Clinical trial NCT04099732
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2019-10-07; Completion date: 2019-12-10
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of this trial is to investigate the relative bioavailability of rosuvastatin (Reference 1, Part 1) and dabigatran (Reference 2, Part 2) given alone and together with BI 1358894 (Test 1, Test 2) following oral administration.

Detailed description:

Arms: arm 1: Reference 1 - Rosuvastatin. Test 1 - Rosuvastatin + BI 1358894 arm 2: Reference 2 - Dabigatran etexilate. Test 2 - Dabigatran etexilate + BI 1358894
Interventions: intervention 1: Rosuvastatin intervention 2: BI 1358894 intervention 3: Dabigatran etexilate
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Capsule

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c27867536-02
EudraCT No.
2019-002763-10
BI Trial No.
1402-0009
BI Investigational
Medicinal Product
BI 1358894
Title
Relative bioavailability of rosuvastatin (Part 1) and dabigatran 
(Part 2) given alone and together with BI 1358894 in healthy 
male subjects (open, single-dose, fixed sequence, two-period
crossover design in each trial part)
Lay Title
A study in healthy men to test the influence of BI 1358894 on the 
amount of the medicines rosuvastatin and dabigatran in the blood
Clinical Phase
I
Clinical Trial 
Leader
Phone: 
 / Fax: 
 
Principal 
Investigator
Phone: 
/ Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date
Version: 2.0
Date: 28 August 2019
Page 1 of 64
Proprietary confidential information
© 2019 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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BI Trial No.: 1402-0009
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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
22 July 2019
Revision date
28 August 2019
BI trial number
1402-0009
Title of trial
Relative bioavailability of rosuvastatin (Part 1) and dabigatran (Part 2) given alone 
and together with BI 1358894 in healthy male subjects (open, non-randomised, 
single-dose, two-period crossover design in each trial part)
Principal Investigator 
Trial site
Clinical phase
I
Trial rationale
BI 1358894 has been characterised to be an inhibitor of P-gp, OATP1B1/1B3 and 
BCRP in-vitro. This trial will be performed to test the inhibitory effect of BI 
1358894 on these drug transporters in-vivo. Dabigatran will be used as model 
substrate for P-gp, rosuvastatin as model substrate for BCRP and OATP1B1/1B3.
Trial objective
To investigate the relative bioavailability of 10 mg rosuvastatin (Part 1) and 150 mg 
dabigatran (Part 2) given alone and together with 200 mg BI 1358894
Trial design
Part 1: non-randomised, open-label, two period crossover design 
Part 2: non-randomised, open-label, two period crossover design
Trial endpoints:
Part 1
Primary endpoints: AUC0-and Cmax of rosuvastatin 
Secondary endpoints: AUC0-tz of rosuvastatin  
Part 2
Primary endpoints: AUC0-and Cmax of dabigatran
Secondary endpoints: AUC0-tz of dabigatran 
Number of subjects 
total entered
28 
each treatment
14 in Part 1, 14 in Part 2
In case more than 2 subjects do not complete the respective trial part according to
protocol, up to 6 replacement subjects may be included into each trial part. Thus, a 
maximum of 20 subjects may participate in each trial part.
Diagnosis
Not applicable


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Main criteria
for inclusion
Healthy male subjects, age of 18 to 55 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Trial product 1
Crestor® 10 mg Filmtabletten
dose
1 tablet (=10 mg rosuvastatin)
mode of admin.
Oral with 240 mL of water after a high-fat, high-calorie breakfast
Trial product 2
Pradaxa® 150 mg Hartkapseln
dose
1 capsule (= 150 mg dabigatran etexilate)
mode of admin.
Oral with 240 mL of water after a high-fat, high-calorie breakfast
Trial product 3
BI 1358894 film-coated tablets; 
dose
mode of admin.
Oral with 240 mL of water after a high-fat, high-calorie breakfast
Duration of treatment
Part 1 (all treatments are given as single dose)
Period 1: 1 tablet Crestor® 10 mg Filmtabletten
Period 2: 1 tablet Crestor® 10 mg Filmtabletten together with 2 tablets BI 1358894
Treatments are separated by a wash-out period of at least 7 days between study drug 
administrations.
Part 2 (all treatments are given as single dose)
Period 1: 1 capsule Pradaxa® 150 mg Hartkapseln
Period 2: 1 capsule Pradaxa® 150 mg Hartkapseln with 2 tablets BI 1358894
Treatments are separated by a wash-out period of at least 7 days between study drug 
administrations.
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to 
the two one-sided t-test procedure, each at a 5% significance level. Since the main 
focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified. The statistical model will be an analysis of 
variance (ANOVA) on the logarithmic scale including effects for subjects and 
treatment. CIs will be calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART – PART 1 
Period
Visit
Day
Planned time (relative to  
drug administration) 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK rosuvastatin 
PK BI 1358894 and 
metabolite7
PK 
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
2/3
1
-3:00
05:00
Admission to trial site
x2,5
x2
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast
0:00
08:00
Drug administration
1:00
09:00
x
x
2:00
10:00
240 mL fluid intake
x
x
3:00
11:00
x
x
x
3:30
11:30
x
4:00
12:00
240 mL fluid intake
x
x
4:30
12:30
x
5:00
13:00
x
x
x
5:30
13:30
x
6:00
14:00
240 mL fluid intake, lunch3
x
x
x
7:00
15:00
x
x
8:00
16:00
Snack (voluntary)3
x
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x
x
2
24:00
08:00
Breakfast (voluntary) 3, 
discharge from trial site
x
x
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
x
x
5
96:00
08:00
Ambulatory visit
x
x
FU
4
8 to 21
End of trial (EoTrial) examination4
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of the trial the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. 
5.
Only urine drug screening and alcohol breath test will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
Only in period 2 (Treatment Test)


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FLOW CHART – PART 2 
Period
Visit
Day
Planned time (relative to  
drug administration) 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK dabigatran 
PK BI 1358894 and 
metabolite 7
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
2/3
1
-3:00
05:00
Admission to trial site
x2,5
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast
0:00
08:00
Drug administration
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
2:30
10:30
x
3:00
11:00
x
x
3:30
11:30
x
4:00
12:00
240 mL fluid intake
x
5:00
13:00
x
x
6:00
14:00
240 mL fluid intake, lunch3
x
x
x
7:00
15:00
x
8:00
16:00
Snack (voluntary) 3
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x
2
24:00
08:00
Breakfast (voluntary) 3, 
discharge from trial site
x
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
x
FU
4
8 to 21
End of trial (EoTrial) examination4
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening, fecal 
occult blood test), demographics (including determination of body height and weight, smoking status and alcohol 
history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic 
samples will be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory (including 
fecal occult blood test), recording of AEs and concomitant therapies. 
5.
Only urine drug screening and alcohol breath test will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
Only in period 2 (Treatment Test)


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART – PART 1.................................................................................4
FLOW CHART – PART 2.................................................................................5
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................14
1.2.2
Rosuvastatin ..........................................................................................16
1.2.3
Dabigatran.............................................................................................16
1.2.4
Residual Effect Period..........................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................18
1.4
BENEFIT - RISK ASSESSMENT ...................................................................18
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 21
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......21
2.1.1
Main objectives......................................................................................21
2.1.2
Primary endpoints ................................................................................21
2.1.3
Secondary endpoint ..............................................................................21
2.2.2.4
Safety and tolerability..............................................................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 24
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................24
3.3.1
Main diagnosis for trial entry..............................................................25
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................25


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3.3.4
Withdrawal of subjects from treatment or assessments ...................27
3.3.4.1
Discontinuation of trial treatment............................................27
3.3.4.2
Withdrawal of consent to trial participation ............................28
3.3.4.3
Discontinuation of the trial by the sponsor..............................28
3.3.5
Replacement of subjects .......................................................................28
4.
TREATMENTS........................................................................................ 29
4.1
INVESTIGATIONAL TREATMENTS ..........................................................29
4.1.1
Identity of the Investigational Medicinal Products ...........................29
4.1.2
Selection of doses in the trial................................................................30
4.1.3
Method of assigning subjects to treatment groups ............................30
4.1.4
Drug assignment and administration of doses for each subject .......30
4.1.5
Blinding and procedures for unblinding ............................................31
4.1.6
Packaging, labelling, and re-supply ....................................................31
4.1.7
Storage conditions.................................................................................32
4.1.8
Drug accountability ..............................................................................32
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................33
4.2.1
Other treatments and emergency procedures....................................33
4.2.2
Restrictions............................................................................................33
4.2.2.1
Restrictions regarding concomitant treatment .........................33
4.2.2.2
Restrictions on diet and life style.............................................33
4.3
TREATMENT COMPLIANCE.......................................................................34
5.
ASSESSMENTS....................................................................................... 35
5.1
ASSESSMENT OF EFFICACY Not applicable..............................................35
5.2
ASSESSMENT OF SAFETY............................................................................35
5.2.1
Physical examination ............................................................................35
5.2.2
Vital signs...............................................................................................35
5.2.3
Safety laboratory parameters..............................................................35
5.2.4
Electrocardiogram................................................................................37
5.2.5
Other safety parameters.......................................................................38
5.2.6
Assessment of adverse events...............................................................38
5.2.6.1
Definitions of adverse events...................................................38
Adverse event ............................................................38
5.2.6.1.1
Serious adverse event ................................................39
5.2.6.1.2
AEs considered ‘Always Serious’.............................39
5.2.6.1.3
Adverse events of special interest .............................39
5.2.6.1.4
Intensity (severity) of AEs.........................................40
5.2.6.1.5
Causal relationship of AEs ........................................40
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................41


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AE collection.............................................................41
5.2.6.2.1
AE reporting to the sponsor and timelines ................42
5.2.6.2.2
Information required..................................................42
5.2.6.2.3
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................43
5.3.1
Assessment of pharmacokinetics .........................................................43
5.3.2
Methods of sample collection...............................................................43
5.3.2.1
Blood sampling for pharmacokinetic analysis of rosuvastatin 
and dabigatran..........................................................................43
5.3.2.2
Blood sampling for pharmacokinetic analysis of BI 1358894 
and BI 1361608........................................................................43
5.3.2.3
Blood sampling for pharmacokinetic analysis
 
.44
5.3.3
Analytical determinations ....................................................................45
5.3.3.1
Analytical determination of rosuvastatin plasma concentration
45
5.3.3.2
Analytical determination of dabigatran plasma concentration 45
5.3.3.3
Analytical determination of BI 1358894 and BI 1361608
plasma concentration ...............................................................45
5.3.3.4
Analytical determination of 
plasma 
concentration............................................................................45
5.4
ASSESSMENT OF BIOMARKER(S) .............................................................46
5.5
BIOBANKING ...................................................................................................46
5.6
OTHER ASSESSMENTS .................................................................................46
5.6.1
Pharmacogenomic evaluation..............................................................46
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................46
6.
INVESTIGATIONAL PLAN.................................................................. 47
6.1
VISIT SCHEDULE............................................................................................47
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................47
6.2.1
Screening................................................................................................47
6.2.2
Treatment period ..................................................................................47
6.2.3
Follow-up period and trial completion ...............................................48
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 49
7.1
STATISTICAL DESIGN – MODEL ...............................................................49
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................49
7.3
PLANNED ANALYSES....................................................................................49
7.3.1
Primary endpoint analyses...................................................................50
7.3.2
Secondary endpoint analyses ...............................................................51
7.3.4
Safety analyses.......................................................................................52


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7.4
INTERIM ANALYSES .....................................................................................52
7.5
HANDLING OF MISSING DATA ..................................................................53
7.5.1
Safety......................................................................................................53
7.5.2
Pharmacokinetics..................................................................................53
7.6
RANDOMISATION ..........................................................................................53
7.7
DETERMINATION OF SAMPLE SIZE ........................................................53
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 55
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................55
8.2
DATA QUALITY ASSURANCE .....................................................................56
8.3
RECORDS..........................................................................................................56
8.3.1
Source documents .................................................................................56
8.3.2
Direct access to source data and documents.......................................57
8.3.3
Storage period of records.....................................................................57
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................58
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......58
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................58
8.6
TRIAL MILESTONES .....................................................................................58
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................59
9.
REFERENCES......................................................................................... 60
9.1
PUBLISHED REFERENCES...........................................................................60
9.2
UNPUBLISHED REFERENCES.....................................................................62
10. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 64
10.1
GLOBAL AMENDMENT 1 .............................................................................64


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ABBREVIATIONS
ADME
Absorption, Distribution, Metabolism and Elimination/Excretion
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
attributable, legible, contemporaneous, original, accurate
ALT
Alanine amino transferase
ANOVA
Analysis of variance
aPTT
Aktivierte partielle Thromboplastinzeit
AST
Aspartate amino transferase
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24h
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
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/Bioanalysis
BCRP
Breast cancer resistance protein
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
Borderline personality disorder
CA
Competent authority
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450 system
DG
Dose group


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DILI
Drug induced liver injury
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECT
Electro-convulsive therapy
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
FDA
Food and Drug Administration
FIM
First in man
FOB
Fecal Occult Blood test
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GFR
Glomerular Filtration Rate
GOT
Global Operation Team
GPT
Glutamic pyruvic transaminase
HMG-CoA
hydroxymethylglutaryl coenzyme A
HPMC
HydroxyPropyl Methocellulose
IB
Investigator’s brochure
ICF
Informed Consent Form
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
INR
International Normalization Ratio
IPD
Important protocol deviation
IQRM
Integrated Quality and Risk Management
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
OATP
Organic anion transporting polypeptide
PD
Pharmacodynamic(s)
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PR
Pulse rate
q.d.
Quaque die, once daily


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QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
RA
Accumulation ratio of the analyte in plasma after multiple dose 
administration over a uniform dosing interval τ
REP
Residual effect period
RR
Respiratory rate
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of product characteristics
SOP
Standard Operating Procedure
SRD
Single-rising dose
T
Test product or treatment
TCPK
Trial Clinical Pharmakokineticist
TRPC
transient receptor potential cation channel
TS
Treated Set
TSAP
Trial statistical analysis plan
TT
Thromboplastin time
tz
Time of last measurable concentration of the analyte in plasma
ULN
Upper limit of normal
WHO
World Health Organization
WOCBP
women of child bearing potential


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1.
INTRODUCTION
Boehringer Ingelheim (BI) is developing BI 1358894, an oral, small-molecule inhibitor of a 
transient receptor potential cation channel, subfamily C, members 4 and 5 (TRPC 4/5) for 
major depressive disorder (MDD). BI 1358894 has been characterised to be an inhibitor of P-
glycoprotein (P-gp), Breast cancer resistance protein (BCRP) and of the Organic anion 
transporting polypeptides (OATP) 1B1 and 1B3 in-vitro. This trial should investigate, 
whether BI 1358894 is also in-vivo an inhibitor of these drug transporters.  
1.1
MEDICAL BACKGROUND
Major depressive disorder is a debilitating disease characterised by low mood and often by 
low self-esteem, low energy, and a loss of interest. It can strongly impact a person’s life and 
health, including significantly increased risk of suicidality, and is difficult to treat, even with 
systematic antidepressant strategies. In the National Institute of Mental Health funded 
STAR*D trial of >4000 patients with nonpsychotic depression, about 30% of the patients did 
not reach remission after 4 different medications [P06-11895] and continued to experience 
residual symptoms [R16-5475] that significantly impacted the patients’ quality of life [R06-
2872]. When monotherapy is insufficient, clinicians employ different augmentation strategies 
including add-on treatment with lithium or atypical antipsychotics. When augmentation 
strategies also fail, convulsive therapies such as electro-convulsive therapy may be used.
Borderline personality disorder (BPD) is a chronic mental disorder with an estimated 
prevalence of around 2% in the general community [R16-5476] and severely impaired quality 
of life [R16-5474]. The main symptom clusters of BPD include impulsive-behavioural 
dyscontrol, cognitive-perceptual symptoms, disturbed interpersonal relations, and affective 
instability. Patients with BPD have high rates of deliberate self-harm and a rate of completed 
suicide that is 50 times higher than in the general population [R16-5477]. Even the presence 
of a single diagnostic feature of BPD is predictive for poor functioning and psychiatric illness 
burden [R16-5483]. Treatment guidelines recommend psychotherapy as the mainstay of 
treatment, but pharmacotherapy is commonly used as an adjunctive, symptom-targeted 
component of treatment. However, no drug is approved for the treatment of BPD.
TRPC4 and TRPC5 form ion channels that are involved in the regulation of neuronal 
excitability. They are most highly expressed in the amygdala, frontal cortex, hippocampus, 
and hypothalamus [R15-3888, R16-5350], which are involved in modulation and processing 
of emotion and affect.
 
 
It is hypothesized that in patients with affective disorders, an overactive amygdala is a major 
contributor to attentional bias to negative stimuli, pessimistic thoughts, and anxiety [R16-
5473] and there is growing evidence supporting the role of amygdala in the emotion 
processing disturbances observed in patients with BPD [R16-5472]. 
 
 


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1.2
DRUG PROFILE


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1.2.2
Rosuvastatin
Rosuvastatin is an HMG-CoA reductase inhibitor indicated for treatment of hypercholesterol-
emia and for prophylaxis of cardiovascular events. Inhibition of HMG-CoA decreases hepatic 
cholesterol production which, in turn, stimulates hepatocellular uptake of low-density 
lipoproteins [R17-2886]. 
After oral administration, maximal rosuvastatin plasma concentrations are reached at ~5 h. 
Oral bioavailability is ~20%, plasma protein binding is ~90%, and volume of distribution is 
~134 L. The liver is a principal compartment of distribution, with hepatocellular uptake being 
mediated mainly by OATP1B1 and, to a lesser degree, by OATP1B3. Elimination is mainly 
via the feces and to a lesser degree, via urine (principally via renal tubular secretion), with a 
t1/2 of 19 h [R17-2886], [P14-07833].
In therapy, the initial rosuvastatin dose is 5-10 mg once daily (q.d.). The daily dose may be 
increased to up to 40 mg [R17-2886].
Adverse reactions to rosuvastatin are normally mild and transient. Myalgia and myopathy 
with concomitant increase of creatine kinase, and, in rare cases, rhabdomyolysis have been 
observed during rosuvastatin therapy. Moreover, as for other HMG-CoA reductase inhibitors, 
a dose-dependent increase of liver transaminases may be observed [R17-2886].
For a more detailed description of the rosuvastatin profile, please refer to the current SmPC
[R19-1574].
1.2.3
Dabigatran 
Pharmacokinetics
Following single dose administration in healthy volunteers, the pharmacokinetic profile of 
dabigatran is characterized by maximum plasma concentration at approximately 1-2 hours 
after oral administration of dabigatran etexilate, a biexponential distribution phase and a 
terminal elimination half-life of about 8-10 hours. With b.i.d. dosing the steady state is 
attained within 3 days, and Cmax at steady state is about 30% higher than after the first dose. 
Dabigatran plasma concentrations and the pharmacokinetic parameters Cmax and AUC 
increased in a dose proportional manner after oral administration of the prodrug dabigatran 
etexilate and after intravenous infusion of dabigatran. The pharmacodynamic parameters 
aPTT, INR, ECT, and TT show close correlation with dabigatran plasma concentrations.
The bioavailability of the dabigatran in the capsule formulation is about 6.5%. After 
treatment with the proton pump inhibitor pantoprazole (increased gastric pH) bioavailability 
is reduced by approximately 20-30%. Co-administration with food results in delay of Cmax 
from 2 to 4 hours; there is no consistent effect on total exposure.


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Neither dabigatran etexilate nor dabigatran interacts with CYPs. No drug-drug interactions 
based on CYP dependent pathways have been identified. Dabigatran etexilate but not the 
active moiety, dabigatran, is a substrate of the efflux transporter P-glycoprotein (P-gp). 
Accordingly, the bioavailability of dabigatran is increased when P-gp inhibitors such as 
verapamil, quinidine, amiodarone, dronedarone or ketoconazole are co-administered. 
However this effect could be significantly reduced by staggered administration of the P-gp 
inhibitor. 
Due to rapid hydrolisation only small amounts of dabigatran etexilate reach systemic 
circulation. Thus, modulators of P-gp can affect intestinal absorption of dabigatran etexilate, 
but not its further disposition. Therefore, the staggered administration of a P-gp inhibitor at 
the time point of maximum dabigatran concentration (tmax) will cause a significantly lower 
increase in dabigatran bioavailability, because a great part of the compound has been already 
absorbed from the intestinal lumen. This effect has been proven for the P-gp inhibitors 
dronedarone [U11-2448-01] and verapamil [U09-1052-01], when given 2 h after dabigatran.    
Co-administration of the suggested P-gp inhibitor clarithromycin did not meaningfully affect 
the PK of dabigatran. Rifampicin, an inducer of P-gp reduced the bioavailability of free and 
total dabigatran. Conversely, the PK of co-administered P-gp substrates like digoxin or the 
inhibitors (clarithromycin, verapamil, quinidine, ketoconazole, amiodarone) was not affected 
by dabigatran etexilate confirming the in vitro results that neither dabigatran etexilate nor its 
intermediate metabolites or the active moiety dabigatran are inhibitors of P-gp. 
In the RE-LY study, the effect of concomitant use of verapamil, amiodarone or all potent P-
gp inhibitors on trough and 2 h dabigatran plasma concentrations was assessed descriptively. 
In RE-LY, a greater than 20% increase was not observed when amiodarone, verapamil, 
diltiazem or any strong P-gp inhibitor was co-administered. These findings were qualitatively 
in agreement to the results of the phase I studies though the magnitude of the effect was on 
average much lower in RE-LY. Accordingly, the difference in event rates (i.e., major or any 
bleeding) and efficacy endpoints (stroke, SEE) in patients receiving or not receiving 
verapamil, amiodarone or diltiazem were not pronounced and not clearly different from 
patients treated concomitantly with warfarin and a P-gp inhibitor [U09-3249-02].
Safety 
Dabigatran and dabigatran etexilate were well tolerated by healthy subjects. Overall, more 
than 1000 healthy volunteers have been included in phase I trials with dabigatran etexilate.
Adverse events were few, mild, and included primarily hematoma at the venipuncture site or 
need for prolonged compression for hemostasis on venous catheter removal at higher doses. 
Major bleedings were not observed in the Phase I trials. At the highest dose of dabigatran 
etexilate studied in humans, 400 mg three times daily as oral solution, 6 of 8 subjects reported 
mild bleeding such as hematoma or prolonged bleeding at a venous puncture site, or gingival 
bleeding [U00-1856].
In a further Phase I study [U06-1614-01] single doses of 600 mg, 750 mg, and 900 mg 
HPMC capsules were planned to be administered to find out the highest tolerable dose. After 
600 mg a 2-fold to 3-fold increase in the main coagulation parameter aPTT was achieved at 2 
to 4 h post dose. The only observed AEs were transient abdominal discomfort and a mild 


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phlebitis at the puncture site in one subject each. The dose levels 750 mg and 900 mg were 
not performed because a full therapeutic effect was already achieved with 600 mg.
For a more detailed description of the dabigatran profile, please refer to the current SmPC
[R18-2734].
1.2.4
Residual Effect Period
Based on an effective half-life of 33 h the Residual Effect Period (REP) of BI 1358894 has 
been determined to be 7 days. The REP for rosuvastatin and dabigatran is approximately 6 
and 3 days, respectively. This is the period after the last dose with relevant measurable drug 
levels and/or pharmacodynamic effects is still likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Based on in-vitro data BI 1358894 is an inhibitor of P-gp, BCRP, OATP1B1/1B3. This trial 
will be performed to test the inhibitory effect of BI 1358894 on these drug transporters in-
vivo. Dabigatran will be used as a model substrate of P-gp (Part 2) and rosuvastatin as a 
model substrate of BCRP and OATP1B1/1B3 (Part 1).
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the successful clinical development 
of BI 1358894 to improve the treatment of patients with major depressive disorder and 
borderline personality disorder. Subjects are exposed to risks of study procedures and risks 
related to the exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.


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Risk related to the administration of rosuvastatin (Part 1)
A single dose of 10 mg rosuvastatin has been well tolerated by healthy subjects in several 
clinical trials [c03246006-01, c08983809-01, c13060859-01]. 
The combined administration of 10 mg rosuvastatin with the OATP1B1/1B3-inhibitor 
rifampin in study 352.2100 increased the rosuvastatin exposure from 6.8 to 77 nmol/L (Cmax) 
and from 94 to 321 nmol/L*h (AUC0-inf.). This increase was well tolerated by healthy subjects 
[c23988236-01]. Comparable effects of rifampin on rosuvastatin exposure have been also 
described by Lai et al [R17-1790] and by Prueksaritanont et al [R15-4771].  
Rifampin is a strong and well characterised inhibitor of OATP1B1/1B3 and is therefore 
recommended for testing OATP inhibition [P12-05791]. Considering this it is assumed, that 
the potential effect of BI 1358894 on the OATP-substrate rosuvastatin does not exceed the 
strong effect of rifampin on rosuvastatin exposure described above. Based on the good 
tolerability observed in study 352.2100 no undue risk to healthy subjects is expected from the 
combined administration of 10 mg rosuvastatin and BI 1358894 in this trial. 
Risk related to the administration of dabigatran (Part 2)
In study 1160.60 a single dose of 600 mg dabigatran etexilate was well tolerated by healthy 
subjects [U06-1614-01]. Taking into account the dose proportional kinetics of dabigatran the 
well tolerated single dose of 600 mg provides a safety margin of 4 to the therapeutic dose of 
150 mg, which is used in Part 2 of this trial.
Dabigatran etexilate is a sensitive substrate of intestinal P-glycoprotein (P-gp). The effect of 
several P-gp inhibitors has been tested in healthy subjects. The strongest effects have been 
seen with a single dose of verapamil (+180% in dabigatran Cmax) and with multiple doses of 
ketoconazole (+150% in dabigatran Cmax und AUC). The observed increase in dabigatran 
exposure has been well tolerated by healthy subjects (1160.74 and 1160.101), which is in line 
with the described safety margin of 4, that has not been exceeded by any P-gp inhibitor.
Verapamil and ketoconazole are well characterized inhibitors of P-gp and therefore 
recommended for testing P-gp inhibition [P12-05791]. Considering that the potential effect of 
BI 1358894 on the P-gp substrate dabigatran etexilate does not exceed the observed strong 
effect of verapamil or ketoconazole on dabigatran exposure and taking into account the 
overall safety margin of 4, which has not been exceeded by any P-gp inhibitor, no undue risk 
to healthy subjects is expected from the combined administration of 150 mg dabigatran 
etexilate and BI 1358894 in this trial.
Drug-induced liver injury (DILI)
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety. See also Section 5.2.6.1.4, adverse events of special interest.


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Overall assessment
Considering the well characterised safety profile of the marketed drugs dabigatran and 
rosuvastatin, the safety profile observed so far with BI 1358894 and taking into account the 
planned single dose administration of all compounds the sponsor feels that the risk to 
participating subjects are minimised and justified when compared to the potential benefit that 
a successful clinical development of BI 1358894 could provide to the treatment of major 
depressive disorder and borderline personality disorder.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of 
 
rosuvastatin (Reference 1, Part 1) and 
 dabigatran (Reference 2, Part 2) given alone 
and together with 
 BI 1358894 (Test 1, Test 2) following oral administration.
2.1.2
Primary endpoints
In Part 1 the following pharmacokinetic parameters will be determined for rosuvastatin:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
In Part 2 the following pharmacokinetic parameters will be determined for dabigatran:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
In Part 1 the following pharmacokinetic parameter will be determined for rosuvastatin:

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)
In Part 2 the following pharmacokinetic parameter will be determined for 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)


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2.2.2.4
Safety and tolerability
Safety and tolerability of rosuvastatin, dabigatran and BI 1358894 will be assessed based on:  

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study consists of 2 trial parts. Each part follows a non-randomised, open-label, two-
period crossover design with a fixed sequence in healthy male subjects in order to compare 
the following test and reference treatments:
Treatments in Part 1

Reference (R1):  tablet Crestor®
 Filmtabletten [rosuvastatin]

Test (T1):  tablet Crestor®
 Filmtabletten together with tablet BI 1358894
Treatments in Part 2

Reference (R2):  capsule Pradaxa®
 Hartkapseln [dabigatran etexilate]

Test (T2):  capsule Pradaxa®
 Hartkapseln together with tablet BI 1358894
All treatments will be given after a high-fat high-calorie breakfast. In both trial parts the 
Reference treatment will always be followed by the Test treatment in a fixed sequence. The
treatment periods are separated by a wash-out phase of at least 7 days between the two drug 
administrations.
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.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between treatments is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
Because of the long terminal half-life of BI 1358894 (> 100 h), a fixed-sequence design was 
selected, in which BI 1358894 will be administered in the second study period only. The 
fixed-sequence design is not expected to lead to systematic errors in the estimation of the 
treatment effects since nonspecific time-effects are unlikely due to the short trial duration.
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 14 healthy male subjects each will enter either Part 1 or Part 2 of the study. 
They will be recruited from the volunteers' pool of the trial site. In case more than 2 subjects 
do not complete the respective trial part according to protocol, up to 6 replacement subjects 
may be included into each trial part. Thus, a maximum of 20 subjects might participate in 
each trial part.


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Only male subjects will be included in the study because no data on reproductive toxicology 
are available at this time.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with 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) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance (including positive or missing faecal occult blood test in Part 2, retest 
allowed)
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 


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11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 24 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked prolongation of QTc interval (such as QTc intervals that are repeatedly greater 
than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
23. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from time point of administration of trial medication until 
30 days thereafter. Sperm donation is not allowed from the time point of drug 
administration until 30 days thereafter.
The following study specific exclusion criteria apply:
24. Known hypersensitivity to rosuvastatin or dabigatran
25. Active liver disease including elevations of serum transaminases exceeding 2 times the 
upper limit of normal
26. Moderate or severe renal impairment (creatinine clearance < 60 ml/min based on 
estimated GFR according to CKD-EPI formula
27. Known myopathy
28. Concomitant treatment with systemic cyclosporine, ketoconazole, itraconazole and 
dronedarone or use of fibrates
29. Hypothyroidism
30. Personal or family history of hereditary muscular disorders
31. History of muscular toxicity with another statin or fibrate
32. Asian ancestry
33. Known active bleeding 


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34. Concomitant treatment with other anticoagulants (e.g. unfractionated heparin, low 
molecular weight heparins, heparin derivatives, oral anticoagulants)
35. Prosthetic heart valves 
36. Subjects who in the investigator’s judgement are perceived as having an increased risk of 
bleeding, for example because of: current or recent gastrointestinal ulceration, presence of 
malignant neoplasms, recent brain or spinal injury, recent brain / spinal/ ophthalmic 
surgery, recent intracranial hemorrhage, known or suspected oesophageal varices, 
arteriovenous malformations, vascular aneurysms, major intraspinal or intracerebral 
vascular abnormalities
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF 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 CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.4), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF


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In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, if at least 2 subjects of the same cohort have drug-related 
severe non-serious adverse events, or if at least 1 drug-related serious adverse event is 
reported
2. Violation of GCP, or the CTP impairing the appropriate conduct of the trial
3. The sponsor decides to discontinue the further development of the investigational product
3.3.5
Replacement of subjects
In case more than 2 subjects do not complete the respective trial part according protocol for 
any reason (including non PK evaluable subjects), the Clinical Trial Leader together with the 
Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects 
will be replaced. The maximum number of replacement subjects is 6 per trial part. Thus the 
total number of exposed subjects will not exceed 20 in each trial part.  A replacement subject 
will be assigned a unique trial subject number.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 1358894 has been manufactured, packed and labelled by BI Pharma GmbH & Co. KG. 
Rosuvastatin and dabigatran will be obtained from a public pharmacy.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the trial product 1 are given below:
Name:
Crestor®
 Filmtabletten
Substance:
rosuvastatin
Pharmaceutical formulation: tablet
Source:
Unit strength:
Posology:
Route of administration:
oral
Duration of use:
2 single doses in Part 1
The characteristics of the trial product 2 are given below:
Name:
Pradaxa®
 Hartkapseln
Substance:
dabigatran etexilate
Pharmaceutical formulation: hard capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
Route of administration:
oral
Duration of use:
2 single doses in Part 2
The characteristics of the trial product 3 are given below:
Substance:
BI 1358894
Pharmaceutical formulation: tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
Route of administration:
oral
Duration of use:
1 single dose in Part 1 and 2


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4.1.2
Selection of doses in the trial
Rosuvastatin and dabigatran are used in standard clinical doses.
In the FIM study 1402-0001 the administration of 
 BI 1358894 (fed conditions)
resulted in an exposure of Cmax = 
 and AUC0-24 = 
 (see 1.2.1). For the 
current trial this dose has been chosen to cover and to exceed the expected therapeutic 
exposure (Cmax,ss of 
 and an AUCss of 
 [c10354149]) to investigate the 
inhibitory effects in a worst-case scenario and to account for potential uncertainties in the 
prediction of the expected therapeutic exposure.
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment sequence investigated in each trial part, and each subject will be 
allocated to the same treatment sequence (R-T). The subjects will be allocated to a study 
subject number by drawing lots prior to first administration of trial medication in the morning 
of Day 1 of Visit 2. Once a subject number has been assigned, it cannot be reassigned to any 
other subject.      
All subjects of the respective study part may be treated in one cohort, i.e. all subjects may 
receive treatment on the same calendar day. In case this is not feasible (e.g., due to logistical 
or recruitment reasons), the group may be split into several cohorts as required. Treatment of 
all subjects on the same calendar day is acceptable (for discussion of study-associated risks 
see Section 1.4).
4.1.4
Drug assignment and administration of doses for each subject
Each trial part follows a two period crossover design. All subjects will receive the 2 
treatments in a fixed sequence (with treatment Reference is always followed by treatment 
Test). The treatments to be evaluated are outlined in the tables below: 
Table 4.1.4: 1
Dosage and treatment schedule in Part 1
Treatment
Substance
Formulation
Unit strength
Dosage
Total  dose
R1
(Reference)
rosuvastatin
tablet
 tablet, single dose
T1 (Test)
rosuvastatin
tablet
 tablet, together with 
BI 1358894
tablet
tablet
Table 4.1.4: 2
Dosage and treatment schedule in Part 2
Treatment
Substance
Formulation
Unit strength
Dosage
Total  dose
R2
(Reference)
dabigatran
hard capsule
capsule, single dose
T2 (Test)
dabigatran
hard capsule
capsule, together with 
BI 1358894
tablet
tablets


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The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
In each treatment period, a high-fat, high-calorie breakfast has to be consumed by the 
subjects within 30 min prior to the planned study drug administration. The composition of the 
standard high-fat, high-calorie breakfast is detailed in Table 4.1.4: 3; this meal is in 
compliance with the FDA guidance ‘Food-Effect Bioavailability and Fed Bioequivalence 
Studies’ [R03-2269]. For restrictions with regard to diet, see Section 4.2.2.2.
Table 4.1.4: 3
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (whole content) for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 
Subjects will be kept under close medical surveillance until 24 h after drug administration. 
During the first 6 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture).
The treatments will be separated by a wash-out phase of at least 7 days.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
Rosuvastatin and dabigatran will be obtained from a public pharmacy. Both drugs will be 
dispensed out of the original, unmodified packages.


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BI 1358894 will be provided by BI. It will be packaged and labelled in accordance with local 
law and the principles of Good Manufacturing Practice. For details of packing and the 
description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
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 in accordance with the recommended (labelled) storage conditions. If 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 contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

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 authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be given in the manner specified in the CTP.
The investigator or designee 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, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee 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.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.


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4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require 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 results of medical 
evaluations are acceptable.
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.
Part 2 only: The intake of analgesics known to inhibit cyclooxygenase (e.g. acetylsalicylic 
acid, ibuprofen and diclofenac) is strongly forbidden starting from 1 week prior to first study
drug administration until last PK-sampling. The same refers to the use of anticoagulants 
(heparins, heparin ointment).
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 6 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 3), the water administered with the drug, and an additional 
240 mL of water at 2 h , 4 h and 6 h post-dose (mandatory for all subjects). From lunch until 
24 h post-dose, total fluid intake is restricted to 2500 mL.
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until last PK 
sampling of the trial.
Poppy-seeds containing products should not be consumed starting 3 days before trial drug 
administration until last PK sampling of the respective treatment period.
Alcoholic beverages are not permitted starting 48 h before trial drug administration until the 
last PK sampling of the respective treatment period.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed during the in-house confinement at the trial site.
Smoking is not allowed during in-house confinement.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.


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Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication 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.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported), 
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.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap Pro 100, 
) at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart.
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. 
Fecal occult blood testing, using an immunochemical test kit for hemoglobin, will be 
performed by the laboratory at the time points indicated in the Flow Chart for Part 2.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A1
B1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes 
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils Bands;  
Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
INR (International Normalization Ratio)
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT
ALT [Alanine transaminase] /GPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
-
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI3
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
X
X
X
X
X
X
X
-
X
-
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium
X
X
X
X
X
X
Urinalysis2 (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
-
-
-
-
-
-
-
-
-
Urine sediment2
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous
epithelial cells, erythrocytes, leukocytes)
1 A to be done at screening examination, B at Follow-up examination. 
2 Microscopic examination if erythrocytes, leukocytes, or protein are abnormal in urine
3 Estimated glomerular filtration rate according to CKD-EPI formula [R12-1392]


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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except drug screening, it is planned to perform these tests during screening only. Drug 
screening will be performed at screening and prior to each treatment period.
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-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410,
or comparable test system) will be performed prior to 
each treatment period, 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
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of 
drug screening tests. These tests will be performed at the trial site using the Multidrogen-
Pipettiertest M-10/14-PDT, or comparable test systems.
FOB plus® test (Part 2 only): The subjects will receive a test tube with an integrated bar for 
stool sampling. On the next occasion they will take three samples from the stool with the 
collection bar and give it into the test tube. The test tubes should be closed carefully to not 
destroy the collection bar. These samples will be analysed for occult blood in faeces by 
immunological reaction according to the manufacturers instruction. As subjects may not be 
able to defecate at the trial site in the morning of the respective visit they may collect the 
specimen at home and bring the test specimen to the trial site.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System,
 
) at the times provided in the Flow Chart. 


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To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
 Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
Not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.


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Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is 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. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the EDC system, an electronic 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.
Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:


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
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained encephalo-
pathy, unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without 
lab results (ALT, AST, total bilirubin) available, the Investigator should make sure 
that these parameters are analysed, if necessary in an unscheduled blood test. Should 
the results meet the criteria of hepatic injury alert, the procedures described in the 
DILI checklist should be followed.
Intensity (severity) of AEs
5.2.6.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
5.2.6.1.6
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 reduced)


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
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
time, 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 carefully 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, intensity of the event, and 
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 until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
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.


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
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 any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis of rosuvastatin and dabigatran
For quantification of rosuvastatin (Part 1) and dabigatran (Part 2) concentrations in plasma, 
2.7 mL of blood will be drawn from an antecubital or forearm vein into an K2-EDTA 
(dipotassium 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 venepuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained per 
analyte and stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of 
plasma. The process from blood collection until transfer of plasma aliquots into the freezer 
should be completed in less than 90 min, with interim storage of blood samples and aliquots 
at room temperature. The time each aliquot was placed in the freezer will be documented.
Until transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. At the analytical laboratory, the plasma 
samples will be stored at approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the CTR is 
archived. It is planned to use the back-up samples (2nd aliquots of rosuvastatin and dabigatran 
samples) to get a profile of BI 1358894. Therefore, the second aliquot will be transferred to 
the analytical laboratory for BI 1358894 analytics after confirmation of TCPK.
5.3.2.2
Blood sampling for pharmacokinetic analysis of BI 1358894 and BI 1361608
For quantification of BI 1358894 and BI 1361608 (Part 1 and 2) concentrations in plasma, 
2.7 mL of blood will be drawn from an antecubital or forearm vein into an K2-EDTA 
(dipotassium 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 venepuncture with a metal needle.


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The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained per 
analyte and stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of 
plasma. The process from blood collection until transfer of plasma aliquots into the freezer 
should be completed in less than 90 min, with interim storage of blood samples and aliquots 
at room temperature. The time each aliquot was placed in the freezer will be documented.
Until transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after CTR is archived. 
5.3.2.3
Blood sampling for pharmacokinetic analysis 
For quantification 
 concentrations in plasma, approx. 2.7 mL of 
blood will be drawn from an antecubital or forearm vein into an K2-EDTA-anticoagulant 
blood drawing tube at the times indicated in the Flow Chart of Trial Part 1. Blood will be 
withdrawn by means of either an indwelling venous catheter or by venepuncture with a metal 
needle.
The EDTA-anticoagulated blood samples will be centrifuged for at least 15 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Centrifugation should be done within 60 
minutes after sampling. One plasma aliquot will be obtained and stored in polypropylene 
tubes. The aliquot should contain at least 1.0 mL of plasma. The process from blood 
collection until transfer of plasma aliquots into the freezer should be completed in less than 
90 min, with interim storage of blood samples and aliquots on ice-bath or refrigerated. 
 
The time each sample 
was placed in the freezer will be documented. Until transfer on dry ice to the analytical 
laboratory, the aliquots will be stored upright at approximately -20°C or below at the trial 
site. At the analytical laboratory, the plasma samples will be stored at approximately -20°C or 
below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations. However, only data related to the analyte will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the CTR is archived.


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5.3.3
Analytical determinations
5.3.3.1
Analytical determination of rosuvastatin plasma concentration
Rosuvastatin concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. 
Plasma samples dedicated to the analysis of rosuvastatin are transferred to:
5.3.3.2
Analytical determination of dabigatran plasma concentration
Dabigatran concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. 
Plasma samples dedicated to the analysis of dabigatran are transferred to:
5.3.3.3
Analytical determination of BI 1358894 and BI 1361608 plasma concentration
BI 1358894 and BI 1361608 concentrations in plasma will be determined by a validated LC-
MS/MS (liquid chromatography tandem mass spectrometry) assay. All details of the 
analytical method will be available prior to the start of sample analysis. 
Plasma samples dedicated to the analysis of BI 1358894 and BI 1361608 are transferred to:
5.3.3.4
Analytical determination of 
plasma concentration
 concentrations in plasma will be determined by a validated LC-
MS/MS (liquid chromatography tandem mass spectrometry) assay. All details of the 
analytical method will be available prior to the start of sample analysis.
Plasma samples dedicated to the analysis 
are transferred to:


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5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
5.6.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
obtained at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the Pharma ADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the CTR. However, the data may be part of the CTR, if necessary.
5.7
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 and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.4 are 
generally used assessments of drug exposure. 


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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 the end of trial examination are provided 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 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, and laboratory tests will be 
± 60 min.
Starting from a planned time of 48 hours after drug administration (and beyond) a time 
window of +/- 120 minutes will be allowed for all procedures.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs recor-
dings have to be done first. Furthermore, if several measurements including venepuncture are 
scheduled for the same time, venepuncture should be the last of the measurements due to its 
inconvenience to the subject and possible influence on physiological parameters.
For planned blood 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 
the determination of pharmacokinetic parameters.
The subjects may have their dinner together in all trial periods.
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
After having been informed about the trial, all subjects will provide 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.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.3).
6.2.2
Treatment period
Each subject is expected to participate in 2 treatment periods (Part 1: Days 1-5 in each period, 
Part 2: Day 1-4 in each period). In both trial parts at least 7 days will separate drug 
administrations in the first and second treatment period.


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On Day 1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of 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
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.6.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as 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 a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the relative bioavailability of 
 
rosuvastatin (Part 1, Reference 1) and 
 dabigatran (Part 2, Reference 2) given alone 
compared to a combined administration with 
 BI 1358894 (Part 1 - Test 1, Part 2 -
Test 2) following oral administration on the basis of the primary and secondary 
pharmacokinetic endpoints, as listed in Sections 2.1.2 and 2.1.3. Both trial parts are designed 
to allow intra-subject comparisons and will be evaluated statistically by use of a linear model 
for logarithmically transformed PK endpoints. 
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments. These pharmacokinetic parameters will be assessed by descriptive statistics.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.3.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of rosuvastatin (Part 1) / dabigatran (Part 2) given alone 
compared with a combined administration with BI 1358894 will be estimated by the ratios of 
the geometric means (test/reference), and their corresponding 2-sided 90% confidence 
intervals (CIs) will be provided. This method corresponds to the two one-sided t-test 
procedure, each at the 5% significance level. Since the main focus is on estimation and not 
testing, a formal hypothesis test and associated acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were entered and treated 
with at least one dose of study drug. The treated set will be used for safety analyses.
Pharmacokinetic analysis set (PKS): This set includes all subjects in the treated set 
(TS) who provide at least one PK endpoint that was defined as primary or secondary 
and was not excluded due to a protocol deviation relevant to the evaluation of PK or 
due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment.
Descriptive and model based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IQRM plan, IPDs will be identified no later than in 
the Report Planning Meeting, and the IPD categories will be updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for rosuvastatin, dabigatran, BI 
1358894 and BI 1361608 will be calculated according to the relevant SOP of the Sponsor 
(001-MCS-36-472). 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
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). 
7.3.1
Primary endpoint analyses
Primary analyses
The primary endpoints (refer to Section 2.1.2) 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).
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subjects and treatment. The effect


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‘subjects’ will be considered as random, whereas ‘treatment’ will be considered as fixed. The 
model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response measured on subject m receiving treatment k,
= the overall mean,
sm = the 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.
where s ~ N(0, σ
) i. i. d. , e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
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 (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
‘subject’ considered as fixed effect.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.4. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the assigned treatment will be discussed in the minutes of the 
Report Planning Meeting or Decision Log).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate 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 the screening period, those between first trial medication intake and end of 
REP (see Section 1.2.4) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ‘follow-up’. 
In case of two or more treatments, the follow-up will be summarized according to the 
previous treatment. These assignments including the corresponding time intervals will be 
defined in detail in the TSAP. Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events 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, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline. Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.


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7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
In each trial part, the subjects receive all treatments in the same order, thus no randomisation 
for the treatment assignment is performed (see also Section 4.1.3).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 14 subjects in each trial part (accounting for up to 2 dropouts 
or non PK evaluable subjects). The planned sample size is not based on a power calculation 
but is considered sufficient to achieve the aims of this exploratory trial. With this sample size, 
the following precision in estimating the ratio of geometric means (test/reference) can be 
expected with 95% probability. Precision is defined as the ratio of upper CI limit to the 
relative BA estimate. Note that the precision is independent of the actual ratio of geometric 
means.
The observed intra-individual coefficient of variation (gCV) for rosuvastatin and for 
dabigatran in previous trials [c08983809-01, c13060859-01, U09-3249-02] were ranging 
from 10% to 30%.
For various assumptions around the gCV, Table 7.7: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (test/reference). For 
illustrative purposes, the expected 90% confidence intervals with 95% tolerance probability 
are displayed for different values of the ratios T/R of geometric means.


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Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a fixed sequence, two period 
crossover trial (N=12)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
10.0
1.103
50.0
45.34
55.14
10.0
10.0
1.103
1.103
100.0
150.0
90.68
136.02
110.28
165.41
20.0
1.214
50.0
41.18
60.72
20.0
20.0
1.214
1.214
100.0
150.0
82.35
123.53
121.43
182.15
30.0
1.334
50.0
37.49
66.68
30.0
30.0
1.334
1.334
100.0
150.0
74.99
112.48
133.36
200.03
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit,  = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to 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 retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the
Phase I unit – the 
validated ClinBase
system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:


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
Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source docu-
ments/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents descry-
bed in Section 8.3.1. The sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) 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.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.


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Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report. The sponsor will submit to the EU database a summary of the final trial results. 
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
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 Clinical Trial Managers, Clinical 
Research Associates, and investigators of participating trial sites
BI 1358894 will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH & Co. 
KG, Biberach, Germany. Rosuvastatin and dabigatran will be obtained from a public 
pharmacy in Germany.
Pharmacokinetic analysis of rosuvastatin and dabigatran is done by 
.
Pharmacokinetic analysis of BI 1358894 and its metabolite is done by 
 
Pharmacokinetic analysis 
 is done by Boehringer Ingelheim Pharma GmbH 
& Co. KG, Biberach, Germany.
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs. 
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P06-11895
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, 
Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath 
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longer-term outcomes in depressed outpatients requiring one or several 
treatment steps: a STAR*D report. Am J Psychiatry 2006;163(11):1905-
1917.
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U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER). 
Guidance for industry: drug interaction studies - study design, data analysis, 
implications for dosing, and labeling recommendations (draft guidance, 
February 2012 (this guidance document is being distributed for comment 
purposes only)). 
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rmation/Guidances/ucm292362.pdf (access date: 14 May 2012) ; U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER); 2012.
P14-07833
Neuvonen PJ, Backman JT, Niemi M. Pharmacokinetic comparison of the 
potential over-the-counter statins simvastatin, lovastatin, fluvastatin and 
pravastatin. Clin Pharmacokinet 2008. 47(7):463-474.
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:1-
9.
R06-2872
Trivedi MH, Rush AJ, Wisniewski SR, Warden D, McKinney W, Downing 
M, Berman SR, Farabaugh A, Luther JF, Nierenberg AA, Callan JA, 
Sackeim HA. Factors associated with health-related quality of life among 
outpatients with major depressive disorder: a STAR*D report. J Clin 
Psychiatry 2006;67(2):185-195.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R12-1392 
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI). A new equation to 
estimate glomerular filtration rate. Ann Intern Med 2009; 150(9):604-612.
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide. 
http://www.statsols.com/wp-
content/uploads/2013/10/nQ70_version2_manual.pdf 
(access date: 20 March 2015) ; Los Angeles: Statistical Solutions; 2007.


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R15-3888
Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao 
GL, Tsvetkov E, Rodig SJ, Veer A van't, Meloni EG, Carlezon WA, 
Bolshakov VY, Clapham DE. Essential role for TRPC5 in amygdala 
function and fear-related behavior. Cell 2009;137(4):761-772.
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Prueksaritanont T, Chu X, Evers R, Klopfer SO, Caro L, Kothare PA, 
Dempsey C, Rasmussen S, Houle R, Chan G, Cai X, Valesky R, Fraser IP, 
Stoch A. Pitavastatin is a more sensitive and selective organic anion-
transporting polypeptide 1B clinical probe than rosuvastatin. Br J Clin 
Pharmacol 2014. 78(3):587-598.
R16-5350
Fowler MA, Sidiropoulou K, Ozkan ED, Phillips CW, Cooper DC. 
Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent 
brain. Plos One 2007;2(6):e573.
R16-5472
Koenigsberg HW, Denny BT, Fan J, Liu X, Guerreri S, Mayson SJ, et al. 
The neural correlates of anomalous habituation to negative emotional 
pictures in borderline and avoidant personality disorder patients. Am J 
Psychiatry 2014;171(1):82-90.
R16-5473
Mandell D, Siegle G, Shutt L, Feldmiller J, Thase ME. Neural substrates of 
trait ruminations in depression. J Abnorm Psychol 2014;123(1):35-48.
R16-5474
IsHak WW, Elbau I, Ismail A, Delaloye S, Ha K, Bolotaulo NI, et al. 
Quality of life in borderline personality disorder. Harvard Rev Psychiatry 
2013;21(3):138-150.
R16-5475
McClintock SM, Husain MM, Wisniewski SR, Nierenberg AA, Stewart 
JW, Trivedi MH, et al. Residual symptoms in depressed outpatients who 
respond by 50 % but do not remit to antidepressant medication. J Clin 
Psychopharmacol 2011;31(2):180-186.
R16-5476
Links PS, Heslegrave R, Reekum R van. Prospective follow-up study of 
borderline personality disorder: prognosis, prediction of outcome, and axis 
II comorbidity. Can J Psychiatry 1998;43(3):265-270.
R16-5477
Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Pfohl B, Widiger TA. 
The borderline diagnosis II: biology, genetics, and clinical course. Biol 
Psychiatry 2002;51(12):951-963.
R16-5483
Ellison WD, Rosenstein L, Chelminski I, Dalrymple K, Zimmerman M. 
The clinical significance of single features of borderline personality 
disorder: anger, affective instability, impulsivity, and chronic emptiness in 
psychiatric outpatients. J Personal Disord 2016;30(2):261-270.
R17-1790
Lai Y, Mandlekar S, Shen H, Holenarsipur VK, Langish R, Rajanna P, et al. 
Coproporphyrins in plasma and urine can be appropriate clinical biomarkers 
to recapitulate drug-drug interactions mediated by organic anion 
transporting polypeptide inhibition. J Pharmacol Exp Ther 2016;358:397-
404.


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R17-2886
Crestor 5 mg/10 mg/20 mg Filmtabletten (AstraZeneca), 
verschreibungspflichtig (Fachinformation (Zusammenfassung der 
Produkteigenschaften/SPC), Stand der Information: Dezember 2016). 2016
R18-2734
Pradaxa 150 mg Hartkapseln (Boehringer Ingelheim) (Fachinformation, 
Stand der Information: Juni 2018). 2018
R19-1574
Crestor 5 mg/10 mg/20 mg Filmtabletten (AstraZeneca), 
verschreibungspflichtig (Fachinformation (Zusammenfassung der 
Produkteigenschaften/SmPC), Stand der Information: Oktober 2018). 2018
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
U00-1856
. Safety, 
pharmacodynamics and pharmacokinetics after multiple oral doses of 50, 
100, 200 and 400 mg BIBR 1048 MS solution administered t.i.d. for 7 days 
to healthy volunteer subjects. An open study, placebo-controlled, 
randomized, double blind at each dose level. Trial 1160.2. 22-Aug-2000.
U06-1614-01 
 Safety, pharmacodynamics and
pharmacokinetics after single oral administration of 600 mg, 750 mg and 
900 mg dabigatran etexilate as capsule in healthy subjects. A randomised, 
placebo-controlled study, double blind at each dose level (1160.60). 28-Jul-
2006.
U09-1052-01
Relative 
bioavailability of a single oral dose of 150 mg dabigatran etexilate with or 
without oral administration of verapamil in two different dosages (240 and 
480 mg daily), two different formulations (IR vs. ER) in healthy male and 
female volunteers (open-label, fixed-sequence design), and relative 
bioavailability of a single oral dose of 150 mg dabigatran given with or 
without a single oral dose of 120 mg verapamil administered at different 
time points related to dabigatran dosing. (1160.74). 30-Mar-2009
U09-3249-02
. Randomized Evaluation of 
Long term anticoagulant therapY (RE LY®) comparing the efficacy and 
safety two blinded doses of dabigatran etexilate with open label warfarin for 
the prevention of stroke and systemic embolism in patients with non-
valvular atrial fibrillation: prospective, multi-centre, parallel-group, non-
inferiority trial (RE-LY STUDY). Trial 1160.26. 05-Jan-2011
U11-2448-01
Relative 
bioavailability of a single dose of 150 mg dabigatran etexilate (capsule) 
when administered alone or in combination with a single dose of 400 mg 
Dronedarone (tablet) or in combination with 400 mg bid Dronedarone 
(tablet) at steady state in healthy male and female volunteers (1160.112). 
19-Oct-2011


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001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c10354149
 Investigator's brochure BI 1358894 in Major Depressive
Disorder and Borderline Personality Disorder, 1402.P1 & 1402.P2, 
23 Nov 2018. 
c03246006-01
. Relative bioavailability of a single 
oral dose of digoxin, furosemide, metformin, and rosuvastatin given alone 
and all together as a cocktail, and investigation of the effect of increased 
doses of metformin or furosemide on relative bioavailability of the other 
cocktail compounds in healthy male subjects. Trial 352.2082. July 2015.
c08983809-01
 The effect of different doses of 
metformin or furosemide on rosuvastatin pharmacokinetics following oral 
administration in healthy male subjects (an open-label, randomised, single-
dose,six-way crossover study). Trial 352.2094. August 2016.
c13060859-01
 Investigation of mutual 
pharmacokinetic interactions of digoxin, furosemide, metformin, and 
rosuvastatin given all together as a probe cocktail for key drug transporters 
(an open-label, randomised, single-dose, five-way crossover study). Trial 
352.2096. July 2017
c23988236-01
 The effect of potent inhibitors of 
drug transporters (verapamil, rifampin, cimetidine, probenecid) on 
pharmacokinetics of a transporter probe drug cocktail consisting of digoxin, 
furosemide, metformin and rosuvastatin (an open-label, randomised, 
crossover trial in three parts). Report 352.2100. 29-Apr-2019


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10.
DESCRIPTION OF GLOBAL AMENDMENT(S)
10.1
GLOBAL AMENDMENT 1
Date of amendment
28 August 2019
EudraCT number
EU number
2019-002763-10
BI Trial number
1402-0009
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
Relative bioavailability of rosuvastatin (Part 1) and 
dabigatran (Part 2) given alone and together with BI 
1358894 in healthy male subjects (open, single-dose, 
fixed sequence, two-period crossover design in each 
trial part)
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
1. Section 3.3.4.3
2. Synopsis, section 3.3, section 3.3.5
3. section 3.3.3
4. title page, synopsis
Description of change
1. trial stopping criterion 1 has been extended
2. maximum number of replacement subjects has 
been defined
3. trial specific exclusion criteria have been added 
based on contraindications given in the SmPC
4. doses of rosuvastatin, dabigatran and BI 1358894 
have been removed from study title
Rationale for change
1-3: request of Competent Authority
4: BI-internal recommendation


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c27867536
2.0
clinical-trial-protocol-version-02
Relative bioavailability of rosuvastatin (Part 1) and dabigatran (Part 2) given alone
and together with BI 1358894 in healthy male subjects (open, single-dose, fixed
sequence, two-period crossover design in each trial part) 
Author-Trial Clinical
Pharmacokineticist
28 Aug 2019 16:19 CEST
Author-Trial Statistician
28 Aug 2019 16:37 CEST
Approval-Therapeutic Area 
29 Aug 2019 09:19 CEST
Verification-Paper Signature
Completion
29 Aug 2019 09:22 CEST
Approval-Team Member Medicine
29 Aug 2019 10:08 CEST
Author-Clinical Trial Leader
29 Aug 2019 17:14 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c27867536
2.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c30563921-01
BI Trial No.:
1402-0009
Title:
Relative bioavailability of rosuvastatin (Part 1) and dabigatran
(Part 2) given alone and together with BI 1358894 in healthy male 
subjects (open, single-dose, fixed sequence, two-period crossover 
design in each trial part)
(including Protocol Amendment No.1 [c27867536-02])
Investigational
Product:
BI 1358894
Responsible trial 
statisticians:
Phone:
Fax:
Date of statistical 
analysis plan:
21 JAN 2020 SIGNED
Version:
1
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3.3 
Safety endpoints ..................................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINTS...................................................................................20
7.4.1
Primary analysis of the primary endpoints......................................................20
7.4.2.1
Further exploratory analyses.................................................................................21
7.5
SECONDARY ENDPOINTS.............................................................................22
7.5.1
Key secondary endpoints....................................................................................22
7.5.2
Secondary endpoints...........................................................................................22
7.6.2
Safety endpoints ..................................................................................................22
7.7
EXTENT OF EXPOSURE.................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................23


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7.8.1
Adverse Events ....................................................................................................23
7.8.2
Laboratory data ..................................................................................................24
7.8.3
Vital signs.............................................................................................................25
7.8.4
ECG......................................................................................................................25
7.8.5
Others...................................................................................................................25
8.
REFERENCES....................................................................................................26
10.
HISTORY TABLE..............................................................................................28


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................12
Table 6.3: 1
Subject sets analysed........................................................................................16
Table 10: 1
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
website: glossary
Term
Definition / description
ALT
Alanine transaminase
AST
Aspartate transaminase
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
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BMI
Body mass index
BWU
Bioavailability/Bioequivalence, Within-Subject Design, uncontrolled
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
gCV
Geometric coefficient of variation
gMean
Geometric mean
LLT
Lower level term
IQRMP
Integrated Quality and Risk Management Plan
λz
Terminal rate constant of the analyte in plasma
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
po
Orally
PKS
Pharmacokinetic parameter analysis set
Q1
1st quartile
Q3
3rd quartile
qd
Once daily


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Term
Definition / description
R 
Reference treatment
RAGe
Report Appendix Generator system
REP
Residual effect period
RPM
Report Planning Meeting
SD
Standard deviation
SOC
System organ class
T
Test treatment
TS
Treated set
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP). 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.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) and pharmacodynamics (PD) parameters will be calculated using 
Phoenix WinNonlinTM software (version 6.3 or higher, Certara USA Inc., Princeton, NJ, 
USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: 
In Part 1 the following pharmacokinetic parameters will be determined for rosuvastatin:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
In Part 2 the following pharmacokinetic parameters will be determined for dabigatran:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP:
In Part 1 the following pharmacokinetic parameter will be determined for rosuvastatin:

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)
In Part 2 the following pharmacokinetic parameter will be determined for 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)


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5.3.3 
Safety endpoints
Section 2.2.2.4 of the CTP: Safety and tolerability of rosuvastatin, dabigatran and 
BI 1358894 will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment sequences 
and selection of doses, please see CTP, Sections 3 and 4.
The study consists of 2 trial parts. It is planned that 14 healthy male subjects each will enter 
either Part 1 or Part 2 of the study. Each part follows a non-randomised, open-label, two-
period crossover design with a fixed sequence in healthy male subjects in order to compare
the test (T1, T2) and reference (R1, R2) treatments as defined in Table 6.1: 1 below. 
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
Part 1
R1
Rosuvastatin, 10 mg tablet, qd
Rosuvastatin
T1
BI 1358894, 2*100 mg tablet + Rosuvastatin, 10 mg tablet, qd
BI+Rosuvastatin
Part 2
R2
Dabigatran etexilate, 150 mg capsule, qd
Dabigatran
T2
BI 1358894, 2*100 mg tablet + Dabigatran etex., 150 mg cap, qd
BI+Dabigatran
Section 1.2.4 of the CTP: Based on an effective half-life of 33 h the Residual Effect Period 
(REP) of BI 1358894 has been determined to be 7 days. The REP for rosuvastatin and 
dabigatran is approximately 6 and 3 days, respectively. This is the period after the last dose 
with relevant measurable drug levels and/or pharmacodynamic effects is still likely to be 
present.
The following separate study phases will be defined for the analyses of adverse events (AEs):
Part 1:

Screening (ranging from 0:00 h on day of informed consent until first administration
time of Rosuvastatin in treatment period 1)


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
On treatment
o
Rosuvastatin alone (labelled “Rosuvastatin”, including REP; i.e. ranging 
from the time of first administration of Rosuvastatin in treatment period 1 until 
6 days thereafter)
o
BI+Rosuvastatin (ranging from time of administration of BI 1358894 + 
Rosuvastatin in treatment period 2 until 7 days thereafter)

Follow-up (FU) (labelled “F/U Rosuvastatin”, “F/U BI+Rosuvastatin”)
o
F/U Rosuvastatin (ranging from the end of REP of Rosuvastatin in treatment 
period 1 until the administration of BI+Rosuvastatin in period 2 or until trial
termination, whatever occurs first)
o
F/U BI+Rosuvastatin (ranging from the end of REP of BI 1358894 in 
treatment period 2 until trial termination)
Part 2:

Screening (ranging from 0:00 h on day of informed consent until first administration
time of Dabigatran in treatment period 1)

On treatment
o
Dabigatran alone (labelled “Dabigatran”) (ranging from the time of first 
administration of Dabigatran in treatment period 1 until 3 days thereafter)
o
BI+Dabigatran (ranging from time of administration of BI 1358894 + 
Dabigatran in treatment period 2 until 7 days thereafter)

Follow-up (FU) (labelled “F/U Dabigatran”, “F/U BI+Dabigatran”)
o
F/U Dabigatran (ranging from the end of REP of Dabigatran in treatment 
period 1 until the administration of BI+Dabigatran in period 2 or until trial
termination, whatever occurs first)
o
F/U BI+Dabigatran (ranging from the end of REP of BI 1358894 in 
treatment period 2 until trial termination)
Section 7.3.4 of the CTP: Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.


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The following AE displays will be provided in the report:
Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the CTR 
displays:
In these displays, the on-treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening and Follow up periods will not be included in this 
analysis.
The following totals will be provided in addition (Section 15.3 only):
a total over all on treatment phases of study part 1 included in this analysis ("Total –
Part 1")
a total over all on treatment phases of study part 2 included in this analysis ("Total –
Part 2")
for ClinicalTrials.gov and EudraCT only: a total over all on treatment phases included in 
this analysis ("Total")
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays screening and follow-up 
periods will be included and no totals will be provided.
Table of vital signs will present results by the above mentioned on treatment phases
(Rosuvastatin, BI+Rosuvastatin or Dabigatran, BI+Dabigatran).
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide. 
In outputs for ClinicalTrials.gov and EudraCT both study parts will be combined in one table.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Section 7.3 of the CTP: Important protocol deviation (IPD) categories will be suggested in 
the IQRM plan, IPDs will be identified no later than in the Report Planning Meeting, and the 
IPD categories will be updated as needed.


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Consistency check listings (for identification of deviations 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, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
an accompanying Excel spreadsheet (3). Categories which are considered to be iPDs in this 
trial are defined in the integrated quality and risk management plan (IQRMP). If the data 
show other iPDs, the definition in the IQRMP will be supplemented accordingly by the time 
of the Report Planning Meeting.
The iPDs will be summarised and listed.
6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were entered and treated with 
at least one dose of study drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation of 
PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he contributes 
only one PK parameter value for one period to the statistical assessment. Descriptive 
and model based analyses of PK parameters will be based on the PKS.
PKS also will be used for the descriptive analyses of PD parameters.
[…]
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.


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Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

A pre-dose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of PK/PD endpoints 
X
Safety parameters
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035 (4)).
Missing data and outliers of PK/PD data are handled according to BI standards (see 001-
MCS-36-472_RD-01) (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before trial medication administration
in each treatment period.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and the end of trial 
examination are provided in the CTP Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, and laboratory tests will be 
± 60 min.
Starting from a planned time of 48 hours after drug administration (and beyond) a time 
window of +/- 120 minutes will be allowed for all procedures.
The acceptable deviations from the scheduled time for PK/PD blood sampling will be:
± 15 min for planned times >0:00 and ≤ 4 h after trial drug administration
± 30 min for planned times > 4h and <48h
± 120 min for planned times ≥ 48h
The pre-dose sample at planned time -3h is to be drawn within a 3 h-period prior to the trial 
drug administration.
Adherence to time windows will be checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement. 


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7.
PLANNED ANALYSIS
If not stated otherwise, the trial parts will be evaluated separately.
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.4 and Section 7.5.2) will
also be performed by 
and will be presented in Section 15.5 of 
the CTR and in Appendix 16.1.13.3.
Descriptive data analysis of PK/PD endpoints and concentrations will be performed by the 
at
and will be 
presented in Section 15.6 and Section 15.7 of the CTR.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (6)) with the exception of those generated for PK-calculations (7).
The individual values of all subjects will be listed, sorted by sequence group, subject number, 
visit and actual treatment (if appropriate). 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK/PD parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile


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The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%). Percentages 
will be rounded to one decimal place and will be based on all subjects in the respective 
subject set whether they have non-missing values or not. The category 'missing' will be 
displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The ADS ADPP (PK parameters) contains column variables indicating inclusion/exclusion 
(APEXC) of a PK parameter and an analysis flag comment (APEXCO). All analyses based 
on the PKS will include parameters if they are not flagged for exclusion, that is APEXC is 
equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (11).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised in total, separately for trial part 1 and part 2.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM. 
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations of trial medication will provide additional confirmation of 
compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
Relative bioavailability of rosuvastation (part 1) and dabigatran (part 2) is to be determined 
on the basis of the primary endpoints AUC0-∞, Cmax (see Section 5.1). 
7.4.1
Primary analysis of the primary endpoints
Section 7.3.1 of the CTP: The statistical model used for the analysis of the primary 
endpoints will be an analysis of variance (ANOVA) model on the logarithmic scale. That is, 
the PK endpoints will be log-transformed (natural logarithm) prior to fitting the ANOVA 
model. This model will include effects accounting for the following sources of variation: 
subjects and treatment. The effect ‘subjects’ will be considered as random, whereas 
‘treatment’ will be considered as fixed. The model is described by the following equation:
ykm = µ + sm + τk + ekm, where

ykm = logarithm of response measured on subject m receiving treatment k,

µ = the overall mean,


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
sm = the effect associated with the mth subject, m = 1, 2, ..., n

τk = the kth treatment effect, k = 1, 2,

ekm = the random error associated with the mth subject who received treatment k.
where sm ~ N(0, σw
2) i. i. d. , ekm ~ N(0, σw
2) i.i.d. and sm, ekm are independent random
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
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 (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the
residual error from the ANOVA and quantiles from the t-distribution. These quantities will
then be back-transformed to the original scale to provide the point estimate and 90% CIs for
each endpoint.
The implementation for this analysis will be accomplished by using the CSD macros. The 
following SAS code can be used:
PROC MIXED DATA=indata;
CLASS subject treatment;
MODEL logkp = treatment / HTYPE = 2 SOLUTION CL alpha=0.1;
RANDOM subject;
LSMEANS treatment /CL alpha=(1-&CONFLEV/100) pdiff=control("Ref_trt");
RUN;


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The secondary PK parameter AUC0-tz for rosuvastatin (part 1) and dabigatran (part 2) will be 
assessed using the same methods as described for the primary endpoints.
7.6.2
Safety endpoints
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 1358894.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
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 and will be based on BI standards as 
presented in “Analysis and Presentation of Adverse Event Data from Clinical Trials –
Display Template” [BI-KMED-BDS-HTG-0041] (8). All analyses of AEs will be based on 
the number of subjects with AEs and not on the number of AEs.
For analysis multiple AE occurrence data on the eCRF will be collapsed into one AE 
provided that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest (AESI))

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to screening or on-treatment phases as defined in Section 6.1.
AEs will be analysed based on actual treatments, as defined in Table 6.1: 1
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 


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etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
According to ICH E3 (9), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant AE 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.
An overall summary of AEs (including AESIs and other significant AEs) will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (9), for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs. In addition, the frequency of subjects with AEs will be summarised by treatment, 
worst intensity, primary system organ class (SOC) and preferred term (PT).
The SOCs and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards [BI-KMED-BDS-HTG-0042] (10). 
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possibly
clinically significant will be flagged in the data listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significantly 
abnormal or not (at the RPM/DBLM at the latest). 


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Descriptive statistics of laboratory data including change from baseline (=screening) will be 
calculated by planned time point based on the worst value of the subject at that planned time 
point (or assigned to that planned time point).
7.8.3
Vital signs
For vital signs (blood pressure and pulse rate), descriptive statistics including change from 
baseline will be calculated by planned time point based on the last value of the subject at that 
planned time point (or assigned to that planned time point). In the listing the difference from 
baseline will also be displayed.
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (if they pre-exist prior to trial inclusion) or will be reported as AEs (if they 
occurred during treatment), and will be analysed as such.
7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition
(i.e., a condition already existent before intake of study drug) or as AE and will be
summarised as such. No separate listing or analysis of physical examination findings will be
prepared.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON.
3.
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED.
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
7.
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
8.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
9.
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.
10. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.
11. 001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, 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
1
21-JAN-2020
None
This is the final TSAP.