657
Manlhiot C, Brandao LR, Schwartz SM, Sivarajan VB, Williams S, Collins 
TH, McCrindle BW. Management and outcomes of patients with occlusive 
thrombosis after pediatric cardiac surgery. J Pediatr 169, 146 - 153 (2016)
P16-07690
Michaels LA, Gurian M, Hegyi T, Drachtman RA. Low molecular weight 
heparin in the treatment of venous and arterial thromboses in the premature 
infant. Pediatrics 114 (3), 703 - 707 (2004)
R04-1182
Guidance for the industry:  general considerations for pediatric 
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of Health and Human Services.  Food and Drug Administration. Center for 
Drug Evaluation and Research (CDER). Center for Biologics Evaluation and 
Research (CBER). 1998.
R06-2150
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.
R06-2299
Hayton WL. Maturation and growth of renal function: dosing renally cleared 
drugs in children. AAPS PharmSci 2002;2(1):3. 
R06-2301
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.
R06-2304
REVIVE Study Group, Massicotte P, Julian JA, Gent M, Shields K, 
Marzinotto V, Szechtman B, Andrew M. An open-label randomized 


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controlled trial of low molecular weight heparin compared to heparin and 
coumadin for the treatment of venous thromboembolic events in children: 
the REVIVE trial. Thromb Res 2003;109:85-92.
R06-2305
Male C, Chait P, Andrew M, Hanna K, Julian J, Mitchell L; et al.  Central 
venous line-related thrombosis in children: association with central venous 
line location and insertion technique.  Blood 2003;101(11):4273-4278. 
R07-2937
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.
R07-2939
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.
R07-2954
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. 
R07-2964
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.
R08-4306
Anderson BJ, Holford NHG. Mechanism-based concepts of size and 
maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48, 303 - 332 
(2008)
R08-4386
Newcombe RG. Interval estimation for the difference between independent 
proportions: comparison of eleven methods. Stat Med 1998;17:873-890.


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R09-1299
Greenland S, Robins JM. Estimation of a common effect parameter from 
sparse follow-up data. Biometrics 1985;41:55-68.
R11-4225
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.
P10-03790
van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wiennen W, Feuring M, 
Clemens A. Dabigatran etexilate – a novel, reversible, oral direct thrombin 
inhibitor: interpretation of coagulation assays and reversal of anticoagulant 
activity. Thromb Haemost 106 (6), 116-117. 2010.
R15-2999
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.
R16-2873
Zitomersky NL, Levine AE, Atkinson BJ, Harney KM, Verhave M, 
Bousvaros A, et al. Risk factors, morbidity, and treatment of thrombosis in 
children and young adults with active inflammatory bowel disease. J Pediatr 
Gastroenterol Nutr 57 (3), 343 - 347 (2013)
R16-2876
Andrade-Campos MM, Montes-Limon AE, Fernandez-Mosteirin N, 
Salvador-Osuna C, Torres M, Lucia-Cuesta JF, et al. Dosing and monitoring 
of enoxaparin therapy in children: experience in a tertiary care hospital.
Blood Coagul Fibrinolysis 24 (2), 194 - 198 (2013)
R16-2877
O'Brien SH, Kulkarni R, Wallace A, Hamblin F, Burr S, Goldenberg NA. 
Multicenter dose-finding and efficacy and safety outcomes in neonates and 
children treated with dalteparin for acute venous thromboembolism. J 
Thromb Haemost 12 (11), 1822 - 1825 (2014)
R16-2878
Ko RH, Michieli C, Lira JL, Young G. FondaKIDS II: long-term follow-up 
data of children receiving fondaparinux for treatment of venous 
thromboembolic events. Thromb Res 134 (3), 643 - 647 (2014)
R16-2879
Warad D, Rao AN, Mullikin T, Graner K, Shaughnessy WJ, Pruthi RK, et 
al. A retrospective analysis of outcomes of dalteparin use in pediatric 
patients: a single institution experience. Thromb Res 136 (2), 229 - 233 
(2015)
9.2
UNPUBLISHED REFERENCES
c01632884
 Dabigatran


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investigator’s brochure (current version – see ISF).
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 female 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 bid) 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
et 
al.  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.
U09-3003-01
. 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. Protocol 1160.88. 
19 February 2010.
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-
valvular atrial fibrillation: prospective, multi-centre, parallel-group, non-


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inferiority trial (RE-LY® STUDY). 1160.26. 16 October 2009.
U09-3885-05
Open-label safety and tolerability of dabigatran etexilate mesilate given for 
3 days at the end of standard anticoagulant therapy in successive groups of 
children aged 2 years to less than 12 years, and 1 year to less than 2 years. 
Protocol 1160.89. 28 March 2011.
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 bid) compared to warfarin (INR 2.0 to 3.0) for the secondary 
prevention of venous thromboembolism. RE-MEDY. 1160.47. 12 July 
2011.
U11-2267-01
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 19 Sep 2011.
U11-2298-01
. A Phase III randomised, double 
blind, parallel-group study of the efficacy and safety of oral dabigatran 
etexilate (150 mg bid) 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
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.
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.


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c09149467
 Analysis of the PK-PD relationship of dabigatran etexilate in 
paediatric patients based on combined data from multiple studies.
n00249900
. BIBR 1048 MS:
Preliminary Neonatal Toxicity Study in the Han Wistar Rat by Oral
(Gavage) Administration. 12 May 2016.
n00251085
 BIBR
1048 MS: Neonatal Toxicity Study in the Han Wistar Rat by Oral (Gavage)
Administration for 8 Weeks followed by a 4-Week Recovery Period. 15
July 2016.


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10.
APPENDICES
10.1
SAFETY AND OTHER CLINICAL LABORATORY EVALUATIONS
Standard Safety Lab Panels may 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 lab tests:
Serum pregnancy test performed on all female patients who have reached menarche 
Prothrombin Time (PT) / INR (International Normalized Ratio)
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 only if 
performing dTT is not feasible)
Anti-factor Xa activity 
Other potential locally evaluated lab tests / exploratory biomarkers:
Diluted Thrombin Time (dTT) to evaluate dabigatran concentration – in case locally required and 
feasible
Safety Lab Panel – only in case of emergency (e.g. bleeding event or emergency surgery)
INR at Visit 2 – to confirm eligibility in case VKA pre-treatment has been already initiated
aPTT at Visit 3 – for expedited bleeding risk assessment in patients < 2 months of age
PT/INR, aPTT or Anti-Factor Xa activity - for routine coagulation monitoring in SOC patients


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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, PK/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

2 to <6 years
Table 10.1.1: 2 
Blood volume chart 2-<6 years

0 to < 2 years
Table 10.1.1: 3 
Blood volume chart 0-<2 years
V1
V2
V3
V4
V5
V6
V7
V8
V9
Chemistry
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
PK
1,2
1,2
2,4
1,2
1,2
1,2
PD
1,2
1,2
1,2
2,4
1,2
1,2
1,2
dTT
1,2
1,2
2,4
1,2
1,2
1,2
Exploratory coagulation markers
1,2
1,2
Total (per visit)
5,5
7,9
9,1
9,1
12,7
9,1
9,1
10,3
5,5
4 weeks interval
5,5
Total (for trial - 4 months)
78,3
31,6
21,8
19,4
V1
V2
V3
V4
V5
V6
V7
V8
V9
Chemistry
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
PK
1,2
1,2
2,4
1,2
1,2
1,2
PD
1,2
1,2
1,2
2,4
1,2
1,2
1,2
dTT
1,2
1,2
2,4
1,2
1,2
1,2
Exploratory coagulation markers
1,2
1,2
Total (per visit)
3,8
6,2
7,4
7,4
11
7,4
7,4
8,6
3,8
4 weeks interval
3,8
Total (for trial - 4 months)
63
24,8
18,4
16
V1
V2
V3
V4
V5
V6
V7
V8
V9
Chemistry
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
PK
1
1
2
1
1
1
PD
1,2
1,2
1,2
2,4
1,2
1,2
1,2
dTT
1,2
1,2
2,4
1,2
1,2
1,2
Exploratory coagulation markers
1,2
1,2
Total (per visit)
2,7
5,1
6,1
6,1
9,5
6,1
6,1
7,3
2,7
4 weeks interval
2,7
Total (for trial - 4 months)
13,4
51,7
20
15,6


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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 in Section 5.2.2.1), 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 an 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, ceruloplasmin, α-1 antitrypsin, 
transferrin, 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, 
Antimitochondrial antibody. The need for hepatitis serology to be assessed by the 
investigator based on patient age and clinical presentation. 
Hormones, tumor marker
TSH


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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 subjects 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
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 starting doses are outlined in the following nomograms, 
which refer to the total amount of dabigatran etexilate to be taken at a single time-point.


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10.3.1
Dosing nomogram (starting doses)

dabigatran etexilate capsules - 50, 75, 110 and 150 mg
Figure 10.3.1: 1 
Age and weight adjusted starting doses using capsules

dabigatran etexilate pellets
Figure 10.3.1: 2
Age and weight adjusted starting doses using pellets
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]
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]


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
dabigatran etexilate OLF - 6.25 mg per mL
Figure 10.3.1: 3
Age and weight adjusted starting doses using OLF
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]


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10.3.2
Dose Adjustment nomogram
10.3.2.1 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
Figure 10.3.2.1: 1 
Up-titration doses using capsules

dabigatran etexilate pellets
Figure 10.3.2.1: 2
Up-titration doses using pellets
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]
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]


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
dabigatran etexilate OLF - 6.25 mg per mL
Figure 10.3.2.1: 3
Up-titration doses using OLF
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]


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10.3.2.2 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
Figure 10.3.2.2: 1 
Down-titration doses using capsules

dabigatran etexilate pellets
Figure 10.3.2.2: 2
Down-titration doses using pellets
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]
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]


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
dabigatran etexilate OLF - 6.25 mg per mL
Figure 10.3.2.2: 3 
Down-titration doses using OLF
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]


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11.DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
01
Date of CTP revision
02 Oct 2014
EudraCT number
2013-002114-12
BI Trial number
1160.106
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open-label, randomized, parallel-group, active-
controlled, multi-centre, non-inferiority study of
dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children
from birth to less than 18 years of age: The
DIVERSITY study
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 trial status. 
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
Section to be changed
Title Page
Description of change
Trial Clinical Monitor
Rationale for change
Personal change


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Number of global amendment
02
Date of CTP revision
28 Jan 2015
EudraCT number
2013-002114-12
BI Trial number
1160.106
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open-label, randomized, parallel-group, active-
controlled, multi-centre, non-inferiority study of
dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children
from birth to less than 18 years of age: The
DIVERSITY study
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 have been
updated to reflect the change of age cut-offs of
strata 2 and 3
Description of change
Based on European Medicines Agency’s
Paediatric Committee (PDCO) final opinion and 
the European Medicines Agency’s decision (dated 
29 September 2014),the age cut-offs of strata 2
and 3 have been changed as follows:

Stratum 2 - from "from 1 to < 12 years of
age" to "from 2 to < 12 years of age"

Stratum 3 - from "from birth to < 1 year of 
age" to " from birth to < 2 years of age"
Rationale for change
The change will facilitate the recruitment in this 
study by allowing for earlier opening of stratum 2 
(based on availability of respective phase IIa PK


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data) and support a more timely completion of the
clinical phase IIb/III program.
Section to be changed
All relevant sections of the CTP have been
updated to modify the minimum number of 
patients required for strata 2 and 3
Description of change
A minimum of 240 evaluable patients for the 
efficacy component of the co-primary endpoint
including a minimum of: 80 patients in age 
stratum 1 (from 12 to < 18 years of age), 75
patients in age stratum 2 (from 12 to < 12 years 
of age) and 25 patients in age stratum 3 (from
birth to < 2 years of age). At least 20 patients in 
stratum 3 must be below one year of age.
Rationale for change
To reflect the change of age cut-offs of strata 2
and 3 based on European Medicines Agency’s 
Paediatric Committee (PDCO) opinion and the
European Medicines Agency’s decision (dated 29 
September 2014)
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


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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
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 10.3
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


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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
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 stratum 2
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 
stratum 3 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 stratum 3 depending 
on completion of phase IIa studies and DMC 
decision
Section to be changed
3.3.2 Inclusion criteria


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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
3.3.3 Exclusion criteria
Description of change
Additional exclusion criterion was introduced:
7)
Patients in stratum 3 (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 1c was changed to:
Any major planned procedure that might put the 
patient at an increased risk of a bleed per
investigator judgment within 5 days of prior to 
taking study medication
Exclusion criterion 6 was modified to list the 
acceptable methods of birth control
Rationale for change
Clarification
Section to be changed
All relevant sections of the CTP
Description of change
It was clarified that all patients who continue
treatment for VTE, regardless of whether this is a 
switch from dabigatran etexilate to SOC or from
one SOC to another, are not considered early 
discontinued. These patients remain in the 
treatment period and should follow the remaining 
visit schedule until the end of the study
Rationale for change
Clarification


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Section to be changed
5.5.2 Methods of sample collection (PK) and
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 PK/PD samples are taken is to be
recorded in the eCRF
Rationale for change
To ensure precise assessment of the 
pharmacokinetic-pharmacodynamic relationship
Section to be changed
Flow Chart footnote L 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
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 B,
3.3.4 Removal of patients from therapy or
assessments and
5.5.1 Pharmacokinetic endpoints
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


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Description of change
Any other investigational drug was added to the 
restricted medications.
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
Section to be changed
All relevant sections of the CTP
Description of change
The assessment of the patient’s ability to swallow 
capsules with test placebo capsules was removed
from the protocol
Rationale for change
In everyday paediatric practice, caregivers are
usually aware about the ability of their child to 
swallow capsules of a size comparable to the 
dabigatran etexilate capsules. In case of any 
unexpected difficulties in acceptance of capsules, 
dabigatran etexilate pellets will be introduced to
the child.


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Number of global amendment
03
Date of CTP revision
26 Nov 2015
EudraCT number
2013-002114-12
BI Trial number
1160.106
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open-label, randomized, parallel-group, active-
controlled, multi-centre, non-inferiority study of
dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children 
from birth to less than 18 years of age: The
DIVERSITY study
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
10.3.2 Dose Adjustment nomogram
10.3.2.1 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
10.3.1 Dosing nomogram (starting doses)
10.3.2 Dose Adjustment nomogram


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Description of change
Dosing nomograms for dabigatran etexilate OLF
have been temporarily removed from the protocol
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 age
stratum 3


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Number of global amendment
04
Date of CTP revision
16 Mar 2016
EudraCT number
2013-002114-12
BI Trial number
1160.106
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open-label, randomized, parallel-group, active-
controlled, multi-centre, non-inferiority study of
dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children 
from birth to less than 18 years of age: The
DIVERSITY study
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
The assessment of thrombus extension at visit 5 
was removed from the protocol. The related
secondary 
 were modified
accordingly


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Rationale for change
To better reflect the clinical routine for follow-up
of patients with VTE. To eliminate potential
unwarranted radiation exposure and to reduce
trial complexity.
In case needed (e.g. suspected recurrent VTE) 
thrombus assessment, using appropriate imaging 
modalities, will be performed during an
unscheduled visit.
Section to be changed
All relevant sections of the CTP
Description of change
The assessment of 12-lead resting-ECG (5 min
supine) at visit 5 was removed from the protocol
Rationale for change
To reduce trial complexity. This additional ECG 
does not follow clinical standard of care and is 
not considered necessary in the context of 
treatment with dabigatran.
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 capsules, pellets
and OLF reconstituted with flavoured or 
unflavoured solvent at days 3(V3), 21 (V5) and
84(V8) or eEOT after randomization was
introduced as other endpoint
Rationale for change
To evaluate the acceptability of capsules, pellets
and OLF reconstituted with flavoured or
unflavoured solvent types in a comparable
number of patients
Section to be changed
FLOW CHART
Description of change
The time window for Visit 4 was extended to +7 
days
Visit 5 should be performed at least 3 days after 
visit 4 (footnote Y)


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Rationale for change
To allow the sites to receive first PK results
before Visit 4 and to adjust the dose of dabigatran 
(if needed) as early as possible.
Section to be changed
FLOW CHART footnote E
Description of change
eEOT visit will not be required in case of 
switching between different types of SOC 
treatments
Rationale for change
To eliminate unnecessary patient procedures. A
patient switching SOC treatment types is still 
considered to be on treatment and eEOT visit is 
not required.
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 as it is
a prerequisite for opening stratum 2
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.


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Section to be changed
3.1 Overall trial design and plan
Description of change
It was clarified that patients requiring VTE 
therapy beyond 3 months have to be switched at
Visit 8 (day 84) to SOC treatment (if randomized
to dabigatran etexilate) or continue SOC
treatment (if randomized to the SOC arm) and
could be maintained on SOC during the follow-up
period. Patients requiring further anticoagulation
for secondary VTE prevention due to unresolved
clinical risk factor may be enrolled in an open-
label secondary prevention trial and their follow-
up visits will be performed within this separate 
study.
Rationale for change
Clarification that patients intended for VTE
treatment for more than 3 months will need to 
switch from dabigatran to SOC after the 12 week 
treatment duration in this study. Patients 
randomized to SOC may remain on this therapy
beyond 3 months.
Section to be changed
3.3.1 Main diagnosis for study entry
3.3.2 Inclusion criteria
Description of change
Example of possible VTE diagnoses were given
It was clarified that patients should be on 
parenteral anticoagulation therapy until 
randomization to trial medication
It was clarified that patients should have 
anticipated requirement for at least 3 months of 
antithrombotic treatment
Rationale for change
Clarification and alignment with the European
Pediatric Investigation Plan (PIP)
Section to be changed
3.3.2 Inclusion criteria


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Description of change
The duration of initial parenteral treatment was 
more precisely defined to be up to 21 days at 
maximum
Rationale for change
To ensure enough time window for screening 
procedures and obtaining safety lab results from
Visit 1
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 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


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Description of change
eGFR retesting during the screening period was
allowed (once)
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
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
Description of change
P-glycoprotein inhibitors intake up until first dose
of study medication will not be 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
10.3 Dosing of Dabigatran etexilate
Description of change
150 mg capsule was introduced


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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 add the derived dabigatran etexilate target
doses based on Hayton calculations for newborns
aged < 1 month and with body weight < 3 kg
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 how to
treat gastrointestinal symptoms such as dyspepsia 
in analogy to recommendations for adults.
Section to be changed
4.2.1 Rescue medication, emergency procedures,
and additional treatment


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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
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


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Section to be changed
10.1
Safety and other clinical laboratory 
evaluations
Description of change
eGFR Schwartz formula has been precisely
defined
Rationale for change
Clarification
Section to be changed
10.3.1 Dosing nomogram (starting doses)
10.3.2 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
10.3.1 Dosing nomogram (starting doses)
10.3.2 Dose Adjustment nomogram
Description of change
Dosing nomograms for dabigatran etexilate


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capsules and pellets have been re-formatted
Rationale for change
To clearly display the age and weight ranges. 
There are no changes to the dosages of 
dabigatran. This change is for clarification only.


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Number of global amendment
05
Date of CTP revision
29 Nov 2016
EudraCT number
2013-002114-12
BI Trial number
1160.106
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open-label, randomized, parallel-group, active-
controlled, multi-centre, non-inferiority study of
dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children 
from birth to less than 18 years of age: The
DIVERSITY study
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
The sample size was reduced from a minimum of
240 to a minimum of 180 evaluable patients for 
the efficacy component of the co-primary
endpoint. The minimum required number of
patients for age stratum 1(from 12 to < 18 years
of age) was reduced from 80 to 60 and for age
stratum 2 (from 2 to < 12 years of age) from 75 to
50.
The minimum required number of 25 patients for 
age stratum 3 (from birth to < 2 years of age) 
remains unchanged. At least 20 patients in
stratum 3 must be below one year of age.


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Rationale for change
The sample size was reduced in order to improve
the feasibility of study completion and results
delivery and at the same time maintain its
objectives and scientific validity
The reduction is affecting strata 1 and 2 only and 
is considered in the statistical approach.
The change has been agreed with Regulatory
Authorities (EMA/PDCO, FDA).
Section to be changed
All relevant sections of the CTP
Description of change
The duration of the follow-up period was reduced
from currently nine months to one month after the 
end of study medication (i.e. after Visit 8, which is 
at 3 months, or eEOT, whatever comes first)
Rationale for change
A follow-up period longer than 28 days will
provide only limited additional information 
related to the study medication. The adverse event 
data that will be observed at Visits 10, 11 and 12 
(i.e. at 6, 9 and 12 months) will be largely
unrelated to the study medication.
The reduction of the follow-up period from
currently 9 months off study drug to one month 
will reduce the number of visits form currently 12 
to 9. For patients who are continuing to receive
dabigatran etexilate as participants in study
1160.108 (long-term secondary VTE prevention)
the follow-up of 12 months will be maintained
unchanged. The follow-up in the 1160.108 study
is more likely to deliver dabigatran-related
information, because patients have the
opportunity to receive dabigatran treatment for
up to 12 months.
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
5.1.1
Endpoints of efficacy


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Description of change
The following secondary endpoints were removed 
and will no longer be assessed:
•
Freedom from recurrence of venous
thromboembolic events at 6, 9 and 12 months
•
Freedom from occurrence of post-
thrombotic syndrome at 6, 9 and 12 months
Rationale for change
Current guideline recommendations are
supporting the concept of three months treatment
duration in 1160.106. Potential events of
recurrence of venous thromboembolic at 6, 9 and
12 months (respectively 3, 6 and 9 months after
the end of 3 months treatment phase) would be 
largely unrelated to the study medication.
The development of post-thrombotic syndrome
(PTS) is a long-term complication after VTE,
which sometimes takes years to develop.
Therefore the potential information loss
regarding PTS is considered minimal.
For patients who are continuing to receive
dabigatran etexilate as participants in the long-
term secondary VTE prevention study (1160.108),
PTS assessment as well as recurrent VTE
assessment will still occur at the 12 months
follow-up time-point.
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
5.1.1
Endpoints of efficacy
Description of change
It was clarified that freedom from thrombus
progression at the end of therapy (day 84 after
randomization or eEOT whichever comes first) 
will be assessed in comparison to baseline
Rationale for change
Clarification
Section to be changed
Flow Chart


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Description of change
The time window for Visit 1 has been extended to
-14 days
The time window for Visit 9 has been changed
from ±7 to +14 days
Rationale for change
To allow for an earlier start of screening
procedures.
To ensure at least one month of Follow-up
Section to be changed
All relevant sections of the CTP
Description of change
Pre-treatment with VKAs during the initial
parenteral treatment is acceptable, provided that
INR has not reached a therapeutic level (INR <
2.0) at the time of randomization.
In such cases, a local INR measurement should be
performed at Visit 2 to confirm eligibility
Rationale for change
To allow for the inclusion of patients treated with
VKAs if the INR has not reached a therapeutic
level (INR < 2.0) and who could benefit from 
participation in the study.
Section to be changed
All relevant sections of the CTP
Description of change
The first trough dabigatran concentration
assessment (at Visit 3) should be supplemented by
a local aPTT measurement for patients < 2 
months.
Baseline aPTT must be also available for these
patients
If the aPTT level at Visit 3 is ≥ 2-fold over aPTT
at baseline or exceeds 100 seconds, the
dabigatran etexilate dose must be down-titrated
Rationale for change
To facilitate an expedited evaluation of the risk of 
bleeding in patients below 2 months based on 
aPTT over baseline ratio and the absolute
(locally available) aPTT value.
Section to be changed
1.2 DRUG PROFILE
2.3 BENEFIT - RISK ASSESSMENT


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Description of change
Summary of phase IIa studies 1160.89 and
1160.105 was provided.
Summary of preclinical toxicology study in 
juvenile rats was provided.
Rationale for change
To provide the final results of the completed
phase IIa PK/PD studies relevant for the patients
to be included in strata 2 and 3.
To provide data on juvenile preclinical studies
that may be relevant to paediatric population < 2 
months of age.
Section to be changed
3.3
SELECTION OF TRIAL POPULATION
Description of change
It was clarified that all patients who received at
least one dose of study medication will be 
considered evaluable
Rationale for change
Clarification
Section to be changed
3.3
SELECTION OF TRIAL POPULATION
Description of change
It was clarified that patients in stratum 3 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
3.3.2
Inclusion criteria
Description of change
For inclusion criterion 2) it was clarified that the 
patient should be clinically stable and should
have been treated with a parenteral anticoagulant
for a minimum of 5 days before being
randomized.


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Rationale for change
The efficacy and safety of dabigatran etexilate in
the first 5 days after VTE has not been established 
in adults. To be consistent with the adult VTE 
treatment program, where the earliest possible 
start of dabigatran etexilate was after 5 days of 
parenteral medication after index VTE.
Section to be changed
3.3.3
Exclusion criteria
3.3.4.1 Removal of individual patients
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 <250ng/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.
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.


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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.
Section to be changed
7.3
Planned analyses
7.3.5
Pharmacokinetic analyses
Description of change
Analysis set for pharmacokinetic analyses has
been defined and will be used for PK/PD
analyses.
Rationale for change
Previously defined Full Analysis Set (FAS) is not 
appropriate for PK/PD analyses. The analysis set 
for PK/PD analyses needs to be modified.


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Section to be changed
7.6
Determination of sample size
Description of change
Sample size has been decreased from 240 to 180
patients and the power values have been updated
accordingly.


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Rationale for change
The sample size was reduced in order to improve
the feasibility of study completion and results 
delivery and at the same time maintain its 
objectives and scientific validity. The change has
been agreed with Regulatory Authorities 
(EMA/PDCO, FDA).
The reduction is affecting the minimum number of 
patients in age strata 1 and 2 only, and power for
the primary endpoints is considered adequate
with this reduced sample size.
Section to be changed
7.6
Determination of sample size
Description of change
Justification of non-inferiority margin for primary
efficacy endpoint has been updated.
Further calculation of the effect size preserved
with the proposed sample size based on a meta-
analysis from published trials, also taking the 
variability in the complete resolution rate without
treatment into consideration, has been added to
this section.
Rationale for change
Justification has been updated as per FDA
recommendation.
Section to be changed
10.3
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
30Oct2017
EudraCT number
2013-002114-12
BI Trial number
1160.106
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open-label, randomized, parallel-group, active-
controlled, multi-centre, non-inferiority study of
dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children 
from birth to less than 18 years of age: The
DIVERSITY study
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
Title Page
Description of change
Trial Clinical Monitor
Rationale for change
Personal change
Section to be changed
Clinical trial protocol synopsis
3.3
Selection of trial population
7.6
Determination of sample size
Description of change
The sample size was reduced from a minimum of
180 to a minimum of 141 evaluable patients for 
the efficacy primary endpoint.
The minimum required number of patients for age


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stratum 2 (from 2 to < 12 years of age) was 
reduced from 50 to 18 and for age stratum 3 
(from birth to < 2 years of age) from 25 to 15.
The minimum required number of patients in 
stratum 3 who must be below one year of age was
reduced from 20 to 8.
The recruitment of patients could be continued
after achieving the minimum total number of 
patients and the minimum number of patients per 
age strata if required by Regulatory Authorities.
Rationale for change
The sample size was reduced in order to improve
the feasibility of study completion and results 
delivery and at the same time maintain its 
objectives and scientific validity
This change has been agreed with Regulatory 
Authorities (EMA/PDCO).
Section to be changed
Clinical trial protocol synopsis
5.1.1
Endpoints of efficacy
7.2
Null and alternative hypotheses
7.3
Planned analyses
Description of change
Freedom from major bleeding events (MBEs) has 
been changed from the co-primary safety
endpoint to a secondary endpoint in the synopsis
and in Section 5.1.1.
Major bleeding events have been removed from
the related null hypotheses from Section 7.2.
The analyses of MBE have been moved from
Section 7.3.1 to Section 7.3.2.
Rationale for change
The FDA has advised to analyse the major
bleeding component of the primary endpoint as a 
secondary endpoint. According to the FDA 
comments, the proposed non-inferiority margin
for major bleeding (9%) would not preserve the 
effect size of the bleeding rate based on the active
control arm and would not permit the non-
inferiority of dabigatran etexilate compared to 
LMWH/VKA to be claimed. As agreed with
Regulatory Authorities (EMA/PDCO, FDA),
major bleeding events will be analysed as a
secondary endpoint in 1160.106.


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Section to be changed
Clinical trial protocol synopsis 
FLOW CHART footnotes
3.1
OVERALL TRIAL DESIGN AND PLAN
4.1
TREATMENTS TO BE
ADMINISTERED
4.2
CONCOMITANT THERAPY,
RESTRICTIONS, AND RESCUE TREATMENT
Description of change
Fondaparinux has been added as standard of
care treatment
Rationale for change
According to the Guidelines of Antithrombotic 
Therapy and Prevention of Thrombosis the use of 
fondaparinux is considered together with low 
molecular weight heparin and unfractionated 
heparin as a possible therapeutic option in the
acute phase of DVT or PE, for both, adult and 
paediatric patients. The use of fondaparinux is 
considered a potential candidate to replace low 
molecular weight heparin in normal clinical 
practice; specifically in children with heparin-
induced thrombocytopenia. Therefore, is 
considered appropriate to include fondaparinux 
as part of standard of care in the comparator arm 
in study 1160.106.
This change has been agreed with Regulatory 
Authorities (EMA/PDCO).
Section to be changed
FLOW CHART footnote A
3.1
OVERALL TRIAL DESIGN AND PLAN
Description of change
Changed “approximate 28 days” to “at least 28 
days” in flow chart footnote A.
Rationale for change
As the term “approximately 28 days” is
ambiguous, PDCO proposed to change it to “at
least 28 days”.
Section to be changed
FLOW CHART footnote T


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Description of change
The collection of post-dose sample for dabigatran
etexilate patients in stratum 3 has been changed 
to optional in flow chart footnote T.
The requirement of post-dose sample collection in
12 patients treated with dabigatran etexilate in
stratum 3 has been deleted.
Rationale for change
The amount of blood volume to be obtained in 
patients in stratum 3 is limited and the post-dose
sample requirements should be the same for all 
patients treated with dabigatran etexilate in all 
age strata.
Section to be changed
6.2.3
End of trial and follow-up period
Description of change
Clarification that patients having switched from 
dabigatran etexilate to SOC are considered as
having early discontinued of dabigatran etexilate 
treatment. However, such patients will still
remain in the trial and be followed as per the visit 
schedule till the end of the study.
Rationale for change
Patients that switch from dabigatran etexilate to 
SOC are considered as having an early 
discontinued of dabigatran etexilate treatment
and remain in the trial to be followed as per the
visit schedule till the end of the study. This was 
not made clear in the previous version of the 
protocol.
Section to be changed
7.6
Determination of sample size
Description of change
Change of the assumptions to estimate how the 
FDA requirement regarding 150 unique patients 
on dabigatran etexilate treatment for at least 3 
months for 1160.106 and 1160.108 combined 
could be met.
The number of patients in 1160.108 has been 
changed from 100 to 120. The percentage of
1160.108 patients who were rolled over from
1160.106 dabigatran etexilate group has been
changed from 40% to 20%.


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Rationale for change
The change in the assumptions on number of
patients in 1160.108 is based on the current
actual enrolment status, projection of 
recruitments and trial timeline for 1160.108. The 
change in the assumptions on the percentage of
patients on dabigatran etexilate rolled over from
1160.106 to 1160.108 is based on the current
actual figures.


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Number of global amendment
07
Date of CTP revision
16 Jan 2018
EudraCT number
2013-002114-12
BI Trial number
1160.106
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open-label, randomized, parallel-group, active-
controlled, multi-centre, non-inferiority study of
dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children 
from birth to less than 18 years of age: The
DIVERSITY study
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 randomisation.
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


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abscess.
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
08
Date of CTP revision
11 September 2018
EudraCT number
2013-002114-12
BI Trial number
1160.106
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open-label, randomized, parallel-group, active-
controlled, multi-centre, non-inferiority study of
dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children 
from birth to less than 18 years of age: The
DIVERSITY study
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
Flow Chart, Footnote Q
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 10.3 Dosing of Dabigatran etexilate
Section 10.3.1 Dosing nomogram (starting doses)
Section 10.3.2 Dose Adjustment nomogram
Description of change
The option to administer pellets was expanded to 
patients < 6 months of age. A preference for the 
usage of OLF over pellets in patients < 12 
months of age was implemented, provided that 
OLF supplies are available to the site.


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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.
Section to be changed
Flow Chart, Flow Chart Footnote X
Description of change
The time window from visit 1 (screening) to visit 
2 (start of study medication) was expanded to 21 
days. The recommendation to collect the 
screening laboratory tests best 10 days before 
Visit 2 was deleted from Footnote X.
Rationale for change
The maximal time period for initial parenteral 
anticoagulation treatment according inclusion 
criterion #2 is 21 days. Expanding the time 
window from visit 1 to visit 2 to 21 days 
facilitates the conduct of screening procedures. 
Section to be changed
Flow Chart, Footnotes D, J and S
Section 3.1 Overall trial design and plan
Section 3.3.4.1 Removal of individual patients
Section 4.1.3 Selection of doses in the trial
Section 6.2.3 End of trial and follow-up period
Description of change
The preferred way of follow-up of patients who 
have discontinued study medication prematurely 
(eEOT, Follow-up Visit 9 after 28 days, further 
follow-up according remaining visit schedule) 
was implemented consistently throughout the 
protocol.
It was added in Section 6.2.3 that for patients 
prematurely discontinued from study medication, 
who are within the follow-up period after Follow-
up Visit 9, the following will be collected: AEs, 
outcome events (e.g. occurrence of PTS, VTE, 
bleeding events, etc.) and use of concomitant 
di
ti
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, Footnote M
Section 5.2.3 Assessment of safety laboratory 
parameters
Appendix 10.1 Safety and other clinical 
laboratory evaluations


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Description of change
The exceptions from the generally central 
laboratory assessments were implemented 
consistently throughout the protocol.
It was added that local lab assessment of PT 
(prothrombin time)/ INR (international 
normalized ratio), aPTT (activated partial 
thromboplastin time) or Anti-Factor Xa activity 
for coagulation monitoring in SOC patients is an 
acceptable alternative to central lab testing.
Rationale for change
To align the wording related to exceptions from 
central laboratory assessments between relevant 
protocol sections. 
To facilitate the coagulation monitoring in SOC 
patients. 
Section to be changed
Flow Chart, Footnotes D, H and W
Description of change
It was added to Footnote D that an unscheduled 
Visit is also to be performed in case a dabigatran 
dose adjustment is needed.
It was added to Footnote H that a complete 
physical examination is required at eEOT Visit 
and Visit 9, additionally to the physical 
examination at Visit 1 and Visit 8.
Two examples for re-dispensation of study 
medication were added to Footnote W. 
Dabigatran etexilate may be re-dispensed at Visit 
3 and at Visit 4.
Rationale for change
To clarify and to correct omissions.
Section to be changed
CTP Synopsis
Section 3.3 Selection of trial population
Description of change
The required patient numbers in stratum 1, 2 and 
3 were expressed as targets rather than as 
minimum numbers. 
Rationale for change
To introduce flexibility in order to adapt for 
different regulatory requirements.
Section to be changed
Section 3.3.2 Inclusion criteria
Description of change
Footnote 2 referring to inclusion criterion #2 was 
clarified. Short-term pre-treatment with VKAs is
permitted if the INR has not yet reached a
therapeutic level (i.e. the INR is still < 2.0). It was 
added that the duration of the initial parenteral 
therapy inclusive VKA treatment if applicable 
must not exceed 21 days. 


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Rationale for change
To provide clarification on pre-treatment with 
VKAs. 
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. 
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 study 
medication 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
It was added that if deemed necessary the type of 
SOC may be changed in SOC patients during the 
treatment period. Concerned patients will not be 
considered as having discontinued study 
medication early, will remain to be on study 
medication and will be followed per the visit 
schedule until the end of the study.
Rationale for change
To clarify that switching of the type of SOC in 
SOC patients is not considered as premature 
study medication discontinuation.


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Section to be changed
Section 3.1 Overall trial design and plan
Section 4.1.4 Drug assignment and 
administration of doses for each patient
Description of change
It was added that patients assigned to take 
dabigatran and 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). In case 
pre-treatment with VKAs has been initiated 
during the screening period, a local INR 
measurement should be performed at Visit 2 to 
confirm eligibility (INR < 2.0).
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 provide guidance on how to switch from the 
alternate therapy to the study medication 
dabigatran etexilate.
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 4.1.7 Storage conditions
Description of change
It was added that for information on storage 
conditions one should refer to the locally 
approved medication label and the STORM 
(Storage condition for Trial Medications) 
document in the ISF. Mentioned storage 
temperatures and the permitted excursion were 
deleted from the protocol.
Rationale for change
To cover all storage conditions applicable in the 
countries participating in the trial.
Section to be changed
Section 4.2.2.1 Restrictions regarding 
concomitant treatment


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Description of change
It was added that fibrinolytic agents should not 
be taken within 48 hours prior to dabigatran 
administration and that P-glycoprotein inducers 
should not be taken within one week to prior 
dabigatran administration.
It was added that generally excluded 
corticosteroids may be included if the benefits of 
corticosteroid therapy clearly outweigh risks.
Rationale for change
To give further guidance on treatment 
restrictions.
Section to be changed
Section 4.3 Treatment Compliance
Description of change
It was added that if an interruption of 
dabigatran etexilate or SOC 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 clarify how to calculate the compliance in 
case of dabigatran etexilate interruptions.
Section to be changed
CTP Synopsis
Section 5.1.1 Endpoints of efficacy


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Description of change
It was clarified that the secondary endpoint 
“Pharmacokinetic and pharmacodynamic 
assessments” is referring to assessments at visit 3 
and to assessments after at least 3 days following 
any dabigatran dose adjustment.
To the secondary endpoint “Frequency of dose 
adjustments” the explanation “(i.e. Number of 
subjects with dose adjustment)” was added.
The secondary endpoint “Number of laboratory
monitoring requirements for dose adjustment 
during the treatment phase” was changed to 
“Number of subjects with laboratory monitoring 
requirements for dose adjustment during the 
treatment phase”.
To the secondary endpoint “Frequency of switch 
of type of anti-coagulation therapy (including 
dabigatran to SOC)” the explanation
“(Frequency of subjects switching the type of 
anti-coagulation therapy including dabigatran 
etexilate to standard of care)” was added.
To the other endpoint “Assessment of 
acceptability of capsules, pellets and OLF”, 
which is assessed at specified days, the respective 
visit numbers were added.
Rationale for change
To clarify the meaning of the respective 
endpoints.
Section to be changed
CTP Synopsis
Description of change
The explanation”(measured as treatment 
discontinuation and adherence)” was added to the 
safety criterion “Global assessment of
tolerability”.
Rationale for change
To correct an omission and align with Section 
5.2.1 Endpoints of safety.
Section to be changed
Flow Chart, Footnote J
Section 5.1.2.2 Venous thromboembolism 
assessment
Description of change
The wording “For day 7 (visit 4)” was deleted 
from the note, which now reads: If clinical 
evaluations warrant imaging (e.g. suspected 
thrombus extension), then per investigator 
judgment, appropriate imaging may be 
performed.


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Rationale for change
To correct the meaning of the respective note. 
Imaging may be performed in case of need any 
time throughout the trial.
Section to be changed
Section 5.7.1 Pharmacodynamics endpoints
Section 5.7.2 Methods of sample collection
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. 
Rationale for change
To clarify and distinguish between dTT (Anti-
Factor IIa activity) and dTT utilized for the 
evaluation of dabigatran etexilate plasma 
concentrations.
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.


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Section to be changed
Flow Chart, Footnote F
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.
Rationale for change
To clarify source data handling in the course of 
the adjudication process.
Section to be changed
Section 10.3 Dosing of Dabigatran etexilate
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. The 
required dabigatran etexilate dose is calculated 
by the IRT System only.
Section to be changed
Abbreviations
Description of change
PT - Prothrombin Time was added to the list of 
abbreviations.
Rationale for change
To correct for an omission regarding 
prothrombin time.


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Number of global amendment
09
Date of CTP revision
06 February 2019
EudraCT number
2013-002114-12
BI Trial number
1160.106
BI Investigational Product
Dabigatran etexilate, BIBR 1048 MS
Title of protocol
Open-label, randomized, parallel-group, active-
controlled, multi-centre, non-inferiority study of
dabigatran etexilate versus standard of care for
venous thromboembolism treatment in children 
from birth to less than 18 years of age: The
DIVERSITY study
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
Section 3.3.4.1 Removal of individual patients
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.


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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 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02102933
16.0
clinical-trial-protocol-revision-09
Open-label, randomized, parallel-group, active-controlled, multi-centre,
non-inferiority study of dabigatran etexilate versus standard of care for venous
thromboembolism treatment in children from birth to less than 18 years of age: The
DIVERSITY study
Approval-Team Member Medicine
07 Feb 2019 12:21 CET
Author-Clinical Trial Leader
07 Feb 2019 12:31 CET
Author-Trial Clinical
Pharmacokineticist
07 Feb 2019 12:51 CET
Approval-Therapeutic Area 
07 Feb 2019 12:55 CET
Author-Trial Statistician
08 Feb 2019 04:45 CET
Verification-Paper Signature
Completion
11 Feb 2019 14:42 CET


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02102933
16.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c02393794-03
BI Trial No.:
1160.106
Title:
Open-label, randomized, parallel-group, active-controlled, multi-
centre, non-inferiority study of dabigatran etexilate versus standard 
of care for venous thromboembolism treatment in children from 
birth to less than 18 years of age: The DIVERSITY study.   
Including Protocol Amendment 2, 3, 4, 5, 6, 7, 8, and 9
[c02102933-09, c02102933-10, c02102933-11, c02102933-12, 
c02102933-13, c02102933-14, c02102933-15, and c02102933-16].  
Investigational
Product:
Dabigatran etexilate, BIBR 1048 MS
Responsible trial 
statistician:
  Tel: 
Email: 
Responsible 
trial clinical 
pharmacokineticist
Tel.: 
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..................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......8
5.
ENDPOINTS ..........................................................................................9
5.1
PRIMARY ENDPOINT ......................................................................................9
5.2
SECONDARY ENDPOINTS..............................................................................9
5.2.1
Key secondary endpoint..................................................................................9
5.2.2
Secondary endpoints .......................................................................................9
................................................................................10
................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS...........................................11
6.1
TREATMENTS..................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS...................................................12
6.3
PATIENT SETS ANALYSED..........................................................................15
.....................................................................................................16
6.5
POOLING OF CENTRES ................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................17
7.
PLANNED ANALYSIS.......................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........18
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................18
7.3
TREATMENT COMPLIANCE .......................................................................18
7.4
PRIMARY ENDPOINTS..................................................................................19
7.5
SECONDARY ENDPOINTS............................................................................23
7.5.1
Key secondary endpoint................................................................................23
7.5.2
Other secondary endpoints...........................................................................23
.................................................................................27
7.7
EXTENT OF EXPOSURE................................................................................27
7.8
SAFETY ANALYSIS.........................................................................................27
7.8.1
Adverse events ...............................................................................................28
8.
REFERENCES.....................................................................................31
..........................................32
.................................................32
.................................................32
.................................................33


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3
3
3
3
10.
HISTORY TABLE...............................................................................37


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LIST OF TABLES
Table 6.1: 1
Labels of treatments for use in the Clinical Trial Report................................11
Table 6.2: 1
Important protocol deviations .........................................................................13
Table 6.3: 1
Patient sets analysed........................................................................................16
Table 10: 1
History table ....................................................................................................38


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ACI
Applied Clinical Intelligence, LLC
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine-aminotransferase 
aPTT
Activated partial thromboplastin time
AST
Aspartate-aminotransferase 
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BRPM
Blinded report planning meeting
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CRNM
Clinically relevant non-major (bleeding event)
eCRF
Electronic Case report form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DE
Dabigatran etexilate
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee
dTT
Diluted thrombin time
ECG
Electrocardiogram
ECT
Ecarin clotting time
eEOT
Early end of treatment
eGFR
Estimated glomerular filtration rate
HPLC
High pressure liquid chromatography
ICH
International Conference on Harmonisation
INR
International normalized ratio
IPD
Important protocol deviation
ISF
Investigator Site File
ITT
Intention-to-treat
IVRS
Interactive voice response system


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Term
Definition / description
KM
Kaplan-Meier
LMWH
Low molecular weight heparin
MBE
Major bleeding event
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MQRM
Medical Quality Review Meeting
MS
Mass spectrometry
OLF
Oral liquid formulation
PD
Pharmacodynamics
PK
Pharmacokinetics
PV
Protocol violation
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SEG
Statistical expert group
SOC
Standard of care
TSAP
Trial statistical analysis plan
VKA
Vitamin K antagonist
VTE
Venous thrombotic event/venous thromboembolism
ULN
Upper limit of normal


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9, 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 including Protocol 
Amendments 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
Freedom from major bleeding events has been changed from the co-primary safety endpoint 
to a secondary endpoint, and major bleeding events have been removed from related null 
hypotheses in the primary analysis in the protocol amendment 6.
Other changes to the statistical analyses are described in protocol amendments.  Please refer 
to latest protocol amendment (Amendment 9, dated 06Feb2019).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The efficacy combined endpoint is the proportion of patients with:

Complete thrombus resolution and;

Freedom from recurrent venous thromboembolism (VTE, including symptomatic and 
asymptomatic, contiguous progression or non-contiguous new thrombus, deep vein 
thrombosis, pulmonary and paradoxical embolism, thrombus progression) and;

Freedom from mortality related to VTE.
All components of the primary efficacy endpoint will be centrally adjudicated by an 
independent blinded 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
Secondary endpoints
The secondary endpoints are:

Freedom from major bleeding events (MBEs), defined as either fatal bleeding; 
clinically overt bleeding associated with a decrease in haemoglobin of at least 20 g/L 
in a 24-hour period; bleeding that is retroperitoneal, pulmonary, intracranial, or 
otherwise involves the central nervous system; or bleeding that requires intervention 
in an operating suite.

Pharmacokinetic (PK) and pharmacodynamics (PD) assessments at Visit 3 (after at 
least six consecutive dabigatran etexilate (DE) doses) and after at least 3 days 
following any DE dose adjustment

Frequency of dose adjustments (i.e. number of patients with dose adjustment)
temporary and permanent discontinuation from therapy ( and number of patients with 
laboratory monitoring requirements for dose adjustment during the treatment phase

Frequency of switch of type of anti-coagulation therapy (including DE to standard of 
care (SOC)) (Frequency of patients switching the type of anti-coagulation therapy 
including DE to SOC and switching from an intended SOC treatment to another)

Freedom from thrombus progression at end of therapy (day 84 after randomisation or 
eEOT, whichever comes first) compared to baseline (i.e. proportion of patients free 
from thrombus progression at end of therapy compared to baseline)

Assessment of the acceptability of an age-appropriate formulation at end of therapy

All bleeding events (i.e. proportion of patients with all bleeding events)

All-cause mortality (i.e. proportion of patients with all-cause mortality)


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
All components of the primary efficacy endpoints, including the proportion of patients 
with complete thrombus resolution, proportion of patients free from recurrent VTE,
and proportion of patients free from VTE related death.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
There are two treatment arms in the study: DE using a dosing algorithm or SOC. The 
assignment of treatment groups will be based on randomization for randomized patient set as 
defined in Section 6.3. Patients will be allocated to one of the following treatments given 
below.
Table 6.1: 1
Labels of treatments for use in the Clinical Trial Report 
Treatment
Long lable 
Short label
A
Dabigatran etexilate
DE
B
Standard of care
SOC
Patients switching from DE to SOC before the end of study will be considered as having
treatment periods defined below. Patients switching from the original SOC treatment to 
another SOC will be considered as no change in the treatment group assignment.
The following periods will be defined:

Screening: day of informed consent to the day prior to first administration of the trial 
treatment (DE or SOC)

On-treatment: day of first administration of trial treatment to last administration of 
trial treatment + 6 days (residual effect period). This on-treatment period will be used 
for analysis of safety endpoints and adverse events (AEs), as specified in Section 
7.8.1.

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 withdraw regarding participation in the trial.

Post-study: For patients not rolled over to the 1160.108 trial, it starts from last follow-
up visit + 1 day up to end of the trial, i.e. the last contact/information received during 
the trial. For patients rolled over to the 1160.108 trial, it starts from last follow-up 
visit + 1 day in 1160.106 to the date of informed consent in 1160.108.  

Intention to treat: day of randomization up to Day 84 (+ 7), including all observed 
time on and off trial medication.

Full follow-up: day of randomization up to day of the last follow-up visit, lost to 
follow-up, death, or consent withdrawn regarding participation in the trial.
Please note: for patients who had not reached the end of a treatment period as defined above 
at EMA interim data cut-off date, the respective treatment period ends at the cut-off date.


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The screening, on-treatment, post-treatment, and post-study periods will be used for the 
summary and listings of AEs. The intention to treat, 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
The following table defines the different categories of important protocol deviations (IPDs). 
The final column describes which IPDs will be used to exclude patients from the different 
patient analysis sets.


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Table 6.2: 1
Important protocol deviations
Category/
Code
Description
Example/Comment
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
No documented diagnosis of clinically 
stable VTE per investigator judgment, 
or not initially treated with parenteral 
anticoagulation therapy (minimum of 5 
to 7 days, but not longer than 21 days)
Inclusion criterion 2 not met
None
A1.3
Anticipated treatment duration with 
anticoagulants for the VTE episode is 
less than 3 month, inclusive of the 
initial parenteral therapy
Inclusion criterion 3 not met
None
A2.1
Patients have 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
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. 
Females who have reached menarche 
and are not using a medically accepted 
contraceptive method per local 
guidelines.
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
Prohibited or restricted medication use 
within one week of the first dose of 
study medication other than 
medication for prior VTE treatment 
and P-glycoprotein inhibitors
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. 
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


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Table 6.2: 1
Important protocol deviations (cont.)
Category/
Code
Description
Example/Comment
Excluded 
from
A
A2.13
Patients or parents/legal guardians 
who are unwilling or unable to 
undergo or permit repeat
of the baseline imaging tests required 
to confirm thrombus resolution at 
study day 84 (or eEOT) or in whom 
repeating such imaging tests at these 
pre-specified time points may not be 
medically in the patient’s best interest
Exclusion criterion 13 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 was after Visit 1 date 
None
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 
randomized treatment. (e.g. wrong dose or 
formulation of DE was administered). 
Wrong dose assigned by investigator. 
None
C1.2
Randomization not followed
Patients not treated according to the 
randomized treatment, except treatment 
switched at a later time
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 DE titration was performed after 
one titration attempt failed, or DE 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 DE developed 
renal dysfunction and were not 
discontinued from DE
Patients with eGFR <50 mL/min/1.73m2
twice on DE and not stopped from DE
None


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Table 6.2: 1
Important protocol deviations (cont.)
This table includes IPDs checked by both automated SAS program and manual reporting. All manual findings 
should be reported in manual IPD log for team review during medical quality review meetings (MQRMs) and 
blinded report planning meetings (BRPMs).
6.3
PATIENT SETS ANALYSED
The patient sets are defined as:

Enrolled set: includes all patients with signed informed consent. The enrolled set will 
be used for disposition summaries. 

Randomized set: This patient set includes all randomized patients in the treatment 
groups to which they were randomized, regardless of being treated or not. 

Treated set: This patient set includes all patients who were dispensed study 
medication (DE or SOC) and were documented to have taken at least one dose of 
study medication.

Pharmacokinetic set (PKS): This patient set includes all dabigatran treated patients 
with at least one evaluable PK measurement and having no protocol deviations
relevant to the evaluation of PK endpoints.

Pharmacodynamic set (PDS): This patient set includes all dabigatran treated patients 
with at least one evaluable PD measurement and having no protocol deviations 
relevant to the evaluation of PD endpoints.
Category/
Code
Description
Example/Comment
Excluded 
from
Z2
Patients with observed new 
thromboembolic event or a clear 
clinical progression of the baseline 
VTE and were not discontinued from 
DE
Patients with new VTE or baseline VTE 
progression (e.g. based on ISTH guidelines)
and not stopped from DE. 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 DE. 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 DE. 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 IMP. Details in protocol 
Section 3.3.4.1.
None


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Summary of patient sets is provided in the following table:
Table 6.3: 1
Patient sets analysed
Class of endpoint
Randomized set
Treated set
PKS, PDS, 
Primary efficacy endpoint 
Primary analysis
Sensitivity 
analysis
Secondary and other endpoints 
Components of 
efficacy 
endpoint
Selected 
secondary 
endpoints
PK, PD related 
secondary 
endpoints 
Safety endpoints 
X
Demographic/baseline 
characteristics
X
Selected secondary endpoints to be analysed on treated set include all secondary endpoints except for 
components of efficacy endpoint and PK/PD related secondary endpoints.
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
All patients will be followed to collect necessary efficacy and safety information, even if 
patients discontinue study medication prematurely. 


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Missing data will not be imputed in general. Specification regarding missing thrombus 
assessment is specified in Section 7.4.
For missing or incomplete AE dates, BI internal procedures and guidelines will be followed
(1). Handling of missing PK/PD data will be performed according to the BI standard 
procedures (2).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline values will be the last available measurements taken prior to first administration of 
DE or SOC (same dates are allowed). 


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7.
PLANNED ANALYSIS
Descriptive statistics for continuous variables will be N (number of patients with non-missing 
values), mean, standard deviation (SD), minimum, median, and maximum. In general, means, 
medians, SDs, will be presented to one more decimal place than the raw data. Minimums and 
maximums will be presented to the same number of decimal places as the raw data. 
Geometric means and geometric coefficients of variation will be used in summaries of PK 
concentration values.
Tabulation 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. A missing category will be displayed if 
and only if there are actually missing values. Percentages will be based on all patients in the 
respective patient set whether they have non-missing values or not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive statistics will be provided for demographics and baseline disease characteristics. 
Baseline characteristics of the patients’ condition will be presented including the type of SOC 
(low molecular weight heparin, vitamin K antagonists, and fondaparinux), the type of leading 
index VTE, days since diagnosis of index VTE prior to randomization, characteristics of the 
index VTE, duration of parenteral anticoagulant treatment prior to randomization, and the 
types of initial parenteral anticoagulant therapy (unfractionated heparin, low molecular 
weight heparin, and etc.). The parenteral anticoagulant for initial treatment will also be listed. 
Other baseline characteristics including patients’ baseline activated partial thromboplastin 
time (aPTT), Ecarin clotting time (ECT) among DE patients, and international normalized 
ratio (INR) and anti-factor Xa among SOC patients will be presented in an accompanying 
listing.
Descriptive statistics for demographics and baseline characteristics will also be presented by
the subgroup of age stratum.
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 World Health 
Organization (WHO) Drug coding dictionary. These will then be summarized by WHO Drug 
ATC coding and listed by patient with each medication taken.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. Average compliance of 
DE patients and SOC patients will be summarized and listed separately 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
Primary analysis
The primary analysis of the primary efficacy endpoint will be performed on the randomized 
set following the intention-to-treat (ITT) principle, based on adjudicated data. For example: 
patients who were originally randomized to DE and later switched to SOC before Day 84, as 
cases of premature termination of the study medication, will be further followed up per the
visit schedule until Day 84. 
The analysis period in the primary analysis starts from the time of randomization to the time 
point of interest, that is, Day 84 ± 7 days.

For patients who die or withdraw consent prior to Day 84 −7 days, the period for the 
primary analysis ends with the date of trial completion (i.e. the date of death, or the 
date of consent withdrawal).  

For patients who discontinue treatment prematurely (for example, due to complete 
thrombus resolution, AE, DE concentration out of target range after one dose 
modification, and so on), the latest available thrombus assessment up to Day 84 + 7 
days will be used for the primary analysis. In particular, thrombus assessment
performed after eEOT but before/at Visit 8 for patients switching from DE to SOC 
will be used for primary analysis. In terms of the recurrent VTE component or VTE-
related mortality component, recurrence or death up to Day 84 + 7 days will be used 
for primary analysis.

Patients who are still being treated and have not yet reached Day 84 ± 7 days at time 
of EMA interim data cut-off will not be included in the analysis
The primary efficacy endpoint contains three components. Given the composite nature of the 
primary endpoint, each component will be evaluated separately, and a joint outcome of 
achieving the primary endpoint will be concluded only if all three components are satisfied.
Component 1: free from VTE-related mortality
Patients with VTE-related death occurring between randomization to Day 84 + 7 days will be 
considered as NOT meeting the endpoint in terms of the component of “freedom from 
mortality related to VTE”, and therefore will not contribute to the proportion of patients 
achieving the primary efficacy endpoint.
Component 2: free from recurrent VTE
The presence of recurrent VTE(s) will be examined throughout the study periods. 
Unscheduled visits would be conducted in case of suspected recurrence of VTE, so the risk of 
failure to detect recurrent VTE would be minimized. Patients with multiple recurrent VTEs 
will be regarded equally as patients with a single recurrent VTE, and only the date of first 
occurrence will be used for analysis.


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
For patients with recurrent VTE(s) from randomization to Day 84 + 7 days, the 
component of “free from recurrent VTE” will be considered as NOT satisfied.

For patients WITHOUT ANY recurrent VTE records:
o
If the entire treatment period is completed (Visit 8 available), the component of 
“free from recurrent VTE” will be considered as satisfied.
o
If patients die (not VTE-related) or withdraw consent prior to Day 84 - 7 days, the 
period for VTE assessment ends with the date of trial termination (i.e. the date of 
death, or the date of consent withdrawal). In the primary analysis, we use last-
observation-carried-forward (LOCF)2, so no record of recurrent VTE will be 
considered as “free from recurrent VTE”. 
 
 
o
If patients discontinue treatment prematurely due to reasons other than death or 
consent withdrawal, they are expected to be followed up for the remainder of
planned study visits and will remain in the randomized set. The decision of 
whether achieving this efficacy endpoint component depends on the timing of 
their last study visit, if

Last study visit1 took place on or after Day 84 + 7 days and there is no 
record of recurrent VTE ever, then the component of “free from recurrent 
VTE” will be considered as satisfied; 

Last study visit took place before Day 84 + 7 days, then this component 
will be considered as missing. In the primary analysis, we use last-
observation-carried-forward (LOCF)2, so no record of recurrent VTE will 
be considered as “free from recurrent VTE”.
 

Patients with VTE recurrence after Day 84 + 7 days will be considered as recurrent VTE
free in the primary analysis, 
1. Early discontinued patients should be followed up based on IIT principle, so the last study visit could be Visit 
9 or further follow-up visit which is available and latest in time.
2. Given minimized risk of not detecting recurrent VTE due to the study design, as well as the low incidence 
rate of recurrent VTE in the study population, we assume patients free from recurrent VTE until the presence of 
contradictory evidence - observed VTE recurrence. 
Component 3: complete thrombus resolution


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Assessment of index VTE status (best overall response) is scheduled on Day 84 ± 7 days 
(Visit 8) for patients who are alive without an early consent withdraw, regardless of the 
treatment status (completion or premature discontinuation) at that time.

The thrombus status assessed at Day 84 ± 7 days will be used for evaluation of this 
component.  If more than one thrombus assessment is available within this time window, 
the one closest to Day 84 will be adopted. Furthermore, if two index assessments 
performed within the time window were equally distant from Day 84 (e.g., an early 
assessment on Day 78 and a late assessment on Day 90), then the thrombus status after 
Day 84 will be adopted.

For patients completing the treatment period OR patients terminating treatment early, if 
the index thrombus assessment during Day 84 ± 7 days is missing, but an early VTE 
assessment was performed, for instance, at an unscheduled visit or an eEOT visit, the 
latest available thrombus status will be carried forward (LOCF) in the primary analysis.  
 

If not any index VTE assessment was performed until Day 84 + 7 days, these patients will 
be considered as having missing data and NOT meeting the criterion of “complete 
thrombus resolution”. 

Patients with index VTE assessment performed only once after Day 84 + 7 days will be 
considered to have missing data and to not achieve the complete thrombus resolution in 
the primary analysis, 
 
 
Age group will be used as stratification factor using a Mantel-Haenszel type weighted 
average of differences with weights as proposed by Greenland and Robins [R09-1299] (3).
The testing hypotheses for the non-inferiority and superiority of the primary endpoint are:
H01: p1C – p1D ≥ 20% vs. H11: p1C – p1D < 20%, where p stands for the proportion of patients
meeting the primary endpoint, the subscript C for SOC, and D for dabigatran etexilate.
H03: p1C – p1D ≥ 0 vs. H13: p1C – p1D < 0.
The details of Cochran-Mantel-Haenszel test and SAS code are provided in Section 9.4.
The non-inferiority of DE to SOC will be claimed if H01 were rejected. The superiority of DE
will be claimed if H03 were rejected.
Upon showing non-inferiority for the primary endpoint, superiority test for the primary 
endpoint will be performed subsequently at one-sided level of 0.05 without multiplicity 
correction.


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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
Major bleeding events (MBEs)
MBEs will be analysed as time-to-event endpoint by Kaplan-Meier method using on-
treatment analysis based on adjudicated data and treated set. The proportion of patients free 
from MBEs at the end of treatment period (84 days (Visit 8) or eEOT) will be provided by 
Kaplan-Meier estimates for the two treatment arms pooling all age groups. Due to the low 
event rate of major bleeding, age group stratification will not be considered. The confidence 
interval of proportion difference will be calculated based on Kaplan-Meier estimates and its 
variances. 
Patients not having MBEs during the on-treatment period and patients who discontinue from 
the trial prematurely without having major bleeding events will be censored. For patients who 
have experienced more than one event during the trial, time to the first occurrence of the 
event will be used for analysis. 


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In case no MBE was observed in one of treatment arms, where the Kaplan-Meier estimate 
cannot be calculated, a descriptive table summarizing all MBEs will be provided. 
PK/PD assessments
Analysis of standard PK/PD parameters will be performed according to 001-MCS-36-
472_RD-01 on PKS, PDS, 
 set as applicable (2).
Scheduled and unscheduled PK and PD data will be analysed separately. Only scheduled PK 
and PD data will be summarized descriptively. Unscheduled PK and PD data will be listed.  
As with unscheduled PK and PD data, PK and PD data collected at dose titration visits will 
be listed separately. The percentage of PK trough results (HPLC−MS/MS) within the target 
range of 50 to <250 ng/ml and outside target range at Visit 3, while at steady state (after at 
least six consecutive dabigatran etexilate doses), and following no more than one dose 
titration (again, at steady state (after at least 3 days following any dabigatran etexilate dose 
adjustment)) will be presented by formulation, by age group, and for patients treated with the 
capped dose and with the uncapped dose.
PK parameters: All concentrations will be listed and summarized descriptively. The 
concentrations will be compared descriptively with the exposure observed in adult patients or 
healthy subjects previously. PK data from this study along with data from other trials in the 
dabigatran program will be used to further refine the adult population PK model (7), allowing 
it to be used for the generation of predictions optimized for paediatric populations. The 
results of this model refinement will be reported separately. 
PD parameters: The following descriptive statistics will be calculated for the PD 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 will be compared to dabigatran concentrations 
determined by HPLC-MS/MS. The comparison will be reported separately. 


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Dose adjustments, switch of therapy, and discontinuation of medication
The number and percentage of patients with dose adjustments (up-titration and down-titration
separately), temporary and permanent discontinuation from therapy, and laboratory 
monitoring requirements for dose adjustment during the treatment phase will be summarized 
descriptively by treatment arm on treated set. For the DE arm, dose adjustments until the 
switch of therapy to SOC will be considered. 
The number of laboratory monitoring requirements per patient for dose adjustment during 
treatment phase will be summarised by the number and percentage of patients requiring 1, 2, 
or more lab monitoring, as well as the mean, SD, min, median, and max of the number of lab 
monitoring requirements per patient. For the DE arm, lab monitoring requirements prior to 
the first switch, if any, to SOC will be counted only.
Frequency of patients switching the type of anti-coagulation therapy, including DE to SOC or 
change from one type of SOC to another (LMWH, VKA, and Fondaparinux) will be provided
descriptively by treatment arm on treated set. For the DE arm, only the switch from DE to 
SOC will be counted, while for the SOC arm, all switches among SOC medication types will 
be counted. Reasons for switch of therapy from DE to SOC and among SOC types will be 
summarized. Frequency of DE treated patients with changes in dose and/or formulation type 
will also be summarized.
Permanent discontinuation from therapy and the reasons will be summarized in the 
disposition table.
Assessment of acceptability
Assessment of acceptability of an age-appropriate formulation at the end of therapy will be 
provided descriptively for DE treated patients.


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Assessment of acceptability of capsules, pellets and OLF reconstituted with flavoured or 
unflavoured solvent at Days 3 (Visit 3), 21 (Visit 5) and 84 (Visit 8), or eEOT after 
randomisation will be summarized descriptively as well. Questions completed by 
investigator, by parent/legal guardian, and by patients (if old enough per investigator 
judgement) will be summarized descriptively.
Thrombus progression
Frequency of patients free from thrombus progression at day 84 ± 7 days after randomization 
(or eEOT, whichever comes first) will be analyzed descriptively by treatment arm and age 
group. Patients without VTE assessments by this time point will be summarized as well.
Mortality related to VTE will be considered as recurrence of VTE.
All bleeding events and all-cause mortality
All adjudicated bleeding events and adjudicated all-cause mortality will be analyzed as time-
to-event endpoint using stratified Cox proportional hazard model with treatment as a 
covariate in the model and age group as the stratification factor. A pooling of age groups 
might be necessary if no events were observed in certain age group.
Patients that do not experience any bleeding events will be included as censored observations 
at the date of patients’ last visit, the date of death not related to bleeding, or the date of data 
cut-off, whichever comes first. Patients being alive at the end of observational period will be 
censored for all-cause mortality at the date of patients’ last date known to be alive, or the date 
of data cut-off whichever comes first. All bleeding events and all-cause mortality based on 
treated set will be analysed descriptively and by Kaplan-Meier estimates for each treatment 
arm.
Incidence of bleeding events including MBEs, CRNM, minor bleeding events, and any 
bleeding events will be presented, as well as incidence of combined endpoint of major and 
CRNM bleeding events.  
Components of efficacy endpoint
All components of the primary endpoint will be analyzed as proportions using adjudicated 
data as the primary analysis in Section 7.4. Concordance between adjudicated events and 
investigator-reported events will also be summarized.
The proportion of patients achieving complete thrombus resolution at visit 8, the proportion 
of patients free from recurrent VTE, and the proportion of patients free from VTE-related 
death will be provided. Time to VTE-related death will be analyzed by Cox proportional 
hazard model with treatment as the covariate. Hazard ratio and p-value for the treatment in 
the model will be reported, and Kaplan-Meier estimates will be provided. 


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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 exposure (in days) is defined as date of last administration of 
DE/SOC – date of first administration of DE /SOC + 1, ignoring the temporary interruptions, 
i.e. intermittent off-treatment periods were considered in the extent of exposure.
For DE treated patients,  listings on exposure, including the actual treatment received, starting 
dose, formulation type, dates of first and last doses, the total treatment time, whether a dose 
adjustment was done, whether patient switched to SOC, and reason for change will be 
provided.
For SOC treated patients, listings on exposure, including the SOC treatment type, medication 
name, dates of first and last doses, the total treatment time, whether a SOC change was done, 
and reason for change will be provided.
Dose adjustment, interruption and discontinuation are analysed as secondary endpoints and 
specified in Section 7.5.
The number and percentage of patients with DE trough plasma concentrations in the target 
range (50 to < 250 ng/mL) and outside target range while on treatment will be presented.
7.8
SAFETY ANALYSIS
The analysis for MBEs is detailed in Section 7.5.


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All safety analyses will be performed on treated set during on-treatment period. 
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (4).
AEs will be coded with the most recent available version of MedDRA referred to in the 
footnote of tables and listings.
All analyses of AEs will be based on the number of patients with AEs (and not on the number 
of AEs). For this purpose, 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 electronic case report form (eCRF), will 
be collapsed into AE episodes provided that all of the following applies:

The same lowest level term was reported for the occurrences;

occurrences were time-overlapping or time-adjacent (the second occurrence started 
at the end date of first occurrence);

Treatment did not change between the onset of occurrences or treatment changed 
between the onset of 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.
The analysis of AEs will be based on the concept of treatment emergent AEs. All AEs
occurring before drug intake will be assigned to ‘screening’. For DE patients not switching to 
SOC, all AEs recorded between first DE intake until 6 days after the last administration of 
DE will be assigned to DE on-treatment period. AEs with onset date after that period will be 
assigned to post-treatment period.  For DE patients who switched to SOC, AEs occurred after 
patients’ last administration of DE plus 6 days and before 6 days after last administration of 
SOC will be assigned to SOC on-treatment period. For patients in SOC arm, all AEs occurred 
between the first drug intake of SOC until 6 days after the last administration of any SOC
will be assigned to the on-treatment period (regardless of switching between types of SOC
treatment). In addition, AEs occurring before first drug intake but worsening in intensity 
during the treatment period will also be assigned to the administrated treatment. For details 
on the treatment definition, see Section 6.1.
All AEs (including bleeding) in the on-treatment period will be tabulated. AEs occurring 
outside the on-treatment period will be summarized in listings only and assigned to
‘screening’, ‘post-treatment’, or ‘post-study’.


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According to ICH E3 (5), AEs classified as ‘other significant’ 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 (5), 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 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. 

Creatinine value shows a ≥2 fold increase from baseline and is above the upper limit 
of normal.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON.
3
Greenland S and Robin JM. Estimation of a common effect parameter from sparse 
follow-up data. Biometrics 1985;41:55-68 [R09-1299]
4
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical 
Trials", current version; IDEA for CON.
5
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
6
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.
7
c09149501-01: “Population pharmacokinetic analysis of dabigatran etexilate using 
combined data from paediatric and adult studies”; BIRDS.


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP.


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Table 10: 1
History table
Version
Date
Author
Sections 
changed
Brief description of change
Final
28-APR-2014
None
This is the final TSAP without any 
modification
Revised
24-AUG-2015
Revised
25-MAR-2019
Title 
page
Addition of CTP amendments. Change 
of trial statistician. Addition of trial 
clinical pharmacokineticist.
4, 
5.1
MBE has been removed from the co-
primary endpoint due to CTP 
amendment dated Oct 30, 2017.
5.2
Addition of MBEs to the secondary 
endpoint. 
5.2, 
Update description of other secondary 
6.1
Update definitions of different periods. 
Explain the effect of EMA interim data 
snapshot on analysis periods.
6.2
Update IPD sub-categories.
6.3
Addition of enrolled set, PKS, 
 
 set. Update definition of 
randomized set and treated set, and 
remove co-primary safety endpoint to 
be aligned with CTP amendment. 
6.6
Update this section.
 
 
 
7.1
Clarification of baseline characteristics 
of patients’ condition.
7.3
Update specification of compliance 
data. 
7.4
Specification and further clarification 
for the primary
 
analyses of primary endpoint, 


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Version
Date
Author
Sections 
changed
Brief description of change
including the analysis set, analysis 
period, strategy of handing missing 
data for components of primary 
endpoint.  
7.5.2
Add analysis plan of MBE to the
secondary endpoint. Update description 
of other secondary endpoints to be 
aligned with CTP amendment.
7.7
Specification of analysis for extent of 
exposure.
7.8
Clarification of analysis for AE, lab 
data, and ECG. Update definition of 
AESI. Addition of global assessment of 
tolerability into ‘Other variables’.