Clinical trial NCT04257032
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2020-02-13; Completion date: 2020-09-23
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objectives of this trial are to investigate the relative bioavailabilities of rosuvastatin (Reference 1, Part 1) and dabigatran (Reference 2, Part 2) given alone and together with BI 1323495 (Test 1, Test 2) following oral administration.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Rosuvastatin intervention 2: Rosuvastatin + BI 1323495 intervention 3: Dabigatran etexilate intervention 4: Dabigatran etexilate + BI 1323495
Intervention descriptions: intervention 1: Tablet intervention 2: Tablets intervention 3: Capsule intervention 4: Capsule and tablets

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:
c29490951-02
EudraCT No.
2019-004245-33
BI Trial No.
1405-0015
BI Investigational
Medicinal Product
BI 1323495
Title
Relative bioavailability of rosuvastatin (Part 1) and dabigatran 
(Part 2) given alone and together with BI 1323495 in healthy 
male subjects (open, single-dose, randomised, two-period 
crossover design in each trial part)
Lay Title
A study in healthy men to test the influence of BI 1323495 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: 22 June 2020
Page 1 of 65
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
22 June 2020
Revision date
Not applicable
BI trial number
1405-0015
Title of trial
Relative bioavailability of rosuvastatin (Part 1) and dabigatran (Part 2) given alone 
and together with BI 1323495 in healthy male subjects (open, single-dose, 
randomised, two-period crossover design in each trial part)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
BI 1323495 has been characterised to be an inhibitor of P-gp, OATP1B1 and BCRP 
in-vitro. This trial will be performed to test the inhibitory effect of BI 1323495 on 
these drug transporters in-vivo. Dabigatran will be used as model substrate for P-gp, 
rosuvastatin as model substrate for BCRP and OATP1B1.
Trial objectives
To investigate the relative bioavailability of 10 mg rosuvastatin (Part 1) and 150 mg 
dabigatran (Part 2) given alone and together with 
 BI 1323495
Trial design
Randomised, open-label, two period crossover design in each trial part
Trial endpoints:
Part 1
Primary endpoints: AUC0-and Cmax of rosuvastatin 
Secondary endpoint: AUC0-tz of rosuvastatin  
Part 2
Primary endpoints: AUC0-and Cmax of dabigatran
Secondary endpoint: AUC0-tz of dabigatran
Number of subjects 
total entered
28: 14 in Part 1 and 14 in Part 2 
each treatment
14
Diagnosis
Not applicable
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) genotyped as UGT2B17 extensive metabolizers
Test product 1
Rosuvastatin (Crestor® 10 mg Filmtabletten)
dose
10 mg (1 tablet) 
mode of admin.
Oral with 240 mL of water after a standardised breakfast


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Test product 2
Dabigatran etexilate (Pradaxa® 75 mg Hartkapseln)
dose
75 mg (1 capsule)
mode of admin.
Oral with 240 mL of water after a standardised breakfast
Test product 3
BI 1323495 
dose
mode of admin.
Oral with 240 mL of water after a standardised breakfast
Duration of treatment
Part 1
Treatment R1: 10 mg rosuvastatin as single dose on study day 1 of period 1 or 2
Treatment T1: 10 mg rosuvastatin + 
g BI 1323495 as single dose on study 
day 1 of period 1 or 2
Drug administrations in period 1 and 2 are separated by a wash-out period of at 
least 7 days.
Part 2
Treatment R2: 75 mg dabigatran as single dose on study day 1 of period 1 or 2
Treatment T2: 75 mg dabigatran + 
 BI 1323495 as single dose on study day 
1 of period 1 or 2
Drug administrations in period 1 and 2 are separated by a wash-out period of at 
least 7 days.
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 sequence, subjects
nested within sequences, period 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
FLOW CHART PART 1 (ROSUVASTATIN)
Period
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory5
PK blood, Rosuvastatin
PK blood, BI 1323495
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 7
SCR
1
-21 to -1
Screening (SCR)1
xA
x
x
1/2 (two identical periods separated by a wash-out of at least 7 days
2/3
1
-2:00
06:00
Admission to trial site2
xB,2,3
x2
x2,8
x2
x2
x2
-0:30
07:30
Standardised breakfast
0:00
08:00
Drug administration
0:30
08:30
x8
1:00
09:00
x
x8
2:00
10:00
240 mL fluid intake
x
x8
3:00
11:00
x
x8
3:30
11:30
x
4:00
12:00
240 mL fluid intake
x
x8
4:30
12:30
x
5:00
13:00
Lunch4
x
x8
x
5:30
13:30
x
6:00
14:00
x
x8
7:00
15:00
x
8:00
16:00
Snack (voluntary)4
x
x8
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x8
x 
2
24:00
08:00
Breakfast (voluntary)4
xB
x
x8
x
x
X
28:30
12:30
Lunch (voluntary)4
X
32:00
16:00
Snack (voluntary)
34:00
18:00
Discharge from trial site
x
x
3
47:00
07:00
Ambulatory visit
x
x
4
71:00
07:00
Ambulatory visit
x
x
5
95:00
07:00
Ambulatory visit
x
x
FU
4
8 to 15
End of trial (EoTrial)
examination6
xC
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. 
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
Includes urine drug screening and alcohol breath test
4.
If several actions are indicated at the same time, the intake of meals will be the last action.
5.
Letters A, B, and C define different sets of safety laboratory examinations (for details refer to Section 5.2.3)
6.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. 
7.
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.
8.
Period with administration of test treatment (rosuvastatin + BI 1323495) only


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FLOW CHART PART 2 (DABIGATRAN)
Period
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory5
PK blood, Dabigatran
PK blood, BI 1323495
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 7
SCR
1
-21 to -1
Screening (SCR)1
xA
x
x
1/2 (two identical periods separated by a wash-out of at least 7 
days
2/3
1
-2:00
06:00
Admission to trial site2
xB,2,3
x2
x2,8
x2
x2
x2
-0:30
07:30
Standardised breakfast
0:00
08:00
Drug administration
0:30
08:30
x
x8
1:00
09:00
x
x8
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x8
2:30
10:30
x
3:00
11:00
x
x8
3:30
11:30
x
4:00
12:00
240 mL fluid intake
x
x8
5:00
13:00
Lunch4
x
x8
x
6:00
14:00
x
x8
8:00
16:00
Snack (voluntary)4
x
x8
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x8
x 
2
24:00
08:00
Breakfast (voluntary)4
xB
x
x8
x
x
x
28:30
12:30
Lunch (voluntary)4
x
32:00
16:00
Snack (voluntary)
34:00
18:00
Discharge from trial site
x
x
3
47:00
07:00
Ambulatory visit
x
x
4
71:00
07:00
Ambulatory visit
x
x
FU
4
8 to 15
End of trial (EoTrial)
examination6
xC
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 and 
faecal 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. 
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
Includes urine drug screening and alcohol breath test
4.
If several actions are indicated at the same time, the intake of meals will be the last action.
5.
Letters A, B, and C define different sets of safety laboratory examinations (for details refer to Section 5.2.3)
6.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory
(including faecal occult blood test), recording of AEs and concomitant therapies. 
7.
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.
8.
Period with administration of test treatment (dabigatran + BI 1323495) only


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
FLOW CHART PART 1 (ROSUVASTATIN).............................................................4
FLOW CHART PART 2 (DABIGATRAN).................................................................5
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................14
1.2.1
BI 1323495 .............................................................................................14
1.2.2
Rosuvastatin ..........................................................................................17
1.2.3
Dabigatran.............................................................................................17
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........................................... 23
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......23
2.1.1
Main objectives......................................................................................23
2.1.2
Primary endpoints ................................................................................23
2.1.3
Secondary endpoint ..............................................................................23
2.2.2.4
Safety and tolerability..............................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 25
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................25
3.3
SELECTION OF TRIAL POPULATION ......................................................25
3.3.1
Main diagnosis for trial entry..............................................................26
3.3.2
Inclusion criteria...................................................................................26
3.3.3
Exclusion criteria ..................................................................................26


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3.3.4
Withdrawal of subjects from treatment or assessments ...................28
3.3.4.1
Discontinuation of trial treatment............................................28
3.3.4.2
Withdrawal of consent to trial participation ............................29
3.3.4.3
Discontinuation of the trial by the sponsor..............................29
3.3.5
Replacement of subjects .......................................................................29
4.
TREATMENTS........................................................................................ 30
4.1
INVESTIGATIONAL TREATMENTS ..........................................................30
4.1.1
Identity of the Investigational Medicinal Products ...........................30
4.1.2
Selection of doses in the trial................................................................31
4.1.3
Method of assigning subjects to treatment groups ............................31
4.1.4
Drug assignment and administration of doses for each subject .......32
4.1.5
Blinding and procedures for unblinding ............................................33
4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................33
4.1.8
Drug accountability ..............................................................................33
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................34
4.2.1
Other treatments and emergency procedures....................................34
4.2.2
Restrictions............................................................................................34
4.2.2.1
Restrictions regarding concomitant treatment .........................34
4.2.2.2
Restrictions on diet and life style.............................................35
4.3
TREATMENT COMPLIANCE.......................................................................35
5.
ASSESSMENTS....................................................................................... 36
5.1
ASSESSMENT OF EFFICACY Not applicable..............................................36
5.2
ASSESSMENT OF SAFETY............................................................................36
5.2.1
Physical examination ............................................................................36
5.2.2
Vital signs...............................................................................................36
5.2.3
Safety laboratory parameters..............................................................36
5.2.4
Electrocardiogram................................................................................38
5.2.5
Other safety parameters.......................................................................39
5.2.6
Assessment of adverse events...............................................................39
5.2.6.1
Definitions of adverse events...................................................39
Adverse event ............................................................39
5.2.6.1.1
Serious adverse event ................................................39
5.2.6.1.2
AEs considered ‘Always Serious’.............................40
5.2.6.1.3
Adverse events of special interest .............................40
5.2.6.1.4
Intensity (severity) of AEs.........................................41
5.2.6.1.5
Causal relationship of AEs ........................................41
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................42


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AE collection.............................................................42
5.2.6.2.1
AE reporting to the sponsor and timelines ................42
5.2.6.2.2
Information required..................................................43
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 BI 1323495, 
rosuvastatin and dabigatran......................................................43
5.5
BIOBANKING ...................................................................................................45
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 period....................................................................................47
6.2.2
Treatment periods.................................................................................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
7.4
INTERIM ANALYSES .....................................................................................53


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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.....................................................................58
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 .....................................................................................59
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................59
9.
REFERENCES......................................................................................... 61
9.1
PUBLISHED REFERENCES...........................................................................61
9.2
UNPUBLISHED REFERENCES.....................................................................62
10. APPENDICES .......................................................................................... 64
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 65
11.1
GLOBAL AMENDMENT 1 .............................................................................65


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
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
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to 24 hours after drug administration
BA
Bioavailability
BCRP
Breast cancer resistance protein
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CF
Cystic fibrosis
CFTR
Cystic fibrosis transmembrane conductance regulator
COPD
Chronic obstructive pulmonary disease
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P450 system
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial


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EudraCT
European Clinical Trials Database
FOB
Faecal occult blood
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
HMG-CoA
Hydroxymethylglutaryl coenzyme A
HPC
Human Pharmacology Centre
IB
Investigator’s brochure
IC
Inhibitory concentration
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
OATP
Organic anion transporting polypeptide
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
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
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SRD
Single-rising dose
T
Test treatment


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tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
XTC
Ecstasy 


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1.
INTRODUCTION
BI 1323495 has been characterised to be an inhibitor of P-glycoprotein (P-gp), Breast cancer 
resistance protein (BCRP) and of the Organic anion transporting polypeptide (OATP) 1B1 in-
vitro. This trial will be performed to investigate whether, and to which extent, BI 1323495 is 
also in-vivo an inhibitor of these drug transporters.
1.1
MEDICAL BACKGROUND


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1.2
DRUG PROFILE
1.2.1
BI 1323495
For a detailed description of the BI 1323495 profile, please refer to the current Investigator’s 
Brochure [c21238478-02].
Clinical experience
At the time of preparing this trial protocol, three Phase I studies with administration of single 
doses of BI 1323495 to healthy male volunteers have been completed, trials 1405-0001 (first-
in-man trial), 1405-0007 (relative BA/food effect), and 1405-0009 (drug interaction with 
itraconazole).
In the single rising dose (SRD) trial 1405-0001, single-dose treatment with up to 600 mg BI 
1323495 or placebo was safe and well tolerated. There was no relationship between the 
occurrence of AEs and dose. Three AEs in subjects receiving BI 1323495 were judged as 
moderate in intensity, all other AEs were classified as mild. No severe or serious AEs were 


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reported. The most frequently reported treatment-emergent AE was headache, reported for 6 
out of 48 subjects (12.5%) receiving BI 1323495 and 2 out of 15 subjects (13.3%) receiving 
placebo. The next-most frequently reported treatment-emergent AEs were fatigue and 
diarrhea, each reported for 2 out of 48 subjects (4.2%) receiving BI 1323495. In one subject 
receiving 300 mg BI 1323495, a mild (<2-fold ULN) and transient elevation of ALT and 
GLDH was reported.
For further details on safety and tolerability as well as on pharmacokinetics and biomarker 
data of the SRD trial refer to the IB (c21238478-02).


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In the food effect trial 1405-0007, a randomised 2-way crossover study to compare the 
relative bioavailability of a single dose of 
 BI 1323495 
administered in 
the fasted state versus fed state (high-fat),
 
Treatment-emergent AEs were reported for 5 out of the 12 treated subjects (41.7%). Adverse 
events were reported for 3 out of 12 subjects (25.0%) in the BI 1323495 fasted treatment 
period and for 2 out of 11 subjects (18.2%) in the BI 1323495 fed treatment period. No 
subjects were reported with AEs in both treatment periods.
Infections and infestations occurred in 2 of the 12 subjects (16.7%): influenza in 1 subject in 
the BI 1323495 fasted treatment period, and otitis externa in 1 subject in the BI 1323495 fed
treatment period. Headache was reported in 2 of the 12 subjects (16.7%), one in each 
treatment period. Mouth injury was reported in 1 of the 12 subjects (8.3%) in the BI 1323495
fasted treatment period. The only investigator-defined drug-related AE was mild headache 
reported for 1 subject [c27223001-01].
Trial 1405-0009, a two-period fixed sequence study in healthy male subjects 
 
 investigated the effects of multiple doses of itraconazole – a 
strong CYP3A4 and P-gp inhibitor - on the relative bioavailability of a single dose of 
 
BI 1323495. The clinical part has been completed and data are currently being evaluated.
Treatment-emergent AEs were reported for 6 out of the 14 treated subjects (42.9%).
Investigator defined drug-related AEs were reported for 3 subjects (21.4%), all of them mild 
or moderate diarrhea under treatment with itraconazole alone or itraconazole + BI 1323495. 
No relevant changes in vital signs, ECG, or laboratory parameters were reported. 
In summary, single doses of BI 1323495 investigated so far in clinical trials with healthy 
subjects were safe and well tolerated. 


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1.2.2
Rosuvastatin
Rosuvastatin is an HMG-CoA reductase inhibitor indicated for treatment of 
hypercholesterolemia and for prophylaxis of cardiovascular events. Inhibition of HMG-CoA 
decreases hepatic cholesterol production, which, in turn, stimulates hepatocellular uptake of 
low-density lipoproteins. In therapy, the initial rosuvastatin dose is 5-10 mg once daily. The 
daily dose may be increased to up to 40 mg [R19-3033]. 
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 [R19-3033, P14-07833].
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 [R19-3033].
For a more detailed description of the rosuvastatin profile, please refer to the current SmPC 
for Crestor® 10 mg tablets [R19-3033].
1.2.3
Dabigatran
Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological 
activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to 
dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, 
competitive, reversible direct thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the 
coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran inhibits 
free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.
Dabigatran is indicated for primary prevention of venous thromboembolic events in adult 
patients who have undergone elective total hip replacement surgery or total knee replacement 
surgery, and for the prevention of ischaemic stroke in patients with atrial fibrillation. The 
recommended daily dose for primary prevention of venous thromboembolism in orthopaedic 
surgery is 220 mg with an initial dose of 110 mg prior to the surgery. In patients with 
moderately impaired renal clearance (30-50 mL/min) the dose should be reduced to 150 mg 
daily (1 capsule of 75 mg bid) [R18-3151].
The absolute bioavailability of dabigatran following oral administration was approximately 
6.5 %. After oral administration in healthy volunteers, the pharmacokinetic profile of 
dabigatran in plasma is characterized by a rapid increase in plasma concentrations with Cmax
attained within 0.5 and 2.0 hours post administration, a bi-exponential distribution phase and 
a terminal elimination half-life of about 11 hours in healthy elderly subjects. Food does not 
affect the bioavailability of dabigatran etexilate but delays the time to peak plasma 
concentrations by 2 hours. 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 


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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 [R18-3151].
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].
For a more detailed description of the dabigatran profile, please refer to the current SmPC for 
Pradaxa® 75 mg hard capsules [R19-3343].
1.2.4
Residual Effect Period
The Residual Effect Period (REP) of BI 1323495, rosuvastatin, and dabigatran, i.e. the period 
after the last dose with measurable drug levels and/or pharmacodynamic effects still likely to 
be present, will be defined as 7 days for each of the 3 products.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Based on in-vitro data BI 1323495 is an inhibitor of P-gp, BCRP, OATP1B1. This trial will 
be performed to test the inhibitory effect of BI 1323495 on these drug transporters in-vivo. 
Rosuvastatin will be used as a model substrate of BCRP and OATP1B1 (trial Part 1) and 
dabigatran as a model substrate of P-gp (Part 2).
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 clinical development of 
BI 1323495. Subjects are exposed to risks of study procedures and risks related to the 
exposure to the trial medication.


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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, as well as in feeling of lightheadedness or in syncope.
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.
Drug-related risks
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.
BI 1323495


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In the SRD, food effect, and itraconazole drug interaction trial, single dose administration of 
up to 600 mg BI 1323495 was well tolerated, with no clinically relevant changes in any 
safety laboratory parameter, ECG, and vital signs observed (ref. Section 1.2.1). The 
occurrence of AEs did not appear to be related to BI 1323495 plasma exposure.
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration when BI 1323495 is administered.
Rosuvastatin
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 trial 352.2100 increased the rosuvastatin exposure from 6.8 to 77 nmol/L (Cmax) 
and from 94 to 321 nmol/L*h (AUC0-∞.). 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 [R18-0241]. Considering this, it is assumed that 
the potential effect of BI 1323495 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 trial 352.2100, no undue risk to healthy subjects is expected from the 
combined administration of 10 mg rosuvastatin and BI 1323495 in this trial.
Dabigatran
In trial 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 daily and of 8 to the dose being used in Part 2 of this trial (75 mg).


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Dabigatran etexilate is a sensitive substrate of intestinal 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 given 1 hour before dabigatran intake (2.8 fold increase of
dabigatran Cmax) and with multiple doses of ketoconazole (2.5 fold increase of dabigatran 
Cmax und AUC) [R19-3343]. The observed increase in dabigatran exposure has been well 
tolerated by healthy subjects, which is in line with the described safety margin of 4 at a dose 
of 150 mg, that has not been exceeded by any P-gp inhibitor. 
No undue risk to healthy subjects is expected from the combined administration of 75 mg 
dabigatran etexilate and BI 1323495 in this trial.
Risk mitigation and monitoring

Careful selection of trial population with compound-specific exclusion criteria (see 
Section 3.3.3)

Only healthy subjects will be included in this trial not requiring concomitant 
medications that could – in principle – trigger combined effects on the 
pharmacokinetics and / or safety of the investigational drugs.

Although relevant alterations are not specifically expected, liver function tests 
including total and direct bilirubin, serum creatinine, urea, electrolyte levels, 
glomerular filtration rate, and blood coagulation parameters will be monitored as part 
of the standard safety laboratory assessments (see Section 5.2.3). Subjects with 
impaired liver, kidney or blood coagulation function will be excluded from 
participation in this trial. Furthermore, monitoring will be done for any signs of 
bleeding or bleeding-related adverse events.

Safety surveillance with close monitoring and in-house confinement up to at least 34 
hours after drug administration
Overall assessment
In summary, BI 1323495 has the potential to become an oral treatment for patients with 
COPD or CF. Based upon preclinical and clinical data with BI 1323495 and clinical 
information from competitor compounds as well as the implemented safety measures 
described above, healthy subjects will not be exposed to undue risks in relation to the 
important information expected from this trial as a basis for further clinical development of 
this compound. 


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Healthy volunteers are not expected to have any direct benefit from participation in this drug-
drug-interaction (DDI) trial.
Considering the medical need of the development of an effective treatment to slow the 
progression of COPD for patients with this disease and reduce exacerbations in patients with 
CF, the Sponsor considers that the benefit outweighs the potential risks and justifies exposure 
of healthy male volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objectives of this trial are to investigate the relative bioavailabilities of 10 mg 
rosuvastatin (Reference 1, Part 1) and 75 mg dabigatran (Reference 2, Part 2) given alone and 
together with 300 mg BI 1358894 (Test 1, Test 2) following oral administration.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for rosuvastatin (Part 1) and 
dabigatran (Part 2):

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
The following pharmacokinetic parameter will be determined for rosuvastatin (Part 1) and 
dabigatran (Part 2):

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 the investigational medicinal products 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 comprises two trial parts. Each part follows a randomised, open-label, two-period 
crossover design in healthy male subjects in order to compare the following test and reference 
treatments: 
Treatments in Part 1

Reference (R1): 10 mg rosuvastatin as single dose on study day 1 of period 1 or 2

Test (T1): 10 mg rosuvastatin together with 
 BI 1323495 as single dose on 
study day 1 of period 1 or 2
Treatments in Part 2

Reference (R2): 75 mg dabigatran etexilate as single dose on study day 1 of period 1
or 2

Test (T2): 75 mg dabigatran etexilate together with 
 BI 1323495 as single dose
on study day 1 of period 1 or 2
All treatments will be given after a standardised meal. Drug administrations in period 1 and 2 
will be separated by at least 7 days. For details refer to Section 4.1.
An overview of all relevant trial activities is provided in the Flow Chart for Part 1 and Part 2. 
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).
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 within each of Parts 1 and 2 of the study, 14 healthy male subjects will 
enter. They will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included in the study because no data on reproductive toxicology 
of BI 1323495 are available at this time.


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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)
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 medications
or their 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 or compromise the subject’s safety by 
participation in the trial (e. g. use of any drug that could reasonably inhibit platelet 
aggregation or coagulation, concomitant treatment with systemic cyclosporine, 
ketoconazole, itraconazole and dronedarone, use of fibrates or 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 baseline prolongation of QT/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.
24. Active clinically relevant bleeding or subjects who in the investigator’s judgement are 
perceived as having an increased risk of bleeding, for example because of blood 
coagulation disorders, 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
25. For Part 1 only: known myopathy, personal or family history of hereditary muscular 
disorders, or history of muscular toxicity with statins or fibrate; Asian ancestry; 
hypothyroidism
26. Subjects with any other condition that would preclude administration of rosuvastatin or 
dabigatran (i.e. contraindicated as per SmPC), such as active liver disease including 
elevations of serum transaminases exceeding 2 times the upper limit of normal, moderate 


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or severe renal impairment (creatinine clearance < 60 ml/min based on estimated GFR 
according to CKD-EPI formula), prosthetic heart valves requiring anticoagulant treatment
27. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
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
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.


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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. Failure to meet expected enrolment goals
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
or suspended if more than 50% of the subjects have drug-related and clinically relevant 
adverse events of moderate or severe intensity. Furthermore a trial part will terminated or 
suspended, if more than two subjects in the respective trial part have drug-related non-
serious adverse events of severe intensity or if at least 1 drug-related serious adverse 
event is reported.
3. Violation of GCP or the CTP impairing the appropriate conduct of the trial-
4. The sponsor decides to discontinue the further development of the investigational product
3.3.5
Replacement of subjects
Subjects withdrawn due to drug related adverse events will not be replaced. 
Subjects not completing the trial for other reasons (including non PK evaluable subjects) may 
be replaced if considered necessary to reach the aim of the trial. The Clinical Trial Leader 
together with the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how 
many subjects will be replaced. A replacement subject will be assigned a unique trial subject 
number, and will be assigned to the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product BI 1323495 has been manufactured by BI Pharma GmbH & Co. 
KG. Rosuvastatin and dabigatran etexilate will be obtained from a public pharmacy.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test products are given below.
Test product 1:
Name:
Crestor® 10 mg Filmtabletten
Substance:
Rosuvastatin
Pharmaceutical formulation: Tablet, film-coated
Source:
Public pharmacy
Holder of marketing
authorisation:
Unit strength:
10 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
2 single doses in Part 1
Test product 2:
Name:
Pradaxa® 75 mg Hartkapseln
Substance:
Dabigatran etexilate
Pharmaceutical formulation: Hard capsule
Source:
Public pharmacy
Holder of marketing
authorisation:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
75 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
2 single doses in Part 2


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Test product 3:
Substance:
BI 1323495
Pharmaceutical formulation: Tablet, film-coated
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
-0-0
Route of administration:
oral
Duration of use:
1 single dose in Part 1 and 2
4.1.2
Selection of doses in the trial
Rosuvastatin and dabigatran are used in the low range of standard clinical doses.
As regards BI 1323495, a single dose has been chosen that is expected to cover and 
potentially exceed the expected therapeutic exposure to investigate the inhibitory effects in a 
worst-case scenario and to account for potential uncertainties in the prediction of the 
expected therapeutic exposure.
Trial medication will be administered in the fed state, as this is the expected mode of drug 
administration for BI 1323495 in the planned indication of CF where a high proportion of 
patients are on continuous treatment with the CFTR modulator drug ivacaftor that needs to be 
taken together with a fat containing meal.
4.1.3
Method of assigning subjects to treatment groups
Prior to the start of the study, subjects willing to participate will be recruited to the trial parts
according to their temporal availability.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
list will be allocated to the subjects by drawing lots. Subjects are then assigned to a treatment 
sequence according to the randomisation list. Once a subject number has been assigned, it 
cannot be reassigned to any other subject. 
The randomisation list will be provided to the trial site in advance. The randomisation 
procedure is described in Section 7.6.
All subjects of the respective trial 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 


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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 part of this trial follows a two period, two-way crossover design. All subjects will 
receive the 2 treatments in randomised order (R-T or T-R). The treatments to be evaluated are 
outlined in Table 4.1.4: 1 below.
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total  dose
Part 1
Reference (R1)
Rosuvastatin
Tablet
10 mg
1 tablet, single dose
10 mg
Test (T1)
Rosuvastatin
BI 1323495
Tablet
Tablet
10 mg
1 tablet, single dose, together with
tablets, single dose
10 mg
Part 2
Reference (R2)
Dabigatran 
etexilate
Capsule
75 mg
1 capsule, single dose
75 mg
Test 2 (T2)
Dabigatran 
etexilate 
BI 1323495
Capsule
Tablet
75 mg
1 capsule, single dose, together 
with
tablets, single dose
75 mg
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 sitting or 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, a standardised normal caloric breakfast (e.g., a roll with cheese, ham, and 
butter) will be served approximately 30 min before drug administration. The subjects must 
completely consume the meal prior to drug intake and consume no other food.
For restrictions with regard to diet, see Section 4.2.2.2.
Subjects will be kept under close medical surveillance until at least 34 h after drug 
administration. During the first 5 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.


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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.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
BI 1323495
BI 1323495 tablets will be provided by BI. They 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.
Rosuvastatin and dabigatran etexilate
Rosuvastatin tablets and dabigatran etexilate capsules will be obtained by the clinical trial site 
from a public pharmacy (European commercial goods). The medication will be dispensed out 
of the original, unmodified packages.
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 BI 1323495 investigational drugs delivered from
the sponsor, provided the 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  


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Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
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 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.
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.
For Part 1: Drugs which are contraindicated to be co-administered with rosuvastatin (ref. 
R19-3033), as well as acetylsalicylic acid or other drugs that may inhibit platelet aggregation 
or coagulation should be avoided during the entire study.
For Part 2: 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 such 
as heparins, heparin ointment, oral anticoagulants (warfarin, rivaroxaban, etc.). Furthermore, 
concomitant systemic administration of strong P-gp inhibitors such as ketoconazole, 
itraconazole, cyclosporine, and dronedarone must be avoided during the entire trial. 


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4.2.2.2
Restrictions on diet and life style
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 after the last PK sample of each 
study period is collected.
Alcoholic beverages are not permitted from 24 hours before the first administration of trial 
medication in Period 1 until the end of trial examination after the last PK sample in Period 2 
is collected.
Poppy-seeds containing foods should not be consumed starting 3 days before the first drug 
administration in each treatment period, in order to avoid false-positive results in the drug-
screen.
Consumption of methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy 
drinks, or chocolate) and smoking are not allowed during in-house confinement.
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 5 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
subjects). From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL.
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.
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, 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 including.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(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 after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
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.
Faecal 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
C1
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
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
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated]
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI2
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
X
X
X
X
X
X
X
--
X
X
--
--
--
--
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
X
X
--
--
X
X
Urinalysis (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
X
X
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
Urine sediment
(microscopic examination 
if erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1
A: parameters to be determined at Visit 1 (screening examination)
B: parameters to be determined at Visit 2 and 3 (for study days and time points refer to Flow Chart)
C: parameters to be determined at Visit 4 (end of trial examination)
2
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 for 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. Alco True 
M®, 
) 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 AccuSign® DOA 10 
test or comparable test systems.
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.
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 
 
shoulders instead of ankles and wrists). 


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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.
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 


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
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:

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, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 


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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)
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)


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
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.

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 immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions the 


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Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send 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.
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 BI 1323495, rosuvastatin and 
dabigatran
For quantification of rosuvastatin (Part 1), dabigatran (Part 2), and BI 1323495
concentrations in plasma, 2.7 mL of blood will be drawn for each analyte 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 per analyte will be 
obtained 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 within 90 min, with interim storage of blood samples on ice-bath or 
refrigerated. 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. 


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5.5
BIOBANKING
Not applicable.


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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 measurements outlined in Section 5.3 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, the end of trial examination, and measurements and 
assessments scheduled to occur ‘before’ trial medication administrations are provided in the 
Flow Chart.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for the assessment of safety (e.g. vital signs, ECG, laboratory tests) will be ± 60 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including 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.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will 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.
6.2.2
Treatment periods
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.
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 34 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, assessments will be done in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK and 
biomarker analysis, refer to Flow Chart, Section 5.3.2 and 5.4.


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The safety measurements performed during the treatment periods are specified in Section 5.2
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 Section 5.2.
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 10 mg 
rosuvastatin (Part 1) and 75 mg dabigatran (Part 2) in plasma when given as oral single dose
together with a single dose of 
 BI 1323495 (Test, T1 and T2) as compared to when 
given alone as oral single dose (Reference, R1 and R2) on the basis of the primary and 
secondary pharmacokinetic endpoints, as listed in Section 2.1.2 and 2.1.3. Each trial part will 
be conducted as a two-treatment, two-period, randomised cross-over design, which allows 
intra-subject comparisons. It will be evaluated statistically by use of a linear model for 
logarithmically transformed PK endpoints.
The assessment of safety is a further objective of this trial, and will be evaluated by 
descriptive statistics for the parameters specified in Section 2.2.2.2.
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 1323495 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 randomized 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/she 
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, and 
BI 1323495 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 in the respective treatment 
period

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 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: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:


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yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment  
k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm 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 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects.
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 randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
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.


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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.
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
For each trial part, subjects will be randomised to one of the 2 treatment sequences in a 1:1 
ratio. The block size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter 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.


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The observed intra-individual coefficient of variation (gCV) for rosuvastatin ranged from 
from 9.0 to 19.7% for AUC and from 14.1 to 28.4% for Cmax, whereas the observed intra-
individual coefficient of variation (gCV) for dabigatran were ~20% for Cmax as well as for 
AUC in previous trials [c08983809-01, c13060859-01, U09-3249-02].
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.
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 2x2 crossover trial (N=12)
gCV [%]
Precision upper 
CI limit / relative 
BA estimate
Ratio [%]*
Lower CI limit 
[%]
Upper CI limit
[%]
10.0
1.105
100
90.50
110.50
10.0
1.105
150
135.74
165.75
10.0
1.105
200
180.99
221.00
20.0
1.219
100
82.01
121.93
20.0
1.219
150
123.02
182.89
20.0
1.219
200
164.03
243.86
30.0
1.342
100
74.54
134.16
30.0
1.342
150
111.80
201.25
30.0
1.342
200
149.07
268.33
*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.


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The consent and re-consenting process should be properly documented in the source 
documentation.
For subjects enrolled during the COVID-19 crisis: In addition to the study specific informed 
consent, separate written consent will be obtained for testing on SARS-CoV-2 infection.
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.


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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:

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 
documents/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 
described in section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.


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8.3.3
Storage period of records
Trial site:
The trial site 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.
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.


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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.
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 within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 of 
 
, 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
The trial medication BI 1323495 will be provided by the
 
. Rosuvastatin and dabigatran supplies will be 
obtained from a public pharmacy in Germany.
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).
Analyses of BI 1323495, rosuvastatin and dabigatran concentrations in plasma will be done 
by 
.


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On-site monitoring will be done 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
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.
P17-01597
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
strategy for the diagnosis, management, and prevention of chronic 
obstructive lung disease (2017 report). http://goldcopd.org/gold-2017-
global-strategy-diagnosis-management-prevention-co pd/ (accessd date: 9 
February 2017) ; Global Initiative for Chronic Obstructive Lung Disease 
(GOLD); 2017.
P19-02318
Cystic Fibrosis Foundation patient registry 2017 annual data report. https://
www.cff.org/Research/Researcher-Resources/Patient-Registry/2017-
Patient-Registry-Annual-Data-Report.pdf (access date. 23 March 2019);
Bethesda: Cystic Fibrosis Foundation; 2018.
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.
R15-4771
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.


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R18-0241
Guidance for industry: clinical drug interaction studies - study design, data 
analysis, and clinical implications (draft guidance, this guidance document 
is being distributed for comment purposes only) (October 2017, clinical 
pharmacology). https://www.fda.gov/downloads/drugs/guidances/
ucm292362.pdf  (access date: 19 January 2018) ; Silver Spring: U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and  Research (CDER); 2017.
R18-3151
Pradaxa 75 mg, 110 mg, 150 mg hard capsules (Boehringer Ingelheim) 
(summary of product characteristics, manufacturer(s) responsible for batch 
release, conditions or restrictions regarding supply and use, other conditions 
and requirements of the marketing authorisation, conditions or restrictions 
with regard to the safe and effective use of the medicinal product, labelling 
and package leaflet, last updated: 15/06/2018). 
https://www.ema.europa.eu/documents/product-information/pradaxa-epar-
product-inf ormation_en.pdf (access date: 15 October 2018); 2018.
R19-3033
Crestor 5 mg/10 mg/20 mg Filmtabletten (AstraZeneca). Fachinformation 
(Zusammenfassung der Produkteigenschaften/SmPC). Stand der 
Information: Juni 2019.
R19-3343
Pradaxa 75 mg Hartkapseln (Boehringer Ingelheim). Fachinformation 
(Zusammenfassung der Produkteigenschaften/SmPC). Stand der 
Information: May 2019.
R94-1529 
Chow SC, Liu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
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.


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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.
c21238478-02
Investigator’s Brochure BI 1323495. COPD. 18 March 2019.
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 April 2019.
c26492551-01
Safety, tolerability, 
pharmacokinetics, and pharmacodynamics of single rising oral doses of BI 
1323495 in healthy male subjects (single-blind, partially randomised, 
placebo-controlled parallel group design). Report 1405-0001. 
04 November 2019.
c27223001-01
. Relative bioavailability of BI 
1323495 following oral administration under fed and fasted conditions in 
healthy male subjects (an open-label, randomised, single-dose, two-period,
two-sequence crossover study). Report 1405-0007. In Progress. 
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 August 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 July 2006.
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 January 2011.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1 
Date of amendment
22 June 2020
EudraCT number
EU number
2019-004245-33
BI Trial number
1405-0015
BI Investigational Medicinal 
Product(s)
BI 1323495
Title of protocol
Relative bioavailability of rosuvastatin (Part 1) and 
dabigatran (Part 2) given alone and together with BI 
1323495 in healthy male subjects (open, single-dose, 
randomised, 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) Flow Chart Part 1
2) Section 3.3.3 Exclusion Criteria
3) Section 8.1 Trial Approval, Subject Information, 
Informed Consent
Description of change
1) Typo corrected
2) Exclusion criterion no. 27 introduced (exclude 
subjects with positive SARS-CoV-2 testing)
3) Specified that separate informed consent for 
SARS-CoV-2 testing will be used.
Rationale for change
Additional measures for risk reduction during
COVID-19 pandemic described


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29490951
2.0
clinical-trial-protocol-version-02
Relative bioavailability of rosuvastatin (Part 1) and dabigatran (Part 2) given alone
and together with BI 1323495 in healthy male subjects (open, single-dose,
randomised, two-period crossover design in each trial part)
Author-Clinical Trial Leader
23 Jun 2020 09:57 CEST
Approval-Team Member Medicine
23 Jun 2020 10:00 CEST
Approval-Clinical Pharmacokinetics
23 Jun 2020 10:11 CEST
Author-Trial Statistician
23 Jun 2020 12:30 CEST
Approval-Therapeutic Area 
23 Jun 2020 12:37 CEST
Verification-Paper Signature
Completion
25 Jun 2020 10:38 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29490951
2.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c31864115-01
BI Trial No.:
1405-0015
Title:
Relative bioavailability of rosuvastatin (Part 1) and dabigatran  
(Part 2) given alone and together with BI 1323495 in healthy male 
subjects (open, single-dose, randomised, two-period crossover 
design in each trial part)
Investigational
Product:
BI 1323495
Responsible trial 
statistician:
Phone:
Fax:
Date of statistical 
analysis plan:
26 OCT 2020 SIGNED
Version:
1
Page 1 of 28
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2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................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 endpoint...............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED ...........................................................................14
6.5
POOLING OF CENTRES..................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................16
7.
PLANNED ANALYSIS ......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........19
7.2
CONCOMITANT DISEASES AND MEDICATION......................................19
7.3
TREATMENT COMPLIANCE ........................................................................19
7.4
PRIMARY ENDPOINTS ...................................................................................19
7.4.1
Primary analysis of the primary endpoints ......................................................20
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoints...............................................................................................21
7.5
SECONDARY ENDPOINTS .............................................................................21
7.5.1
Key secondary endpoints ....................................................................................21
7.5.2
Secondary endpoint.............................................................................................21
7.7
EXTENT OF EXPOSURE .................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse Events ....................................................................................................23
7.8.2
Laboratory data...................................................................................................24
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG ......................................................................................................................25
7.8.5
Others ...................................................................................................................25
8.
REFERENCES ....................................................................................................26


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10.
HISTORY TABLE..............................................................................................28


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................11
Table 6.2: 1
Important protocol deviations...........................................................................13
Table 6.3: 1
Subject sets analysed ........................................................................................15
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
CARE
Clinical data Analysis and Reporting Environment
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
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 of non-missing observations
P10
10th percentile
P90
90th percentile
po
Orally
PKS
Pharmacokinetic parameter analysis set
Q1
1st quartile
Q3
3rd quartile


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Term
Definition / description
qd
Once daily
R 
Reference treatment
RAGe
Report Appendix Generator system
REP
Residual effect period
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) 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: 
The following pharmacokinetic parameters will be determined for rosuvastatin (Part 1) and 
dabigatran (Part 2):

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 endpoint
Section 2.1.3 of the CTP: 
The following pharmacokinetic parameter will be determined for rosuvastatin (Part 1) and 
dabigatran (Part 2):

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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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, Part 1 with rosuvastatin and Part 2 with dabigatran. It is 
planned that within each part of the study, 14 healthy male subjects will enter. Each part 
follows an open-label, randomized, two-period, two-way crossover design in order to 
compare the test (B, D) and reference (A, C) 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
A
Rosuvastatin, 10 mg tablet, qd
Rosu
B
BI 1323495, 6*50 mg tab + Rosuvastatin, 10 mg tab, qd
BI+Rosu
Part 2
C
Dabigatran etexilate, 75 mg capsule, qd
Dabi
D
BI 1323495, 6*50 mg tab + Dabigatran etex, 75 mg caps, qd 
BI+Dabi
Section 1.2.4 of CTP:
The Residual Effect Period (REP) of BI 1323495, rosuvastatin, and dabigatran, i.e. the period
after the last dose with measurable drug levels and/or pharmacodynamic effects still likely to 
be present, will be defined as 7 days for each of the 3 products.
The following study phases in Part 1 and Part 2 will be defined for the analysis of adverse 
events (AEs):

Screening (ranging from 0:00 h on day of informed consent until first administration
of study medication in treatment period 1)

On treatment (ranging from the time of administration of test or reference treatment 
until administration time of next study drug dose or until 0:00 h on day 7 after time of 
administration, whatever occurs first)
  labelled Rosu, BI+Rosu, Dabi, BI+Dabi


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
Follow-up (F/U) (ranging from 0:00 h on day 7 after the time of administration of test
or reference treatment until administration time of next study drug dose or until 0:00 h
on day after trial termination date, whatever occurs first)
labelled F/U Rosu, F/U BI+Rosu,  F/U Dabi, F/U BI+Dabi
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.
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 phases will not be included in this analysis.
The following totals will be provided in addition:
For Section 15.3:
a total over all on treatment phases in study Part 1 (“Total - Part 1”)
a total over all on treatment phases in study Part 2 (“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.
Tables of vital signs and laboratory values will present results by the above mentioned on 
treatment phases.
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.
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 
the decision log. Categories which are considered to be iPDs in this trial are defined in the 
integrated quality and risk management plan (IQRMP). An overview of the defined iPDs and 
if they could potentially lead to exclusion from defined analysis sets (see 6.3) is given in
Table 6.2: 1. The decision on exclusion of subjects from analysis sets will be made at the 
latest at the Report Planning Meeting, after discussion of exceptional cases and implications 
for analyses. 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.
Table 6.2: 1
Important protocol deviations 
Category/
Code
Description
Exclusion 
from 
A
Inclusion/Exclusion Criteria
A1
Inclusion Criteria Not Met
PKS
A2
Exclusion Criteria Violated
PKS
B
Informed consent
B1
Informed consent not available/not done
TS / PKS
B2
Informed consent too late
none
C
Trial medication and randomization
C1
Incorrect trial medication taken
PKS
C2
Randomisation not followed
PKS
C3
Non-compliance
PKS
C5
Incorrect intake of trial medication
PKS
C6
Improper washout between treatments
PKS
D
Concomitant medication
D1
Prohibited medication use
PKS
E
Missing data 
E1
Certain deviations from procedures used to measure primary or 
secondary data
PKS


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6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were randomized 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/she
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.
The two trial parts  will be analysed separately, if not stated otherwise. Therefore, the two 
analysis sets will be split into TS/PKS of the Rosuvastatin part  and TS/PKS of the Dabigatran 
part.
The primary and secondary analysis will be performed in the PKS. The PKS will also be used 
for the descriptive analyses of PD/biomarker parameters.
Section 7.3 of the CTP:
Pharmacokinetics
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
F
Incorrect timing
F1
Certain deviations from time schedule used to measure primary or 
secondary data
PKS
G
Other trial specific important deviations
G1
Incorrect intake of meal
PKS


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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 in the respective 
treatment period

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 endpoints 
X
Analyses of PD/biomarker endpoints
X
Safety parameters 
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
Exposure
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 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, the end of trial examination, 
and measurements and assessments scheduled to occur ‘before’ trial medication 
administrations are provided in the CTP Flow Chart.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time
for the assessment of safety (e.g. vital signs, ECG, laboratory tests) will be ± 60 min.
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.
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.
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 endpoints and concentrations will be performed by
 as of the department 
at
 and will be presented in Section 15.6 of the CTR and in Appendix 16.1.13.5.
Descriptive data analysis of PD/biomarker parameters will be performed by 
 
as of the 
at 
and will be presented in Section 15.7 of the CTR and 
Appendix 16.1.13.6.
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 following BI standards 
for PK/PD analysis (7).
The individual values of all subjects will be listed, sorted by treatment sequence, 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 and PD 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


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For PK and 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
The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK and PD 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 and PD parameters
The ADS “ADPP” (PK parameters) or “ADYP” (PD parameters) contains column variables 
APEXC and APEXCO indicating inclusion/exclusion (APEXC) of a PK or PD 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 and PD concentrations
The ADS “ADPC” (PK concentrations per time-point or per time-interval) or “ADYC” (PD
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” (3).


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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 by treatment sequence and in total.
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
The primary endpoints for Part 1 (rosuvastatin) and Part 2 (dabigatran) are AUC0-∞and Cmax
(see Section 5.1). The primary analysis of these endpoints will be performed using an analysis 
of variance model for relative bioavailability of rosuvastatin or dabigatran, respectively.


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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 logtransformed (natural logarithm) prior to fitting the ANOVA 
model. This model will include effects accounting for the following sources of variation: 
sequence, subjects within sequences, period and treatment. The effect 'subjects within 
sequences' will be considered as random, whereas the other effects will be considered as 
fixed. The model is described by the following equation:
yijkm = µ + ζi + sim + πj + τk + eijkm, where

yijkm = logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,

µ = the overall mean,

ζi = the ith sequence effect, i=1,2,

sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni

πj = the jth period effect, j=1,2,

τk = the kth treatment effect, k = 1, 2,

eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where sim ~ N(0, σB
2) i.i.d. , eijkm ~ N(0, σw
2) i.i.d. and sim, eijkm 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 based on 
PKS. The following SAS code can be used:


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PROC MIXED DATA=indata; 
CLASS subject treatment sequence period; 
MODEL logkp = treatment sequence period / DDFM=KR; 
RANDOM subject(sequence); 
LSMEANS treatment / PDIFF CL ALPHA=0.1; 
ESTIMATE 'T-R' treatment -1 1; 
RUN;
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoints
Section 7.3.1 of the CTP: The same statistical model as stated above will be repeated for the 
primary endpoints but with all sources of variation (‘sequence’, ‘subjects within sequences’, 
‘period’, ‘treatment’) considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed
descriptively.
The sensitivity analysis with fixed effects will be performed by fitting the model described 
above, but using all effects as fixed. This analysis will be done using PROC GLM The 
following SAS code can be used:
PROC GLM DATA=indata; 
CLASS subject treatment sequence period; 
MODEL logkp = treatment sequence period subject; 
LSMEANS treatment / PDIFF CL ALPHA=0.1; 
RUN;
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 endpoint
The secondary PK parameter AUC0-tz for rosuvastatin (part 1) and dabigatran (part 2) will be 
assessed statistically using the same methods as described for the primary endpoints.


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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.
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.


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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) and [BI-KMED-BDS-HTG-0066] (11). All 
analyses of AEs will be based on the number of subjects with AEs and not on the number of 
AEs.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to ‘screening’, ‘on treatment’ or ‘follow-up’ phases as defined in
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
According to the clinical study protocol, adverse events of special interest (AESI) will be 
analysed:
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, 
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), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced
or interrupted).
An overall summary of 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 
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 


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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 at the latest). 
Descriptive statistics of laboratory data including change from baseline 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.


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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 on treatment), and will be analysed as such.
No separate ECG listing will be provided.
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 (if they occurred on
treatment) 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.
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
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. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials”, current version; KMED


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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
26-OCT-2020
None
This is the final TSAP