Clinical trial NCT02815670
Conditions: Hemorrhage
Sponsor: Boehringer Ingelheim
Start date: 2016-09-07; Completion date: 2019-10-19
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The trial objective is to demonstrate the safety of idarucizumab, as assessed by the occurence of patients with drug related adverse events (including immune reactions) and all-cause mortality in paediatric venous thromboembolism patients treated with dabigatran in ongoing clinical trials who require emergency surgery/urgent procedures or patients who have life-threatening or uncontrolled bleeding which requires urgent intervention, when rapid reversal of the anticoagulant effect of dabigatran is needed.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Idarucizumab
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08884404-01
EudraCT No.:
EU Trial No:
2015-002177-37
BI Trial No.:
1321.7
BI Investigational 
Product(s):
Idarucizumab
Title:
Single dose, open label, uncontrolled, safety trial of intravenous 
administration of idarucizumab to paediatric patients enrolled 
from ongoing phase IIb/III clinical trials with dabigatran 
etexilate for the treatment and secondary prevention of venous 
thromboembolism.
Lay Title:
Reversal of dabigatran anticoagulant effect with idarucizumab.
Clinical Phase:
III 
Trial Clinical 
Monitor:
                                              
                                         
             
       
              
Phone: 
/ Fax: 
       
Coordinating 
Investigator:
         
           
                   
    
   
   
Phone:
/ Fax:
Status:
Final Protocol
Version and Date:
Version: 1.0
Date: 4 February 2016
Page 1 of 77
Proprietary confidential information.
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company: Boehringer Ingelheim
Name of finished product:
Praxbind
Name of active ingredient:
Idarucizumab
Protocol date:
4 February 2016
Trial number:
1321.7
Revision date:
Title of trial:
Single dose, open label, uncontrolled, safety trial of intravenous 
administration of idarucizumab to paediatric patients enrolled from 
ongoing phase IIb/III clinical trials with dabigatran etexilate for the 
treatment and secondary prevention of venous thromboembolism.
Coordinating
Investigator:
Phone: 
/ Fax: 
Trial sites:
Multi-centre trial, approximately 25 to 40 sites
Clinical phase:
III
Objectives:
To demonstrate the safety of idarucizumab, as assessed by the 
occurrence of patients with drug related adverse events (including 
immune reactions) and all-cause mortality in paediatric venous 
thromboembolism (VTE) patients treated with dabigatran in ongoing 
clinical trials who require emergency surgery/urgent procedures or 
patients who have life-threatening or uncontrolled bleeding which 
requires urgent intervention, when rapid reversal of the anticoagulant 
effects of dabigatran is needed.
Methodology:
Open label, uncontrolled, case series
No. of patients: 
Approximately 5 patients
total entered:
Approximately 5 patients
each treatment:
Not applicable (there is only one treatment, idarucizumab)
Diagnosis :
Patients from trials 1160.106 and 1160.108 in selected sites in 10 
countries treated with dabigatran etexilate who require rapid reversal 
of the anticoagulant effect of dabigatran prior to emergency 
surgery/urgent procedures or patients who exhibiting signs and 
symptoms of life-threatening or uncontrolled bleeding requiring 
urgent medical intervention are eligible.


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Name of company: Boehringer Ingelheim
Name of finished product:
Praxbind
Name of active ingredient:
Idarucizumab
Protocol date:
4 February 2016
Trial number:
1321.7
Revision date:
Main criteria
for inclusion:
Group A:
Patients who are taking dabigatran etexilate and have life-threatening 
or uncontrolled bleeding requiring urgent medical or surgical 
intervention.
Group B: 
Patients who are taking dabigatran etexilate who are not bleeding, but 
do require emergency surgery/urgent procedures for a condition other 
than bleeding, where therapeutic anticoagulation with dabigatran is 
undesirable.
Test product(s):
Idarucizumab in buffered solution for injection 50 mL/vial, 50
mg/mL
dose:
The total dose is up to 5g based on patient’s weight, given as rapid 
infusions/injections, divided in two equal parts administered no more 
than 15 minutes apart.
mode of 
administration:
Intravenous
Comparator products:
Not applicable
dose:
Not applicable
mode of 
administration:
Not applicable
Duration of treatment
Two equal parts of idarucizumab administered no more than 
15 minutes apart.
Endpoints
Primary endpoint: 
The primary endpoint is the safety of idarucizumab in a paediatric 
population as assessed by the occurrence of drug-related adverse 
events (including immune reactions) and all-cause mortality during 
the trial.
Secondary endpoints: 

Percent change of coagulation tests (dTT, ECT) at 30 minutes 
post-dose compared to pre-dose. 

Time to achieve complete reversal of dabigatran effect, based 
on coagulation tests (dTT and ECT). 


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Name of company: Boehringer Ingelheim
Name of finished product:
Praxbind
Name of active ingredient:
Idarucizumab
Protocol date:
4 February 2016
Trial number:
1321.7
Revision date:

Duration of complete reversal of dabigatran effect sustained at 
24 hours post-dose, based on coagulation tests (dTT and 
ECT). 

Cessation of bleeding (Group A patients only).*

Bleeding status and other clinical conditions that may 
contribute to bleeding (Group A patients only) during the 
trial.*

Development of treatment-emergent antidrug antibodies 
(ADA) with cross reactivity to idarucizumab at 30 days post-
dose of idarucizumab.*
*This is a safety issue.
Safety criteria:
Adverse events, local tolerability,  immune reactions, thrombo-
embolic events, mortality, vital signs (blood pressure (BP), heart rate 
(HR)), laboratory tests (including hepatic and renal function, 
haematology, clinical chemistry, coagulation parameters, antidrug 
antibodies against idarucizumab).
Statistical methods:
Descriptive statistics for efficacy, safety and PK/PD endpoints will be 
reported, if deemed appropriate. For most endpoints, data will be 
listed due to limited number of patients. Sufficient numbers of treated 
patients to do subgroup analysis are not expected. The two patient 
groups (life-threatening or uncontrolled bleeding patients and those 
requiring emergency surgery/urgent procedures) will be summarized 
separately and together, with an overall conclusion, if possible.


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FLOW CHART
Investigations/Tests
and Procedures
Screening 
Period
Treatment Period 
Safety Follow-Up Period
Visit Number
1
2.1
2.2
3
4
5
(End of 
Trial)
Visit Description
Patient 
screening1
(baseline)
Dosing
(vial 1)
Dosing
(vial 2)
24-hours 
after 
dosing
7 days 
after 
dosing
30 days 
after 
dosing
Visit Day(s)
1
1
1
2
7
30
Time window for visit
no later 
than 15 
minutes 
after vial 1
± 2 hours
± 3 days
+ 7 days
Informed consent / assent2
X
Inclusion / exclusion criteria
X
Confirm current dabigatran
etexilate use
X
Medical History
X
Demographics
X
Physical Exam
X
Height
X
Weight
X
Body Temperature
X
Vital Signs (blood pressure and 
heart rate)
X
X 3
X3
X3
X3
X
Bleeding assessment4
X
X
X
X
X
X
Surgery/Procedure assessment5
X
X
X
X
X
X
Trial Drug Administration6
X
X
PK/PD Blood Draw7
X
X
X
Blood draw for idarucizumab 
antidrug antibodies7
X
X
Local Safety Blood Draw8
X
X
Optional local aPTT/other local 
tests8
(X)
(X)
(X)
Pregnancy Testing9
X
X
Trial drug accountability
X
ECG
X
X
Adverse Events
X
X
X
X
X
X
Concomitant therapies 
X
X
X
X
X
X
Re-start anticoagulant therapy10 
(if applicable)
(X)
Conclusion of patient 
participation11
X


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1 Due to the need for urgent care in these patients, it is anticipated that the majority of screening 
procedures will have already been performed as part of the hospitalisation and diagnosis procedures. 
These procedures should not be repeated for the purpose of the trial. Any trial procedures that were 
not performed as part of routine care must only be performed after informed consent has been 
obtained.
Collection of medical history and other standard of care information up to the time of consenting 
must be provided as source documents as part of the study screening procedures and will be 
collected on the eCRF.
2 The informed consent (and if applicable assent) should be obtained per local legislations and 
guidelines from the patient and/or the patient’s legally accepted representative where applicable 
before any trial procedures are performed.
3 Blood pressure and heart rate will be measured approximately hourly while the patient is in the 
emergency or similar department, then approximately every 6 to 8 hours for the next 72 hours or 
until discharge, whichever comes first.
4 Bleeding severity for the index bleed (Group A) or any unusual bleed associated with surgery 
(Group B). Bleeding assessments during Treatment Period should be done at or near times of blood 
draws. The 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), refer to section 5.3.5.
5 Group B patients only (refer to section 3.3.1). Surgery/procedure assessments during Treatment 
Period should be done at or near times of blood draws.
6 Actual times for the start and end of the dosing of idarucizumab is to be recorded.
7 Refer to appendix 10.2 for detailed blood draw schedules. The pre-dose lab assessment is the 
baseline lab assessment.
Pre-dose and between vials sampling: central blood sampling for pharmacodynamic biomarkers 
(dTT, ECT, aPTT, TT), pharmacokinetics (dabigatran and idarucizumab concentration) will occur 
immediately prior to administration of each vial of idarucizumab. Blood sampling for idarucizumab 
ADA will only occur prior to vial 1 administration.
Post-dose sampling: central blood sampling for pharmacodynamic biomarkers (dTT, ECT, aPTT, 
TT), pharmacokinetics (dabigatran and idarucizumab concentrations) will be collected at 30 minutes 
(± 10 minutes), 4 hours (± 30 minutes), 12 hours (± 1 hour) and 24 hours (± 2 hours) post-dose. 
Blood sampling for idarucizumab ADA will occur 30 days (+7 days) post-dose.  
Blood sampling could be withheld or reduced per Investigator’s judgement, e.g. if limited by blood 
volume, bleeding and/or distress considerations especially in very young children. E.g. omission of 
exploratory coagulation markers, reduced frequency of safety labs during the treatment period, etc.
Refer to appendix 10.3 for detailed information (priority order of lab parameters).The decision for
reduced blood collection in those cases will be documented in the medical notes and CRF.
Time will be recorded for every blood sample taken.  


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8 Includes Haematology and Chemistry. Optional local blood draws for aPTT and other local lab 
testing may be done at the discretion of the treating physician to facilitate patient clinical 
management.
9 Local urine or other appropriate spot pregnancy test in female adolescents of child bearing potential 
(patients who have reached menarche). More frequent testing can be done if required by the local 
regulation and/or authority or per Investigator’s judgement. Enrolment of pregnant patients is not 
allowed.
10 Re-start of anticoagulant therapy, if applicable, can be a return to dabigatran etexilate for patients 
from Group B. Patients from Group A have to be switched to a standard of care anticoagulant 
medication.
11 Also needs to be completed if the patient withdraws prematurely following first vial of trial 
medication or at any later time point prior end of trial.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................13
1.1
MEDICAL BACKGROUND.............................................................................13
1.2
DRUG PROFILE................................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....19
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................19
2.2
TRIAL OBJECTIVES........................................................................................19
2.3
BENEFIT - RISK ASSESSMENT.....................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
3.1.
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.1.1
Administrative structure of the trial .................................................................23
3.2.
DISCUSSION OF TRIAL DESIGN..................................................................24
3.3.
SELECTION OF TRIAL POPULATION .......................................................24
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Removal of patients from therapy or assessments...........................................27
3.3.4.1
Removal of individual patients .............................................................................27
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................28
4.
TREATMENTS...................................................................................................30
4.1
INVESTIGATIONAL TREATMENTS ...........................................................30
4.1.1
Identity of the Investigational Medicinal Products..........................................30
4.1.2
Selection of doses in the trial..............................................................................30
4.1.3
Method of assigning patients to treatment groups...........................................32
4.1.4
Drug assignment and administration of doses for each patient......................32
4.1.5
Blinding and procedures for unblinding...........................................................33
4.1.5.1
Blinding.................................................................................................................33
4.1.5.2
Unblinding and breaking the code ........................................................................33
4.1.6
Packaging, labelling, and re-supply...................................................................33
4.1.7
Storage conditions...............................................................................................33
4.1.8
Drug accountability.............................................................................................33
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................34
4.2.1
Other treatments and emergency procedures..................................................34
4.2.2
Restrictions ..........................................................................................................35


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4.2.2.1
Restrictions regarding concomitant treatment ......................................................35
4.2.2.2
Restrictions on diet and life style..........................................................................35
4.2.2.3
Restrictions regarding women of childbearing potential......................................35
4.3
TREATMENT COMPLIANCE........................................................................36
5
VARIABLES AND THEIR ASSESSMENT ....................................................37
5.1
TRIAL ENDPOINTS..........................................................................................37
5.1.1
Primary Endpoint ...............................................................................................37
5.1.2
Secondary Endpoints..........................................................................................37
............................................................................................38
5.2
ASSESSMENT OF EFFICACY........................................................................39
5.3
ASSESSMENT OF SAFETY.............................................................................39
5.3.1
Physical examination ..........................................................................................39
5.3.2
Vital Signs............................................................................................................39
5.3.3
Safety laboratory parameters ............................................................................39
5.3.4
Electrocardiogram ..............................................................................................40
5.3.5
Other safety parameters.....................................................................................41
5.3.5.1
Bleeding assessment .............................................................................................41
5.3.5.2
Assessment of other conditions potentially contributing to bleeding...................42
5.3.6
Assessment of adverse events.............................................................................42
5.3.6.1
Definitions of AEs ................................................................................................42
5.3.6.2
Adverse event collection and reporting ................................................................44
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................46
5.4.1
Assessment of Pharmacokinetics.......................................................................46
5.4.2
Methods of sample collection .............................................................................47
5.4.3
Analytical determinations ..................................................................................47
5.4.3.1
Analytical determination of idarucizumab plasma concentrations.......................47
5.4.3.2
Analytical determination of dabigatran plasma concentrations............................48
5.5
ASSESSMENT OF BIOMARKERS.................................................................48
5.5.1
Biobanking...........................................................................................................48
5.5.2
Coagulation biomarkers.....................................................................................48
5.5.3
Methods of sample collection .............................................................................48
5.5.4
Analytical determinations ..................................................................................49
5.6
OTHER ASSESSMENTS...................................................................................49
5.6.1
Idarucizumab antidrug antibodies assay..........................................................49
5.6.2
Methods of sample collection .............................................................................49
5.6.3
Analytical determination of idarucizumab antidrug antibodies ....................49
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................50
6
INVESTIGATIONAL PLAN.............................................................................51
6.1
VISIT SCHEDULE.............................................................................................51
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................51
6.2.1
Screening Period .................................................................................................51
6.2.2
Treatment Period ................................................................................................52
6.2.3
Safety Follow-Up Period.....................................................................................53


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7
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................55
7.1
STATISTICAL DESIGN - MODEL.................................................................55
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................55
7.3
PLANNED ANALYSES.....................................................................................55
7.3.1
Primary endpoint analyses.................................................................................55
7.3.2
Secondary endpoint analyses .............................................................................56
...............................................................................56
7.3.4
Safety analyses.....................................................................................................57
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................57
7.4
INTERIM ANALYSIS .......................................................................................57
7.5
HANDLING OF MISSING DATA ...................................................................57
7.6
RANDOMISATION ...........................................................................................58
7.7
DETERMINATION OF SAMPLE SIZE .........................................................58
8
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................59
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................59
8.2
DATA QUALITY ASSURANCE ......................................................................60
8.3
RECORDS...........................................................................................................60
8.3.1
Source documents ...............................................................................................60
8.3.2
Direct access to source data and documents.....................................................61
8.3.3
Storage period of records ...................................................................................61
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................62
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........62
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................62
8.6
TRIAL MILESTONES.......................................................................................62
9
REFERENCES....................................................................................................64
9.1
PUBLISHED REFERENCES............................................................................64
9.2
UNPUBLISHED REFERENCES......................................................................66
10
APPENDICES.....................................................................................................68
10.1
SAFETY AND OTHER CLINICAL LABORATORY EVALUATIONS.....68
10.2
TIME SCHEDULE FOR BLOOD SAMPLING..............................................68
10.3
ESTIMATED TOTAL BLOOD VOLUME .....................................................72
11
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................77


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ABBREVIATIONS
ADA
Anti Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
AF
Atrial Fibrillation
ALQ
Above upper Limit of Quantification
ALT
Alanine-Aminotransferase
aPTT
activated Partial Thromboplastin Time
AST
Aspartate-Aminotransaminase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BID
bis in die (twice daily dosing)
BLQ
Below lower Limit of Quantification
BP
Blood Pressure
CA
Competent Authority
CHO
Chinese Hamster Ovary (cells)
CI
Confidence Interval
CML
Local Clinical Monitor 
Cpre
Concentration of the analyte in plasma prior to first trial medication dose
CRA
Clinical Research Associate
CRO
Contract Research Organisation
CTP
Clinical Trial Protocol
CVL
Central Venous Line
DEDP
Drug Exposure During Pregnancy
DMC
Data Monitoring Committee
dTT
diluted Thrombin Time
DVT
Deep Vein Thrombosis
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
ECT
Ecarin Clotting Time  
EDC
Electronic Data Capture
EDTA
Ethylenediamine Tetraacetic Acid
eGFR
Estimated Glomerular Filtration Rate
EOT
End of Treatment
ER
Emergency Room
EudraCT
European Clinical Trials Database
Fab
Monoclonal Antibody Fragment
FAS
Full Analysis Set
FEIBA
Factor Eight Inhibitor Bypassing Activity
GFR
Glomerular Filtration Rate
GMP
Good Manufacturing Practice 
HFI
Hereditary Fructose Intolerance
HPC
Human Pharmacology Centre
HR
Heart Rate
IB
Investigator’s Brochure
IC50
Half Maximal Inhibitory concentration


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IEC
Independent Ethics Committee
IMP
Investigational Medicine Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ISTH
International Society for Thrombosis and Haemostasis
i.v.
intravenous
K
Potassium (chemical element)
LPDD
Last Patient Drug Discontinuation
MBE
Major Bleedings
MedDRA
Medical Dictionary for Drug Regulatory Activities
Na
Sodium (chemical element)
NOA
Not Analysed
NOR
No Valid Result
NOS
No Sample Available 
NVAF
Non-Valvular Atrial Fibrillation
PD
Pharmacodynamics
PE
Pulmonary Embolism
PIP
Paediatric Investigation Plan
PK
Pharmacokinetics
PCC
Prothrombin Complex Concentrate
RBC
Red Blood Cells
RDC
Remote Data Capture 
REP
Residual Effect Period, after the last dose of medication with measurable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SD
Standard Deviation
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SSC
Scientific and Standardization Committee
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBMA
Trial Biomarker Analyst
TBV
Total Blood Volume
TCM
Trial Clinical Monitor
TCPK
Trial Clinical Pharmacokineticist
TDMAP
Trial Data Management and Analysis Plan
TSTAT
Trial Statistician
TT
Thrombin Time
TBV
Total Blood Volume
ULN
Upper Limit of Normal 
VTE
Venous Thromboembolism (Venous Thrombotic Event)


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Anticoagulation therapy is a mainstay of treatment and prevention of pathologic thrombosis 
in different clinical settings. Several direct oral anticoagulants have been developed, with 
efficacy comparable to or better than Vitamin K antagonists such as warfarin. However, for 
all anticoagulants, bleeding, including life-threatening and uncontrolled bleeding, remains a 
relevant side effect. With the increasing use of direct oral anticoagulants such as dabigatran
etexilate, there is an unmet medical need for reversal agents that could be used in rare or 
uncommon emergency situations to reverse the anticoagulant effects of these drugs. 
Dabigatran is a direct thrombin inhibitor, a potent anticoagulant that is the active principle of 
the prodrug, dabigatran etexilate (Pradaxa). This drug has been approved for short term 
treatment in the prevention of thromboembolism following orthopaedic surgery and for 
chronic treatment for stroke prevention in patients with non-valvular atrial fibrillation 
(NVAF). Furthermore, dabigatran etexilate is approved for treatment of deep vein thrombosis 
(DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.
Dabigatran treatment in non-valvular atrial fibrillation patients in the RE-LY trial showed 
superior efficacy over warfarin with the 150 mg bis in die (BID) dose with similar bleeding 
rate and non-inferiority with the 110 mg BID dose, with an improved bleeding profile 
(P09-11669)
As with all anticoagulants, bleeding was the most common side effect in the RE-LY trial, 
with major bleeding occurring at a rate of approximately 3% /year and life-threatening 
bleeding at a rate of 1.5% /year in patients with NVAF.
The RELY extension trial, RELY-ABLE (P13-08115) provided additional safety information 
for a large cohort of patients which continued the same dose of dabigatran etexilate as 
assigned in the RE-LY trial. During additional 2.5 years of treatment with maximum 
exposure of over six years in both trials, the long-term safety of dabigatran etexilate was
confirmed. The rate of bleedings was consistent with those seen in RE-LY.
In a pooled analysis of acute venous thromboembolism (VTE) treatment studies, the rate of 
major bleedings (MBE) was lower in patients taking dabigatran etexilate compared to 
warfarin patients (2.1 vs 3.6 MBE/100 patient-years) (P13-16985)
Post-marketing surveillance has also shown that major and fatal bleeding events have been 
reported in some patients taking dabigatran since its approval (U11-2616-01). In the subset of 
patients where demographic data is available, the majority (57%) had renal clearance <30
mL/min and were elderly (over 75 years). While the observed cases are not in excess of the 
rates of bleeding seen in the RE-LY trial, an effective method of reversing the anticoagulant 
effect of dabigatran in patients would be desirable under exceptional circumstances. In 
addition to this, the need for immediate reversal of anticoagulation in patients on dabigatran 
etexilate who require emergency surgery, for example a patient with acute appendicitis, is 
another intended use of the reversal agent.


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Similar to in adults, the use of a reversal agent could complement the management of life-
threatening bleeding events or urgent surgery in the paediatric population, but in a 
vanishingly small number of patients.
Dabigatran etexilate is not yet licensed for use in paediatric patients. The target indication for 
dabigatran etexilate in paediatric patients is VTE treatment/secondary prevention. The 
incidence of symptomatic thrombosis is approximately 5.1 per 100,000 live births, 2.4 per 
1000 neonatal intensive care admissions and 1 case per 100,000 paediatric patients 
(R06-2301; R07-2937; P94-81556). Recent studies have shown that the incidence of VTE in 
children is increasing, creating a new epidemic in paediatric tertiary care (R13-4252; 
R13-4256). The annual rate of VTE in USA was increased over time to 58 cases per 10,000 
hospital admissions (R09-5148), paediatrics 2009). About 50% of paediatric thromboses 
occur in children aged 12-18 years. Teenage girls have twice the rate of VTE compared to 
teenage boys, due to the use of oral contraceptives and due to pregnancy. Over 50% of VTEs 
in children occur in the upper venous system secondary to the use of central venous lines 
(CVL).
Dabigatran etexilate exposure worldwide is in excess of 5 million patient-years in adults.
However, only bleeding events arising from clinical trials in paediatric patients, off label use 
or unintentional use/suicide attempts could account for any bleeding events observed in 
children to date. 
For the assessment of off-label use data from all reporting sources have been considered, 
nearly all evaluated patients were adults. Taking global exposure of dabigatran etexilate into 
account, off-label use ranged, between 2.9% and 3.6% of all assessable cases, depending 
upon definition (cases reporting only off-label indications resp. all cases reporting any off-
label indication together with labelled indications) (s00034702-01).
Worldwide 37 case reports on the use of dabigatran etexilate in children have been received 
by Boehringer Ingelheim (BI) since launch of Pradaxain March 2008 (s00034702-01). The 
reporting sources were spontaneous (25), Health Authorities (5), literature (5) and clinical 
trials (2). In 9 (24.3%) of the 37 cases a bleeding event has been reported. These events, 
except of those received from clinical trials, have occurred in off-label use of dabigatran 
etexilate. There were 5 case reports of dabigatran etexilate overdose (1.65g – 6g dabigatran 
etexilate) in children; in none of these children the intake of dabigatran etexilate was 
associated with bleeding. Based on the data provided, there is currently little off label use of 
dabigatran in children.
Clinical trials of dabigatran etexilate in paediatric patients are described in the EMA-
approved Paediatric Investigation Plan (PIP) for dabigatran etexilate. The PIP requires the 
investigation of the condition “Venous Thromboembolic Events treatment (secondary venous 
thrombotic event prevention)”. The PIP also includes a waiver for the indications “primary 
venous thrombotic event prevention” and “thromboembolic event prevention in atrial 
fibrillation” (EMEA-000081-PIP01-07-M07). Therefore, the potential future commercial use 
of idarucizumab will be limited to the paediatric population receiving dabigatran etexilate for 
the treatment /secondary prevention of VTEs. 


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To date, clinical trials of dabigatran etexilate in paediatric patients in the indication of 
treatment of VTE have been limited to early stage pharmacokinetics and formulation studies. 
There have not been any reports of bleeding or risk of bleeding associated with the need for 
urgent intervention in these trials. Clinical investigations with dabigatran etexilate in the 
paediatric population are targeted to be concluded in coming years.
Idarucizumab (Praxbind) is a specific reversal agent for dabigatran and is currently 
approved in several countries worldwide (including USA and European Union) in adult 
patients treated with dabigatran etexilate when rapid reversal of its anticoagulant effects is 
required (P16-00177).
Three randomised, double-blind, placebo-controlled Phase I studies in 283 subjects 
(224 treated with idarucizumab) were conducted to assess the safety, efficacy, tolerability, 
pharmacokinetics and pharmacodynamics of idarucizumab, given alone or after 
administration of dabigatran etexilate. The investigated population consisted of healthy 
subjects and subjects exhibiting specific population characteristics covering age, body 
weight, race, sex and renal impairment. In these studies the doses of idarucizumab ranged 
from 20 mg to 8 g and the infusion times ranged from 5 minutes to 1 hour.
Representative values for pharmacokinetic and pharmacodynamics parameters were 
established on the basis of healthy subjects aged 45-64 years receiving 5 g idarucizumab.
A prospective, open-label, non-randomized, uncontrolled trial (RE-VERSE AD) is currently 
ongoing (at time of finalising this protocol) to investigate the treatment of adult patients who 
presented with dabigatran-related life-threatening or uncontrolled bleeding (Group A) or who 
required emergency surgery or urgent procedures (Group B). The primary endpoint was the 
maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after 
the administration of idarucizumab, based on central laboratory determination of dilute 
thrombin time (dTT) or ecarin clotting time (ECT). A key secondary endpoint is the 
restoration of haemostasis.
An interim analysis of RE-VERSE AD included data for the first 90 adult patients: 
51 patients with serious bleeding (Group A) and 39 patients requiring an urgent procedure 
(Group B) (P15-06362; P15-12457). 
Complete reversal (100%) of the anticoagulant effect of dabigatran as measured by dilute 
thrombin time (dTT) or ecarin clotting time (ECT) after administration of idarucizumab was 
achieved in all but one patient. Unbound sum dabigatran serum concentrations fell below 
20 mg/mL (a level that produces little or no anticoagulant effect) immediately after 
administration of idarucizumab, resulting in normalisation of dTT and ECT. Normal 
intraoperative haemostasis was reported in 92% of patients who underwent an urgent 
procedure. At 12 and 24 hours after idarucizumab administration, 93% and 79% of patients 
respectively had unbound sum dabigatran serum concentrations < 20 ng/mL; whether patients 
with rising dabigatran concentrations would benefit from another dose of idarucizumab is not 
known.
The safety and efficacy of idarucizumab in children is not yet established and will be 
investigated in this trial.


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Clinical trials of idarucizumab in paediatric patients are described in the EMEA-approved 
Paediatric Investigation Plan for idarucizumab (EMEA-001438-PIP01-13).
The target population of this trial will be patients who are being treated with dabigatran 
etexilate within the currently running paediatric clinical trials for treatment (trial 1160.106) 
or secondary prevention (trial 1160.108) of VTE.
Trial 1160.106 is an active-controlled, open-label, randomized, parallel-group, trial designed 
to confirm a proposed dabigatran etexilate dosing algorithm and to assess the safety and 
effectiveness of dabigatran etexilate compared to standard of care for treatment of VTE in
children from birth to less than 18 years of age. 
Trial 1160.108 is an open label, single arm prospective cohort trial designed to assess the 
safety of dabigatran etexilate for secondary prevention of VTE in children from birth to less 
than 18 years of age. 
Based on the adult RE-LY trial results (P09-11669) and the planned recruitment in the above
two paediatric studies, it is expected to have two or three bleeds requiring urgent intervention 
in these two trials. However, given that the primary risk factors for bleeding are age > 75 
years and high drug exposure (due to low creatinine clearance), the bleed rates in children 
may be much lower than those seen in RE-LY. Regardless of which probabilities apply, these 
numbers are clearly insufficient by themselves to reach reliable conclusions regarding safety 
and efficacy of idarucizumab in children.
Nevertheless, the availability of idarucizumab as reversal agent in these trials could further 
improve the benefit/risk assessment of dabigatran etexilate use even if treatment of only a 
few patients with idarucizumab is possible.
1.2
DRUG PROFILE
Drug Substance and Drug Product
Idarucizumab (BI 655075) is a humanized Fab (antibody fragment) targeting the direct 
thrombin inhibitor, dabigatran. Idarucizumab was generated from a mouse monoclonal 
antibody against dabigatran. The monoclonal antibody was humanized and reduced to a Fab.
Idarucizumab is manufactured from Chinese hamster ovary (CHO) cells, using standard 
mammalian cell culture and protein purification techniques. Purification has included an initial
capture step (affinity chromatography) and additional chromatography steps to remove process
related impurities, as well as virus inactivating and reducing steps such as acid treatment and 
nanofiltration.
The Drug Product is a solution for injection filled aseptically into sterile glass vials 
containing 50 mL with concentration 50 mg/mL (total 2,500 mg/vial).
Idarucizumab is a Fab designed to bind to dabigatran and remove its anticoagulant effect, 
thereby reversing anticoagulation in the patient. As such, idarucizumab contains no Fc 
component and is, therefore, devoid of reactions associated with Fc receptors, such as 


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cytotoxic effect or functions through complement or interactions with Fcγ receptors or
neonatal Fc receptors (FcRn).
It is expected that most patients will only be treated once. Exposure to the reversal agent a
second time, for a new event that may be weeks or even years after the first event, is expected 
to be infrequent or rare.
Pharmacology
Idarucizumab binds to dabigatran with an affinity (Kd) of 2.7 pM.  This is ~270-fold more 
potent than the binding affinity of dabigatran for thrombin. It was also tested in vitro in 
human plasma using a modified thrombin time assay (Figure 1.2: 1, left). First dabigatran 
was added in a known concentration (7 nM) to prolong the thrombin clotting time (set to 
100%). Increasing concentrations of idarucizumab were then added and reversal of the
clotting time was measured. Figure 1.2: 1, left, illustrates the reversal of the thrombin clotting
time by idarucizumab, with a half maximal inhibitory concentration (IC50) of 2.4 Nm.  
Further studies using human whole blood (Figure 1.2: 1, right), illustrate a reversal effect of
dabigatran similar to that in plasma, indicating low non- specific binding of idarucizumab to 
other cellular components in blood.
A.
Plasma:
B. Whole Blood:
Figure 1.2: 1 The reversal of anticoagulant activity of dabigatran by idarucizumab in human 
plasma (A) and whole blood (B). (U13-1986-01)
Reversal of anticoagulation was then tested in a rat model in vivo. Dabigatran was given as 
initial bolus and then continuous infusion to achieve steady state plasma levels of ~ 190 
ng/ml. When measuring the thrombin time ex vivo, dabigatran prolonged the thrombin time 
to approximately 100 seconds from a baseline of 25 seconds (Figure 1.2).  Giving a single 
bolus of idarucizumab at an equimolar dose at t=0 completely reversed the anticoagulant 
activity of dabigatran within one minute to baseline (dark purple line).  This reversal by a 
single bolus was maintained for the 30 minute dabigatran infusion.  Measurement of aPTT 
also resulted in a similar pattern.
0
10
20
30
40
0
10
20
30
40
50
60
70
80
90
100
BI 655075 (nM)
Thrombin Clotting Time
(% of control)
IC50 = 2.4 nM
0.1
1
10
100
0
10
20
30
40
50
60
70
80
90
100
IC50
Plasma
11.80
IC50
Whole Blood
13.16
BI 655075-CHO [nM]
Clotting time (% of control)


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Figure 1.2: 2 The neutralization of dabigatran activity measured as thrombin time after 
addition of BI 655075 at t = 0. Data expressed as mean ± SE, n = 4-6 
(U13-1986-01)
Further pharmacology studies have been performed in a rat tail cut bleeding model.  
Dabigatran etexilate was administered orally at a dose of 30 mg/kg.  Forty five minutes after 
oral administration of dabigatran etexilate, idarucizumab (33 mg/kg or 0.69 µmol/kg) was 
administered as a single bolus and bleeding was also reversed within 5 min. This effect was 
also maintained for up to 2 hours after the single bolus dose.  Further sampling for up to 
6 hours did not result in any re-emergence measurable dabigatran anticoagulation in the 
circulation.
The reversal of the anticoagulant effect of dabigatran was also tested in these experiments.  
Using the diluted thrombin time, it could be demonstrated that the functional dabigatran 
levels achieved were approximately 1200 nM or ~ 600 ng/mL prior to idarucizumab 
administration.  This is far in excess of therapeutic levels of dabigatran achieved in subjects 
receiving the 150 mg BID dose (peak/trough 184/90 ng/mL) (P10-03790).  Anticoagulation 
was completely reversed within 5 min of idarucizumab administration. However, a small 
amount of functional dabigatran anticoagulant activity was measurable 30 min after 
administration (~120 nM, or 60 ng/mL) and remained at this low level for the duration of the 
experiment.  This level of dabigatran anticoagulation did not result in bleeding.
Thus, these studies demonstrate a potent, rapid and specific reversal of the anticoagulant and 
bleeding effects of dabigatran both in human plasma in vitro and in the rat. 
For a more detailed description of the idarucizumab drug profile, please refer to the current 
Investigator’s Brochure (IB) (U12-3431).
-20
0
25
50
75
100
125
0
5
10
15
20
25
30
BI 655075 0.3 µmol/kg
Control
0.3 + 0.1 mol/kg/hr BIBR 953
Time (min)
Thrombin time (seconds)
Control + BI00655075  0.3 µmol


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Idarucizumab has been examined in adult patients treated with dabigatran etexilate when 
rapid reversal of its anticoagulant effects was required (P15-06362). The safety and efficacy 
of idarucizumab in children is not yet established and will be investigated in this trial.
The present trial will be performed in the context of the PIP of idarucizumab as agreed with 
the European Medicines Agency. The proposed indication of idarucizumab are patients 
treated with dabigatran etexilate who require emergency surgery/urgent procedures where 
rapid reversal of the anticoagulant effects of dabigatran is needed or patients who have life-
threatening or uncontrolled bleeding which requires urgent intervention. 
Some anticoagulants have a specific reversal agent that can be used when rapid reversal is 
required, e.g. protamine sulphate is used for the heparins. Current recommendations for 
management of bleeding with the new agents are symptomatic and non-specific. They 
include supportive measures such as replacing fluid volumes, administering fresh frozen 
plasma and/or packed red blood cells and identifying the site of bleeding (P10-03790). 
There are two possible scenarios where paediatric use of idarucizumab might occur, bleeding 
associated with VTE treatment/secondary VTE prevention (potential future dabigatran 
etexilate paediatric indication), or requirement for emergency surgery or urgent intervention 
while receiving dabigatran etexilate. Without such data, the comparison of the aetiology or 
outcomes of these conditions in children with the same conditions in the adult population 
becomes extremely difficult. One cannot compare prevalence, incidence, treatment methods, 
or alternative treatments. Therefore evaluations of the similarities/differences of the condition 
between adult and paediatric populations are currently theoretical. It is however reasonable to 
assume that dabigatran associated bleeding or risk of excessive bleeding in case of 
emergency surgery can occur in a paediatric population. 
This trial is designed to demonstrate the safety of idarucizumab in paediatric patients. The 
reversal of anticoagulant activity will be demonstrated by analysing the biomarker data in a 
central laboratory, independent of the clinical management of the patient. Changes in these 
biomarkers will not be used to make clinical decisions about patient care. Patient outcomes 
will, however, be collected and reported.
2.2
TRIAL OBJECTIVES
The trial objective is to demonstrate the safety of idarucizumab, as assessed by the 
occurrence of patients with drug related adverse events (including immune reactions) and all-
cause mortality in paediatric VTE patients treated with dabigatran in ongoing clinical trials 
who require emergency surgery/urgent procedures or patients who have life-threatening or 
uncontrolled bleeding which requires urgent intervention, when rapid reversal of the 
anticoagulant effects of dabigatran is needed.


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2.3
BENEFIT - RISK ASSESSMENT
Administration of idarucizumab to a dabigatran etexilate treated patient will reverse the 
anticoagulant effect of dabigatran. 
Idarucizumab (Praxbind) is a specific reversal agent for dabigatran and is currently 
approved in several countries (including USA and the European Union) in adult patients 
treated with dabigatran etexilate (Pradaxa) when rapid reversal of its anticoagulant effects 
is required:
•
For emergency surgery/urgent procedures
•
In life-threatening or uncontrolled bleeding.
The safety of idarucizumab has been evaluated in 224 healthy subjects as well as in an 
ongoing phase III trial 123 adult patients, who required emergency surgery/urgent procedures 
or had life-threatening or uncontrolled bleeding and were under treatment with dabigatran 
etexilate. No drug related adverse reactions have been identified in this interim evaluation.
The safety and efficacy of idarucizumab in children below the age of 18 years have not yet 
been established. Paediatric dosing of idarucizumab is considered proportional to the 
patient’s body weight (refer to section 4.1.2)
The potential risk of immune reactions, if occurring, will be managed under expert care in the 
emergency room (ER) or similar department.
Compared to adult renal function, the human infant has decreased renal blood flow during the 
first months of life, but increased glomerular filtration rate (GFR) thereafter (R04-1541).
GFR in humans increases after birth and reaches adult levels at 1-2 years of age. Immature 
glomeruli are present for the first months after birth and glomerular maturation and filtration 
increase during early infancy. GFR in children above 1-2 years of age is in general higher 
compared to adults.
Literature review has revealed no information regarding differences in protein size filtration 
of glomeruli in children versus adults. Therefore, it is assumed that idarucizumab will be 
filtered by the kidneys of children in a manner similar to adults, albeit more slowly in 
neonates, but somewhat quicker in infants due to the differences in GFR.
The idarucizumab formulation contains 220 mM sorbitol as an excipient, i.e., 40 mg/mL, 
which may be of concern in individuals with Hereditary Fructose Intolerance (HFI). HFI is a 
relatively rare genetic disorder estimated to occur in 1 in 20,000 individuals that results in 
intolerance of fructose-containing food. HFI generally becomes apparent during weaning, 
when foods containing fructose are introduced into the diet and signs of intolerance become 
evident, e.g., vomiting, nausea, abdominal pain, and sweating, associated with 
hypoglycaemia and metabolic acidosis (R13-1338). As sorbitol is metabolized to fructose, 
precautions related to HFI are relevant to foods and pharmaceutical formulations containing 
sorbitol. It is suggested that sorbitol (fructose) exposure in paediatric patients with HFI be 
limited to 40 mg/kg (R13-1336; R13-1337), which is equivalent to 1 mL/kg of the 


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idarucizumab formulation, to avoid biochemical changes. Therefore, children with known 
HFI will be excluded from the trial.
Juvenile toxicity
Idarucizumab will be excreted by the kidneys. It may bind to the megalin/cubulin receptors in 
the proximal tubules and undergo re-uptake and catabolism in the proximal tubule cell 
lysozymes, and the amino acids re-used by the body. Alternately, it is excreted into the urine 
and perhaps a small amount is catabolized by the liver. It is recognized that dabigatran bound 
to idarucizumab is likely also to be taken up through megalin/cubulin into renal proximal 
tubule cells, with potential for toxicity.  However, there is no evidence of renal proximal 
tubule cell toxicity in the animal studies conducted. In a pivotal 2-week monkey study, 
monkeys received dabigatran etexilate orally, followed 1.5 hour later by intravenous 
idarucizumab. Therefore, monkeys were exposed for 14 consecutive days to the dabigatran:
idarucizumab complex, with no evidence of toxicity observed in the kidneys (i.e., no clinical 
pathology or microscopic changes). Toxicity studies showed no target organ toxicity 
following administration of idarucizumab.
Juvenile animal studies are only conducted when organ systems affected or potentially 
affected by the compound are immature or notably different between adults and the targeted 
paediatric population.  As nephrogenesis is complete at birth in humans and renal capacity in 
children is equivalent to or better than that of adults, there is no reason to perform juvenile 
animal studies to support trials in children. Therefore, no juvenile animal studies have been 
performed or are planned with idarucizumab.
Blood sampling
Blood sampling for all parameters listed for this trial (safety laboratory, pharmacokinetics 
and biomarkers) together with blood sampling in trial 1160.106 or 1160.108) should not 
exceed the maximum blood volume limits recommended by the European Commission 
(R10-4959) nor the maximum specified in local guidelines (if applicable). Refer to section 
5.3.3 and appendix 10.3.
Given the expected benefits from reversal of dabigatran effects in paediatric patients 
requiring emergency surgery/urgent procedures or those patients with life-threatening or 
uncontrolled bleeding, the available adult safety data and the safety precautions in this trial, 
the current benefit/risk assessment is considered to be favourable.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1.
OVERALL TRIAL DESIGN AND PLAN
The trial will be an open-label, multicentre, multinational trial, with a single treatment arm, 
consisting of idarucizumab. The target population will be patients who are being treated with 
dabigatran etexilate within the currently running paediatric clinical trials for treatment (trial 
1160.106) or secondary prevention (trial 1160.108) of VTE. 
The patients may either require emergency surgery/urgent procedures where therapeutic 
anticoagulation would, in the opinion of the treating clinician, unduly increase the risk of 
intra- and post-operative bleeding, or patients may have life-threatening or uncontrolled 
bleeding which requires urgent intervention.
There are two separate but related elements in this trial, the pharmacologic reversal of 
dabigatran and the clinical management of the patients. The biomarker tests to demonstrate 
reversal will be done in a central laboratory, temporally and geographically removed from the 
sites managing patients. The Investigator will make clinical decisions dependent only on the 
status of the patient and any local tests or lab parameters, including local clotting tests (such 
as a PTT).
Dosing of idarucizumab will not be affected by a local lab test. The Investigator may or may 
not see rapid resolution of bleeding, or adequate control of bleeding during surgery, 
depending on the patient and the elements contributing to the bleed. It is important to 
understand that the selection of patients, the dose of the reversal agent and the management 
of the patients are not dependent on the measurement of dabigatran reversal. Analyses of 
correlations between the reversal effect and clinical outcomes will be undertaken after 
completion of the trial (if feasible). 
Reversal of anticoagulant activity will be recorded in all patients treated with idarucizumab 
(unless blood sampling is limited by blood volume, bleeding and/or distress considerations 
especially in very young children based on Investigator’s judgement).
The patients may be identified in ambulances or at the emergency or similar department of 
participating hospitals. After determination that the patient has been treated with dabigatran 
etexilate in an ongoing trial, the informed consent/assent process will occur and visit 
procedures as described in section 6 will be followed.
Due to the need for urgent care in these patients, it is anticipated that the majority of 
screening procedures as noted in the Flow Chart will already have been performed as part of 
the hospitalisation and diagnosis procedures. These procedures should not be repeated for the 
purpose of the trial. Any trial procedures that were not yet performed as part of routine care 
must only be performed after informed consent (and assent if applicable) has been obtained.
Collection of medical history and other standard of care information up to the time of 
consenting must be provided as source documents as part of the study screening procedures 
and will be collected on the eCRF.


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During the emergency situation, until the last visit in this trial (Visit 5), the patients will 
participate in the dabigatran trial 1160.106 or 1160.108 and in this trial, at the same time with 
the unscheduled visit procedures of the 1160.106 or 1160.108 being applied together with the 
screening procedures for this trial. 
After Visit 5 in this trial, patients remain in the 1160.106 or in the 1160.108 trial according to 
the applicable protocol. 
Procedures, results and adverse events occurring during the time of participation in this trial 
will be recorded in both trials, i.e. 1321.7 and 1160.106 or 1160.108, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim. Patients will be enrolled from dabigatran 
trial 1160.106 or trial 1160.108 in approximately 25 to 40 sites in about 10 countries.
A Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre trial. Tasks and responsibilities are defined in a contract. 
The same data-monitoring committee (DMC) as established for dabigatran paediatric trials 
1160.106 and 1160.108, independent of the sponsor will be used to assess the progress of the 
clinical trial, including a safety and efficacy assessment at specified intervals, and to 
recommend to the sponsor whether to continue, modify, or stop the trial. The tasks and 
responsibilities of the DMC will be specified in a charter. The DMC will maintain written 
records of all its meetings. Since this is an open-label trial, all information sent to the DMC is 
unblinded.
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in the Investigator Site File (ISF).
Boehringer Ingelheim has appointed a Trial Clinical Monitor (TCM), responsible for 
coordinating all required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and internal SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.


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Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
The safety laboratory investigations will be performed at the Investigator’s site as well as the 
ECGs.
A logistic central laboratory service and an Interactive Response Technology (IRT) vendor 
will be used in this trial. Details will be provided in the logistic Central Laboratory Manual
and IRT Manual, available in ISF.
3.2.
DISCUSSION OF TRIAL DESIGN
The current trial is designed to evaluate safety in paediatric patients who received dabigatran 
within the currently running paediatric clinical trials with dabigatran (1160.106 and 
1160.108) and require emergency surgery/urgent procedures or have life-threatening or 
uncontrolled bleeding, as well as to track the clinical course and outcomes of the patients 
during their acute episode requiring reversal of anticoagulation.  
Each patient will have an assessment of immune reactions, adverse events and mortality. 
Safety assessment is the primary goal. Clinical endpoints such as patient status, whether the 
bleeding stops or diminishes may vary widely depending on the clinical situation, will be 
evaluated. Local measurements of coagulation and central pharmacodynamics (PD) 
(biomarkers) and pharmacokinetic (PK) measurements will also be evaluated. By providing 
baseline and post-treatment clotting time assessments, each patient acts as his own control.
  
This trial will evaluate use of idarucizumab in a paediatric population during the development 
of dabigatran etexilate (1160.106 and 1160.108 clinical trials) in the target paediatric 
indication (VTE treatment/ secondary prevention) where idarucizumab could be provided as 
reversal agent for dabigatran. 
Recruitment of patients will be challenging. The frequency and timing of emergency surgery 
or bleeding in this paediatric population cannot be predicted in advance. Is also difficult to 
predict, where the patient will be treated for the bleeding. Furthermore, for a variety of 
clinical reasons, some patients may be treated with intensive support and symptomatic 
treatments such as red blood cell transfusion instead of actual reversal of anticoagulation.
As a result the number of suitable patients for recruitment in this trial will be low. To not 
limit the patient potential for this trial, there is no staggered (age-dependent) recruitment 
approach. However, due to the age related staggered approach in trials 1160.106/1160.108, 
it is expected that first patients in trial 1321.7 will be in age range of 12 to 18 years.
3.3.
SELECTION OF TRIAL POPULATION
Eligible paediatric patients from trial 1160.106 or 1160.108 treated with dabigatran etexilate 
who require emergency surgery/urgent procedures requiring rapid reversal of the 
anticoagulant effect of dabigatran prior to these emergency surgery/urgent procedures or 


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patients who exhibiting signs and symptoms of life-threatening or uncontrolled bleeding 
requiring urgent medical intervention, could participate.
Recruitment of patients is expected to be slow with an average rate of less than 1-2 patients 
per year. The target number of total entered (treated and evaluable) patients in this trial is 
five.
A log of all patients enrolled into the trial (i.e. for those patients signed informed consent 
/assent was provided) will be maintained in the ISF at the investigational site irrespective of 
whether they have been treated with investigational drug or not.
Should the same patient present twice during his/her participation in trial 1160.106 or in trial 
1160.108 with the need for a reversal of the anticoagulant effect of dabigatran according to 
the selection criteria below, this will be allowed, irrespective of the time elapsed between 
previous participation in the trial and the new participation. 
In line with protocols 1160.106 or 1160.108, this is only possible for dabigatran etexilate 
treated patients from group B (refer to section 3.3.1) requiring an emergency procedure or 
surgery who can be re-started dabigatran etexilate treatment after their treatment with 
idarucizumab, patients from Group A (refer to section 3.3.1), with a major bleeding, have to 
switch to standard of care after the bleeding episode.
3.3.1
Main diagnosis for trial entry
There are two separate groups of patients with different diagnoses:
Group A:  
Patients who are taking dabigatran etexilate and have life-threatening or uncontrolled 
bleeding requiring urgent medical or surgical intervention.
Group B:
Patients who are taking dabigatran etexilate who are not bleeding, but do require emergency 
surgery/urgent procedures for a condition other than bleeding, where therapeutic 
anticoagulation with dabigatran is undesirable.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Patients taking dabigatran etexilate in the paediatric trials 1160.106 or 1160.108 are eligible 
for this trial if they meet the following criteria:


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Group A:
1. Overt bleeding judged by the treating physician to require a reversal agent.
2. Currently taking dabigatran etexilate in the context of a clinical trial with dabigatran 
etexilate (1160.106 or 1160.108).
3. Male or female patients from 0 to less than 18 years of age at the time of informed 
consent/assent for participation in trial 1160.106 or in trial 1160.108.
4. Female patients of childbearing potential (defined as having experienced menarche) 
must have followed the contraception requirements according to the dabigatran trial 
1160.106 or trial 1160.108 in which they are enrolled.
5. Written informed consent provided by the patient (and/or the patient’s legally 
accepted representative) and assent provided by the patient (if applicable) at the time 
of informed consent signature in accordance with GCP and local legislation prior to 
admission to the trial. If the child is unable to give assent at the time of the 
emergency, the assent, when applicable will be obtained as soon as feasible. 
Group B:
1. A condition requiring an emergency surgery or invasive procedure where adequate 
haemostasis is required. Emergency is defined as need for surgery or intervention 
within the following 8 hours.
2. Currently taking dabigatran etexilate in the context of a clinical trial with dabigatran 
etexilate (1160.106 or 1160.108).
3. Male or female patients from 0 to less than 18 years of age at the time of informed 
consent/assent for participation in trial 1160.106 or in trial 1160.108.
4. Female patients of childbearing potential (defined as having experienced menarche) 
must have followed the contraception requirements according to the dabigatran trial 
1160.106 or trial 1160.108 in which they are enrolled.
5. Written informed consent provided by the patient (and/or the patient’s legally 
accepted representative) and assent provided by the patient (if applicable) at the time 
of informed consent signature in accordance with GCP and local legislation prior to 
admission to the trial. If the child is unable to give assent at the time of the 
emergency, the assent, when applicable will be obtained as soon as feasible. 


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3.3.3
Exclusion criteria
Group A:
1. Patients with minor bleeding (e.g. epistaxis, haematuria) who can be managed with 
standard supportive care.
2. Patients with no clinical signs of bleeding.
3. Patients with body weight < 2.5 kg
4. Contraindications to trial medication including known hypersensitivity to the drug or 
its excipients; e.g. patients with known hereditary fructose intolerance who may 
react to sorbitol.
5. Female patients who are pregnant, nursing, or who plan to become pregnant while in 
the trial.
Group B:
1. A surgery or procedure which is elective or where the risk of uncontrolled or 
unmanageable bleeding is low.
2. Patients with body weight < 2.5 kg
3. Contraindications to trial medication including known hypersensitivity to the drug or 
its excipients; e.g. patients with known hereditary fructose intolerance who may 
react to sorbitol.
4. Female patients who are pregnant, nursing, or who plan to become pregnant while in 
the trial.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 
careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal.
Screening failures
Patients who do not meet one or more of the entry criteria or discontinue prior to trial 
medication treatment will be considered as screening failures. They have to be recorded as 
screening failure in eCRFs and no further follow-up is required.


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Withdrawal trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient and/or the patient’s legally accepted representative withdraws consent for trial 
treatment or trial participation, without the need to justify the decision,

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication,

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy),

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the Investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future.
If the patient and/or the patient’s legally accepted representative withdraws informed consent 
for trial treatment or trial participation prior trial treatment, the trial will end for that patient. 
Patient has to be recorded as screening failure in eCRF and no further follow-up is required.
Once a patient receives trial medication, all observations outlined in the protocol should be 
performed.  
Withdrawal of trial participation:
If a patient and/or the patient’s legally accepted representative withdraws trial participation 
after receiving trial treatment, the last trial visit (Visit 5) should be performed and the 
information recorded in the eCRFs. All available data from patients who discontinued during 
the trial, for whatever reason, will be included in the analysis. Early discontinuations must be 
reported to the sponsor.
For all patients the reason for withdrawal must be recorded in the eCRF. These data will be 
included in the trial database and reported.
Trial treatment is defined as patients who have received at least one vial of trial medication. 
Completion of the trial is defined as patients who complete all trial visits.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Advice of the independent DMC, decision by an Independent Ethics Committee (IEC)
/Institutional Review Board /(IRB) or Competent Authority (CA)
2. Failure to meet expected enrolment goals overall or at a particular trial site
3. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
4. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract disturbing the 
appropriate conduct of the trial


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The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The sole treatment for administration in this trial is idarucizumab, a humanized monoclonal 
antibody fragment (Fab), administered intravenously as two consecutive infusions over 5 to 
10 minutes each or as two bolus injections. There is no comparator treatment.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product idarucizumab
Substance:
Idarucizumab (BI 655075)
Pharmaceutical formulation:
Solution for injection/infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co KG 
Germany
Unit strength:
2.5 g per 50 mL vial
Posology
Up to 5.0 g (dose divided in two equal parts)
Route of administration:
Intravenous
Idarucizumab drug product (50mg/ml) is formulated as a buffered, isotonic, preservative-free 
solution of idarucizumab in a buffer consisting of 22 mM sodium acetate, 220 mM Sorbitol, 
0.2 g/L (0.02w%) Polysorbate 20 and water for injection. Idarucizumab is a colourless to 
slightly yellow, clear to slightly opalescent solution, with an osmolality of 27-330 mOsm/kg 
and a pH of 5.3-5.7.
4.1.2
Selection of doses in the trial
Paediatric dosing of idarucizumab is considered proportional to the patient’s body weight 
from 300 mg to 5000 mg, where 5000 mg is a reference dose of the patient with body weight 
of 71 kg and above. This is based on the assumption that also the total body load of 
dabigatran at a given plasma concentration range scales approximately with weight. A target 
plasma concentration range for dabigatran is targeted with a nomogram-based dosing in the 
current paediatric dabigatran program (refer to protocol 1160.106/.108).
Based on the assumption that dabigatran plasma levels achieved in children are in the same 
range as for adults, the approach was taken to down-scale idarucizumab paediatric dosing 
based on body weight.


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This dosing approach assumes that distribution of dabigatran in children is not significantly 
different from adults, and that the dabigatran load per kg of body weight is similar.
Therefore, dose calculation based on body weight extrapolates the overwhelming 
idarucizumab dose concept from adults to children (P15-06362).
The overwhelming dose concept makes potential minor differences in dabigatran load per kg 
irrelevant for efficacy. 
Also taking the WHO growth standards for paediatric population into consideration, the body 
weight category below 10 kg was split into two groups. Actually, this group represents the 
paediatric population below one year, and it is split into new-borns and infants below 6 kg 
and older infants from 6 to 10 kg (refer to the Table 4.1.2: 1). Infants with body weight below 
2.5 kg are not included in Boehringer Ingelheim’s VTE paediatric program; therefore, this 
group will not be included in the idarucizumab paediatric program.
For determination of the weight category of a patient, the patient’s weight will be rounded up 
or down to the kilogram with a cut off at 0.5 kg. For example, a patient’s weight from 5.000 
kg up to 5.499 kg will be rounded down to 5 kg while a patient’s weight from 5.500 kg up to 
5.999 kg will be rounded up to 6 kg for calculation of the dose to be administered.
It is expected that the mechanism of action of idarucizumab will be identical in paediatric and 
adult populations since it involves the binding affinity of two external molecules, dabigatran 
and idarucizumab. The affinity of idarucizumab for dabigatran is extremely high and specific. 
Whether the binding of the two molecules takes place in the circulation of children or adults 
should not make any difference. Based on the preclinical information, the mechanism of 
action, and the expected clearance of idarucizumab, the renal function of the patient may 
however play a critical role in the clearance of the idarucizumab-dabigatran complex. 
Differences in the amount of dabigatran, the amount of idarucizumab, or clearance of either 
agent might affect the time course of the effect.
The target human dose for adults was estimated based on equimolar neutralization of the total 
body load of dabigatran. This approach has previously been used to successfully calculate the 
dose of an anti-digoxin Fab to treat digoxin overdose (R11-1174). Total body burden of 
dabigatran was calculated using two distinct approaches:

Based on observed peak dabigatran concentration multiplied by the known volume of 
distribution and

Based on the dose and taking into account a dabigatran bioavailability of about 6.5% 
as well as an accumulation of about 1.7 fold.
Both approaches result in similar amounts for dabigatran total body burden. An idarucizumab 
dose of 1.4 or 2 grams was therefore calculated to neutralize dabigatran anticoagulation based 
on mean dabigatran exposure after 150 or 220 mg dabigatran etexilate BID, respectively, in 
adults. For details of the calculations refer to the Investigator’s brochure (U12-3431).  
An overwhelming dose of 5 g is being used in adults, as determined by modelling, to 


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neutralize anticoagulant activity of dabigatran in patients with higher dabigatran exposure 
(90 percentile).
Table 4.1.2: 1
Idarucizumab paediatric dosing according to body weight
Weight (kg)
Idarucizumab paediatric dosing according to body weight*
from
to
Rounded idarucizumab total 
dose, mg
Rounded idarucizumab total 
dose, ml
Application 
schedule of 
idarucizumab
(split dose 
applications) 
2.5
5
300
6
2 x 3 ml
6
10
600
12
2 x 6 ml
11
20
1250
25
2 x 12.5 ml
21
30
1850
37
2 x 18.5 ml
31
40
2500
50
2 x 25 ml
41
50
3100
62
2 x 31 ml
51
60
3750
75
2 x 37.5 ml
61
70
4350
87
2 x 43.5 ml
71
80
5000
100
2 x 50 ml
81
90
5000
100
2 x 50 ml
91
100**
5000
100
2 x 50 ml
* Based on adult dose for 80 kg patient of 5000 mg Idarucizumab
**A patient with body weight > 100 kg will be dosed with 5000 mg idarucizumab as well.
4.1.3
Method of assigning patients to treatment groups
There is only one treatment group in this trial. If applicable, the pharmacist or designee will 
dispense the trial medication.
4.1.4
Drug assignment and administration of doses for each patient
Drug dispensing may occur via the hospital pharmacy or a secure storage location in the 
emergency or similar department of the trial centre. Each 50 mL vial contains 2500 mg of 
idarucizumab. For both Group A and Group B, the first part of the dose (from vial 1) should 


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be administered as a rapid IV infusion with (in order of preference), a 5 min infusion with an 
infusion pump, a 10-15 min drip, or iv push with a syringe; followed by the second part of the 
dose (from vial 2), no later than 15 minutes after the end of the first part of the dose. 
The infusion/injection is recommended to be filtered using an in-line 0.2 µm filter.
The detailed preparation procedures for the injections and the material to be used for the 
preparation can be found in the “Guidelines for IMP Management, Dispensing and 
Administration” which is stored in the ISF.
4.1.5
Blinding and procedures for unblinding
4.1.5.1 Blinding
Not applicable. There is only one treatment in this open-label trial.
4.1.5.2 Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP).  
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
Trial medication may only be administered to trial patients according to the protocol and 
prepared in strict observance of the preparation procedures and conditions as described in the 
ISF.
4.1.8
Drug accountability
The Investigator or Pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,


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
Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the principal Investigator,

For USA, availability of Form 1572.
The Investigator or Pharmacist or investigational drug storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each 
patient, and the return to the sponsor or warehouse / drug distribution centre or alternative 
disposal of unused products. If applicable, the sponsor or warehouse / drug distribution centre 
will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. 
At the time of return to the sponsor or appointed 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.
All used (empty or partially filled) vials should be saved for verification by the CRA in 
accordance with local practice. Once verified, the vials will be destroyed on site according to 
the facility policy for destruction of biologic material. Used vials should be kept in the kit 
box if possible. Any patient information placed on the vial must be de-identified (e.g. any 
pharmacy labelling that contains patient name or date of birth) or removed.
All unused trial medication will be returned to BI (or designated contractor) at the end of the 
trial or at the time of stock replacement when IMP is past the expiration date. Details of the 
return procedure are provided in the ISF. Throughout the duration of the trial, drug receipt, 
usage and return must be documented and verified. Any discrepancies in drug supplies will 
be noted and explained.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
For patients who continue to bleed, supportive care with blood products such as fresh frozen 
plasma, fresh or packed red blood cells, or packed platelets are permitted. Administration of 
activated prothrombin complex concentrates (e.g. FEIBA) or recombinant Factor VIIa, or 
concentrates of coagulation factors II, VII, IX, or X may be considered, even though their use 
has not been evaluated in clinical trials. Dabigatran can be haemodialysed out of the patient’s 
circulation. Approximately 60% of the drug can be removed over 2-3 hours: however, there is 
limited clinical data supporting this approach (P13-01830, P13-04186).


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Prior treatment with the dabigatran reversal agent carries a theoretical risk of anti-
idarucizumab antibody formation, a possible immune reaction to the reversal agent and 
possible decrease of the efficacy of the reversal agent.
Administration of dabigatran etexilate to a bleeding patient or a patient requiring emergency 
surgery should be interrupted. There are no known restrictions on other drugs at this time.
Some idarucizumab may remain circulating for up to 24 hours after infusion (less than 1% of 
the dose in patients with normal renal function, but somewhat more in patients with renal 
insufficiency or failure). This may impact the expected efficacy of reinstituted 
anticoagulation with dabigatran. 
In patients who stopped taking dabigatran etexilate due to an emergency surgery or other 
invasive procedure (Group B patients, refer to section 3.3.1), dabigatran etexilate treatment 
can be re-initiated 24 hours after administration of idarucizumab, if the patient is clinically 
stable and adequate haemostasis has been achieved. Re-initiation of dabigatran etexilate is 
not allowed in Group A patients.
If there is an urgent indication to re-start anticoagulation after trial treatment, the clinician 
must evaluate the risk-benefit ratio of doing so in the specific patient. The clinician may then 
choose to give one or more doses of a parenteral antithrombotic such as low molecular 
weight heparin as a bridging therapy at any time prior to re-initiation of dabigatran. In 
patients with creatinine clearance <30 mL/min dabigatran should not be re-started until the 
renal function has been corrected, or a longer term alternative anticoagulant should be 
chosen. Re-institution of anticoagulation is not a requirement of this trial, but is left to the 
discretion of the treating physician.
4.2.2.2
Restrictions on diet and life style
Not applicable.
4.2.2.3
Restrictions regarding women of childbearing potential 
Female patients who are not of reproductive potential (i.e. pre-pubertal) are not considered to 
have childbearing potential and therefore do not need to use contraception to be eligible for 
the trial.
Female patients who have reached menarche are considered to have childbearing potential 
and must use acceptable method(s) of birth control as indicated in trial 1160.106 or 1160.108 
wherein the patients are enrolled.


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4.3
TREATMENT COMPLIANCE
The trial drug is administered as an intravenous injection/infusion in the emergency or similar 
department of the trial centre. The administrations start and stop times of the first and second 
injection/infusion for administration of the total dose will be recorded. Any interruptions or 
discontinuations of infusions will also be recorded. Refer to Section 4.1.4 for method of 
administration.


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5
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint
The primary endpoint is the safety of idarucizumab in a paediatric population as assessed by 
the occurrence of drug-related adverse events (including immune reactions) and all-cause 
mortality during the trial.
5.1.2
Secondary Endpoints
The reversal of anticoagulant activity and formation of antidrug antibodies (ADA) will be 
recorded in all patients (unless limited by blood volume, bleeding and/or distress 
considerations, especially in very young children). 
Reversal of the anticoagulant effect of dabigatran at time t is defined as: a
Reversal () = predose coagulation test −postdose coagulation test at time 
predose coagulation test −ULN
 × 100%
Values equal to or higher than 100% will be interpreted as complete reversal of the 
anticoagulant effect. The reversal of anticoagulant activity will be based on central lab
measurements.
The following are the secondary endpoints: 

Percent change of coagulation tests (dTT, ECT) at 30 minutes post-dose compared to 
pre-dose.

Time to achieve complete reversal of dabigatran effecta, based on coagulation tests 
(dTT and ECT).

Duration of complete reversal of dabigatran effecta sustained at 24 hours post-dose, 
based on coagulation tests (dTT and ECT).

Cessation of bleeding (Group A patients only).b

Bleeding status and other clinical conditions that may contribute to bleeding (Group A 
patients only) during the trial.b

Development of treatment-emergent ADA with cross reactivity to idarucizumab at 
30 days post-dose of idarucizumab.b
a
The ULN for each marker has been determined using data from idarucizumab 
phase I trials 1321.1 (U13-1773-01) and 1321.2 (c02742738). It was calculated as the 
(arithmetic) mean + 2*SD using all data collected prior to the dosing of dabigatran


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and the data from patients who were on placebo as well as pre-dose data from idarucizumab 
alone treatment (as available). SD denotes the standard deviation.  
b
This is a safety issue.


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5.2
ASSESSMENT OF EFFICACY
The efficacy of idarucizumab will be assessed based on the central laboratory measurement 
of anticoagulant activity by dTT and ECT (secondary endpoints), aPTT and TT (further 
endpoints) tests. Further endpoints include the measurement of the unbound sum (free) 
plasma concentrations of dabigatran.
5.3
ASSESSMENT OF SAFETY
Adverse events, local tolerability, immune reactions, thrombotic events, mortality, vital signs 
blood pressure, heart rate, laboratory tests (including hepatic and renal function, 
haematology, clinical chemistry and idarucizumab ADA) will all be part of the safety 
assessment.
5.3.1
Physical examination
A complete physical examination (including cardiac, neurological, dermatological, 
pulmonological examinations, etc), height/length (in cm), body weight (in kg) and body 
temperature in °C will be performed at screening with record of abnormalities on the Medical 
History/Baseline Conditions eCRF page. Weight measurement should be done on the age-
appropriate scale and preferably in the same conditions as used to measure the dabigatran 
dose in the 1160.106 or 1160.108 trial wherein the patient is enrolled.
New abnormal findings or worsening of baseline conditions detected in later examinations 
during the trial will be recorded as AEs on the appropriate eCRF page.
5.3.2
Vital Signs
Blood pressure and heart rate will be recorded at time points noted in the Flow Chart.
5.3.3
Safety laboratory parameters
Safety laboratory parameters will be performed by the local laboratories of the trial centres as 
noted in Flow Chart. Standard safety lab panel may include when feasible, the following 
measurements:


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Haematology:
Red blood cell count, haemoglobin, haematocrit, white blood cell count and differential, 
platelets
Chemistry:
Glucose, albumin, total protein, sodium, potassium, chloride, urea, creatinine, alanine 
aminotransaminases (ALT), aspartate aminitransaminases (AST), alkaline phosphatase, total 
bilirubin or conjugated (direct)/unconjugated (indirect)
Pregnancy test (if applicable):
Local urine or other appropriate spot pregnancy test in female adolescents of child bearing 
potential (patients who have reached menarche) at time points as noted in the Flow Chart . 
More frequent testing can be done if required by the local regulation and/or authority or per 
Investigator’s judgement. Enrolment of pregnant patients is not allowed.
Lab abnormalities:
Any local lab abnormalities should be followed-up per Investigator’s judgement.
Blood sampling volume:
All efforts should be made to use the lowest amount of blood per sample as technically 
possible by using special paediatric collection systems. Blood sampling for this trial and for
dabigatran trial 1160.106 or 1160.108 should not exceed the maximum blood volume limits 
recommended by the European Commission nor the maximum specified in local guidelines 
(if applicable), i.e. blood loss should not exceed 3% of the total blood volume (TBV) over 
four weeks and should not exceed 1% of the TBV at any single time (R10-4556; R10-4959).
Blood sampling could be withheld or reduced per Investigator’s judgement, e.g. if limited by 
blood volume, bleeding and/or distress considerations especially in very young children.
Cross reporting of lab results might be applied (across studies 1160.106, 1160.108 and this 
trial) in order not to increase the blood volume required for analysis. 
Refer to appendix 10.2 for further details of blood sampling.
Blood draws for pharmacokinetics, biomarkers, ADA can be found in section 5.4, section 5.5
and section 5.6. Refer also to the Flow Chart.
5.3.4
Electrocardiogram
An ECG will be performed 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 


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(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 Investigator’s judgement) 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 patient source notes.
5.3.5
Other safety parameters
5.3.5.1
Bleeding assessment
Bleeding severity for the index bleed (Group A) or any unusual bleed associated with surgery 
(Group B) will be assessed at baseline by the treating clinician and where possible will be 
classified according to recommendations made by the Perinatal and Paediatric Haemostasis 
Subcommittee during the 56th-58th Scientific and Standardization Committee (SSC) 
Meetings of the ISTH (R11-4225).
Baseline assessment:

Overt bleeding that, in the opinion of the treating physician is severe, ongoing, 
possibly related to dabigatran use, and requires reversal of the anticoagulant effect.
Bleeding assessment
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 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.


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
In cases where haemoglobin or haematocrit values are not available for Group A 
patients during the conduct of the trial then bleeding assessments may be assessed 
retrospectively based on data associated with the post-dose time points.
5.3.5.2
Assessment of other conditions potentially contributing to bleeding
Any other clinical condition that may contribute to bleeding such as major trauma or the use 
of antiplatelets, etc. will be assessed as well.
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation or 

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.


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Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC system. These events 
should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
No AESIs have been defined for this trial.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 


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


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Figure 5.3.6.2: 1
Types of AEs to be reported according to the trial period. No 
AESIs have been identified for this trial.
The REP is defined as 24 hours after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment, please refer to section 7.3.4. Events which occurred after the REP will be 
considered as post treatment events.
Events leading to emergency surgery/urgent procedures qualifying for enrolment in this trial 
will be captured as an SAE or Outcome Event in the current dabigatran trial (trial 1160.106 
or 1160.108) as appropriate.
Bleeding events qualifying for enrolment in this trial (index bleeding events) will be captured 
as SAE in the current dabigatran trial (trial 1160.106 or 1160.108).
AE reporting to sponsor and timelines
The Investigator must report SAEs and non-serious AEs which are relevant for the reported 
SAE, on the BI SAE form via fax immediately (within 24 hours) to the sponsor’s unique 
entry point (country specific contact details will be provided in the ISF). The same timeline 
applies if follow-up information becomes available. In specific occasions the Investigator
could inform the sponsor upfront via telephone. This does not replace the requirement to 
complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. 
The following should also be recorded as an (S)AE in the eCRF and SAE form 
(if applicable):
Worsening of the underlying disease or of other pre-existing conditions,
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.


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If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy an SAE form must be completed 
in addition.
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Pharmacokinetic endpoints are listed in section 5.1.3 under further endpoints.
Idarucizumab plasma concentrations will be listed. Due to the infrequent blood sampling it is 
not planned to calculate PK parameters. 
If feasible, PK parameters for idarucizumab may be estimated using pharmacometric 
methods. In that case, the respective results are not planned to be presented in the clinical trial 
report but in a separate, stand-alone report.  
In addition, the following PK parameter will be determined for sum dabigatran, as feasible:
Cpre (concentration of the analyte in plasma prior to first idarucizumab administration)
In addition, the following PK parameter will be determined for unbound sum dabigatran, as 
feasible:
Cpre (concentration of the analyte in plasma prior to first idarucizumab administration)


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5.4.2
Methods of sample collection
The total amount of blood for central lab assessments of pharmacokinetics of idarucizumab, 
and dabigatran and the anti-drug antibody assay is indicated in appendix 10.2.
Blood collection supplies for central lab measurements will be provided.
K-EDTA blood samples will be collected at time points specified in the Flow Chart and in 
appendix 10.2 order to prepare plasma for use in the following assays:
Pharmacokinetic (PK) assays:
1. Idarucizumab
2. Dabigatran (as specified below)

“sum” dabigatran = total amount of dabigatran in plasma (after sample hydrolysis, 
i.e. comprising the sum of unconjugated plus glucuronide conjugated dabigatran)

“unbound sum” dabigatran = fraction of “sum” dabigatran (after plasma 
ultrafiltration, i.e. the sum of unconjugated plus glucuronide conjugated 
dabigatran, that is neither bound to idarucizumab nor to plasma proteins)
Actual clock times must be recorded for every sample. For the early time points after drug 
administration, samples should be obtained from a site that is remote from the idarucizumab 
infusion. If this is not possible an appropriate volume of blood should be voided prior to
sampling per treated physician’s judgement. Start the blood sampling with K-EDTA 
collection tubes followed by Na-Citrate tubes (for biomarker sampling, refer to 
section 5.5.3). Immediately after blood sampling, the drawing tubes should be gently inverted 
about 10 times and transferred into an ice water bath for temporary storage until 
centrifugation. Centrifugation will be done within 30 minutes after sample collection. Plasma 
will be transferred to new appropriately-labelled polypropylene tubes and stored in an upright 
position at about -20°C or below. Plasma samples should be shipped to the central logistic lab 
preferably within one day after the 24 hours post-dose blood sampling.
For clear identification of the samples, the sample labels should be completed carefully with 
the required information.
For further details on sample handling and shipment, refer to ISF / lab manual.
Validated methods will be used for all analytes. 
5.4.3
Analytical determinations
A central lab will process and ship samples to the analytical labs involved.
5.4.3.1
Analytical determination of idarucizumab plasma concentrations
Idarucizumab concentrations will be determined using validated enzyme-linked 
immunosorbent assay (ELISA) methods. Detailed descriptions of the assays will be available 
prior to the start of sample analysis.


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Samples will be analysed at:
The sponsor may appoint other laboratories for method development and sample analysis, if 
necessary.
5.4.3.2
Analytical determination of dabigatran plasma concentrations
Concentrations of dabigatran will be determined by validated HPLC-MS/MS assays (high 
performance liquid chromatography, tandem mass spectrometry) at
Plasma samples will be analysed at:
The sponsor may appoint other laboratories for method development and sample analysis, if 
necessary.
5.5
ASSESSMENT OF BIOMARKERS
5.5.1
Biobanking
This is not applicable in this trial.
5.5.2
Coagulation biomarkers
Coagulation biomarkers are the basis for determination of efficacy in this trial. In some 
countries or regions some biomarkers maybe only for investigational use (e.g. diluted 
Thrombin Time).
Biomarker assays will be measured in a central laboratory.
1. Ecarin Clotting Time (ECT)
2. diluted Thrombin Time (dTT)
3. activated Partial Thromboplastin Time (aPTT)
4. Thrombin Time (TT)
The following parameter will be calculated for ECT, dTT, aPTT and TT as feasible:

Epre (value of the biomarker assay determined in a plasma sample prior to 
administration of idarucizumab)
5.5.3
Methods of sample collection
Blood will be collected into sodium citrate collection tubes (3.2%) to obtain at least 500 µL 
(microL) citrate plasma at each time point for central laboratory evaluation of dTT, ECT, 


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aPTT and TT at planned time points as noted in the Flow Chart and indicated in
appendix 10.2 and appendix 10.3. For further details on sample handling and shipment please 
refer to the central lab manual.
5.5.4
Analytical determinations
The blood coagulation parameters activated partial thromboplastin time (aPTT), ecarin 
clotting time (ECT), diluted thrombin time (dTT, FIIa inhibition by Hemoclot® assay) and 
thrombin time (TT) will be investigated.
Samples will be analysed at: 
The sponsor may appoint other laboratories for method development and sample analysis, if 
necessary.
5.6
OTHER ASSESSMENTS
5.6.1
Idarucizumab antidrug antibodies assay
An antidrug antibodies assay will be performed for idarucizumab at planned time points as 
noted in Flow Chart.
5.6.2
Methods of sample collection
K-EDTA blood samples will be collected at time points specified in the Flow Chart and in 
appendix 10.2 order to prepare plasma.
5.6.3
Analytical determination of idarucizumab antidrug antibodies
Human anti-idarucizumab antibodies will be detected in human plasma samples by a 
validated bridging ECL method. Samples will be screened for ADA. Putative positive 
samples will be tested in a confirmation assay, and positive samples will also be titered and 
characterized for epitope specificity. Detailed descriptions of the assays will be available 
prior to the start of sample analysis.
Samples will be analysed at:
The sponsor may appoint other laboratories for method development and sample analysis, if 
necessary.


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5.7
APPROPRIATENESS OF MEASUREMENTS
The choice of central lab measurement of coagulation tests dTT, ECT for secondary 
endpoints is explained in section 3.2. Clinical outcomes such as bleeding reduction, bleeding 
cessation, duration of hospitalisation, and clinical status of the patient will be recorded.
Coagulation tests such as dTT, ECT, aPTT and TT, are the tests used in the evaluation of a 
medication with this mechanism of action.
Some tests may be for investigational use only in specific countries, e.g. dTT. It cannot be 
excluded that co-medications such as volume expanders affect the accuracy of these 
parameters. In case of dTT, the plasma sample is 8 fold diluted with standardized plasma 
prior to measurement, ensuring that the effect is minimal. Preclinical data show little impact 
of coagulation factor concentrates on the reversal with idarucizumab; animal studies of PCCs 
show some improvement in bleeding.
Non-standard tests such as dabigatran levels, anti idarucizumab antibody levels will be 
evaluated to fully elucidate the action of the trial medication and determine the ability of 
idarucizumab to be effective for subsequent uses in the same patient.


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6
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
A summary of scheduled assessments for the trial is presented in the Flow Chart. The trial
data will be collected at the time of the visit and by medical record review.
Eligible patients will receive trial medication after meeting inclusion and exclusion criteria.  
All patients who receive trial medication will be followed up for 30 days.
A patient visit may be rescheduled as long as it is within the acceptable time windows of the 
protocol. Every effort should be made to have the patient adhere to the visit schedule. 
Patients who prematurely withdrawn from trial medication must undergo End of Trial
(Visit 5) procedures.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening Period
Visit 1 (Day 1): Screening Period (Baseline):
When a patient presents to the investigative team, given consent by the patient (and/or the 
patient’s legally accepted representative) and assent provided by the patient (if applicable and 
feasible to provide by the patient at the time of the emergency), meets all inclusion/exclusion 
criteria, the patient will be eligible to participate in the trial. 
Due to the need for urgent care in these patients, it is anticipated that the majority of 
screening procedures will have already been performed as part of the hospitalisation and 
diagnosis procedures. These procedures should not be repeated for the purpose of the trial. 
Any trial procedures that were not performed as part of routine care must only be performed 
after informed consent (and assent if applicable) has been obtained.
Collection of medical history and other standard of care information up to the time of 
consenting must be provided as source documents as part of the study screening procedures 
and will be collected on the eCRF.
After obtaining informed consent (and assent if applicable) for the trial the following 
procedures will be performed unless they have already been performed as part of routine 
procedures for hospitalisation and diagnosis:

Bleeding assessments for the index bleed (Group A) or any unusual bleed associated 
with surgery (Group B, if applicable). 

Surgery/procedure assessment (Group B, if applicable).

Perform local urine or other appropriate spot pregnancy test in female adolescents of 
child bearing potential (patients who have reached menarche). Enrolment of pregnant 
patients is not allowed.


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
Draw blood for local lab safety evaluation 

ECG

Record concomitant therapy

Record adverse events

Record demographics, medical history and physical examination (including height, 
weight and temperature) and vital signs.
6.2.2
Treatment Period
Trial medication will consist of two vials of 2.5g idarucizumab (total dose up to 5.0g, 
according to body weight, refer to Table 4.1.2: 1) administered no longer than 15 minutes 
apart. In most cases, written informed consent (and assent if applicable) and treatment with 
the trial medication will be on the same day.
Blood sampling could be withheld or reduced per Investigator’s judgement, e.g. if limited by 
blood volume, bleeding and/or distress considerations especially in very young children.
Visit 2.1 (Day 1 continued):
Observations and Procedures:

Draw blood immediately prior to vial 1 administration for central lab parameters 
(biomarkers, PK and ADA). Record time of blood draw (= baseline lab assessment).

Administer first dosing from first vial of trial medication. Record start and stop time 
of administration.

Bleeding assessments for the index bleed (Group A) or any unusual bleed associated 
with surgery (Group B, if applicable). 

Surgery/procedure assessments (Group B, if applicable).

Measure blood pressure and heart rate approximately hourly while the patient is in the 
emergency department (or similar department), then approximately every 6 to 8 hours 
for the next 72 hours or until patient is discharged, whichever comes first.

Record adverse events

Record concomitant therapies

Optional (local) aPTT measurement or other local test
Visit 2.2 (Day 1 continued):
Observations and Procedures:

Draw blood immediately prior to vial 2 administration, for central lab parameters 
(biomarkers, PK). Record time of blood draw.

Administer second dosing from second vial of trial medication no later than 
15 minutes after the completion of the first vial. Record start and stop time of 
administration.


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
Draw blood 30 minutes (± 10 minutes), 4 hours (± 30 minutes) and 12 hours 
(± 1 hour) post-dose for central lab parameters (biomarkers and PK). Record time of 
blood draw.

Bleeding assessments for the index bleed (Group A) or any unusual bleed associated 
with surgery (Group B). Bleeding assessments at or near times of blood draws.

Surgery/procedure assessments at or near times of blood draws (Group B patients).

Measure blood pressure and heart rate approximately hourly while the patient is in the 
emergency or similar department, then approximately every 6 to 8 hours for the next 
72 hours or until patient is discharged, whichever comes first.

Record adverse events

Record concomitant therapies

Perform trial drug accountability

Optional (local) aPTT measurement or other local test
6.2.3
Safety Follow-Up Period
Visit 3: 24-hour after dosing (+/- 2 hours)
Blood sampling could be withheld or reduced per Investigator’s judgement, e.g. if limited by 
blood volume, bleeding and/or distress considerations especially in very young children.
Observations and procedures

Draw blood 24 hours post-dose for central lab parameters (biomarkers and PK). 
Record time of blood draw.

Draw blood 24 hours post-dose for local lab safety evaluation. Record time of blood 
draw.

Bleeding assessment for the index bleed (Group A) or any unusual bleed associated 
with surgery (Group B). Bleeding assessment at or near time of blood draw.

Surgery/procedure assessment at or near time of blood draw (Group B patients).

Measure blood pressure and heart rate approximately hourly while the patient is in the 
emergency department (or similar department), then approximately every 6 to 8 hours 
for the next 72 hours or until patient is discharged, whichever comes first.

Record adverse events

Record concomitant therapies

Re-start appropriate anticoagulant therapy (at treating physician/Investigator
discretion)

Optional (local) aPTT measurement or other local test


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Visit 4: 7 days after dosing (+/- 3 days)
Observations and procedures

Bleeding assessment for the index bleed (Group A) or any unusual bleed associated 
with surgery (Group B). 

Surgery/procedure assessment (Group B patients only).

Measure blood pressure and heart rate (approximately hourly if the patient is still in 
the emergency or similar department, then approximately every 6 to 8 hours for the 
next 72 hours or until patient is discharged), whichever comes first.

ECG

Record adverse events

Record concomitant therapies
Visit 5: End of Trial 30 days after dosing (+ 7 days)
Blood sampling could be withheld or reduced per Investigator’s judgement, e.g. if limited by 
blood volume, bleeding and/or distress considerations especially in very young children.
Observations and procedures:

Bleeding assessment for the index bleed (Group A) or any unusual bleed associated 
with surgery (Group B). Bleeding assessment at or near time of blood draw.

Surgery/procedure assessment at or near time of blood draw (Group B patients only).

Measure blood pressure and heart rate

Draw blood for central lab parameters (ADA). Record time of blood draw.

Perform local urine or other appropriate spot pregnancy test in female adolescents of 
child bearing potential (patients who have reached menarche). 

Record adverse events

Record concomitant therapies

Conclusion of patient participation


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7
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This trial has a single treatment group with no control group. It is a case series open-label 
trial to assess the safety of idarucizumab and to evaluate the reversal of the anticoagulant 
effects of dabigatran by intravenous administration of idarucizumab to paediatric patients 
treated with dabigatran etexilate who have life-threatening or uncontrolled bleeding or who 
have require emergency surgery/urgent procedures. The two patient groups (patients having 
life-threatening or uncontrolled bleeding and those requiring emergency surgery/urgent
procedures) will be summarized separately and together, with an overall conclusion, if 
possible.
The primary and secondary endpoints will be reported using descriptive statistics or using 
listings due to limited number of patients in each group. Descriptive statistics will be 
performed, when appropriate from a sample size perspective. Statistical inference will not be 
performed. Sufficient numbers of treated patients to do subgroup analysis are not expected.
7.2
NULL AND ALTERNATIVE HYPOTHESES
There is no hypothesis testing for this trial.
7.3
PLANNED ANALYSES
Safety and efficacy analyses will be based on all treated patients who have received any 
idarucizumab from a vial. For different efficacy, PK, or PD endpoints, the number of
evaluable patients may be different. Details of patient set analysed will be specified in the 
TSAP. Analysis of safety and efficacy endpoints will be descriptive in nature. The efficacy 
analysis for reversal will also exclude patients with a pre-dose coagulation test value below 
the ULN. Baseline will be defined as the last available measurement before dosing of 
idarucizumab (pre-dose). Details regarding the definitions of important protocol violations 
will be provided in the TSAP.
7.3.1
Primary endpoint analyses
There is no primary efficacy endpoint. The primary safety endpoint is defined in 
section 5.1.1.
Occurrence of drug-related adverse events (including immune reactions) and all-cause 
mortality during the trial (from the start of dosing until 30 days after the end of dosing) will 
be reported.  
Potential specific risks that could be caused by ADA, such as local injection site reactions, 
systemic hypersensitivity, including anaphylaxis or immune complex disease, are considered 
as immune reactions, and will be assessed clinically and reported descriptively.
As to summary of other adverse events, refer to section 7.3.4.


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7.3.2
Secondary endpoint analyses
Percent change from baseline of coagulation tests (dTT and ECT) at 30 minutes post-dose
will be summarized descriptively. 
Time to achieve complete reversal and duration of complete reversal of dabigatran effects
sustained at 24 hours post-dose based on coagulation tests (dTT and ECT) will be reported by 
listing the reversal values at planned time points and using flags to show whether complete 
reversal is achieved.  
For Group A patients only, the cessation of bleeding will be reported using a binary outcome 
(Yes/No) descriptively.
Bleeding status and other clinical conditions that may contribute to bleeding (Group A 
patients only) during the trial will be reported descriptively.
Development of treatment-emergent ADA with cross reactivity to idarucizumab at 30 days 
post-dose of idarucizumab will be summarized using a binary outcome 
(Yes/No) descriptively.  


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7.3.4
Safety analyses
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned. 
Parameters to be evaluated for safety are described in section 5.3. Details will be included in 
the TSAP.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. Standard BI summary tables and listings will be produced. All AEs will be 
classified according to the following trial periods: screening, on-treatment, and post-
treatment. All AEs with an onset date/time after the 1st vial of trial medication up to one day
after the last administration of trial 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. 
Frequency, severity, and causal relationship of all AEs (including bleeding) in the on-
treatment period will be tabulated in total by system organ class and preferred term after 
coding accordingly to the current version of the MedDRA. AEs in the screening and post-
treatment period will be listed.
Other laboratory data, vital signs and physical examinations data will be reported 
descriptively.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Pharmacokinetic and pharmacodynamic parameters in this trial will be evaluated 
descriptively as feasible and appropriate, and calculated according to the BI standards. For 
ADA, positivity at different time points and titer value will be considered. If necessary, 
further analyses will be specified in the TSAP.
7.4
INTERIM ANALYSIS
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
With respect to efficacy and safety evaluations, it is not planned to impute missing values. 
The reversal of anticoagulation cannot be defined if either the pre-dose or all post-dose 
coagulation test is missing. However, missing or incomplete AE dates will be imputed 
according to BI standards.  
Handling of missing PK data will generally be performed according to the BI standards.
Drug concentration data identified with below the lower limit of quantification (BLQ) will be 
displayed as such and not replaced by zero at any time point (this rule also applies to the lag 
phase, including the pre-dose values) with the exception of unbound sum dabigatran. For this 
analyte, data identified with BLQ following the administration of idarucizumab may be 
replaced with the lower limit of quantification, until measurable concentrations re-occur. 
The appropriate time frame will be decided by the Trial Clinical Pharmacokineticist (TCPK)
and described in the CTR.


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With respect to pharmacodynamic evaluations it is not planned to impute missing values. 
However, clotting times may exceed the maximum clotting time of 500s recorded by the 
coagulometer, indicating the presence of high concentrations of dabigatran, for example in 
pre-dose idarucizumab samples. If the blood clotting time exceeds 500s, above the upper
limit of quantification (ALQ) will be reported. For calculation of reversal of the 
anticoagulation effect, ALQ values may be replaced by 500s. In that case ALQ values will be 
discussed on an individual basis within the trial team (including TCM, Trial Biomarker 
Analyst (TBMA), TCPK and Trial Statistician (TSTAT) and decisions will be documented in 
the CTR. There are no rules for evaluation. BLQ values as well as pharmacodynamic data 
identified with no sample available (NOS), no valid result (NOR), and not analysed (NOA)
will not be considered.
7.6
RANDOMISATION
This trial has a single treatment group without randomisation.
7.7
DETERMINATION OF SAMPLE SIZE
The design of this trial (including the definition of endpoints and sample size) has been 
agreed with the European Medicines Agency’s Paediatric Committee.
Sample size (approximately 5 patients) is determined based on feasibility.


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8
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonised standards for Medical Devices (ISO 14155, current version).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, 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 (and/or the patient’s legally accepted representative) and assent (if applicable) 
according to ICH / GCP and to the regulatory and legal requirements of the participating 
country. However, due to the need for urgent care in these patients collection of medical 
history and other standard of care information up to the time of consenting must be provided 
as part of the study screening procedures and will be collected on the eCRF. 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 and/or the patient’s legally accepted representative.”
The Investigator must give a full explanation to trial patients (and/or the patient’s legally 
accepted representative as appropriate) based on the patient information form. A language 


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understandable to the patient (and/or the patient’s legally accepted representative as 
appropriate) should be chosen, technical terms and expressions avoided, if possible. The 
patient (and/or the patient’s legally accepted representative) must be given sufficient time to 
consider participation in the trial (if feasible in this emergent situation). The Investigator
obtains written consent of the patient’s own free will with the informed consent form after 
confirming that the patient (and/or the patient’s legally accepted representative as 
appropriate) understands the contents. The Investigator must sign (or place a seal on) and 
date the informed consent form. If a trial collaborator has given a supplementary explanation, 
the trial collaborator also signs (or places a seal on) and dates the informed consent.
Where permitted by local regulatory body and approved by local Ethics Committee an 
adjusted Informed Consent procedure may be used due to the nature of the emergent medical 
condition of the patient (e.g. verbal informed consent followed by written informed consent 
by patient and/or patient’s legally accepted representative).
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions. The consent and re-consenting 
process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
Electronic Case Report Forms for individual patients will be provided by the sponsor. For 
drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient and/or the patient’s 
legally accepted representative, documented in their medical records, would be acceptable.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.


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For the eCRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations).

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed).

Dates of Patient’s visits, including dispensing of trial medication.

Medical history (including trial indication and concomitant diseases, if applicable).

Medication history.

Adverse events and outcome events (onset date (mandatory), and end date (if available)).

Serious adverse events (onset date (mandatory), and end date (if available)).

Concomitant therapy (start date, changes).

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available).

ECG results (original or copies of printouts).

Completion of Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). The CRA and auditor may review all eCRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in section 8.3.1. The sponsor will also monitor compliance with the protocol and 
ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
the national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial. The end of the trial is defined as the date of the last visit of the last patient in the whole 
trial (“Last Patient Out”). The “Last Patient Drug Discontinuation” (LPDD) date is defined 
as the date on which the last patient at an individual trial site ends trial medication (as 
scheduled per protocol or prematurely). Individual Investigators will be notified of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring with the trial medication until 
30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.


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


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9
REFERENCES
9.1
PUBLISHED REFERENCES
P94-81556
Andrew M., David M., Adams M., Ali K., Anderson R., Barnad D., Bernstein 
M., Brisson L., Cairney B., DeSai D., Grant R., Israels S., Jardine L., Luke B., 
Massicotte P., Silva M. Venous thromboembolic complications (VTE) in 
children: First analyses of the Canadian registry of VTE. Blood 1994; 83 (5), 
1251 - 1257.
P09-11669
Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., Parekh A., 
Pogue J., Reilly P.A., Themeles E., Varrone J., Wang S., Alings M., Xavier 
D., Zhu J., Diaz R., Lewis B.S., Darius H., Diener H.C., Joyner C.D., 
Wallentin L. RE-LY Steering Committee and Investigators. Dabigatran versus 
warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12), 1139 
- 1151.
P10-03790
Ryn J. van, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, 
Clemens A. Dabigatran etexilate - a novel, reversible, oral direct thrombin 
inhibitor: interpretation of coagulation assays and reversal of anticoagulant 
activity. Thromb Haemost 103 (6), 1116 - 1127 (2010).
P13-01830
Khadzhynov D., Wagner F., Formella S., Wiegert E., Moschetti V., Slowinski 
T., Neumayer H.H., Liesenfeld K.H., Lehr T., Haertter S., Friedman J., Peters 
H., Clemens A. Effective elimination of dabigatran by haemodialysis: a phase 
I single-centre study in patients with end-stage renal disease. Thromb Haemost 
2013; 109, 596 - 605.
P13-04186
Liesenfeld K.H., Staab A., Haertter S., Formella S., Clemens A., Lehr T.
Pharmacometric characterization of dabigatran hemodialysis. Clin 
Pharmacokinet 2013; 52 (6), 453 - 462.
P13-08115
Connolly S.J., et al. The long-term multicenter observational study of 
dabigatran treatment in patients with atrial fibrillation: (RELY-ABLE) study. 
Circulation 2013; 128 (3), 237 - 243.
P13-16985
Schulman S, Kakkar A.K., Goldhaber S.Z., Schellong S., Eriksson H., 
Mismetti P., Vedel Christiansen A., Friedman .J, Maulf F. le, Peter N., Kearon 
C., RE-COVER II Trial Investigators. Treatment of acute venous 
thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 
2014; 129 (7), 764 - 772.
P15-06362
Pollack C.V., Reilly P.A., Eikelboom J, Glund S., Verhamme P., Bernstein 
R.A., Dubiel R., Huisman M.V., Hylek E.M., Kamphuisen P.W., Kreuzer J., 
Levy J.H., Sellke F.W., Stangier J., Steiner T., Wang B., Kam .CW., Weitz J.I. 


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Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373 (6), 511 - 520.
P15-12457
Idarucizumab (Praxbind) - an antidote for dabigatran. Med Lett Drugs Ther
2015; 57 (1482), 157 - 158.
P16-00177
Eikelboom J.W., Daniel J. Quinlan D.J., Ryn, J. Van, Weitz J.I. Idarucizumab. 
The Antidote for Reversal of Dabigatran. Circulation 2015; 132: 2412 - 2422.
R04-1541
Zoetis T, Hurtt M.E. Species comparison of anatomical and functional renal 
development. Birth Defects Res (B) 2003; 68, 111 - 120.
R06-2301
Ommen C.H. van, Heijboer H., Buller H.R., Hirasing R.A., Heijmans H.S.A., 
Peters M. Venous thromboembolism in childhood: a prospective two-year 
registry in The Netherlands. J Pediatr 2001: 139 (5), 676 - 681.
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.
R09-5148
Raffini L.J., Huang Y., Witmer C., Feudtner C. A significant increase in 
venous thromboembolism in hospitalized children in the USA from 2001 to 
2007. 22nd Cong of the International Society on Thrombosis and Haemostasis 
(ISTH), Boston, 11 - 16 Jul 2009. J Thromb Haemost 7 (CD) (Suppl 2), Abstr 
AS-TU-055 (2009)
R10-4556
European Medicines Agency (EMEA), ICH topic E 11: clinical investigation 
of medicinal products in the paediatric population: step 5: note for guidance on 
clinical investigation of medicinal products in the paediatric population 
(January 2001, CPMP/ICH/2711/99), www.emea.eu.int (2006).
R10-4959
European Commission. Ethical considerations for clinical trials on medicinal 
products conducted with the paediatric population: recommendations of the ad 
hoc group for the development of implementing guidelines for Directive 
2001/20/EC relating to good clinical practice in the conduct of clinical trials 
on medicinal products for human use (final 2008).
http://ec.europa.eu/health/files/eudralex/vol-10/ethical_considerations_en.pdf 
(access date 19.08.2010)
R11-11740
Flanagan R.J., Jones A.L. Fab antibody fragments: some applications in 
clinical toxicology. Drug Safety, 2004; 27 (14), 1115 - 1133.
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.


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R13-1336
Mock D.M., Perman J.A., Thaler M.M., Morris R.C. Chronic fructose 
intoxication after infancy in children with hereditary fructose intolerance: a 
cause of growth retardation. N Engl J Med 1983; 309 (13), 764 - 770.
R13-1337 
Cox T.M. Therapeutic use of fructose: professional freedom, 
'pharmacovigilance' and Europe. Q J Med 1995; 88, 225 - 227.
R13-1338
Cox T.M. Iatrogenic deaths in hereditary fructose intolerance.
Arch Dis Child 1993; 69, 413 - 415.
R13-4252
Rajgopal R., Bear M.K., Butcher M.K., Shaughnessy S.G. The effects of 
heparin and low molecular weight heparins on bone. Thromb Res 2008; 122, 
293 - 298.
R13-4256
Vu L.T., Nobuhara K.K., Lee H., Farmer D.L. Determination of risk factors 
for deep venous thrombosis in hospitalized children. J Pediatr Surg 2008; 43, 
1095 - 1099. 
EMEA-000081-PIP01-07-M07: Dabigatran etexilate Paediatric Investigational Plan.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-000081-PIP01-
07-M07/pip_000040.jsp&mid=WC0b01ac058001d129
EMEA-001438-PIP01-13: Idarucizumab Paediatric Investigational Plan.
http://www.ema.europa.eu/ema/index.jsp%3Fcurl%3D/index.jsp?curl=pages/medicines/pips/
EMEA-001438-PIP01-13/pip_001159.jsp&mid=WC0b01ac058001d129
9.2
UNPUBLISHED REFERENCES
U11-2616-01 Periodic Safety Update Report Pradaxa Dabigatran etexilate hard capsules,   
75 mg, 110 mg 19 Sep 2010 to 18 Sep 2011.
U12-3431
Idarucizumab Investigator’s brochure. Current version.
U13-1773-01
. Randomised, double-blind, 
placebo-controlled Phase I study in healthy male volunteers to investigate 
safety, tolerability and pharmacokinetics of single rising doses of BI 655075 
(part 1) and to explore the dose of BI 655075 effective to reverse dabigatran 
anticoagulant activity (part 2), in preparation.
U13-1986-01
 In vitro binding affinity of BI 655075 for 
dabigatran and the functional neutralization of the anticoagulant activity of 
dabigatran and its acylglucuronides by BI 655075 in vitro in a modified 


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thrombin time assay. Draft version. 30 Oct 2013.
c02742738
Randomised, double-blind, single dose, placebo-controlled, two-way cross-
over Phase Ib study to investigate the safety, tolerability, pharmacokinetics 
and pharmacodynamics of BI 6555075 and to establish the efficacy of BI 
655075 (1321.2).
s00034702-01 Periodic Safety Update Report Pradaxa Dabigatran etexilate hard capsules,   
75 mg, 110 mg, 19 Mar 2015 to 18 Sep 2015.


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10
APPENDICES
10.1
SAFETY AND OTHER CLINICAL LABORATORY EVALUATIONS
Standard safety lab panel may include when feasible parameters as described in section 5.3.3.
Estimated Glomerular Filtration Rate (eGFR) for children should be based on the Schwartz 
formula. This employs serum creatinine (mg/dL), the child's height (cm) and a constant to 
estimate the glomerular filtration rate:
eGFR (Schwartz) = (0.41 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
10.2
TIME SCHEDULE FOR BLOOD SAMPLING
Blood volumes to be collected for central lab parameters and local safety lab measurements 
will depend on available tube sizes and age of the patient as specified in Table 10.2.: 1 and 
Table 10.2: 2. The sponsor may decide on other tubes sizes, if necessary. In such case total 
blood volume of the blood sampling may differ.
Cross reporting of lab results might be applied (across studies 1160.106, 1160.108 and this 
trial) in order not to increase the blood volume required for analysis. 
Pre-dose and between vials sampling: central blood sampling for pharmacodynamic 
biomarkers (dTT, ECT, aPTT, TT), pharmacokinetics (dabigatran and idarucizumab 
concentration) will occur immediately prior to administration of each vial of idarucizumab. 
Blood sampling for idarucizumab ADA will only occur prior to vial 1 administration.
Post-dose sampling: central blood sampling for pharmacodynamic biomarkers (dTT, ECT, 
aPTT, TT), pharmacokinetics (dabigatran and idarucizumab concentrations) will be collected 
at 30 minutes (± 10 minutes), 4 hours (± 30 minutes), 12 hours (± 1 hour) and 24 hours (± 2 
hours) post-dose. Blood sampling for idarucizumab ADA will occur 30 days (+7 days) post-
dose. 
In Table 10.2.: 1, general required blood volumes are indicated for age category < 6 years of 
age. For children < 6 years of age, available tube sizes for central lab parameters are 1.2 mL, 
and 2.7 mL EDTA monovettes and 1.4 mL Na Citrate monovettes. For all central lab 
parameters and local safety lab measurements about 29 to 37 mL blood will be required 
during the trial.
In Table 10.2.: 2, general required blood volumes are indicated for age category ≥ 6 years of 
age. For children ≥ 6 years of age, available tube sizes for central lab parameters are 3.0 mL 


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EDTA vacutainers and 2.7 mL Na Citrate vacutainers. For all central lab parameters and local 
safety lab measurements about 43 to 49 mL blood will be required during the trial.
All efforts should be made to use the lowest amount of blood per sample as technically 
possible by using special paediatric collection systems (R10-4556; R10-4959). Blood 
sampling for this trial and for dabigatran trial 1160.106 or 1160.108 should not exceed the 
maximum blood volume limits recommended by the European Commission (R10-4959) nor 
the maximum specified in local guidelines (if applicable), i.e. blood loss should not exceed 
3% of the total blood volume (TBV) over four weeks and should not exceed 1% of the TBV 
at any single time. 
Blood sampling could be withheld or reduced per Investigator’s judgement, e.g. if limited by 
blood volume, bleeding and/or distress considerations especially in very young children. 
Refer to appendix 10.3 for several reduced blood draw schedules.
All invasive procedures in this trial must be performed only by qualified and experienced 
health care professionals/physicians with paediatric expertise, with limited attempts to draw 
blood and/or establish an intravenous (IV) line based on Investigator’s judgement.
Prior to venipuncture, a topical (percutaneous) analgesia to reduce pain associated with 
venipuncture, e.g. amethocaine gel or lidocaine-prilocaine (Emla) cream should be applied on 
the skin. This should be done according to standard paediatric procedures, and may be 
omitted only in patients who explicitly refuse it. 


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Table 10.2: 1
Blood draw schedule (patients < 6 years of age)
Time
EDTA*
Na 
Citrate**
Local 
Safety 
Lab***
Total blood 
volume
Visit 1
1
Screening
2 to 6 mL
2 to 6 mL
Visit 2.1
2
Baseline (just 
prior vial 1)
2.7 mL
1.4 mL
4.1 mL
Administer Idarucizumab Vial 1
Visit 2.2
3
Just prior vial 2
2.7 mL
1.4 mL
4.1 mL
Administer Idarucizumab Vial 2
Visit 2.2
4
30 minutes
(± 10 minutes)
2.7 mL
1.4 mL
4.1 mL
5
4 hours
(± 30 minutes)
2.7 mL
1.4 mL
4.1 mL
6
12 hours
(± 1 hour)
2.7 mL
1.4 mL
4.1 mL
Visit 3
7
24 hours
(± 2 hours)
2.7 mL
1.4 mL
2 to 6 mL
6 to 10 mL
Visit 4
8
Day 7
(± 3 days)
Visit 5
9
Day 30
(+ 7 days)
1.2 mL
1.2 mL
Total blood volume
29 to 37 mL
*EDTA K3 = PK assays, idarucizumab ADA 
**Na Citrate = Biomarkers (dTT, ECT, aPTT, TT)
***Amount of mL will depend on tube sizes used by local lab.


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Table 10.2: 2
Blood draw schedule (patients ≥ 6 years of age)
Time
EDTA*
Na 
Citrate**
Local 
Safety 
Lab***
Total blood 
volume
Visit 1
1
Screening
3 to 6 mL
3 to 6 mL
Visit 2.1
2
Baseline (just 
prior vial 1)
3.0 mL
2.7 mL
5.7 mL
Administer Idarucizumab Vial 1
Visit 2.2
3
Just prior vial 2
3.0 mL
2.7 mL
5.7 mL
Administer Idarucizumab Vial 2
Visit 2.2
4
30 minutes
(± 10 minutes)
3.0 mL
2.7 mL
5.7 mL
5
4 hours
(± 30 minutes)
3.0 mL
2.7 mL
5.7 mL
6
12 hours
(± 1 hour)
3.0 mL
2.7 mL
5.7 mL
Visit 3
7
24 hours
(± 2 hours)
3.0 mL
2.7 mL
3 to 6 mL
9 to 12 mL
Visit 4
8
Day 7
(± 3 days)
Visit 5
9
Day 30
(+ 7 days)
3.0 mL
3.0 mL
Total blood volume
43 to 49 mL
*EDTA = PK assays, idarucizumab ADA 
**Na Citrate = Biomarkers (dTT, ECT, aPTT, TT)
***Amount of mL will depend on tube sizes used by local lab.


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10.3
ESTIMATED TOTAL BLOOD VOLUME 
The estimated Total Blood Volume (TBV) will depend on age and gender and will be 
calculated with following formula:
Total Blood Volume = Weight * Average Blood Volume
Table 10.3.1:
Approximate (average) blood volume per age category.
Age category
Approximate (average)  blood volume (mL/Kg)
Term newborn infant 
80 - 90 (85)
Infants 
80
Children (> 3 months)
70-80
Adolescents
women
65
men
75
For children the approximate total blood volume may vary between 70 - 80 mL/Kg. In order 
to be conservative, 70 mL/Kg will be used to calculate the total blood volume (TBV).
Examples of TBV calculations: 
Infant of 1.5 year old, weight 10 Kg:
-
Allowed blood loss at any single time (1% of TBV): 8 mL
-
Allowed blood loss over four weeks (3% of TBV): 24 mL
Child of 12 years old, weight 45 Kg:
-
Allowed blood loss at any single time (1% of TBV): 31.5 mL
-
Allowed blood loss over four weeks (3% of TBV): 94.5 mL
Adolescent (male) of 15 years old, weight 60 Kg:
-
Allowed blood loss at any single time (1% of TBV): 45 mL
-
Allowed blood loss over four weeks (3% of TBV): 135 mL
Blood sampling could be withheld or reduced per Investigator’s judgement, e.g. if limited by 
blood volume, bleeding and/or distress considerations especially in very young children.
If blood sampling is reduced, central lab parameters will be analysed in a priority order as 
indicated below:
1) Sum dabigatran pre-dose (baseline)
2) All coagulation biomarkers pre-dose, 30 minutes and 24 hours post-dose 
3) Idarucizumab ADA pre-dose and 30 days post-dose
4) PK idarucizumab at time points pre-dose; 30 minutes and 24 hours post-dose
5) All coagulation biomarkers at time points prior vial 2, 4 hours and 12 hours post-dose
6) PK idarucizumab at time points prior vial 2, 4 hours and 12 hours post-dose


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7) Unbound sum dabigatran at all time points as noted in Flow Chart
In below tables a few scenarios are displayed if collected blood volumes are limited. 
Table 10.3: 1
Reduced blood draw schedule (patients < 6 years of age):
Maximal 29 mL central lab/local safety blood draw (e.g. no EDTA blood 
collection prior vial 2, 4 hours and 12 hours post-dose; i.e. no measurement of 
unbound sum dabigatran and no PK idarucizumab prior vial 2, 4 hours and 12 
hours post-dose)
Time
EDTA
Na 
Citrate
Local 
Safety Lab
Total blood 
volume
Visit 1
1
Screening
2 to 6 mL
2 to 6 mL
Visit 2.1
2
Baseline (just 
prior vial 1)
2.7 mL
1.4 mL
4.1 mL
Administer Idarucizumab Vial 1
Visit 2.2
3
Just prior vial 2
1.4 mL
1.4 mL
Administer Idarucizumab Vial 2
Visit 2.2
4
30 minutes
(± 10 minutes)
2.7 mL
1.4 mL
4.1 mL
5
4 hours
(± 30 minutes)
1.4 mL
1.4 mL
6
12 hours
(± 1 hour)
1.4 mL
1.4 mL
Visit 3
7
24 hours
(± 2 hours)
2.7 mL
1.4 mL
2 to 6 mL
6 to 10 mL
Visit 4
8
Day 7
(± 3 days)
Visit 5
9
Day 30
(+ 7 days)
1.2 mL
1.2 mL
Total blood volume
21 to 29 mL


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Table 10.3: 2
Reduced blood draw schedule (patients < 6 years of age):
Maximal 25 mL central lab/local safety blood draw (e.g. no blood collection 
prior vial 2, 4 hours and 12 hours post-dose; i.e. no measurement of 
biomarkers, unbound sum dabigatran and no PK idarucizumab prior vial 2, 4 
hours and 12 hours post-dose)
Time
EDTA
Na 
Citrate
Local 
Safety Lab
Total blood 
volume
Visit 1
1
Screening
2 to 6 mL
2 to 6 mL
Visit 2.1
2
Baseline (just 
prior vial 1)
2.7 mL
1.4 mL
4.1 mL
Administer Idarucizumab Vial 1
Visit 2.2
3
Just prior vial 2
Administer Idarucizumab Vial 2
Visit 2.2
4
30 minutes
(± 10 minutes)
2.7 mL
1.4 mL
4.1 mL
5
4 hours
(± 30 minutes)
6
12 hours
(± 1 hour)
Visit 3
7
24 hours
(± 2 hours)
2.7 mL
1.4 mL
2 to 6 mL
6 to 10 mL
Visit 4
8
Day 7
(± 3 days)
Visit 5
9
Day 30
(+ 7 days)
1.2 mL
1.2 mL
Total blood volume
17 to 25 mL


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Table 10.3: 3
Reduced blood draw schedule (patients ≥6 years of age):
Maximal 40 mL central lab/local safety blood draw (e.g. no EDTA blood 
collection prior vial 2, 4 hours and 12 hours post-dose; i.e. no measurement of 
unbound sum dabigatran and no PK idarucizumab prior vial 2, 4 hours and 12 
hours post-dose)
Time
EDTA
Na 
Citrate
Local 
Safety Lab
Total blood 
volume
Visit 1
1
Screening
3 to 6 mL
3 to 6 mL
Visit 2.1
2
Baseline (just 
prior vial 1)
3.0 mL
2.7 mL
5.7 mL
Administer Idarucizumab Vial 1
Visit 2.2
3
Just prior vial 2
2.7 mL
2.7 mL
Administer Idarucizumab Vial 2
Visit 2.2
4
30 minutes
(± 10 minutes)
3.0 mL
2.7 mL
5.7 mL
5
4 hours
(± 30 minutes)
2.7 mL
2.7 mL
6
12 hours
(± 1 hour)
2.7 mL
2.7 mL
Visit 3
7
24 hours
(± 2 hours)
3.0 mL
2.7 mL
3 to 6 mL
9 to 12 mL
Visit 4
8
Day 7
(± 3 days)
Visit 5
9
Day 30
(+ 7 days)
3.0 mL
3.0 mL
Total blood volume
34 to 40 mL


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Table 10.3: 4
Reduced blood draw schedule (patients ≥ 6 years of age):
Maximal 32 mL central lab/local safety blood draw (e.g. no blood collection 
prior vial 2, 4 hours and 12 hours post-dose; i.e. no measurement of 
biomarkers, unbound sum dabigatran and no PK idarucizumab prior vial 2, 4 
hours and 12 hours post-dose)
Time
EDTA
Na 
Citrate
Local 
Safety Lab
Total blood 
volume
Visit 1
1
Screening
3 to 6 mL
3 to 6 mL
Visit 2.1
2
Baseline (just 
prior vial 1)
3.0 mL
2.7 mL
5.7 mL
Administer Idarucizumab Vial 1
Visit 2.2
3
Just prior vial 2
Administer Idarucizumab Vial 2
Visit 2.2
4
30 minutes
(± 10 minutes)
3.0 mL
2.7 mL
5.7 mL
5
4 hours
(± 30 minutes)
6
12 hours
(± 1 hour)
Visit 3
7
24 hours
(± 2 hours)
3.0 mL
2.7 mL
3 to 6 mL
9 to 12 mL
Visit 4
8
Day 7
(± 3 days)
Visit 5
9
Day 30
(+ 7 days)
3.0 mL
3.0 mL
Total blood volume
26 to 32 mL


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11
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
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
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08884404
1.0
clinical-trial-protocol
Single dose, open label, uncontrolled, safety trial of intravenous administration of
idarucizumab to paediatric patients enrolled from ongoing phase IIb/III clinical trials
with dabigatran etexilate for  the treatment and secondary prevention of venous
thromboembolism
Approval-Trial Clinical Monitor
08 Feb 2016 10:59 CET
Approval-Biostatistics
08 Feb 2016 22:42 CET
Approval-Therapeutic Area
09 Feb 2016 08:15 CET
Author-Pharmacokinetics
09 Feb 2016 13:54 CET
Approval-Team Member Medicine
09 Feb 2016 14:53 CET
Verification-Paper Signature
Completion
09 Feb 2016 15:24 CET


Boehringer Ingelheim 
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 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08884404
1.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c09126655-02
BI Trial No.:
1321.7
Title:
Single dose, open label, uncontrolled, safety trial of intravenous 
administration of idarucizumab to paediatric patients enrolled from 
ongoing phase IIb/III clinical trials with dabigatran etexilate for the 
treatment and secondary prevention of venous thromboembolism.
Investigational
Product:
Idarucizumab
Responsible trial 
statistician:
Phone: 
Date of statistical 
analysis plan:
31 JUL 2017 SIGNED
Version:
Final 
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINTS.....................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoints......................................................................................8
................................................................................8
................................................................................8
................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENT.....................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................10
6.3
PATIENT SETS ANALYSED...........................................................................11
....................................................................................................11
6.5
POOLING OF CENTRES .................................................................................11
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................11
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................12
7.
PLANNED ANALYSIS......................................................................................13
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........13
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................13
7.3
TREATMENT COMPLIANCE........................................................................13
7.4
PRIMARY ENDPOINTS...................................................................................14
7.5
SECONDARY ENDPOINTS.............................................................................14
7.5.1
Key secondary endpoints....................................................................................14
.............................................................................14
.............................................................................15
7.7
EXTENT OF EXPOSURE.................................................................................16
7.8
SAFETY ANALYSIS..........................................................................................16
7.8.1
Adverse events.....................................................................................................16
7.8.2
Laboratory data ..................................................................................................17
7.8.3
Vital signs.............................................................................................................17
7.8.4
ECG......................................................................................................................17
7.8.5
Others...................................................................................................................17
8.
REFERENCES....................................................................................................18
.............................................................................19
10.
HISTORY TABLE..............................................................................................20


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LIST OF TABLES
Table 6.2: 1
Important protocol violations ...........................................................................10
Table 6.3: 1
Patient sets analysed .........................................................................................11
Table 10: 1
History table .....................................................................................................20


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Antidrug antibodies
AE
Adverse event
AESI
Adverse events of special interest
ALQ
Above upper Limit of Quantification
ATC
Anatomical Therapeutic Chemical
aPTT
activated Partial Thromboplastin Time
BI
Boehringer Ingelheim
BLQ
Below lower Limit of Quantification
BRPM
Blinded report planning meeting
CRF
Case report form 
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
dTT
diluted Thrombin Time
ECT
Ecarin Clotting Time  
ICH
International Conference on Harmonisation
IPV
Important protocol violation
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
NOA
Not Analysed 
NOR
No Valid Result
NOS
No Sample Available
PCC
Prothrombin Complex Concentrate
PD
Pharmacodynamics
PDS
Pharmacodynamic set
PK
Pharmacokinetics
PT
Preferred term
REP
Residual Effect Period, after the last dose of medication with measurable 
drug levels or pharmacodynamic effects still likely to be present
SD
Standard deviation
SOC
System organ class
TBMA
Trial Biomarker Analyst
TCM
Trial Clinical Monitor


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Term
Definition / description
TCPK
Trial Clinical Pharmacokineticist
TS
Treated set 
TSAP
Trial statistical analysis plan
TSTAT
Trial statistician
TT
Thrombin Time
ULN
Upper Limit of Normal
WHO
World Health Organization


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomisation.”
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
Sample size is estimated to be approximately 5 patients.  Depending on the actual sample size, 
listings only may be provided while the descriptive summaries specified in the protocol may 
not be displayed.  


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary endpoint is the safety of idarucizumab in a paediatric population as assessed by 
the occurrence of drug-related adverse events (including immune reactions) and all-cause 
mortality during the trial.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint is defined.
5.2.2
Other Secondary endpoints

Percent change of coagulation tests (dTT and ECT) at 30 minutes post-dose compared to 
pre-dose.

Time to achieve complete reversal of dabigatran effect, based on coagulation tests (dTT 
and ECT).

Duration of complete reversal of dabigatran effect sustained at 24 hours post-dose, 
based on coagulation tests (dTT and ECT).

Cessation of bleeding (Group A patients only).

Bleeding status and other clinical conditions that may contribute to bleeding (Group A 
patients only) during the trial.

Development of treatment-emergent ADA with cross reactivity to idarucizumab at 
30 days post-dose of idarucizumab.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
It is planned to include approximately 5 patients in this trial. All patients will receive 
idarucizumab (short label: Ida), which will be administered intravenously as two equal 
consecutive infusions over 5 to 10 minutes each or as two bolus injections no more than 15 
minutes apart.  
The residual effect period (REP) is defined as 1 day after the last trial medication application. 
The following treatment period will be defined:

Screening: day of informed consent to day of first idarucizumab administration. If same 
day, then the period before first vial administration of idarucizumab.

On-treatment: time of first administration of idarucizumab to time of last administration 
of idarucizumab + 1 day.

Post-treatment: time after last idarucizumab administration + 1 day, to day of end of trial
visit (Visit 5) or consent withdraw.
As it may take up to 5 days for some potentially drug related reactions to show up, 5-day REP 
will also be considered as sensitivity analysis.   
6.2
IMPORTANT PROTOCOL VIOLATIONS
No per protocol set will be defined for this study; however patients with potentially important 
protocol violations (IPVs) will be documented. The following is the list of potentially IPVs.  
Table 6.2: 1
Important protocol violations
Category /
Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1.1
Inclusion criterion 2 for Group A 
or B not met
Patient not currently treated with dabigatran 
etexilate in the context of a clinical trial with 
dabigatran etexilate (1160.106 or 1160.108)
PDS
A1.2
Inclusion criteria 1, 3, and/or 4 for 
Group A or B not met
Inclusion criteria 1, 3, and /or 4 not met as 
specified in the protocol.
PDS
A2
Exclusion criteria not met
Exclusion criteria not met as specified in the 
protocol
PDS
B
Informed consent
B1
Informed consent/assent not 
available/not done
Informed consent/assent date missing
All
B2
Informed consent/assent too late
Informed consent/assent date <actual 
consent/assent date> was after Visit 1 date 
<Visit 1 date>
None
C
Trial medication and 
randomisation
C1
Incorrect amount of trial 
medication taken
Only one vial or more than two vials of 
idarucizumab was administered.
None
C2
Actual dose given and the dose 
based on patient’s body weight do
not match
Actual dose given collected in eCRF and the 
dose based on patient’s body weight (see CTP 
Table 4.1.2: 1) do not match
None
KEY:
PDS – Pharmacodynamic set


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All categories listed in Table 6.2: 1 will be checked automatically. Additional IPVs may be 
identified manually during the course of the study and will be assessed during the Medical 
and Quality Review meetings (MQRM). If the list of IPVs needs to be enlarged, it will be 
documented in the Blinded Report Planning Meeting (BRPM) / Database Lock Meeting 
minutes before database lock.
6.3
PATIENT SETS ANALYSED
Two analysis sets will be used for the data analysis in this trial:

Treated set (TS): includes all patients who received any dose of idarucizumab. The TS 
will be used to assess safety, clinical endpoints, demographics and baseline 
characteristics, concomitant diagnosis/therapy and medical history, as well as PK 
endpoints and ADA.  

Pharmacodynamic set (PDS): comprises all patients in the TS who provided at least one 
evaluable pre-dose and at least one post-dose observation for PD endpoints or biomarker 
measures. The PDS will be used for PD endpoint analyses. Note that for different PD 
endpoints or biomarkers, the number of evaluable patients may be different.
Table 6.3: 1
Patient sets analysed 
Patient set
Class of endpoint
Treated set
PDS
Primary endpoints 
X
Secondary and further endpoints 
Clinical endpoints;  
idarucizumab PK 
endpoint*; ADA
Dabigatran PK endpoint; 
PD endpoints (biomarkers)
Safety endpoints 
X
Demographic/baseline endpoints
X
* Only if at least one post-dose evaluable blood sample is available. 
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
With respect to efficacy and safety evaluations, it is not planned to impute missing values. 
The reversal of anticoagulation cannot be defined if either the pre-dose or all post-dose 
coagulation test is missing, or if the pre-dose coagulation test is below the ULN. Patients in 
such case will be considered as not evaluable for the corresponding biomarker.


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Missing or incomplete AE dates will be imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (2).
Handling of missing PK data will generally be performed according to the BI standards (3).
Drug concentration data identified with below the lower limit of quantification (BLQ) will be 
displayed as such and not replaced by zero at any time point (this rule also applies to the lag 
phase, including the pre-dose values) with the exception of unbound sum dabigatran. For this 
analyte, data identified with BLQ following the administration of idarucizumab may be 
replaced with the lower limit of quantification, until measurable concentrations re-occur. 
The appropriate time frame will be decided by the Trial Clinical Pharmacokineticist (TCPK) 
and described in the CTR.
With respect to pharmacodynamic evaluations it is not planned to impute missing values. 
However, clotting times may exceed the maximum clotting time of 500s recorded by the 
coagulometer, indicating the presence of high concentrations of dabigatran, for example in 
pre-dose idarucizumab samples. If the blood clotting time exceeds 500s, above the upper limit 
of quantification (ALQ) will be reported. For calculation of reversal of the anticoagulation 
effect, ALQ values may be replaced by 500s. In that case ALQ values will be discussed on an 
individual basis within the trial team (including TCM, Trial Biomarker Analyst (TBMA), 
TCPK and Trial Statistician (TSTAT) and decisions will be documented in the CTR. There 
are no rules for evaluation. BLQ values as well as pharmacodynamic data identified with no 
sample available (NOS), no valid result (NOR), and not analysed (NOA) will not be 
considered.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Unless otherwise specified, baseline value will be the last available measurement taken prior 
to administration of idarucizumab (same day is allowed). 


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7.
PLANNED ANALYSIS
This trial has a single treatment group with no control group. Approximately 5 patients will be 
enrolled in this trial.  The primary and secondary endpoints will be reported using descriptive 
statistics or using listings due to limited number of patients in each group. Descriptive 
statistics will be performed by patient groups (patients having life-threatening or uncontrolled 
bleeding and those requiring emergency surgery/urgent procedures) and together, when 
appropriate from a sample size perspective. Statistical inference will not be performed.
Descriptive statistics for continuous variables will generally be N (number of patients with 
non-missing values), mean, standard deviation (SD), minimum, median, and maximum. In 
general, means, medians, 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/PD data.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
If patients entered the trial more than once (i.e. patients need a reversal of the anticoagulant 
effect of dabigatran again for a new and independent event), each time will be treated as an 
independent case. The patient will be assigned different patient identification number for each 
time of enrolment. The cases will be analysed independently as if from different patients.  
This is only possible for patients from group B.  
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographic and baseline characteristics will be summarized descriptively or listed only 
depending on the number of patients.  
7.2
CONCOMITANT DISEASES AND MEDICATION
The concomitant medications taken at baseline and those taken while on treatment will be 
coded using the WHO Drug coding dictionary. These will be listed by patient.  
Listing of patients’ exposure to dabigatran prior to entering the trial will be presented, 
including the time of last dabigatran intake, daily dose and dabigatran indication.
Medical history and baseline disease will be listed, as well as the baseline bleeding 
assessment.  
7.3
TREATMENT COMPLIANCE
Only a listing is planned for this section of the report. The information on the start and end 
date and time of each vial of idarucizumab and actual administered volume will be provided. 


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7.4
PRIMARY ENDPOINTS
There is no primary efficacy endpoint. 
As the primary safety endpoints, occurrence of drug-related adverse events (including 
immune reactions) and all-cause mortality during the trial (from the start of dosing until 30 
days after the end of dosing) will be listed. Reason of death will be also listed. 
Potential specific risks that could be caused by ADA, such as local injection site reactions, 
systemic hypersensitivity, including anaphylaxis or immune complex disease, are considered
as immune reactions, and will be assessed clinically and listed.
As to summaries of other adverse events, refer to Section 7.8.1.
7.5
SECONDARY ENDPOINTS
Secondary endpoints will be listed based on treated set or pharmacodynamic set according to 
the nature of endpoints.
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Other Secondary endpoints
Percent change from baseline of coagulation tests (dTT and ECT) at 30 minutes post-dose 
will be summarized descriptively or listed only if deemed appropriate. 
Reversal of the anticoagulant effect of dabigatran at time t is defined as:
Reversal (t) = predose coagulation test −postdose coagulation test at time t
predose coagulation test −ULN
× 100%
Values equal to or higher than 100% will be interpreted as complete reversal of the 
anticoagulant effect. The reversal of anticoagulant activity will be based on central lab 
measurements and calculated for coagulation tests, dTT and ECT, separately.  Reversal 
cannot be defined for patients with dTT or ECT pre-dose measurement value less than ULN; 
such patients are considered as not evaluable for reversal related endpoints.  The ULN was 
determined by using data from studies 1321.1 and 1321.2, calculated as the (arithmetic) mean 
+ 2 * standard deviation (SD) by using all data collected prior to the dosing of dabigatran and 
the data from patients who were on placebo, as well as pre-dose data from idarucizumab alone 
treatment (as available). 
Time to achieve complete reversal will be reported by listing the calculated reversal values at 
planned time points and using flags to show whether complete reversal is achieved at planned 
time points.  
Duration of complete reversal, defined as the time period from when a patient first achieves 
complete reversal, up to the earliest time point among the following: middle point between 
last observation of 100% reversal and subsequent observation, 24 hours post-dose or re-


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starting the treatment of dabigatran or other anticoagulation. Duration of complete reversal 
can be defined only for those patients who achieved complete reversal.  
For Group A patients only, the cessation of bleeding within 24 hours will be reported in a 
listing.
For Group A patients only, bleeding status will be assessed during treatment period and be 
summarized descriptively or listed only if deemed appropriate.  Other clinical conditions that 
may contribute to bleeding (Group A patients only) during the trial, such as major trauma or
the use of antiplatelets, will also be reported.  
The blood sample for idarucizumab ADA is scheduled to be collected prior to vial 1 
administration and at Day 30 post-dose.  If a patient doesn’t have ADA pre-dose and has 
ADA at Day 30, this patient is considered as having treatment-emergent ADA.  Development 
of treatment-emergent ADA with cross reactivity to idarucizumab at 30 days post-dose of 
idarucizumab will be reported using a binary outcome (Yes/No).  


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7.7
EXTENT OF EXPOSURE
Two vials of idarucizumab will be administered no more than 15 minutes apart. Number of 
vials received, the duration of each vial, time between start of first vial to end of second vial 
will be listed. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned. 
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs.
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:

All AE attributes are identical ((LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, and outcome).

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).
For further details on summarization of AE data, please refer to (2, 4).
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till last drug 
intake + residual effect period (24 hours) will be assigned to the trial medication. In addition, 
AEs occurring before first drug intake but with worsening in intensity during the treatment 
period will also be assigned to the trial medication. All adverse events occurring before first 


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drug intake will be assigned to ‘screening’ and all adverse events occurring after the residual 
effect period will be assigned to ‘post-treatment’ (for listings only). For details on the 
treatment definition, see Section 6.1.
According to ICH E3 (5), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events 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 Monitor/Investigator at a Medical Quality Review 
Meeting.
An overall summary of adverse events, including the summaries of related adverse events, 
serious adverse events and other significant adverse events according to ICH E3 (5), will be 
presented using data for the entire study period. All AEs including those in the screening, 
treatment and post-treatment periods will be listed.
No adverse events of special interest (AESI) have been defined for this trial.
7.8.2
Laboratory data
The laboratory data will be listed.  Local aPTT test results will be listed separately.  
7.8.3
Vital signs
Clinically relevant changes in vital signs and/or physical examination results since 
baseline/visit 1 must be recorded as an adverse event on the “Adverse Event” eCRF page and 
will be analysed accordingly. Vital signs will be listed.  
7.8.4
ECG
Clinically relevant findings of ECG will be recorded on “Medical History / Baseline 
Condition” or “Adverse Events” eCRF pages and will be listed accordingly.
7.8.5
Others
Not applicable. 


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8.
REFERENCES
1
CPMP/ICH/363/96: “Statistical Principles for Clinical Trials”, ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCG-156_RD-01: “Handling of missing and incomplete AE dates”, current 
version; IDEA for CON.
3
001-MCS 36-472: “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics”, current version; IDEA for CON.
4
001-MCG-156: “Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries”, 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


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial 
22-JUL-16
None
This is the initial TSAP with necessary 
information for trial conduct.  This initial 
TSAP is based on the protocol finalized on 
04Feb2016.  
Final
31-JUL-17
None
This is the final TSAP without any
modification.  This final TSAP is based on 
the protocol finalized on 04Feb2016.  
Changes to the planned analysis are 
summarized in Section 4 and detailed in the 
corresponding sections of the SEAP.