Clinical trial NCT03343704
Conditions: Hemorrhage
Sponsor: Boehringer Ingelheim
Start date: 2018-03-26; Completion date: 2020-07-02
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to demonstrate reversal of the anticoagulant effect of dabigatran in patients treated with dabigatran etexilate who have uncontrolled or life-threatening bleeding requiring urgent intervention, and in patients treated with dabigatran etexilate who require emergency surgery or other invasive procedure.

The secondary objectives are to assess the reduction or cessation of bleeding, evaluate the clinical outcomes, safety and the pharmacokinetics of dabigatran in the presence of idarucizumab.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Idarucizumab
Intervention descriptions: intervention 1: Intravenous

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c16458864-01
BI Trial No.:
1321-0019
BI Investigational 
Product(s):
Idarucizumab （BI655075）
Title:
A Phase III, case series clinical study of the reversal of the 
anticoagulant effects of dabigatran by intravenous administration 
of idarucizumab (BI 655075) in patients treated with dabigatran 
etexilate who have uncontrolled bleeding or require emergency 
surgery or procedures.
Lay Title:
This study looks at the effects of idarucizumab in patients who 
take dabigatran and need emergency surgery or are bleeding
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone:
 Fax:
Principal 
Investigator < or >
Coordinating 
Investigator:
Phone:
Status:
Final Protocol
Version and Date:
Version:
Date:
1
01 June 2017
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2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Finished product 
name
Idarucizumab
Active ingredient 
name:
Idarucizumab （BI655075）
Protocol date
01 June 2017
Revision date
Trial number
1321-0019
Title of trial:
A Phase III, case series clinical study of the reversal of the 
anticoagulant effects of dabigatran by intravenous administration of 
idarucizumab (BI 655075) in patients treated with dabigatran etexilate 
who have uncontrolled bleeding or require emergency surgery or 
procedures.
Principal 
Investigator < for 
single-centre trial 
or > Coordinating 
Investigator< for 
multi-centre trial if 
applicable >:
Phone:
Trial site(s):
Multi-centre trial
Clinical phase:
III
Objective(s):
The primary objective is to demonstrate reversal of the anticoagulant 
effect of dabigatran.  The secondary objectives are the assessment of 
bleeding, clinical outcomes and safety and the pharmacokinetics of 
dabigatran in the presence of idarucizumab.
Methodology:
Open label, uncontrolled, case series
Number of patients 
entered: 
20
Number of patients 
20


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on each treatment:
Diagnosis :
There are two separate groups of patients with different diagnoses:
Group A.  Patients who are taking dabigatran etexilate and 
have uncontrolled or life-threatening bleeding requiring urgent 
medical or surgical intervention
Group B.  Patients who are taking dabigatran etexilate who 
may not be bleeding, but do require an emergency surgery or 
other invasive procedure for a condition other than bleeding,
where therapeutic anticoagulation with dabigatran etexilate is 
undesirable
Main in- and 
exclusion criteria

Group A-Dabigatran etexilate -treated patients seen in the 
Emergency Department (ED) or similar department of a hospital 
who exhibit signs and symptoms of (overt) uncontrolled bleeding 
requiring urgent medical or surgical intervention.
OR

Group B-Dabigatran etexilate treated patients seen in the 
Emergency Department or similar department of a hospital who 
require emergency surgery or other medical procedure 
necessitating rapid reversal of the anticoagulant effect of 
dabigatran prior to surgery/procedure.
AND
Establish that the patient is being treated with dabigatran etexilate.
Test product(s):
Idarucizumab in buffered solution for injection, 50 mL/vial, 50 
mg/mL
dose:
The total dose is 5 g (two 2.5g vials). A single vial contains 2.5g of 
idarucizumab.  Patients will receive a 2.5g vial of study medication 
and a second 2.5g vial within the next 15 minutes. In rare instances, 
an additional 5 g dose is justified.
mode of 
administration:
Intravenous
Comparator 
products:
Not applicable
dose:
Not applicable


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mode of 
administration:
Not applicable
Duration of 
treatment:
Two vials of idarucizumab administered no more than 15 minutes 
apart.
Endpoints
Efficacy will be based on central laboratory determination of reversal 
of the anticoagulant effect of dabigatran, using several coagulation 
tests (thrombin time (TT), diluted thrombin time (dTT), ecarin 
clotting time (ECT), activated partial thromboplastin time (aPTT), 
and local assessment of aPTT. No dosing or patient management 
decisions are based on central lab determination of reversal. Dosing 
of idarucizumab will not be affected by a local lab test.
Primary endpoint:
The primary study endpoint is the maximum reversal of the 
anticoagulant effect of dabigatran, based on central laboratory 
determination of dTT or ECT, at any time point from the end of the 
first infusion up to 4 hours after the completion of the second 
infusion.
Secondary endpoints:

Time to cessation of bleeding (for Group A only) since first 
infusion up to 24 hours after the completion of second 
infusion. Bleeding status will be categorized before and at 
several time points after treatment.

Occurrence of major bleeding (for Group B only) 
intraoperatively and up to 24 hours post-surgery.

Minimum unbound sum (free) dabigatran concentrations at 
any time point since end of the first infusion up to 4 hours 
after the completion of the second infusion.

Reversal of aPTT and TT, at any time point since end of the 
first infusion up to 4 hours after the completion of the second 
infusion. 
Safety criteria:
Adverse events, local tolerability, immune reactions, thrombotic 
events, mortality, vital signs (BP, PR), laboratory tests (including 
hepatic and renal function, hematology, clinical chemistry, 
coagulation parameters, cytokines and ADA(anti-idarucizumab 
antibody)).


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Type and location of bleeding will be evaluated.
Statistical methods:
Descriptive statistics for efficacy, safety and PK/PD endpoints will be 
calculated.  Confidence limits will be provided when appropriate. The 
two patient groups (bleeding patients and those requiring emergency 
surgery/procedures) will be analysed separately and together, with an 
overall conclusion, if possible. Among bleeding patients, those with 
intracranial hemorrhage (ICH) will be analyzed separately in 
deference to expected differences in management strategies and 
functional outcomes in these patients vs those with other hemorrhagic 
diagnoses. 
 
Other subgroups of bleeds of similar type (e.g. 
gastrointestinal, trauma) will be analysed separately where cohort size 
permits.


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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 study)
Visit Description
Patient 
screening
Vial 1
Vial 
2
24-
hours 
after 
vial 2
7 days 
after vial 
2
30 days after 
vial 2
Visit Day(s)
1
1
1
(no 
later 
than 
15 
min 
after 
vial 
1)
2
(± 2 
hours)
7
(± 3 
days)
30
(±7 days)
Informed consent1,2
X
Inclusion / exclusion criteria
X
Confirm dabigatran
etexilate use
X
Medical History
X
Demographics
X
Physical Exam16 and Vital 
Signs, Temperature2
X9
X13,14
X 13,14
X13,14
X13,14,9
X13
Bleed assessment3,4
X
X
X
X
X
X
Surgery/Procedure 
assessment4
X
X
X
X
X
X
Study Drug Administration5
X
X
PK/PD Blood Draw6
X
X
X
X
Local Safety Blood Draw
X10,11,12
X11
X10,12
Pregnancy Testing7,2
X
X
Study drug accountability
X
ECG2
X
X
Adverse Events4
X
X
X
X
X
X
Concomitant therapies 
X
X
X
X
X
X
Conclusion of patient 
participation8
X
1-
Written informed consent. 
2-
Due to the need for urgent care in these patients, collection of medical history and other standard of care information 
(e.g. laboratory values, vital signs, weight, ECG) within 24 hours prior to inform consent may be collected on the CRF 
in order to prevent unnecessary repetition of procedures.
3-
Four bleeding assessment classifications: 1) ISTH, 2) TIMI, 3) GUSTO, 4) Glasgow Coma Scale (for ICH patients)


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4-
Sites may be requested to provide redacted source documents for specified adverse events.  These source documents 
may include, but are not limited to: progress notes, discharge summaries, lab results, ECGs, consult reports, autopsy 
report, MRI or CT scans and other test results.
5-
In rare instances during the same hospitalization, e.g. 2 to 24 h after the initial 5 g dose, a patient may experience a re-
start of bleeding or have a potential for a life-threatening bleed or have a need for an additional emergency 
surgery/procedure, coupled with re-elevation of local clotting tests. In such cases an additional 5 g dose is justified and 
the patient should be allocated a new patient number.  Blood sampling times are the same as with the first 5 g dose or as 
logistics permit (Prior to administration of the third vial, just prior to the fourth vial, as well as between 10 and 30 min, 
1, 2, 4, 12, 24 hours, and 30 days after the end of the infusion of the fourth vial).  Other study procedures and tests 
should be performed per protocol.
6-
Blood sampling for central PD (biomarker) and pharmacokinetic (PK) measurements and/or anti-drug antibodies will 
occur: Prior to administration of the first vial, just prior to the second vial, as well as between 10 and 30 min, 1, 2, 4, 12, 
24 hours, and 30 days after the end of the infusion of the second vial. For details refer to Table 5.3.2.1: 1. Time will be 
recorded for every blood sample taken.  Actual time for the start and end of the infusion will be recorded.
7-
Local urine or other appropriate spot pregnancy test in women of childbearing potential. Recruitment of pregnant 
patients is allowed only after a careful evaluation/discussion of the risks and benefits of study participation between the 
treating physician and patient, unless it is against local regulations.
8-
Conclusion of patient participation also needs to be completed if the patient withdraws prematurely following first vial 
of study medication.
9-
Includes modified Rankin Scale (mRS) assessment for ICH cohort only
10- Includes Hematology and Chemistry
11- Draw blood for local lab aPTT at baseline, just prior to the second vial, 10 to 30 minutes, and 12 hour after second vial.
12- Additional local lab testing may be done at the discretion of the treating physician to facilitate patient clinical 
management.
13- Blood pressure, heart rate only.
14- Blood pressure and heart rate hourly while the patient is in the emergency or similar department, then every 4 hours for 
the next 72 hours or until discharge.
16- A physical examination includes height and body weight and height will only be collected on visit 1.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
1.2
DRUG PROFILE................................................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................25
1.4
BENEFIT - RISK ASSESSMENT.....................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........27
2.1.1
Main objectives....................................................................................................27
2.1.2
Primary endpoint(s)............................................................................................27
2.1.3
Secondary endpoint(s) ........................................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................31
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................32
3.3
SELECTION OF TRIAL POPULATION .......................................................33
3.3.1
Main diagnosis for trial entry ............................................................................33
3.3.2
Inclusion criteria .................................................................................................33
3.3.3
Exclusion criteria ................................................................................................34
3.3.4
Withdrawal of patients from therapy or assessments .....................................34
3.3.4.1
Withdrawal from trial treatment ...........................................................................35
3.3.4.2
Withdrawal of consent for trial participation........................................................36
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................36
4.
TREATMENTS...................................................................................................37
4.1
INVESTIGATIONAL TREATMENTS ...........................................................37
4.1.1
Identity of the Investigational Medicinal Products..........................................37
4.1.2
Selection of doses in the trial..............................................................................37
4.1.3
Method of assigning patients to treatment groups...........................................38
4.1.4
Drug assignment and administration of doses for each patient......................38
4.1.5
Blinding and procedures for unblinding...........................................................38
4.1.5.1
Blinding.................................................................................................................38
4.1.5.2
Unblinding and breaking the code ........................................................................38


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4.1.6
Packaging, labelling, and re-supply...................................................................38
4.1.7
Storage conditions...............................................................................................39
4.1.8
Drug accountability.............................................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................40
4.2.1
Other treatments and emergency procedures..................................................40
4.2.2
Restrictions ..........................................................................................................40
4.2.2.1
Restrictions regarding concomitant treatment ......................................................40
4.2.2.2
Restrictions on diet and life style..........................................................................40
4.2.2.3
Restrictions regarding women of childbearing potential......................................41
4.3
TREATMENT COMPLIANCE........................................................................41
5.
ASSESSMENTS..................................................................................................42
5.1
ASSESSMENT OF EFFICACY........................................................................42
5.2
ASSESSMENT OF SAFETY.............................................................................42
5.2.1
Physical examination ..........................................................................................42
5.2.2
Vital signs.............................................................................................................42
5.2.3
Safety laboratory parameters ............................................................................43
5.2.4
Electrocardiogram ..............................................................................................43
5.2.5
Other safety parameters.....................................................................................43
5.2.6
Assessment of adverse events.............................................................................43
5.2.6.1
Definitions of AEs ................................................................................................43
5.2.6.2
Adverse event collection and reporting ................................................................47
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................49
5.3.1
Assessment of pharmacokinetics .......................................................................49
5.3.2
Methods of sample collection .............................................................................49
5.3.2.1
Pharmacokinetic, anti-drug antibody, and biomarker assays................................49
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................53
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................53
5.4.1
Endpoints based on biomarkers ........................................................................54
5.5
OTHER ASSESSMENTS...................................................................................54
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................56
6.
NVESTIGATIONAL PLAN..............................................................................57
6.1
VISIT SCHEDULE.............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................57
6.2.1
Screening and run-in period(s)..........................................................................57
6.2.2
Treatment period(s)............................................................................................58
6.2.3
Follow up period and trial completion..............................................................59


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................61
7.1
STATISTICAL DESIGN - MODEL.................................................................61
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................61
7.3
PLANNED ANALYSES.....................................................................................61
7.3.1
Primary endpoint analyses.................................................................................61
7.3.2
Secondary endpoint analyses .............................................................................61
7.3.4
Safety analyses.....................................................................................................63
7.4
INTERIM ANALYSES ......................................................................................64
7.5
HANDLING OF MISSING DATA ...................................................................64
7.5.1
Plasma concentration – time profiles ................................................................64
7.5.2
Pharmacokinetic parameters.............................................................................64
7.5.3
Pharmacodynamic parameters..........................................................................65
7.6
RANDOMISATION ...........................................................................................65
7.7
DETERMINATION OF SAMPLE SIZE .........................................................65
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........66
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................66
8.2
DATA QUALITY ASSURANCE ......................................................................67
8.3
RECORDS...........................................................................................................67
8.3.1
Source documents ...............................................................................................67
8.3.2
Direct access to source data and documents.....................................................69
8.3.3
Storage period of records ...................................................................................69
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................69
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........69
8.6
TRIAL MILESTONES.......................................................................................70
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................70
9.
REFERENCES....................................................................................................72
9.1
PUBLISHED REFERENCES............................................................................72
9.2
UNPUBLISHED REFERENCES......................................................................72
10.
APPENDICES.....................................................................................................74
10.1
ADVERSE EVENTS DURING TREATMENT IN STUDY 1321.1, PARTS 
1 AND 2, IN ORDER OF FREQUENCY .........................................................74
10.2
BLOOD DRAW SCHEDULE@........................................................................77
10.3
CLINICAL LABORATORY EVALUATIONS...............................................77
10.4
GLASGOW COMA SCALE AND MODIFIED RANKIN SCALE ..............78
10.5
PHARMACOKINETIC METHODS................................................................81
10.6
CLINICAL EVALUATION OF LIVER INJURY ..........................................82
10.6.1
Introduction.........................................................................................................82
10.6.2
Procedures ...........................................................................................................82


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................84
11.1
GLOBAL AMENDMENT 1 ..............................................................................84
11.2
GLOBAL AMENDMENT 2 ..............................................................................85


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ABBREVIATIONS
ACT
ADAs
AE
AESI
ALQ
ALT
AST
Activated Clotting Time
Anti-drug Antibodies
Adverse Event
Adverse Event of Special Interest
Above the Lower Limit of Quantification
Alanine Transaminase
Aspartate Transaminase
AUC
aPTT
BI
BI 655075
BID
BLQ
BP
Cpre
Cmax
Area under the Curve
Activated Partial Thromboplastin Time
Boehringer Ingelheim
Idarucizumab
Twice Daily
Below the Lower Limit of Quantification
Blood Pressure
Concentration of the Analyte in Plasma Prior to First Dose
Concentration Maximum
CA
CHO
Competent Authority
Chinese Hamster Ovary Cells
CML
Clinical Monitor Local
CRA
Clinical Research Associate
CRF
Case Report Form
CTR
DE
DILI
dTT
ECG
Clinical Trial Report
Dabigatran Etexilate
Drug Induced Liver Injury
Diluted Thrombin Time
Electrocardiogram
eCRF
ECT
ED
ECL
Electronic Case Report Form
Ecarin Clotting Time
Emergency Department
Electro Chemiluminescence
EDTA
ELISA
Ethylendiaminetetracetic Acid
Enzyme-Linked Immunosorbant Assay
EudraCT
Fab
European Clinical Trials Database
Monoclonal Antibody Fragment
FDA
FFP
GCS
Food and Drug Administration
Fresh frozen plasma
Glasgow Coma Scale
GCP
GUSTO
Good Clinical Practice
Global Utilization of Streptokinase and Tissue Plasminogen Activator for 
Occluded Coronary Arteries
HPLC-MS/MS
HR
ICH
ICU
High Performance Liquid Chromatography, Tandem Mass Spectrometry
Heart Rate
Intracranial Hemorrhage
Intensive Care Unit
IEC
Independent Ethics Committee


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INR
International Normalised Ratio
IRB
Institutional Review Board
ISF
ISTH
Investigator Site File
International Society for Thrombosis and Hemostasis
i.v.
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
LAR
Legally Authorized Representative
MedDRA
mg
Medical Dictionary for Drug Regulatory Activities
Milligram
NC
NOA
NOAEL
NOP
NOR
NOS
Not Calculated
Not Analysed
No Observed Adverse Effect Level
No Peak Detectable
No Valid Result
No Sample Available
OPU
PCC
PD
PK
Operative Unit
Prothrombin Complex Concentrates
Pharmacodynamics (equivalent to biomarkers)
Pharmacokinetics
p.o.
per os (oral)
PR
Pulse Rate
PTT
Partial Thromboplastin Time
RBC
RDC
RE-LY
Red Blood Cell
Remote Data Capture
Randomized Evaluation of Long-term Anticoagulant Therapy
RE-VERSE-AD
rFVIIa
SAE
RE-VERSal Effects of Idarucizumab on Active Dabigatran
Recombinant Factor VIIa
Serious Adverse Event
SD
SOP
Standard Deviation
Standard Operating Procedure
SUSARs
tmax
t1/2
Suspected Unsuspected Serious Adverse Events
Time From Dosing to Maximum Concentration
Terminal Half-Life
TIMI
Thrombolysis in Myocardial Infarction
TSAP
TT
ULN
Vss
VTE
Trial Statistical Analysis Plan
Thrombin Time
Upper Limit of Normal
Distribution Volume in the Steady State
Venous Thrombotic Events


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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 novel 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 or fatal bleeding, remains a relevant 
side effect. With the increasing use of novel oral anticoagulants such as dabigatran, for 
patients with life-threatening or uncontrolled bleeding, reversal agents that could be used in 
rare or uncommon emergency situations to reverse the anticoagulant effects of these new 
drugs may offer additional benefits.  An ideal antidote would be safe, specific, immediately 
effective, and easy to administer.
Dabigatran is the active principle of the prodrug dabigatran etexilate, a direct thrombin 
inhibitor, which has been shown to be effective for:

Primary prevention of venous thromboembolic events (VTE) in adult patients who
have undergone elective total hip replacement surgery or total knee replacement 
surgery.

Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial 
fibrillation with one or more risk factors.
The pivotal phase III trial for prevention of stroke and systemic embolism, RE-LY (U09-
3249-02) (P09-11669), was conducted in over 18,000 patients with atrial fibrillation and 
demonstrated major bleeding rates of approximately 3%/year and life-threatening bleeding 
rates of approximately 1.5%/year for dabigatran etexilate 150 mg bid. The rate of major 
bleeding was numerically lower, and the rate of life-threatening bleeding was significantly 
lower than that of warfarin, even in the absence of a dabigatran antidote. Fatal bleeding 
occurred at a rate of approximately 0.2%/year for dabigatran and 0.3%/year for warfarin. 
Outcomes of major bleeding with dabigatran were as good or better than warfarin with a 
trend towards lower mortality for dabigatran-treated subjects (P13-12677).
Post marketing experience has confirmed that major and life-threatening bleeding, including 
fatal bleeding, have occurred in patients taking dabigatran etexilate since its approval (U11-
2616-01). The estimated bleeding rates from post-marketing surveillance are not in excess of 
the rates of bleeding seen in the RE-LY trial and are similar to or lower than warfarin. 
Dabigatran associated bleeding has been normally managed with standard supportive care in 
most cases, with the possibility of hemodialysis in selected patients.  Temporary 
discontinuation of dabigatran should occur if there is active pathological bleeding. Besides 
well established measures for treatment of bleeding certain patients could still benefit from 
additional measures such as immediate reversal of anticoagulation.  
Recently, idarucizumab, a specific reversal agent for dabigatran, which is the subject of this 
investigational protocol, has become available in many countries for the management of 
dabigatran-associated bleeds that require more than supportive care and for patients being 


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treated with dabigatran who require emergency surgery or other procedures where there is a 
high risk of bleeding (P13-01830, P13-04186). 
1.2
DRUG PROFILE
Drug Substance and Drug Product
Idarucizumab 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 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 
cytotoxic effect or functions through complement or interactions with Fcγ receptors or 
neonatal Fc receptors (FcRn).
Idarucizumab binds dabigatran with an affinity that is about 300 times as high as that 
observed with thrombin. Consequently, idarucizumab binds free and thrombin-bound 
dabigatran and neutralizes its activity. In healthy young volunteers with normal renal 
function, in volunteers who were 65 to 80 years of age, and in volunteers who were 45 to 80 
years of age with mild or moderate renal impairment, the administration of idarucizumab
produced immediate and complete reversal of the anticoagulant effects of dabigatran without 
procoagulant effects.(6-8) Given these findings, a prospective cohort study was undertaken to 
examine the efficacy and safety of idarucizumab for the reversal of the anticoagulant effects 
of dabigatran in patients who presented with serious bleeding or who required urgent surgery 
or intervention. The results from the first 90 patients enrolled in the study of the Reversal 
Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) have been published and are 
summarized here.
Clinical Studies
RE-VERSE AD (P15-06362), a Clinical Study in Patients
We undertook a prospective cohort study to determine the safety of 5 g of intravenous
idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients 
who had serious bleeding (group A) or required an urgent procedure (group B). The primary 
end point was the maximum percentage reversal of the anticoagulant effect of dabigatran 


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within 4 hours after the administration of idarucizumab, on the basis of the determination at a 
central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end 
point was the restoration of hemostasis.
RESULTS
This interim analysis included 90 patients who received idarucizumab (51 patients in group A 
and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an 
elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% 
(95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% 
of the patients, an effect that was evident within minutes. Concentrations of unbound 
dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 
patients in group A who could be assessed, hemostasis, as determined by local investigators,
was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a 
procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately 
abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic 
event occurred within 72 hours after idarucizumab administration in a patient in whom 
anticoagulants had not been reinitiated.
CONCLUSIONS
Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes.
Based on data from RE-VERSE AD, it is expected that the vast majority of patients will only 
be treated once. Additional exposure to the antidote, for a new event that may be weeks or 
even years after the first event, is expected to be infrequent or rare. In rare instances during 
the same hospitalization, e.g. 2 to 24 h after the initial 5 g dose, a patient may experience a 
re-start of bleeding or have a potential for a life-threatening bleed or have a need for an 
additional emergency surgery/procedure, coupled with re-elevation of local clotting tests. In 
such cases, an additional 5 g dose is justified.
Phase I data
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 an 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.


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A. Plasma:
B. Whole Blood:
Figure 1.2: 1: The reversal of anticoagulant activity of dabigatran by BI 655075 
(idarucizumab) in human plasma (A) and whole blood (B).
Source data U13-1986-01
Reversal of anticoagulation was tested in a rat model in vivo.  Dabigatran was given as an 
initial bolus with 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: 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.  This reversal by a single bolus of 
idarucizumab 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 idarucizumab at t = 0. Data expressed as mean ± SE, n = 8.
Source Data: Investigator Brochure (U12-3431-02), Figure 5.1.1.5: 1A
A first-in-human trial (trial number 1321.1) [U13-1773-01] was performed according to a 
double-blind, randomized, single rising dose and placebo-controlled (within dose groups) 
design in young healthy male volunteers.
The primary objectives of the single rising dose first-in-human trial were to investigate safety, 
tolerability, and pharmacokinetics of single rising intravenous doses of idarucizumab (Part 1) 
and to explore the effect of different doses of idarucizumab administered at or close to the 
steady state of dabigatran (Part 2). 
In Part 1 (dose groups 1 to 13), 110 subjects were allocated to placebo or single doses of 
idarucizumab (either as long (1 h) or short (5 min) infusion). The doses of idarucizumab in 
dose groups 1 to 10 (long infusion) were 20 mg, 60 mg, 200 mg, 600 mg, 1200 mg, 2000 mg, 
3000 mg, 4000 mg, 6000 mg, and 8000 mg; the doses of idarucizumab in dose groups 11 to 
13 (short infusion) were 1000 mg, 2000 mg, and 4000 mg. 
In Part 2 (dose groups 14 to 16), 35 subjects were allocated to placebo or single doses of 
idarucizumab as short infusion (1000 mg, 2000 mg and 4000 mg). All subjects in Part 2 were 
dosed to dabigatran steady state and a single dose of idarucizumab was administered around 
the Cmax of dabigatran following the 7th dose on day 4.
Pharmacokinetics


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Plasma concentration time-profiles of idarucizumab were obtained with 1 hour infusion or 5 
min infusion with or without dabigatran etexilate 220 mg bid. The pharmacokinetics were 
dose-linear across the range of doses. The highest exposure was achieved with infusion of 
8000 mg over 1 hour. Cmax was achieved around the end of idarucizumab infusion, followed 
by a rapid mono- to biphasic decline in plasma concentrations. Initial half-live of 
idarucizumab was short ranging from gMean 0.658 to 0.906 hours. A terminal phase was 
detected for idarucizumab doses of 600 mg and higher. Terminal half-life (t1/2) for these 
doses ranged from gMean 4.54 to 8.99 hours. The key PK parameters for the three dose 
groups (1, 2, and 4 g idarucizumab) who received dabigatran are shown in Table 1.2: 1. They 
were similar to the values seen with the corresponding doses of idarucizumab alone.
The distribution volume in the steady state (Vss) after idarucizumab infusion was 
approximately two times the plasma volume, suggesting that the dilution space for 
idarucizumab was limited to approximately the blood compartment. Over the entire dose 
range from 20 mg to 8000 mg, the clearance of idarucizumab was approximately constant, 
ranging from gMean 30.0 to 53.9 mL/min. 
It is assumed that a major fraction of idarucizumab was eliminated by renal catabolism. 
Relevant amounts of idarucizumab were detected in urine after administration of 
idarucizumab doses of 1000 mg or larger, with the largest amount of idarucizumab excreted 
in the first urine collection interval. After increasing the dose of idarucizumab infused over 5 
min from 1000 mg to 4000 mg, the fraction of idarucizumab dose excreted into urine from 0-
4 hours [fe0-4 (%)] increased from 10.7 to 38.9%. The increase in the fraction of dose 
excreted with higher idarucizumab doses suggests the saturation of catabolism/re-uptake 
processes in the kidney.
Table 1.2: 1
Comparison of key pharmacokinetic parameters (N, gMean and gCV [%]) of 
idarucizumab by treatment (dose groups 14-16, 5 min infusion)
220 mg DE+
1000 mg (N=9)
220 mg DE+
2000 mg (N=9)
220 mg DE+
4000 mg (N=8)
gMean
gCV
[%]
gMean
gCV
[%]
gMean
gCV
[%]
AUC0-∞
[nmol*h/L]
6480
17.1
16600
10.7
30900
14.1
Cmax
[nmol/L]
5410
13.5
12500
21.5
25800
25.1
t½
[h]
4.97
31.1
8.99
21.6
7.92
11.3
t½,2
[h]
0.708
9.41
0.755
10.8
0.733
10.6
fe0-4
[%]
8.18
90.6
26.2
23.4
40.2
30.5
CL
[mL/min]
53.8
17.1
41.9
10.7
45.1
14.1
Vss
[L]
6.30
22.0
6.90
29.2
6.37
21.6
1 initial half life
Source data: [U13-1773-01, Table 11.5.2.2.1: 2]


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Binding of dabigatran and reversibility of dabigatran anticoagulant effect
In the three groups pre-treated with dabigatran etexilate, there was a rapid and substantial 
increase in plasma concentrations of sum dabigatran immediately after idarucizumab dosing, 
indicating redistribution of dabigatran into the plasma compartment due to the high binding 
affinity of idarucizumab to dabigatran. Importantly, the increase in sum dabigatran 
concentrations (also referred to as "total" dabigatran) was associated with abolished or nearly 
abolished anticoagulation, suggesting dabigatran was immediately neutralized through 
binding to idarucizumab (see Figure 1.2: 4).
The neutralizing effect was confirmed by measuring the concentration of unbound sum 
dabigatran before and after idarucizumab administration (see Figure 1.2: 3). “Unbound sum 
dabigatran” reflects the fraction of total dabigatran that is neither bound to plasma proteins 
nor to idarucizumab. This fraction is available to bind thrombin and thus considered 
pharmacologically active.
Immediately after end of idarucizumab infusion, unbound sum dabigatran concentrations 
were below-or close to- the lower limit of quantification in all dose groups, whereas placebo 
infusion had no effect on unbound sum dabigatran concentrations. The sustainability of the 
effect was idarucizumab dose dependent. Following administration of 2 or 4 g idarucizumab, 
gMean unbound sum dabigatran plasma concentrations remained below 10 ng/mL over the 
entire 72 hour observation period.


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Source data: 1321.1: [U13-1773-01]
Figure 1.2: 3: Comparison of individual and gMean AUC2-24,ss values of unbound sum 
dabigatran after multiple oral administration of 220 mg DE bid with single iv. 
infusion of 1 to 4 g idarucizumab or placebo over 5 min.
Baseline measurements for the clotting parameters dTT, ECT and aPTT were taken from 
each subject before first dabigatran etexilate administration. A steady-state dabigatran 
pharmacodynamic profile was obtained after the 5th dabigatran etexilate dose. After the 7th 
and final dose of dabigatran etexilate (administered at time point 72 hr), sampling for clotting 
parameters continued for 74 h. Doses of 1, 2 or 4 g idarucizumab or placebo were 
administered as 5 min infusion at approximately Cmax after administration of the 7th 
dabigatran etexilate dose.
As expected, dabigatran etexilate administration in the absence of idarucizumab resulted in 
prolongation of clotting times as measured by all clotting parameters. At the end of 
idarucizumab infusion on day 4 and independent of idarucizumab dose, clotting times 
immediately dropped to baseline (i.e. below upper limit normal). Placebo infusion did not 
reverse the prolonged clotting time. The mean clotting time vs. time profiles for dTT is 
shown in in Figure 1.2: 3. Results with the other parameters were similar (see the 
idarucizumab Investigator’s Brochure for additional details).
At 30 min after administration of 1000 mg idarucizumab, mean clotting times of all clotting 
assays increased above baseline, suggesting a partial return of dabigatran anticoagulant effect.
Following administration of 2000 mg (2 g) idarucizumab, mean dTT coagulation times 
remained at baseline over the entire measurement period of 72 hours. For ECT, mean 
Individual data
gMean (N=9/9/9/8)
Unbound sum dabigatran AUC2-24,ss [ng*h/mL]
0
200
400
600
800
1000
1200
1400
1600
1800
DE + placebo (d4)
DE + 1000 mg (d4)
DE + 2000 mg (d4)
DE + 4000 mg (d4)


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coagulation times were at or below the estimated upper limit of normal from 6 to 16 hours 
after end of idarucizumab infusion, with the 8 hour value being slightly above the threshold. 
After administration of 4000 mg (4 g) idarucizumab, mean dTT, ECT and aPTT clotting 
times remained at baseline over the entire measurement period.
Taken together, the results of clotting time measurements suggest that idarucizumab 
administration results in immediate, complete and sustained reversal of dabigatran-mediated 
anticoagulation.
--- Mean baseline (N=86) = 31.785 (s), normal upper reference limit (N=86) = 33.394 (s)
Source data: 1321.1: [U13-1773-01, preliminary data, report in preparation]
Figure 1.2: 4 Mean effect-time profiles (+/- SD) of dTT after multiple oral administration of 
220 mg DE bid with single i.v. infusion of 1, 2, 4 g idarucizumab or placebo 
over 5 min at planned time 73 hours and 55 min (1 hour and 55 min after last 
dabigatran etexilate dose.
Target Clinical Dose
A PK/PD binding model characterizing the pharmacokinetic interaction of dabigatran and 
idarucizumab was developed using preclinical data and the human data from 1321.1 to assist 
in dose and regimen selection for subsequent trials. The calculation of the required dose of 
idarucizumab is based on a 1:1 stoichiometry of the binding of the Fab to dabigatran and the 
calculated total body load of dabigatran, reflected by the plasma concentrations and estimated 
volume of distribution. The dose selection also assumes that there are no dose-related safety 
issues (see section below on safety).
220 mg DE bid (d3) N=35
220 mg DE bid + placebo 5 min infusion N=9
220 mg DE bid + 1000 mg BI 655075 (d4) N=9
220 mg DE bid + 2000 mg BI 655075 (d4) N=9
220 mg DE bid + 4000 mg BI 655075 (d4) N=8
dTT [s]
25
30
35
40
45
50
55
60
65
70
75
Time [hours]
-24
0
48
52
56
60
72
74
76
78
80
82
84
86
90
98
122
146


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The PK data from study 1321.1 show that immediate and complete reversal of dabigatran 
effects could be accomplished with short intravenous infusions of the 1, 2, and 4 g doses of 
idarucizumab. Duration of effect was dose-dependent. Based on plasma concentration data 
from RE-LY patients, it was calculated that a 2 g dose of idarucizumab would neutralize the 
body load of a patient in RE-LY whose concentrations were at approximately the 70th 
percentile of the range of concentrations seen in RE-LY. That also meant that bleeding 
subjects with higher body loads might not achieve complete and sustained reversal with the 2 
g dose. It is also known that the primary characteristics predicting bleeding in RE-LY 
patients are age >75 years and renal dysfunction. 
Therefore a dose for reversal in bleeding patients was selected that would cover some of the 
highest concentrations seen in RE-LY, namely in patients with moderate renal dysfunction, 
most of whom are older. A dose of 5 g was calculated to cover the total body load of at least 
99% of all RE-LY patients with moderate renal dysfunction, based on trough concentrations 
or more than 90% of these patients based on their peak concentrations. 
The potential safety margin for a 10 g dose was evaluated.  Idarucizumab plasma levels and 
exposure in preclinical studies support administration of 5 g to 10 g to humans. Compared to 
healthy volunteers aged 45 - 64 years that received a 5 g dose of idarucizumab, maximum 
plasma and exposure levels of 7-fold and 3 to 5-fold were reached in preclinical species at the 
No Observed Adverse Effect Level (NOAEL), based on mean Cmax and AUC0-24 levels of 
25,000 nM and 37,000 nM·h reached in clinical trial 1321.2. These multiples remain 
unchanged if 10 g idarucizumab is administered as an initial 5 g dose followed by an 
additional 5 g dose greater than 24 hours later, as this regimen reflects the daily idarucizumab 
administration received by rats and monkeys in preclinical studies of 4- and 2-weeks duration, 
respectively. If idarucizumab is administered as a 10 g dose, multiples of exposure in 
preclinical species at the NOAEL decrease to 3-fold and 1 to 2-fold maximum plasma and 
exposure levels, respectively, based on estimated (modelled) human Cmax and AUC0-24 
levels of 60,361 nM and 85,263 nM·h. In the event of impaired creatinine clearance (i.e., 
CrCL = 40 mL/min), the multiple between human maximum plasma levels and those in 
preclinical species decreases to 2-fold, with no effect on multiples of total exposure.
Safety in Patients
In the interim analysis of the RE-VERSE AD trial, among 90 patients followed for up to 90 
days there were 18 deaths overall, with 9 in each study group; 10 deaths were due to vascular
causes, including 5 fatal bleeding events. Death within 96 hours after treatment appeared to 
be related to the index event (2 patients had septic shock, 3 had intracranial hemorrhage, and
1 each had multiorgan failure, hemodynamic collapse, respiratory failure, and cardiac arrest),
whereas all the later deaths appeared to be associated with coexisting conditions.   
Thrombotic events, classified as early (≤72 hours after idarucizumab administration) or late 
(>72 hours after administration), occurred in five patients: deep-vein thrombosis and 
pulmonary embolism occurred in one patient 2 days after treatment; deep-vein thrombosis, 
pulmonary embolism, and left atrial thrombus occurred in one patient 9 days after treatment; 
deep-vein thrombosis alone occurred in one patient 7 days after treatment; nonurred in one 
patient 7 days after treatment occurred in one patient 13 days after treatment; and ischemic 


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stroke occurred in one patient 26 days after treatment. None of these patients were receiving 
antithrombotic therapy when the events occurred. A total of 21 patients (13 patients in group 
A and 8 in group B) had serious adverse events during study participation. In addition to the 
18 deaths and the thrombotic events that occurred in 5 patients, these events included 
gastrointestinal hemorrhage (in 2 patients) and postoperative wound infection, delirium, right 
ventricular failure, and pulmonary edema (in 1 patient each). Some patients had more than 
one event.
Safety in Healthy Volunteers
In part 1of study 1321.1, out of 110 subjects, 21 received placebo and 89 received single dose 
of idarucizumab. In subjects on treatment, 10 subjects in the placebo group (47.6%) and 32 
subjects in idarucizumab group (28.5%) reported at least one AE. Out of these, 6 adverse 
events in 5 subjects were considered as drug related by investigator whereas only 3 of these 
in subjects who received idarucizumab: mild headache and erythema on the infusion site 
(2000 mg 1 h. Infusion), migraine (8000 mg 1 h. Infusion) and probably drawn by the study 
procedures. 
In part 2, all 35 subjects received 7 doses of 220 mg dabigatran etexilate; then 9 received 
placebo and 26 received single dose of idarucizumab on day 4. A total of 27 out of 35 
subjects on treatment (77.1%) in Part 2 reported at least 1 AE during the treatment period of 
the trial. Out of these, 6 adverse events in 5 subjects were considered as drug related whereas 
4 were related to dabigatran treatment (1 epistaxis, 3 episodes of haematuria) of which 2 of 
these were in subjects who received idarucizumab (feeling hot and erythema at the injection 
site; 1000 mg group). All were of mild intensity and had resolved without sequelae at the end 
of the observation period. No relationship between study drug dose and incidence of drug-
related AEs was observed for either part 1 or part 2 of the study.
An overview of all AEs reported during the treatment period for parts 1 and 2 is given in 
Appendix 10.1. Screening and post-treatment events were not included.
No deaths or other serious AEs, no protocol-specified significant AEs (i.e. events that were 
suggestive for cytokine release), and no AEs leading to discontinuation of the trial drug were 
reported in this trial.
No clinically relevant finding was reported as an AE regarding ECG recordings, physical 
examination, and vital sign measurements during the study. No clinically relevant changes 
were observed in vital signs, and main cardiac intervals (PR, RR, QRS, QT, and QTc) were 
unaffected. Cardiac telemetry did not reveal any abnormalities in rhythm or ST-T deviations.
With respect to laboratory parameters, there were no relevant abnormalities compared to 
placebo for laboratory, including clinical chemistry, haematology, coagulation parameters 
and urinalysis. The only remarkable finding was a dose-dependent increase in low molecular 
weight proteins and urine proteins observed in Part 1 and Part 2, which occurred immediately 
after dosing of idarucizumab and returned to normal levels within 4 to 12 h after 
administration of idarucizumab. The fact that these came back to normal soon after the 
idarucizumab administration and that there were no corresponding urine changes indicating 


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acute tubular injury (such as an increase in glycosuria) suggest that this phenomenon does not 
indicate tubular injury, but instead, reflects saturation of tubular uptake processes for the 
reabsorption of small (< or = ~70 kDa) proteins from the filtrate.
Anti-Drug Antibodies (idarucizumab ADA)
Of a total of 145 subjects, 19 subjects (13.1%) had positive titers at baseline (pre-dose) which 
tended to persist at the subsequent sampling times at end-of-study, and at 4 weeks and 3 
months follow up. For placebo-treated subjects (N=36) the incidence of positive titers at 
baseline was 19.4% (7 of 36). For patients who received idarucizumab, 11.0% (12 of 109) 
had positive titers at baseline. Positive titers before administration of idarucizumab that 
persist at 4 weeks and  3 months follow up suggest the presence of interfering ADAs. These 
are thought to be pre-existing, non-specific anti-Fab antibodies, unrelated to idarucizumab.
There were no subjects on verum or placebo who developed new, persistently positive titers 
after treatment. Two subjects in the 60 mg dose group (Patients
and 
) and one subject 
in the 4000 mg 5 min infusion group (patient 
) were negative at pre-dose sampling but 
had positive titers (values of 1.0, 2.0, and 4.0, respectively) at the end of study visit. 
Subsequent assays in these patients at the 4 week and 3 month follow up visits were all 
negative. 
These data indicate that in healthy volunteers, single doses of idarucizumab ranging from 20 
mg to 8 g are not associated with the formation of ADAs.
Safety Conclusions
Overall, good safety and tolerability of idarucizumab administered alone up to 8000 mg 1 
hour or 4000 mg 5 min infusion, and up to 4000 mg 5 min infusion at the steady state of 
dabigatran were observed in young healthy male volunteers. There were no notable safety 
findings during the trial, and no indication of a safety risk for the subjects who participated in 
the trial. None of the safety data presented a safety issue for further clinical trials.
For a more detailed description of the idarucizumab profile please refer to the current 
Investigator’s Brochure (IB).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Until recently, management of serious bleeding in patients on dabigatran etexilate, including 
life-threatening or fatal bleeding, consisted of supportive care, administration of blood or 
blood products and consideration of hemodialysis to remove the drug. A small fraction of 
patients who are treated with dabigatran etexilate and who have co-morbidities may require 
emergency surgery or other invasive procedures related to those co-morbidities, e.g. cardiac 
catheterization for a patient with acute coronary syndrome, surgery for a patient with acute 
appendicitis or major trauma without overt bleeding on presentation. 


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The availability of idarucizumab in many countries now allows for the use of a direct and 
specific reversal agent for dabigatran that is effective in the potentially life-threatening 
conditions described above. Until now, in China, idarucizumab has not been available. This 
trial is designed to confirm the therapeutic benefit of idarucizumab in Asian patient 
population. The reversal of the anticoagulant effects of dabigatran by idarucizumab, a 
monoclonal antibody fragment, has been demonstrated in volunteers and in patients (see RE-
VERSE AD). This trial is designed to verify the reversibility of the dabigatran anticoagulant 
effect by idarucizumab in Asian patients and to support the approval of a Biologic License 
Application (BLA). The reversal will be demonstrated by analyzing the biomarker data in a 
central laboratory, independent of the clinical management of the patient. Patient outcomes 
will be collected and reported.
1.4
BENEFIT - RISK ASSESSMENT
Administration of idarucizumab to a dabigatran etexilate -treated patient reverses the 
anticoagulant effect of dabigatran.  The data from a clinical study in patients and a Phase I 
study of idarucizumab clearly show that at therapeutic doses, , immediate, complete and 
sustained reversal of the anticoagulant effect of dabigatran is achieved.  Since the 
pharmacologic effect of dabigatran may be a factor contributing to uncontrolled or life-
threatening bleeding in some patients, the bleeding may be reduced or stopped in the 
presence of a specific antidote.  In patients who are treated with dabigatran etexilate who are 
not bleeding but require emergency surgery or other invasive procedure due to other 
morbidities, the administration of the antidote has the potential to allow immediate 
intervention without risk of excessive bleeding during the surgery or procedure. 
Preclinical toxicological evaluations of idarucizumab in rats and monkeys have not identified 
any target organ toxicity.  Phase I data in 145 healthy volunteers have demonstrated the 
safety of single doses of idarucizumab up to a dose of 8 g.  Phase III data in patients have not 
identified any adverse reactions. The incidence of thrombotic events is low and judged to be 
related to the underlying thrombotic risk in this patient population. No consistent pattern of 
drug-related adverse events or laboratory changes indicative of a safety issue has been 
observed. Potential risks to patients include possible immune reactions to the humanized 
antibody fragment, including anaphylaxis, neutralization of idarucizumab, formation of 
antibodies against dabigatran, , or lack of local tolerability or renal damage,.  No hepatic 
impairment has been detected in patients to date. Nevertheless, hepatic toxicity has been 
reported for some drugs so it will be assessed in this study.
Given the positive results of the interim analysis of the RE-VERSE AD trial, i.e. the 
expected reversal of dabigatran effects in bleeding patients or those requiring emergency 
intervention, the available human safety data and the safety precautions in the study, the 
current benefit/risk assessment is considered to be favorable.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective is to demonstrate reversal of the anticoagulant effect of dabigatran in 
patients treated with dabigatran etexilate who have uncontrolled or life-threatening bleeding 
requiring urgent intervention, and in patients treated with dabigatran etexilate who require 
emergency surgery or other invasive procedure.  
The secondary objectives are to assess the reduction or cessation of bleeding, evaluate the 
clinical outcomes, safety and the pharmacokinetics of dabigatran in the presence of 
idarucizumab.
2.1.2
Primary endpoint(s)
The primary endpoint is the maximum reversal of anticoagulant effect of dabigatran based on 
central laboratory determination of diluted thrombin time (dTT) or ecarin clotting time (ECT), 
at any time point from the end of the first infusion up to 4 hours after the completion of the 
last infusion. 
2.1.3
Secondary endpoint(s)
Secondary efficacy endpoints include:

Time to cessation of bleeding (for Group A only) since first infusion up to 24 hours 
after the completion of second infusion. 

Occurrence of major bleeding (for Group B only) intraoperatively and up to 24 hours 
post-surgery.

Minimum unbound sum (free) dabigatran concentrations at any time point since the
end of first infusion up to 4 hours after the completion of the last infusion (Cmin,1).

Reversal of anticoagulation as measured by activated partial thromboplastin time
(aPTT) and thrombin time (TT), at any time point since the end of first infusion up to 
4 hours after the completion of the last infusion. 
Secondary safety endpoints include:

Numbers of patients with Adverse events including local tolerability since the first 
infusion up to 5 days after the completion of the second infusion and since informed 
consent up to 30 days (±7 days) after the completion of the second infusion 


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
Numbers of patients with Serious adverse events since the first infusion up to 5 days 
after the completion of the second infusion and since informed consent up to 30 days (
±7 days) after the completion of the second infusion

Numbers of patients with Adverse reactions (adverse events related to treatment) 
since the first infusion up to 5 days after the completion of the second infusion and 
since informed consent up to 30 days (±7 days) after the completion of the second 
infusion

Number of patients with immune reactions assessed by AE collection since the first 
infusion up to 5 days after the completion of the second infusion and since informed 
consent up to 30 days (±7 days) after the completion of the second infusion

Number of patients with thrombotic events (ischemic stroke, myocardial infarction, 
pulmonary embolism, deep vein thrombosis, systemic embolism) since the first 
infusion up to 5 days after the completion of the second infusion and since informed 
consent up to 30 days (±7 days) after the completion of the second infusion


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Further safety endpoints

Clinically relevant changes in laboratory parameters, including renal and hepatic 
function

Blood pressure and heart rate hourly while in emergency department and every 4 
hours for the next 72 hours


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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, multicenter, multinational study, with a single treatment arm, 
idarucizumab.  The target population will be patients who have been treated with dabigatran 
etexilate who either have uncontrolled bleeding requiring medical intervention, or who need 
emergency surgery or a procedure for a condition other than bleeding where therapeutic 
anticoagulation would, in the opinion of the treating clinician, unduly increase the risk of 
intra- and post-operative bleeding.
There are two separate but related elements in this study, 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 separated 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 if 
available, e.g. aPTT. 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 antidote 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. 
The patients may be identified in ambulances or the Emergency Department or similar 
department of participating hospitals.  After determination that the patient has been treated 
with dabigatran etexilate, the informed consent process will occur. Due to the need for urgent 
care in these patients, collection of medical history and other standard of care information 
(e.g. laboratory values, vital signs, weight, ECG) up to the time of consenting may be 
collected on the CRF.
The determination of whether the patient is being treated with dabigatran etexilate will be 
based on information provided by the patient, by a patient representative (family 
member/relative), or the patient’s physician.  Baseline (pre-dose) blood samples for PK/PD 
measurements will be taken in all patients.  After the pre-dose samples are taken, 
idarucizumab will be administered.  All patients will receive 5 g of idarucizumab, 
administered as two separate infusions of 2.5 g, no more than 15 minutes apart. In rare 
instances, an additional 5 g dose is justified (see Section 4.1.2). Further blood sampling will 
occur just prior to the second 2.5g infusion, between 10 and 30 minutes after the second 
infusion and 1, 2, 4, 12, 24 hours and 30 days after the second dose.  Actual sampling time 
will be recorded.  The patient will be monitored for bleeding, adverse events and clinical 
status throughout the study.  The duration of the study for each patient is 30 days.  In the first 
24 hours, approximately 137 ml of blood will be taken depending on available tube size.  A 
total of approximately 140 mL of blood will be taken during the study overall, depending on 
available tube size. If a patient requires an additional 5 g dose of idarucizumab, 
approximately 137 mL (baseline to 24 hours) of additional blood may be drawn.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A trial in healthy male volunteers receiving dabigatran etexilate has demonstrated the reversal 
of dabigatran effects compared to placebo (study number 1321.1).  A study in patients has 
also demonstrated safety and efficacy (study number 1321.3). The current trial is designed to 
verify the previously observed reversal of the anticoagulant effects of dabigatran in patients 
that received dabigatran etexilate and have uncontrolled bleeding or require emergency 
surgery or invasive procedures, as well as to track the clinical course and outcomes of the 
patients.  Thus, each patient will have an assessment of pre-treatment coagulation status and 
clinical status (baseline) followed by post-treatment measurements to determine the extent of 
reversal of dabigatran and the clinical course of the patient.  By providing baseline and post-
treatment clotting assessments, each patient acts as his own control.  Demonstration of 
reversal of dabigatran effects in patients via central lab measurements is the primary goal, 
although this information will not be available to the treating physician at the time of the 
bleed or surgery. Clinical endpoints such as patient status, whether the bleeding stops or 
diminishes may vary widely depending on the clinical situation so these will be secondary 
endpoints. In addition, patients treated for dabigatran-associated intracranial hemorrhage 
(ICH) will be analyzed separately, as treatment options and prognoses are very different for 
these patients than for those with hemorrhage elsewhere in the body. Accordingly, for the 
ICH cohort, a modified Rankin Score (mRS) assessment will be performed on Day 1 and Day 
7 follow-up (or the date of hospital discharge if the patient discharge before Day 7). In 
addition, where available, comparisons of sequential CT scans of ICH patients performed as 
part of the standard of care at the institution will be done to estimate blood volumes.
Recruitment of patients is challenging. The frequency and timing of bleeding or emergency 
surgery in dabigatran etexilate -treated patients cannot be predicted in advance. Where the 
patient will be treated for the bleeding is also difficult to predict. With major bleeding events 
that require hospitalization occurring at a rate of 2-3 events per 100 patient-years of 
dabigatran etexilate treatment, these factors mean that even large community or academic 
hospitals treat only a handful of patients a year, at most. Furthermore, for a variety of clinical 
reasons, some patients may be treated with intensive support and red blood cell transfusion 
instead of actual reversal of anticoagulation.  For these reasons, this trial will include 
approximately 30 hospitals. We anticipate approximately 2 years will be required to recruit 
the target number of patients.
The bleeding cases eligible for this study require urgent intervention and will be life-
threatening in some cases. Fatal bleeds have occurred. Supportive care alone may not be 
sufficient to stop the bleeding. Therefore the inclusion of a control group (supportive care 
without the antidote) is regarded as unethical and so all patients will receive the antidote in an 
open-label manner. It may require only a relatively small number of cases to demonstrate that 
reversibility is achieved. 
The trial will include a single arm consisting of a fixed dose of idarucizumab calculated to 
achieve reversal in at least 99% of patients. There are no widely available tests to determine 


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whether a smaller dose might suffice in some patients, so different doses will not be 
compared. 
3.3
SELECTION OF TRIAL POPULATION
This trial will be conducted as a multicenter, multinational trial in Asian patients with 
duration of approximately 2 years.  It is expected approximately 30 sites will participate in 
this study.  The recruitment of patients who meet the inclusion/exclusion criteria is expected 
to be slow with an average rate of less than 1 patient per site per year.  There is no upper age 
limit for the study.  The average age of patients in the RE-LY study was 71 years old.  Forty 
percent of RE-LY patients were 75 years old or greater.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
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 uncontrolled or life-
threatening bleeding requiring urgent medical or surgical intervention
Group B.  Patients who are taking dabigatran etexilate who may not be bleeding, but do 
require an emergency surgery or other invasive procedure for a condition other than bleeding, 
where therapeutic anticoagulation with dabigatran etexilate 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
1. ≥18 years at screening.
2. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to 
father a child must be ready and able to use highly effective methods of birth control per 
ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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consistently and correctly. A list of contraception methods meeting these criteria is 
provided in the patient information.
3. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
4. Currently taking dabigatran etexilate
5. They meet the following criteria:
Group A: Overt bleeding judged by the physician to require a reversal agent.
OR
Group B: A condition requiring emergency surgery or invasive procedure where adequate 
hemostasis is required.  Emergency is defined as within the following 8 hours.
3.3.3
Exclusion criteria
Group A:
1. Patients with minor bleeding (e.g. epistaxis, hematuria) who can be managed with 
standard supportive care.
2. Patients with no clinical signs of bleeding.
3. Contraindications to study medication including known hypersensitivity to the drug or its 
excipients (subjects with hereditary fructose intolerance may react to sorbitol).
Group B:
1. A surgery or procedure which is elective or where the risk of uncontrolled or 
unmanageable bleeding is low.
2.
Contraindications to study medication including known hypersensitivity to the drug or its 
excipients (subjects with hereditary fructose intolerance may react to sorbitol).
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see sections 3.3.4.1 and 
3.3.4.2 below.


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Every effort should be made to keep the treated patients in the trial: if possible on tretament, 
or at least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures during inform consent, as well as the
explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and CRF.
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

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.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the CRF. These data will be included in the trial database and reported.
Categorization of withdrawal is as follows:
1. Patient discontinues treatment but completes protocol procedures-Patient refuses to 
receive all study medication but completes all of the protocol specified procedures.
2. Patient discontinues treatment but has some protocol procedures-Patient refuses to 
receive all the study medication but completes some of the protocol specified procedures.
3. Patient discontinues treatment and does not want to complete any protocol procedures-
Patient refuses to receive all the study medication and does not want to complete any of 
the protocol specified procedures, but is willing to be followed with phone calls.
4. Patient discontinues treatment and does not want to be contacted at all-Patient refuses to 
receive all the study medication and does not want to complete any of the protocol 
specified procedures, does not want any type of contact at all (consent withdrawn).
Once a patient receives study medication, all observations outlined in the protocol should be 
performed.  If a patient withdraws after receiving study medication, the last study visit 


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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.
Completion of treatment is defined as patients who have received 5g (or 10 g if applicable) of 
study medication and have at least one post study drug blood sample.  Completion of the 
study is defined as patients who complete all study visits.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see section 3.3.4.1
above.
3.3.4.3
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. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial
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 as an intravenous infusion.  There is no comparator 
treatment.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product 1:
Substance:
Idarucizumab (BI 655075)
Pharmaceutical formulation:
Intravenous solution
Source:
Boehringer Ingelheim 
Unit strength:
2.5g per vial
Posology
5.0g (in rare instances an additional 5 g dose is 
justified. See Section 4.1.2)
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 colorless 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
The dose is 5.0g, administered as two separate 2.5g vials given no more than 15 minutes 
apart. As described in Section 1.2 under Target Clinical Dose, a dose of 5 g of idarucizumab 
is calculated to completely reverse the effect of dabigatran in at least 99% of patients. The 
full 5 g must be administered to all patients and the treating physician may give the second 
infusion as soon as judged necessary after the first dose but no later than 15 minutes after 
completion of the infusion the first dose. In rare instances during the same hospitalization, 
after the initial 5 g dose, a patient may experience a re-start of bleeding or have a potential for 
a life-threatening bleed or have a need for an additional emergency surgery/procedure, 
coupled with re-elevation of local clotting tests. In such cases, an additional 5 g dose is 
justified.


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4.1.3
Method of assigning patients to treatment groups
There is only one treatment group in this study.  If applicable, the pharmacist or designee will 
dispense the study medication.
4.1.4
Drug assignment and administration of doses for each patient
Drug dispensing may occur via the hospital pharmacy, a secure storage location in the 
Emergency Department, or other secure location such as the blood bank.  Each 50 ml vial 
contains 2.5g of idarucizumab.  For both Group A and Group B, the first vial of the drug 
should 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 a second vial 
of 2.5g idarucizumab no later than 15 minutes after the end of the first dose. The 
infusion/injection may be filtered using an in-line 0.2 µm filter. The infusion of each vial 
should take no longer than 5-10 minutes.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Not applicable. There’s only one treatment arm in this open-label study.
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.


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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.
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 clinical trial protocol by the IRB / ethics committee ,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics.
The investigator < and/or > pharmacist < and/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< and/or >appointed CRO, the investigator / pharmacist / investigational drug storage 
manager must verify that all unused drug supplies have been returned by the clinical trial
investigators and that no remaining supplies are in the investigator’s possession.


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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 (RBCs), or packed platelets are permitted.  
Administration of activated prothrombin complex concentrates (PCCs, e.g. FEIBA) or 
recombinant Factor VIIa, or concentrates of coagulation factors II, IX, or X may be 
considered, even though their use has not been evaluated in clinical trials.  Dabigatran can be 
hemodialysed out of the patient’s circulation.  Approximately 60% of the drug can be 
removed over 2-3 hours (P13-01830), (P13-04186).
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Prior treatment with the dabigatran antidote carries a theoretical risk of anti-idarucizumab 
antibody formation, a possible immune reaction to the antidote and possible diminution of the 
efficacy of the antidote.
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 active idarucizumab may remain circulating for up to 24 hours after infusion (less than 
1% of the dose in subjects with normal renal function, but somewhat more in subjects with 
renal insufficiency or failure).  This may impact the expected efficacy of re-instituted 
anticoagulation with dabigatran etexilate.  Re-anticoagulation with any agent should only be 
considered after the patient who has experienced major bleeding or surgery is deemed 
clinically stable and adequate hemostasis has been achieved. If there is an urgent indication to 
re-start anticoagulation after study 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
prior to re-initiation of dabigatran etexilate. In patients with creatinine clearance <30 mL/min 
dabigatran etexilate 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.


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4.2.2.3
Restrictions regarding women of childbearing potential 
Women of childbearing potential must use the contraception methods described in the patient
information.
4.3
TREATMENT COMPLIANCE
The study drug is administered as an intravenous infusion.  The administration start and stop 
times of the first and second infusions will be recorded.  Any interruptions or 
discontinuations of infusions will also be recorded. See Section 4.1.4 for method of 
administration.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Efficacy will be based on central laboratory determination of reversal of the anticoagulant 
effect of dabigatran, using several coagulation tests [thrombin time (TT), diluted thrombin 
time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and 
local assessment of aPTT. aPTT will be measured both locally and centrally.
Reversal of anticoagulant effect will be characterized by the maximum reversal achieved for 
each patient, the time to maximum reversal and the duration of reversal. The proportion of 
patients achieving at least 100% reversal will also be calculated. No dosing or patient 
management decisions are based on central lab determination of reversal. Dosing of 
idarucizumab will not be affected by a local lab test. Maximum reversal of the anticoagulant 
effect of dabigatran is defined as
	
 =  	
	  −  	
	 
 	
	  −% 
× %
Values equal to or higher than 100% will be interpreted as complete reversal of the 
anticoagulant effect.
The ULN will be determined using data from 1321.1 and 1321.2.  It will be calculated as the 
(arithmetic) mean + 2*SD using all data collected prior to the dosing of dabigatran and the 
data from subjects who were on placebo as well as pre-dose data from idarucizumab alone 
treatment (as available), SD denotes the standard deviation.  
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A physical examination will be performed at the time points specified in the flowchart. It 
includes height and body weight.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flowchart, prior to blood 
sampling.


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This includes systolic and diastolic blood pressure, temperature and heart rate (electronically 
or by palpation count for 1 minute) in a seated position after 5 minutes of rest. 
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed include hematology, chemistry, aPTT and any 
applicable local lab testing to facilitate patient clinical management. For the sampling time 
points please see the flowchart.
All analyses will be performed by local laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
5.2.4
Electrocardiogram
Electrocardiograms (ECG) will be performed at baseline and on day seven (Visit 4) of the 
study. The investigator or a designee will evaluate whether the ECG is normal or abnormal 
and whether it is clinically relevant, if abnormal. ECGs may be repeated for quality reasons 
and the repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
5.2.5
Other safety parameters
Not applicable  
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse event


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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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which 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 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs Considered “Always Serious”


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Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and AE reporting to sponsor and timelines”
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 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC 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. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the eDC 
system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:


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Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgement 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. 
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.


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
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.
5.2.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until the individual patient’s end of trial:
-
all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial:
the investigator does not need to actively monitor the patient for AEs but should only report 
related SAEs and related AESIs of which the investigator may become aware of by any 
means of communication, e.g. phone call. Those AEs should however, not be reported in the 
CRF.
Figure 5.2.6.2: 1
AE and AESIs report 
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 


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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 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal
relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable” , or no further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner. 
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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Studies and not the SAE form is to be 


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completed. If there is an SAE and/or AESI associated with the pregnancy an SAE form must 
be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For pharmacokinetic endpoints that are determined as secondary endpoints and further 
endpoints, refer to Section 2.1.3 and 2.2.2. 
5.3.2
Methods of sample collection
5.3.2.1
Pharmacokinetic, anti-drug antibody, and biomarker assays 
A total amount of approximately 105 mL blood will be taken per patient during the course of 
the study for central lab assessment of pharmacokinetic, anti-drug antibody and biomarker 
purposes.  In addition, approximately 35mL of blood will be drawn for local aPTT and safety 
lab assessments.
Blood collection supplies for central lab measurements will be provided.
K-EDTA and/or Na Citrate blood samples will be collected at time points specified in the 
Flow Chart and as summarized in Table 5.3.2.1: 1 below in order to prepare plasma for use in 
the following assays:
Pharmacokinetic (PK) assays:
1. idarucizumab
2. dabigatran (as specified below)
o
“sum” dabigatran = total amount of dabigatran in plasma (after sample 
hydrolysis, i.e. comprising the sum of unconjugated plus glucuronide 
conjugated dabigatran)
o
“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)
Biomarker assays:


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1. Ecarin Clotting Time (ECT)
2. diluted Thrombin Time (dTT)
3. activated Partial Thromboplastin Time (aPTT)
4. Thrombin Time (TT)
For assays, blood will be collected from a forearm vein in a blood drawing tube with the 
appropriate anticoagulant at time points indicated in the Flow Chart and in Table 5.3.2.1: 1. 
For a complete list of central and local blood draws, see Appendix 10.2. If it is not possible to 
obtain venous blood, blood can be collected from an arterial access. Whether the blood 
collection is venous or arterial should be documented in the e-CRF.


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Table 5.3.2.1: 1
Summary of blood sampling schedule (approximate volumes)@
K-EDTA blood
Na-citrate blood
Analytes →
Timepoint ↓
PK 
assays 
(1 & 2)
Total 
volume*
Biomarker 
assays        (1-
4)
Total 
volume*
Baseline
X
12 mL
X
4.5 mL
Vial #1 (no blood)
just prior to vial 2
X
6 mL
X
4.5 mL
Vial #2 (no blood)                 
                                                      
between 10-30min
X
6 mL
X
4.5 mL
60min +/- 15 min
X
6 mL
X
4.5 mL
2hour +/- 30 min
X
6 mL
X
4.5 mL
4hour +/- 30 min
X
6 mL
X
4.5 mL
12hour +/- 1 hour
X
6 mL
X
4.5 mL
24hour +/- 2 hour
X
6 mL
X
4.5 mL
Day 30
3 mL
*Sample volumes may vary depending on the availability of sample collection tubes, 
therefore the indicated blood volumes per sampling time point are approximate and actual 
volumes may differ slightly. The total volumes as indicated in 5.3.2.1 will not be exceeded.
@ If a patient requires an additional 5 g dose of idarucizumab see Section 10.2 for 
additional details.
Actual clock times must be recorded for every sample.  For the early time points after drug 
administration, samples should be obtained from the forearm not used in the idarucizumab 
infusion. If this is not possible an appropriate volume of blood should be voided prior to 
sampling. Start the blood sampling with K-EDTA collection tubes followed by Na-Citrate 
tubes. Immediately after blood sampling, the drawing tubes should be gently inverted 10 
times and transferred into an ice water bath for temporary storage until centrifugation.


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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 lab within 
1 week.
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 chapter 10 / lab manual.
Validated methods will be used for all analytes. Analyses will be conducted at laboratories 
specified in Section 5.3.3 and Section 5.4.2.  The sponsor may appoint other laboratories for 
method development and sample analysis, if necessary.
After completion of the study, the plasma samples obtained for pharmacokinetic and anti-
drug antibody assays may be used for further methodological investigations, e.g., for stability 
testing. The study samples will be discarded after completion of the additional investigations 
but not later than 5 years after the final study report has been signed.
Unused samples for biomarker analysis may be used for coagulation assay development and 
validation purposes, e.g., method comparison or sample stability studies. These analyses may 
be performed in laboratories 
, if necessary. The study 
samples will be discarded after completion of the additional investigations but not later than 5
years after the final study report has been signed.


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5.3.4
Pharmacokinetic – pharmacodynamic relationship
Refer to section 7.3.5
5.4
ASSESSMENT OF BIOMARKER(S)


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5.4.1
Endpoints based on biomarkers
Biomarker endpoints are the basis for determination of efficacy in this trial. Some biomarkers 
may be only for investigational use, for example, the dTT assay is investigational in USA.
Ecarin clotting time (ECT), diluted Thrombin Time (dTT), activated Partial Thromboplastin 
Time (aPTT) and Thrombin Time (TT) will be measured in a central laboratory. 
For biomarker endpoints that are determined as primary or secondary endpoints refer to 
Section 2.1. Further endpoints based on biomarkers include:
For ECT, dTT, aPTT and TT as feasible:

Epre (value of the biomarker assay determined in a plasma sample prior to 
administration of idarucizumab)

Epre,1 (value of the biomarker assay determined in a plasma sample after the first, but 
prior to the second administration of idarucizumab)
5.5
OTHER ASSESSMENTS
Investigators may also draw blood for routine laboratory parameters according to the standard 
of care to evaluate the patient’s clinical status and manage patient care.  In addition, 
investigators may also evaluate vital signs, hemodynamics and other parameters as part of 
patient management and stabilization. These parameters, (blood pressure, heart rate, 
hematology, hemodynamics) will be used to determine clinical status of the patient.
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 three different scales: major or life-threatening bleeding (ISTH 
definition), and the TIMI and GUSTO classifications [ISTH: International Society for 
Thrombosis and Hemostasis, GUSTO: Global Strategies for Opening Occluded Coronary 
Arteries, TIMI: Thrombolysis In Myocardial Infarction]. For ICH patients with serial CT 
scans performed as standard of care at baseline and e.g. 24 hours, an estimate of changes in 
intracranial blood volume will be made. and sites will be requested to submit de-identified 


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copies of the scans for review by the EAC. Glasgow Coma Scale and Modified Rankin Scale 
will also be assessed for ICH patients.
Baseline assessment:

Overt bleeding that, in the opinion of the treating physician is severe, ongoing, possibly 
related to dabigatran etexilate use, and requires reversal of the anticoagulant effect
In cases where haemoglobin or haematocrit values are not available for Group A patients 
during the conduct of the study then bleeding scales may be assessed retrospectively based on 
data associated with the 1 hour, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours post dose 
time points.
ISTH Bleeding Classification
Major bleeding must satisfy one or more of the following criteria:

Overt bleeding associated with a reduction in hemoglobin of at least 2 g/dL or leading to 
a transfusion of at least 2 units of blood or packed cells

Symptomatic bleeding in a critical area or organ: intraocular, intracranial, intraspinal or 
intramuscular with compartment syndrome, retroperitoneal, intra-articular or pericardial 
bleeding
Major bleeding is classified as life-threatening if one or more of the following criteria are 
met:

Fatal bleeding, symptomatic intracranial bleeding, a reduction in hemoglobin of at least 5 
g/dL, transfusion of at least 4 units of blood or packed cells, bleeding associated with 
hypotension requiring use of intravenous inotropic agents, or bleeding necessitating 
surgical intervention.
TIMI Bleeding Classification
Major
Intracranial hemorrhage or a ≥5 g/dL decrease in the hemoglobin concentration or 
a ≥15% absolute decrease in the hematocrit
Minor
    Observed blood loss: ≥3 g/dL decrease in the hemoglobin concentration or 
≥10% decrease in the hematocrit
No observed blood loss: ≥4 g/dL decrease in the hemoglobin concentration or ≥12% decrease 
in the hematocrit
Minimal  Any clinically overt sign of hemorrhage (including imaging) that is associated with 
a <3 g/dL decrease in the hemoglobin concentration or _<9% decrease in the 
hematocrit


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*All TIMI definitions take into account blood transfusions, so that hemoglobin and 
hematocrit values are adjusted by 1 g/dL or 3%, respectively, for each unit of blood 
transfused. Therefore, the true change in hemoglobin or hematocrit if there has been an 
intervening transfusion between two blood measurements is calculated as follows: 
Δ Hemoglobin =_ [baseline Hgb - post-transfusion Hgb] + [number of transfused units];
Δ_ Hematocrit _ [baseline Hct - post-transfusion Hct] + [number of transfused units x 3].
GUSTO Bleeding Classification
Severe or life-threatening 
Either intracranial hemorrhage or bleeding that causes 
hemodynamic compromise and requires intervention
Moderate
Bleeding that requires blood transfusion but does not result in hemodynamic 
compromise
Mild
Bleeding that does not meet criteria for either severe or moderate bleeding
Glasgow Coma Scale and Modified Rankin Scale
Patients with intracranial hemorrhage will be assessed by the Glasgow Coma Scale and, at 
final follow-up, Modified Rankin Scale (see Appendix 10.4) 
5.6
APPROPRIATENESS OF MEASUREMENTS
The choice of central lab measurement of coagulation tests dTT or ECT as the primary 
endpoint was explained in Section 3.2. Clinical outcomes such as bleeding reduction, 
bleeding cessation, 
 and 
clinical status of the patient (including 
 for ICH patients, mRS at 30 days) will 
be recorded as secondary endpoints.
The use of the coagulation tests, thrombin time (TT), diluted thrombin time (dTT), ecarin 
clotting time (ECT), activated partial thromboplastin time (aPTT) are standard tests used in 
the evaluation of a medication with this mechanism of action. 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 plasma expanders on 
the reversal with idarucizumab; animal studies of PCCs show some improvement in bleeding. 
As these coagulation markers are widely used in clinical practice, potential effects need to be 
considered. Nevertheless we will carefully tabulate the use of these concomitant therapies.
Non-standard tests such as dabigatran levels, anti idarucizumab antibody levels will be 
evaluated to fully elucidate the action of the study medication and determine the ability of 
idarucizumab to be effective for subsequent uses in the same patient.


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6.
NVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
A summary of scheduled assessments for the study is presented in the Flow Chart.  The study 
data will be collected at the time of the visit and by medical record review.
During the screening visit at any time of day or night, eligible patients receiving dabigatran
etexilate who are exhibiting signs and symptoms of uncontrolled bleeding requiring urgent 
medical intervention, or who require emergency surgery or other medical procedure requiring 
rapid reversal of the anticoagulant effect of dabigatran prior to surgery/procedure may be 
asked to participate.
Eligible patients will receive study medication after meeting inclusion and exclusion criteria.  
All patients who receive study 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 study medication must undergo end-of-study 
(Visit 5) procedures.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
Visit 1 (Day 1): Screening Period (Baseline)
When a patient presents to the investigative team, gives consent, meets all 
inclusion/exclusion criteria and it is confirmed that the patient has been taking dabigatran
etexilate, the patient will be eligible to participate in the study. Due to the need for urgent 
care in these patients, collection of medical history and other standard of care information 
(e.g. laboratory values, vital signs, weight, ECG) up to the time of consenting may be 
collected on the CRF.
After obtaining informed consent for the study the following procedures will be performed:

Bleeding or surgery/procedure assessment

Perform spot urine or other appropriate pregnancy test if applicable. Recruitment of 
pregnant patients is allowed only after a careful evaluation/discussion of the risks and 
benefits of study participation between the treating physician and patient, unless it is 
against local regulations.

Baseline blood draw for central biomarker, PK and local lab safety evaluation 

ECG


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
Glasgow Coma Scale (GCS) and Modified Rankin Score (mRS) if ICH cohort

Record concomitant therapy

Record adverse events

Record demographics, medical history and physical examination (including height, 
weight and temperature)
o
Complete medical records do not need to be available prior to study entry.  A 
verbal medical history can be used to verify that the patient meets all of the 
inclusion and none of the exclusion criteria, but must be verified using 
medical records following enrolment in the study.  Three documented attempts 
(2 phone calls and 1 written) must be made to obtain medical records.  If 
unable to obtain the medical records the study coordinator must contact the 
CML.
6.2.2
Treatment period(s)
Study medication will consist of two vials of 2.5g idarucizumab (total dose 5.0g) 
administered no longer than 15 minutes apart.  In most cases, patients will sign the consent 
form and receive study medication on the same day.
Visit 2.1 (Day 1 continued):
Observations and Procedures:

Administer first vial (2.5g) of study medication.  Record start and stop time of 
administration

Bleeding or surgery/procedure assessments

Measure blood pressure and heart rate hourly while the patient is in the emergency 
department (or similar department), then every 4 hours for the next 72 hours or until 
patient is discharged

Record adverse events

Record concomitant therapies
Visit 2.2 (Day 1 continued):
Observations and Procedures:

Draw blood for both central and local laboratories just prior to the infusion of second 
vial of study medication.  Record time of blood draw

Administer second vial (2.5g) of study medication no later than 15 minutes after the 
completion of the first vial.  Record start and stop time of administration

Draw blood for both central and local laboratories between 10 and 30 minutes, and 1, 
2, 4 and 12 hours after the second vial of study medication.  Record times of blood 
draws

Bleeding or surgery/procedure assessments at or near times of blood draws


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
Measure blood pressure and heart rate hourly while the patient is in the emergency 
department (or similar department), then every 4 hours for the next 72 hours or until 
patient is discharged.

Record adverse events

Record concomitant therapies

In rare instances during the same hospitalization, e.g. 2 to 24 h after the initial 5 g 
dose, a patient may experience a re-start of bleeding or have a potential for a life-
threatening bleed or have a need for an additional emergency surgery/procedure, 
coupled with re-elevation of local clotting tests. In such cases an additional 5 g dose is 
justified and the patient should be allocated a new patient number. Blood sampling 
times are the same as with the first 5 g dose or as logistics permit (Prior to 
administration of the third vial, just prior to the fourth vial, as well as between 10 and 
30 min, 1, 2, 4, 12, 24 hours, and 30 days after the end of the infusion of the fourth 
vial).  Other study procedures and tests should be performed per protocol.

Perform study drug accountability
6.2.3
Follow up period and trial completion
Visit 3 (24-hour after completion of the second vial ± 2 hours)
Observations and procedures

Draw blood for both central and local laboratories for patients while in the cardiac 
cath lab 24 hours after the end of the second vial of study medication.  Record time of 
blood draw.

Bleeding or surgery/procedure assessments

Measure blood pressure and heart rate hourly while the patient is in the emergency 
department (or similar department), then every 4 hours for the next 72 hours or until 
patient is discharged.

Record adverse events

Record concomitant therapies

Re-start appropriate anticoagulant therapy (investigator discretion)
Visit 4 (7 days +/- 3 days after the second vial)
Observations and procedures

Bleeding or surgery/procedure assessment

Measure blood pressure and heart rate hourly while the patient is in the emergency 
department (or similar department), then every 4 hours for the next 72 hours or until 
patient is discharged

ECG

Modified Rankin Score (mRS) if ICH cohort

Record adverse events

Record concomitant therapies
Visit 5 (End of Study, 30 days +/- 7 days after the second vial)
Observations and procedures

Bleeding or surgery/procedure assessment


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
Measure blood pressure and heart rate

Draw blood for central laboratories

Perform urine or other appropriate pregnancy test if applicable

Record adverse events

Record concomitant therapies

Modified Rankin Score (mRS) if ICH cohort

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 with reversal 
of anticoagulation effect in each patient determined by pharmacodynamic parameters 
(Section 5.1).  There is no statistical model for this trial. Assessment of efficacy will be based 
on descriptive statistics, with confidence limits provided when appropriate.
7.2
NULL AND ALTERNATIVE HYPOTHESES
There is no hypothesis testing for this trial.
7.3
PLANNED ANALYSES
Safety summaries will be based on all patients who have received at least one vial of 
idarucizumab.  The primary analysis will include patients who have received any 
idarucizumab and have a pre-dose and at least one PD measurement within 4 hours after the 
administration of the 2nd vial of idarucizumab.  Other efficacy analyses will include patients 
who have received one or two vials of idarucizumab and have pre-dose and at least one post-
dose PD measurement.  Therefore the number of patients included in the efficacy analysis 
may be different for different endpoints.
Efficacy endpoints are defined in Section 2.1.  Analysis of efficacy and safety endpoints will 
be descriptive in nature. The efficacy analysis for reversal will also exclude patients with a 
pre-dose coagulation test value below 100% ULN.
7.3.1
Primary endpoint analyses
For the primary endpoint, the median and other quantiles of the calculated reversal of the 
anticoagulation effect will be summarized.  
7.3.2
Secondary endpoint analyses
For secondary efficacy endpoints, the following analyses are planned:

For cessation of bleeding (for Group A only): the time to cessation of bleeding will be 
summarized using descriptive statistics, such as, median, or proportions as appropriate, 
by type of bleedings. Bleeding status will be categorized before and at several time 
points after treatment. For ICH patients, this will depend on availability of follow up CT 


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scans. ICH patients will not be included in this analysis if no regular follow-up CT scans 
are available.

The occurrence of major bleeding (for Group B only) will be summarized descriptively.  
Frequency, proportions and confidence limits will be provided when appropriate. For 
those subjects for whom an intraoperative blood loss is quantitatively recorded, those 
data will be collected.

Minimum level of unbound sum dabigatran concentration at any time since end of the 
first infusion up to 4 hours after the completion of second infusion will be summarized 
descriptively. The percentage change of unbound sum dabigatran from pre-dose value to 
the lowest post-dose value will also be summarized.

Median and other quantiles of reversal of aPTT and TT at any time point since end of the 
first infusion up to 4 hours after the completion of the second infusion will be 
summarized.
For secondary safety endpoints, refer to safety analyses in Section 7.3.4.


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7.3.4
Safety analyses
The safety analyses will be descriptive in nature and will be based on BI standards. 
Parameters to be evaluated for safety are described in Section 5.2. Details will be included in 
the TSAP.
AEs will be coded using the MedDRA dictionary and tabulated by system organ class and 
preferred term. All AEs will be classified according to the following trial periods: screening, 
treatment, safety follow-up. All AEs with an onset date/time after the 1st vial of trial 
medication up to 5 days after the last intake of study medication will be assigned to the 
treatment period for evaluation. In addition, AEs with onset date before start of the trial 
treatment but with worsening in intensity during the treatment will also be assigned to the on-
treatment period. Other AEs will be assigned to the screening or post-treatment period, 
respectively. All AEs (including bleeding) in the treatment period will be tabulated in total 
and according to seriousness, severity and possible relationship to trial medication. AEs in 
the screening or follow-up period will be listed.
Laboratory data will be analysed both quantitatively and qualitatively.
For assessment of liver function, frequency of patients with elevated ALT/AST or bilirubin 
will be tabulated. The frequency of potential Hy’s Law patients will be provided.
Other lab data, vital signs and physical examinations data will be reported descriptively.


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7.4
INTERIM ANALYSES
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. 
7.5.1
Plasma concentration – time profiles
Handling of missing PK data will generally be performed according to the relevant Corporate 
Procedure of the Sponsor (001-MCS-36-472, current version).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analyzed), or NOP (no peak detectable) 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). Drug concentration data identified with BLQ (below the lower limit of 
quantification) 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 TCPK and 
described in the CTR.
Descriptive statistics of concentrations at specific time points will be calculated only when at 
least 2/3 of the individuals have concentrations within the validated concentration range. The 
overall sample size to decide whether the “2/3 rule” is fulfilled will be based on the total 
number of samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, NOA are 
included).
7.5.2
Pharmacokinetic parameters
For the noncompartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ will 
be set to zero. All other BLQ values of the profile will be ignored. The lag phase is defined as 
the period between time zero and the first time point with a concentration above the 
quantification limit. BLQ values for unbound sum dabigatran data will be handled 
exceptionally; BLQ values will be replaced by the lower limit of quantification which is 
defined as 1 ng/mL.
The individual pharmacokinetic parameters can be calculated and listed separately. Every 
effort will be made to include all concentration data in an analysis. If not possible, a case to 
case decision is required whether the value should only be excluded from half-life estimation 


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or the complete analysis. If a concentration is only excluded from half-life determination, it 
will be used for all other calculations (e.g. descriptive statistics) and for graphical 
presentation. If a concentration value is excluded from all calculations, it will not be 
presented graphically or used for the calculation of descriptive statistics and parameter 
determination. However the excluded concentration itself will be listed in the clinical trial 
report associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated" (NC).
7.5.3
Pharmacodynamic parameters
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 lower 
limit of quantification (ALQ) will be reported. For calculation of reversal of the 
anticoagulation effect, ALQ values may be replaced by 500s. BLQ values as well as 
pharmacodynamic data identified with NOS, NOR and NOA will not be considered.
7.6
RANDOMISATION
This trial has a single treatment group without randomisation.
7.7
DETERMINATION OF SAMPLE SIZE
The sample size is based only on practical considerations of the frequency of bleeding on 
dabigatran, the recruitment rates and the number of clinical trial sites that will be initiated.  
The recruitment of patients who meet the inclusion/exclusion criteria is expected to be slow 
with an average rate of less than 1 patient per site per year.  With an expected 30 sites 
participating in this study, we anticipate to enroll a total of 20 patients over a period of 1.5 to 
2 years or until sufficient patients are enrolled to satisfy the regulatory requirements or until 
idarucizumab is commercially available in that country.  


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
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 < add if EU countries participate and the protocol falls under the EU 
regulation 536/2014 > the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) < add if Japan participates > and other relevant 
regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 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, as well as 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 (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”


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The investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient 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.
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
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
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 patient. 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 CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient 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 


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previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see section 8.3.2). The investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone number, social security number) have properly 
been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, 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)

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.


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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 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 site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and 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 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
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


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need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed insent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out”). The “Last Patient Drug Discontinuation” (LPDD) date is defined as 
the date on which the last patient at an individual trial site ends trial medication (as scheduled 
per protocol or prematurely). Individual investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LPDD at their site. Early termination of the 
trial is defined as the premature termination of the trial due to any reason before the end of 
the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF. The investigators will have access to the 
BI clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic 
ISF. 
BI has appointed a Trial Clinical Monitor, 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.


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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 BI 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.
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.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P09-11669
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et.al. RE-
LY Steering Committee and Investigators. Dabigatran versus warfarin in patients 
with atrial fibrillation. N Engl J Med 2009; 361 (12): 1139 – 1151
P13-01830
Khadzhynov D, Wagner F, Formella S, Wiegert E, Moschetti V, Slowinski T, et.al. 
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 KH, Staab A, Haertter S, Formella S, Clemens A, Lehr T. 
Pharmacometric characterization of dabigatran hemodialysis. Clin Pharmacokinet 
2013; 52 (6): 453 – 462
P13-12677
P15-06362
Majeed A, Hwang HG, Connolly SJ, Eikelboom JW, Ezekowitz MD, Wallentin L, 
et.al. Management and outcomes of major bleeding during treatment with dabigatran 
or warfarin. Circulation 2013; 128 (21): 2325 - 2332 ()
Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel 
R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, 
Stangier J, Steiner T, Wang B, Kam CW, Weitz JI. Idarucizumab for dabigatran 
reversal. New England Journal of Medicine, online first, published on June 22, 2015, 
DOI: 10.1056/NEJMoa1502000 N Engl J Med 2015. 373(6):511-520.
9.2
UNPUBLISHED REFERENCES
U09-3249-02
 Randomized Evaluation of Long term 
anticoagulant therapY (RE-LY®) comparing the efficacy and safety of two blinded 
doses of dabigatran etexilate with open label warfarin for the prevention of stroke 
and systemic embolism in patients with non-valvular atrial fibrillation: prospective, 
multi-centre, parallel-group, non-inferiority trial (RE-LY® STUDY). 16 October 
2009. Date of revision: 05 January 2011.
U11-2616-01
Periodic Safety Update Report Pradaxa Dabigatran etexilate hard capsules, 75 mg, 
110 mg 19 Sep 2010 to 18 Sep 2011.
U12-3431-02
Investigator’s Brochure. 1321.P1. Version 3. 19 Dec 2013.


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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 thrombin time assay. Draft 
version. 30 Oct 2013.
001-MCS-
36-472
Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics


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10.
APPENDICES
10.1
ADVERSE EVENTS DURING TREATMENT IN STUDY 1321.1, PARTS 1 AND 2, IN ORDER OF FREQUENCY
Placebo groups are pooled. Doses of 1000, 2000, and 4000mg with and without dabigatran pre-treatment are pooled. The 5 minute and 1 hour 
infusions are pooled.
Dose in mg
0 
(Placebo)
DE 
alone
20
60
200
600
1000
1200
2000
3000
4000
6000
8000
Totals
Number treated
36
35
6
6
6
5
15
6
27
6
20
6
6
145
Number of AEs 
during treatment*
19
32
3
2
9
2
11
1
13
5
8
1
4
53%
91%
50%
33%
150%
40%
122%
17%
62%
83%
57%
17%
67%
Adverse Event
Injection site 
reactions#
3
3
2
1
6
2
1
1
1
20
Headache
4
3
1
3
1
2
1
2
17
Nasopharyngitis
2
1
1
2
1
7
Dizziness
1
2
1
1
1
1
7
Back pain
1
1
1
2
1
1
7
Presyncope
5
5
Constipation
2
1
3
Diarrhea
1
1
1
3
Pain in extremity
1
1
1
3
Hematuria
3
3
Migraine
1
1
2
Syncope
1
1
2


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Dose in mg
0 
(Placebo)
DE 
alone
20
60
200
600
1000
1200
2000
3000
4000
6000
8000
Totals
Number treated
36
35
6
6
6
5
15
6
27
6
20
6
6
145
Number of AEs 
during treatment*
19
32
3
2
9
2
11
1
13
5
8
1
4
53%
91%
50%
33%
150%
40%
122%
17%
62%
83%
57%
17%
67%
Adverse Event
Epistaxis
1
1
2
Abdominal pain
1
1
2
Dyspepsia
1
1
2
Muscle spasms
1
1
2
Musculoskeletal 
stiffness
1
1
2
Asthenia
1
1
2
Chest pain
1
1
2
Bronchitis
1
1
Tonsillitis
1
1
Dizziness 
postural
1
1
Disgeusia
1
1
Cough
1
1
Palpitations
1
1
Oropharyngeal 
pain
1
1
Abdominal 
discomfort
1
1


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Dose in mg
0 
(Placebo)
DE 
alone
20
60
200
600
1000
1200
2000
3000
4000
6000
8000
Totals
Number treated
36
35
6
6
6
5
15
6
27
6
20
6
6
145
Number of AEs 
during treatment*
19
32
3
2
9
2
11
1
13
5
8
1
4
53%
91%
50%
33%
150%
40%
122%
17%
62%
83%
57%
17%
67%
Adverse Event
Abdominal pain 
upper
1
1
Dysphagia
1
1
Flatulence
1
1
Nausea
1
1
Myalgia
1
1
Chest discomfort
1
1
Fatigue
1
1
Feeling hot
1
1
Influenza like 
illness
1
1
Glycosuria
1
1
Polyuria
1
1
Except for injection site reactions, all AEs are preferred terms
* expressed as number of subjects with events; subjects may report more than one event
#includes infusion site swelling (2 subjects), Injection site hematoma (2), infusion site erythema (2), erythema (2), skin reaction (1), 
skin irritation (9), catheter site pain (4), and application site irritation (2)


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10.2
BLOOD DRAW SCHEDULE@
Time
EDTA
Na Citrate
Local 
aPTT
Safety 
Lab 
Max. 
Blood 
Vol 
(mL)
Visit 1
1*
Baseline
12 mL
4.5 mL
3 mL
7 mL
26.5
Visit 
2.1
Vial #1 (no blood draw)
Visit 2.2
2*
just prior to vial 
#2
6 mL
4.5 mL
3 mL
7 mL
20.5
Vial #2 (no blood draw)
3*
between 10-30min
6 mL
4.5 mL
3 mL
7 mL
20.5
4
1 hour +/- 15 min
6 mL
4.5 mL
10.5
5
2hour +/- 30 min
6 mL
4.5 mL
10.5
6
4hour +/- 30 min
6 mL
4.5 mL
10.5
7
12hour +/- 1 hour
6 mL
4.5 mL
3 mL
7 mL
20.5
Visit 3
8
24hour +/- 1
2 hour
6mL
4.5 mL
7 mL
17.5
Visit 4
Day 7 +/- 3 days
0
Visit 5
9
Day 30 +/- 7 days
3 mL
3
APPROXIMATE 
TOTAL BLOOD 
VOLUME (MLS)
57
36
12
35
140
*Critical samples for assessment of efficacy
EDTA= PK assays, anti-ADA (anti-idarucizumab antibodies)
Na Citrate= Biomarkers,.
@ If a patient requires an additional 5 g dose of idarucizumab, approximately 137mL 
(baseline to 24 hours) of additional blood may be drawn
10.3
CLINICAL LABORATORY EVALUATIONS
Central Lab Evaluations
PK
1. BI 655075
2. anti-BI 655075 antibodies
3. Dabigatran (sum and unbound sum)
PD
1. TT
Local Lab Evaluations
Standard Safety Lab Panel
Chemistry Panel (includes liver 
function)
ALT (SGPT)
AST (SGOT)


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2. aPTT
3. dTT
4. ECT
CK (creatine kinase)
CK-MB or Troponin if CK is elevated
Albumin
Alkaline Phosphatase
Bilirubin, Total
BUN
Calcium
Cholesterol, Total
Chloride
Glucose
Potassium
Protein, Total
Sodium
Triglycerides
Creatinine
Hematology Panel
Red Cell Count
Red Cell Indices (MCV, MCH, MCHC)
White Cell Count
White Cell Differential
Hemoglobin
Hematocrit
Platelet Count
aPTT
Pregnancy Test (urine or other rapid 
test)
10.4
GLASGOW COMA SCALE AND MODIFIED RANKIN SCALE
Glasgow Coma Scale
Eye Opening Response 
• Spontaneous--open with blinking at baseline 4 points 
• To verbal stimuli, command, speech 3 points 
• To pain only (not applied to face) 2 points 
• No response 1 point 


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Verbal Response
• Oriented 5 points 
• Confused conversation, but able to answer questions 4 points 
• Inappropriate words 3 points 
• Incomprehensible speech 2 points 
• No response 1 point 
Motor Response
• Obeys commands for movement 6 points 
• Purposeful movement to painful stimulus 5 points
• Withdraws in response to pain 4 points 
• Flexion in response to pain (decorticate posturing) 3 points 
• Extension response in response to pain (decerebrate posturing) 2 points 
• No response 1 point
References
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. Lancet 1974; 81-84. 
Teasdale G, Jennett B. Assessment and prognosis of coma after head injury. Acta Neurochir 
1976; 34:45-55. 
Categorization: Coma: No eye opening, no ability to follow commands, no word 
verbalizations (3-8) 
Head Injury Classification: Severe Head Injury----GCS score of 8 or less Moderate Head 
Injury----GCS score of 9 to 12 Mild Head Injury----GCS score of 13 to 15 (Adapted from: 
Advanced Trauma Life Support: Course for Physicians, American College of Surgeons, 
1993). 


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Disclaimer: Based on motor responsiveness, verbal performance, and eye opening to 
appropriate stimuli, the Glascow Coma Scale was designed and should be used to assess the 
depth and duration coma and impaired consciousness. This scale helps to gauge the impact of 
a wide variety of conditions such as acute brain damage due to traumatic and/or vascular 
injuries or infections, metabolic disorders (e.g., hepatic or renal failure, hypoglycemia, 
diabetic ketosis), etc. Glasgow Coma Scale (continued from previous page) May 9, 2003 
Page 2 of 2 
Education is necessary to the proper application of this scale. Teasdale G, Kril-Jones R, van 
der Sande J. Observer variability in assessing impaired consciousness and coma. J Neurol 
Neurosurg Psychiatry 1978; 41:603-610; Rowley G, Fielding K. Reliability and accuracy of 
the Glasgow Coma Scale with experienced and inexperienced users. Lancet 1991; 337:535-
538). The predictive value of the GCS, even when applied early, is limited (Waxman K, 
Sundine MJ, Young RF. Is early prediction of outcome in severe head injury possible? Arch 
Surg 1991; 126:1237-1242). 
Despite these and other limitations (Eisenberg HM. Outcome after head injury: Part I: general 
Considerations, in Becker DP, Povlishock JR (eds): Central Nervous System Trauma Status 
Report, 1985. Washington, DC: U.S. Government Printing Office, 1988:271-280), health care 
practitioners continue to use this practical scale widely. 
Source: Adapted from Glasgow Coma Scale, Womack Army Medical Center, Fort Bragg, 
NC.
Modified Rankin Scale
Score
Description
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual 
duties and activities
2
Slight disability; unable to carry out all previous activities, but able to 
look after own affairswithout assistance
3
Moderate disability; requiring some help, but able to walk without 
assistance
4
Moderately severe disability; unable to walk without assistance and 
unable to attend to own bodily needs without assistance


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5
Severe disability; bedridden, incontinent and requiring constant nursing 
care and attention
6
Dead
References
Rankin J. “Cerebral vascular accidents in patients over the age of 60.”
Scott Med J 1957;2:200-15
Bonita R, Beaglehole R. “Modification of Rankin Scale: Recovery of motor function after 
stroke.”
Stroke 1988 Dec;19(12):1497-1500
Van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. “Interobserver 
agreement for the assessment ofhandicap in stroke patients.”
Stroke 1988;19(5):604-7
10.5
PHARMACOKINETIC METHODS
Cpre, Cmin,1, Cmax and tmax: Individual Cmax and tmax values will be directly determined from the 
plasma concentration time profiles of each patient. If the same Cmax concentration occurs at 
different time points, tmax is assigned to the first occurrence of Cmax.
gMean, gCV: The geometric mean (gMean) and coefficient of variation, gCV (given in %), 
will be calculated by the formulae:

)
ln(x
exp
)
ln(x
exp
gMean
i
n
1
i
i
n
1









1
))
Var(ln(x
exp
100
gCV(%)
i



where


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

2
n
1
i
i
i
i
)
ln(x
)
ln(x
1
n
1
))
Var(ln(x





10.6
CLINICAL EVALUATION OF LIVER INJURY 
10.6.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.6.1 (Protocol-Specified 
Significant Events), are to be further evaluated using the following procedures:
10.6.2
Procedures
Repeat the following lab tests: ALT, AST, and bilirubin (total and direct) - within 48 to 72 
hours. If ALT and/or AST >3 fold ULN combined with an elevation of total bilirubin >2 fold 
ULN are confirmed, results of the laboratory parameters described below must be made 
available to the investigator and to BI as soon as possible.
In addition, 

obtain a detailed history of current symptoms and concurrent diagnoses and 
medical history according to the “DILI checklist” provided in the ISF 

obtain history of concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets according to the “DILI checklist” 
provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home 
and work place exposure) according to the “DILI checklist” provided in the 
ISF;
and report these via the CRF.
Clinical chemistry 
alkaline phosphatase, albumin, PT or INR, CK, CK-MB or Troponin , coeruloplasmin, α-1 
antitrypsin, transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides


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Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG.  If anti-IgM and anti-
IgG are not available, total anti Hep D can be performed), Hepatitis E (Anti-HEV, Anti-HEV 
IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody (titer), Anti-nuclear 
antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-mitochondrial antibody
<project dependent:> Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), 
herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis 
(IgG, IgM)>
Hormones, tumormarker
TSH
Haematology
Thrombocytes, eosinophils

Provide abdominal ultrasound to rule out biliary tract, pancreatic or 
intrahepatic pathology, e.g. bile duct stones or neoplasm.

Initiate close observation of patients by repeat testing of ALT, AST, and total 
bilirubin (with fractionation by total and direct) at least weekly until the 
laboratory ALT and / or AST abnormalities stabilize or return to normal, then 
according to the protocol. Depending on further laboratory changes, additional 
parameters identified e.g. by reflex testing will be followed up based on 
medical judgement and Good Clinical Practices (GCP).


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol
11.1
GLOBAL AMENDMENT 1
Date of amendment
EudraCT number
EU 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


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11.2
GLOBAL AMENDMENT 2
Date of amendment
EudraCT number
EU 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c16458864
1.0
clinical-trial-protocol-version-01
A Phase III, case series clinical study of the reversal of the anticoagulant effects of
dabigatran by intravenous administration of idarucizumab (BI 655075) in patients
treated with dabigatran etexilate who have uncontrolled bleeding or require
emergency surgery or procedures.
Approval–Clinical Monitor
02 Jun 2017 03:23 CEST
Author-Trial Statistician
02 Jun 2017 04:46 CEST
Approval-Team Member Medicine
02 Jun 2017 18:04 CEST
Author-Trial Clinical
Pharmacokineticist
05 Jun 2017 03:56 CEST
Approval-Therapeutic Area 
05 Jun 2017 20:17 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c16458864
1.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c21239352-02
BI Trial No.:
1321.19
Title:
A Phase III, case series clinical study of the reversal of the
anticoagulant effects of dabigatran by intravenous administration
of idarucizumab (BI 655075) in patients treated with dabigatran
etexilate who have uncontrolled bleeding or require emergency 
surgery or procedures.
Investigational
Product:
Idarucizumab, BI 655075
Responsible trial 
statistician:
Tel:
Fax
Email:
Date of statistical 
analysis plan:
08 JUL 2019 SIGNED
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................5
3.
INTRODUCTION..................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......8
5.
ENDPOINTS ..........................................................................................9
5.1
PRIMARY ENDPOINT ......................................................................................9
5.2
SECONDARY ENDPOINTS..............................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................14
6.1
TREATMENT....................................................................................................14
6.2
IMPORTANT PROTOCOL DEVIATIONS...................................................14
6.3
PATIENT SETS ANALYSED..........................................................................15
6.5
POOLING OF CENTRES ................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................17
7.
PLANNED ANALYSIS.......................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........19
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................19
7.3
TREATMENT COMPLIANCE .......................................................................19
7.4
PRIMARY ENDPOINT ....................................................................................20
7.5
SECONDARY ENDPOINTS............................................................................20
7.5.1
Key secondary endpoint................................................................................20
7.5.2
Other secondary endpoints...........................................................................20
7.7
EXTENT OF EXPOSURE................................................................................22
7.8
SAFETY ANALYSIS.........................................................................................23
7.8.1
Adverse events ...............................................................................................23
7.8.2
Laboratory data.............................................................................................24
7.8.3
Vital signs.......................................................................................................24
7.8.4
ECG ................................................................................................................24


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7.8.5
Others .............................................................................................................24
8.
REFERENCES.....................................................................................26
10.
HISTORY TABLE...............................................................................28


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LIST OF TABLES
Table 6.2: 1
Handing of important protocol deviations (iPDs)...........................................14
Table 6.2: 1
(continued) Handing of important protocol deviations (iPDs)........................15
Table 6.3: 1
Patient sets analysed........................................................................................16
Table 10: 1
History table ....................................................................................................28


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ACT
Activated clotting time
AE
Adverse event
AESI
Adverse event of special interest
aPTT
Activated partial thromboplastin time
ATC
Anatomical therapeutic chemical
BI
Boehringer Ingelheim
BRPM
Blinded report planning meeting
CI
Confidence interval
CHF
Congestive heart failure
eCRF
electronic case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
DMC
Data Monitoring Committee
dTT
Diluted thrombin time
ECG
Electrocardiogram
ECT
Ecarin clotting time
FFP
Fresh frozen plasma
GI bleeding
Gastrointestinal bleeding
HPLC
High pressure liquid chromatography
ICH
International Conference on Harmonisation
ICH
Intracerebral hemorrhage
Ida
Idarucizumab
iPD
important protocol deviation
KM
Kaplan-Meier


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Term
Definition / description
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MQRM
Medical Quality Review Meeting
PCC
Prothrombin complex concentrate
PD
Pharmacodynamics
PDS
Pharmacodynamics set
PK
Pharmacokinetics
PKS
Pharmacokinetics set
RBC
Red blood cell
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation
SEE
Systemic embolic event
SEG
Statistical expert group
TIA
Transient ischemic attack
TS
Treated set
TSAP
Trial statistical analysis plan
TT
Thrombin time
ULN
Upper limit of normal
VTE
Venous thrombotic event/venous thromboembolism
WHO
World Health Organization


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.
Pharmacokinetic (PK) and pharmacodynamic (PD) parameters will be calculated using 
WinNonlinTM software (professional Network version 6.3, Pharsight Corporation, Mountain 
View, CA 94041-1530, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is the maximum reversal of anticoagulant effect of dabigatran based on
central laboratory determination of diluted thrombin time (dTT) or ecarin clotting time (ECT),
at any time point from the end of the first infusion up to 4 hours (planned time, a maximum 
30 minutes time window will be allowed) after the completion of the last infusion.
Maximum reversal of the anticoagulant effect of dabigatran is defined as
Reversal = predose coagulation test −minimum postdose coagulation test
predose coagulation test −100% ULN
× 100%
Values equal to or higher than 100% will be interpreted as complete reversal of the 
anticoagulant effect. Patients in the PDS (defined in section 6.3) that have the predose and at 
least one postdose coagulation test (dTT or ECT) result will be included in the corresponding 
analysis. The definition of reversal will also apply to central testing of biomarkers activated 
partial thromboplastin time (aPTT) and thrombin time (TT).
The values of the upper limit of normal (ULN) are determined using data from 1321.1 and 
1321.2 as shown in table 5.1: 1.  
Table 5.1: 1
Upper limit of normal for PD/biomarker parameters
dTT [s]
ECT [s]
aPTT [s]
TT [s]
ULN
35.54
41.26
39.80
14.22
5.2
SECONDARY ENDPOINTS
The same secondary endpoints will be analyzed as defined in the CTP, section 2.1.3, with a 
few clarification remarks.
Secondary efficacy endpoints include:

Time to cessation of bleeding (for Group A only) since the first infusion up to 24 
hours after the completion of the second infusion. The bleeding status will be assessed 
before and at several time points after treatment.

Occurrence of major bleeding (for Group B only) intraoperatively and up to 24 hours 
post-surgery.


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
Minimum unbound sum (free) dabigatran concentrations at any time point since the 
end of the first infusion up to 4 hours (planned time) after the completion of the last 
infusion (Cmin,1). A maximum 30 minutes time window will be allowed. Samples 
collected later than 4.5 hours after the completion of the last infusion will not be 
included in analysis of this endpoint.

Reversal of anticoagulation as measured by aPTT and TT, at any time point since the 
end of the first infusion up to 4 hours (planned time) after the completion of the last 
infusion. A maximum 30 minutes time window will be allowed. Samples collected 
later than 4.5 hours after the completion of the last infusion will not be included in
analysis of this endpoint.
Secondary safety endpoints include:

Numbers of patients with adverse events including local tolerability since the first 
infusion up to 5 days after the completion of the second infusion and since informed 
consent up to 30 days (±7 days) after the completion of the second infusion 

Numbers of patients with serious adverse events since the first infusion up to 5 days 
after the completion of the second infusion and since informed consent up to 30 days (
±7 days) after the completion of the second infusion

Numbers of patients with adverse reactions (adverse events related to treatment) since 
the first infusion up to 5 days after the completion of the second infusion and since 
informed consent up to 30 days (±7 days) after the completion of the second infusion

Number of patients with immune reactions assessed by AE collection since the first 
infusion up to 5 days after the completion of the second infusion and since informed 
consent up to 30 days (±7 days) after the completion of the second infusion. Immune 
reactions refer to hypersensitivity identified by narrow SMQ 20000214 and those 
identified by MedDRA preferred terms pyrexia, malaise, urticaria, pruritus, arthralgia, 
rash.

Number of patients with thrombotic events (ischemic stroke, myocardial infarction, 
pulmonary embolism, deep vein thrombosis, systemic embolism) since the first 
infusion up to 5 days after the completion of the second infusion and since informed 
consent up to 30 days (±7 days) after the completion of the second infusion. The
thrombotic events will be coded using MedDRA based on reported AEs and identified 
by narrow SMQs 20000081 “embolic and thrombotic events” and 20000047 
“myocardial infarction”. 


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
C4 (the concentration of unbound sum dabigatran 4 hours after administration)

C12 (the concentration of unbound sum dabigatran 12 hours after administration)

C24 (the concentration of unbound sum dabigatran 24 hours after administration)
Additional pharmacokinetic parameters for sum dabigatran and unbound sum dabigatran may 
be calculated as appropriate.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
It is planned to include about 20 patients in this trial. All patients will receive idarucizumab 
(short label: Ida). 
The following treatment period will be defined:

Screening: day of informed consent to start time of the first administration of 
idarucizumab. If on the same day, then the period before the first administration of 
idarucizumab.

On-treatment: start time of the first administration of idarucizumab to 5 days after the 
end time of the last administration of idarucizumab.

Post-treatment: 5 days after the end time of the last administration of idarucizumab to 
day of the end of study visit (visit 5) or consent withdraw. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Table 6.2: 1
Handing of important protocol deviations (iPDs)
Category/
Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1.1
Inclusion criteria 1 for Group A or B 
not met
Patient < 18 years at screening
PKS/PDS
A1.2
Inclusion criteria 3 for Group A or B 
not met
No signed and dated written informed 
consent prior to admission to the trial
All
A1.3
Inclusion criterion 4 for Group A or 
B not met
Patient not currently taking dabigatran 
etexilate
PKS/PDS
A1.4
Inclusion criteria 5A for Group A or 
Inclusion criteria 5B for Group B 
not met
No overt bleeding requiring a reversal agent 
for Group A or no condition requiring 
emergency surgery or invasive procedure 
where adequate hemostasis is required for 
Group B 
PKS/PDS


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Table 6.2: 1
(continued) Handing of important protocol deviations (iPDs)
Category/
Code
Description
Requirements
Excluded 
from
A2
Exclusion criteria met
Met exclusion criteria as specified in the 
protocol
PKS/PDS
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing
All
B2
Informed consent late
Informed consent date <actual consent 
date> was after Visit 2.1 date <Visit 2 date>
None
C
Trial medication and 
randomization
C1
Incorrect trial medication taken
Only one vial or more than two vials 
(except for required repeated treatment) of 
idarucizumab was administered.
None
All categories will be checked automatically. This list will be updated if additional important protocol deviations are 
detected during the trial conduct.
6.3
PATIENT SETS ANALYSED
The following analysis sets will be used for the data analysis in this trial:

Screened set (SCR): include all patients who were screened for this trial with 
informed consent given.

Treated set (TS): include all patients who are administered with idarucizumab. The 
TS will be used to assess safety, clinical endpoints, demographics and other baseline 
characteristics as well as concomitant diagnosis/therapy and medical history.

Pharmacokinetic set (PKS): comprise all patients in the TS who provided at least one 
PK endpoint. The PKS will be used for all PK analyses. Note that for different PK 
endpoints, the number of evaluable patients might be different.

Pharmacodynamic set (PDS): comprise 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 the primary efficacy endpoint and all 


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PD/biomarker endpoints. Note that for different biomarkers or PD endpoints, the 
number of evaluable patients might be different.
Table 6.3: 1
Patient sets analysed
Patient Set
Class of endpoint
SCR
TS
PKS
PDS
Primary endpoint
X
Secondary
 
efficacy endpoints 
Clinical 
endpoints
PK endpoints
PD endpoints 
Secondary
 
safety endpoints 
X
 
Disposition
X
Demographic/baseline 
endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing data will not be imputed in general. 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 100% ULN. Patients in such cases will be considered as not 
evaluable for the corresponding biomarker. 
For missing or incomplete AE dates, BI internal procedures and guidelines will be followed
(1). Handling of missing PK/PD data will be performed according to the BI standard 
procedures (2, 3).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline values will be the last measurements taken prior to the administration of the first 
vial of idarucizumab (same day is allowed). If not available, the values reported at the 
screening visit will be taken as baseline values. For lab values, baseline is the one observed 
closest but prior to idarucizumab administration.


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7.
PLANNED ANALYSIS
Descriptive statistics for continuous variables will generally be N (number of patients with 
non-missing values), mean, standard deviation (SD), minimum, median, maximum. In 
general, means, medians, SDs, will be presented to one more decimal place than the raw data. 
Minimums and maximums will be presented to the same number of decimal places as the raw 
data. Geometric means and geometric coefficients of variation will be used in summaries of 
PK concentration values.
Tabulations of frequencies for categorical data will include all possible categories, unless 
otherwise specified (e.g. adverse event terms) and will display the number of observations in 
a category as well as the percentage (%) relative to the respective treatment group. 
Percentages will be rounded to one decimal place. A missing category will be displayed if 
and only if there are actually missing values. Percentages will be based on all patients in the 
respective patient set whether they have non-missing values or not.
In rare cases, if patients enter the trial more than once (i.e. patients need antidote 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.
If a patient receives more than 5g idarucizumab under a single index event, the patient will be 
assigned a different patient number each time the patient receives an additional 5g 
idarucizumab and the data collected since the second 5g dose will be associated with 
subsequent patient number(s) other than the original patient number at enrolment. The 
demographic and baseline characteristics will be summarized per individual patient, i.e., for 
these patients, demographic and baseline characteristics from the original patient number will 
be used. For the analyses of efficacy endpoints, only data collected under the original patient 
number at enrolment will be included. Efficacy introduced by more than 5g idarucizumab 
will be described/discussed separately. PK/PD parameters will also be reported separately.
For the analyses of safety endpoints, data will be pooled together and presented in summary 
tables as if only one patient number is used. Some rules will be followed for listings of raw 
data.

For baseline and demographic data, patients will be listed once under the first patient 
number.

For individual efficacy data, all listings will only show data collected under the first 
patient number.

For individual safety and lab data, all listings will show combined data collected 
under all patient numbers used, identified by the first patient number.


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
The following efficacy and safety listings will be repeated to show information 
collected under all patient numbers, in a sequence without combining.
o
Reasons for all surgeries
o
All bleeding information
o
Individual patient central lab and dabigatran concentration
o
Patients with adverse events by group, primary system organ class and 
preferred term
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive statistics will be provided for demographics and baseline characteristics.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be summarised descriptively. The concomitant medications taken 
at baseline and those taken while on treatment will be coded using the WHO Drug coding 
dictionary. These will then be summarized by WHO Drug ATC coding and listed by patient 
with each medication taken.
Descriptive summary of patients’ exposure to dabigatran prior to entering the trial will be 
summarized, including the time of last dabigatran intake, daily dose and dabigatran 
indication.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The proportion of patients 
received one, two or partial vials of idarucizumab will be provided.


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7.4
PRIMARY ENDPOINT
For the primary endpoint, the median and 1st, 5th, 10th and 25th percentile of the calculated 
maximum reversal of the anticoagulation effect among all evaluable patients will be 
calculated, using each coagulation test separately (ECT and dTT). The 95% confidence 
interval for median and the percentiles will be calculated based on distribution-free method. 
Detailed SAS code is included in section 9.1.
Reversal cannot be defined for patients with biomarker test (dTT, ECT, aPTT or TT) pre-
dose value less than 100% ULN (not evaluable).
7.5
SECONDARY ENDPOINTS
Secondary endpoints will be analysed based on TS, PKS or PDS according to the nature of 
endpoints. 
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Other secondary endpoints
Time to cessation of bleeding (for Group A only) since the end of first infusion up to 24 
hours after the completion of second infusion will be summarized descriptively for patients 
(by ICH and non ICH patients if feasible based on sample size) whose bleeding is assessable 
within 26 hours (assessment at 24 hours with up to 2 hour time window allowed by protocol). 
ICH patients will not be included in this analysis if no follow-up CT scans are available. For 
non-ICH patients, patient who dies within 26 hours will be censored at the time of death, and 
all others censored at 24 hour if they do not stop bleeding prior to 26 hours. Median, 25th and 
75th percentile of time to cessation of bleeding will be estimated by Kaplan-Meier method. 
Probability of stopping bleeding at landmark times (1, 2, 3, 4, 12 and 24 hours, etc.) will be 
provided. 
The frequency of occurrence of major bleeding (for Group B only) intraoperatively and up to 
24 hours post-surgery will be summarized descriptively. The 95% Clopper-Pearson
confidence interval will be calculated for the frequency. 
Minimum unbound sum dabigatran concentrations at any time point since the end of first 
infusion up to 4 hours after the completion of the last infusion (Cmin,1) will be summarized for 
all evaluable patients descriptively. A maximum 30 minutes delay in sample collection will 


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be allowed to include the result in the analysis.
Maximum reversal of anticoagulation as measured by aPTT and TT, at any time point since 
the end of first infusion up to 4 hours after the completion of the last infusion will be 
summarized similarly as the primary endpoint. Only central biomarker testing result will be 
used for this endpoint. Local assessment of aPTT will be explored as further endpoint. A 
maximum 30 minutes delay in sample collection will be allowed to include the result in the 
analysis.
Safety endpoints will be summarized descriptively. The details of AE handling is stated in 
section 7.8. Standard AE tables will be created for both on-treatment period and the entire 
study period. Special safety tables and listings (e.g. outcome event tables) will be created for 
the entire study period only, unless specified otherwise. Patients with thrombotic events will 
be summarized descriptively.


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7.7
EXTENT OF EXPOSURE
Two 2.5g vials of idarucizumab will be administered no more than 15 minutes apart. The 
exposure will be summarized by the number and proportion of patients received one, two or 
partial vials of idarucizumab. In addition, the duration of infusion of each vial, the time 
between start of the first vial and end of the second vial will be descriptively summarized. 


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (4).
AEs will be coded with the most recent available version number of MedDRA referred to in 
the footnote of tables and listings.
All analyses of AEs will be based on the number of patients with AEs (and not on the number 
of AEs). AEs occurrences, i.e. AEs entries on the eCRF (electronic case report form), will be 
collapsed into AEs episodes provided that all of the following applies:
the same lowest level term was reported for the occurrences;
the occurrences were time-overlapping or time-adjacent (time-adjacency of second 
occurrences is given if the second occurrence started at the end date if first 
occurrence);
treatment did not change between the onset of the occurrences or treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. All adverse events occurring before the administration of first vial idarucizumab will 
be assigned to ‘screening’. All AEs recorded after first vial of idarucizumab and until 5 days 
after the last dose of idarucizumab will be assigned to the on-treatment period. AEs with 
onset date after the on-treatment period will be assigned to post-treatment period. 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.
All AEs in the on-treatment period and the entire study period will be tabulated in total and 
according to seriousness, severity and possible relationship to trial medication. AEs in the 
entire study period will be listed.
According to ICH E3 (5), AEs classified as ‘other significant’ will include those non-serious 
and non-significant AEs with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or


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(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Report Planning Meeting. 
An overall summary of adverse events will be presented. 
Frequency of patients with adverse events will be summarised by type of patient (group A, 
group B), primary system organ class and preferred term. Separate tables will be provided for 
patients with other significant adverse events according to ICH E3, for patients with serious 
adverse events, protocol-specified adverse events of special interest (AESI) as well as for 
patients with drug related AEs. The system organ classes will be sorted according to the 
standard sort order specified by EMA (European Medicines Agency). Preferred terms will be 
sorted by frequency (within system organ class).
In addition, frequency of subjects with AESI and non-serious adverse events that exceed 5%-
threshold will be summarised by primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (6). Descriptive statistics will be calculated over time and for the difference from 
baseline including post examination values. Baseline is understood as the last available 
measurement before the first administration of idarucizumab. 
Frequency tables of changes with respect to the reference range between baseline and last 
value on treatment will also be presented.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
No ECG data will be collected or analysed. Any clinically significant new abnormal findings 
in ECG after the first screening ECG will be reported as adverse events and summarized 
descriptively.
7.8.5
Others
Outcome events (pulmonary embolism, deep vein thrombosis, transient ischemic attack, 
myocardial infarction, systemic embolism, hemorrhagic stroke, ischemic stroke, other stroke, 
bleeding, death) are identified using narrow SMQs (20000081 “embolic and thrombotic 


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events”, 20000047 “myocardial infarction”) and MedDRA preferred terms. Frequency of 
events will be summarized descriptively for Group A and Group B.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
001-MCS-36-472: “Standards and processes for analyses performed within Clincal 
Pharmacokinetics/Pharmacodynamics”, current version; IDEA for CON.
3
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON.
4
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical 
Trials", current version; IDEA for CON.
5
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
6
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.


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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
15-Dec-17
None
This is the initial TSAP with necessary 
information for trial conduct.
Final
08-Jul-19
None
This is the final TSAP without any 
modification.