Clinical trial NCT04679948
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2020-12-21; Completion date: 2021-03-17
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The trial will be performed to assess the influence of BI 730357 on the pharmacokinetics of caffeine, warfarin, omeprazole and midazolam.

Detailed description:

Arms: arm 1: Cocktail treatment will be followed by the Test treatment (Cocktail + BI 730357) in a fixed sequence. The treatment periods are separated by a wash-out phase of at least 20 days between the two cocktail administrations.
Interventions: intervention 1: Percoffedrinol® intervention 2: Coumadin® intervention 3: Antra MUPS® intervention 4: Midazolam-ratiopharm® intervention 5: BI 730357
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Gastro-resistant tablet intervention 4: Oral solution intervention 5: Film-coated tablet

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:
c31764080-02
EudraCT No.
2020-002506-51
BI Trial No.
1407-0039
BI Investigational
Medicinal Product
BI 730357
Title
The effect of multiple doses of BI 730357 on the single dose 
pharmacokinetics of caffeine, warfarin, omeprazole and 
midazolam administered orally as a cocktail in healthy subjects 
(an open-label, two-period fixed sequence design trial)
Lay Title
A study in healthy people to test whether BI 730357 influences 
the amount of caffeine, warfarin, omeprazole, and midazolam 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: 12. November 2020
Page 1 of 82
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
24 September 2020
Revision date
12 November 2020
BI trial number
1407-0039
Title of trial
The effect of multiple doses of BI 730357 on the single dose pharmacokinetics of 
caffeine, warfarin, omeprazole and midazolam administered orally as a cocktail in 
healthy subjects (an open-label, two-period fixed sequence design trial)
Principal Investigator
Trial site
Human Pharmacology Centre, Boehringer Ingelheim Pharma GmbH & Co. KG, 
Biberach an der Riß, Germany
Clinical phase
I
Trial rationale
Based on in vitro data, BI 730357 and its metabolite CD 6975 are potential inducers
of CYP1A2, CYP2C9, CYP2C19 and CYP3A4 at anticipated human therapeutic 
exposure.
 
 
. Therefore, this trial is aimed to investigate the influence of BI 730357 
and its metabolite on the activity of CYP1A2, CYP2C9, CYP2C19, and CYP3A by 
using in vivo probe drugs recommended as sensitive substrates.
Trial objective
To assess the influence of multiple doses of BI 730357 on single dose 
pharmacokinetics of cytochrome P450 (CYP) probe substrates, as a means of 
predicting drug-drug interactions. The probe drugs are caffeine (for CYP1A2), 
warfarin (for CYP2C9), omeprazole (for CYP2C19), and midazolam (for CYP3A).
Trial design
Open-label, non-randomized, two-period fixed sequence design 
Trial endpoints
AUC0-∞and Cmax as primary endpoints for the probe drugs caffeine, warfarin 
(specifically S-warfarin), omeprazole and midazolam when administered without 
BI 730357 and co-administered with BI 730357 at steady-state 
Number of subjects 
total entered
16
each treatment
16
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male and female subjects, age of 18 to 55 years (inclusive), body mass 
index (BMI) of 18.5 to 29.9 kg/m2 (inclusive)


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Trial product 1
Percoffedrinol® N 50 mg Tabletten (tablet strength: 50 mg)
dose
100 mg caffeine (2 tablets) as single doses in treatments T and R
mode of admin.
Oral with 240 mL of water after a standardized meal
Trial product 2
Coumadin® 5 mg (tablet strength: 5 mg)
Dose
10 mg warfarin sodium (2 tablets) as single doses in treatments T and R
mode of admin.
Oral with 240 mL of water after a standardized meal
Trial product 3
Antra MUPS® 20 mg magensaftresistente Tabletten (tablet strength: 20 mg)
Dose
20 mg omeprazole (1 tablet) as single doses in treatments T and R
mode of admin.
Oral with 240 mL of water after a standardized meal
Trial product 4
Midazolam-ratiopharm® 2 mg/mL orale Lösung (strength: 2 mg/mL)
Dose
2 mg midazolam (1 mL) as single doses in treatments T and R
mode of admin.
Oral with 240 mL of water after a standardized meal
Trial product 5
BI 730357 film-coated tablets (tablet strength: 100 mg)
dose
300 mg BI 730357 (3 tablets) twice daily for 20 days in treatment T only
mode of admin.
Oral with 240 mL of water after a standardized meal
Duration of treatment
Treatment R: Drug cocktail alone in Period 1 (Visit 2):
Single dose of 100 mg caffeine, 10 mg warfarin, 20 mg omeprazole and 2 mg 
midazolam administered as drug cocktail (Day 1).
Treatment T: Drug cocktail plus BI 730357 in Period 2 (Visit 3):
Multiple doses of 300 mg BI 730357 administered twice daily on 20 days (Day -14 
to Day 6) combined with a single dose of 100 mg caffeine, 10 mg warfarin, 20 mg 
omeprazole and 2 mg midazolam administered as drug cocktail on the 15th day of 
BI 730357 treatment (Day 1, one hour after the morning dose of BI 730357).
The cocktail treatments will be separated by a wash-out of at least 20 days.
Statistical methods
For each probe drug, the effect of drug-drug interactions will be estimated by the 
ratios (co-administration with BI 730357 vs. probe drug alone) of the geometric 
means for the primary endpoints. Additionally, their two-sided 90% confidence 
intervals (CIs) will be provided. This method corresponds to the two one-sided t-
tests procedure, each at a 5% significance level. Since the main focus is on 
estimation and not testing, a formal hypothesis test and associated acceptance range 
is not specified. The statistical model will be an analysis of variance (ANOVA) on 
the logarithmic scale including effects for ‘subjects’ and ‘treatment’. CIs will be 
calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to 
intake of drug cocktail12 per 
visit) [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Blood sample for PK of  
BI 730357 and metabolite
Blood sample for PK of  
drug Cocktail 13
Safety laboratory 8
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
A
x
x
x
Period 1 / Treatment R (Drug cocktail alone)
2
-1
-26:00
07:00
Ambulatory visit
B7
x
-13:00
20:00
Admission to trial site
x5
x
1
-2:00
07:00
x2
x2
x2
x2
-1:30
07:30
Standardized breakfast
0:00
09:00
Administration of drug cocktail 12
0:30
09:30
x
1:00
10:00
x
1:30
10:30
x
x
x
2:00
11:00
240 mL fluid intake
x
3:00
12:00
x
4:00
13:00
240 mL fluid intake, thereafter lunch9
x
x
6:00
15:00
x
7:30
16:30
Extended snack (voluntary)
8:00
17:00
x
10:30
19:30
Standardized dinner
12:00
21:00
x
x
2
24:00
09:00
Breakfast 9
x
C
x
28:00
13:00
Lunch
31:30
16:30
Snack (voluntary)
34:30
19:30
Dinner9
x
3
48:00
09:00
x
C
x
x
48:05
09:05
Breakfast (voluntary),
discharge from trial site
4
71:00
08:00
Ambulatory visit
x
x
5
95:00
08:00
Ambulatory visit
x
x
6
119:00
08:00
Ambulatory visit
x
x
7
143:00
08:00
Ambulatory visit
x
B
x


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Period
Visit
Day
Planned time (relative to 
intake of drug cocktail12 per 
visit) [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Blood sample for PK of  
BI 730357 and metabolite
Blood sample for PK of  
drug Cocktail 13
Safety laboratory 8
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Period 2 / Treatment T (Drug cocktail plus BI 730357)
3
-14
-338:30
06:30 Ambulatory visit, standardized breakfast 9
x11,2
x2
x2
x2
-338:00
07:00 Administration of BI 730357
-326:30
18:30 Ambulatory visit, standardized dinner 9
x
-326:00
19:00 Administration of BI 730357
-13
-314:30
06:30 Ambulatory visit, standardized breakfast 9
x
-314:00
07:00 Administration of BI 730357
-302:30
18:30 Ambulatory visit, standardized dinner 9
x
-302:00
19:00 Administration of BI 730357
-12
-290:30
06:30 Ambulatory visit, standardized breakfast 9
x
-290:00
07:00 Administration of BI 730357
-278:30
18:30 Ambulatory visit, standardized dinner 9
x
-278:00
19:00 Administration of BI 730357
-11
-266:30
06:30 Ambulatory visit, standardized breakfast 9
x
-266:00
07:00 Administration of BI 730357
-254:30
18:30 Ambulatory visit, standardized dinner 9
x
-254:00
19:00 Administration of BI 730357
-10
-242:30
06:30 Ambulatory visit, standardized breakfast 9
x
-242:00
07:00 Administration of BI 730357
-230:30
18:30 Ambulatory visit, standardized dinner 9
x
-230:00
19:00 Administration of BI 730357
-9
-218:30
06:30 Ambulatory visit, standardized breakfast 9
x
-218:00
07:00 Administration of BI 730357
-206:30
18:30 Ambulatory visit, standardized dinner 9
x
-206:00
19:00 Administration of BI 730357
-8
-194:30
06:30 Ambulatory visit, standardized breakfast 9
B2
x2
x2
x2
-194:00
07:00 Administration of BI 730357
-182:30
18:30 Ambulatory visit, standardized dinner 9
x
-182:00
19:00 Administration of BI 730357
-7
-170:30
06:30 Ambulatory visit, standardized breakfast 9
x
-170:00
07:00 Administration of BI 730357
-158:30
18:30 Ambulatory visit, standardized dinner 9
x
-158:00
19:00 Administration of BI 730357
-6
-146:30
06:30 Ambulatory visit, standardized breakfast 9
x
-146:00
07:00 Administration of BI 730357
-134:30
18:30 Ambulatory visit, standardized dinner 9
x
-134:00
19:00 Administration of BI 730357
-5
-122:30
06:30 Ambulatory visit, standardized breakfast 9
x
-122:00
07:00 Administration of BI 730357
-110:30
18:30 Ambulatory visit, standardized dinner 9
x
-110:00
19:00 Administration of BI 730357
-4
-98:30
06:30 Ambulatory visit, standardized breakfast 9
x
-98:00
07:00 Administration of BI 730357
-86:30
18:30 Ambulatory visit, standardized dinner 9
x
-86:00
19:00 Administration of BI 730357
-3
-74:30
06:30 Ambulatory visit, standardized breakfast 9
x
-74:00
07:00 Administration of BI 730357
-62:30
18:30 Ambulatory visit, standardized dinner 9
x
-62:00
19:00 Administration of BI 730357


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Period
Visit
Day
Planned time (relative to 
intake of drug cocktail12 per 
visit) [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Blood sample for PK of  
BI 730357 and metabolite
Blood sample for PK of  
drug Cocktail 13
Safety laboratory 8
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Period 2 / Treatment T (Drug cocktail plus BI 730357)
3
-2
-50:30
06:30 Ambulatory visit, standardized breakfast 9
x
-50:00
07:00 Administration of BI 730357
-38:30
18:30 Ambulatory visit, standardized dinner 9
x
-38:00
19:00 Administration of BI 730357
-1
-25:30
07:30 Ambulatory visit, standardized breakfast 9
x
-25:00
08:00 Administration of BI 730357
x3
B3
-14:00
19:00 Admission to trial site
x2,5
x2,10
-13:30
19:30 standardized dinner 9
-13:00
20:00 Administration of BI 730357
x3
1
-2:00
07:00
x2
x2
x2
-1:30
07:30 Standardized breakfast 9
-1:00
08:00 Administration of BI 730357
x3
0:00
09:00 Administration of drug cocktail 12
x3
x3
x3
0:30
09:30
x
x
1:00
10:00
x
x
1:30
10:30
x
x
x
x
2:00
11:00 240 mL fluid intake
x
x
3:00
12:00
x
x
4:00
13:00 240 mL fluid intake, thereafter lunch9
x
x
x
6:00
15:00
x
x
7:30
16:30 Extended snack (voluntary)
8:00
17:00
x
x
10:30
19:30 Standardized dinner 9
x
11:00
20:00 Administration of BI 730357
x3
12:00
21:00
x
2
22:30
07:30 Standardized breakfast 9
x
23:00
08:00 Administration of BI 730357
x3
24:00
09:00
x
C
28:00
13:00 Lunch
31:30
16:30 Extended snack (voluntary)
34:30
19:30 Standardized dinner 9
x
35:00
20:00 Administration of BI 730357
x3
3
46:30
07:30 Standardized breakfast 9
x2
x2
47:00
08:00 Administration of BI 730357
x3
48:00
09:00
x
C
48:05
09:05 Discharge from trial site
58:00
19:00 Ambulatory visit, standardized dinner 9
x
58:30
19:30 Administration of BI 730357
4
70:00
07:00 Ambulatory visit, standardized breakfast 9
x
70:30
07:30 Administration of BI 730357
71:00
08:00
x
82:00
19:00 Ambulatory visit, standardized dinner 9
x
82:30
19:30 Administration of BI 730357
5
94:00
07:00 Ambulatory visit, standardized breakfast 9
x
94:30
07:30 Administration of BI 730357
95:00
08:00
x
106:00
19:00 Ambulatory visit, standardized dinner 9
x
106:30
19:30 Administration of BI 730357


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Period
Visit
Day
Planned time (relative to 
intake of drug cocktail12 per 
visit) [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Blood sample for PK of  
BI 730357 and metabolite
Blood sample for PK of  
drug Cocktail 13
Safety laboratory 8
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
2
3
6
118:00
07:00 Ambulatory visit, standardized breakfast 9
x
118:30
07:30 Administration of BI 730357
119:00
08:00
x
130:00
19:00 Ambulatory visit, standardized dinner 9
x
130:30
19:30 Administration of BI 730357
7
143:00
08:00 Ambulatory visit
x
B
x
x
FU
4
13 to 
20
End of trial (EoTrial) examination4
D
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 pregnancy test in 
women and 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 2h prior to the next standardized 
breakfast or standardized breakfast indicated at the same time
3.
The time is approximate; the procedure is to be performed within 15 min before the drug administration indicated at the 
same time
4.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory
(including pregnancy test in women), recording of AEs and concomitant therapies, 
 
5.
Only urine drug screening and alcohol breath test as well as pregnancy test in women will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated prior to first administration of trial medication.  
8.
Letter A, B, C and D define different sets of safety laboratory examinations (see Section 5.2.3)
9.
If several actions are indicated at the same time, the intake of meals will be the last action.
10.
11. Only pregnancy test in women will be done at this time
12. Oral cocktail of CYP probe drugs consisting of caffeine, warfarin, omeprazole, and midazolam
13. PK sampling for drug cocktail includes sampling at the following planned times relative to administration of the cocktail 
with CYP probe drugs [h:min]:
0 (within 2h predose), 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 for omeprazole and midazolam, 
0 (within 2h predose), 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00, 48:00 for caffeine, 
0 (within 2h predose), 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00, 48:00, 71:00, 95:00, 119:00, 143:00 
for warfarin.     


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c31764080-02
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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................15
1.2.1
BI 730357 ...............................................................................................15
1.2.1.1
Nonclinical drug safety............................................................15
1.2.1.2
Non-clinical pharmacokinetics ................................................17
1.2.1.3
Clinical pharmacokinetics........................................................17
1.2.1.4
Clinical safety in healthy subjects............................................18
1.2.2
Compounds of the CYP probe cocktail...............................................19
1.2.2.1
Caffeine 20
1.2.2.2
Warfarin...................................................................................20
1.2.2.3
Omeprazole..............................................................................20
1.2.2.4
Midazolam ...............................................................................20
1.2.3
Residual Effect Period..........................................................................21
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................21
1.4
BENEFIT - RISK ASSESSMENT ...................................................................21
1.4.1
Procedure-related risks ........................................................................21
1.4.2
Drug-related risks and safety measures..............................................22
1.4.2.1
BI 730357.................................................................................22
1.4.2.2
Caffeine 23
1.4.2.3
Warfarin...................................................................................24
1.4.2.4
Omeprazole..............................................................................24
1.4.2.5
Midazolam ...............................................................................24
1.4.2.6
Drug-induced liver injury ........................................................25
1.4.2.7
Safety measures .......................................................................25
1.4.3
Overall assessment of benefit-risk ratio..............................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......27
2.1.1
Main objectives......................................................................................27
2.1.2
Primary endpoints ................................................................................27
2.1.3
Secondary endpoint ..............................................................................27


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2.2.2.2
Safety and tolerability..............................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for trial entry..............................................................31
3.3.2
Inclusion criteria...................................................................................31
3.3.3
Exclusion criteria ..................................................................................31
3.3.4
Withdrawal of subjects from treatment or assessments ...................33
3.3.4.1
Discontinuation of trial treatment............................................34
3.3.4.2
Withdrawal of consent to trial participation ............................35
3.3.4.3
Discontinuation of the trial by the sponsor..............................35
3.3.5
Replacement of subjects .......................................................................35
4.
TREATMENTS........................................................................................ 36
4.1
INVESTIGATIONAL TREATMENTS ..........................................................36
4.1.1
Identity of the Investigational Medicinal Products ...........................36
4.1.2
Selection of doses in the trial................................................................37
4.1.3
Method of assigning subjects to treatment groups ............................38
4.1.4
Drug assignment and administration of doses for each subject .......38
4.1.5
Blinding and procedures for unblinding ............................................39
4.1.6
Packaging, labelling, and re-supply ....................................................39
4.1.7
Storage conditions.................................................................................39
4.1.8
Drug accountability ..............................................................................40
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................40
4.2.1
Other treatments and emergency procedures....................................40
4.2.2
Restrictions............................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment .........................41
4.2.2.2
Restrictions on diet and life style.............................................41
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
ASSESSMENTS....................................................................................... 43
5.1
ASSESSMENT OF EFFICACY.......................................................................43
5.2
ASSESSMENT OF SAFETY............................................................................43
5.2.1
Physical examination ............................................................................43
5.2.2
Vital signs...............................................................................................43
5.2.3
Safety laboratory parameters..............................................................43
5.2.4
Electrocardiogram................................................................................45


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5.2.6
Assessment of adverse events...............................................................46
5.2.6.1
Definitions of adverse events...................................................46
Adverse event ............................................................46
5.2.6.1.1
Serious adverse event ................................................47
5.2.6.1.2
AEs considered ‘Always Serious’.............................47
5.2.6.1.3
Adverse events of special interest .............................48
5.2.6.1.4
Intensity (severity) of AEs.........................................49
5.2.6.1.5
Causal relationship of AEs ........................................49
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................51
AE collection.............................................................51
5.2.6.2.1
AE reporting to the sponsor and timelines ................52
5.2.6.2.2
Information required..................................................52
5.2.6.2.3
Pregnancy ..................................................................52
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................52
5.3.1
Assessment of pharmacokinetics .........................................................52
5.3.2
Methods of sample collection...............................................................53
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................53
5.4
ASSESSMENT OF BIOMARKER(S) .............................................................55
5.5
BIOBANKING ...................................................................................................55
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................55
6.
INVESTIGATIONAL PLAN.................................................................. 56
6.1
VISIT SCHEDULE............................................................................................56
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................56
6.2.1
Screening period....................................................................................56
6.2.2
Treatment periods.................................................................................57
6.2.3
Follow-up period and trial completion ...............................................57
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 58
7.1
STATISTICAL DESIGN – MODEL ...............................................................58
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................58
7.3
PLANNED ANALYSES....................................................................................58


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7.3.1
Primary endpoint analyses...................................................................60
7.3.2
Secondary endpoint analyses ...............................................................61
7.3.4
Safety analyses.......................................................................................61
7.4
INTERIM ANALYSES .....................................................................................62
7.5
HANDLING OF MISSING DATA ..................................................................63
7.5.1
Safety......................................................................................................63
7.5.2
Pharmacokinetics..................................................................................63
7.6
RANDOMISATION ..........................................................................................63
7.7
DETERMINATION OF SAMPLE SIZE ........................................................63
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 65
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................65
8.2
DATA QUALITY ASSURANCE .....................................................................66
8.3
RECORDS..........................................................................................................66
8.3.1
Source documents .................................................................................66
8.3.2
Direct access to source data and documents.......................................67
8.3.3
Storage period of records.....................................................................68
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................68
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......68
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................68
8.6
TRIAL MILESTONES .....................................................................................69
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................69
9.
REFERENCES......................................................................................... 71
9.1
PUBLISHED REFERENCES...........................................................................71
9.2
UNPUBLISHED REFERENCES.....................................................................73
10. APPENDICES .......................................................................................... 76
10.1
COLUMBA-SUICIDE SEVERITY RATING SCALE..................................76
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 82
11.1
GLOBAL AMENDMENT 1 .............................................................................82


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
attributable, legible, contemporaneous, original, accurate (dimensions of 
data integrity)
ANOVA
Analysis of variance
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours
AUC0-96
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 96 hours
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
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
BI
Boehringer Ingelheim
b.i.d.
Bis in die (twice a day)
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
C-SSRS
Columbia-Suicide Severity Rating Scale
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450
D
Day
DDI
Drug-drug interaction
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid


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ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EMA
European Medicines Agency
EoTrial
End of trial
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (US)
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
HPC
Human Pharmacology Centre
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IL
Interleukin
IPD
Important protocol deviation
IQRM
Integrated quality and risk management
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NOAEL
No observed adverse event level
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
PUVA
Psoralen ultraviolet A
q.d.
Quaque die (once daily)
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


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RAUC0-∞,M/P
Ratio of metabolite AUC0-∞to parent AUC0-∞
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual effect period
RORγ
Retinoic acid-related orphan receptor γ (full length protein)
RORγt
Retinoic acid-related orphan receptor γt (splice variant of RORγ protein)
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or test treatment
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
UN
Unstructured
UNR
Unstructured correlation
V
Visit
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WOCBP
Woman of childbearing potential
XTC
Ecstasy 


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1.
INTRODUCTION
BI 730357 is an antagonist of the retinoic acid-related orphan receptor (ROR)γt . It is being 
developed as an oral therapy for the treatment of patients with plaque psoriasis (PsO), as well 
as other Th17-mediated diseases. RORγt antagonism is a novel mechanism of action.
The trial will be performed to assess the influence of BI 730357 on the pharmacokinetics of 
caffeine (CYP1A2 probe drug), warfarin (CYP2C9 probe drug), omeprazole (CYP2C19 
probe drug) and midazolam (CYP3A4 probe drug).
1.1
MEDICAL BACKGROUND
RORγt is a nuclear hormone receptor/transcription factor expressed in Th17 cells (i.e., a 
subset of T helper cells which produce interleukin 17, and other signalling molecules) and in 
distinct subsets of lymphoid cells, including natural killer cells, innate lymphoid cells, and 
γδ T cells. 
 
 
 
 
 
1.2
DRUG PROFILE
1.2.1
BI 730357
1.2.1.1
Nonclinical drug safety
General and safety pharmacology studies conducted with BI 730357 showed an acceptable 
profile for clinical trials. Please refer to the Investigator’s Brochure (IB) [c09228382! "#$ 
%#$& '#%()&*& +&*,-)..
 
 
 
 
 
 
 


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1.2.1.3
Clinical pharmacokinetics
In single rising dose (SRD) evaluation of BI 730357 administered to healthy male subjects, 
exposure to BI 730357 increased in a dose-proportional manner for solution between 2 and 8 
mg and for tablet up to 50 mg, and thereafter increased in a less than dose-proportional 
manner, with approximately 1.5-fold increase in exposure with each 2-fold increase in dose, 
up to 400 mg in the fasted state. After administration of 800 mg BI 730357 under fed 
conditions, a maximum exposure of 77,900 nM*h (AUC0-inf) and of 2,470 nM (Cmax) was 
achieved. BI 730357 was cleared from plasma with a terminal half-life ranging from 20.0 to 
29.8 hours after single dose administration. Exposure was 27% greater following 
administration of the 25 mg tablet under fed compared to fasted conditions, and continued to 
increase at higher doses with food, suggesting a positive food effect for BI 730357.
 
 
 
 
 
Following administration of multiple rising doses (trial 1407-0002), BI 730357 exposure 
increased in an approximately dose-proportional manner from 25 mg to 100 mg, and in a less 
than dose-proportional manner from 100 mg to 200 mg, in the fasted state. When 
administered in the fed state, higher BI 730357 plasma levels and exposures were observed, 
with a delayed peak in concentrations compared to fasted conditions. Median tmax values 
ranged from 1.00 to 2.75 hours in the fasted state, and increased to 2.55 to 4.00 hours in the 


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fed state. In the highest dose group of the MRD study (400 mg qd, fed conditions) a 
maximum exposure of 35,500 nM*h (AUCτ,ss) and of 2,210 nM (Cmax,ss) was achieved.
Concentrations following multiple dosing appeared to be approximately double those 
following a single dose, with no relevant difference seen between 2- and 4-week profiles. 
Steady state was reached after approximately 7 days for all dose groups.
 
  
 
 
BI 730357 is a sensitive CYP3A substrate. Co-administration of itraconazole increased the 
exposure of BI 730357 by factor 9.3 (AUC0-∞) and 1.7 (Cmax).  
Administration of BI 730357 at doses of up to 400 mg once daily to healthy male subjects 
had no clinically-relevant effect on the pharmacokinetics of midazolam, a sensitive CYP3A 
substrate.
For a more detailed description of the BI 730357 PK profile, please refer to the current IB 
[c09228382].
1.2.1.4
Clinical safety in healthy subjects
Up to now, BI 730357 has been administered in 7 completed Phase I trials to more than 200 
healthy subjects.
Trial 1407.1: In this trial, 66 subjects were exposed to BI 730357 (54 in the SRD part, 12 in 
the bioavailability (BA) part). In the SRD part, single doses from 8 mg to 800 mg were
tested. Drug-related adverse events (AEs) were reported by 4 subjects on BI 730357 (3x 
headache, 1x oropharyngeal pain). These AEs were of mild or moderate (1 x headache) 
intensity and did not show any dose dependency. In the BA part no drug-related AEs were 
reported [c16462083].
Trial 1407-0002: This trial investigated the tolerability of BI 730357 after administration of 
multiple rising doses (25 mg to 400 mg) over 14 days. A total of 63 healthy subjects has been 
exposed to BI 730357. Among these 12 subjects reported drug-related AEs. These AEs were 
of mild or moderate intensity and did not show any dose dependency. Drug-related AEs 
reported by more than 1 subject comprise headache (4 subjects) and diarrhea (3 subjects). 
One subject in the 50 mg (fed) dose group developed a seborrhoic dermatitis on the 12th
treatment day which lasted for 100 hours. This subject was not dosed on Day 13 and 14 and 
the AE was assessed to be not drug-related by the investigator [c25766034].
Trial 1407-0014: This trial investigated the effect of itraconazole on BI 730357 kinetics in 
14 healthy subjects. For this purpose single doses of 50 mg BI 730357 have been 
administered with and without multiple doses of itraconazole. In the ‘BI 730357 alone’ 
period no drug-related AEs were reported. After combined administration of BI 730357 on 


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top of itraconazole, drug-related headache (mild) and nausea (moderate) were reported by 
one subject each [c27699953]. 
Trial 1407-0015: In this trial 18 Japanese healthy subjects were exposed to rising single doses 
of BI 730357 (50 to 200 mg). No drug-related AEs were reported [c27425119].
Trial 1407-0031: In this trial 6 healthy subjects were exposed to 50 mg C-14 labelled 
BI 730357. Mild headache was the only drug-related AE reported by one subject 
[c26494034].
Trial 1407-0032: This trial investigated the relative bioavailability of different solid oral 
formulations of BI 730357. For this purpose single doses of 50 mg (Part 1: 2 periods, 14 
subjects), 100 mg (Part 3: 3 periods, 15 subjects) and 200 mg (Part 2: 2 periods, 14 subjects) 
were administered to healthy subjects. In Part 1 drug-related AEs comprised headache (4 
cases) and diarrhea (1 case). In Part 2 drug-related headache was reported by 8 of 14 subjects. 
In Part 3 drug-related AEs comprised headache (2 cases) and nausea with vomiting (1 case). 
All drug-related AEs were of mild or moderate intensity [c28904523].
Trial 1407-0033: In this trial the absolute bioavailability of BI 730357 was investigated by 
administration of 50 mg tablets and 100 µg C-14 labelled BI 730357 given as intravenous 
microtracer to 6 healthy subjects. The only drug-related AE was an increased erection (mild)  
reported by 1 subject [c27700144].
For a more detailed description of the BI 730357 profile, please refer to the current IB 
[c09228382].
1.2.2
Compounds of the CYP probe cocktail
The potential induction or inactivation of the cytochrome P450 (CYP) isozymes CYP1A2, 
CYP2C9, CYP2C19 and CYP3A by BI 730357 will be investigated by the combined 
administration of the probe substrates caffeine, warfarin, omeprazole, and midazolam (partial 
 cocktail [P10-00100]).
All the substances of the 
 cocktail are approved drugs. For side effects and 
further details, please refer to the summaries of product characteristics of caffeine [R14-
3265], warfarin [R18-2602], omeprazole [R20-1236], and midazolam [R19-1961]. 
A validation study has confirmed that the probe substrates of the 
cocktail are
safe and do not interact with each other when used in combination [P10-00100]. The 
 cocktail was designed to overcome potential disadvantages of other four- and five-
probe cocktails [P04-02457]. In comparison with the well-known ‘Cooperstown 5+1 
cocktail’ [P03-09924], intravenous midazolam was replaced by oral midazolam in order to 
reflect combined CYP3A activity in the intestine and liver, and dextromethorphan was 
substituted by metoprolol which appears to be a better CYP2D6 probe substrate with less 
intra-individual variability. Furthermore, the omeprazole dose could be reduced from 40 mg 
to 20 mg, and in contrast to mandatory co-administration of vitamin K1, the investigator has 
now the responsibility to monitor the necessity of administering the warfarin antidote. In the 
current trial, a partial 
cocktail consisting of caffeine, warfarin, omeprazole,
and midazolam is used. Metoprolol is omitted, as investigation of BI 730357 effects on 
CYP2D6 is not required.


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1.2.2.1
Caffeine
Caffeine is the most-commonly used substance for CYP1A2 phenotyping. The first step in its 
metabolism is almost exclusively mediated by CYP1A2. Orally-administered caffeine is well 
absorbed by the small intestine within 45 minutes of ingestion, and then distributed
throughout all tissues of the body. Peak blood concentrations are reached within 1 to 2 hours. 
Its volume of distribution is 0.52 to 1.06 L/kg. It has been shown that CYP1A2-mediated 
caffeine clearance accounts for more than 95% of overall caffeine elimination from plasma. 
In healthy adults, the elimination half-life of caffeine is 4 to 5 hours. Caffeine and its 
metabolites are predominantly eliminated by renal excretion [P05-10983, R06-0327, 
R14-1378].
1.2.2.2
Warfarin
Warfarin sodium is an anticoagulant which acts by inhibiting vitamin K-dependent 
coagulation factors [R18-2602]. Warfarin sodium is completely absorbed after oral 
administration with the peak concentration attained within the first 4 hours. Its volume of 
distribution is 0.12 L/kg. Orally-administered warfarin sodium is a racemic mixture of the 
R-and S-enantiomers. The half-life of R-warfarin sodium ranges from 37 to 89 hours, while 
that of S-warfarin sodium ranges from 21 to 43 hours. Approximately 80 to 85% of 
S-warfarin elimination occurs through 6- or 7-hydroxylation via CYP2C9. Thus, the PK of 
S-warfarin is used to quantify real-time CYP2C9 activity [R98-2274]. 
The anticoagulant effect generally starts within 24 hours after drug administration. However, 
peak anticoagulant effect may occur between 72 to 96 hours. The duration of action of a 
single dose of racemic warfarin is 2 to 5 days [R18-2602].
1.2.2.3
Omeprazole
Omeprazole is a proton pump inhibitor applied to treat ulcers, heartburn, gastroesophageal 
reflux, and Zollinger-Ellison syndrome [R20-1236]. The formation of 5-hydroxyomeprazole, 
the major primary metabolite of omeprazole, is dependent on CYP2C19 activity. In addition, 
omeprazole is metabolised by CYP3A to omeprazole sulphone. Since the affinity of 
omeprazole to CYP2C19 is 10 times higher than to CYP3A, omeprazole interferes with the 
metabolism of substrates for CYP2C19 but not of substrates for CYP3A [P96-3991]. 
Omeprazole has a small volume of distribution (0.3 L/kg). The plasma half-life is 
approximately 40 min. Plasma clearance was determined to be 0.3 to 0.6 L/min.
1.2.2.4
Midazolam
Midazolam is a short acting benzodiazepine which is used for the treatment of insomnia and 
as sedative premedication before surgical or diagnostic procedures. It has a volume of 
distribution of 0.7 to 1.2 L/kg at steady state. Its elimination half-life in young healthy 
volunteers ranges from 1.5 to 2.5 hours. The plasma clearance was determined to be 300 to 
500 mL/min. Midazolam is almost completely eliminated by biotransformation to 
1-hydroxymidazolam, and this process is mediated by CYP3A enzymes [R19-1961, 
R06-0294]. In contrast to testosterone or erythromycin, which have also been proposed as 
probes to monitor CYP3A activity, midazolam is metabolised specifically by CYP3A, and 


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does not serve as a substrate for other CYP450 isoenzymes or the drug transporter P-
glycoprotein (P-gp). Intravenous midazolam is a sensitive in vivo probe of hepatic CYP3A 
activity, whereas orally-administered midazolam is metabolised by both intestinal and hepatic 
CYP3A.
1.2.3
Residual Effect Period
The Residual Effect Period (REP) of the cocktail is 9 days, referring to warfarin, the drug 
with the longest half-life among the cocktail components. This is the period after the last dose 
with measurable drug levels and/or pharmacodynamic effects still likely to be present.
The Residual Effect Period (REP) of BI 730357 is 7 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Drug-drug interactions (DDI) are complex and have proven to be a major challenge for 
health care providers. One of the questions that must be addressed before new drugs can be 
safely administered is whether there is a drug interaction with other medications taken by the 
patient for the treatment of co-morbidities. Therefore the interaction potential of a new 
compound is regularly evaluated during clinical drug development.
Based on in vitro data, BI 730357 and its metabolite CD 6975 are potential inducers of 
CYP1A2, CYP2C9, CYP2C19, and CYP3A4 at anticipated human therapeutic exposure 
levels. However, the predictive value of in vitro data is limited, and the probability of DDIs 
can entirely be assessed only with in vivo data in humans.
 
 
Therefore, this trial is aimed to investigate the influence of BI 730357 and its metabolite on 
the activity of CYP1A2, CYP2C9, CYP2C19, and CYP3A by using in vivo probe drugs 
recommended by both the FDA [P12-05791] and EMA [P15-06991] as sensitive substrates 
for the respective CYP enzymes and that do not interact among each other when administered 
together.
Results of this DDI trial will provide for a general signal of potentially important DDI upon 
which further exploration can be based.
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 development of BI 730357,
which may help to treat patients with PsO or other Th-17 related diseases. Subjects are 
exposed to risks of study procedures and risks related to the exposure to the trial medication.
1.4.1
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 


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nerve injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an 
indefinite period.
ECG electrodes may cause local and typically transient skin reactions.
The total volume of blood withdrawn per subject during the entire trial 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.
1.4.2
Drug-related risks and safety measures
1.4.2.1
BI 730357
As the nature of the target and the mechanism of action of BI 730357 are well understood 
from pre-clinical studies, comparable compounds have been tested by other companies 
before, and the animal models are believed to be predictive for the effects in humans, 
BI 730357 is not seen as a high-risk compound.
Up to the present, BI 730357 has been administered to more than 200 healthy subjects. In 
these trials BI 730357 has been well tolerated. The most frequent drug-related AE is 
headache (in single trial parts up to 25-50% of exposed subjects reported drug-related 
headache). Further drug-related events that have been reported by more than one subject so 
far comprise diarrhea and nausea. All drug-related AEs were of mild or moderate intensity 
(see Section 1.2.1.4). Specific changes of laboratory values, vital signs or ECG parameters 
have not been described so far.
In the highest dose group of the MRD trial 1407-0002, 400 mg BI 730357 were administered 
over 28 days. This resulted in a mean exposure of 2,210 nmol/l (Cmax,ss) and 35,500 nmol/l*h 
(AUCτ,ss), which was well tolerated by healthy subjects. In this trial, 300 mg b.i.d. will be 
administered over 20 days to healthy volunteers. Corresponding to model-based simulated 
medians (and 95% confidence intervals), the expected exposure of this dosing regimen is for 
Cmax,ss 4,130 nmol/l (3,530; 4,710) and for AUCτ,ss 82,700 nmol/L*h (71,500; 93,900), which 
exceeds the exposure of the highest MRD dose group by factor 1.9 (Cmax) and 2.3 (AUC).
The expected exposure is about 62% (Cmax) and 65% (AUC) of the NOAEL-exposure (6,600 
nmol/l for Cmax and 127,400 nmol/L*h for AUC0-24) seen in the 4-week dog study (see 
Section 1.2.1.1).
In the SRD trial 1407.1, the administration of 800 mg BI 730357 under fed conditions 
resulted in an exposure of 2,470 nmol/L (Cmax) and 77,900 nmol/L*h (AUC0-∞), which was 
well tolerated by healthy subjects. 
Since preclinical data indicate that BI 730357 has phototoxicity potential, direct exposure to 
the sun or exposure to solarium radiation is not allowed during the entire study, and use of 
sunscreens is mandatory in that time (see Section 4.2.2.2).
As with other immune-targeted therapies, impaired host defense is a theoretical target-related 
toxicity, potentially resulting in increased risk of infection and/or malignancy. Th17 cells 
play an important role in defense against extracellular bacteria and fungi at mucosal surfaces 
[R16-3166, R16-3149]. IL-17 antagonists are associated with increased infections 
[R13-2643]. Homozygous, but not heterozygous RORγ knockout mice have a high incidence 
of T-cell lymphoma, thought to originate in the thymus [R16-2630]. While the translatability 


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of the knockout phenotype to pharmacological RORγ antagonism and to humans is unknown, 
this raises the hypothetical concern for clinical T-cell lymphoma risk. The exact cause of 
T-cell lymphomas in RORγ knockout mice is not fully understood, but changes in 
homeostasis in the thymus, such as thymocyte apoptosis and proliferation, are thought to play 
a role. AEs and SAEs consistent with malignancy, and specifically those representing 
lymphoma, are to be carefully monitored and evaluated throughout the BI 730357 clinical 
development program. Based on the data obtained with BI 730357 so far, the increased risk 
of infection and/or malignancy is considered to be extremely small.
Currently, information about the immune response in patients with SARS-CoV-2 infection is 
sparse and inconclusive. In severe cases of COVID-19, morbidity associated with SARS-
CoV-2 infection may be attributed to immune activation and inflammation, with high levels 
of pro-inflammatory cytokines activated by RORγt. To date, there is no reliable evidence 
suggesting a link between the inhibition of the RORγt pathway and susceptibility to SARS-
CoV-2 infections. Nonetheless, as with other immunomodulatory treatments, BI 730357 may 
potentially increase the risk of infections in healthy volunteers participating in clinical trials.
Therefore, several risk mitigation measures (e.g., repeated laboratory tests for SARS-CoV-2 
infection, exclusion of subjects with a history or findings indicative of a SARS-CoV-2 
infection, close monitoring of AEs) are considered for this clinical trial. Trial conduct and
protocol-defined procedures do not impose additional risk to trial participants. To address 
potential risks associated with operational aspects related to the participation in clinical trials 
in the context of the COVID-19 pandemic, different risk mitigation measures are considered 
based on local requirements and development of the pandemic. Any subject with suspected or 
diagnosed SARS-CoV-2 infection should be treated according to standard of care, and 
discontinuation of trial medication should be considered.
 
 
Considering the good tolerability of BI 730357 observed so far in healthy subjects and taken 
into account the planned safety measures (two cohorts, twice daily visits in the outpatient 
phase of BI 730357 dosing, safety lab, vital signs and ECG monitoring) no undue risk to 
healthy subjects is expected from participation in this study.
1.4.2.2
Caffeine
Caffeine has a large therapeutic window. Fluvoxamine, a potent inhibitor of CYP1A2, caused 
a 5-fold increase of caffeine-AUC in healthy subjects, but no side effects attributed to the 
intake of caffeine have been reported [P14-11944]. Comparable to this trial, a dose of 100 mg 
caffeine has been used. In contrast to fluvoxamine, BI 730357 is expected to be an inducer of 
CYP1A2. Therefore an undue safety risk to healthy subjects cannot be expected from 
potential BI 730357 interaction with caffeine.
Smoking and contraceptive steroids are known inducers and inhibitors of CYP1A2, 
respectively [P12-05791]. Subjects currently smoking or ex-smokers who quit smoking less 
than 30 days prior to screening examination, as well as subjects using hormonal 


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contraceptives or hormonal replacement therapy less than 30 days before the first 
administration of trial medication will be excluded from participation in this trial for potential 
interaction via CYP1A2.
1.4.2.3
Warfarin
The selected dose of 10 mg warfarin is commonly used as loading and maintenance dose 
during oral anticoagulation therapy, and is lower than the dose range (20-30 mg) which often 
has been used in DDI studies in the past. Following single dose administration, the 
anticipated bleeding risk of 10 mg warfarin is considered to be low. In previous DDI trials 
with warfarin, prothrombin time and INR values remained inside the reference ranges after 
single doses of 10 mg warfarin [U09-1674-04, c03142665] or increased up to 2-times upper 
normal limit at 36 h to 56 h after single dose administration of 25 mg warfarin 
[U10-2984-01].
The effect of warfarin on the production of vitamin K-dependent coagulation factors can be 
easily monitored by means of laboratory tests and clinical observation, and antagonised by 
administration of vitamin K1. This trial includes safety laboratory before and after each 
warfarin administration. In case of excessive anticoagulation, further warfarin treatment 
should be avoided. Considering the fact that BI 730357 is expected to be an inducer of 
CYP2C9, co-administration of BI 730357 may reduce warfarin exposure. Therefore, safety 
risks to healthy subjects resulting from warfarin administration are unlikely in this study.
1.4.2.4
Omeprazole
The therapeutic standard dose of omeprazole is 20 mg to 40 mg daily. In the treatment of
Zollinger-Ellison syndrome, daily doses of up to 80 mg may be required. Omeprazole has a
large therapeutic window. Fluvoxamin, a potent inhibitor of CYP2C19, caused a 4.5 fold
increase of omeprazole exposure in healthy subjects (P14-11944). No side effects attributed
to the intake of omeprazole have been reported by the authors. Comparable to this trial, doses 
of 20 mg omeprazole have been used.
Considering the fact that BI 730357 is expected to be an inducer of CYP2C19, co-
administration of BI 730357 and omeprazole may reduce omeprazole exposure. Therefore, an 
undue safety risk to healthy subjects cannot be expected from omeprazole intake in this trial.
1.4.2.5
Midazolam
The administration of an oral dose of 2 mg midazolam is without a major sedative effect 
[P10-00100]. The therapeutic dose of midazolam is 7.5 mg to 15 mg. Considering the fact 
that BI 730357 may act as an inactivator of CYP3A4, the chosen dose of 2 mg provides a 
sufficient safety margin. The subjects will be kept in-house at the trial site for 48 hours after 
dosing, covering the full elimination of midazolam.
Furthermore, the potential inactivation of CYP3A4 is expected to be outweighed by a 
concurrent induction effect on CYP3A. In MRD trial 1407-0002 (see Section 1.2.1.3 and 
1.2.1.4), the exposure of midazolam, a sensitive CYP3A4 substrate, was not impacted by  
BI 730357 doses of up to 400 mg q.d. administered under fed conditions (BI 730357 Cmax,ss
of 2,210 nM) [c09228382].


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If the net effect of BI 730357 should be an induction of CYP3A4, the midazolam exposure 
after administration of 2 mg will be reduced. Therefore, no undue safety risk to healthy 
subjects is expected from potential BI 730357 interaction with midazolam.
1.4.2.6
Drug-induced liver injury
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.
1.4.2.7
Safety measures
For safety measures and assessments in detail, such as screening examination, AE/CT 
questioning, laboratory examinations, in-house periods, daily outpatient visits, ECG/vital 
signs measurements, or assessment of SIB, refer to the Flow Chart and Section 5.2. The 
safety measures are adequate to address the potential risks of the trial drugs to the volunteers.
1.4.3
Overall assessment of benefit-risk ratio
BI 730357 is a novel RORγt antagonist that has been adequately characterised in pre-clinical 
studies. Non-clinical BI 730357 safety data demonstrated an acceptable profile to support 
clinical trials in males and females, including women of childbearing potential. 
 
 This trial is required for the development of BI 730357. 
The resulting data are used to inform concomitant medication restrictions in planned patient 
trials.
Under consideration of their properties, all four probe substrates of the trial (caffeine,
warfarin, omeprazole, and midazolam) are appropriate for phenotyping drug-metabolizing 
enzymes, are safe to use alone and in combination [P10-00100, P03-09924, P10-05867], and 
have, with exception of warfarin, a very large therapeutic window.
All doses chosen were based on the clinical tolerability of the probe drugs and the ability to 
assess reliable PK parameters. Taken together, there is no relevant risk arising from potential 
inactivation of metabolism of the probe substrates. Inactivation of enzymes is fully reversible 
once the interacting agent is discontinued. In case BI 730357 would induce CYP isoenzymes, 
this effect would lead to a decrease in exposure of probe drugs in Visit 3 and is therefore not 
increasing the risk.
The trial design is optimised to collect as much and as relevant information as possible on the 
inhibition and induction potential of BI 730357 without exposing participating volunteers to 
undue risk. However, there is always the potential of serious AEs (SAEs) occurring with 
intake of trial medication. Safety will be ensured by monitoring the subjects during 


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treatments on a once daily or twice daily basis under the supervision of a physician, which 
includes hospitalisation periods during administration of probe substrates as well as regular 
laboratory and clinical assessments and verbal communication about AEs. If the investigator 
should have any clinical concern, the safety of the subjects will be of paramount importance. 
The investigator will have the discretion to remove subjects from the trial should there be any 
safety concerns or if the subject’s wellbeing is at jeopardy.
Previously, a comparable cocktail study was performed at the trial site with another 
investigational product. In this trial, the probe drugs midazolam (2 mg), warfarin (10 mg), 
omeprazole (20 mg), metoprolol (50 mg), caffeine (100 mg), and digoxin (0.25 mg) (full 
Cocktail + digoxin) were well tolerated by the subjects [c03142665].
Overall, considering the good tolerability of BI 730357 observed so far in healthy subjects 
and in patients, the sponsor feels that the benefit of a successful development of BI 730357 
outweighs the potential risks to healthy participants.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to assess the influence of multiple doses of BI 730357 on 
single dose kinetics of cytochrome P450 (CYP) probe substrates, as a means of predicting 
drug-drug interactions. These probe drugs substrates are caffeine (for CYP1A2), warfarin (for 
CYP2C9), omeprazole (for CYP2C19), and midazolam (for CYP3A).
2.1.2
Primary endpoints
The following primary endpoints will be determined for the probe drugs caffeine, warfarin 
(specifically S-warfarin), omeprazole, and midazolam when administered without BI 730357 
and when co-administered with BI 730357 at BI 730357 steady-state:

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
Not applicable.


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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 730357 and the probe drugs will be assessed based on:  

AEs (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
This trial is designed to assess the effects of BI 730357 on the activity of CYP1A2, CYP2C9, 
CYP2C19, and CYP3A, by utilizing a cocktail of probe drugs which contains specific 
substrates for these CYP enzymes. The trial will assess long-term effects of BI 730357 on 
CYP enzymes after achievement of steady-state levels of BI 730357 and after adaptation of 
CYP enzyme levels following continuous administration of BI 730357.
The trial will be performed as an open-label, two-treatment, two-period fixed sequence 
design trial in healthy male and female subjects enrolled at a single site. Sixteen subjects will 
receive the following oral treatments (for details refer to Section 4.1.):
Reference Treatment R (Trial Visit 2)

100 mg caffeine, 10 mg warfarin, 20 mg omeprazole, and 2 mg midazolam together 
as cocktail and single dose in the morning of Day 1 of Visit 2 
Test treatment T (Trial Visit 3)

100 mg caffeine, 10 mg warfarin, 20 mg omeprazole, and 2 mg midazolam together 
as cocktail and single dose in the morning of Day 1 of Visit 3 (1 hour after the 
morning dose of BI 730357)

300 mg BI 730357 as multiple dose every 12 hours over 20 days in the morning and 
evening on Day -14 to Day 6 of Visit 3 
There will be an interval of at least 20 days between the single-dose administrations of the 
cocktail on Day 1 of Visit 2 and on Day 1 of Visit 3.
For a single subject the schedule of trial participation can be displayed as follows:

Screening examination (Visit 1): up to 21 days

Treatment period 1 (Visit 2): 7 days

Treatment period 2 (Visit 3): 20 days

EoTrial examination (Visit 4): up to 13 days
Considering the flexible time frame for screening and follow-up examination the expected 
total trial duration for a single subject is about 6-9 weeks.
The trial population will be divided into 2 cohorts. The first cohort should not contain more 
than 6 subjects. The dosing of the 2nd cohort will start at the earliest 6 days after starting the 
dosing in the preceding first cohort.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
A schematic diagram of the trial design is displayed in Figure 3.1: 1 below.


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Figure 3.1: 1
Trial design
The drug cocktail consists of 100 mg caffeine, 10 mg warfarin, 20 mg omeprazole and 2 mg
midazolam, administered as single oral dose on Day 1 of Period 1 and Period 2. Twice daily 
doses of 300 mg BI 730357 will be administered from Day -14 to Day 6 of Period 2.  
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For PK trials comparing different treatments, the crossover design is preferred because of its 
efficiency: since each subject serves as his own control, the comparison between treatments is 
based on an intra-subject comparison, thus removing inter-subject variability from the 
comparison between treatments [R94-1529].
Because of the long half-life of BI 730357 and its metabolite and its suspected induction 
potential on various cytochrome enzymes and to avoid overlapping inhibitory effects, a two-
period fixed sequence design was selected, with administration of BI 730357 in the second 
treatment period (Visit 3) only. This design is not expected to lead to systematic errors in the 
estimation of the treatment effects, since nonspecific time-effects are unlikely due to the short 
trial duration.
All probe drugs used in this trial are listed as sensitive in vivo probes for drug-drug 
interaction trials by both the FDA [P12-05791] and EMA [P12-10638]. 
Caffeine, warfarin, omeprazole and midazolam, are components of the validated
cocktail [P10-00100]. The cocktail approach is an effective way to assess the drug-
drug interaction (DDI) potential of development compounds that are expected (based on 
preclinical data) to affect more than one metabolic pathway or are potential gene inducers. A 
great advantage of the cocktail approach is the reduced number of subjects that will be 
exposed to the development compound (as perpetrator drug) compared to single DDI studies
[P04-02212]. In these cases the performance of so called cocktail studies is accepted by 
regulatory authorities (P12-05791, P12-10638).
A dosing duration of seven days is adequate to ensure achievement of PK steady state of BI 
730357, and further seven days to cover transient metabolic effects (e.g. induction of CYPs 
1A2, 2C9, 2C19, or 3A) that may affect the PK of the probe drug substrates.


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For this PK drug-drug interaction trial, open-label treatment is acceptable, because the 
primary and secondary endpoints of this trial are PK endpoints derived from measurement of 
plasma concentrations of BI 730357. These endpoints are not expected to be affected by 
knowledge of treatment.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy subjects (if feasible at least 4 of each sex) will enter the study. 
They will be recruited from the volunteers' pool of the trial site.
A log of all subjects enrolled into the trial (i.e., who have signed informed consent) will be 
maintained in the Investigator Site File (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 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
5. Either male subject, or female subject who meet any of the following criteria from at least 
30 days before the first administration of trial medication until 30 days after trial 
completion:
-
Use of non-hormonal intrauterine device plus condom for birth control
-
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) 
-
Surgically sterilised (including hysterectomy or bilateral tubal occlusion)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in 
questionable cases a blood sample with levels of FSH above 40 U/L and estradiol 
below 30 ng/L is confirmatory)
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


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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
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 (except appendectomy or 
simple hernia repair) that could interfere with the PK of the trial medication
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Current smoker or ex-smoker who quit smoking less than 30 days prior to screening
examination
14. Use of nicotine replacement devices within 2 weeks prior to first administration of trial 
medication or during the trial 
15. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day for 
males)
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 in males or repeatedly greater than 470 ms in females) or 
any other relevant ECG finding at screening


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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 trial
23. Subjects who, in the investigator’s judgement, are perceived as having an increased risk 
of bleeding, for example because of:
-
haemorrhagic disorder or bleeding diathesis,
-
trauma or surgery within the last 4 weeks or as long as an excessive risk of bleeding
persists after these events,
-
planned surgery during trial participation,
-
history of arteriovenous malformation or aneurysm,
-
history of gastroduodenal ulcer disease or gastrointestinal haemorrhage, or
-
history of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intraarticular 
bleeding
24. Within 10 days prior to administration of trial medication, use of any drug that could 
affect blood coagulation (e.g., acetylsalicylic acid, heparin)
25. Thrombocytopenia (platelet count less than 100 /nL) or low haemoglobin count 
(haemoglobin less than 11.6 g/dL for females and 13.5 g/dL for males) at screening
26. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt,
aborted attempt, or preparatory acts or behaviour)
27. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought without method, intent or plan; active suicidal thought with method but 
without intent or plan; active suicidal thought with method and intent but without specific 
plan; or active suicidal thought with method, plan and intent)
28. For female subjects:
-
positive pregnancy test, pregnancy, or plans to become pregnant within 30 days after 
study completion,
-
concomitant use of hormonal replacement therapy or hormonal contraceptives,
-
lactation period
29. 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.


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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 1.2.3), 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 must be withdrawn by the investigator from trial treatment if any of the 
following discontinuation criteria apply:
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 pregnancy, 
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
6.
 
 
 
 
 
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 (no. 2 is mandatory discontinuation criterion):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, SAEs, or any safety information invalidating the earlier 
positive benefit-risk-assessment. More specifically, the trial will be terminated if more 
than 50% of the subjects have drug-related and clinically-relevant AEs of moderate or
severe intensity, or if at least 1 drug-related SAE 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
In case more than 4 subjects do not complete the trial (including non PK-evaluable subjects), 
the Clinical Trial Leader together with the Trial Pharmacokineticist and the Trial Statistician 
are to decide, if and how many subjects will be replaced. A replacement subject will be 
assigned a unique trial subject number.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product BI 730357 will be provided by BI Pharma GmbH & Co. KG, 
Germany. Caffeine, warfarin, omeprazole, and midazolam will be obtained from a public 
pharmacy.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the trial products are given below:
Trial product 1 (CYP1A2 probe substance)
Brand Name:
Percoffedrinol® N 50 mg Tabletten
Substance:
Caffeine
Pharmaceutical formulation:
Tablet
Source:
Unit strength:
50 mg
Posology:
2 – 0 – 0
Route of administration:
Oral
Duration of use:
Single dose on Day 1 of Visits 2 and 3 (2 days in total)
Trial product 2 (CYP2C9 probe substance)
Brand Name:
Coumadin® 5 mg
Substance: 
Warfarin sodium
Pharmaceutical formulation:
Tablet
Source:
Unit strength:
5 mg 
Posology:
2 – 0 – 0
Route of administration:
Oral
Duration of use:
Single dose on Day 1 of Visits 2 and 3 (2 days in total)
Trial product 3 (CYP2C19 probe substance)
Brand Name:
Antra MUPS® 20 mg magensaftresistente Tabletten
Substance: 
Omeprazole
Pharmaceutical formulation:
Gastro-resistant tablet
Source:
Unit strength:
20 mg  
Posology:
1 – 0 – 0
Route of administration:
Oral
Duration of use:
Single dose on Day 1 of Visits 2 and 3 (2 days in total)


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Trial product 4 (CYP3A4 probe substance)
Brand Name:
Midazolam-ratiopharm® 2 mg/mL orale Lösung
Substance: 
Midazolam
Pharmaceutical formulation:
Oral solution
Source:
Unit strength:
2 mg/mL  
Posology:
1 mL – 0 – 0
Route of administration:
Oral
Duration of use:
Single dose on Day 1 of Visits 2 and 3 (2 days in total)
Trial product 5 (BI investigational product)
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
3 – 0 – 3
Route of administration:
Oral
Duration of use:
Multiple doses from Day -14 to Day 6 of Visit 3 
(20 days in total) 
4.1.2
Selection of doses in the trial
Single doses of caffeine 100 mg, warfarin 10 mg, omeprazole 20 mg, and midazolam 2 mg 
are standard doses used in clinical DDI trials. The doses were selected based on their 
tolerability and the ability to show a PK interaction if present. For caffeine, 100 mg was 
chosen as it is approximately the amount of caffeine in one cup of coffee. For warfarin, 
10 mg is commonly used as starting and maintenance dose for oral anticoagulation. For 
omeprazole, a dose of 20 mg once a day is used in the treatment of symptomatic gastro-
oesophageal reflux disease and duodenal ulcer. For midazolam, an oral dose of about 2 mg 
should lead to significant systemic exposure without major sedative effect [P10-00100]. 
According to DDI-guidelines, the exposure of the offender drug should be similar to the 
exposure seen under clinical conditions in patients. 
 
 


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4.1.3
Method of assigning subjects to treatment groups
There is only one treatment sequence investigated in this trial, and each subject will be 
allocated to the same treatment sequence (R-T). The subjects will be allocated to a trial
subject number by drawing lots prior to first administration of trial medication. Once a 
subject number has been assigned, it cannot be reassigned to any other subject.
Reference and test treatments will be administered in the sequence specified in the Flow 
Chart.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a two-period fixed sequence design trial. All subjects will receive BI 730357 and 
probe drugs in a fixed order. The treatments to be evaluated are outlined in Table 4.1.4: 1
below.
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substances
Formulation, 
Regimen
Unit 
Strength 
(mg)
Number of
units/volume 
administered
Total Daily 
Dose 
(mg)
Study
Visit (V),
Day (D)
Reference 
(R)
   Caffeine
+ Warfarin
+ Omeprazole
+ Midazolam
tablet, q.d.
tablet, q.d.
tablet, q.d.
oral solution, q.d.
50
5
20
2/mL
2 tablets
2 tablets
1 tablet
1 mL
100
10
20
2
V2, D1
V2, D1
V2, D1
V2, D1
Test
(T)
   BI 730357
tablet, b.i.d.
100
3 tablets
600
V3, D-14 to D6
   Caffeine
+ Warfarin
+ Omeprazole
+ Midazolam
tablet, q.d.
tablet, q.d.
tablet, q.d.
oral solution, q.d.
50
5
20
2/mL
2 tablets
2 tablets
1 tablet
1 mL
100
10
20
2
V3, D1
V3, D1
V3, D1
V3, D1
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g., reconstitution), if correct dosage cannot be ensured 
otherwise.
At each dosing occasion the trial medication should be administered within 2 minutes. The 
liquid and oral components of the CYP probe cocktail should be administered in the same 
order for all subjects. 
The cocktail administrations will be separated by a wash-out of at least 20 days.
A standardised meal (1 bread roll with 15 mg butter, sliced cheese and sliced sausage, and a 
cup of water or decaffeinated coffee without sugar) will be served 30 min before each 
BI 730357 administration. The standardized meals must be completely consumed prior to 
drug administration. To assure comparable conditions for the cocktail administration, the 


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standardised meal will also be served 90 min before the planned dosing of the CYP probe 
cocktail of reference treatment R. All meals are to be consumed within 30 minutes.
Subjects will be kept in-house under close medical surveillance until 48 hours following 
administration of the CYP-probe cocktail (containing caffeine, warfarin, omeprazole, and 
midazolam).
During the first 4 hours after administration of the CYP-probe cocktail on Day 1, and the first 
2 hours after all other trial drug administrations, subjects are not allowed to lie down (i.e., no 
declination of the upper body of more than 45 degrees from upright posture), except for 
medical reasons or for recording of 12-lead ECG and vital signs measurements.
For restrictions with regard to diet, see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
This Phase I trial is not randomized and will be handled in an open fashion throughout (that 
is, during the conduct, including data cleaning and preparation of the analysis). This is 
considered acceptable because the potential for bias seems to be low and does not outweigh 
practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
BI 730357
BI 730357 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.
Caffeine, warfarin, omeprazole, and midazolam
Caffeine, warfarin, omeprazole, and midazolam will be obtained as commercial products by 
the clinical trial site from a public pharmacy. The drug 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 
Clinical Trial Manager (as provided in the list of contacts) is to be contacted immediately.


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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority, e.g., competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be 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 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 Clinical Trial Leader. 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 AEs 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.
No bleeding events are expected in this trial, as warfarin is given as a single dose. In case of 
excessive anticoagulation with or without bleeding, further warfarin administration should be 
avoided and if necessary treated by administration of oral or parenteral vitamin K1. In case of 
minor bleeding, 5 to 10 mg vitamin K1 may be given as a single oral dose. If minor bleeding 
progresses to major bleeding, give 10 to 20 mg (rarely up to 50 mg) parenteral vitamin K1. In 
emergency situations of severe haemorrhage, clotting factors can be returned to normal by 
administering 200 to 500 mL of fresh whole blood or fresh frozen plasma, or by giving 
commercial prothrombin complex concentrate.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Known inhibitors/inducers of CYPs 1A2, 2C9, 2C19, or CYP3A should be avoided during 
the entire trial. Particularly, hormonal oral contraceptives, hormonal replacement therapy, and 
nicotine replacement devices are not allowed due to potential for CYP1A2 inhibition.
4.2.2.2
Restrictions on diet and life style
Poppy seed-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.
While admitted to the trial site, 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 within 10 hours before and 4 hours after intake of the CYP probe cocktail
(except breakfast served 90 minutes before administration).
Subjects will be advised to not consume any food within 2 hours before and 1 hour after 
administration of BI 730357 other than the meals provided at the site before drug intake.
On PK profile days (Day 1 of Visits 2 and 3), from 1 hour 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 and 4 hours after intake of the CYP probe substrates (mandatory for all subjects). 
From lunch until dinner, total fluid intake is restricted to 2000 mL on these days. Outside 
these times, water and fluids, which are not excluded for this trial (see succeeding sentences),
may be consumed ad libitum.
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication in Visit 2 until after 
the last PK sample of Visit 3 is collected.
Alcoholic beverages are not permitted from 2 days before the first administration of trial 
medication in Visit 2 until after the last PK sample in Visit 3 is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed within 12 hours before and during the in-house confinement at the 
trial site.
Smoking is not allowed starting from 30 days prior to screening until EoTrial examination.
Excessive physical activity (such as competitive sport) should be avoided during the entire 
trial, starting with the screening examination until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation, treatment with ultraviolet light 
(e.g., PUVA), or medication with known phototoxicity potential (e.g., doxycycline) should be 


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avoided from the first administration of trial medication until the EoTrial examination. The 
use of sunscreens is mandatory in that time.
If female subjects of child-bearing potential are included, adequate contraception is to be 
maintained throughout the course of the trial (see Section 3.3.2 for adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results of alcohol history not mandatory to be entered into CRF 
or to be reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, physical 
examination, and assessment of suicidal ideation and behaviour using the C-SSRS 
(‘baseline/screening scale’). At the end of trial examination, it will include review of vital 
signs, 12-lead ECG, laboratory tests, physical examination,
 
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap Pro 100, 
) at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 minutes 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 hours. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. The same applies to time points scheduled after breakfast.
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. 


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
D1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leukocytes 
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
--
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
--
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes;  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 
Prothrombin time - INR (International Normalization Ratio)
X
X
X
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
Hormones
Thyroid Stimulating Hormone 
X
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
Cholesterol, total 
X
X
X
X
X
X
X
X
X
X
X
--
X
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium
X
X
X
X
X
X
--
--
--
X
X
X
Urinalysis (Stix) 2
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
Urine sediment 2
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1 A, B, C and D are different sets of laboratory values. The Flow Chart details at which time point which set is 
to be investigated. 
2 Microscopic examination if erythrocytes, leukocytes, nitrite or protein are abnormal in urine


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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 pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
each administration of the drug cocktail, prior to the first administration of BI 730357, and as 
part of the end of trial examination. Drug screening will be performed at screening and  upon 
admission on the eve of Day 1 of Visit 2 and Visit 3.
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)
Interferon-γ release assay to tuberculosis (qualitative), e.g.  
QuantiFERON®-TB Gold Test
Pregnancy test (urine) 
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g., AlcoTrue®
M, 
) will be performed upon admission on the 
eve of Day 1 of Visit 2 and Visit 3, 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 and pregnancy tests. These tests will be performed at the trial site using 
M-10/14-PDT Surestep Multiline test and HCG-K20 test, respectively, 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. 


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To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 second duration after subjects have rested for at least 5 
minutes in a supine position. ECG assessment will always precede all other study procedures 
scheduled for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally-printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
 
 
 
 
 
 
 
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
An 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.


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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 SAE is defined as any AE which fulfils at least one of the following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.


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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 
make sure that these parameters are analyzed, 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.

Severe infections (grading according to Rheumatology Common Toxicity Criteria 
(RCTC) developed by OMERACT [R13-3515])

Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including polyomavirus-
associated nephropathy, cytomegalovirus, posttransplant lymphoproliferative disorder 
(Epstein-Barr virus), progressive multifocal leukoencephalopathy, bartonellosis 
(disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), hepatitis B virus reactivation, herpes 
simplex (invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, penicillium marneffei, sporothrix 
schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), trypanosoma cruzi Infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), hepatitis C virus progression.


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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)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged


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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.


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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 contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions the 
Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.2.6.2.4
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Studies (Part A and Part B) as well 
as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Studies and not the SAE form is to be 
completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE form must 
be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of PK, 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 PK
parameters. 


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5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
General aspects for all analytes
Blood samples for PK analyses will be withdrawn by means of either an indwelling venous 
catheter or by venepuncture with a metal needle from an antecubital or forearm vein.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, 
planned sampling time, and the analyte (e.g., ‘BI 730357’ or ‘CYP cocktail’).
After completion of the trial, the plasma samples, the left-over, and/or back-up aliquot may 
be used for further methodological investigations (e.g., for stability testing or assessment of 
further metabolites (including, if applicable, re-analysis of parent compound). However, only 
data related to the analyte and/or its metabolite(s) including anti-drug antibodies (if 
applicable) will be generated by these additional investigations. The trial samples will be 
discarded after completion of the additional investigations but not later than 5 years after the 
CTR is archived.
The results of any further investigations are not planned to be part of the CTR, but can be 
included into the CTR if necessary.
BI 730357 and metabolite CD6975
For quantification of plasma concentrations of BI 730357 and its metabolite CD 6975, 
2.7 mL of blood will be taken into K2-EDTA (dipotassium ethylenediaminetetra-acetic acid 
as anticoagulant) blood-drawing tubes at the times indicated in the Flow Chart.
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. From each sample, 2 plasma aliquots 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 and 
aliquots at room temperature. Due to sensitivity of the metabolite to direct sunlight, blood 
samples and aliquots should not be exposed to direct sunlight. 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.
Cocktail probe drugs
For quantification of plasma concentrations of caffeine, warfarin, omeprazole, and 
midazolam (compounds of the CYP probe cocktail) and their relevant metabolites, 7.5 mL of 
blood will be taken into separate K2-EDTA blood-drawing tubes at the times indicated in the 
Flow Chart.


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The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
about 2000 g to 4000 g and 4 to 8 °C. From each sample, 4 plasma aliquots will be obtained
(two primary aliquots, two back-up aliquots) and stored in polypropylene tubes. For the 
analysis of CYP probes (caffeine, warfarin, omeprazole, and midazolam, and their relevant 
metabolites) in plasma, the primary aliquots should contain at least 1.0 mL and 0.5 mL of 
plasma. The back-up aliquots 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 
60 min, with interim storage of blood samples in ice water or on ice 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 back-up aliquots will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the two primary 
aliquots. At the analytical laboratory, the plasma samples will be stored at approximately       
-20 °C or below until analysis. 


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5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Sections 2.1.2, 
2.1.3, 2.2.2.1, and 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 and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 of Visit 2 and Days -14, -8, -1, 1, and 3  of Visit 3 are to be 
performed and completed within a 2 hour-period prior to the next standardized breakfast or 
standardized breakfast planned at the same time, if not indicated otherwise in the Flow Chart.
For ambulatory administration of BI 730357 prior to Day -1 of Visit 3 and after Day 5 of 
Visit 3, a time window of ± 70 minutes will be allowed.
Following cocktail administration in Visits 2 and 3, the acceptable deviation from the 
scheduled time for vital signs, ECG, and laboratory tests will be ± 30 min on Day 1, 
± 45 minutes from 24 hours onwards, and ± 70 minutes from 119 hours onwards.
If scheduled in the Flow Chart at the same time as a meal, 12-lead ECG recordings, vital 
signs, and blood sampling 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.
The acceptable deviation from the scheduled time for all meals on Day 2 in Period 1 is ± 1 
hour, to allow that subjects may have their meal together.
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 PK parameters.
For cocktail PK blood sampling on Days 6-7 of Visits 2 and 3, a time window of 
± 60 minutes will be allowed.
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 trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, 
, and physical examination, refer to 
Sections 5.2.3 to 5.2.5.


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6.2.2
Treatment periods
All subjects will undergo the following treatments (for details refer to Section 4.1):

100 mg caffeine, 10 mg warfarin, 20 mg omeprazole, and 2 mg midazolam together 
as cocktail and single oral dose on Day 1 of Visits 2 and 3

300 mg BI 730357 b.i.d. as multiple oral doses over 20 days from Day -14 until Day 6 
of Visit 3  
On the evening of Day -1 of Visits 2 and 3, the study participants will be admitted to the trial 
site and kept under close medical surveillance there until the morning of Day 3 of these visits, 
respectively, i.e., for at least 48 hours following administration of the cocktail containing the 
CYP probe drugs. The subjects will then be allowed to leave the trial site after formal 
assessment and confirmation of their fitness. Days on which the subjects are hospitalized are 
given in the Flow Chart. On all other study days, subjects will be treated in an ambulatory 
fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
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, assessment of SIB,
and physical examination during the follow-up period, see Sections 5.2.1 to 5.2.6.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically-
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The primary objective of this trial is to investigate whether there is a drug-drug interaction 
between BI 730357 (as the perpetrator) and any of the drugs of the CYP probe cocktail 
(caffeine, S-warfarin, omeprazole, and midazolam; described in Section 1.2.2). Hence, the 
PK of the components of the CYP probe cocktail given as single doses without BI 730357 
(Reference R) and given as single doses at steady state administration of BI 730357 (Test T) 
is analysed on the basis of the primary PK endpoints, as listed in Section 2.1.2. The trial is 
designed to allow intra-subject comparisons, and will be evaluated statistically by use of a 
linear model for logarithmically transformed PK endpoints. 
 
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The PK of the probe drugs given alone and given at steady state administration of BI 730357 
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-tests procedure, each at the 5% significance level. Since 
the main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were entered and treated 
with at least one dose of study drug. The treated set will be used for safety analyses.
PK 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 and was not 
excluded due to a protocol deviation relevant to the evaluation of PK or due to PK 
non-evaluability (as specified in the following subsection ‘Pharmacokinetics’). Thus, 
a subject will be included in the PKS, even if he contributes only one PK parameter 
value for one period to the statistical assessment. Descriptive and model based 
analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IQRM plan, IPDs will be identified no later than in 
the Report Planning Meeting, and the IPD categories will be updated as needed.


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Pharmacokinetics
The PK parameters listed in Section 2.1 for the probe drugs will be calculated by means of 
non-compartmental analysis. Noncompartmental PK parameters will be calculated based on 
actual sampling times using a validated PK software (Phoenix® WinNonlin® 6.3). 
Descriptive statistics will be used to evaluate plasma concentration data and PK parameters. 
The derivation of PK parameters is described in BI internal SOP (001-MCS-36-472). Further 
details on analysis will be described in the TSAP. 
Plasma concentration data and parameters of a subject will be included in the statistical 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

Use of restricted medications
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 of probe drugs 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 PK parameters. Concentrations used in the PK 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). 


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7.3.1
Primary endpoint analyses
Primary analyses
The primary endpoints (refer to Section 2.1.2) will be calculated according to the BI Standard 
Operating Procedure (SOP) ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/ Pharmacodynamics’ (001-MCS-36-472).
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subjects and treatment. The effect 
‘subject’ will be considered as random, whereas ‘treatment’ will be considered as fixed. The 
model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response measured on subject m receiving treatment k ,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
 
 
In addition to the model based approach, all parameters will be calculated and analysed 
descriptively.


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7.3.2
Secondary endpoint analyses
Not applicable.
7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.3) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.


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For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the 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 Treatment R intake and end of REP (see 
Section 1.2.3) will be assigned to the Treatment R period, those between first administration 
in Treatment T and end of REP (see Section 1.2.3) will be assigned to Treatment T 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 5.2.6.1.4), and
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. 
Relevant ECG findings will be reported as AEs.
 
 
 
7.4
INTERIM ANALYSES
No interim analysis is planned.


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7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
In this trial, subjects receive all treatments in the same order, thus no randomisation for the 
treatment assignment is performed (see also Section 4.1.3).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 16 subjects in the trial, account for up to 4 dropouts. The 
planned sample size is not based on a power calculation, but is considered sufficient to 
achieve the aims of this exploratory trial. With this sample size, the following precision in 
estimating the ratio of geometric means (test/reference) can be expected with 95% 
probability. Precision is defined as the ratio of upper CI limit to the relative BA estimate. 
Note that the precision is independent of the actual ratio of geometric means.
The observed intra-individual coefficient of variation (gCV) for the probe drugs ranged 
between 10% to over 30% in previous trials. Also, they appeared to depend on which CYP 
drug was evaluated. Therefore the following Table 7.7: 1 provides an overview of the two-
sided 90% confidence interval of the gMean ratio (T/R) and precision (upper confidence 
limit/ lower confidence limit) that are expected with 95% probability, based on various
assumptions around the gCVs and a sample size of N=12 evaluable subjects.
Table 7.7: 1
Expected precision and two-sided 90% confidence intervals around 
the ratios of geometric means (T/R) for different gCVs in a two-
period fixed sequence design trial (N=12)
gCV
Precision
90% CI for respective gMean %ratio (T/R)
20%
50%
80%
200%
10%
1.10
(18.14, 22.06)
(45.34, 55.14)
(72.55, 88.22)
(181.36, 220.55)
20%
1.21
(16.47, 24.29)
(41.18, 60.72)
(65.88, 97.15)
(164.70, 242.86)
30%
1.33
(15.00, 26.67)
(37.49, 66.68)
(59.99, 106.68)
(149.98, 266.71)
Thus, based on a sample size of N=12 evaluable subjects and assuming a gCV of 30% for the 
PK endpoint of the probe drug, the precision of the 90% CI would be 1.33. If the gMean ratio 
would be 20%, then the 90% CI is expected to range approximately from 15% to 27%.


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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].


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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.
Within 1 year after trial termination the Sponsor will submit a summary of the CTR covering 
all relevant results of the trial to the Competent Authority and to the Independent Ethics 
Committee.
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.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
For subjects enrolled during the COVID-19 pandemic: 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 Human Pharmacology Centre (HPC) – Boehringer Ingelheim's Phase I unit – the 
validated ClinBaseTM 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.


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Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g., re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

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 


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regulatory inspector (e.g., FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
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 and external facilities storing biological samples from clinical trial 
participants 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 (e.g. 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 data


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Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’).
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 ethics committee/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 Human Pharmacology Centre (HPC) of BI Pharma GmbH 
& Co. KG, Biberach, Germany, 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 (CT 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 Manager (CT Manager), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
(BI 730357) or will be obtained by the clinical trial site from 
a public pharmacy (caffeine, midazolam, omeprazole, and warfarin).
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
).


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The analyses of plasma concentrations of caffeine, midazolam, omeprazole, and warfarin and 
their metabolites as well as of BI 730357 will be performed under the responsibility of the 
 
at suitable contract research organisations.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organization 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
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Zhang Y, Kashuba ADM, Rowland E, Bertino JS. Combined phenotypic 
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acetyltransferase-2, and xanthine oxidase activities with the 'Cooperstown 
5 + 1 cocktail'. Clin Pharmacol Ther 2003; 74 (5); 437-47.
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Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, 
Desai M, Miller M, Hall SD. The effect of echinacea (Echinacea purpurea 
root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther 2004; 75 
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ZhouH, Tong Z, McLeod JF. 'Cocktail' approaches and strategies in drug 
development: valuable tool or flawed science? J Clin Pharmacol 2004; 44 
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Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in clinical 
practice: why, how, and when? Basic Clin Pharmacol Toxicol 2005; 
97(3): 125-134.
P10-00100
Turpault S, Brian W, Horn R van, Santoni A, Poitiers F, Donazzolo Y, 
Boulenc X. Pharmacokinetic assessment of a five-probe cocktail for CYPs 
1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 2009; 68(6): 928-935.
P10-05867
Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien HC, White N, 
Jennings SH, Choi SO, Li J, Wagner MJ, La-Beck NM, Drulak M, Sabo 
JP, Castles MA, MacGregor TR, Kashuba ADM. A phenotype-genotype 
approach to predicting CYP450 and P-glycoprotein drug interactions with 
the mixed inhibitor/inducer tipranavir/ritonavir. Source:Clin Pharmacol 
Ther 2010; 87(6) ;735-742. 
P12-10638
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions: 
final (21 June 2012, CPMP/EWP/560/95/Rev. 1). 
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eline/2012/0 7/WC500129606.pdf (access date: 14 September 2012); 
2012.
P14-11944
Christensen M. Low daily 10-mg and 20-mg doses of fluvoxamine inhibit 
the metabolism of both caffeine (cytochrome P4501A2) and omeprazole 
(cytochrome P4502C19). Clin Pharmacol Ther 2002; 71(3): 141.


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P12-05791
U.S. Department of Health and Human Services Food and Drug 
Administration. Center for Drug Evaluation and Research (CDER). 
Guidance for industry: drug interaction studies - study design, data 
analysis, implications for dosing, and labeling recommendations (draft 
guidance, February 2012 (this guidance document is being distributed for 
comment purposes only)). Website: 
fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/ucm292362.pdf (access date: 14 May 2012); U.S. Department of 
Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER); 2012.
P15-06991
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions (21 
June 2012, CPMP/EWP/560/95/rev. 1 corr. 2). 
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eline/2012/0 7/WC500129606.pdf (access date: 8 July 2015); London: 
European Medicines Agency (EMA); 2012.
P96-3991
Andersson T. Pharmacokinetics, metabolism and interactions of acid 
pump inhibitors: focus on omeprazole, lansoprazole and pantoprazole. 
Clin Pharmacokinet 1996; 31(1): 9-28.
R06-0294
Data sheet: Hypnovel, midazolam 5 mg/5 ml and 15 mg/3 ml ampoules 
(date of preparation: 17 September 2002). 
http://www.medsafe.govt.nz/profs/Datasheet/h/Hypnovelinj.htm (2002).
R06-0327
Kalow W, Tang BK. The use of caffeine for enzyme assays: a critical 
appraisal. Clin Pharmacol Ther 1993; 53(5): 503-514.
 
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
 
R13-2643
Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, 
Higgins PDR, Wehkamp J, Feagan BG, Yao MD, Karczewski M, 
Karczewski J, Pezous N, Bek S, Bruin G, Mellgard B, Berger C, Londei 
M, Bertolino AP, Tougas G, Travis SPL, Secukinumab in Crohn's Disease 
Study Group. Secukinumab, a human anti-IL-17A monoclonal antibody, 
for moderate to severe Crohn's disease: unexpected results of a 
randomised, double-blind placebo-controlled trial. Gut 2012;61 
(12):1693-1700.
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, Tsuji 
W, et.al. Standardizing assessment and reporting of adverse effects in 


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rheumatology clinical trials II: the Rheumatology Common Toxicity 
Criteria v.2.0. J Rheumatol 34:6. 1401-1414. 2007.
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Caffeine (from Wikipedia, the Free Encyclopaedia). 
http://en.wikipedia.org/ wiki/Caffeine#Sources_and_consumption (access 
date: 26 March 2014).
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Percoffedrinol® N 50 mg Tabletten (Aristo Pharma), Fachinformation, 
May 2014.
R16-2630
Ueda E, Kurebayashi S, Sakaue M, Backlund M, Koller B, Jetten AM. 
High incidence of T-cell lymphomas in mice deficient in the retinoid-
related orphan receptor RORgamma. Cancer Res 2002;62(3):901-909.
R16-3149
Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of  
interleukin-17 function in disease. Immunology 2010;129:311-321.
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Miossec P. Clinical implications of Th17/IL-17: diseases that may benefit 
from manipulating the Th17 pathway. Eur J Immunol 2009;39:667-669.
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Coumadin 5 mg, Tabletten (Bristol-Myers Squibb), Fachinformation/ 
Zusammenfassung der Merkmale des Arzneimittels, Stand der 
Information: Juni 2017.
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Midazolam-ratiopharm 2 mg/ml orale Loesung (ratiopharm), 
Fachinformation, Stand der Information: August 2018.
R20-1236
Antra Mups 10 mg, 20 mg magensaftresistente Tabletten (AstraZeneca), 
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SmPC, Stand der Information: Mai 2018.
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Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.
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Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major 
importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 
525-538.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c09228382
Investigator Brochure BI 730357. Psoriasis - 1407.P01; Current version.


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c03142665
 The effect of multiple 
doses of BI 187004 on the single dose pharmacokinetics of cytochrome 
P450 substrates (caffeine, warfarin, omeprazole, metoprolol and 
midazolam) and a P-glycoprotein substrate (digoxin) administered orally 
in an open-label, one-sequence trial in healthy subjects. 1307.19. 08-Sep-
2015.
c16462083
 CTR 1407-0001, A partially 
randomised, single-blind, placebo-controlled trial to investigate safety, 
tolerability, pharmacokinetics and pharmacodynamics of single rising 
doses of BI 730357 administered as oral solution and tablets to healthy 
human subjects, and a randomized, open-label, single-dose, three-way 
cross-over bioavailability comparison of BI 730357 as tablet versus oral 
solution and tablet with and without food; July 2018.
c25766034
CTR 1407-0002, Phase Ib 
evaluation of the safety and tolerability and effect on midazolam 
metabolism of the administration of multiple rising doses of BI 730357 to 
healthy volunteers. April 2019.
c26494034
CTR 1407-0031, A phase I, 
open-label, single-dose trial to investigate metabolism and 
pharmacokinetics of BI 730357 BS (C-14) administered as oral solution in 
healthy male volunteers. September 2019.
c27425119
CTR 1407-0015, Safety, 
tolerability, and pharmacokinetics of single rising oral doses of BI 730357 
in Japanese healthy male subjects (double-blind, randomised, placebo-
controlled, parallel group design). November 2019.
c27699953
CTR 1407-0014, Relative 
bioavailability of a single oral dose of BI 730357 when administered alone 
or in combination with multiple oral doses of itraconazole in healthy male 
subjects (an open-label, one-way crossover study). December 2019.
c27700144
 CTR 1407-0033, Investigation of 
pharmacokinetics and absolute oral bioavailability of BI 730357 
administered as an oral dose with an intravenous microtracer dose of BI 
730357 BS (C-14) in healthy male volunteers. January 2020.
c28904523
CTR 1407-0032, Relative 
bioavailability of intended commercial formulations (iCF) of BI 730357 
versus BI 730357 trial formulation 1 and bioavailability comparison of 
three different iCF batches following oral administration in healthy 
subjects (an open-label, single-dose, randomised, 2-way and 3-way 
crossover trial). February 2020.
U09-1674-04
 
Relative bioavailability of a single oral dose of warfarin (10 mg q.d.) after 


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co-administration with multiple oral doses of BI 1356 (5 mg q.d.) 
compared to the bioavailability of a single oral dose of warfarin (10 mg 
q.d.) alone in healthy male volunteers (an open label, two periods, fixed-
sequence, clinical phase I study). 1218.28. 14-Jul-2009.
U10-2984-01
 Relative bioavailability of 
both BI 10773 and warfarin and pharmacodynamics of warfarin after co-
administration compared to multiple oral doses of BI 10773 (25 mg once 
daily) and a single oral dose of warfarin (25 mg) alone in healthy male 
volunteers (an open-label, crossover, clinical phase I study). 1245.18. 30-
Nov-2010.


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10.
APPENDICES
10.1
COLUMBA-SUICIDE SEVERITY RATING SCALE


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
12 November 2020
EudraCT number
2020-002506-51
BI Trial number
1407-0039
BI Investigational Medicinal 
Product
BI 730357
Title of protocol
The effect of multiple doses of BI 730357 on the 
single dose pharmacokinetics of caffeine, warfarin, 
omeprazole and midazolam administered orally as a 
cocktail in healthy subjects (an open-label, two-
period fixed sequence design trial)
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
3.3.4.1
Description of change
Clarification in the first sentence that an individual 
subject must be withdrawn from trial treatment by 
the investigator if any of the following 
discontinuation criteria apply.
 
Rationale for change
Objections of the competent authority and ethics 
committee regarding the discontinuation criteria


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c31764080
2.0
clinical-trial-protocol-version-02
The effect of multiple doses of BI 730357 on the single dose pharmacokinetics of
caffeine, warfarin, omeprazole and midazolam administered orally as a cocktail in
healthy subjects (an open-label, two-period fixed sequence design trial)
Author-Clinical Trial Leader
13 Nov 2020 12:55 CET
Author-Trial Statistician
13 Nov 2020 13:06 CET
Approval
Medicine
13 Nov 2020 13:21 CET
Author-Trial Clinical
Pharmacokineticist
13 Nov 2020 14:50 CET
Verification-Paper Signature
Completion
13 Nov 2020 18:38 CET
Approval-Team Member Medicine
16 Nov 2020 13:37 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c31764080
2.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c35156017-01
BI Trial No.:
1407-0039
Title:
The effect of multiple doses of BI 730357 on the single dose 
pharmacokinetics of caffeine, warfarin, omeprazole and midazolam 
administered orally as a cocktail in healthy subjects (an open-label, 
two-period fixed sequence design trial)
(Revised Protocol including Amendment 1 [c31764080-02])
Investigational
Products:
BI 730357
Responsible trial
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
12 APR 2021 SIGNED
Version:
1
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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....................................................13
6.3
SUBJECT SETS ANALYSED ...........................................................................13
6.5
POOLING OF CENTRES..................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................15
7.
PLANNED ANALYSIS ......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........18
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 ......................................................19
 
7.5
SECONDARY ENDPOINTS .............................................................................21
7.5.1
Key secondary endpoints ....................................................................................21
7.5.2
Secondary endpoint.............................................................................................21
7.7
EXTENT OF EXPOSURE .................................................................................23
7.8
SAFETY ANALYSIS..........................................................................................23
7.8.1
Adverse Events ....................................................................................................23
7.8.2
Laboratory data...................................................................................................25
7.8.3
Vital signs.............................................................................................................25
7.8.4
ECG ......................................................................................................................25
7.8.5
Others ...................................................................................................................26
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............27
9. 
REFERENCES ....................................................................................................28


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11.
HISTORY TABLE..............................................................................................30


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................11
Table 6.3: 1
Subject sets analysed ........................................................................................15
Table 11: 1
History table .....................................................................................................30


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
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
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CSD
Company Standard Displays
C-SSRS
Columbia - Suicide Severity Rating Scale
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
F/U
Follow Up
gCV
Geometric coefficient of variation
gMean
Geometric mean
λz
Terminal rate constant of the analyte in plasma
LLT
Lower level term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile


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


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3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on trial objectives, trial 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,
).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by
), 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.
In Section 1.2.3 of  the CTP the following REP of cocktail was defined:
The Residual Effect Period (REP) of the cocktail is 9 days, referring to warfarin, the drug with the 
longest half-life among the cocktail components. This has been modified, as after 7 days, exposure 
from a single dose of warfarin is negligible or a new onset of PD effects is very unlikely. 
Therefore, the REP has been adapted to 7 days for all study drugs (cocktail as well as BI 730357). 
AEs occurring 7 days after warfarin administration of the "cocktail alone" treatment are thus 
attributable to the multiple doses of BI 730357 administered from this time onward in the "BI 
alone" study phase.  AEs occurring 7 days after warfarin administration of treatment T 
("BI+Cocktail") are thus to be assigned to the BI 730357 multiple doses of the "BI+Cocktail" 
phase.
In Section 7.3 of the CTP the following was defined: 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. Due to SOP changes, the 
IPD categories are no longer available in the IQRM plan but included in an IPD specification file
(3). The IPD categories originally defined in the IQRM plan were transferred to this IPD 
specification file. Minor changes regarding the IPD categories were performed only.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: 
The following primary endpoints will be determined for the probe drugs caffeine, warfarin 
(specifically S-warfarin), omeprazole, and midazolam when administered without BI 730357 
and when co-administered with BI 730357 at BI 730357 steady-state:

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
This section is not applicable as no secondary endpoints have been defined in the CTP.
5.3
FURTHER ENDPOINTS
Pharmacokinetic (PK) endpoints
Other pharmacokinetic parameters of the probe drugs (and metabolites) are further study 
endpoints. In addition, PK endpoints will be calculated as appropriate for BI 730357 at steady 
state and, if feasible, for the metabolite CD 6975. For more details see CTP Section 2.2.2.1. 
Safety and tolerability endpoints
Section 2.2.2.2 of the CTP: Safety and tolerability of BI 730357 and the probe drugs will be 
assessed based on:

AEs (including clinically-relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Assessment of suicidal ideation and behaviour (SIB) based on C-SSRS


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products and selection of doses, please see 
CTP Sections 3 and 4.
The study will be performed as an open-label, two-treatment, two-period fixed sequence 
design. A drug cocktail, including caffeine, warfarin, omeprazole and midazolam, will be 
administered alone (Reference treatment R) or with BI 730357 (Test treatment T). In total, it 
was planned to assign 16 healthy male and female subjects to the fixed sequence R-T. 
There will be a washout period of at least 20 days between the cocktail administrations.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
R
Cocktail:
100 mg caffeine, 10 mg warfarin, 20 mg omeprazole, 2 mg midazolam 
(Day 1)
Cocktail
T
BI 730357 + Cocktail:
300 mg BI 730357 b.id. for 20 days (Day -14 to Day 6) combined with 
drug cocktail (Day 1, 1h after morning dose of BI 730357).
BI+Cocktail
Section 1.2.3 of CTP:
The Residual Effect Period (REP) of the cocktail is 9 days, referring to warfarin, the drug 
with the longest half-life among the cocktail components. […].
The Residual Effect Period (REP) of BI 730357 is 7 days.
The following study phases will be defined for the analysis of adverse events (AEs):


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
Screening
o
Ranging from 0:00h on day of informed consent until administration time of 
drug cocktail in treatment period 1.

On treatment (labelled “Cocktail”, “BI”, “BI+Cocktail”)
o
Cocktail alone (”Cocktail”): Ranging from the time of administration of drug 
cocktail alone in treatment period 1 until 7 days (168 h) thereafter OR until 
first administration of BI 730357, whatever occurs first.
o
BI alone (“BI”): Ranging from the time of first administration of BI 730357 
until time of administration of drug cocktail in treatment period 2 OR until 7 
days (168h) after the last administration of BI 730357, if subject discontinues 
treatment prior to administration of drug cocktail.
o
BI + Cocktail (“BI+ Cocktail”): Ranging from time of administration of drug 
cocktail in treatment period 2 until 7 days (168h) after the last administration 
of BI 730357 OR until 7 days (168h) after administration of drug cocktail, 
whatever occurs later.

Follow-up (labelled “F/U Cocktail”, “F/U BI”, “F/U BI+Cocktail”)
o
F/U Cocktail: Ranging from the end of REP of drug cocktail in treatment 
period 1 (7 days) until the first administration of BI 730357 in period 2 or until 
trial termination, whatever occurs first.
o
F/U BI - if applicable - Ranging from the end of REP of the last BI 730357 
administration in treatment period 2 (7 days) until trial termination, if subject 
discontinues treatment prior to administration of drug cocktail.
o
F/U BI+Cocktail: Ranging from the end of REP of either BI 730357 or drug 
cocktail (whatever occurs later) in treatment period 2 until trial termination.
Section 7.3.4 of the CTP: Note that AEs occurring after the last per-protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only, and will not 
be captured in the trial database.
The following AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening and follow-up periods will not be included in 
this analysis. 
The following totals will be provided in addition (Section 15.3 only):
a total over all on treatment phases involving BI ("BI Total on treatment")
a total over all on treatment phases included in this analysis ("Total on treatment")
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:
Screening 
On treatment (labelled with the name of the study treatment (short label))


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Follow-up drug cocktail (labelled "F/U Cocktail")
Follow-up BI+Cocktail (labelled "F/U BI+Cocktail")
Follow-up BI (labelled "F/U BI") – only if applicable
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:
a total over all on treatment phases involving BI ("BI Total")
a total over all study phases ("Total")
For detailed information on the handling of the treatments refer to Technical TSAP ADS plan 
and Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
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).
Categories which are considered to be iPDs in this trial were defined in the integrated quality 
and risk management plan (IQRMP) prior to trial initiation. The iPD list was transferred into 
the iPD specification file (due to changes in the SOP) (3). Within this transfer some minor 
adaptations were done to comply with new naming conventions and categorisations. IPDs will 
be identified no later than in the Report Planning Meeting and the iPD categories in the iPD 
specification file will be updated as needed. If any iPDs are identified, they are to be 
summarised into categories and will be captured in the RPM minutes (the decision log) and in 
the iPD specification file. The decision on exclusion of subjects from analysis sets will be 
made after discussion of exceptional cases and implications for analyses.
The iPDs will be summarised and listed.
6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were entered and treated 
with at least one dose of study drug (Cocktail or BI 730357). The treated set will be 
used for safety analyses.


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
PK 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 and was not 
excluded due to a protocol deviation relevant to the evaluation of PK or due to PK 
non-evaluability (as specified in the following subsection ‘Pharmacokinetics’). Thus, a 
subject will be included in the PKS, even if he contributes only one PK parameter 
value for one period to the statistical assessment.  Descriptive and model based 
analyses of PK parameters will be based on the PKS.
[…]
Plasma concentration data and parameters of a subject will be included in the statistical 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

Use of restricted medications
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 of probe drugs 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.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of PK 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.
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 BI-KMED-
TMCP-MAN-0012 (5) and BI-KMED-TMCP-MAN-0014 (6).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before administration of drug cocktail 
in each treatment period.
Section 6.1 of the CTP: Study measurements and assessments scheduled to occur ‘before’ 
trial medication administration on Day 1 of Visit 2 and Days -14, -8, -1, 1, and 3 of Visit 3 
are to be performed and completed within a 2 hour-period prior to the next standardized 
breakfast or standardized breakfast planned at the same time, if not indicated otherwise in the 
CTP Flow Chart.


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For ambulatory administration of BI 730357 prior to Day -1 of Visit 3 and after Day 5 of 
Visit 3, a time window of ± 70 minutes will be allowed. 
Following cocktail administration in Visits 2 and 3, the acceptable deviation from the 
scheduled time for vital signs, ECG, and laboratory tests will be ± 30 min on Day 1, ± 45 
minutes from 24 hours onwards, and ± 70 minutes from 119 hours onwards.
[…]
The acceptable deviation from the scheduled time for all meals on Day 2 in Period 1 is ± 1 
hour, to allow that subjects may have their meal together.
[…]
For cocktail PK blood sampling on Days 6-7 of Visits 2 and 3, a time window of ± 60 minutes 
will be allowed.
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
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 the 
at 
 and will be 
presented in Section 15.6 of the CTR.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (7)) with the exception of those generated for PK-calculations following BI standards 
for PK/PD analysis (8).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number and visit. The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile


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The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK parameters will be calculated 
using the individual values with the number of decimal places as provided by the evaluation 
program. Then the individual values as well as the descriptive statistics will be reported with 
three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories available in 
the eCRF 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.
Exclusion of PK parameters
The ADS “ADPP” (PK parameters) contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS “ADPC” (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental 
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (6) and BI-KMED-
TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (9).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised in total.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the trial 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 (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
For each probe drug (caffeine, (S-)warfarin, omeprazole, midazolam), the effect of drug-drug 
interactions will be investigated on the basis of the primary PK endpoints AUC0-∞and Cmax
(see Section 5.1)
7.4.1
Primary analysis of the primary endpoints
Section 7.3.1 of the CTP:
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subjects and treatment. The effect 
‘subject’ will be considered as random, whereas ‘treatment’ will be considered as fixed. The 
model is described by the following equation:
ykm = + sm +k +  ekm , where
ykm = logarithm of response measured on subject m receiving treatment k,


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= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k,
where  ~ (0, 
) i.i.d.,  ~ (0, 
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see CTP 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:
PROC MIXED DATA=indata; 
CLASS subject treatment; 
MODEL logpk = treatment / DDFM=KR; 
RANDOM subject; 
LSMEANS treatment / PDIFF CL ALPHA=0.1; 
ESTIMATE 'T-R' treatment -1 1; 
RUN;


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoint
This section is not applicable as no secondary endpoint has been specified in the protocol


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7.7
EXTENT OF EXPOSURE
Descriptive statistics by substance (BI 730357, Caffeine, Warfarin, Omeprazole, Midazolam) 
are planned for this section of the report based on the TS. The date and time of drug 
administrations 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.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and NOT on the number of AEs. BI 
standards as presented in “Analysis and Presentation of Adverse Event Data from Clinical 
Trials – Display Template” [BI-KMED-BDS-HTG-0041] (10) and [BI-KMED-BDS-HTG-
0066] (11) will be applied. 
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.
According to the clinical trial 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:


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
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
[…]

Severe infections (grading according to Rheumatology Common Toxicity Criteria 
(RCTC) developed by OMERACT […])

Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including polyomavirus-
associated nephropathy, cytomegalovirus, posttransplant lymphoproliferative disorder 
(Epstein-Barr virus), progressive multifocal leukoencephalopathy, bartonellosis 
(disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), hepatitis B virus reactivation, herpes 
simplex (invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, penicillium marneffei, sporothrix 
schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), trypanosoma cruzi Infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), hepatitis C virus progression.
According to ICH E3 (12), 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 
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.


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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] (13). 
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
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate). In the listing the difference from baseline will also be 
displayed.
For vital signs, descriptive statistics 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).
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment), and will be analysed as such.
No separate ECG listing will be provided.


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7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition
(i.e., a condition already existent before intake of study drug) or as AE and will be
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.
 
 


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database at trial initiation.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON.
3.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED. 
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
5.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
6.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies”, current version; KMED.
7.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
8.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and 
Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
9.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; KMED.
10. BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
11. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical trials”, 
current version, KMED.
12. 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.
13. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
12-APR-21
None
This is the final TSAP