Clinical trial NCT03070171
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-03-21; Completion date: 2017-06-20
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objective of this trial is to establish the bioequivalence of tablet formulation of dabigatran etexilate compared to commercial capsule formulation following oral administration under fasted condition.

The secondary objective is the evaluation and comparison of several pharmacokinetic parameters between the treatments.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: dabigatran etexilate
Intervention descriptions: intervention 1: single dose

Protocol documents:
Prot_001.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c11669965-01
BI Trial No.:
1160.271
BI Investigational
Product:
Pradaxa® (Prazaxa® in Japan), Dabigatran etexilate, BIBR 1048 MS
Title:
Bioequivalence of tablet formulation of dabigatran etexilate 
compared to commercial capsule formulation following oral 
administration in healthy male subjects (an open-label, 
randomised, single-dose, replicate design in a two-treatment,
four-period, two-sequence crossover study)
Clinical Phase:
I
Trial Clinical Monitor:
Address: 
Phone:
Fax: 
Principal Investigator:
Address: 
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version: 1.0
Date:10 Feb 2017
Page 1 of 54
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written 
permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Pradaxa® (Prazaxa® in Japan)
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
Not applicable
10 Feb 2017
1160.271
Title of trial:
Bioequivalence of tablet formulation of dabigatran etexilate compared to commercial 
capsule formulation following oral administration in healthy male subjects (an open-
label, randomised, single-dose, replicate design in a two-treatment, four-period, two-
sequence crossover study)
Principal Investigator:
Address: 
Phone: 
Fax:
Trial site:
Address:
Phone: 
Fax:
Clinical phase:
I
Objective:
To establish the bioequivalence of tablet formulation of 110 mg dabigatran etexilate 
compared to commercial capsule formulation
Methodology:
Randomised, single-dose ,open-label, replicate design in a two-treatments, four-
period, two-sequence crossover design
No. of subjects: 
total entered:
160
each treatment:
160 (80 subjects in the each treatment sequences)
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 20 to 40 years, body mass index (BMI) of 18 to 
25 kg/m2
Test product:
Dabigatran etexilate tablet formulation: (T)
dose:
110 mg
mode of admin.:
Oral with 200 mL of water after an overnight fast of at least 10 h
Comparator product:
Dabigatran etexilate capsule formulation (R)
dose:
110 mg
mode of admin.:
Oral with 200 mL of water after an overnight fast of at least 10 h
Duration of treatment: One day (single dose) for each treatment period


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Pradaxa® (Prazaxa® in Japan)
Name of active ingredient:
Dabigatran etexilate, BIBR 1048 MS
Protocol date:
Trial number:
Revision date:
Not applicable
10 Feb 2017
1160.271
Criteria for
pharmacokinetics:
Primary endpoints: AUC0-tz and Cmax of free dabigatran
Secondary endpoints: AUC0-tz and Cmax of total dabigatran and AUC0-of both free 
dabigatran and total dabigatran
Further parameters of interest: time from dosing to the maximum measured 
concentration of both free dabigatran and total dabigatran in plasma (tmax), z, terminal 
half-life of both free dabigatran and total dabigatran in plasma (t1/2) ,
AUCt1-t2, %AUCtz-, MRTpo, CL/F, Vz/F 
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead electrocardiogram (ECG), vital signs 
(blood pressure [BP], pulse rate [PR]) 
Statistical methods:
The assessment of bioequivalence will be based upon two-sided 90% confidence 
intervals (CIs) for the ratios of the geometric means (test/reference) for the primary 
and secondary endpoints using an acceptance range of 80.0-125.0%. This method is 
equivalent to the two one-sided t-tests procedure, each at the 5% significance level. 
The statistical model will be an ANOVA on the logarithmic scale including effects for 
‘sequence’, ‘subjects nested within sequences’, ‘period’ and ‘treatment’. CIs will be 
calculated based on the residual error from ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory2
PK blood
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
Within 
28 days 
before 
first 
drug 
administ
ration
Screening (SCR)1
X
X
X
1/2/3/4
2/3
/4/
5
-1
-12:00
21:00
Admission to trial site
X
X
1
-1:00
08:00
Allocation to treatment (visit 2 only)
X 3
X 3
X 3
0:00
09:00
Drug administration
0:30
09:30
X
1:00
10:00
X
1:30
10:30
X
2:00
11:00
200 mL fluid intake
X
X
3:00
12:00
X
4:00
13:00
200 mL fluid intake, thereafter lunch4
X
6:00
15:00
X
8:00
17:00
X
11:00
20:00
Dinner
12:00
21:00
X
X 
2
24:00
09:00
Breakfast4
X
X
X
X
36:00
21:00
X
3
48:00
09:00
X
X
48:30
09:30
Discharge from trial site
EOT
6
5 to 14
days 
after
day 1 
of Visit 
57
End of trial (EOT) examination5
X
X
X
X
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of height and body weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
Breath alcohol test and safety laboratory. Safety laboratory to be taken and to be medically evaluated within 24 hours
prior to administration of trial drug. Samples for safety laboratory will be collected after the subjects have fasted for at 
least 10 hours except for Visit 1. Breath alcohol test will be performed at screening and within 24 hours prior to each 
treatment period, and may be repeated at any time during the trial.
3.
The time is approximate; the procedure can be acceptable to be performed and completed within 3 h prior to drug 
administration.
4.
If several actions are indicated at the same time point, the intake of meals will be the last action.
5.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
In case of premature discontinuation, 5-14 days after the last drug administration


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS.............................................................................................8
1.
INTRODUCTION.................................................................................... 10
1.1
MEDICAL BACKGROUND............................................................................10
1.2
DRUG PROFILE...............................................................................................10
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 14
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................14
2.2
TRIAL OBJECTIVES.......................................................................................14
2.3
BENEFIT - RISK ASSESSMENT ...................................................................14
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 16
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................16
3.1.1
Administrative structure of the trial...................................................16
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................17
3.3
SELECTION OF TRIAL POPULATION ......................................................18
3.3.1
Main diagnosis for study entry............................................................18
3.3.2
Inclusion criteria...................................................................................18
3.3.3
Exclusion criteria ..................................................................................18
3.3.4
Removal of subjects from therapy or assessments.............................20
3.3.4.1
Removal of individual subjects................................................20
3.3.4.2
Discontinuation of the trial by the sponsor..............................20
3.3.5
Replacement of subjects .......................................................................21
4.
TREATMENTS........................................................................................ 22
4.1
TREATMENTS TO BE ADMINISTERED....................................................22
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................22
4.1.2
Method of assigning subjects to treatment groups ............................23
4.1.3
Selection of doses in the trial................................................................23
4.1.4
Drug assignment and administration of doses for each subject .......23
4.1.5
Blinding and procedures for unblinding ............................................24
4.1.6
Packaging, labelling, and re-supply ....................................................24
4.1.7
Storage conditions.................................................................................24
4.1.8
Drug accountability ..............................................................................25


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4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................25
4.2.1
Other treatments and emergency procedures....................................25
4.2.2
Restrictions............................................................................................26
4.2.2.1
Restrictions regarding concomitant treatment .........................26
4.2.2.2
Restrictions on diet and life style.............................................26
4.3
TREATMENT COMPLIANCE.......................................................................27
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 28
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................28
5.1.1
Endpoints of efficacy.............................................................................28
5.1.2
Assessment of efficacy...........................................................................28
5.2
SAFETY..............................................................................................................28
5.2.1
Endpoints of safety................................................................................28
5.2.2
Assessment of adverse events...............................................................28
5.2.2.1
Definitions of adverse events...................................................28
5.2.2.2
Adverse event collection and reporting ...................................31
5.2.3
Assessment of safety laboratory parameters......................................33
5.2.4
Electrocardiogram................................................................................35
5.2.5
Assessment of other safety parameters...............................................35
5.2.5.1
Vital signs ................................................................................35
5.2.5.2
Medical examinations..............................................................35
5.2.5.3
Local tolerability......................................................................36
5.3
OTHER ...............................................................................................................36
5.3.1
Pharmacogenomic evaluation..............................................................36
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................36
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................36
5.5.1
Pharmacokinetic endpoints..................................................................36
5.5.1.1
Primary endpoints ....................................................................36
5.5.1.2
Secondary endpoints ................................................................36
5.5.2
Methods of sample collection ...............................................................37
5.5.2.1
Plasma sampling for pharmacokinetic analysis .......................37
5.5.2.2
Urine sampling for pharmacokinetic analysis..........................38
5.5.3
Analytical determinations ....................................................................38
5.5.3.1
Analytical determination of analyte plasma concentration......38
6.
INVESTIGATIONAL PLAN.................................................................. 39
6.1
VISIT SCHEDULE............................................................................................39
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................39
6.2.1
Screening period....................................................................................39
6.2.2
Treatment periods.................................................................................39
6.2.3
End of trial and follow-up period........................................................40


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 41
7.1
STATISTICAL DESIGN – MODEL ...............................................................41
7.1.1
Objectives...............................................................................................41
7.1.2
Endpoints...............................................................................................41
7.1.3
Model......................................................................................................41
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................42
7.3
PLANNED ANALYSES....................................................................................43
7.3.1
Primary analyses...................................................................................43
7.3.2
Secondary analyses ...............................................................................44
7.3.4
Safety analyses.......................................................................................44
7.3.5
Interim analyses ....................................................................................45
7.3.6
Pharmacokinetic analyses ....................................................................45
7.4
HANDLING OF MISSING DATA ..................................................................46
7.4.1
Safety......................................................................................................46
7.4.2
Plasma drug concentration - time profiles..........................................46
7.4.3
Pharmacokinetic parameters...............................................................46
7.5
RANDOMISATION ..........................................................................................46
7.6
DETERMINATION OF SAMPLE SIZE ........................................................47
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 48
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................48
8.2
DATA QUALITY ASSURANCE .....................................................................48
8.3
RECORDS..........................................................................................................49
8.3.1
Source documents .................................................................................49
8.3.2
Direct access to source data and documents.......................................49
8.3.3
Storage period of records.....................................................................49
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................49
8.5
STATEMENT OF CONFIDENTIALITY.......................................................49
9.
REFERENCES......................................................................................... 51
9.1
PUBLISHED REFERENCES...........................................................................51
9.2
UNPUBLISHED REFERENCES.....................................................................51
10. APPENDICES .......................................................................................... 53
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 54


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BE
Bioequivalence
BI
Boehringer Ingelheim
b.i.d.
Bis in die, twice daily
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CrCl
Creatinine clearance
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
DE
Dabigatran etexilate
ECG
Electrocardiogram
EOT
End of trial
GCP
Good Clinical Practice
ICSR
Individual Case Safety Reports
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
MRTpo
Mean residence time of the analyte in the body after oral administration
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result


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NOS
No sample available
NVAF
Non-valvular atrial fibrillation
PCI
Percutaneous coronary intervention
P-gp
P-glycoprotein
PK
Pharmacokinetics
PKS
PK parameter analysis set
PR
Pulse rate
q.d.
Quaque die, once daily
R
Reference treatment
RE-LY
Randomised Evaluation of Long-Term Anticoagulant Therapy with 
Dabigatran Etexilate
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SE
Systemic embolism
SOP
Standard Operating Procedure
SPAF
Stroke prevention in patients with non-valvular atrial fibrillation
T
Test treatment
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
ULN
Upper limit of normal
VTE
Venous thromboembolism
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Dabigatran etexilate (DE) has been developed as an orally active anticoagulant and was 
granted in 2011 for the indication of the stroke prevention in patients with non-valvular atrial 
fibrillation (SPAF) in Japan. Globally, the first marketing authorisation for SPAF was granted 
in the US in 2010.
In addition to SPAF, DE has also been developed for the prevention and treatment of venous 
thromboembolism (VTE) in patients with undergoing hip or knee surgery, for the acute 
treatment and secondary prevention of VTE, and for reduction in cardiovascular 
complications in patients with acute coronary syndrome including those following an index 
myocardial infarction. First marketing authorization for DE was granted in 2008 in the 
European Union and the European Economic Area for the indication “Primary prevention of 
VTE in adult patients who have undergone elective total hip replacement surgery or total 
knee replacement surgery”. In 2014, the two indications acute VTE treatment and secondary 
VTE prevention was approved in the US. Marketing authorization for DE has been granted in 
more than 108 countries world-wide.
DE is recommended as the first choice medicine as well as warfarin for SPAF according to 
the 2013 edition of the Guidelines for pharmacotherapy of atrial fibrillation Japanese 
Circulation Society 2013) [R15-5604] in Japan and widely used in medical practice.
The prevalence of atrial fibrillation increase with age. It occurs in about 1% of those under 60 
years of age but in about 6 % of those over 80 years of age (Fuster, et al.,2001) [R03-1231]. 
However, currently only available formulation for DE is a capsule containing tartaric acid 
starter pellets coated with the active ingredient. Due to size of the capsules (i.e., No.2 capsule 
in size for 75 mg formulation and No.1 capsule in size for 110 mg formulation), this 
formulation has a limitation in administration for elderly patients who have difficulty in 
swallowing. Thus, more convenient formulation of DE (i.e., a tablet), which is smaller than 
commercial capsule, has high medical needs.
1.2
DRUG PROFILE
Pharmacokinetics
The pharmacokinetics (PK) profile of dabigatran in plasma is characterized by a rapid 
increase in plasma concentrations with maximum measured concentration of the analyte in 
plasma (Cmax) attained within 0.5 and 2.0 hours post administration, and half-life depending 
on renal function (see the reference [c01632884-04] for prolongation of half-life with decline 
in renal function). Dabigatran Cmax and area under the curve increase in a dose proportional 
manner. Dabigatran is eliminated primarily by the kidneys with urinary excretion accounting 
for approximately up to 80% of the dose administered intravenously.
In phase I drug-drug interaction studies, there was no significant influence of DE on the PK 
of atorvastatin, diclofenac or digoxin (P-glycoprotein [P-gp] substrate), and the exposure of 
dabigatran was not significantly altered by these drugs. DE and dabigatran are not 


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metabolised by the cytochrome P450 system [U01-1602] and have no in vitro effects on 
human cytochrome P450 enzymes. There was, however, an effect on DE bioavailability after 
co-administration with some P-gp inhibitors or inducers. The maximum increase, 
approximately 2.5 fold, in dabigatran exposure was observed after single and multiple doses 
of co-administered ketoconazole while chronic rifampicin reduced the dabigatran exposure to 
1/3 of control values. However, co-administration of P-gp inhibitors (such as amiodarone, 
quinidine and verapamil) in the Randomised Evaluation of Long-Term Anticoagulant 
Therapy with DE (RE-LY) had much smaller effects (increase of dabigatran plasma 
concentration of up to 16%) [U09-3249-02] than those observed in phase I studies. 
In the relative bioavailability (BA) study (i.e.1160.246) of tablet formulation of DE, time 
from dosing to maximum measured concentration of the analyte in plasma (tmax) and terminal 
half-life (t1/2) were 1.50 hours for tmax and ranged 8 to 9 hours for t1/2. In comparison with the 
capsule formulation, the adjusted gMean ratio of tablet formulation was approximately 110 % 
for both Cmax and AUC0-tz [c09145064-01].
Safety and Efficacy
In Japan, the indication to reduce the risk of stroke and systemic embolism (SE) in patients 
with non-valvular atrial fibrillation (NVAF) was approved in 2011 based on the result of the 
RE-LY study, a phase III, prospective, randomised, open-label, multinational study of stroke 
prevention in subjects with NVAF at risk of stroke. Over 700 Japanese subjects/patients have 
received DE in phase I, II, and III studies. Globally including Japan, the effects of DE have 
been investigated in more than 27 000 subjects/patients in the clinical studies. Overall, more 
than 1,000 healthy volunteers have been included in phase I studies with DE.
A total of 72 Japanese healthy subjects have been included in 4 phase I studies ([U05-3052], 
[U06-3091], [U05-3334], and [U06-3420]) at a daily dose from 50 mg through 300 mg. The 
method of administration was single dose of 50, 150, 220, and 300 mg and multiple doses of 
150 mg q.d, 220 mg q.d, and 150 mg b.i.d.
Gastrointestinal disorder was a relatively frequently reported adverse event (AE) and 11 
events occurred in 10 subjects treated with a daily dose of more than 220 mg (flatulence, 
abdominal pain, nausea, periodontitis, upper abdominal pain, and gingival bleeding). For the 
bleeding event, gingival bleeding and haematuria were observed in 1 subject each. In the 
patient with haematuria, the score of blood urine test was changed from 1+ at baseline to 3+ 
after treatment with a single dose of 300 mg. 
In addition to the phase I trials mentioned above, a total of 35 Japanese healthy subjects have 
been included in the relative BA study of tablet formulation of DE at a daily dose of 110 mg
[c09145064-01]. 
2 AEs, eosinophil count increased and upper respiratory tract infection, were reported after 
treatment with a single dose of 110 mg in the relative BA study. Eosinophil count increased 
was considered to be related to DE by the investigator. The intensity of these AEs was mild 
or moderate and no bleeding event was observed in the trial.
In the RE-LY study, a total of 18 113 patients were randomised to one of two blinded doses 
of DE (110 mg b.i.d. or 150 mg b.i.d.) or to warfarin (international normalised ratio [INR] 


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2.0-3.0) [U09-3249-02][c03032935-01]. Details of safety and efficacy in the RE-LY study 
are described briefly as follows:
In the RE-LY study, DE 150 mg b.i.d. was demonstrated to be superior to warfarin for the 
prevention of stroke and SE and reduced the rate of intracranial haemorrhage compared to 
warfarin. In addition, DE 150 mg b.i.d. showed similar rate of major bleeding compared to 
warfarin [P09-11669]. DE 110 mg b.i.d. was demonstrated non-inferior to warfarin for the 
primary endpoint of stroke and SE and reduced rate of intracranial haemorrhage, major 
bleeding, and total bleeding. 
Subjects treated with DE had a slightly higher incidence of AEs compared with warfarin 
(78.6%, 78.3%, and 75.9% for DE 110 mg b.i.d., 150 mg b.i.d. and warfarin, respectively). 
Gastrointestinal AEs were reported more frequently for DE treatment. There was no evidence 
of increased frequencies on DE compared to warfarin in transaminase elevations, or 
concomitant transaminase and bilirubin elevations. Instead, the abnormalities were more 
frequent on warfarin. Transaminase elevations <2x upper limit of normal (ULN) were 
common (27 to 31%) in this population. For transaminases >3x ULN, the overall frequency 
was 1.7 to 2.0%. For potential Hy’s Law cases, there were 11 subjects (0.2%) on DE 110 mg 
b.i.d., 14 subjects (0.2%) on DE 150 mg b.i.d., and 21 subjects (0.4%) on warfarin. All but 
four of these cases (three subjects with DE, one subject with warfarin) had identifiable 
alternative causes.
Post-marketing experience
Overall including Japan, taking all granted indications into consideration, experience with 
marketed product of 6 478 207 patient-years has been gained since first launch (period: 18 
March 2008 to 31 August 2016). In total, during the post-marketing experience period, BI 
received a total of 166190 individual adverse events from 90 860.
Haemorrhagic events are the most commonly reported post-marketing adverse drug reactions. 
In approximately 42% of all Individual Case Safety Reports (ICSRs), a haemorrhagic 
event(s) is reported. Approximately 52% of these cases are serious, and approximately 8% of 
all haemorrhage cases have a fatal outcome. Approximately 50% of all haemorrhagic events 
reported are from the gastrointestinal tract.
Gastrointestinal disorders are reported in approximately 40% of the ICSRs. The events are
haemorrhagic in nature in approximately 38%. The non-haemorrhagic events are in over 85% 
non-serious. The most commonly reported non-haemorrhagic gastrointestinal events are
“dyspepsia”, “diarrhoea”, “abdominal discomfort” and “nausea”.
Ongoing studies in Japan
In Japan, the following clinical studies are ongoing for DE: RE-SPECT ESUS (Secondary 
stroke prevention in patients with stroke of undetermined source), RE-DUAL PCI (Efficacy 
and safety in patient with NVAF that undergo a percutaneous coronary intervention [PCI] 
with stenting), RE-CIRCUIT (Safety of uninterrupted treatment with DE in NVAF patients 
undergoing a first ablation procedure), and GLORIA AF (Global registry program on long-
term oral anti-thrombotic treatment in patients with atrial fibrillation).


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For more detailed description of DE profile, please refer to the current Investigator’s 
Brochure [c01632884-04].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
According to the Japanese Guideline for Bioequivalence Studies of Generic Products [R07-
0628, R12-3703], bioequivalence (BE) trial with health volunteers is required to be 
conducted to guarantee the therapeutic equivalence of generic products against original 
drug.BE trial is essential for the tablet formulation of DE to be approved by the regulatory as 
well as delivered to the patients for commercial use.
In the previous relative BA study, PK parameters were obtained preliminary. Based on the 
results from the study as well as manufacturability a tablet formulation was considered to be 
the best to confirm BE with capsule formulation in this study.
This study is conducted to meet requirements from the regulatory agency using the tablet 
formulation which was selected according to the results from the previous study.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to establish the bioequivalence of tablet formulation of 
110 mg DE compared to commercial capsule formulation following oral administration under 
fasted condition. 
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between the treatments. 
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this trial is without any (therapeutic) benefit for healthy subjects. Their 
participation in the trial, however, is of major importance to the development of tablet 
formulation of DE. The subjects are exposed to the risks of the trial procedures and the risks 
related to the exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to veinipuncture for blood sampling.
The total volume of blood withdrawn during the entire trial per subject will be around 285
mL. No health-related risk to healthy subjects is expected from this blood withdrawal.


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Drug-related risks and safety measures
The most significant potential risk associated with DE is a minor bleeding tendency at doses 
600 mg and higher per day during steady state in Caucasian healthy volunteers [U00-1856]. 
For Japanese healthy volunteers, bleeding event was observed after treatment with a single 
dose of 300 mg.For details of adverse events in Japanese subjects included in phase I trials, 
see the Section 1.2.
In Japan, DE has market authorisation with the dose regimen of 150 mg b.i.d. (reduction to 
110 mg b.i.d. should be considered for the patients aged 70 and older, with moderate renal 
failure [creatinine clearance 30-50 mL/min], or with history of gastrointestinal haemorrhages, 
or those who are receiving P-gp inhibitors). The risks to the subjects are low after a single 
dose of 110 mg which is the dosage selected for the present study. Regardless of the low 
bleeding risk and the overall good tolerability of the available formulations of DE, subject’s 
safety will be ensured by the monitoring of subjects for both expected and unexpected AEs 
clinically, verbally, and by laboratory monitoring. Based upon preclinical and clinical 
information, healthy subjects will not be exposed to undue risks from this trial.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The trial will be performed as a randomised, single-dose, open-label, replicate design in, two-
treatment, four-period, two-sequence crossover trial in healthy male subjects in order to 
compare the test treatment (T) to the reference treatment (R). The subjects will be randomly 
allocated to the two treatment sequences (T-R-R-T or R-T-T-R). The treatments will be 
single dose of 110 mg DE / formulation tablet in the fasting state (T) and single dose of 110
mg DE / formulation capsule in the fasting state (R). For details refer to Section 4.1.
R(Reference treatment): DE commercial capsule formulation
T(test treatment): DE tablet formulation
Figure 3.1: 1
Trial Design
There will be a washout period of at least 4 days between the treatments.
Figure 3.1: 2
Example of the timing of drug administration and washout period
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
NBI (Nippon Boehringer Ingelheim Co., Ltd) has appointed a Trial Clinical Monitor, 
responsible for coordinating all required activities, in order to 


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-
manage the trial in accordance with applicable regulations and internal standard 
Operating Procedures (SOP)s,
-
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 participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany and NBI. 
The trial will be conducted at 
 under the 
supervision of the Principal Investigator. 
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
.
The analyses of free, nonconjugated dabigatran and of total dabigatran concentrations in 
plasma will be performed at the contract research organisation
, 
On-site monitoring will be performed by NBI.
Data management and statistical evaluation will be done by NBI or a contract research 
organization appointed by NBI 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 investigator site file (ISF).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For bioequivalence trials, the crossover design is preferred due to its efficiency: since each 
subject serves as his own control, the comparison between formulations is based on a 
comparison within subjects rather than between subjects. This trial design therefore removes 
intersubject variability from the comparison between formulations [cf. R94-1529].
Blinding is not necessary. The open-label treatment is not expected to bias results, since the 
trial endpoints are derived from measurement of plasma concentrations of the analyte 
provided by a bioanalytical laboratory which is blinded to treatment allocation.
Inter-individual variability of trough and post dose plasma concentrations of total dabigatran 
was high after oral administration (HPMC Capsule) of DE at steady state (74-82%)
[c01632884-04]. Inter-individual variability in Cmax of post dose plasma concentrations of 
total dabigatran was higher than 50 %[c09145064-01]. Thus, it is necessary for this BE study 
to be conducted with large number of subjects between the tablet formulation and the capsule 
formulation.


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According to the Japanese Guideline for Bioequivalence Studies of Generic Products [R07-
0628, R12-3703], blood sampling should be performed at least 7 times, including zero time, 1 
point before Cmax, 2 points around Cmax and 3 points during the elimination phase, and should 
be continued until AUC0-tz becomes over 80% of the Area under the concentration-time curve 
of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) . If 
the half-life of the parent substance or active metabolite of the measured active ingredient is 
very long, collect samples for at least 72 hours. The washout period should be more than 5 
times the t1/2. In this trial, 13 blood samplings up to 48 hours after administration are 
necessary to evaluate the PK profile and they cover the entire points for fulfilling the 
requirement of the Guideline.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 160 healthy male subjects will enter the trial . They will be recruited from 
the volunteers' pool of the trial site. Subjects will be randomised to one of two sequences
which vary in the treatment sequence. Each treatment group consists of 80 subjects.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The trial will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the investigator’s assessment, based on a complete 
medical history including a physical examination, vital signs (blood pressure [BP], pulse 
rate [PR]), 12-lead electrocardiogram (ECG), and clinical laboratory tests 
2. Age ≥20 and ≤40 years old at informed consent
3. BMI ≥18 and ≤25 kg/m2 at screening
4. Signed and dated written informed consent prior to admission to the trial in accordance 
with Good Clinical Practice (GCP) and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic 
blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45
to 90 bpm at screening. Based on the clinical judge by the investigator, repeated 
measurements are allowed.


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3. Any laboratory value outside the reference range before randomisation that the 
investigator considers to be of clinical relevance
4. Any evidence of a concomitant disease considered as clinically relevant by the 
investigator
5. Any relevant bleeding history considered by the investigator
6. Any history or evidence of blood dyscrasia, haemorrhagic diathesis, severe 
thrombocytopenia, cerebrovascular haemorrhage, bleeding tendencies associated with 
active ulceration or overt bleeding of gastrointestinal, respiratory or genitourinary tract or 
any disease or condition with haemorrhagic tendencies
7. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
8. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
9. Planned surgeries within four weeks following the end-of trial examination
10. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
11. History of relevant orthostatic hypotension, fainting spells, or blackouts
12. Chronic or relevant acute infections
13. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
14. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl.Qc/QTc interval prolongation)
15. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
16. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
17. Inability to refrain from smoking in-house confinement at the trial site
18. Alcohol abuse (consumption of more than 30 g per day: e.g., 750 mL of beer, 1.5 gous
[equivalent to 270 mL] of Sake)
19. Drug abuse or positive drug screening
20. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
21. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
22. Inability to comply with dietary regimen of trial site
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with trial requirements, or has a condition 
that would not allow safe participation in the trial
For study restrictions, refer to Section 4.2.2.


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3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events, or diseases)
4. An adverse event or clinically significant laboratory change or abnormality occurred that 
is considered by the investigator to warrant discontinuation of treatment. 
5. Clinical evidence of prolongation of coagulation, i.e., prolonged bleeding at the
venipuncture site (defined as >15-minute compression necessary)
6. Sustained minor bleedings which cannot be controlled by local haemostasis, or any other 
bleeding event considered clinically relevant by the investigator.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at trial assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
Residual effect period (REP) (see Section 5.2.2.2), the discontinued subject should if possible 
be questioned for AEs and concomitant therapies at or after the end of the REP in order to 
ascertain collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported that is
considered to be unacceptable.


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2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the clinical trial protocol (CTP) by a trial site or investigator, 
disturbing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
The trial site will be reimbursed for reasonable expenses incurred in case of trial termination 
(except in case of the third reason).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique trial subject number, and will be 
assigned to the same treatment as the subject he replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Among the investigational product, commercial capsule formulation of DE has been 
manufactured by BI Pharma GmbH & Co. KG and the colour (light blue opaque cap and 
cream-coloured opaque body) of the capsule is different from the colour (light blue opaque 
cap and light blue opaque body) of the capsule marketed in Japan.
The film coated tablets 110 mg have been developed for BE study. The excipients used for 
the tablets are fumaric acid, D-mannitol, hydroxypropylcellulose, hypromellose (2208), 
magnesium stearate, crospovidone (type A), partially hydrolyzed polyvinyl alcohol, sucrose 
esters of fatty acids, titanium oxide, and polysorbate 80. The tablet formulations have been 
manufactured by Qualitech Pharma.
The molecular weight of DE (free base) is 627.7 g/mol. DE is administered as 
methanesulfonic acid salt. Dose refers to a dose of the free base. The conversion factor is 
0.867; 627.7 mg of DE free base equals 723.8 mg of DE methanesulfonic acid salt. A dose of 
DE was calculated as a free base.
4.1.1
Identity of BI investigational product and comparator products
The characteristics of the test product are given below:
Substance:
Dabigatran Etexilate (BIBR 1048)
Pharmaceutical formulation: Tablet, film coated
Source:
Nippon Boehringer Ingelheim Co., Ltd
Unit strength:
110 mg
Posology:
1-0-0
Route of administration:
p.o.
The characteristics of the reference product are given below:
Substance:
Dabigatran Etexilate (BIBR 1048)
Pharmaceutical formulation: Capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
110 mg
Posology:
1-0-0
Route of administration:
p.o.


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4.1.2
Method of assigning subjects to treatment groups
The randomisation list of trial subject numbers and assigned treatment sequences will be 
provided to the trial site in advance.
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. After providing the consent to this trial, the subjects willing to participate 
can choose convenient visit dates on a first come, first-served basis: as soon as approximately 
20 subjects have been allocated to 1 of 8 treatment groups in 8 different periods, the 
following subjects will be allocated to one of the other treatment groups in 8 different 
periods. Therefore, the allocation of subjects to treatment groups is not influenced by trial 
personnel, but only by the subjects’ temporal availability. As the trial includes healthy 
subjects from a homogenous population, relevant imbalances between the treatment 
sequences are not expected. 
At the beginning of the treatment phase (in the morning of Day 1 of Visit 2), subjects will be 
allocated to a subject number according to the randomisation list. Within the treatment 
sequence, subjects will be allocated in their order of providing the consent to the trial (that is, 
the first subject consented will be the first treated).No subject number for a screening failure 
subject will not be allocated. However, if the screening failure subject experiences a serious 
adverse event (SAE), specified subject number will be allocated to collect the safety 
information of the subject. 
Considering the screening failure, some substitute subjects will be available. 
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
As the standard clinical dose, 75 mg and 110 mg are available. Between 2 dosages, 110 mg is 
used for this study. Because in principle, BE study is conducted using higher dosage 
according to Guideline for Bioequivalence Studies for Different Oral Solid Dosage Forms
[R07-0628].
4.1.4
Drug assignment and administration of doses for each subject
This trial is replicable design in a two-treatment, four-period, two-sequence crossover study
with a. All subjects will receive 2 difference treatments in four periods in randomised order. 
The treatments to be evaluated are outlined in Table 4.1.4: 1 below.
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total  dose
T (Test)
Dabigatran etexilate
Tablet
110 mg
1 tablet on day 1
110 mg
R (Reference)
Dabigatran etexilate
Capsule
110 mg
1 capsule on day 1
110 mg
The medication will be administered as a single oral dose together with about 200 mL of 
water to a subject in the sitting/standing position under supervision of the investigating 


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physician or an authorised designee. The so-called four-eye principle (two-person rule) 
should be applied for administration of trial medication. Administration will be performed 
following an overnight fast starting no later than 10 h before scheduled dosing. 
Subjects will be kept under close medical surveillance until 48 h following drug 
administration. During the first 2 h after drug administration, they are not allowed to lie down 
(i.e. no declination of the upper body of more than 45 degrees from upright posture). For 
restrictions with regard to diet see Section 4.2.2.2.
Treatment sequence is shown in Table 4.1.4: 2
Table 4.1.4: 2
Treatment period and allocated medication
Treatment 
Sequence 
Period 1
Period 2
Period 3
Period 4
1
T
R
R
T
2
R
T
T
R
R: Reference products, refer to the Table 4.1.4:1
T: Test products, refer to the Table 4.1.4:1
The treatments will be separated by a wash-out period of at least 4 days. 
4.1.5
Blinding and procedures for unblinding
Not applicable because this is an open-label trial.
4.1.6
Packaging, labelling, and re-supply
Tablet formulation will be provided by Nippon Boehringer Ingelheim Co., Ltd. Capsule 
formulation will be provided by Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, 
Germany.
The clinical trial supply of tablet formulations consists of boxes enclosing aluminium 
pouches in which the trial medication is packed in press through package (PTP) sheets. 
The clinical trial supply of capsule formulation consists of bottles holding the trial 
medication. 
All packages mentioned above are labelled with trial identification.
For details of packaging and the description of the label, refer to the ISF.
Examples of the labels will be available in the ISF.
No re-supply is planned.
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 (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 


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correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the institutional review board (IRB) / ethics 
committee 

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated CTP
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused trial medication must be returned to the sponsor. Receipt, 
usage and disposal must be documented on the respective forms. Account must be given for 
any discrepancies. 
The investigator / pharmacist must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the return to the sponsor.
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator / pharmacist will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP, and that reconcile all investigational products 
received from the sponsor. At the time of the return to the sponsor, the investigator / 
pharmacist must verify that all unused or partially used drug supplies have been returned by 
the clinical trial subject and that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
A specific reversal agent (idarucizumab) has been approved in Japan. When clinically 
indicated and available, it can be given to a patient from commercial supply. If the specific 
reversal agent for dabigatran is given, information surrounding the clinical circumstances, 
treatment and clinical outcome will be collected on the CRF.
In case of adverse events in need of treatment, the investigator can authorise symptomatic 
therapy. In those cases, subjects will be treated as necessary and, if required, kept under 
supervision at the trial site or transferred to a hospital until all medical evaluation results have 
returned to an acceptable level.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on trial days) on the appropriate pages of the CRF.
For detailed concomitant use of DE with other treatments, see the latest IB
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 10 h before and 4 h after drug 
intake.
From 1 hour before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 200 mL of water at 2 hours and 4 hours post-dose 
(mandatory for all subjects). From lunch until 24 hours post-dose, total fluid intake is 
restricted to 3000 mL.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products including St. John's wort (Hypericum perforatum) are not permitted starting 7 
days before the first administration of trial medication until after the last PK sample of each 
trial period is collected.
Alcoholic beverages are not allowed 7 days prior to the admission to the trial site until 
discharge.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 24 h before until 24 h after each administration of trial 
medication.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the completion of end of trial 
examination.
In order to minimise the risk of acquiring a potential bleeding, all subjects will be instructed
of the following precautions:

be alert to early signs of bleeding such as occurring of teeth brushes, pain in the 
abdomen, lower back or side of the body. If any of these symptoms occur, the subject 
has to get in touch with the trial physician immediately.

take care to avoid cuts or other injuries. Be careful especially when using knives, 
razors, nail clippers, and other sharp objects. Check with a physician for the best way 
to clean the teeth and mouth without injuring the gums.


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4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety of the investigational drugs will be assessed based on: 

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3). 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
An SAE is defined as any AE which:

results in death, 

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 
or 

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious events, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse event.
The following events will be handled as ‘deemed serious for any other reason’. An AE which 
possibly leads to disability will be reported as an SAE.
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as given 
above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system, a remote data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.


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Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
No AESIs have been defined for this trial.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
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 


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of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards through the residual effect period (REP), 
until an individual subject’s end of trial: 
o
All AEs (serious and non-serious). 
o
The only exception to this rule are AEs (non-serious) in Phase I trials in 
healthy volunteers, when subjects discontinue from the trial due to screening 
failures prior to administration of any trial medication. In these cases, the 
subjects’ data must be collected at trial site but will not be entered in the CRF 
or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report relevant SAEs and relevant of which 
 may become aware 
of.


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The REP for DE, when measurable drug levels or pharmacodynamic effects are still likely to 
be present, is defined as 3 days after each administration of DE. Therefore, all AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment and as off treatment 4 days and greater after each administration of DE; please see 
Section 7.3.4. Events which occurred after the REP will be considered as post treatment 
events.
The follow-up period describes the period of time from the last administration of trial 
medication including the REP until the end of trial examination (last per protocol contact).
AE reporting to sponsor and timelines
The Investigator must report SAEs and non-serious AEs which are relevant for the reported 
SAE, on the BI SAE form via fax immediately (within 24 hours of awareness) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 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. The same timeline applies 
if follow-up information becomes available.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (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 on the 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.
All AEs
SAEs
All


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If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h except for Visit 1. The subjects have fasted for at least 6 hours at Visit 1. Overnight 
fasting is not required at the discretion of the investigator or designee for retests. 
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count should be performed if the investigator consider 
that further examination is necessary based on the results of automatic WBC differential
regardless of the abnormality of the count.
Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit 
Haemoglobin 
Red blood cell count (RBC) 
White blood cell count (WBC)
Platelet count  
Automatic WBC differential 
(relative)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC(if the 
investigator considers follow up is 
necessary)
Polymorphnuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Total protein
Electrolytes
Sodium
Potassium


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
Test name 
Urinalysis1 (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment1 (microscopic
examination if erythrocytes, leukocytes 
nitrite or protein are abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1
Urinalysis/urine sediment only at screening and end of trial (EOT).
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for Alcohol test and drug screening, it is planned to perform these tests during 
screening only. Drug screening will be performed at screening.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/ methylenedioxyamphetamine (MDA)
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/ methylenedioxymethamphetamine 
(MDMA)/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Syphilis test (rapid plasma reagin [RPR]
Treponema pallidum [TP] antibody method)
Alcohol test
Breath alcohol test
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
at screening and within 24 hours prior to each treatment period, and may be repeated at any 
time during the trial at the discretion of an investigator or designee. The results will not be 
included in the CTR.


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The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at the local 
laboratory of the trial site.
Laboratory data will be transmitted electronically from the laboratory to the database of BI.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph at the time points given in the Flow Chart. 
All ECGs will be recorded for a 10-sec duration after the subjects have rested for at least 5 
min in a supine position. ECG assessment will always precede all other trial procedures of the 
same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the ECG quality. 
Electrode placement will be performed according to the method of Wilson, Goldberger and 
Einthoven. 
All locally printed ECGs will be evaluated by the investigator or a designee. ECGs may be 
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the repeated ECG will be used for analysis. Additional (unscheduled) ECGs 
may be collected by the investigator for safety reasons. 
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm if possible. Repeated measurements can be performed based on 
the investigator’s consideration.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination with 
determination of body weight.


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5.2.5.3
Local tolerability
Not applicable.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Pharmacogenetic measurements are not planned.
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The pharmacokinetic parameters and measurements outlined in 
Section 5.5 are generally used assessments of drug exposure. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs. 
Exact time points of plasma sampling will be documented in the CRFs by the medical 
personnel. The actual sampling times will be used for determination of pharmacokinetic 
parameters.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be determined for free dabigatran:
AUC0-tz (area under the concentration-time curve of free dabigatran in plasma over the 
time interval from 0 to the time of the last quantifiable data point)
Cmax (maximum plasma concentration of free dabigatran)
5.5.1.2
Secondary endpoints
Additionally the following secondary endpoints will be evaluated:

AUC0-tz (area under the concentration-time curve of total dabigatran in plasma over 
the time interval from 0 to the time of the last quantifiable data point)

Cmax (maximum plasma concentration of total dabigatran)

AUC0-∞(area under the concentration-time curve of total dabigatran in plasma over 
the time interval from 0 extrapolated to infinity)


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
AUC0-∞(area under the concentration-time curve of free dabigatran in plasma over 
the time interval from 0 extrapolated to infinity)
 
 
 
 
 
5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of dabigatran plasma concentrations, 3 mL of blood will be taken from an 
antecubital or forearm vein into an K3-EDTA (tripotassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will be 
withdrawn by means of either an indwelling venous catheter or by venipuncture with a metal 
needle.
The EDTA-anticoagulated blood samples will be immediately placed in an ice/water bath (0-
4°C) until centrifuged at 4 to 8°C and about 2500 g for 10 minutes for plasma preparation. 
Centrifugation is to be started within 30 minutes after blood sampling. Following the 
centrifugation, plasma will be transferred to two pre-labelled polypropylene storage tubes (at 
least 0.5 mL in the first tube, the remainder in the second tube – back-up). Storage tubes will 
be frozen in an upright position at about -70°C or below as soon as possible, within max. 90 
minutes after blood withdrawal. During handling blood/plasma samples will be continuously 
kept refrigerated (ice/water bath or cooled centrifuge). Until shipment on dry ice to the 
analytical laboratory, the plasma samples will be stored at about -70°C or below at the 
clinical site and at the analytical laboratory until analysis. The back-up samples will be 
shipped to the analytical lab shortly after the shipment of the first aliquot samples.
Generally, PK samples will be uniquely labelled with trial number, subject number, visit 
number (according to Flow Chart), planned time (according to Flow Chart) and “PK-1” (first 
aliquot) or “PK-2” (second aliquot).
Further details to the information on sampling are provided in the ISF and/or lab manual.


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5.5.2.2
Urine sampling for pharmacokinetic analysis
Not applicable.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
Concentrations of free, nonconjugated dabigatran and of total dabigatran after alkaline
cleavage of glucuronic acid conjugates will be determined by a validated high performance 
liquid chromatography, tandem mass spectrometry (HPLC-MS/MS) assay with a lower limit 
of quantification of 1.0 ng/mL at the contract research organisation
During sample analysis, the bioanalyst will be blinded to subject allocation and will have no 
access to the random code.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Trial measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration. 
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ±30 minutes before 24 hours from DE administration. For procedures ≥24 hour, 
tolerance will be ±60 minutes.
If several measurements including venipuncture are scheduled for the same time, 
venipuncture should be the last of the measurements due to its inconvenience to the subject 
and possible influence on physiological parameters. Furthermore, the intake of meals and 
water will be the last action.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
6.2.2
Treatment periods
If upon completion of screening, a subject has been determined eligible to enter the trial by 
the investigator, the subject will be randomised to one of 2 treatment sequences in the 
morning of Day 1 of Visit 2 prior to the drug administration. 
Each subject will be given one dose of assigned trial medication in the morning of Day 1 of 
each period orally by the investigating physician or his/her designee.
If a subject displays any significant changes in blood pressure and/or pulse rate that may 
indicate a bleeding disorder after receiving dabigatran, the subject will receive appropriate
treatment and will not receive trial medication in the following treatment periods. Adequate 


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diagnostic measures will be taken as soon as possible to investigate whether the subject has 
the bleeding disorder that might be causally related to previous dabigatran treatment.
Each subject is expected to participate in four treatment periods (Days -1, 1, 2, and 3 in each 
period). The treatment periods will be separated by at least 4 days between drug 
administrations.
On Day -1 of each treatment period trial participants will be admitted to the trial site and kept 
under close medical surveillance for at least 48 h following drug administration. The subjects 
will then be allowed to leave the trial site after formal assessment and confirmation of their 
fitness.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.5.2. 
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from
screening until the EOT examination.
6.2.3
End of trial and follow-up period
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
visit the trial site undergo the examination to check the subject’s safety where applicable, and 
then undergo the EOT examination 5 to 14 days after the day of last treatment.
All abnormal values (including laboratory parameters) that are considered clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to establish the bioequivalence of tablet formulation of 
110 mg DE compared to commercial capsule formulation following oral administration under 
fasted condition. The trial is designed to allow intra-subject comparisons and will be 
evaluated statistically by use of an appropriate linear model.
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between the treatments. The secondary objective(s) will be assessed by 
descriptive statistics.
The assessment of safety and tolerability will be an additional objective of this trial, and will 
be evaluated by descriptive statistics.
7.1.2
Endpoints
Bioequivalence is to be determined on the basis of the primary endpoints (see Section 5.5.1).
Safety and tolerability will be determined on the basis of the parameters specified in Section 
5.2.1.
7.1.3
Model
The statistical model used for the analysis of primary and secondary endpoints will be an 
ANOVA (analysis of variance) model on the logarithmic scale. This model will include 
effects accounting for the following sources of variation: ‘sequence’, ‘subjects within 
sequences’, ‘period’ and ‘treatment’. The effect ‘subjects within sequences’ will be 
considered as random, whereas the other effects will be considered as fixed. The model is 
described by the following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response (endpoint, see Section 5.5.1) measured on subject m in 
sequence i receiving treatment k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., 80
j = the jth period effect, j = 1, 2, 3,4


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k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
It is assumed that random errors were normally distributed and different formulation can have 
different variability, that is e~
(0, 
). 
7.2
NULL AND ALTERNATIVE HYPOTHESES
The assessment of bioequivalence will be based upon two-sided 90% confidence intervals 
(CIs) for the ratio of the geometric means (test/reference) for the primary and secondary 
endpoints using an acceptance range of 80.0-125.0%. This method is equivalent to the two 
one-sided t-tests procedure, each at the 5% significance level (on the log scale).
In general, the hypothesis of inequivalence is tested:
Null hypothesis H0 (Inequivalence):
δ
μ
μ
δ
μ
μ
R
T
R
T





or
where 
T

and 
R

are the means of the log-transformed endpoint for the test and 
reference treatments, respectively, and δ is the bioequivalence limit that defines the 
acceptance range on the logarithmic scale.
Thus the null hypothesis is that the difference of the population average responses is either 
less than or equal to the lower bound or greater than or equal to the upper bound of the 
acceptance range.
Alternative hypothesis Ha (Equivalence):
δ
μ
μ
δ
R
T




i.e. the difference of the population average responses is both greater than the lower 
bound and less than the upper bound of the acceptance range.
In this trial, the bioequivalence limit δ is ln(1.25). By back-transforming (exponentiating), 
this translates to an acceptance range of 80.00 to 125.00% for the ratio of the geometric 
means (test/reference) for endpoints on the original (linear) scale.
The above null hypothesis H0 of inequivalence and its alternative Ha can be decomposed into 
two one-sided null hypotheses, H01 and H02, with their accompanying alternatives:
H01:
δ
μ
μ
R
T



vs.
Ha1:
δ
μ
μ
R
T



H02:
δ
μ
μ
R
T


vs.
Ha2:
δ
μ
μ
R
T


Due to the nature of normal-theory confidence intervals, the test of the null hypothesis H0 at 
the level of significance of = 0.05 is equivalent to carrying out two one-sided tests of the 
above null hypotheses H01 and H02 each at the level of significance of = 0.05. The rejection 


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of both null hypotheses at the = 0.05 level is equivalent to the inclusion of the 90% 
confidence interval for 
R
T
μ
μ 
in the acceptance range (-δ, δ).
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The pharmacokinetic endpoints listed in Section 5.5.1 will be calculated according to the BI 
SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Pharmacokinetic parameters of a subject will be included in the analysis unless the subject 
has an important protocol violation relevant for the evaluation. Whether a protocol violation 
is important will be decided no later than in the Report Planning Meeting.
Reasons for exclusion of single pharmacokinetic parameters may be:

The subject experiences emesis at or before two times median tmax. Median tmax is to 
be taken either from the median tmax for the reference product or from median tmax for 
the test product, depending on whether the subject had experienced emesis after taken 
the test or the reference product. Median tmax is to be determined excluding the 
subjects experiencing emesis.

Time deviations

Use of restricted medications 

A pre-dose concentration is >5% of the Cmax value of that subject
The subject set for the evaluation of PK endpoints (PK parameter analysis set [PKS]) will 
include all treated subjects that provide at least one observation for at least one primary 
endpoint without important protocol violations with respect to the statistical evaluation of PK 
endpoints. It will also be decided in the Report Planning Meeting which subjects are to be 
included in the PKS.
Point estimates of bioavailability, the ratios of the geometric means (test/reference) for the 
primary and secondary endpoints (see 5.5.1.1, 5.5.1.2), and their two-sided 90% confidence 
intervals (CIs) will be provided.
To this end, the PK endpoints will be log transformed (natural logarithm) prior to fitting the 
ANOVA model (cf. Section 7.1.3). For each endpoint, the difference between the expected 
means for log(T)-log(R) will be estimated by the difference in the corresponding adjusted 
means (LeastSquares Means), and a two-sided 90% confidence interval based on the 
t-distribution will be computed. These quantities will then be back-transformed to the original 
scale to provide the point estimate and 90% CIs for each endpoint.
Bioequivalence is considered established if the 90% confidence intervals of both ratios of the 
geometric means for the primary endpoints (see Section 5.5.1.1) are contained in the pre-
defined acceptance range (see Section 7.2). Therefore, no adjustment of the level of 
significance is necessary.


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7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will statistically be assessed using the same 
methods as described for the primary endpoints. AUC0-∞will be calculated using the AUC0-∞
based on observed and predicted last concentrations, and for statistical analysis, AUC0-∞
based on both observed and predicted last concentrations will be used.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.3.4
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is,
all subjects who received at least one dose of trial drug), will be included in the safety
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
The analyses will be done by ‘treatment at onset’.


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Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used for the evaluation of categorical (qualitative) data, and tabulations of descriptive 
statistics will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until end of the residual 
effect period (see 5.2.2.2) will be assigned to the treatment period. Events after the residual 
effect period but prior to next intake or end of trial examination will be summarized as ‘post-
treatment’, those after the end of trial examination will be assigned to ‘post-trial’. These 
assignments including the corresponding time intervals will be defined in detail in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. 
Frequency, severity and causal relationship of AEs will be tabulated by treatment, system 
organ class and preferred term. SAEs and other significant AEs (according to ICH E3) will be 
listed separately.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
Relevant ECG findings will be reported as AEs.
7.3.5
Interim analyses
No interim analysis is planned.
7.3.6
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for DE will be calculated according to 
the relevant SOP of the Sponsor (001-MCS-36-472). Pharmacokinetic analyses will be 
performed using validated software programs, normally. Phoenix Winnonlin (Pharsight®) 
with applications validated for the respective purpose. Graphs and tables will be generated 
using validated customised SAS® macros or appropriate graphic software. A reference to the 
software used, e.g., name, will be indicated in the clinical trial report.
Subjects who are not included in the PKS (refer to Section 7.3.1.) will be reported with their 
individual plasma concentrations and individual pharmacokinetic parameters; however, they 
will not be included in descriptive statistics for plasma concentrations, pharmacokinetic 
parameters or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 


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pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ (below limit of quantification), 
but less than or equal to 5% of the subject’s Cmax value, the subject’s data without any 
adjustments will be included in all pharmacokinetic measurements and calculations.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure of the Sponsor (001-MCS-36-472).
Drug concentration data identified with no sample available (NOS), no valid result (NOR), 
not analysed (NOA), BLQ, or no peak detectable (NOP) will be displayed as such and not 
replaced by zero at any time point (this rule also applies also to the lag phase, including the 
predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP 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. 
7.5
RANDOMISATION
Subjects will be randomised to one of the two treatment sequences in a 1:1 ratio. 
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable. 
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to 3.3.5).


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7.6
DETERMINATION OF SAMPLE SIZE
The sample size for the trial was determined assuming a geometric mean of 110% 
(tablet/capsule) and an intra-subject coefficient of variation (gCV) of 70% for AUC or Cmax
based on the following possible scenarios. The gCV for capsule formulation were observed as 
49.67% for Cmax and 49.83% for AUC in trial 1160.117*. The gCV for tablet formulation 
were observed as 62.9% for Cmax and 69.3% for AUC in trial 1160.246. The Geometric mean 
ratio of AUC and Cmax was observed as 1.08 (tablet/capsule) in trial 1160.246.
Since both endpoints of tablet and capsule formulations are highly variable, possible outcome 
scenarios are conservatively assumed to detect possible bioequivalence. It is assumed that 
gCV for both formulations can be variable from 50% to 70% as observed in gCV for test 
formulation in further analysis of the pilot BA study of 1160.246 and geometric mean ratio 
can be increased from 1.08 to 1.10. 
Based on the scenarios and the sample size of 160, the power to reject the null hypothesis of 
bio-inequivalence for one parameter (for AUC or Cmax) in favour of equivalence at the 5% 
level of significance is displayed in Table 7.6: 1 under various assumptions for the intra-
subject ratio.
Table 7.6: 1
Power for concluding bioequivalence in a replicate design crossover 
trial (N=160) based on a geometric mean of 110% and a geometric 
coefficient of variation of 70% and an acceptance range of 80-125% 
for different expected ratios of means (tablet/capsule) and gCVs
Given Sample Size 160
Possible gCV
0.5
0.6
0.7
Possible
Geometric mean 
ratio
1.08
98.8%
94.3%
89.2%
1.09
98.4%
93.9%
86.9%
1.1
94.7%
90.8%
81.7%
1)
Ratio of the geometric means (tablet/capsule) for a PK endpoint defined by exp(µT)/exp(µR) (cf. Section 7.2)
From Table 7.6:1, a sample size of 152 will have at least 80% power to conclude 
bioequivalence if the ratio is between 108% and 110%, that is not more than 10% different 
from the ratio of 100% that reflects perfect equivalence and the gCV is between 50% and 
70%. 160 subjects should be recruited in the trial.
If bioequivalence cannot be demonstrated because of an insufficient sample size, an 
extension of the trial can be performed by adding not less than half the number of subjects in 
the initial trial.
The calculation was performed as described by Diletti et al [R94-1445] using SAS 9.4..
*Trial 1160.117 is an open-label, randomised, single dose, replicate design in a two 
treatments, four periods crossover phase I study to compare two different capsule 
formulations of dabigatran etexilate and its sample size was 180 subjects. The true gCVs of 
its reference capsule formulation are assumed to be identical to those of the capsule 
formulation used in this study.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs and the Japanese GCP regulations 
(Ministry of Health and Welfare Ordinance No. 28, March 27, 1997).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remain the 
responsibility of the subject’s treating physician.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective 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 a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’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 subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the trial master file.


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8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’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.


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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. Dabigatran versus warfarin in patients with atrial fibrillation. New 
Engl J Med. 2009. 361(12): 1139-1151.
R94-1445
Diletti E, Hauschke D, Steinijans VW. Sample size determination for 
bioequivalence assessment by means of confidence intervals. Int J Clin 
Pharmacol Ther Toxicol 1992; 30 (suppl 1): S51-S58.
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
R03-1231
Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al. 
ACC/AHA/ESC guidelines for the management of patients with atrial 
fibrillation: executive summary: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines 
and the European Society of Cardiology Committee for Practice Guidelines 
and Policy Conferences (Committee to Develop Guidelines for the 
Management of Patients with Atrial Fibrillation). Circulation 
2001;104:2118-2150.
R07-0628
National Institute of Health Sciences (NIHS). Guideline for bioequivalence 
studies of generic products (amendment 2, November 2006). 13F; Original 
in Japanese. 2006
R12-3703
Guideline for bioequivalence studies of generic products (English 
translation of attachment 1 of division-notification 0229 no. 10 of the 
Pharmaceutical and Food Safety Bureau, dated February 29, 2012). 
Website:nihs.go.jp/drug/be-guide(e)/Generic/GL-E_120229_BE.pdf (access 
date: 20 August 2012); 2012.
R15-5604
Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013).Original in 
Japanese. Website：j-circ.or.jp/guideline/pdf/JCS2013_inoue_h.pdf (access 
date: 3 November 2015); Japanese Circulation Society (JCS) (2013)
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c01632884-04
Dabigatran etexilate(BIBR 1048MS) Investigator’s Brochure Current 
version.
c03032935-01
Randomised Evaluation of Long term anticoagulant therapy (RE-LY®) 
comparing the efficacy and safety of two blinded doses of DE 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). BI Trial No. 
1160.26. 20 March 2015.


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c09145064-01
Relative bioavailability of dabigatran after single oral administration of five 
different tablet formulations of dabigatran etexilate compared to 
commercial capsule formulation in healthy male subjects (an open-label, 
randomised, single-dose, six-period, five-sequence crossover study). BI 
Trial No. 1160.246. 6 December 2016.
U00-1856
Safety, pharmacodynamics and pharmacokinetics after multiple oral doses 
of 50, 100,200 and 400 mg BIBR 1048 MS solution administered t.i.d. for 7 
days to healthy volunteer subjects. An open study, placebo-controlled, 
randomised, double blind at each dose level. BI Trial No. 1160.2. 22
U01-1602
 Investigation of the human cytochrome P450
enzymes involved in the metabolism of [14C]BIBR 1048 MS and 
[14C]BIBR 953 ZW. Study no. B1765. 16 August 2001.
U05-3052
 Safety, pharmacokinetics and 
pharmacodynamics after single rising oral doses of 50, 150 and 350 mg 
BIBR 1048 MS as capsules in healthy subjects of Japanese and Caucasian 
origin. Double-blind at each dose level, placebo-controlled, randomised 
study 1160.28 19 May 2005.
U05-3334
 Safety, pharmacokinetics and 
pharmacodynamics after multiple oral doses of BIBR 1048 MS capsule 
(150 mg b.i.d., 7 days) in healthy Japanese male subjects (Open label 
study). 1160.55. 21 October 2000.
U06-3091
 Safety, pharmacokinetics and 
pharmacodynamics after single (150 mg, 220 mg and 300 mg) and multiple 
(150 mg and 220 mg q.d. and 150 mg b.i.d.) rising oral doses of BIBR 1048 
MS/capsules in healthy male subjects of Japanese and Caucasian origin 
(Open label study). 1160.29. 23 February 2006.
U06-3420
Pharmacokinectics, safety 
and pharmacodynamics after multiple oral doses of dabigatran etexilate 
capsule (110 mg and 150 mg b.i.d., 7 day) in healthy Japanese and 
Caucasian male subjects (open label study). 1160.61. 05 December 2006.
U09-3249-02
Randomised Evaluation of Long term anticoagulant therapy (RE-LY®) 
comparing the efficacy and safety of two blinded doses of DE 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). BI Trial No. 
1160.26.16 October 2009. Revision No. 1 dated05 January 2011.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11669965
1.0
clinical-trial-protocol-version-01
Bioequivalence of tablet formulation of dabigatran etexilate compared to commercial
capsule formulation following oral administration in healthy male subjects (an
open-label, randomised, single-dose, replicate design in a two-treatment, four-period,
two-sequence crossover study)
Author-Trial Clinical Monitor
14 Feb 2017 06:19 CET
Author-Trial Clinical
Pharmacokineticist
14 Feb 2017 07:39 CET
Approval-Team Member Medical
Affairs
14 Feb 2017 08:41 CET
Approval-Therapeutic Area 
15 Feb 2017 17:45 CET
Author-Trial Statistician
16 Feb 2017 04:26 CET
Verification-Paper Signature
Completion
17 Feb 2017 00:44 CET


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11669965
1.0

SAP_000.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c17636581-01
BI Trial No.:
1160.271
Title:
Bioequivalence of tablet formulation of dabigatran etexilate
compared to commercial capsule formulation following oral 
administration in healthy male subjects (an open-label, randomised, 
single-dose, replicate design in a two-treatment, four-period, two-
sequence crossover study)
Investigational
Product(s):
Pradaxa® (Prazaxa® in Japan), Dabigatran etexilate, BIBR 1048 
MS
Responsible trial 
statistician(s):
Address: 
 
Phone:
Date of statistical 
analysis plan:
12/JUL/2017 SIGNED
Version:
Final
Page 1 of 18
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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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................5
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................6
5.
ENDPOINTS(S) ....................................................................................................7
5.1
PRIMARY ENDPOINT(S) ..................................................................................7
5.2
SECONDARY ENDPOINT(S) ............................................................................7
.................................................................................7
5.4
OTHER VARIABLE(S) .......................................................................................7
6.
GENERAL ANALYSIS DEFINITIONS ............................................................9
6.1
TREATMENT(S)..................................................................................................9
6.1.1
TREATMENT REGIMENS / STUDY INTERVALS.......................................9
6.2
IMPORTANT PROTOCOL VIOLATIONS .....................................................9
6.3
SUBJECT SETS ANALYSED...........................................................................11
.....................................................................................................11
6.5
POOLING OF CENTRES .................................................................................11
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................12
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................12
7.
PLANNED ANALYSIS......................................................................................13
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........13
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................13
7.3
TREATMENT COMPLIANCE........................................................................13
7.4
PRIMARY ENDPOINT(S) ................................................................................13
7.5
SECONDARY ENDPOINT(S) ..........................................................................13
...............................................................................14
7.7
EXTENT OF EXPOSURE.................................................................................14
7.8
SAFETY ANALYSIS..........................................................................................14
7.8.1
Adverse events.....................................................................................................14
7.8.2
Laboratory data ..................................................................................................15
7.8.3
Vital signs.............................................................................................................15
7.8.4
ECG......................................................................................................................15
7.8.5
Others...................................................................................................................15
8.
REFERENCES....................................................................................................16
...............................................................................17
10.
HISTORY TABLE..............................................................................................18


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LIST OF TABLES
Table 6.1.1: 1 Treatment regimens/Intervals.............................................................................9
Table 6.2: 1
Important protocol violations...........................................................................10
Table 6.3: 1
Subject sets analysed........................................................................................11
Table 10: 1
History table .....................................................................................................18


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
CTP
Clinical Trial Protocol
ICH
International Conference On Harmonisation
MedDRA
Medical Dictionary For Regulatory Activities
PK
Pharmacokinetics
PV
Protocol Violation
RPM
Report Planning Meeting
SD
Standard Deviation
TSAP
Trial Statistical Analysis Plan


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There are no changes in the planned analysis of the study.


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
No efficacy endpoints will be evaluated in this trial. Primary endpoints are defined in CTP 
(see Section 5.5.1.1).
5.2
SECONDARY ENDPOINT(S)
Secondary endpoints are defined in CTP (see Section 5.5.1.2).
5.4
OTHER VARIABLE(S)
Safety of the investigational drugs will be assessed based on:  
•
Adverse events (including clinically relevant findings from the physical examination)
•
Safety laboratory tests
•
12-lead ECG
•
Vital signs (blood pressure, pulse rate)
Demographic data:
•
Gender (male)
•
Ethnicity (Not Hispanic/Latino)


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•
Race (Asian)
•
Age [years]=integer[(date of informed consent – date of birth)/365.25]
•
Height [cm]
•
Weight [kg]
•
Body mass index (BMI) [kg/m2] = weight [kg] at screening / (height [m] at screening)2
•
Smoking status (Never smoked, Ex-smoker, Currently smokes)
•
Alcohol status (Does not drink any alcohol; Drinks alcohol, but to an extent that would 
not interfere with participation in trial; Drinks alcohol to an extent that could interfere 
with participation in trial)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
6.1.1
TREATMENT REGIMENS / STUDY INTERVALS
There will be 10 phases in this trial: 
screening, the first reference treatment (Ref 1), the second reference treatment (Ref 2) , the 
first tablet treatment (Test 1) , the second tablet treatment (Test 2), Washout 1 - 3, Post-
treatment and post-study.
The treatment regimens/intervals in which a subject can lie during the course of the trial are 
defined as Table 6.1.1: 1. 
Table 6.1.1: 1 Treatment regimens/Intervals.
Label
Sort 
order
Start date (CRF)
Start time (CRF/derived)
Screening
00
Date of informed consent
0:00
Ref 1
01
Date of the first Ref
administration
Time of the first Ref
administration
Ref 2
02
Date of the second Ref
administration
Time of the second Ref
administration
Test 1
03
Date of the first Test 
administration
Time of the first Test 
administration
Test 2
04
Date of the second Test 
administration
Time of the second Test 
administration
Washout 1
05
Date of last administration of 
Period 1
Time of last administration in 
Period 1 + 1 minute
Washout 2
06
Date of last administration of 
Period 2
Time of last administration in 
Period 2 + 1 minute
Washout 3
07
Date of last administration of 
Period 3
Time of last administration in 
Period 3 + 1 minute
Post-
treatment
09
Date of last administration 
Time of last administration + 1 
minute
Post-study
99
Date of EOT + 1
0:00
KEY: Ref (Reference treatment): DE commercial capsule formulation; Test (Tablet Formulation): investigational 
formulation
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects in the 
database (i.e., treated subjects and subjects with serious AE (SAE) which the investigator 
considered related to the screening procedure). Consistency check listings (for identification 
of violations of time windows) and a list of
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will
be provided to be discussed at the report planning meeting (RPM). At this meeting, it will be 
decided whether a discrepant data value can


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be used in analyses or whether it must be corrected in the clinical database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation (PV). For definition of important PVs, and for the process of identification of these,
refer to the Boehringer Ingelheim reference document 'Protocol Violation Handling 
Definitions' (7).
If any important PVs are identified, they are to be summarised into categories and will be 
captured in the RPM minutes via accompanying Excel spreadsheet (8) [001-MCS-50-
413_RD-02]. The following table contains the categories which are considered to be 
important PVs in this trial. If the data show other important PVs, this table will be 
supplemented accordingly by the time of the RPM.
If substantial numbers of PVs are reported at the RPM, a decision about summarising
the PVs in a tabular format will be made. Otherwise, only a PV listing will be provided.
Table 6.2: 1
Important protocol violations 
Category / 
Code
Description
Requirements/Comment
Excluded 
from
A
Entrance criteria not met
A1.1
Inclusion criteria violated
Automatically detectable
None
A2
Exclusion criteria violated
Automatically detectable
PKS
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date is missing or 
informed consent is not given.
Automatically detectable
All
B2
Informed consent too late
Informed consent date  was after screening 
visit
Automatically detectable
None
C
Trial medication and 
randomisation
C1
Non-compliance with trial 
medication
No trial drug administration.
Automatically detectable
TS and 
PKS
C2
Incorrect trial medication taken
e.g. trial medication was swapped,
Manually detectable
None
C3
Improper intake of trial 
medication
Manually detectable
PKS
C4
Improper washout between
treatments
Washout period has to be more than 3 days.
Automatically detectable
PKS
D
Concomitant medication
D1
Administration of any drugs 
and/or intake of any foods which 
might influence the results of PK.
For example;
Administration of any drugs before or 
during the trial
Violation of restricted lifestyle 
Manually detectable.
PKS
E
Missing data
E1
Certain violations of procedures 
used to measure primary or 
secondary data
Violations of procedures which may lead to 
invalid measurements with respect to
primary or secondary PK endpoints.
Manually detectable
PKS
F
Incorrect timing
F1
Certain violations of time schedule 
used to measure primary or 
PK sample taken too early/too late
Manually detectable
PKS


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Category / 
Code
Description
Requirements/Comment
Excluded 
from
secondary data
6.3
SUBJECT SETS ANALYSED

Randomised set (RS):
This subject set includes all randomised subjects, whether treated or not.

Treated set (TS):
This subject set includes all subjects from the RS who were dispensed study 
medication and were documented to have taken at least one dose of investigational 
treatment.

Pharmacokinetic set (PKS):
This subject set includes all subjects from the TS who provide at least one observation 
for at least one primary endpoint that was not excluded according to the description 
above. Thus, a subject will be included in the PKS, even if he contributes only one 
primary endpoint value for one period to the statistical assessment.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to populations will be made at latest at the RPM.
The following table summarizes which subject sets will be used for the different analyses.
Table 6.3: 1
Subject sets analysed
Class of endpoint
RS
TS
PKS
Disposition, exposure
X
Important PVs
X
Primary endpoints 
X
Secondary and further endpoints 
X
Safety endpoints 
X
Demographic/baseline endpoints
X
X
6.5
POOLING OF CENTRES
Pooling centres is not planed in the study, since the study is conducted in one site.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects, who discontinued from the trial due to screening failures prior to 
administration of any trial medication, will not be included in the CTR except for those with 
SAE which the investigator considered related to the screening procedures. The safety data of 
treated subjects who were withdrawn from the trial prematurely will be reported as far as 
available. All withdrawals will be documented and the reason for withdrawal recorded.
Handling of missing data is described in section 7.4 of the CTP. Additionally, handling 
missing data is described as follows:
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (3).
Missing data and outliers of PK data are handled according to (2).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline values of laboratory data and value of vital sign for safety analysis will be 
defined as the last values before drug administration of period 1.
In this trial, calculated visits will not be planned.


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7.
PLANNED ANALYSIS
In general, a set of descriptive statistics to be displayed for continuous variables in the 
clinical trial report will be as follows:
Non-pharmacokinetic variables:
For End-Of-Text tables, the set of summary statistics is: N, mean, standard deviation (SD), 
min, median, and max.
Tabulation of frequencies for categorical or categorised data will include all possible 
categories and display number of observations (subjects) with the percentage relative to the 
respective treatment sequence / regimen. Percentages will be rounded to one decimal place. 
The category missing will be displayed if and only if there are actually missing values. 
Percentages will be based on all subjects in the respective subject set whether they have non-
missing values or not.
Pharmacokinetic variables:
The analysis of standard PK parameters will be performed according to (2).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medication will be coded 
according to the most recent version of the World Health Organisation – Drug Dictionary.
Only listing is planned for this section of the report.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM and described in the CTR.
7.4
PRIMARY ENDPOINT(S)
The analysis will be performed as defined in the CTP, Sections 7.1, 7.2 and 7.3.1. 
7.5
SECONDARY ENDPOINT(S)
The analysis will be performed as defined in the CTP, Sections 7.1, 7.2 and 7.3.2. 


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7.7
EXTENT OF EXPOSURE
Only listing is planned for this section of the report.
7.8
SAFETY ANALYSIS
The analysis will be performed as defined in the CTP. All safety analyses will be performed 
on the treated set.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.The analyses of AEs will be 
descriptive in nature. All analyses of AEs will be based on the number of subjects with AEs 
and not on the number of AEs.
For analysis of AE attributes such as duration, severity, etc. multiple AE occurrence data on 
the CRF, will be collapsed into AE episodes provided that all of the following applies:
•
The same MedDRA lowest level term was reported for the occurrences
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day after the 
end of the first occurrence)
•
Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
For further details on summarization of AE data, please refer (3,4).
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between the first drug intake till 3 days 
after last drug intake will be assigned to the treatments period. During the treatment period, 
all adverse events occurring after a drug intake till 3 days after the drug intake will be 
assigned to ‘on-treatment’ and those occurring after on-treatment period till the next drug 
intake will be assigned to ‘off-treatment’. All adverse events occurring before first drug 
intake will be assigned to ‘screening’ and all adverse events occurring after last drug intake + 
3 days will be assigned to ‘post-treatment’ (for listings only).
According to ICH E3 (5), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 


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therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting.
An overall summary of adverse events will be presented.
The frequency of subjects with adverse events will be summarised by treatment, primary 
system organ class and preferred term (mention MedDRA levels to be displayed in the 
tables). 
The system organ classes will be sorted by default alphabetically. Preferred terms will be 
sorted by frequency (within system organ class).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature by treatment sequence and will 
be based on BI standards (6). 
Clinically relevant findings in laboratory data will be reported as AEs and will be analysed as 
part of AE analysis.
The last value on-treatment is defined as the last non-missing value observed during ‘on-
treatment period’ (See section 7.8.1).
7.8.3
Vital signs
Only descriptive statistics by treatment sequence and planned visit are planned for this 
section of the report.
Clinically relevant findings in vital signs data will be reported as AEs and will be analysed as 
part of AE analysis.
7.8.4
ECG
ECG data will not be listed but clinically relevant abnormal findings will be reported as 
adverse events.
7.8.5
Others
No other parameter will be analysed.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
3.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON.
4.
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", version 5; IDEA for CON.
5.
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports,
current version
6.
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
7.
001-MCS-50-413_RD-01: "Protocol Violation Handling Definitions", current version; 
IDEA for CON.
8.
001-MCS-50-413_RD-02: "Important Manual Protocol Violations Spreadsheet", 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
16-JUN-2017
None
This is the initial TSAP with necessary 
information for trial conduct.
Final
12-JUL-2017
Section 
5, 6 and 
7
Details for analysis are specified.
For iPV Table 6.1.1: 1, “none or PKS”
and “All” was replaced with “PKS” and 
“TS and PKS” for clarification. iPV 
categories have not been changed.