Conditions: Non-alcoholic Fatty Liver Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
The primary objective of this trial is to investigate the relative Bioavailability (BA) of tablet formulation of Dabigatran etexilate (DE) with and without co-administration of rabeprazole in healthy male subjects.

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

Detailed description:

Arms:
arm 1: Dabigatran etexilate given without rabeprazole and then Dabigatran etexilate given without rabeprazole.

Interventions: intervention 1: Dabigatran Etexilate intervention 2: Rabeprazol sodium
Intervention descriptions: intervention 1: Tablet, film coated intervention 2: Tablet

Protocol document:
Prot_001.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c13837712-01
BI Trial No.:
1160.270
BI Investigational
Product:
Pradaxa® (Prazaxa® in Japan), Dabigatran etexilate, BIBR 1048 MS
Title:
Relative bioavailability of tablet formulation of dabigatran etexilate 
with and without co-administration of rabeprazole in healthy male 
subjects (an open-label, single-oral-dose, two-period, single-arm
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: 20 April 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
20 Apr 2017
1160.270
Title of trial:
Relative bioavailability of tablet formulation of dabigatran etexilate with and without 
co-administration of rabeprazole in healthy male subjects (an open-label, single-oral-
dose, two-period, single-arm study)
Principal Investigator: 
Address: 
Phone:
Fax: 
Trial site:
Address
 
Phone
Fax: +
Clinical phase:
I
Objective:
To investigate relative bioavailability of a tablet formulation of dabigatran etexilate 
with and without co-administration of rabeprazole in healthy male subjects
Methodology:
Open-label, single-oral-dose, two-period, single-arm study
No. of subjects: 
total entered:
36
each treatment:
36
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
dose:
110 mg single dose with and without a single dose of rabeprazole 20 mg 
mode of admin.:
Oral with 200 mL of water after an overnight fast of at least 10 hours


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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
20 Apr 2017
1160.270
Comparator product:
Not applicable
dose:
mode of admin.:
Duration of treatment: One day (single dose) for dabigatran etexilate at Visit 2 and Visit 3, and 5 days for 
rabeprazole at Visit 3
Criteria for 
pharmacokinetics:
Primary endpoints: AUC0-tz and Cmax of total dabigatran
Secondary endpoints: AUC0-tz and Cmax of free dabigatran and AUC0-of both free
dabigatran and total dabigatran
 
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:
Relative bioavailability will be estimated by the ratios of the geometric means (test
treatment/reference treatment) for the primary and secondary endpoints. Additionally, 
their two-sided 90% confidence intervals (CIs) will be provided. The statistical model 
will be an ANOVA on the logarithmic scale including effects for ‘subjects’ 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 therapy3
SCR
1
Within 
28 days 
before 
first DE 
administ
ration
Screening (SCR)1
X
X
X
1/2
2/3
-44
-100:00
06:00
Rabeprazole administration (Visit 3 only) 
-3
-76:00
06:00
Rabeprazole administration (Visit 3 only) 
-2
-52:00
06:00
Rabeprazole administration (Visit 3 only) 
-1
-28:00
06:00
Rabeprazole administration (Visit 3 only)
-18:00
16:00
Admission to trial site (Visit 2 only)
X
X
1
-4:00
06:00
Rabeprazole administration (Visit 3 only) 5
-3:00
07:00
Insert the pH sensor6
-1:00
09:00
X 7
X7
X 7
0:00
10:00
Drug administration (DE)
0:30
10:30
X
1:00
11:00
Pharmacogenomics sampling8
X
1:30
11:30
X
2:00
12:00
200 mL fluid intake9
X
X
3:00
13:00
X
4:00
14:00
200 mL fluid intake, thereafter lunch9
X
6:00
16:00
X
8:00
18:00
X
11:00
21:00
Dinner
12:00
22:00
X
X 
2
24:00
10:00
Breakfast9
X
X
X
X
36:00
22:00
X
3
48:00
10:00
X
X
48:30
10:30
Discharge from trial site (Visit 3 only)
EOT
4
5 to 14
days 
after
Day 1 
of Visit 
310
End of trial (EOT) examination11
X
X
X
X
DE: Dabigatran Etexilate, study drug
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 body height and 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 study 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, 24 hours prior to administration 
of DE in Visit 2 and may be repeated at any time during the study. 
3.
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.


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4.
Pre-medication of rabeprazole will be started at the following day of Day 3 of Visit 2.
5.
Rabeprazole will be administrated 4 hour prior to administration of DE on Day 1 of Visit 3
6.
Inserting the pH sensor to be completed within approximately 3 hours prior to DE administration. Intragastric pH will 
be checked at predose, 15, 30 minutes, 1, 2 hours after drug administration of DE. The pH sensor is removed after 
collecting gastric pH at 2 hours after DE administration. Data will be collected and entered in the electric case report 
form.
7.
The time is approximate; the procedure is to be performed and completed within 3 hours prior to DE administration.
8.
Genotyping of cytochrome P450 2C19 (CYP2C19) is mandatory. Pharmacogenomics sample will be taken together 
with the pharmacokinetics sample at 1 hour after administration of DE on Day 1 of Visit 2, but can be taken at 
subsequent visit.
9.
If several actions are indicated at the same time point, the intake of meals or water will be the last action.
10.
In case of premature discontinuation, 5-14 days after the last DE administration
11.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 11
1.1
MEDICAL BACKGROUND............................................................................11
1.2
DRUG PROFILE...............................................................................................11
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 15
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................15
2.2
TRIAL OBJECTIVES.......................................................................................15
2.3
BENEFIT - RISK ASSESSMENT ...................................................................15
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 18
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................18
3.1.1
Administrative structure of the trial...................................................18
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................19
3.3
SELECTION OF TRIAL POPULATION ......................................................19
3.3.1
Main diagnosis for study entry............................................................19
3.3.2
Inclusion criteria...................................................................................19
3.3.3
Exclusion criteria ..................................................................................20
3.3.4
Removal of subjects from therapy or assessments.............................21
3.3.4.1
Removal of individual subjects................................................21
3.3.4.2
Discontinuation of the trial by the sponsor..............................22
3.3.5
Replacement of subjects .......................................................................23
4.
TREATMENTS........................................................................................ 24
4.1
TREATMENTS TO BE ADMINISTERED....................................................24
4.1.1
Identity of BI investigational product and comparator product......24
4.1.2
Method of assigning subjects to treatment groups ............................25
4.1.3
Selection of doses in the trial................................................................25
4.1.4
Drug assignment and administration of doses for each subject .......25
4.1.5
Blinding and procedures for unblinding ............................................26
4.1.6
Packaging, labelling, and re-supply ....................................................26
4.1.7
Storage conditions.................................................................................26
4.1.8
Drug accountability ..............................................................................26


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................27
4.2.1
Other treatments and emergency procedures....................................27
4.2.2
Restrictions............................................................................................27
4.2.2.1
Restrictions regarding concomitant treatment .........................27
4.2.2.2
Restrictions on diet and life style.............................................27
4.3
TREATMENT COMPLIANCE.......................................................................28
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 29
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................29
5.1.1
Endpoints of efficacy.............................................................................29
5.1.2
Assessment of efficacy...........................................................................29
5.2
SAFETY..............................................................................................................29
5.2.1
Endpoints of safety................................................................................29
5.2.2
Assessment of adverse events...............................................................29
5.2.2.1
Definitions of adverse events...................................................29
5.2.2.2
Adverse event collection and reporting ...................................32
5.2.3
Assessment of safety laboratory parameters......................................34
5.2.4
Electrocardiogram................................................................................36
5.2.5
Assessment of other safety parameters...............................................36
5.2.5.1
Vital signs ................................................................................36
5.2.5.2
Medical examinations..............................................................36
5.2.5.3
Local tolerability......................................................................36
5.3
OTHER...............................................................................................................37
5.3.1
Pharmacogenomic evaluation..............................................................37
5.3.1.1
Methods and timing of sample collection................................37
5.3.1.2
Analytical determinations........................................................37
5.3.2
Intragastric pH......................................................................................37
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................37
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................37
5.5.1
Pharmacokinetic endpoints..................................................................38
5.5.1.1
Primary endpoints....................................................................38
5.5.1.2
Secondary endpoints................................................................38
5.5.2
Methods of sample collection...............................................................39
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................39
5.5.2.2
Urine sampling for pharmacokinetic analysis..........................39
5.5.3
Analytical determinations ....................................................................39
5.5.3.1
Analytical determination of analyte plasma concentration......39
5.5.3.2
Analytical determination of analyte urine concentration.........39
6.
INVESTIGATIONAL PLAN.................................................................. 40
6.1
VISIT SCHEDULE............................................................................................40


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................40
6.2.1
Screening period....................................................................................40
6.2.2
Treatment periods.................................................................................40
6.2.3
End of trial and follow-up period........................................................41
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 42
7.1
STATISTICAL DESIGN – MODEL ...............................................................42
7.1.1
Objectives...............................................................................................42
7.1.2
Endpoints...............................................................................................42
7.1.3
Model......................................................................................................42
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................43
7.3
PLANNED ANALYSES....................................................................................43
7.3.1
Primary analyses...................................................................................43
7.3.2
Secondary analyses ...............................................................................44
7.3.3
Safety analyses.......................................................................................44
7.3.4
Interim analyses ....................................................................................45
7.3.5
Pharmacokinetic analyses ....................................................................45
7.3.6
Pharmacogenomic analysis ..................................................................45
7.4
HANDLING OF MISSING DATA ..................................................................45
7.4.1
Safety......................................................................................................45
7.4.2
Plasma drug concentration - time profiles..........................................45
7.4.3
Pharmacokinetic parameters...............................................................46
7.5
RANDOMISATION ..........................................................................................46
7.6
DETERMINATION OF SAMPLE SIZE ........................................................46
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 47
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................48
8.2
DATA QUALITY ASSURANCE .....................................................................48
8.3
RECORDS..........................................................................................................48
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......................................................................................... 50
9.1
PUBLISHED REFERENCES...........................................................................50
9.2
UNPUBLISHED REFERENCES.....................................................................50
10. APPENDICES .......................................................................................... 53
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 54


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
AMP
Auxiliary Medicinal Product
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 
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/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P 450
DE
Dabigatran etexilate
DNA
Deoxyribonucleic acid
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
MedDRA
Medical Dictionary for Regulatory Activities
MRTpo
Mean residence time of the analyte in the body after oral administration
NBI
Nippon Boehringer Ingelheim Co., Ltd.
NIMP
Non-investigational medicinal product


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NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
NVAF
Non-valvular atrial fibrillation
PCI
Percutaneous coronary intervention
P-gp
P-glycoprotein
PK
Pharmacokinetics
PKS
PK parameter analysis set
PPI
Proton pump inhibitor
PR
Pulse rate
q.d.
Quaque die, once daily
rabeprazole
Rabeprazole sodium
RE-LY
Randomised Evaluation of Long-term anticoagulant therapY with 
dabigatran etexilate
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard Operating Procedure
SPAF
Stroke prevention in patients with non-valvular atrial fibrillation
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 MI. 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 of acute VTE treatment and 
secondary VTE prevention were approved in the US, and worldwide registration is ongoing. 
Marketing authorisation 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 Society2013) [R15-5604] in Japan and widely used in medical practice.
The prevalence of atrial fibrillation increases 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 available formulation for DE is only 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 to 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 the anticoagulant 
effects reached steady-state levels on or before the time of the first assessment after 4-10 days 
of DE 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. Pharmacodynamics (PD) 
(anticoagulant) activity is closely correlated with dabigatran plasma concentrations. 
Dabigatran is eliminated primarily by the kidneys with urinary excretion accounting for 


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approximately up to 80% of the dose administered intravenously. The absolute bioavailability 
(BA) of the current capsule formulation of DE is approximately 6.5%.
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 
metabolised by the cytochrome P450 (CYP) system [U01-1602] and have no in vitro effects 
on human CYP enzymes, while, there was drug-drug interaction after co-administration with 
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 dabigatran etexilate (RE-
LY) had much smaller effects (increase in dabigatran plasma concentration of up to 16%) 
[U09-3249-02] than those observed in phase I studies. 
In the relative bioavailability study compared to commercial capsule formulation in healthy 
male subjects (i.e., 1160.246) of tablet formulation of DE. it was demonstrated that the 
adjusted gMean ratio of tablet formulation to capsule formulation as reference was 
approximately 110 % for both Cmax and area under the concentration-time curve of the 
analyte in plasma over the time interval t1 to t2 (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. 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 1000 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 
methods of administration were single dose of 50, 110, 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 
subject 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 were
included in the relative BA study of tablet formulation of DE at a daily dose of 110 mg 
[c09145064-01]. 
Two 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 


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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] 
2.0-3.0) [c03032935-01，U09-3249-02]. Details of safety and efficacy in the RE-LY study 
are described briefly as follows:
DE 150 mg b.i.d. was demonstrated to be superior to warfarin for the prevention of stroke 
and SE, reduced the rate of intracranial haemorrhage compared to warfarin, and also 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 4
of these cases (3 subjects with DE, 1 subject with warfarin) had identifiable alternative causes.
Post-marketing experience
Overall including Japan, taking all granted indications into consideration, experience with 
marketed product of 6478207 patient-years has been gained since first launch (period: 18 
March 2008 to 31 August 2016). In total, during the post-marketing experience period, 
Boehringer Ingelheim (BI) received a total of 166190 individual AEs from 90860.
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 approx. 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] 


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with stenting), and GLORIA AF (Global registry program on long-term oral anti-thrombotic 
treatment in patients with atrial fibrillation).
Combination use of the capsule formulation of DE with proton pump inhibitor (PPI)
BI investigated the drug interaction for co-administration with one of the PPI (pantoprazole). 
When the capsule formulation of DE was co-administered with pantoprazole, a decrease in 
dabigatran area under the plasma concentration-time curve (AUC) of approximately 30% was
observed [U03-1353].
In the Phase III study, RE-LY, co-administration with PPI did not result in lower trough 
levels and on average only slightly reduced post-dose concentrations of DE (-11%). 
Accordingly, PPI co-administration was not associated with a higher incidence of stroke or 
SEE, especially in comparison with warfarin plus PPIs. Hence, the reduced BA by 
pantoprazole co-administration seemed to be of no clinical relevance [U09-3249-02]. 
Rabeprazole sodium (abbreviated as rabeprazole in this clinical trial protocol [CTP])
Rabeprazole is one of the commonly used PPI in many countries and approved for gastric 
ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, and zollinger-Ellison syndrome 
in Japan. 
Rabeprazole is transformed to the active form (sulfenamid form) at parietal cells in acidic 
conditions, and acts by modification of SH-groups of the proton pump (H+, K+,-ATPase) 
causing inhibition of enzyme activity resulting suppression of acid secretion. It is believed 
that the recovery of enzyme activity is mainly due to drug elimination from the active site, or 
that glutathione may be involved in the elimination of the active drug. It is mainly 
metabolized by non-enzymatic reduction reaction. Other metabolism is due to demethylation 
which involving the hepatic enzymatic metabolism of CYP2C19, and the sulfone-form 
products due to sulfonation
In human, actions of inhibition of gastric acid secretion and increase reaction of intragastric 
pH are investigated. When rabeprazole was administered to healthy adult male volunteers at 
10 mg or 20 mg once a day, gastrinstimulated acid output was significantly decreased from 
the 1st day of administration. Administration of rabeprazole at 5, 10, and 20 mg once a day 
all resulted in a significantly increased intragastric pH in healthy adult men.
The most common side effects with rabeprazole are diarrhoea, elevation of alkaline 
phosphatase, and constipation [R17-0224]. 
For a more detailed description of the DE profile please refer to the current Investigator’s 
Brochure [c01632884-04] and for rabeprazole to the current package insert in Japan.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Physicochemical profiles of dabigatran show that the solubility of dabigatran considerably
drops at neutral pH range. Therefore, it is considered that increase in intragastric pH caused 
by co-administration with PPI results in decrease of absorption due to low solubility. It was 
already demonstrated that exposure to dabigatran is decreased about 30-40% with co-
administration with PPI after single administration of DE capsule [U03-1353]. Hence, it is 
important to investigate and assess the influence of co-administration of PPI on the extent of 
absorption of DE with new tablet formulation containing distinct additive. 
Rabeprazole will be used in this trial as co-administrated PPI because it is widely used in 
Japan and is expected to sufficiently increase gastric pH in healthy volunteers. In addition, 
metabolic profile of rabeprazole is relatively similar to that of pantoprazole, which was used 
as PPI in the previous relative BA studies.
In this BA study, relative BA of tablet formulation with and without PPI will be investigated 
to obtain the information regarding the influence of gastric pH on exposure to dabigatran.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the relative BA of 110 mg of tablet
formulation of DE with and without co-administration of rabeprazole in healthy male 
subjects.
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between the treatments. 
The assessment of safety will be an additional objective of this trial.
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 study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of tablet 
formulation of DE. The subjects are exposed to the risks of the study 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 


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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 study per subject will be around 160
mL. No health-related risk to healthy subjects is expected from this blood withdrawal.
The use of an indwelling glass microelectrode in the stomach for the purpose of 
intragastric pH examination may be accompanied by nausea, epistaxis, sore throat and also, 
the accidental breathing in of gastric acid into the lungs while inserting a glass microelectrode.
In addition, in rare cases shock or symptoms of toxicosis might be caused by local aesthesis
while inserting the glass microelectrode.
Drug-related risks and safety measures
The most significant potential risk associated with DE is a minor bleeding tendency at doses 
higher than 600 mg per day during steady state in healthy volunteers [U00-1856]. For 
Japanese healthy volunteers, bleeding event was observed after treatment with a single dose 
of 300 mg. For details of AEs 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 [CrCl 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. 
Rabeprazole
Rabeprazole and DE have different metabolic pathways. The main metabolic pathway of 
rabeprazole is non-enzymatic reduction reaction in plasma and via CYP2C19, while DE is 
converted to dabigatran by esterase catalysed hydrolysis. In addition, there are no overlap in 
their safety profiles [R17-0224, c01632884-04]. Thus, it is not expected to increase severity 
or frequency of AE of DE and rabeprazole by co-administration.
There are no trials which investigated the effect of co-administration of DE with rabeprazole.
However, there are 6 trials that examined the effect of co-administrations of capsule 
formulation of DE with pantoprazole (PPI), which has similar metabolic profile with 
rabeprazole, to healthy subjects. Most of those trials did not cause any AEs which were 
considered as study drug related. Two trials experienced the study drug related AEs, gingiva 
bleeding, flatulence and hematoma. However, those were all of mild intensity and recovered 
without any therapies. There were no unexpected AEs in those trials. Further, all events were 
expected as side effect of DE and PPI. In addition, AEs which were considered as not study 
drug related were mostly accidental events (e.g., common cold), which were diagnosed as 
mild to moderate [U03-1878, U00-1855, U01-1665, U02-1100, U02-1451, U02-1611, U03-
1069, U03-1353].


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Based upon the above information, healthy subjects will not be exposed to undue risks from 
this trial. However, subject’s safety will be ensured carefully by the clinical observation, and 
by laboratory monitoring. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as an open-label, single-oral-dose, two-period, single-arm trial 
in healthy male subjects in order to compare BA of DE with and without rabeprazole. The 
subjects will be allocated to a treatment sequence, DE without rabeprazole and then DE with 
rabeprazole. To make sure to increase intragastric pH, 20 mg of rabeprazole will be 
administrated once daily on Day -4 to -1of Visit 3 (pre-medication). Pre-medication of 
rabeprazole starts at the following day of Day 3 of Visit 2. The treatments will be a single 
dose of 110 mg of DE with or without rabeprazole in a fasting state on Day 1 in both Visit 2 
and Visit 3. For details refer to Section 4.1.
Figure 3.1: 1
Trial Design
There will be a period of 6 days between administrations of DE. At least 4 days of washout 
are required in consideration of the period when measurable drug levels effects are still likely 
to be present. The interval of DE administrations satisfies this requirement.
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 BI.
Nippon Boehringer Ingelheim Co., Ltd. (NBI) has appointed a Trial Clinical Monitor, 
responsible for coordinating all required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites. 
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI, 
Biberach, Germany and NBI. 


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The trial will be conducted a
 under the 
supervision of the Principal I
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 
organisation 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
A fixed sequence design was selected to avoid long-term burden of being hospitalised healthy 
volunteers although potential sequence-effects would be included in treatment effects. The 
fixed-sequence design is not expected to lead to systematic errors in the estimation of the 
treatment effects, because the trial duration is short enough to eliminate nonspecific time-
effects.
Blinding is not necessary. The open-label treatment is not expected to bias results, since the 
study endpoints are derived from measurement of plasma concentration of the analyte 
provided by a bioanalytical laboratory which is blinded to the treatment sequence. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 36 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
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 study 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:


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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 at informed consent
3. Body mass index (BMI) of 18 ≥and ≤25 kg/m2 at screening
4. Signed and dated written informed consent prior to admission to the study 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 BP outside the range of 90 to 140 mmHg, diastolic blood 
pressure outside the range of 50 to 90 mmHg, or PR outside the range of 45 to 90 bpm at 
screening
3. Any laboratory value outside the reference range before administration of DE that the 
investigator considers to be of clinical relevance
4. Any evidence of a concomitant disease judged 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. Any history of hypochlorhydria or achlorhydria
9. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
10. Planned surgeries within four weeks following the end-of trial examination
11. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
12. History of relevant orthostatic hypotension, fainting spells, or blackouts


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13. Chronic or relevant acute infections
14. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
15. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
16. 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
17. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
18. Inability to refrain from smoking at trial site
19. 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)
20. Drug abuse or positive drug screening
21. Blood donation of more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
22. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
23. Inability to comply with dietary regimen of trial site
24. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
For study restrictions, refer to Section 4.2.2.
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


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3. The subject is no longer able to participate for other medical reasons (such as surgery, 
AEs, or diseases)
4. An AE 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 study 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 AEs 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 AEs of moderate or severe intensity, or 
if at least one drug-related serious AE is reported that is considered to be unacceptable.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP, or the contract with BI 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.


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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 study subject number.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The film coated tablet 110 mg have been developed. The excipients used for the tablet 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 Co.,Ltd..
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 product
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:
Day 1 in Visit 2 and Visit 3: 1-0-0
Route of administration:
p.o.
Duration of use:
One day (single dose) for each treatment
The characteristics of the Non-investigational medicinal product (NIMP) / Auxiliary 
Medicinal Product (AMP) are given below:
Name:
Pariet®
Substance:
Rabeprazol sodium
Pharmaceutical formulation: Tablet
Source:
Eisai Co., Ltd.
Unit strength:
20 mg
Posology:
Day -4 to Day 1 in Visit 3: 1-0-0
Route of administration:
p.o.
Duration of use:
Five days (single dose)


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4.1.2
Method of assigning subjects to treatment groups
After it has been determined that the subject meets all eligibility criteria, a unique subject 
number will be assigned. The number should be recorded on all electric CRFs and 
correspondence regarding the subject. 
Once a subject number has been assigned, it cannot be reassigned to any other subject.
4.1.3
Selection of doses in the trial
As the standard clinical dose, 75 mg and 110 mg of DE capsule are available. Between 2 
dosages, 110 mg is used for this study because 110 mg b.i.d. is more common as the initial 
dose in elderly patients [P16-00895].
The dose of rabeprazole selected for this trial reflects higher standard clinical doses.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a single arm study. All subjects will receive the two treatments in a specified
order: Single dose of dabigatran etexilate without (Visit 2) and with (Visit 3) rabeprazole. 
Rabeprazole will be administrated at 6:00 on Day -4 to Day 1 of Visit 3. 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
Dabigatran 
etexilate
with 
rabeprazole
(Test)
Dabigatran 
etexilate
and
Rabeprazole 
sodium 
Tablet
Tablet
110 mg
20 mg
1 tablet on Day 1
2 tablet from Day -4 to day 1 in 
Visit 3
110 mg
20 mg 
Dabigatran 
etexilate
without 
rabeprazole
(Reference)
Dabigatran 
etexilate
Tablet
110 mg
1 tablet on Day 1
110 mg
The medications 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 
physician or an authorised designee. The so-called four-eye principle (two-person rule) 
should be applied for administration of trial medication. Administration of medications for 
each Period 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 DE
administration. During the first 2 h after DE administration, they are not allowed to lie down 


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(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.
The treatments of DE will be separated by a wash-out phase 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 of DE and rabeprazole will be provided by NBI.
The clinical trial supply of tablet formulations and rabeprazole consists of boxes enclosing 
aluminium pouches in which the trial medication is packed in press through package sheets.
Boxes of tablet formulations are labelled with trial identification and not with rabeprazole.
For details of packaging and the description of the label, refer to the ISF.
Examples of the labels will be available in the ISF.
The telephone number of the trial site is given in the subject information form.
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 
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 investigational drug storage manager will receive the investigational drugs delivered by 
the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB 

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site

Approval/notification of the regulatory authority, e.g., competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol
Only authorized 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 medication will be disposed locally by the trial site upon 
written authorization by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 


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The investigational drug storage manager must maintain records of the product’s delivery to 
the trial site, the inventory at the site, the use by each subject, and the disposal of unused 
products. 
These records will include dates, quantities, and batch / serial numbers, expiry (‘use-by’) 
dates. The investigational drug storage manager 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 disposal, the 
investigational drug storage manager 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) for DE 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 DE is given, information surrounding the clinical circumstances, treatment 
and clinical outcome will be collected on the CRF.
In case of AEs 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.
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 study 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 4h and after DE
intake.
From 1 h before drug intake until lunch on Day 1 for each Period, fluid intake is restricted to 
the water administered with the drug, and an additional 200 mL of water at 2 h and 4 h post-
dose of DE (mandatory for all subjects). From lunch until 24 h post-dose of DE, total fluid 
intake is restricted to 3000 mL. 


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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 
Visit 3 is collected.
Alcoholic beverages are not allowed for 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 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 blushes, 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.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of DE and rabeprazole in the study 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 drug will be assessed based on:  

AE(including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (BP, PR)
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
A serious adverse event (SAE) is defined as any AE which:

results in death, 

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

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.
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 


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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 
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 


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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 study 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 (serious and 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 which 
 may become aware of.


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The REP for DE, when measurable drug levels effects are still likely to be present, is defined 
as 3 days after the last administration of DE. Therefore, all AEs which occurred through the 
treatment phase and throughout the REP will be considered as on treatment; please see 
Section 7.3.3. 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 and any possible interactions between the investigational 
drug and a NIMP / AMP.
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.
SAEs
SAEs
REP
REP


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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 or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively and the investigator considers as necessary.
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 automatic
differential WBC is abnormal)
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 
Direct 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
and the investigator considers as 
necessary)
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.
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, it is planned to perform these tests during screening only.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV antigen and 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 24 hours prior to administration of DE in Visit 2, and may be repeated at any 
time during the study 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 Tables 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 study 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 BP as well as PR or heart rate (heart rate is considered to be equal to 
pulse rate) will be measured by a BP monitor  at the times indicated in the Flow Chart, after 
subjects have rested for at least 5 min in a sitting position. All recordings should be made 
using the same type of BP recording instrument on the same arm if possible.
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.
5.2.5.3
Local tolerability
Not applicable.


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5.3
OTHER
5.3.1
Pharmacogenomic evaluation
All subjects will be asked for one mandatory blood sample for exploratory, prespecified 
pharmacogenomic analyses of CYP2C19 in order to predict the CYP2C19 metabolizer status 
(e.g., poor, intermediate, extensive or ultrarapid metabolizer). Data will be part of the CTR. 
All remaining samples will be destroyed no later than three months after the report archived.
5.3.1.1
Methods and timing of sample collection
One sample of maximum 8.5 mL blood per subject for pre-specified testing will be taken at 
Visit 2 in a PAXgene Blood DNA sampling tube. If not feasible at Visit 2, the sample can 
also be taken at a later visit.
Further details to the information on sampling are provided in the ISF and/or lab manual.
5.3.1.2
Analytical determinations
DNA will be extracted from blood samples according to standard molecular genetics methods 
and analysed by TaqMan® or other standard genotyping technologies at BI.
5.3.2
Intragastric pH
Intragastric pH will be measured by a portable pH monitor. Glass microelectrode will be 
nasally inserted and placed in the subject’s gastric body on the day of DE administration. 
Data will be collected at predose, 15, 30, 60, 120 minutes after DE administration. The data 
will be entered in the eCRF and will be part of the CTR.
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 scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety of an orally administered drug, and are widely used in clinical trials. 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.


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5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be determined for total dabigatran:

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)

Cmax (maximum measured concentration of the analyte in plasma)
5.5.1.2
Secondary endpoints
The following secondary endpoints will be evaluated:

AUC0-tz (area under the concentration-time curve of free dabigatran in plasma over 
the time interval from 0 extrapolated to the last quantifiable data point)

Cmax (maximum measured concentration of free dabigatran in plasma) 

AUC0-∞(area under the concentration-time curve of free dabigatran in plasma over 
the time interval from 0 extrapolated to infinity)

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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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 a 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.
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
5.5.3.2
Analytical determination of analyte urine concentration
Not applicable.


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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.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3hour-period prior to the 
trial drug administration. 
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
within 24 hours after DE administration will be ±30 minutes. Procedures of 24 hours and 
later after DE administration, tolerance will be ±60 minutes.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 12-
lead ECG recordings have to be done first. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, 12-lead ECG recordings should be the first of 
the measurements and venepuncture should be the last one due to its inconvenience to the 
subject and possible influence on physiological parameters.
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 study.
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 given one dose of DE in the morning of Day 1 of Visit 2 
(Period 1) and Visit 3 (Period 2). Rabeprazole will be administrated from Day -4 of Visit 3 
(Period 1), the following day of Day 3 of Visit 2 (Period 1), to Day 1 of Visit 3 (Period 2) 
under supervision of the investigating physician or his/her designee.
If a subject displays any significant changes in BP and/or PR 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 period. Adequate diagnostic measures will 


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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 two treatment periods (Days -1, 1, 2, and 3 for 
Visit 2 [Period 1] and Days -4, -3, -2, -1, 1, 2, and 3 for Visit 3 [Period 2]). The day of DE 
administration in each period should be separated by at least 4 days.
On Day -1 of Visit 2 (Period 1), trial participants will be admitted to the trial site and kept 
under close medical surveillance for at least 48 h following DE drug administration. The 
subjects will be allowed to leave the trial site after formal assessment and confirmation of 
their fitness at the day 3 of Visit 3 (Period 2). 
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 end of trial 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 judged 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 investigate the relative BA of 110 mg of tablet 
formulation of DE with and without co-administration of rabeprazole in healthy male subjects.
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between the treatments. The secondary objective will be assessed by descriptive 
statistics.
The assessment of safety will be an additional objective of this trial, and will be evaluated by 
descriptive statistics.
7.1.2
Endpoints
Relative BA is to be determined on the basis of the primary and secondary pharmacokinetic 
endpoints (see Section 5.5.1).
Safety 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: ‘subjects’ and ‘treatment’. The 
effect ‘subjects’ will be considered as random, whereas the other effects will be considered as 
fixed. The model is described by the following equation:
ykm = + sm + k+ ekm, where
ykm = logarithm of response (endpoint, see Section 5.5.1) measured on subject m 
receiving treatment k,
= intercept,
sm = the random effect associated with the mth subject, m = 1, 2, ..., n
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received
treatment k.


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7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative BA of dabigatran tablet with or without co-administration of rabeprazole will be 
estimated by the ratios of the geometric means (test treatment/reference treatment) for the 
primary and secondary PK endpoints. Additionally, their two-sided 90% confidence intervals 
(CIs) will be provided. No hypothesis will be tested.
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 
Standard Operating Procedure (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 treatment or from median tmax
for the test product, depending on whether the subject had experienced emesis after 
taken the test or the reference treatment. 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 (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 BA, the ratios of the geometric means (test treatment/reference treatment) 
for the primary (see 5.5.1.1), and their two-sided 90% 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% CI 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.


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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.
7.3.3
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 study 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’.
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 next intake or the 
end of trial visit will be assigned to the preceding treatment, and those after the end of trial 
examination will be assigned to ‘post-study’. 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 trial (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-study’. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
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.


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7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug 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 CTR.
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 
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 below limit of quantification (BLQ), 
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.
7.3.6
Pharmacogenomic analysis
The genotypes/phenotypes of the enzymes in Section 5.3.1 will be explored descriptively and 
graphically for any impact on the PK of dabigatran.
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 NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ, or NOP (no peak detectable) 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). 


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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
Randomisation is not planned for the study.
7.6
DETERMINATION OF SAMPLE SIZE
The sample size was determined to assure a precise estimation of the relative BA ratio in 
terms of a desired precision represented by the half-width of the 90% CI of the point estimate 
on the logarithmic scale.
In a previous trial 1160.246, intra-individual and inter-individual gCVs of Cmax were 
observed as 64% and 34% respectively and those of AUC0-tz were 64% and 33%. By back-
transforming intra-individual and inter-individual gCVs to logarithmic scale, the intra-
individual and inter-individual variances were obtained as 0.35 and 0.11 for Cmax and 0.33 
and 0.35 for AUC0-tz , respectively. An expected correlation between twice-repeated 
measurements (Cmax and AUC0-tz for each subject) is calculated as
Corr(X	
, X	) =


 
,
where 
X	 is observed Cmax or AUC0-tz for th subject in period j in the logarithmic scale
σ
 is intra-individual variance and σ
 inter-individual variance in the logarithmic scale.
Based on expected correlation of 0.237 and standard deviation of 0.673 (on the logarithmic 
scale) for Cmax, a sample size of 36 subjects can achieve that a 90% CI for the ratio of the 
geometric means (test treatment/reference treatment) for Cmax will be obtained with 
probability 84.9% for a desired precision of half-width 0.2624 on the logarithmic scale. 
Similarly, the sample size can achieve 84.9% for the precision for AUC0-tz.
The following table shows the summary of the calculation.


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Table 7.6: 1
Expected precisions for endpoints and their detailed calculation (N=36).
Cmax
AUC0-tz
intra gCV
0.64 
0.64 
inter gCV
0.34 
0.33 
intra variance
0.35 
0.35 
inter variance
0.11 
0.10 
total variance
0.45 
0.45 
Total SD
0.673 
0.668 
Correlation on log-scale
0.237 
0.225 
precision of half-width
0.2624 
0.2624 
Total N
36
36
alpha error
0.10 
0.10 
prob(<CI half)
0.849 
0.849 
The calculation was performed using the PROC Power of the commercial software SAS
. 
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) remains the 
responsibility of the subject’s treating physician.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).


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The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
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 Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to 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.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.


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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 
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.
P16-00895
Inoue H, Uchiyama S, Atarashi H, Okumura K, Koretsune Y, Yasaka M, 
Yamashita T, Ohnishi M, Yagi N, Fukaya T, J-Dabigatran Surveillance 
Investigators Post-marketing surveillance on the long-term use of 
dabigatran in Japanese patients with nonvalvular atrial fibrillation: 
preliminary report of the J-dabigatran surveillance.
J Arrhythmia 32 (2), 145 - 150 (2016)I
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.
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)
R17-0224
Production information-Pariet tablets 20 mg:April 2016 (25th version)
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.
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.


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U00-1855
Bioavailability of BIBR 
 BIBR 1048 MS film-
coated tablet administered b.i.d. for 3 days or 200 mg BIBR 1048 MS with 
and without pretreatment with pantoprazole to healthy volunteer subjects. 
Two groups, 2-way crossover, randomised, open trial. 21 July 2000; 
Amendment 1. 1160.14. 21 February 2002.
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.
U01-1665
Bioavailability of BIBR 
953 ZW after single oral doses of 12.5, 25, 50 or 100 mg BIBR 1048 MS 
film-coated tablet with and without pre-treatment with pantoprazole to 
healthy subjects. Four groups, 2-way crossover, randomised, open trial. 
1160.15. 30 July 2001.
U02-1100
 Internal Re 
Bioavailability of BIBR 953 WZ after single oral doses of two different 50 
mg capsules of BIBR 1048 MS with and without co-administration of 
pantoprazole in healthy subjects relative to solution. Two groups, 3-way 
crossover, randomised, open trial port. 1160.17. 13 November 2001.
U02-1451
 Bioavailability of BIBR 953 ZW after 50 
mg ofBIBR 1048 MS (oral prodrug ofBIBR 953) in 4 experimental 
formulations relative to drinking solution of BIBR 1048 MS, each treatment 
given bid over 3 days, in healthy subjects. Intraindividual comparison (5-
way crossover), randomised, open. For each of the 5 treatments, 
investigation of 2 conditions: with and without Pantoprazole 
(intraindividual, open comparison). 1160.31. 22 May 2002.
U02-1611
Bioavailability of BIBR 953 ZW after 50 
mg of BIBR 1048 MS (oral prodrug of BIBR 953) in 4 experimental 
formulations relative to drinking solution of BIBR 1048 MS, each treatment 
given bid over 3 days, in healthy subjects. Intraindividual comparison (5-
way crossover), randomised, open. For each of the 5 treatments, 
investigation of 2 conditions: with and without Pantoprazole 
(intraindividual, open comparison). 1160.32. 12 November 2002.
U03-1069
Bioavailability of BIBR 953 ZW after 50 
mg of BIBR 1048 MS (oral prodrug of BIBR 953) in 2 experimental 
formulations relative to drinking solution of BIBR 1048 MS, each treatment 
given bid over 3 days in healthy subjects. Intraindividual comparison (3-
way crossover) with and without Pantoprazole, randomised, open. 1160.33. 
10 February 2003.


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U03-1353
 Bioavailability of BIBR 953 ZW after 150 
mg of BIBR 1048 (oral pro-drug of BIBR 953) administered as capsule 
with and without coadministration of Pantoprazole as well as under the 
influence of food in healthy subjects. A three-way crossover, randomised, 
open trial. 1160.34. 27 May 2003.
U03-1878
 Pharmacokinetics of BIBR 953 ZW after 
150 mg of BIBR 1048 (oral pro-drug of BIBR 953) administered as capsule 
twice daily over seven days with or without Pantoprazole co-treatment to 
healthy male and female elderly subjects. 1160.1. 08 December 2003.
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13837712
1.0
clinical-trial-protocol-version-01
Relative bioavailability of tablet formulation of dabigatran etexilate with and without
co-administration of rabeprazole in healthy male subjects (an open-label,
single-oral-dose, two-period, single-arm study)
Approval-Therapeutic Area 
23 Apr 2017 20:59 CEST
Author-Trial Clinical Monitor
24 Apr 2017 01:31 CEST
Author-Trial Clinical
Pharmacokineticist
24 Apr 2017 02:18 CEST
Author-Trial Statistician
24 Apr 2017 08:29 CEST
Approval-Team Member Medical
Affairs
26 Apr 2017 18:40 CEST
Verification-Paper Signature
Completion
27 Apr 2017 09:13 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13837712
1.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c17618627-01
BI Trial No.:
1160.270
Title:
Relative bioavailability of tablet formulation of dabigatran etexilate with 
and without co-administration of rabeprazole in healthy male subjects 
(an open-label, single-oral-dose, two-period, single-arm study)
Investigational
Product(s):
Pradaxa® (Prazaxa® in Japan), Dabigatran etexilate, BIBR 1048 MS
Responsible trial 
statistician(s):
Address:
Phone
 Fax: 
Date of statistical 
analysis plan:
23 AUGUST 2017 SIGNED
Version:
Final
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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 ..........................................................................................7
5.1
PRIMARY ENDPOINTS....................................................................................7
5.2
SECONDARY ENDPOINTS..............................................................................7
5.2.1
Key secondary endpoints................................................................................7
5.2.2
Other secondary endpoints.............................................................................7
..................................................................................7
..................................................................................7
6.
GENERAL ANALYSIS DEFINITIONS.............................................9
6.1
TREATMENTS....................................................................................................9
6.1.1
Treatment regimens / study intervals............................................................9
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................10
6.3
SUBJECT SETS ANALYSED..........................................................................12
.....................................................................................................12
6.5
POOLING OF CENTRES ................................................................................12
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................12
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................13
7.
PLANNED ANALYSIS.......................................................................14
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........14
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................14
7.3
TREATMENT COMPLIANCE .......................................................................14
7.4
PRIMARY ENDPOINTS..................................................................................14
7.5
SECONDARY ENDPOINTS............................................................................14
7.5.1
Key Secondary endpoints .............................................................................14
7.5.2
Other Secondary endpoints..........................................................................15
..................................................................................15
7.7
EXTENT OF EXPOSURE................................................................................15
7.8
SAFETY ANALYSIS.........................................................................................15
7.8.1
Adverse events ...............................................................................................15
7.8.2
Laboratory data.............................................................................................16
7.8.3
Vital signs.......................................................................................................16
7.8.4
ECG ................................................................................................................17
7.8.5
Others .............................................................................................................17
8.
REFERENCES.....................................................................................18
................................................................19
10.
HISTORY TABLE...............................................................................20


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LIST OF TABLES
Table 6.1.1: 1
Treatment regimens/Intervals.......................................................................9
Table 6.2: 1
Important PVs..................................................................................................11
Table 6.3: 1
Subject sets analysed.......................................................................................12
Table 10: 1
History table ....................................................................................................20


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the Trial statistical analysis plan (TSAP)
Term
Definition / description
AE
Adverse event
BMI
Body mass index
CTP
Clinical Trial Protocol
DE
Dabigatran etexilate
EOT
End of treatment
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetics
PKS
Pharmacokinetic set
PV
Protocol violation
REP
Residual effect period
RPM
Report planning meeting
SD
Standard deviation
TS
Treated set
TSAP
Trial statistical analysis plan


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


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The intragastric pH of dabigatran will be explored descriptively.
If there are subjects with considerable high gastric pH, i.e. gastric pH values greater than 5.5
at baseline (1) in reference treatment (dabigatran etexilate alone), ANOVA analyses of 
primary and secondary endpoints (for the model refer to CTP 7.1.3) will in addition be 
conducted separately for subjects with considerable high gastric pH at baseline and subjects 
excluding considerable high gastric pH at baseline as appropriate with respect to number of 
subjects in the respective groups.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
There is no primary endpoint for efficacy. The primary endpoints will be used as defined in
the CTP, Section 5.5.1.1 as PK endpoints.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
There are no key secondary endpoints in this trial.
5.2.2
Other secondary endpoints
The other secondary endpoints will be used as defined in the CTP, Section 5.5.1.2.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
6.1.1
Treatment regimens / study intervals
There will be 7 phases in this trial: 
screening, treatment period (dabigatran (Period 1), washout, rabeprazole (Period 2) and 
dabigatran + rabeprazole (period 2)), 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
dabigatran
(Period 1)
01
Date of administration in
Period 1
Time of administration in 
Period 1
Washout 
02
Date of administration in
Period 1
Time of administration in 
Period 1 + 1 minute
rabeprazole
(Period 2)
03
Date of first administration of 
rabeprazole in Period 2
Time of first administration of
rabeprazole in Period 2
dabigatran + 
rabeprazole
(Period 2)
04
Date of first administration of 
dabigatran in Period 2
Time of first administration of 
dabigatran in Period 2
Post-treatment
05
Date of last administration in
Period 2
Time of last administration in 
Period 2 + 1 minute
Post-study
99
Date of EOT + 1
0:00


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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 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' (2).
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 (3). 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.
The following Table 6.2: 1 gives the important PVs for this trial.


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Table 6.2: 1
Important PVs
Category
/Code
Description
Requirements/Comment
Excluded 
from
A
Entrance criteria not met
A1
Inclusion criteria violated
Inclusion criteria No.1, 2 and 3
Automatically detectable.
None
A2
Exclusion criteria violated
Automatically detectable.
PKS
B
Informed consent
B1
Written Informed consent 
not given
Inclusion criteria No.4
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
Manually detectable.
None
C3
Incorrect 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 secondary data
PK sample taken too early/too late.
Manually detectable.
PKS
KEY:
TS = Treated set, PKS = Pharmacokinetic set


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6.3
SUBJECT SETS ANALYSED

Enrolled set (ES):
This subjects set includes all subjects who enrolled into this trial (i.e., having given 
informed consent), whether treated or not.

Treated set (TS):
This set includes all subjects who were provided with study medication and were 
documented to have taken at least one dose of investigational treatment. 

Pharmacokinetic set (PKS):
The PKS includes 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.
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
ES
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
This section is not applicable, because the study was performed in only one centre.
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.


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Handling of missing data is according to the CTP, section 7.4. Additionally, handling 
information of missing data is shown as follows:

Missing data and outliers of PK data are handled according to (4).

Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”). (5)
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 (4).
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 ENDPOINTS
The analysis will be performed as defined in the CTP, Section 7.3.1.
7.5
SECONDARY ENDPOINTS
7.5.1
Key Secondary endpoints
There are no key secondary endpoints in this trial.


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7.5.2
Other Secondary endpoints
The analysis will be performed as defined in the CTP, Section 7.3.2. 
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 TS.
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 summarisation of AE data, please refer to (5, 6).
The residual effect period (REP) for Dabigatran etexilate (DE) is defined as 3 days after the 
last administration of DE. Therefore, all AEs which occurred through the treatment phase and 
throughout the REP are considered as treatment emergent.
The analysis of AEs will be based on the concept of treatment emergent AE. That means that 
all AEs occurring between the first intakes of dabigatran till 3 days after will be assigned to 
treatment “dabigatran” (or “reference”) in period 1. In period 2 all AEs occurring between 
the first intake of rabeprazole until before the intake of dabigatran will be assigned to 
“rabeprazole“, then after the intake of dabigatran until 3 days later to “dabigatran+ 
rabeprazole” or “test”.  AEs occurring after “dabigatran” but after the REP in period 1 will be 
assigned to ‘washout’.  AEs occurring after “dabigatran+ rabeprazole” but before EOT will 


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be assigned to ‘post-treatment’.  All AEs occurring before first drug intake will be assigned to 
'screening' and all AEs occurring after EOT will be assigned to 'post-study'.
According to ICH E3 (7), AEs classified as ‘other significant’ needs to be reported and will
include those non-serious with
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant
therapy as identified by the Clinical Monitor/Investigator at a RPM/database lock (DBL)
meeting.
An overall summary of AEs will be presented.
The frequency of subjects with AEs occurring in “dabigatran”, “rabeprazole“ and 
“dabigatran+ rabeprazole” will be summarised by treatment, primary system organ class and 
preferred term (MedDRA levels to be displayed in the tables). 
Separate tables will be provided for subjects with other significant AEs according to ICH E3 
(7), for subjects with significant non-serious AEs (only if these are defined for the project) 
and for subjects with serious AEs.
The table for the subject with non-serious AEs occurring with incidence in preferred term 
greater than 5 % will be provided. Additionally, occurred AEs will be listed.
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 and will be based on BI 
standards (8), descriptive statistics with original values will be provided by period for 
baseline, on-treatment values and for changes from baseline. Clinically relevant findings in 
laboratory data will be reported as AEs and will be analysed as part of AE analysis.
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of subjects within and outside the reference range at baseline and the 
last measurement on treatment. Frequency tables for categorical laboratory values categorised 
by value at baseline and last value on treatment will be shown.
The last value on-treatment is defined as the last non-missing value observed during 
‘dabigatran’ or ‘dabigatran+ rabeprazole’ 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.


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7.8.4
ECG
ECG data will not be listed but clinically relevant abnormal findings will be reported as AEs.
7.8.5
Others
Only descriptive statistics by treatment or PGx phenotype are planned for intragastric pH.


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8.
REFERENCES
1
Guideline for Bioequivalence Studies of Generic Products: Q & A (original in 
Japanese), Attachment 1 of Clerical Notification of Pharmaceutical and Food
Safety Bureau, dated 29 February 2012.
2
001-MCS-50-413_RD-01: "Protocol Violation Handling Definitions", current 
version; IDEA for CON.
3
001-MCS-50-413_RD-02: "Important Manual Protocol Violations Spreadsheet", 
current version; IDEA for CON.
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON;
5
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version IDEA for CON;
6
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", Version 5; IDEA for CON.
7
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
8
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Initial
08-June-17
None
Final
23-Aug-17
Section 
5, 6 and 
7
Details for analysis are specified.