Clinical trial NCT03004404
Conditions: Healthy Volunteers
Sponsor: Boehringer Ingelheim
Start date: 2017-01-12; Completion date: 2017-08-15
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the Single Rising Dose (SRD) part (trial part 1) is to investigate the safety and tolerability of BI 730357 in healthy subjects following oral administration of single rising doses after fasting and/or non-fasting conditions. The secondary objective is the exploration of the pharmacokinetics (PK) including dose proportionality, and pharmacodynamics of BI 730357 after single dosing.

The objective of the Bioavailability (BA) part (trial part 2) will be to explore the relative bioavailability of tablet fasted versus oral solution fasted and the influence of food on the bioavailability of tablet fasted versus tablet fed.

Detailed description:

Arms: arm 1: Participants were administered on Day 1 a single oral dose of 2 milligram (mg) of BI 730357 powder for reconstitution of an oral solution (PfoS) reconstituted in solvent for oral solution 2 milliliter (mL) (Macrogol 400 (Polyethylene glycol 400) together with about 240 milliliter (mL) of water in fasted state.

One authorized employee of the trial site was witness of the administration of the trial medication. arm 2: This arm comprises all placebo treated participants in trial part SRD, regardless of the dose group in which they were treated. Participants of the first cohort of each dose group (DG) were not randomized. In the second cohort of each DG participants were assigned to active treatment or placebo in a 3:1 allocation ratio. arm 3: Participants were administered on Day 1 a single oral dose of 8 milligram (mg) of BI 730357 powder for reconstitution of an oral solution (PfoS) reconstituted in solvent for oral solution 8 milliliter (mL) (Macrogol 400 (Polyethylene glycol 400) together with about 240 milliliter (mL) of water in fasted state.

One authorized employee of the trial site was witness of the administration of the trial medication. arm 4: Participants were administered on Day 1 a single oral dose of 25 milligram (mg) of BI 730357 film-coated tablet together with about 240 milliliter (mL) of water in fasted state. One authorized employee of the trial site was witness of the administration of the trial medication. arm 5: Participants were administered on Day 1 a single oral dose of 50 milligram (mg) of BI 730357 film-coated tablet together with about 240 milliliter (mL) of water in fasted state. One authorized employee of the trial site was witness of the administration of the trial medication. arm 6: Participants were administered on Day 1 a single oral dose of 100 milligram (mg) of BI 730357 film-coated tablets (2x50mg) together with about 240 milliliter (mL) of water in fasted state. One authorized employee of the trial site was witness of the administration of the trial medication. arm 7: Participants were administered on Day 1 a single oral dose of 200 milligram (mg) of BI 730357 film-coated tablets (4x50mg) together with about 240 milliliter (mL) of water in fasted state. One authorized employee of the trial site was witness of the administration of the trial medication. arm 8: Participants were administered on Day 1 a single oral dose of 200 milligram (mg) of BI 730357 film-coated tablets (8x50mg) together with about 240 milliliter (mL) of water in fasted state. One authorized employee of the trial site was witness of the administration of the trial medication. arm 9: The same participants conformed the Dose group (DG) 8 and DG 9. DG 8: Participants were administered on Day 1 a single oral dose of 200 milligram (mg) of BI 730357 film-coated tablets (8x50mg) together with about 240 milliliter (mL) of water, 30 minutes (min) prior dose administration the participants consumed a standard continental breakfast.

DG 9: Participants were administered on Day 1 a single oral dose of 200 milligram (mg) of BI 730357 film-coated tablets (8x50mg) together with about 240 milliliter (mL) of water, 30 minutes (min) prior dose administration the participants consumed a standard high fat breakfast.

Both treatment periods were separated by a wash-out phase of at least 14 days between drug administration of DG 8 and DG 9. One authorized employee of the trial site was witness of the administration of the trial medication. arm 10: Participants were administered on Day 1 a single oral dose of 200 milligram (mg) of BI 730357 film-coated tablets (16x50mg) together with about 240 milliliter (mL) of water, 30 minutes (min) prior dose administration the participants consumed a standard high fat breakfast. One authorized employee of the trial site was witness of the administration of the trial medication. arm 11: Participants were orally administered 25 mg of BI 730357 as film-coated tablet (Reference treatment R) in fasted state.

Followed by 25 mg of BI 730357 film-coated tablet in a fed state (test treatment T2), a high-fat, high-calorie breakfast was served 30 min before dose administration.

Participants received 25 mg of BI 730357 powder for reconstitution of an oral solution (PfOS) reconstituted in solvent for oral solution 2.5 milliliter (mL) (Macrogol 400 (Polyethylene glycol 400) (test treatment T1) in fasted state.

The 3 treatments were administered with 240 mL of water and were separated by a washout period of at least 8 days. One authorized employee of the trial site was witness of the administration of the trial medication. arm 12: Participants were orally administered 25 mg of BI 730357 as film-coated tablet (Reference treatment R) in fasted state.

Participants received 25 mg of BI 730357 powder for reconstitution of an oral solution (PfOS) reconstituted in solvent for oral solution 2.5 milliliter (mL) (Macrogol 400 (Polyethylene glycol 400) (test treatment T1) in fasted state.

Followed by 25 mg of BI 730357 film-coated tablet in a fed state (test treatment T2), a high-fat, high-calorie breakfast was served 30 min before dose administration.

The 3 treatments were administered with 240 mL of water and were separated by a washout period of at least 8 days. One authorized employee of the trial site was witness of the administration of the trial medication. arm 13: Participants were orally administered 25 mg of BI 730357 film-coated tablet in a fed state (test treatment T2), a high-fat, high-calorie breakfast was served 30 min before dose administration.

Followed by 25 mg of BI 730357 as film-coated tablet (Reference treatment R) in fasted state.

Participants received 25 mg of BI 730357 powder for reconstitution of an oral solution (PfOS) reconstituted in solvent for oral solution 2.5 milliliter (mL) (Macrogol 400 (Polyethylene glycol 400) (test treatment T1) in fasted state.

The 3 treatments were administered with 240 mL of water and were separated by a washout period of at least 8 days. One authorized employee of the trial site was witness of the administration of the trial medication. arm 14: Participants were orally administered 25 mg of BI 730357 film-coated tablet in a fed state (test treatment T2), a high-fat, high-calorie breakfast was served 30 min before dose administration.

Participants received 25 mg of BI 730357 powder for reconstitution of an oral solution (PfOS) reconstituted in solvent for oral solution 2.5 milliliter (mL) (Macrogol 400 (Polyethylene glycol 400) (test treatment T1) in fasted state.

Followed by 25 mg of BI 730357 as film-coated tablet (Reference treatment R) in fasted state.

The 3 treatments were administered with 240 mL of water and were separated by a washout period of at least 8 days. One authorized employee of the trial site was witness of the administration of the trial medication. arm 15: Participants received 25 mg of BI 730357 powder for reconstitution of an oral solution (PfOS) reconstituted in solvent for oral solution 2.5 milliliter (mL) (Macrogol 400 (Polyethylene glycol 400) (test treatment T1) in fasted state.

Followed by 25 mg of BI 730357 as film-coated tablet (Reference treatment R) in fasted state.

Participants were orally administered 25 mg of BI 730357 film-coated tablet in a fed state (test treatment T2), a high-fat, high-calorie breakfast was served 30 min before dose administration.

The 3 treatments were administered with 240 mL of water and were separated by a washout period of at least 8 days. One authorized employee of the trial site was witness of the administration of the trial medication. arm 16: BA Part: T1/T2/R Participants received 25 mg of BI 730357 powder for reconstitution of an oral solution (PfOS) reconstituted in solvent for oral solution 2.5 milliliter (mL) (Macrogol 400 (Polyethylene glycol 400) (test treatment T1) in fasted state.

Participants were orally administered 25 mg of BI 730357 film-coated tablet in a fed state (test treatment T2), a high-fat, high-calorie breakfast was served 30 min before dose administration.

Followed by 25 mg of BI 730357 as film-coated tablet (Reference treatment R) in fasted state.

The 3 treatments were administered with 240 mL of water and were separated by a washout period of at least 8 days. One authorized employee of the trial site was witness of the administration of the trial medication.
Interventions: intervention 1: Placebo intervention 2: BI 730357 intervention 3: BI 730357
Intervention descriptions: intervention 1: Placebo intervention 2: powder for reconstitution of an oral solution (PfoS) intervention 3: BI 730357 film-coated tablet

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c11248385-04
EudraCT No.:
BI Trial No.:
2016-003047-11
1407.1
BI Investigational
Product:
BI 730357
Title:
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 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
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax:
Principal Investigator:
Phone:
Fax:
Status:
Final Protocol (Revised Protocol based on global amendment 3)
Version and Date:
Version: 4.0
Date: 05 May 2017
Page 1 of 90
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 730357
Protocol date:
Trial number:
Revision date:
05 May 2017
13 October 2016
1407.1
Title of trial:
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 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
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate the safety, tolerability, pharmacokinetics incl. dose proportionality, and 
pharmacodynamics of BI 730357 (single rising dose [SRD] part), and the relative 
bioavailability of the tablet formulation versus oral solution as well as the influence of 
food on the bioavailability of the tablet formulation (bioavailability [BA] part).
Methodology:
SRD part:
Single rising dose, partially randomized, single-blind, placebo-controlled, 
parallel group design. 
BA part: 
Single dose, randomised, open-label, intra-individual three-way cross-
over  comparisons of the relative bioavailability of tablet fasted versus 
oral solution fasted, and tablet fasted versus tablet fed
No. of subjects: 
total entered:
841
each treatment:
SRD part:
721 (6 on active drug and 2 on placebo at each of 10 dose levels)
BA part:
12 (all on active drug)
1 In dose group (DG) 8 (400 mg BI 730357 or placebo with continental breakfast) and DG 9
(400 mg BI 730357 or placebo with high-fat breakfast) the same subjects will be included for 
an intra-individual comparison of two different diets
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 45 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 730357
Protocol date:
Trial number:
Revision date:
05 May 2017
13 October 2016
1407.1
Test products:
SRD part: BI 730357 as a powder for oral solution (1 mg/mL formulation) or 
film-coated tablet (25 mg and 50 mg formulations)
BA part:
BI 730357 as a powder for oral solution (10 mg/ml) in treatment T1 and
as film-coated tablet (25 mg) in treatment T2
dose:
SRD part: 2 and 8 mg as powder for oral solution (PfOS) and 25, 50, 100, 200,
400 and 800 mg as film-coated tablet   
BA part:
25 mg2 as film-coated tablet and PfOS
2The BA part will only start when at least the 100 mg dose is tested during the 
SRD part and have been safe and well tolerated.
mode of admin.:
SRD part: Oral with 240 mL of water in fasted state (doses from 2 mg to 400 mg, 
inclusive) or in fed state (400 mg dose after continental breakfast, doses 
of 400 and 800 mg after high-fat breakfast)
BA part:
Oral with 240 mL of water in fasted and fed state (high-fat breakfast)
Comparator products: SRD part: Placebo solution or placebo tablets 
BA part:
BI 730357 as film-coated tablet (25 mg) in treatment R
dose:
SRD part:
Not applicable (matching placebo)
BA part: 
25 mg as film-coated tablet
mode of admin.:
SRD part:
Oral with 240 mL of water in fasted state (matching placebo from 2 mg to 
400 mg, inclusive) or in fed state (matching placebo to 400 mg after 
continental breakfast, matching placebo to 400 and 800 mg after high-fat 
breakfast)
BA part: 
Oral with 240 mL of water in fasted state
Duration of treatment: SRD part: 1 single dose 
BA part: 
3 single doses separated by a washout period of at least 8 days
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 730357 is the number [N (%)] 
of subjects with adverse reactions.
Further criteria: AEs including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead electrocardiogram (ECG), continuous 
ECG monitoring, vital signs (blood pressure [BP], pulse rate [PR])
Criteria for 
pharmacokinetics:
Secondary endpoints: AUC0-∞and Cmax of BI 730357
 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 730357
Protocol date:
Trial number:
Revision date:
05 May 2017
13 October 2016
1407.1
Criteria for
pharmacodynamics:
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
SRD part: Dose proportionality will be explored under fasted conditions using a 
regression model. A 95% confidence interval for the slope will be computed.
BA part: Relative bioavailability will be estimated by the ratios of the geometric 
means (tablet / PfOS, tablet fed / tablet fasted) for the secondary endpoints. 
Additionally, their two-sided 90% confidence intervals (CIs) will be provided. Since 
the main focus is on estimation and not testing, an acceptance range was not specified. 
The statistical model will be an ANOVA on the logarithmic scale including effects for 
‘sequence’, ‘subjects nested within sequences’, ‘period’ and ‘treatment’.  CIs will be 
calculated based on the residual error from ANOVA.


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FLOW CHART FOR THE SINGLE RISING DOSE PART
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
10, 11
PK urine
10.12
Blood sampling for 
biomarkers10,13
12-lead ECG
Continuous ECG 
monitoring
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -1
Screening (SCR)1
x
x14
x
2/3*
-3 to -1
-72:007
08:00
Ambulatory visit
x
x
1
-2:00
06:00
Admission to trial site in visits 2-3, 
allocation to treatment2 in visit 2 only
x2,5
x2
x2
x2
x2,9
x2
x2
x2
-0:30
07:30
Standard breakfast in dose groups 8-10 16
0:00
08:00
Drug administration
▲
▲
0:30
08:30
x
│
x9
│
x
x
1:00
09:00
x
│
x9
│
x
x
1:30
09:30
x
│
│
2:00
10:00
240 mL fluid intake
x
│
x
x9
│
x
x
2:30
10:30
x
│
│
3:00
11:00
x
│
x9
│
x
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x8
┼
x
x9
│
x
x
5:00
13:00
x
│
x9
│
x
x
6:00
14:00
x
x
│
x
x9
▼
x
x
8:00
16:00
Snack (voluntary)3
x
┼
x9
x
x
10:00
18:00
Dinner3
x
│
x9
x
x
12:00
20:00
x
┼
x9
x
x 
2
24:00
08:00
Breakfast (voluntary)3,
discharge from trial site
x
x
┼
│
x
x9
x
x
34:00
18:00
Ambulatory visit
x
│
x9
x
x
3
48:00
08:00
Ambulatory visit
x
▼
x
x9
x
x
4
72:00
08:00
Ambulatory visit
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
8
168:00
08:00
Ambulatory visit
x15
x
x
x
5
9 to 13
End of trial (EOT) examination 4
x
x14
x
x
*  Only one treatment period (Visit 2) for dose groups 1-7 and 10. Two identical treatment periods separated by a wash-out 
phase of at least 14 days between drug administration for dose group (DG) 8 (Visit 2) and DG 9 (Visit 3). In DGs 8-9 
the same subjects will be included.
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 (including rhythm strip of at least 15 minutes), 
safety laboratory (including drug screening), demographics (including determination of body height and weight, 
smoking status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion 
criteria. Pharmacogenetic samples will be collected if needed.
2.
The time is approximate; the respective procedure is to be performed and completed within 3 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to (first) drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs and 
concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.


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7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this
ambulatory visit including the safety laboratory can be omitted, if the screening examination is performed on 
Days -3, -2 or -1. 
8.
Two blood sample for stability testing will be taken at this time point (refer to Section 5.5.2.4)
9.
The ECG recording has to be performed as triple at this time point
10. Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject
11. Including blood sample for metabolite identification (refer to Section 5.5.2.2)
12. A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24 and 24-48 h.
13. Two blood samples should be collected: 4.3 mL in sodium citrate tubes and 4.5 mL in lithium heparin tubes.
14. The ECG will be recorded as single ECG at this time point
15. Only haematology, automatic WBC differential and lymphocytes subtypes (refer to Table 5.2.3: 1) at this time point
16. Standard continental breakfast (see Table 4.1.4: 3) in DG 8 and standard high-fat breakfast (see Table 4.1.4: 4) in DGs 9 
and 10


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FLOW CHART FOR THE BIOAVAILABILITY PART
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
8
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -1
Screening (SCR)1
x
x10
x
2/3/4*
-3 to -1
-72:007
08:00
Ambulatory visit
x
x
1
-2:00
06:00
Admission to trial site in visits 2-4, 
allocation to treatment in visit 2 only2
x2,5
x2
x10,2
x2
x2
-0:30
07:30
Standard breakfast9
0:00
08:00
Drug administration
0:30
08:30
x
1:00
09:00
x
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x10
x
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x10
x
x
5:00
13:00
x
6:00
14:00
x
x10
x
x
8:00
16:00
Snack (voluntary)3
x
x
10:00
18:00
Dinner3
x
x10
x
12:00
20:00
x
x 
2
24:00
08:00
Breakfast (voluntary)3, discharge from trial site
x
x
x10
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x10
x
x
4
72:00
08:00
Ambulatory visit
x
x
5
96:00
08:00
Ambulatory visit
x
x
8
168:00
08:00
Ambulatory visit
x11
x
x
5
9 to 13
End of trial (EOT) examination4
x
x10
x
x
* Three identical treatment periods separated by wash-out phases of at least 8 days between each drug administration
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the respective procedure is to be performed and completed within 3 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to the first drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs and 
concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.


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7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to each administration of study drug; 
this ambulatory visit including the safety laboratory can be omitted, if the screening examination is performed on 
Days -3, -2 or -1. 
8.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject
9.
Standard breakfast only in one treatment period under fed condition
10. The ECG will be recorded as single ECG at this time point. However, the number of ECGs per time point may be 
increased to three ECGs based on the preliminary ECG results obtained during the SRD part of this trial.
11. Only haematology, automatic WBC differential and lymphocytes subtypes (refer to Table 5.2.3: 1) at this time point.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART FOR THE SINGLE RISING DOSE PART.........................5
FLOW CHART FOR THE BIOAVAILABILITY PART..............................7
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 25
2.2
TRIAL OBJECTIVES.......................................................................................28
2.3
BENEFIT - RISK ASSESSMENT ...................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 32
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................32
3.1.1
Administrative structure of the trial...................................................34
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................35
3.3
SELECTION OF TRIAL POPULATION ......................................................35
3.3.1
Main diagnosis for study entry............................................................36
3.3.2
Inclusion criteria...................................................................................36
3.3.3
Exclusion criteria ..................................................................................36
3.3.4
Removal of subjects from therapy or assessments.............................37
3.3.4.1
Removal of individual subjects................................................37
3.3.4.2
Discontinuation of the trial by the Sponsor .............................38
3.3.5
Replacement of subjects .......................................................................38
4.
TREATMENTS........................................................................................ 39
4.1
TREATMENTS TO BE ADMINISTERED....................................................39


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4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................39
4.1.2
Method of assigning subjects to treatment groups ............................41
4.1.3
Selection of doses in the trial................................................................42
4.1.4
Drug assignment and administration of doses for each subject .......42
4.1.5
Blinding and procedures for unblinding ............................................44
4.1.5.1
Blinding....................................................................................44
4.1.5.2
Procedures for emergency unblinding .....................................45
4.1.6
Packaging, labelling, and re-supply ....................................................45
4.1.7
Storage conditions.................................................................................45
4.1.8
Drug accountability ..............................................................................45
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................46
4.2.1
Other treatments and emergency procedures....................................46
4.2.2
Restrictions............................................................................................46
4.2.2.1
Restrictions regarding concomitant treatment .........................46
4.2.2.2
Restrictions on diet and life style.............................................46
4.3
TREATMENT COMPLIANCE.......................................................................47
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 48
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................48
5.1.1
Endpoints of efficacy.............................................................................48
5.1.2
Assessment of efficacy...........................................................................48
5.2
SAFETY..............................................................................................................48
5.2.1
Endpoints of safety................................................................................48
5.2.2
Assessment of adverse events...............................................................48
5.2.2.1
Definitions of adverse events...................................................48
5.2.2.2
Adverse event collection and reporting ...................................51
5.2.3
Assessment of safety laboratory parameters......................................53
5.2.4
Electrocardiogram................................................................................55
5.2.4.1
12-lead resting ECG.................................................................55
5.2.4.2
Continuous ECG monitoring ...................................................57
5.2.5
Assessment of other safety parameters...............................................57
5.2.5.1
Vital signs ................................................................................57
5.2.5.2
Medical examinations..............................................................57
5.3
OTHER...............................................................................................................57
5.3.1
Pharmacogenomic evaluation..............................................................57
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................58
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................58
5.5.1
Pharmacokinetic endpoints..................................................................58
5.5.1.1
Secondary endpoints................................................................58


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5.5.2
Methods of sample collection...............................................................59
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................59
5.5.2.2
Plasma sampling for metabolism analysis ...............................60
5.5.3
Analytical determinations ....................................................................62
5.5.3.1
Analytical determination of analyte plasma concentration......62
5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....63
6.
INVESTIGATIONAL PLAN.................................................................. 64
6.1
VISIT SCHEDULE............................................................................................64
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................64
6.2.1
Screening period....................................................................................64
6.2.2
Treatment periods.................................................................................65
6.2.3
End of trial period.................................................................................65
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 66
7.1
STATISTICAL DESIGN – MODEL ...............................................................66
7.1.1
Objectives...............................................................................................66
7.1.2
Endpoints...............................................................................................66
7.1.3
Model......................................................................................................66
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................68
7.3
PLANNED ANALYSES....................................................................................68
7.3.1
Primary analyses...................................................................................68
7.3.2
Secondary analyses ...............................................................................69
7.3.3
Safety analyses.......................................................................................70
7.3.4
Preliminary PK analyses......................................................................71
7.3.5
Pharmacokinetic analyses ....................................................................71
7.3.6
Biomarker analysis ...............................................................................72
7.3.6.1
Analysis of target engagement biomarkers..............................72
7.4
HANDLING OF MISSING DATA ..................................................................72
7.4.1
Safety......................................................................................................72
7.4.2
Plasma drug concentration - time profiles..........................................72
7.4.3
Pharmacokinetic parameters...............................................................72
7.5
RANDOMISATION ..........................................................................................73
7.6
DETERMINATION OF SAMPLE SIZE ........................................................73


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 75
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................75
8.2
DATA QUALITY ASSURANCE .....................................................................75
8.3
RECORDS..........................................................................................................76
8.3.1
Source documents .................................................................................76
8.3.2
Direct access to source data and documents.......................................76
8.3.3
Storage period of records.....................................................................76
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................77
8.5
STATEMENT OF CONFIDENTIALITY.......................................................77
8.6
COMPLETION OF TRIAL..............................................................................77
9.
REFERENCES......................................................................................... 78
9.1
PUBLISHED REFERENCES...........................................................................78
9.2
UNPUBLISHED REFERENCES.....................................................................79
10. APPENDICES .......................................................................................... 80
 
 
 
 
6
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 87


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
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
CLR, t1-t2
Renal clearance of the analyte in plasma from the time point t1 to t2
Cmax
Maximum measured concentration of the analyte in plasma
Cmin
Minimum measured concentration of the analyte in plasma
CNS
Central nervous system
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P450
DILI
Drug induced liver injury
DG
Dose group
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EEG
Electroencephalograph 
EMG
Electromyogram
EOT
End of trial


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fet1-t2
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2
FIM
First-in-man
gCV
Geometric coefficient of variation
hERG
Human-ether-à-go-go related gene
HR
Heart rate
hLXRα
human liver X receptor α
hPXR
human pregnane X receptor
IC50
50% inhibitory concentration
IEC
Independent Ethics Committee
IL
Interleukin
IRB
Institutional Review Board
ISF
Investigator site file
ITE
Indirect target engagement
LC-MS/MS
Liquid chromatography tandem mass spectrometry
!z
Terminal rate constant of the analyte in plasma
MACS
Magnetic-activated cell sorting
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in Safety Testing 
MRTpo
Mean residence time of the analyte in the body after oral administration
NC
Not calculated
NOA
Not analysed
NOAEL
No observed adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PAD
Pharmacologically active dose
PD
Pharmacodynamic(s)
PE
Polyethylene
PEG
Polyethylene glycol
PfOS
Powder for reconstitution of an oral solution
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
PCR
Polymerase chain reaction
QD
Quaque die, once daily


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QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SfOS
Solvent for Oral Solution
SOP(s)
Operating Procedure(s)
SRD
Single-rising dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test product or treatment
Th
T helper type
TMF
Trial master file
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
tz
Time of last measurable concentration of the analyte in plasma
TDMAP
Trial Data Management and Analysis Plan
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vd
Volume of distribution
Vz/F
Apparent volume of distribution during the terminal phase after
extravascular administration
WOCBP
Women of childbearing potential


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT


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The primary objective of the SRD part (trial part 1) is to investigate the safety and tolerability 
of BI 730357 in healthy subjects following oral administration of single rising doses after 
fasting and/or non-fasting conditions. The secondary objective is the exploration of the 
pharmacokinetics (PK) including dose proportionality,
of BI 730357 
after single dosing. 
The objective of the BA part (trial part 2) will be to explore the relative bioavailability of 
tablet fasted versus oral solution fasted and the influence of food on the bioavailability of 
tablet fasted versus tablet fed.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of a new 
orally available drug, which might improve the therapy 
 The 
subjects are exposed to the risks of the study procedures and the risks related to the exposure 
to the trial medication.


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Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
As the nature of the target and the mechanism of action of BI 730357 are well understood, 
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.
The pharmacological effects of BI 730357 are dose dependent and no evidence for prolonged 
or irreversible effects has been observed. Single doses up to 400 mg BI 739357 are supported 
by preclinical safety data.
During this clinical trial each subject will receive not more than 15 ml solvent consisting of 
PEG 400. PEG 400 is polyethylene glycol with an average molecular weight of 400. 
Polyethylene glycols are commonly used in a variety of pharmaceutical formulations 
including parenteral and oral preparations. They are generally regarded as safe, non-toxic, 
and non-irritant [R99-0697]. PEG 400 was well tolerated, without serious or significant 
adverse events, with doses up to 15 mL per day for 14 days in healthy volunteers [U02-1602].
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers:
∃
Careful dose selection as described in Section 2.1. In addition, dose escalation will be 
shallow and both, starting dose 
) have ample safety margins with respect to
the preclinical findings. Finally, dose selection was based on a sound preclinical 
package including 4 week toxicological studies (not only 2 weeks).
∃
Preliminary measurement of BI 730357 plasma concentrations and preliminary 
determination of PK parameters (Cmax, AUC0-24 see Section 7.3.4).
 
 
 Further dose progression 
would only be allowed after a safety interim analysis and filing and approval of a 
substantial CTP amendment.
∃
An extensive safety laboratory will be performed with special focus on full blood 
exam (see Flow Chart).


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∃
For safety reasons, during the single rising dose part each dose group of 8 subjects 
(6 on active, 2 on placebo) will be divided into two cohorts of 4 subjects each (3 on 
active, 1 on placebo). These two cohorts will be separated by at least 48 hours 
(between 1st subject of each cohort),
 
. The first cohort will be dosed in a single blinded, fixed sequence fashion 
(active - placebo - active - active) and the drug administration will be separated by at 
least 60 min between the first 3 subjects. This design ensures that between first and 
second active dose of each dose level there is a time interval of at least 2 hours, which 
is expected to be sufficient to detect relevant acute effects of BI 730357. If BI 730357 
was safe and well tolerated during these initial administrations, the remaining subjects 
of the respective dose level could be dosed as close as 10 minutes apart.
∃
A thorough ECG monitoring including continuous ECG measurement over 6 hours 
post dose to cover the anticipated period of highest drug exposure and additional 
repeated single 12-lead ECGs over 48 hours following drug administration. Dose 
escalation would be stopped as soon as at least 2 subjects at one dose level showed 
relevant QT prolongation (see Section 3.3.4.2 for details).
∃
The subjects will stay at the trial site (BI Human Pharmacology Centre) for at least 
24 hours after study drug administration at each dose level.
 
 
 
∃
During in house-confinement the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events.
∃
Only if the respective dose of BI 730357 was safe and showed acceptable tolerability
and if no stopping criterion was met (refer to Section 3.3.4.2), the next higher dose 
will be given at least 6 days later (referring to the 1st subject of each dose group).
∃
Treatments of the BA part (dosing of 25 mg BI 730357) will only start if the 100 mg
dose level of the SRD part was safe and showed acceptable tolerability. 
∃
As reproductive toxicity studies have not yet been conducted, women of child-bearing 
potential will not be enrolled in this study.
∃
 
 
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 5.2.2.1.
In summary, although not tested in humans to date, BI 730357 has the potential to become an 
oral treatment for 
Based upon preclinical data for 


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BI 730357 and clinical information from competitor compounds as well as the implemented 
safety measures described above, healthy subjects will not be exposed to undue risks in 
relation to the important information expected from this trial as a basis for further clinical 
development of this compound. Healthy volunteers are not expected to have any direct 
benefit from participation in this FIM clinical trial with BI 730357, as is the usual case in 
such Phase I trials. Considering the medical need of the development of a safer and more 
effective treatment for 
, the Sponsor considers that the benefit 
outweighs the potential risks and justifies exposure of healthy human volunteers.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This first-in-man trial will be conducted in healthy male volunteers at a single centre.
A total of 72 healthy male subjects is planned to participate in 10 sequential groups of 
8 subjects each during the SRD part, and in a group of 12 subjects during the BA part. Within 
each dose group of the SRD part, 6 subjects will receive the active drug and 2 will receive 
placebo. In the BA part, 12 subjects will receive the active drug. The dose groups to be 
evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Planned dose groups
Trial part
SRD
BA
Dose Group (DG)
1
2
3
4
5
6
7
8
9
10
Fasting condition predose
fasted
fed2
fed3
fasted/
fed
Dose (mg) as oral solution
2
8
--
--
--
--
--
--
--
--
25
Dose (mg) as tablets
--
--
25
50
100
200
400
400
400
800
25
Number of subjects
8
8
8
8
8
8
8
8
8
8
12
Subjects receiving placebo
2
2
2
2
2
2
2
2
2
2
0
Subjects receiving active drug
6
6
6
6
6
6
6
6
6
6
12
Subject number1
1
Respective reserve subject numbers will be provided for dose groups 1-7 and BA part
2
Intake of a standard continental breakfast prior to drug administration
3
Intake of a standard high-fat breakfast prior to drug administration
4
In DG 8 (400 mg/placebo with continental breakfast) and DG 9 (400 mg/placebo with high-fat breakfast) the same 
subjects will be included and treated with the same treatments (i.e. always with active or with placebo) for an intra-
individual comparison of the two different diets (after washout period of at least 14 days)
SRD part
The first part of the trial, the SRD part, is designed as single-blind, partially randomised, and 
placebo-controlled within parallel dose groups. Only one dose is tested within each dose 
group. The groups will be treated consecutively in ascending order of doses. Each group is 
divided into 2 cohorts of 4 subjects each (3 on active drug and 1 on placebo). On the first 
study day within each dose group, the first cohort will be treated in a single-blind manner in 
the following order: first subject (active) followed at least 1 h later by the second subject 
(placebo) followed at least 1 h later by the third subject (active) followed at least 10 min later 
by the fourth subject (active).
If BI 730357 treatment is safe and showed acceptable tolerability in the first cohort, the 
subjects in the second cohort will be treated not earlier than 2 days later in a single-blind 
randomised manner. In the second cohort, a time interval of at least 10 min will be 


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maintained between each administration of the trial drug to the individual subjects. A time 
interval of at least 6 days will be maintained between the first drug administration in the 
previous dose group and the first drug administration of the subsequent dose group. The 
decision to proceed to the next dose group will be based upon the safety, tolerability, and 
pharmacokinetic data of the preceding dose groups. The next dose will only be given if, in the 
opinion of the Investigator, no safety concerns arose in the preceding dose group (i.e. no 
dose-limiting events occurred) and if none of the pre-specified trial-specific stopping criteria 
were met (refer to Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation during the SRD 
part. Furthermore, an unscheduled safety review meeting can be requested anytime for any 
reasonable cause by the Principal Investigator (or an authorised deputy) or the Sponsor of the 
study, e.g. because of any unforeseen adverse events, etc. Dose escalation will only be 
permitted if no safety concerns exist in the opinion of the Principal Investigator (or an 
authorised deputy) and the Trial Clinical Monitor (or an authorised deputy). 
The minimum data set for review consists of the following data:
∃
AEs in the current and preceding dose groups up to at least 48h post dosing, including 
clinically relevant findings from ancillary safety testing listed below (Note: AEs may 
be ongoing at the time of Safety Reviews and AE information may be subject to 
change prior to Database Lock)
∃
Results from 12-lead EGG and continuous ECG monitoring in the current and 
preceding dose groups.
∃
Vital signs in the current and preceding dose groups
∃
Clinical laboratory tests in the current and preceding dose groups
∃
Preliminary PK data as per Section 7.3.4. 
∃
Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the trial clinical monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 
face-to-face or by video/telephone conference. The trial clinical monitor is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (or an authorised deputy) and filed in the ISF and TMF.
The Investigator is allowed to alter the scheduled dose levels (e.g. add an intermediate dose 
level) within the planned and approved dose range or to prolong in-house confinement on the 
basis of experience gained during the study. In this case, the total number of subjects in this 
trial might increase. The Investigator and/or the Sponsor should stop dose escalation in case 
the safety evaluation leads to concerns that would not allow higher dosing.


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BA part
The BA part will be performed in a randomised, open-label, single dose, three-way crossover 
fashion. Subjects will be administered BI 730357 as tablet in a fasting state (reference 
treatment R), as oral solution (PfOS) in fasted conditions (test treatment T1) and as tablet 
after a standardised high-fat breakfast (test treatment T2). The three treatments will be 
separated by a washout period of at least 8 days between study drug administrations. Subjects 
will be allocated randomly to one of the six treatment sequences: R/T1/T2, R/T2/T1, 
T1/R/T2, T1/T2/R, T2/R/T1, T2/T1/R.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedures (SOPs),
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors, Clinical 
Research Associates, and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany.
The trial will be conducted at the Human Pharmacology Centre of BI Pharma GmbH & Co. 
KG, Biberach, Germany, under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
The analyses of BI 730357 concentrations in plasma and urine will be performed at the 
Department of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The gene expression and protein analysis will be performed by the laboratories of the 
Translational Medicine & Genomics & Technologies Unit, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The digitally recorded 12-lead ECGs of the SRD part will be sent to a specialised contract 
research organisation (
, 
) for evaluation.
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 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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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 730357 and the risk to subjects will be 
minimized by studying sequentially ascending doses. For safety reasons the first cohort of 
each dose level will be treated in a fixed treatment sequence (Active-Placebo-Active-Active). 
The dose level being investigated at any time will be known to subjects, but single-blind 
conditions regarding each subject’s treatment (active or placebo) will be maintained for both 
cohorts of each dose level.
The disadvantage of this trial design is a possible observer bias with regard to the dose-
depending effects as well as time effects, but it has the virtue of minimizing subject risk by 
sequentially studying ascending doses. As time-effects are expected to be small relative to the 
differences between the doses in the broad range investigated, unbiased comparisons between 
treatments can still be expected.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety and tolerability. Each dose group consists of 8 subjects with 6 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. 6 subjects per active treatment group are in general considered 
as sufficient for the exploratory evaluation of pharmacokinetics. 
For the BA part comparing bioavailability of BI 730357 following administration as tablet in 
the fasted state versus oral solution (PfOS) in fasted state as well as tablet in the fasted state 
versus tablet under fed conditions, the crossover design is viewed favourable due to its 
efficiency: since each subject serves as his own control, the comparison between the 
treatments is based on a comparison within subjects rather than between subjects. Thus the 
inter-subject variability is removed from the comparison between treatments [R94-1529]. 
Blinding is not possible because the treatments are distinguishable.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 84 healthy male will enter the study. Subjects will be recruited from the 
volunteers' pool of the trial site. 
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available. With respect to the embryo-fetal risk coming from the treatment of 
male subjects with BI 730357, where it is theoretically possible that relevant exposure to 
BI 730357 may be achieved in women of childbearing potential (WOCBP) from exposure to 
seminal fluid, male contraception (condom or abstinence) should be used in order to avoid 
exposure of an existing embryo/fetus [R16-0373] (see 3.3.3, exclusion criterion 23).
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.


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3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial if they meet the following criteria:
1. Healthy male according to the Investigator’s assessment, 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 45 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the Investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 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 judged as clinically relevant by the Investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)


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14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more 30 g per day for males)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the Investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
23. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from the first administration of trial medication until 
30 days after last administration of trial medication
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
4. An AE or clinically significant laboratory change or abnormality occurred that the 
Investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension or hypertension, or of clinically relevant changes in 
ECG requiring intervention 
5. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.


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A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the Sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported 
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP by a trial site or Investigator, disturbing the appropriate 
conduct of the trial
4. The Sponsor decides to discontinue the further development of the investigational product
5. Dose escalation will be stopped as soon as at least 2 subjects at one dose level on active 
drug showed relevant individual QT prolongation, i.e. a QTc increase of greater 60 ms 
from baseline in connection with absolute QT or QTc greater than 500 ms, which has 
been confirmed by a repeat ECG recording
6. Dose escalation will be stopped based on preliminary PK results (plasma) as soon as 
measured (in at least one subject) or estimated Cmax / AUC0-24 of BI 730357 exceed 
(upper limit of acceptable exposure in this trial, see Section 
2.1). 
3.3.5
Replacement of subjects
In case that there are less than 4 subjects on active per dose level in DG 1-7 of the SRD part 
or less than 9 subjects in the BA part, who do not complete the trial, the trial clinical monitor 
together with the trial pharmacokineticist and the trial statistician are to decide if and how 
many subjects will be replaced. There is no replacement in the SRD part for DGs 8, 9 and 10. 
A replacement subject will be assigned a unique study subject number possessing the same 
treatment, as the subject 
 replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational products have been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator products
SRD part 
The characteristics of the test product for dose groups 1-2 are:
Substance:
BI 730357
Pharmaceutical formulation:
Powder for oral solution
Source:
BI Pharma GmbH & Co. KG
Drug in bottle:
20 mg
Unit strength:
1.0 mg/mL (concentration in prepared solution)
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Single dose
Component for reconstitution: The oral solution for dosing will be prepared as detailed in the 
reconstitution instruction given in Appendix 10.1 using a solvent containing polyethylene 
glycol (PEG) 400 (Macrogol 400). The solvent will be supplied in separate 60 mL amber 
glass bottles and will also be used as placebo solution (see Appendix 10.1).
The characteristics of the test product for dose group (DG) 3 are:
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG
Unit strength:
25 mg
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Single dose
The characteristics of the test product for dose groups 4-10 are:
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG
Unit strength:
50 mg
Posology:
1-0-0 (DG 4), 2-0-0 (DG 5), 4-0-0 (DG 6), 8-0-0 (DG 7, 
DG 8 and DG 9) or 16-0-0 (DG 10) 
Route of administration:
p.o.


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Duration of use:
Single dose
The characteristics of the reference product (placebo) for dose groups 1-2 are: 
Substance:
Matching placebo containing PEG 400 (Macrogol 400)
Pharmaceutical formulation:
Oral solution
Source:
BI Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Single dose 
The placebo solution will be prepared as detailed in the instruction given in Appendix 10.1.
The characteristics of the reference product (placebo) for dose group 3 are: 
Substance:
Placebo matching in size and weight to 25 mg tablet
Pharmaceutical formulation:
Film-coated tablets
Source:
BI Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
1-0-0 
Route of administration:
p.o.
Duration of use:
Single dose
The characteristics of the reference product (placebo) for dose groups 4-10 are: 
Substance:
Placebo matching in size and weight to 50 mg tablet
Pharmaceutical formulation:
Film-coated tablets
Source:
BI Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
1-0-0 (DG 4), 2-0-0 (DG 5), 4-0-0 (DG 6), 8-0-0 (DG 7, 
DG 8 and DG 9) or 16-0-0 (DG 10)
Route of administration:
p.o.
Duration of use:
Single dose
Components for reconstitution: The oral solution for dosing will be prepared as detailed in 
the reconstitution instruction given in Appendix 10.1 using a solvent containing PEG 400
(Macrogol 400). The solvent will be supplied in separate 60 mL amber glass bottles. 


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BA part 
The characteristics of test product T1 are:
Substance:
BI 730357
Pharmaceutical formulation:
Powder for oral solution
Source:
BI Pharma GmbH & Co. KG, Germany
Drug in bottle:
200 mg
Unit strength:
10.0 mg/mL (concentration in prepared solution)
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Single dose
The characteristics of test product T2 and reference product R are:
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG
Unit strength:
25 mg
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Single dose
The 25 mg and 50 mg tablets may be used to allow intermediate dose levels if necessary.
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects of the SRD part will be contacted in writing and 
informed about the planned visit dates. The subjects willing to participate will be recruited to 
dose groups according to their temporal availability. As soon as enough subjects have been 
allocated to 1 of the 18 dose cohorts (2 cohorts per dose group), the following subjects will be 
allocated to one of the other dose cohorts. Therefore, the allocation of subjects to dose 
cohorts is not influenced by trial personnel, but only by the subjects’ temporal availability. As 
the study includes healthy subjects from a homogenous population, relevant imbalances 
between the dose groups are not expected. 
The randomisation list with study subject numbers and allocated treatments (SRD part) or 
treatment sequences (BA part) will be provided to the trial site in advance. In both parts of 
the trial, the allocation of subjects to study subject numbers will be performed prior to the 
first administration of trial medication. For this purpose, the subjects will be allocated to a 
study subject number (= medication number) by drawing lots. Once a subject number has 
been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.5.


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4.1.3
Selection of doses in the trial
For the SRD part, oral doses in the range of 2 mg to 800 mg have been selected in order to 
assess the safety and tolerability of BI 730357 in healthy male volunteers, and to investigate 
the PK of 
 The selected doses cover a safe starting dose in the 
sub-therapeutic range, the estimated therapeutic range and potentially supra-therapeutic doses 
within the levels determined by toxicological investigations (see Section 1.2).
The intra-individual comparisons of the BA part investigating the relative bioavailability of 
tablet fasted versus tablet fed and of tablet fasted versus oral solution fasted are planned to be 
conducted with a dose of 25 mg as it is assumed that this dose covers the therapeutic range 
and might be used in the subsequent clinical development.
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Tables 4.1.4: 1 (SRD part) and 4.1.4: 2 (BA 
part) below. The number of units / dose volume for placebo corresponds to the number of 
units / dose volume of the respective dose level.
Table 4.1.4: 1
BI 730357 and placebo treatments for the SRD part
Dose
group
Fasting 
condition 
predose
Substance
Pharmaceutical 
form
Unit       
strength
Number of units /dose   
volume per administration
Total 
dose
1
fasted
BI 730357
oral solution
1 mg/mL
2 mL 
2 mg
2
fasted
BI 730357
oral solution
1 mg/mL
8 mL 
8 mg
3
fasted
BI 730357
film-coated tablet
25 mg
1 tablet
25 mg
4
fasted
BI 730357
Film-coated tablet
50 mg
1 tablet
50 mg
5
fasted
BI 730357
Film-coated tablet
50 mg
2 tablets
100 mg
6
fasted
BI 730357
Film-coated tablet
50 mg
4 tablets
200 mg
7
fasted
BI 730357
Film-coated tablet
50 mg
8 tablets
400 mg
8
fed1
BI 730357
Film-coated tablet
50 mg
8 tablets
400 mg
9
fed2
BI 730357
Film-coated tablet
50 mg
8 tablets
400 mg
10
fed2
BI 730357
Film-coated tablet
50 mg
16 tablets
800 mg
1-2
fasted
Placebo*
oral solution
--
identical to active treatment
--
3-7
fasted
Placebo*
Film-coated tablet
--
identical to active treatment
--
8-10
fed
Placebo*
Film-coated tablet
--
identical to active treatment
--
*   Subjects receiving placebo are equally distributed across dose groups
1   Drug administration after a standard continental breakfast
2   Drug administration after a standard high-fat breakfast 
3   Identical to active treatment


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Table 4.1.4: 2
BI 730357 film-tablets and oral solution for the BA part 
Treatment
Substance
Pharmaceutical 
form
Unit       
strength
Number of units /   
dose volume per 
administration
Total 
Dose
T1 (oral solution fasted)
BI 730357
oral solution
10 mg/mL
2.5 mL
25 mg
T2 (tablet fed)
BI 730357
Film-coated tablet
25 mg
1 tablet
25 mg
R   (tablet fasted)
BI 730357
Film-coated tablet
25 mg
1 tablet
25 mg
The oral solutions for dosing will be prepared according to the reconstitution instruction 
given in Appendix 10.1 under the responsibility of the Investigator. The Investigator can 
decide at any time to discontinue dosing or to decrease the dose escalation by adding 
intermediate doses in case of intolerability or due to safety concerns.
The trial medication will be administered to the subjects, while in a sitting or standing 
position, as an oral dose together with about 240 mL of water under supervision of the
investigating physician or an authorised designee in the morning of Day 1. The so-called 
four-eye principle (two-person rule) should be applied for administration of trial medication 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise. Administration will be performed following an overnight fast, which is to start no 
later than 10 h before the scheduled dosing. 
In treatment T2 (tablet fed) of the BA part and dose groups 9 (400 mg BI 730357 or placebo) 
and 10 (800 mg BI 730357 or placebo) of the SRD part, a high-fat, high-calorie breakfast will 
be served 30 min before drug administration. In dose group 8 (400 mg BI 730357 or placebo) 
of the SRD part, a standard continental (normal-fat, normal-calorie) breakfast will be served 
30 min before drug administration. The test meals must be completely consumed prior to 
drug administration. The composition of the standard high-fat, high-calorie breakfast will be 
in compliance with the FDA guidance ‘Food-Effect Bioavailability and Fed Bioequivalence 
Studies’ [R03-2269] as detailed in Table 4.1.4: 3. The composition of the standard 
continental breakfast will be detailed in Table 4.1.4: 4.
Table 4.1.4: 3
Composition of the high-fat, high-calorie meal
Ingredients
kcal
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 


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Table 4.1.4: 4
Composition of the continental breakfast
Ingredients
kcal
Sum1
458
1
The total caloric content was supplied approximately as following: 88 kcal as protein, 133 kcal 
as carbohydrate, and 237 kcal as fat.
Subjects will be kept under close medical surveillance until at least 24 h following drug 
administration. During the first 6 hours after drug administration subjects of the SRD part 
will be confined to bed with a bed inclination angle of at least 45 degrees unless lower or 
supine positioning is required for trial-related measurements (e.g. recording of 12-lead ECG). 
During the first 4 hours after drug administration subjects of the BA part will only be allowed 
to lie down if supine positioning is required for trial-related measurements (e.g. recording of 
12-lead ECG). For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In the present trial, treatments of the SRD part will be blinded to subjects only. With the 
rising dose design, single-blind conditions regarding the subjects' treatment (active or 
placebo) are maintained within each dose group, however the current dose level will be 
known to subjects and Investigators. Treatments of the BA part will be open-label.
The database of this trial will be handled open-label, because no bias with regard to data 
cleaning of safety measures is expected. This is considered acceptable because the potential 
for bias seems to be low and does not outweigh practical considerations. The bioanalyst will 
be blinded for the BA part only.
The bioanalyst of analytical laboratory and the trial pharmacokineticist may receive the 
randomisation codes of the SRD part prior to official unblinding to perform the preliminary 
PK analysis. He or she will treat the codes confidentially.
In addition, the drug metabolism scientist may receive the randomisation codes prior to 
official unblinding to perform metabolites in safety testing analysis (MIST). He or she will 
confirm in writing that the codes will be treated confidentially.
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded with respect to the treatment within each dose level and also with regard to 
the recording date and time as well as time the points of the ECGs. The interval 
measurements for a given subject will be performed in a random and blinded sequence by a 
single technician. No more than two different blinded readers will evaluate the ECGs of the 
study.


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4.1.5.2
Procedures for emergency unblinding
As this trial will be conducted single-blinded (SRD part) or open-label (BA part), the 
treatment information will be known. Therefore, no emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Smaller boxes and/or 
bottles within the clinical trial supply containers will be labelled with:
∃
BI trial number
∃
Name of product and strengths or identification code
∃
Pharmaceutical dosage form, quantity of dosage units 
∃
Route and mode of administration
∃
Term ‘For Clinical Trial Use’ (domestic language)
∃
Sponsor name and address
∃
Storage conditions
∃
Use-by date
∃
Subject or medication number
∃
Batch number
∃
Visit number (BA part only)
The telephone number of the Sponsor and name, address and telephone number of the trial 
site are given 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. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The Investigator will receive the investigational drugs delivered by the Sponsor when the 
following requirements are fulfilled:
∃
Approval of the trial protocol by the IRB / ethics committee


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∃
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 as documented in the form ‘Trial Staff List’ may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The Investigator must maintain records of the product’s delivery to the trial site, the 
inventory at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
Investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the Sponsor. At the time of disposal, the Investigator must verify that all unused or partially 
used drug supplies have been returned by the clinical trial subject and that no remaining
supplies are in the Investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the Investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
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.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake (except for the beverages served with the 
breakfast in the SRD or BA part) is restricted to the water administered with the drug, and an 
additional 240 mL of water served at 2 h and 4 h post-dose (mandatory for all subjects). From 
lunch until discharge from the study centre, liquid intake is restricted to additional 3 litres. 


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During the days of urine collection, subjects will be advised to drink at least 1.5 litres per 
day. 
Alcoholic beverages, 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 starting 4 days before the first administration of trial medication until after the last 
PK sample of each study period is collected.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 10 h before until 24 h after administration of trial 
medication.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 730357 is the number [N (%)] of 
subjects with adverse reactions.
 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:
∃
results in death, 
∃
is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
∃
requires inpatient hospitalisation or prolongation of existing hospitalisation,
∃
results in persistent or significant disability or incapacity, 
∃
is a congenital anomaly/birth defect, 
or 
∃
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as given 
above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system, a remote data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.


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The following are considered as AESIs in this trial:
∃
Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients 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 these parameters are analysed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described in 
the DILI checklist should be followed.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∃
The event is consistent with the known pharmacology of the drug 
∃
The event is known to be caused by or attributed to the drug class.
∃
A plausible time to onset of the event relative to the time of drug exposure.
∃
Evidence that the event is reproducible when the drug is re-introduced
∃
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
∃
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).


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∃
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∃
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
∃
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∃
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∃
Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the Investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful written record of all AEs shall be kept by the Investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
∃
From signing the informed consent onwards through the residual effect period (REP), 
until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) 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 


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these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.
∃
After the individual subject’s end of trial: 
o
The Investigator does not need to actively monitor the subject for AEs but 
should only report relevant SAEs and relevant AESIs of which 
 may 
become aware of.
The REP for BI 730357, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known for this first-in-human trial. Therefore, all 
AEs reported until the end of trial examination (last per protocol contact) will be considered 
on treatment; please see Section 7.3.3.
AE reporting to Sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours of 
awareness) 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
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (if applicable). The Investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and on the SAE form (if 
applicable):


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∃
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 trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h (excluding 6-hour post-dose sample). Overnight fasting is not required at the 
discretion of the Investigator or designee for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Table 5.2.3: 1
Routine laboratory tests
Functional lab 
group
Test name 
A1
B2
C3
D4
E5
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelets
Reticulocyte count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential 
(relative and absolute)
Neutrophils 
Eosinophils 
Basophils 
Monocytes 
Lymphocytes 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
X
X
Manual differential WBC 
(if automatic differential 
WBC is abnormal)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin Time (Quick and INR)
X
X
X
X
X
X
--
--
X
X
1 A: parameters to be determined at visit 1 (screening examination)
2 B: parameters to be determined at visits 2-4 on Days -3 to -1 (for time point, refer to Flow Chart)
3 C: parameters to be determined at visits 2-4 on Days 1 to 4 (for time points, refer to Flow Chart)
4 D: parameters to be determined at visits 2-4 on Day 8 (for time point, refer to Flow Chart)
5 E: parameters to be determined at visit 5 (end of trial examination)


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Table 5.2.3: 1 Routine laboratory tests (cont.)
Functional lab 
group
Test name 
A1
B2
C3
D4
E5
Enzymes
Aspartate aminotransferase (AST/GOT) 
Alanine aminotransferase (ALT/GPT) 
Alkaline phosphatase (AP)
Gammaglutamyl transferase (GGT)  
Lactate dehydrogenase
Lipase
X
X
X
X
X
X
X
X
X
X
X
--
X
X
X
X
X
--
--
--
--
--
--
--
X
X
X
X
X
X
Substrates
Plasma glucose
Creatinine
Total bilirubin 
Direct bilirubin
Total protein
C-Reactive Protein (CRP) 
Urea in serum
Phosphate in serum
Total cholesterol 
Triglycerides
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
X
*Electrolytes
Calcium
Sodium
Potassium
X
X
X
X
X
X
X
X
X
--
--
--
X
X
X
Hormones
Thyroid stimulating hormone (TSH)
X
--
--
--
--
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine RBC
Urine WBC
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic examination 
if erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (e.g. 
presence of sediment bacteria, casts in sediment, 
squamous epithelial cells, erythrocytes,
leukocytes)
--
1 A: parameters to be determined at visit 1 (screening examination)
2 B: parameters to be determined at visits 2-4 on Days -3 to -1 (for time point, refer to Flow Chart)
3 C: parameters to be determined at visits 2-4 on Days 1 to 4 (for time points, refer to Flow Chart)
4 D: parameters to be determined at visits 2-4 on Day 8 (for time point, refer to Flow Chart)
5 E: parameters to be determined at visit 5 (end of trial examination)
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.
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 


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CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to each administration of trial 
medication on Day 1 (for time points refer to Flow Chart).
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed prior to each treatment at time points 
indicated in the Flow Chart, 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 Table 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
 with the exception of 
the drug screening tests. These tests will be performed at the trial site using e.g. MAHSAN® -
–Kombi/DOA10 rapid test.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for a 10-sec duration after the subjects 
have rested for at least 5 min in a supine position. The site personnel will be instructed to 
assure a relaxed and quiet environment so that all subjects are at complete rest during the 
recordings. ECG assessment will always precede all other study procedures of the same time 
point (except blood drawing from an intravenous cannula which is already in place) to avoid 
impact of sampling on the ECG quality.


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All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). 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). Precise electrode placement will be marked with an 
indelible mark on the skin to allow reproducible placement throughout the study.
ECGs will be recorded as single ECGs or as triple ECGs (three single ECGs recorded within
180 sec) as indicated in the Flow Chart. 
All locally printed ECGs will be evaluated by the Investigator or a designee.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation). For time points with triple ECGs, all three single ECGs 
will be repeated. For the repeats due to quality reasons, only the repeated ECG recordings 
will be sent to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Additional (unscheduled) ECGs may be collected by the Investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths. 
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of cardiac 
safety during the study, the QT and QTcB values generated by the ECG machines or their 
manual corrections by the Investigators will be used. In doubtful cases, ECGs may be sent 
upfront for centralised evaluation (see below). In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the Investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
For blinding arrangements see Section 4.1.5.


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Assessed ECGs will comply with the ICH E14 guidance document and supplements [R05-
2311, R13-0801, R13-4095] as well as the FDA requirements for annotated digital ECGs 
[R09-4830].
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored during the SRD part by means of 
continuous 3-lead ECG recording for at least 15 min before (for baseline assessment) and 6 h 
following drug administration using patient monitors (e.g. Carescape B450, GE Healthcare
GmbH, Freiburg, Germany). Abnormal findings will be recorded as AEs if judged clinically 
relevant by the Investigator but no other data will be transferred to the database.
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm if possible.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG
(including rhythm strip of at least 15 minutes), laboratory tests, and a physical examination. 
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, and a physical examination.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
taken at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the
pharmacogenomic data in the final report. However, the data may be part of the report if 
necessary.


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
and biomarkers in an appropriate way. The scheduled measurements will allow monitoring of
changes in vital signs, standard laboratory values, and ECG parameters that might occur as a 
result of administration of trial medication. The safety assessments are standard, are accepted 
for evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are 
generally used assessments of drug exposure. The biomarkers and measurements outlined in 
Section 5.6 are of exploratory nature only.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Exact time points of plasma sampling will be derived from the study management system 
ClinBase™ and documented in the CRFs by the medical personnel or sent as electronic files
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic endpoints will be determined if feasible:
5.5.1.1
Secondary endpoints
∃
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)


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 730357 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into an K3-EDTA (tripotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene tubes. The first aliquot should contain at least 0.5 mL plasma. The process 
from blood collection until transfer of plasma aliquots into the freezer should be completed 
within 90 min, with interim storage of blood samples on crashed ice between blood collection 
and centrifugation. For each aliquot the time when the sample was placed in the freezer will 
be documented. Until transfer on dry ice to the analytical laboratory, the aliquots will be 
stored upright at about -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 about -20°C or 
below until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as matrix and 
analyte may also be provided. 
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.


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5.5.2.2
Plasma sampling for metabolism analysis
Additional K3-EDTA plasma samples for the identification of drug metabolites will be 
investigated in the 25 mg dose group. Based on the knowledge gained during the trial 
conduct, e.g. from preliminary PK results, the dose group may be changed. The change will
be implemented via a non-substantial CTP Amendment.
The blood samples will be drawn in parallel to PK samples on Days 1 to 5 of the SRD part 
(see Flow Chart). At each of these time points, 2.7 ml blood will be needed for metabolite 
analysis. Apart from the storage temperature (see below) the blood samples will be processed 
in the same way as the PK samples described in Section 5.5.2.1. 
Two plasma aliquots will be obtained and stored in polypropylene cryotubes. The first aliquot 
(labelled as MIST-1 samples), should contain at least 0.5 mL of plasma. The remaining 
plasma will be the second aliquot (labelled as MIST-2 samples). The process from blood 
collection to the transfer of plasma aliquots into the freezer should be completed within 
90 min, with interim storage of blood samples on crashed ice between blood collection and 
centrifugation. Until transfer on dry ice to the metabolism laboratory, the aliquots will be 
stored at the trial site. Samples will be positioned upright and will be frozen at approximately 
-70°C. The second aliquot will be shipped to the metabolism laboratory after the metabolism 
scientist has acknowledged safe arrival of the first aliquot. At the metabolism laboratory, the 
plasma samples will be stored at about -70°C until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time and ‘MIST-1 or ‘MIST-2’. Further information 
such as matrix and analyte may also be provided. 
Plasma samples dedicated to metabolism investigation are transferred to:
Department of Drug Metabolism & Pharmacokinetics
Boehringer Ingelheim Pharmaceuticals, Inc 
Pharmaceuticals, Inc.
175 Briar Ridge Road
Room R&D 1515
Ridgefield, CT 06810, USA.
Phone: 
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
the drug metabolism will be reported separately but not included in the CTR of this trial. The 
study samples will be discarded after completion of the experiments but not later than 5 years 
after the final study report has been signed. 


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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
BI 730357 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. 
As described in Section 4.1.5, the bioanalyst will be blinded for the BA part only. For the 
SRD part he/she will be unblinded.


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5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
Starting from 72 h post administration a deviation from the scheduled time for PK and 
biomarker sampling of ±70 min is acceptable.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 15 min for the first 6 h after trial drug administration and ± 30 min thereafter.
Starting from 72 h post administration a deviation from the scheduled time for vital signs, 
ECG and laboratory tests of ±70 min is acceptable.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned individual plasma concentration sampling times and urine collection intervals 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.  
Pharmacogenomic genotyping will be performed in those volunteers whose genotypes are not 
known (for details see Section 5.3). 


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6.2.2
Treatment periods
Study participants will be admitted to trial site at least 1 hour prior to administration of the 
trial medication. They will be kept under close medical surveillance for at least 24 hours 
following drug administration. Thereafter the subjects will be allowed to leave the trial site 
after formal assessment and confirmation of their fitness. Afterwards the study will be 
performed in an ambulatory fashion until the end-of-study examination.
For DGs 1-7 and 10 of the SRD part, each subject will receive one dose of the respective trial 
medication (BI 730357 or placebo) at visit 2. In DGs 8 and 9 of the SRD part, the same 
subjects will be included and each subject will be treated with the same trial medication 
(either always active or always placebo), i.e. they will receive the respective trial medication 
at first in DG 8 (Visit 2) following a standard continental breakfast and in DG 9 (Visit 3) 
following a high-fat breakfast. The treatments of DG 8 and DG 9 are separated by a wash-out 
phase of at least 14 days between each drug administration.
The participants of the BA part will receive the respective trial medication (BI 730357) at 
visit 2, 3 and 4. Details on treatments and procedures of administration are described in 
Section 4.1.4.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, refer to Flow Chart and Section 5.5.2. 
The safety measurements performed during the treatment period are specified in Section 5.2. 
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the Investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
SRD Part:
The primary objective of the first (SRD) part of this trial is to investigate the safety and 
tolerability of BI 730357 by using descriptive statistics for all endpoints comparing active 
dose groups to placebo. The primary endpoint is defined in Section 5.2.1. Inferential statistics 
is not planned (as explained in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) of BI 730357. 
Endpoints as specified in 5.5.1 will be analysed by descriptive statistics. Secondary endpoints 
as defined in Section 5.5.1.1 will be subjected to analysis of dose proportionality by use of 
the power model.
BA Part:
The primary objective of the second part of the study is to investigate relative bioavailability 
of 25 mg BI 730357 as oral solution (Test 1, T1) and 25 mg BI 730357 given as tablet after a 
standardised high-fat breakfast (Test 2, T2), each compared to 25 mg BI 730357 as tablet in a 
fasting state (Reference, R)
The secondary objective is the evaluation and comparison of several PK parameters between 
the treatments. The secondary objectives will be assessed by descriptive statistics.
7.1.2
Endpoints
The primary endpoint to describe safety and tolerability of BI 730357 will be the number (% 
subjects) with drug-related AEs. The collection of parameters pertaining to these 
investigations is described in detail in Section 5.2.1.
The secondary pharmacokinetic endpoints to be used for the assessment of dose 
proportionality and relative bioavailability are specified in Section 5.5.1.1.
7.1.3
Model
SRD part:
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints. 
The model consists of a regression model applied to log-transformed data under fasting 
conditions. The corresponding ANCOVA model includes the logarithm of the dose as a 
covariate. 
ij
i
ij
ε
)
X
exp(
)
exp(Y
%
&
&
%
∋
(
)


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Together with 
and 
, taking natural logarithms converts this model 
to a linear form as follows:
where
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, …, 7, j = 1, 2, …, 8;
) 
intercept parameter;
slope parameter;
logarithm of dose i;
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model. Based on the estimate for slope 
parameter (β), a 2-sided 95% CI for the slope will be computed. Perfect dose proportionality 
would correspond to a slope of 1. The assumption of a linear relationship between the log-
transformed pharmacokinetic endpoint and the log-transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
BA part: Investigation of relative bioavailability
Relative bioavailability is primarily to be determined on the basis of the parameters AUC0-∗
and Cmax (cf. Section 5.5). Those parameters will be ln-transformed (natural logarithm) prior 
to fitting the model.
The statistical model used for the analysis of AUC0-∗and Cmax will be an ANOVA (analysis 
of variance) model on the logarithmic scale.  This model will include effects accounting for 
the following sources of variation: ‘sequence’, ‘subjects within sequences’, ‘period’ and 
‘treatment’. The effect ‘subjects within sequences’ will be considered as random, whereas the 
other effects will be considered as fixed. For tests on subject, period, and treatment effects, 
the denominator sum of squares will be the sum of squares for error; while for tests on 
sequence effects, the denominator will be the sum of squares for subjects. The model is 
described by the following equation
yijkm = + + ,i + sim + −j + .k + eijkm,  where
yijkm = logarithm of response (endpoint, see Section 7.1.3) measured on subject m in 
sequence i receiving treatment k in period j,
+ = the overall mean,
,i = the ith sequence effect, i = 1, 2, …, 6
)
exp()
∋
)%
)
exp(
ε
ij
ij
/
∋
%
ij
i
ij
ε
X
β
α
Y
0
&
0
∋
ij
Y
β
i
X
ij
ε


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sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
−j = the jth period effect, j = 1, 2, 3
.k = the kth treatment effect, k = 1, 2
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
The difference between the expected means for test treatments and reference treatment 
log(Ti)-log(R), i=1,2, will be estimated by the difference in the corresponding Least Square 
Means (point estimate) and two-sided 90% confidence intervals based on the t-distribution 
will be computed. These quantities will then be back-transformed to the original scale to give 
the point estimator (geometric mean) and interval estimates for the ratio between response 
under test and response under reference.
Pairwise comparisons will be done for:
•
Oral solution (PfOS) fasted (Test 1/T1) vs tablet fasted (Reference)
•
Tablet fed (Test 2/T2) vs tablet fasted (Reference)
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of different dose groups of BI 730357 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
In the SRD part, for the evaluation of dose proportionality, a two-sided 95% confidence 
interval (CI) of the slope will be computed. However, the CI will have to be interpreted in the 
perspective of the exploratory character of the study, i.e. as interval estimate for effects in the 
present data.
The relative bioavailability of BI 730357 will be estimated by the ratios of the geometric 
means (test/reference) for the secondary PK endpoints. Additionally, their two-sided 90% 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 on testing, an acceptance 
range was not specified, that is, no hypothesis will be tested.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.


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7.3.2
Secondary analyses
The secondary parameters (see Section 5.5.1) will be calculated according to the relevant 
corporate procedure of the Sponsor ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472, current version). 
Pharmacokinetic parameters of a subject will be included in the analysis unless the subject 
has an important protocol violation relevant for the evaluation. Whether a protocol violation 
is important will be decided no later than in the Report Planning Meeting. 
Reasons for exclusion of single pharmacokinetic parameters may be:
∃
The subject experiences emesis at or before two times median tmax. Median tmax is to 
be determined for the test product excluding the subjects experiencing emesis.
∃
The subject experiences emesis at any time during the labelled dosing interval.
∃
Time deviations
∃
Use of restricted medications 
The subject set for the evaluation of PK endpoints (PKS) will include all treated subjects that 
provide at least one observation for at least one primary endpoint without important protocol 
violations with respect to the statistical evaluation of PK endpoints. It will also be decided in 
the Report Planning Meeting which subjects are to be included in the PKS. 
Excluded subjects will be listed with their individual plasma concentrations and individual 
pharmacokinetic parameters, however, will not be included in descriptive statistics for plasma 
concentrations, pharmacokinetic parameters or other statistical assessment.
SRD Part: Assessment of dose proportionality
Dose proportionality of the secondary pharmacokinetic endpoints under fasting conditions 
will be explored based on the regression model described in Section 7.1.3. Based on the 
estimate for slope parameter ((), a 2-sided 95% CI for the slope will be computed. Perfect 
dose proportionality would correspond to a slope of 1. The assumption of a linear relationship 
between the log-transformed pharmacokinetic endpoint and the log-transformed dose will be 
checked.
If dose proportionality over the entire dose range under fasting conditions investigated cannot 
be shown, an attempt will be made to identify dose ranges, where dose proportionality can be 
assumed.
BA Part: Assessment of relative bioavailability
Point estimates of bioavailability, the ratios of the geometric means (test/reference) for the 
secondary endpoints (see 5.5.1.1), and their two-sided 90% CIs will be provided.
To this end, the PK endpoints will be log transformed (natural logarithm) prior to fitting the 
ANOVA model (cf. Section 7.1.3). For each endpoint, the difference between the expected 
means for log(Ti)-log(R) will be estimated by the difference in the corresponding adjusted 
means (LeastSquares Means), and a two-sided 90% confidence interval based on the 
t-distribution will be computed. These quantities will then be back-transformed to the original 
scale to provide the point estimate and 90% CIs for each endpoint.


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7.3.3
Safety analyses
Safety analyses will be performed in accordance with BI standards. 
All treated subjects (that is, all subjects who received at least one dose of study drug), will be 
included in the safety evaluation. Safety analyses will be descriptive in nature and will be 
based on BI standards.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’. 
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the end of trial visit 
will be assigned to the treatment period, and those after the end of trial examination will be 
assigned to ‘post-study’. These assignments including the corresponding time intervals will 
be defined in detail in the TSAP.
Additionally, further treatment intervals (analysing treatments) may be defined 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 post-study 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 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the derivation of further ECG parameters based on the ECG variables 
 
. The baseline value of an ECG variable is defined as the mean of 
the triple ECG measurements prior to drug administration. The derivation of the quantitative 
and qualitative ECG endpoints and their analyses will be described in the TSAP.


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7.3.4
Preliminary PK analyses
A preliminary analysis of PK parameters (AUC0-24 and Cmax of BI 730357) provided as 
individual values and geometric means of at least the first cohort per dose level, will be 
performed for 
∃
all dose levels up to n-2 before proceeding to dose level n (with n ≤50 mg)
∃
all dose levels up to n-1 before proceeding to dose level n (with n > 50 mg)
(Note: Data from the first cohorts of the above mentioned dose levels will be sufficient as 
long as the data from at least 2 subjects on active were available)
A preliminary analysis of pharmacodynamic biomarkers is not planned.
In contrast to the final PK/PD calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows or not. Therefore, minor deviations of preliminary and final results may occur. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification. The preliminary 
results will be distributed to the Investigator and the trial team. 
Depending on preliminary data on safety, tolerability, changes of dosing schedule (e.g. 
additional intermediate doses) or planned times for PK/biomarker-sampling, additional 
preliminary PK-analysis may be performed based on the request of the trial clinical monitor, 
the Investigator, or trial clinical pharmacokineticist. Preliminary PK data will be distributed 
to the Investigator. No formal interim report will be written.
No inferential statistical preliminary analysis is planned. However, after each dose group the 
Investigator (or 
 deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data already obtained has been performed.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 730357 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.1.) will be reported with their 
individual plasma / urine concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma / urine concentrations, 
pharmacokinetic parameters.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 


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the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis. 
∃
If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g. descriptive statistics) and for graphical presentation.
∃
If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However the excluded concentration itself will be listed in the clinical trial 
report associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated" (NC).
7.3.6
Biomarker analysis
7.3.6.1
Analysis of target engagement biomarkers
 
 
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).


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For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
SRD part: Each dose group will be divided into two cohorts. The subjects of the first cohort 
will not be randomised to maintain a treatment sequence of active-placebo-active-active due 
to safety reasons. In the second cohort of each dose level the subjects will be assigned to 
active or placebo treatment using a 3:1 allocation ratio. 
BA part: Subjects will be randomized to one of the six treatment sequences R/T1/T2, 
R/T2/T1, T1/T2/R, T1/R/T2, T2/T1/R, T2/R/T1 in a 1:1:1 ratio. 
The Sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable. 
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
SRD part
It is planned to include a total of 72 subjects in this study part. The planned sample size is not 
based on a power calculation. The size of 8 subjects per dose group (6 on active treatment, 
and 2 on placebo) is commonly used in single-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics [R95-0013].
BA part
It is planned to enter 12 subjects in this trial part, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial.
With this sample size, the following precision of the ratio of geometric means (test/reference)
can be expected. Precision is defined as the ratio of upper to lower confidence interval limit.
Note that the precision is independent of the actual ratio of geometric means. For this First-
in-Man trial, no information on intra-subject variability is available. Therefore, Table 7.6: 1
provides an overview on the achievable precision for estimating the ratio of geometric means 
(test/reference) for three different gCV. For illustrative purposes, the expected 90% 
confidence intervals with 95% coverage probability are displayed for different values of 
geometric means ratios T/R in the three-period three-sequence crossover design.


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Table 7.6.1
Expected two-sided 90% confidence intervals for different gCVs and 
ratios T/R (N=12)
gCV[%]
Ratio1 [%]
Precision (upper CI 
limit/lower CI limit)
90% CI [%]
20
80
0.175
(67.17, 95.28)
100
0.175
(83.97, 119.10)
125
0.175
(104.96, 148.87)
150
0.175
(125.95, 178.64)
200
0.175
(167.93, 238.19)
25
80
0.217
(64.38, 99.41)
100
0.217
(80.47, 124.27)
125
0.217
(100.59, 155.33)
150
0.217
(120.71, 186.40)
200
0.217
(160.94, 248.53)
30
80
0.259
(61.74, 103.65)
100
0.259
(77.18, 129.57)
125
0.259
(96.47, 161.96)
150
0.259
(115.77, 194.35)
200
0.259
(154.36, 259.14)
The expected 90% confidence interval limits in the table were derived by
CI limitupper, lower = 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 [R12-0972] using R Version 3.0.3.
1)
Ratio of geometric means (test/reference) for a PL endpoint is defined by exp(μT)/exp(μR)


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The Investigator should inform the Sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
As a general rule, no trial results should be published prior to finalisation of the CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the Investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the Investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor or 
Sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the Investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.


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8.3
RECORDS
CRFs for individual subjects will be provided by the Sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the Human Pharmacology Centre – Boehringer Ingelheim's Phase I unit the validated 
ClinBaseTM system is operated 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
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data is entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
The Investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The Investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R03-2269
  Guidance for industry: food-effect bioavailability and fed bioequivalence   
studies. In: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER); 
2002. p. 1-9.
R05-2311
ICH E14: the clinical evaluation of QT/QTc interval prolongation and   
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonised  
tripartite guideline, recommended for adoption at step 4 of the ICH 
process on 12 May 2005 by the ICH Steering Committee). 
www.emea.eu.int; 2005. p. 1-14.
R09-1400
European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals: step 4: note for guidance on non-
clinical safety studies for the conduct of human clinical trials and 
marketing authorization for pharmaceuticals (June 2009, 
CPMP/ICH/286/95). http://www.emea.europa.eu; 2009.
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 
2005). 2005.
R12-0972
Kupper LL, Hafner KB. How appropriate are popular sample size 
formulas? Am Stat 1989;43(2):101-105.
R13-0801
  Guidance for industry: E14 clinical evaluation of QT/QTc interval  
prolongation and proarrhythmic potential for non-antiarrhythmic drugs:  
questions and answers (R1) (ICH, October 2012). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInf
ormation/Guida nces/ucm073161.pdf (access date: 22 February 2013) ; 
U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and  Research (CDER), 
Center for Biologics Evaluation and Research (CBER); 2012.
R13-4095
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): ICH guideline E14 - questions and answers: step 
5 (May 2012, EMA/CHMP/ICH/310133/2008). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guid
eline/2009/0 9/WC500002878.pdf (access date: 13 September 2013) ; 
London: European Medicines Agency (EMA); 2012.
R13-5279
Elmore SA. Enhanced histopathology of the thymus. Toxicol Pathol 
2006;34(5): 656-665.


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R16-0373
Recommendations related to contraception and pregnancy testing in 
clinical trials (final version - 2014-09-15). 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contracep
tion.pdf (access date: 2 February 2016) ; Clinical Trial Facilitation Group 
(CTFG), Head of Medicine Agencies (HMA); 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.
R94-1529
Chow SC, Liu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.
R95-0013
Broom C. Design of first-administration studies in healthy man. In: 
O'Grady J, Linet OI, editors. Early Phase Drug Evaluation in Man. 
London: Macmillan Press; 1990. p. 206-213.
R99-0697
Ma TY, Hollander D, Krugliak P, Katz K. PEG 400, a hydrophilic 
molecular probe for measuring intestinal permeability. Gastroenterology 
1990;98(1):39-46.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics. Current version
c09228382-01
 Investigator’s Brochure: BI 730357 Psoriasis (ankylosing 
spondylitis, psoriatic arthritis, asthma, inflammatory bowel disease)
1407.P1 (P2, P3, P4, P5) 29-Sep-2016.
U02-1602
  
. Safety of total daily doses 
of 5, 10, 15 and 20 mL PEG 400 administered orally to healthy male 
human subjects once (QD) or twice (BID) for 14 days. A single center, 
multiple rising dose study, placebo controlled, double-blinded at each 
dose level. IKP Trial No. 071/01-02.PEG. 13-Sep-2002.


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10.
APPENDICES


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
01 December 2016
EudraCT number
2016-003047-11
BI Trial number
1407.1
BI Investigational Product(s)
BI 730357
Title of protocol
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 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
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard – IRB / IEC / 
Competent Authority to be 
notified of change with request 
for approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Synopsis, pages 25, 26, 35, 36, 37
2. Synopsis, pages 49, 58
3. Page 30
Description of change
1. Deletion of “50 mg Dose” in the BA part
2. Minor editorial changes
3. Change of upper age to 45 years (incl)
Rationale for change
1. To address request by the EC 
2. Corrections 
3. To address request by the CA


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Number of global amendment
2
Date of CTP revision
19 January 2017
EudraCT number
2016-003047-11
BI Trial number
1407.1
BI Investigational Product(s)
BI 730357
Title of protocol
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 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
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard – IRB / IEC / 
Competent Authority to be 
notified of change with request 
for approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Section 2.1, last paragraph on page 22, line 6
2. Section 2.1, last paragraph on page 22, line 7
3. Section 2.1, last paragraph on page 22, line 11
4. Section 2.3, paragraph 5 on page 24, line 4
5. Section 3.3.4.2, last paragraph, last line  
Description of change
1.
‘132,000’ corrected into ‘1,320,000’ 
2.-5. ‘13,200’ corrected into ‘132,000’  
Rationale for change
1.
Correction of AUC0-24 value for male dog at 
60 mg/kg/day (from 132,000 to 1,320,000
nM*h) according to Investigator’s Brochure 
for BI 730357 (Table 5.3:2, page 42, column 
4).
2.-5. Correction of AUC0-24 values for the 
maximum acceptable human exposure (from 
13,200 to 132,000 nM*h). 


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Number of global amendment
3
Date of CTP revision
05 May 2017
EudraCT number
2016-003047-11
BI Trial number
1407.1
BI Investigational Product(s)
BI 730357
Title of protocol
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 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
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard – IRB / IEC / 
Competent Authority to be 
notified of change with request 
for approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Synopsis, pages 2-3    
2. Flow chart for the SRD part, pages 5-6
3. Section 1.2.5, pages 20-24
4. Section 2.1, pages 25, 27, 28
5. Section 2.2, page 28
6. Section 2.3, page 31
7. Section 3.1, page 32 
8. Section 3.3, page 35
9. Section 3.3.5, page 40
10. Section 4.1, pages 41-45
11. Section 6.2.2, page 66
12. Section 7.1.3, page 68
13. Section 7.3.2, page 71
14. Section 7.6, page 74


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BI Trial No.: 1407.1
c11248385-04
Trial Protocol
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
3
Description of change
1. Number of subjects in the SRD part increased 
by 16, administration of 400 mg and 800 mg
BI 730357 or placebo under fed conditions 
added, option for additional subjects removed 
2. Visit 3 and standard breakfast added 
3. Preliminary clinical data on safety, tolerability 
and PK from the SRD and BA part presented
4. 800 mg dose added, paragraph to ‘maximum 
dose and dose escalation‘ amended 
5. Fasting conditions specified for SRD part
6. Update on observed half-life
7. Number of subjects increased, option for 
additional subjects removed, 3 additional dose 
groups (DGs) added in Table 3.3:1
8. No replacement for DGs 8, 9 and 10
9. Number of subjects increased, option for 
additional subjects removed
10. DGs 8-10 added; maximum dose and number 
of dose cohorts adapted, DGs 8-10 added in 
Table 4.1.4: 1, high-fat breakfast and 
continental breakfast added in the SRD part, 
composition of standard continental breakfast 
added (Table 4.1.4:4)
11. Treatments periods of DGs 8-9 described
12. Investigation of dose proportionality under 
fasting conditions only
13. Investigation of dose proportionality under 
fasting conditions only
14. Number of subjects in the SRD part increased
Rationale for change
The highest exposures observed in this trial after 
the 400 mg dose under fasting conditions (Cmax of 
755 nM, AUC0-24 of 9,453 nM*h) are significantly 
below the predicted exposures at 400 mg (Cmax of 
2,547 nM and AUC0-24 of 42,458 nM*h) and the 
acceptable exposure limit of this trial (Cmax of 
5,920 nM, and AUC0-24 of 132,400 nM*h). Since 
we observed a 36% increase in exposure in the fed 
versus fasted condition, it is planned to investigate 
3 additional DGs in the fed condition to further 
evaluate safety and PK of higher BI 730357 
exposures, including the influence of food (normal 
and high-fat diet) on higher doses. The results will 
support the testing of higher exposures during the 
planned multiple-rising dose trial and further 
clinical development. 


 
 
 
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c16606849 -01
BI Trial No.:
1407.1
Title:
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 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 “Including Protocol 
Amendment 1, 2, and 3 [c11248385-04]”
Investigational
Product:
BI 730357
Responsible trial 
statisticians:
Phone:
Fax:
Phone: 
Fax: 
Date of statistical 
analysis plan:
22 SEP 2017 SIGNED
Version:
Final
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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.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................9
5.
ENDPOINTS........................................................................................................10
5.1
PRIMARY ENDPOINT......................................................................................10
5.2
SECONDARY ENDPOINTS .............................................................................10
5.2.1
Key secondary endpoints ....................................................................................10
5.2.2
Secondary endpoints ...........................................................................................10
................................................................................10
................................................................................12
6.
GENERAL ANALYSIS DEFINITIONS...........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL VIOLATIONS....................................................16
6.3
SUBJECT SETS ANALYSED ...........................................................................18
.....................................................................................................19
6.5
POOLING OF CENTRES..................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................20
7.
PLANNED ANALYSIS ......................................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........23
7.2
CONCOMITANT DISEASES AND MEDICATION......................................24
7.3
TREATMENT COMPLIANCE ........................................................................24
7.4
PRIMARY ENDPOINT......................................................................................24
7.5
SECONDARY ENDPOINTS .............................................................................24
7.5.1
Key secondary endpoint......................................................................................24
7.5.2
Secondary endpoints ...........................................................................................24
................................................................................27
7.7
EXTENT OF EXPOSURE .................................................................................29
7.8
SAFETY ANALYSIS..........................................................................................29
7.8.1
Adverse events .....................................................................................................29
7.8.2
Laboratory data...................................................................................................30
7.8.3
Vital signs.............................................................................................................31
7.8.4
ECG ......................................................................................................................31
7.8.5
Others ...................................................................................................................34
8.
REFERENCES ....................................................................................................35
.36
.36
.37


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10.
HISTORY TABLE..............................................................................................38


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR (SRD Part).......................................14
Table 6.1: 2
Labels for treatments for use in the CTR (BA Part).........................................15
Table 6.1: 3
Overview of treatments for intra-individual comparison .................................15
Table 6.2: 1
Important protocol violations ...........................................................................17
Table 6.3: 1
Subject sets analysed ........................................................................................19
Table 6.7: 1
Time schedule of 12-lead ECG recordings (SRD part)....................................21
Table 10: 1
History table .....................................................................................................38


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis Dataset
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AST
Aspartate Aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below The Lower Limit Of Quantification
BMI
Body Mass Index
BWC
Bioavailability/Bioequivalence, Within-Subject Design, Time-Controlled
BWU
Bioavailability/Bioequivalence, Within-Subject Design, Time-Uncontrolled
CARE
Clinical Data Analysis and Reporting Environment
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation
DB
Dose Proportionality, Between-Subject Design
DBLM
Database Lock Meeting
DG
Dose Group
ECG
Electrocardiogram
ECGPKS
ECG PK Set
eCRF
Electronic Case Report Form
EudraCT
European Union Drug Regulating Authorities Clinical Trials
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
HR
Heart Rate


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Term
Definition / description
ICH
International Conference On Harmonisation
LLT
Lower Level Term
Max
Maximum
mRNA
Messenger Ribonucleic Acid
Mean
Arithmetic Mean
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
N
Number non-missing Observations
NC
Not Calculated
NOA
Not Analysed
NOP
No Peak Detectable
NOR
No Valid Result
NOS
No Sample Available
O*C
Oracle Clinical
PD
Pharmacodynamic(s)
PDS
Pharmacodynamic Set
PfOS
Powder For Oral Solution
PK
Pharmacokinetic(s)
PKS
PK Parameter Analysis Set
po
per oral
POC
Percent Of Control
PR
Pulse Rate
PT
Preferred Term
PV
Protocol Violation
qd
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
RAGe
Report Appendix Generator system
REP
Residual Effect Period


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Term
Definition / description
RPM
Report Planning Meeting
RS
Randomised Set
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
SP
Sampling Point
SRD
Single Rising Dose
T
Treatment
T1/T2
Test treatment 1/2
Tb
Tablet
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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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 study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of adverse event (AE) data or laboratory 
data; Report Appendix Generator system (RAGe) for compilation/formatting of the clinical 
trial report (CTR) appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Analysis of dose proportionality will only be performed on the fasted dose groups receiving 
tablets because it is known from previous studies that Pharmacokinetics differ considerably 
for administration of Powder for Oral Solution (PfOS). 
All other analyses as planned in the revised trial protocol (based on all amendments) will be 
performed and are described in more detail in this TSAP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
CTP: Primary endpoint to assess safety and tolerability of BI 730357 is the number [N (%)] 
of subjects with adverse reactions.
Please note that adverse reactions are defined and analysed as drug-related AEs.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
As no key secondary endpoints have been specified in the CTP, this section is not applicable.
5.2.2
Secondary endpoints
For the single rising dose (SRD) and the bioavailability (BA) part the secondary PK 
parameters are:
CTP: 

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)
 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
SRD part:
In total, it was planned to include 72 healthy male volunteers in the SRD part of this trial.
Each of the 10 sequential groups includes 8 subjects (6 active, 2 placebo) and is divided into 
two cohorts. The first cohort will be treated in a fixed sequence and the second cohort will be 
randomised.
In dose groups (DG) 1-7 and 10 each subject will receive one oral dose of BI 730357 or
Placebo respectively at Visit 2, Day 1.
In DG 8 (400 mg/placebo with continental breakfast; Visit 2, Day 1) and DG 9 
(400 mg/placebo with high-fat breakfast; Visit 3, Day 1) the same subjects will be included 
and treated with the same treatments (i.e. always with active or with placebo) for an intra-
individual comparison of the two different diets (after washout period of at least 14 days).
BA part:
In total, it was planned to include 12 healthy male volunteers in the BA part of this trial. Each
subject will receive BI 730357 as tablet (Tb) in a fasting state (reference treatment R), as oral 
solution (PfOS) in a fasting state (test treatment T1) and as tablet after a standardised high fat 
breakfast (test treatment T2) in an open label, randomised manner.
For details of dosage and formulation see Table 6.1: 1 and Table 6.1: 2 below.


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Table 6.1: 1
Labels for treatments for use in the CTR (SRD Part)
Dose 
group
Treatment
Short label
1-10
M/N/U/V
Placebo solution / tablet, po, qd 
Placebo total
1-7
M/N
Placebo solution / tablet, po, qd
Placebo fast
8
U
Placebo tablet, po, qd, fed continental
Placebo fed1
9-10
V
Placebo tablet, po, qd, fed high-fat
Placebo fed2
8-10
UV*
Placebo tablet, po, qd, fed continental/high-
fat
Placebo fed
1
A
BI 730357, 1 mg/mL solution, 2 mg, po, qd
2mg PfOS fast
2
B
BI 730357, 1 mg/mL solution, 8 mg, po, qd
8mg PfOS fast
3
C
BI 730357, tablet, 25 mg, qd 
25mg Tb fast
4
D
BI 730357, tablet, 50 mg , qd
50mg Tb fast
5
E
BI 730357, tablet, 2*50 mg, qd
100mg Tb fast
6
F
BI 730357, tablet, 4*50 mg, qd
200mg Tb fast
7
G
BI 730357, tablet, 8*50 mg, qd
400mg Tb fast 
8
S
BI 730357, tablet, 8*50 mg, qd, fed 
continental
400mg Tb fed1
9
T
BI 730357, tablet, 8*50 mg, qd, fed high-fat
400mg Tb fed2
8-9
ST*
BI 730357, tablet, 8*50 mg, qd, fed
continental/high-fat
400mg Tb fed
10
K
BI 730357, tablet, 16*50 mg, qd, fed high-
fat
800mg Tb fed2
fed1 means intake of standard continental breakfast prior to drug administration
fed2 means intake of standard high-fat breakfast prior to drug administration
fed means intake of either standard continental or standard high-fat breakfast prior to drug 
administration
*: Placebo fed / 400mg Tb fed will be included in the same analyses in which within the BA 
part only the total group would be displayed, otherwise Placebo fed / 400mg Tb fed will be 
split into fed1 for subjects with continental breakfast and fed2 for subjects with high-fat 
breakfast
CTP: The placebo control group in the safety evaluation will consist of all placebo treated 
subject, regardless of the dose group in which they were treated.
This is applicable to the placebo control groups total, fast, fed1, fed2 and fed. 


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Table 6.1: 2
Labels for treatments for use in the CTR (BA Part)
Treatment
Short label
X (R)
BI 730357, tablet, 25 mg, fasted, qd
25mg Tb fast
Y (T2)
BI 730357, tablet, 25 mg, fed high-fat, qd
25mg Tb fed2
Z (T1)
BI 730357, 10 mg/mL solution, 25 mg,
fasted, po, qd
25mg PfOS fast 
Table 6.1: 3
Overview of treatments for intra-individual comparison 
Study part
Test treatment (T)
Reference treatment (R)
SRD
400mg Tb fed2
400mg Tb fed1
BA
25mg PfOS fast
(T1)
25mg Tb fast
(R)
25mg Tb fed2
(T2)
25mg Tb fast
(R)
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00 h on day of informed consent until administration time 
of study drug)

On-treatment
(SRD part:
DGs 1-7, 10: ranging from administration time of study drug until end of trial-
termination date
DG 8 and 9: separately for each treatment, ranging from administration time of study 
drug until administration time of next study drug dose or end of trial-termination date
BA part:
separately for each treatment, ranging from administration time of study drug until 
administration time of next study drug dose or end of trial-termination date)
Please note that all AEs reported between start of trial drug administration and the last per-
protocol contact will be considered on treatment (i.e. no follow-up period is considered in this 
trial).
Displays of AEs will be presented separately for the treatments described in Table 6.1: 1 and 
Table 6.1: 2. In the SRD part, the subjects in DG 8 and 9 will be handled separately, but 
counted only once in total.


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Two types of AE displays will be provided in the report:
A) Section 15.3 (separate for SRD and BA part) and Appendix 16.1.9.2.8 (for 
ClinicalTrials.gov (separate for SRD and BA part) and EudraCT (SRD and BA part
combined)) 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 will not be included in this analysis. 
The following totals will be provided in addition:

a total over all BI-treated phases included in this analysis, DG A-G, S, T, ST and K 
(“Total BI”)

a total over all on-treatment phases included in this analysis ("Total on-treatment")
(Section 15.3 only)
B) Section 15.4 and Appendix 16.1.9.2.8 (except for ClinicalTrials.gov and EudraCT) of the 
CTR displays:

Screening 

On-treatment (labelled with the name of the study treatment (short label))
In Section 16.1.9.2.8 AE tables (separate for SRD and BA part), the following totals will be 
provided in addition:

a total over all study phases ("Total")
For detailed information on the handling of the treatments in the O*C views refer to Technical 
TSAP ADS (analysis data set) plan.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all randomised subjects.
Listings of protocol deviations and of unresolved discrepancies will be provided to be 
discussed at the combined report planning and database lock meeting (RPM/DBLM), e.g. 
deviations in drug administration, in blood sampling etc. At this meeting, it will be decided
whether the discrepant data can be used as they are or whether the data have to be corrected in 
the clinical database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation. A protocol violation (PV) is important if it affects the rights or safety of the study 
subjects or if it can potentially influence the primary outcome measure(s) for the respective 
subjects in a way that is neither negligible nor in accordance with the study objectives. This 
last category of important PV forms the basis for the decision of whether a subject does or 
does not belong to an analysis set. PVs that do not influence the subject's rights and safety or 
the evaluability of the subjects for the main study objectives are called non-important PVs.
These are only considered when checking the trial quality in general.


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If any important PVs are identified, they are to be summarised into categories and will be 
captured in the RPM/DBLM minutes via an accompanying Excel spreadsheet [001-MCS-50-
413_RD-02] (2). The following table contains the categories which are considered to be 
important PVs in this trial. If the data show other important PVs, this table will be 
supplemented accordingly by the time of the RPM/DBLM.
Table 6.2: 1
Important protocol violations
Category
/Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C3
Non-compliance
C4
Incorrect intake of trial medication
C5
Improper washout between treatments
D
Concomitant medication
D1
Prohibited medication use 
D2
Mandatory medication not taken
D3
Improper washout of concomitant medication
E
Missing data 
E1
Certain violations of procedures used to measure secondary data
F
Incorrect timing1
F1
Certain violations of time schedule used to measure secondary data
G
Other trial specific important violations
G1
Incorrect intake of meal before administration of treatment
G2
PVs affecting safety and rights
1 Time deviations will only be flagged as important PV, when leading to exclusion of the entire subject from an analysis set
Source: ‘Protocol Violation Handling Definitions’ [001-MCS-50-413_RD-01] (3)


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6.3
SUBJECT SETS ANALYSED

Randomised set (RS): 
This subject set includes all randomised subjects, whether treated or not.

Treated set (TS):
This subject set includes all subjects from the RS who were dispensed study 
medication and were documented to have taken at least one dose of investigational 
treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for safety 
analysis.
CTP: Pharmacokinetic parameters of a subject will be included in the analysis unless the 
subject has an important protocol violation relevant for the evaluation. Whether a protocol 
violation is important will be decided no later than in the Report Planning Meeting.
Reasons for exclusion of single pharmacokinetic parameters may be:

The subject experiences emesis at or before two times median tmax. Median tmax is to be 
determined for the test product excluding the subjects experiencing emesis.

The subject experiences emesis at any time during the labelled dosing interval.

Time deviations

Use of restricted medications
The subject set for the evaluation of PK endpoints (PKS) will include all treated subjects that
provide at least one observation for at least one secondary endpoint without important 
protocol violations with respect to the statistical evaluation of PK endpoints. It will also be 
decided in the Report Planning Meeting which subjects are to be included in the PKS.
Excluded subjects will be listed with their individual plasma concentrations and individual
pharmacokinetic parameters, however, will not be included in descriptive statistics for 
plasma concentrations, pharmacokinetic parameters or other statistical assessment.

PK parameter analysis set (PKS):
This subject set includes all evaluable subjects from the TS of the SRD part or BA part
who were treated with BI 730357 and who provide at least one secondary PK endpoint 
(AUC0-∞or Cmax) that was not excluded according to the description above.
In the SRD part, it is used for assessment of dose proportionality under fasting 
conditions and for intra-individual comparison of fed conditions
In the BA part, it is used for assessment of the bioavailability and food effect.

Pharmacodynamic set (PDS):
This subject set includes all evaluable subjects from the TS of the SRD part who 
provide at least one evaluable observation for one of the exploratory biomarkers and 
without important protocol violations relevant to the evaluation of PD.
It is used for the PD (biomarker) analysis (SRD part).


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
ECG PK Set (ECGPKS):
This subject set includes all subjects from the TS of the SRD part who provide at least 
one pair of a valid drug plasma concentration and a corresponding (i.e. time-matched) 
ECG endpoint to be used in the exposure-response analysis. Note that the placebo 
subjects will be included, with zero plasma concentrations.
Table 6.3: 1
Subject sets analysed
Analysis set
Class of endpoint
RS
TS
PKS
PDS
ECGPKS
Primary and further safety 
endpoints 
X
Secondary and further PK 
endpoints 
X
PD endpoints 
X
Demographic/baseline 
endpoints
X
Important PVs/Disposition
X
PK-ECG exposure-response
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 7.4.
The only exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).


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Missing plasma concentrations and pharmacokinetic parameters
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-36-
472_RD-01) (5).
Plasma concentration-time profiles and descriptive statistics of concentration data
CTP: Drug concentration data identified with NOS (no sample available), NOR (no valid 
result), NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values).
Pharmacokinetic parameters and their descriptive statistics
CTP: For the non-compartmental analysis, concentration data identified with NOS, NOR or 
NOA will generally not be considered. Concentration values in the lag phase identified as 
BLQ or NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The 
lag phase is defined as the period between time zero and the first time point with a 
concentration above the quantification limit.
Missing pharmacodynamic parameters
Pharmacodynamic parameters and their descriptive statistics
Missing PD values will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before trial drug administration in each 
treatment period. 
CTP: Exact times of measurements outside the permitted time windows will be documented. 
The acceptable time windows for screening and end of trial examination are given in the 
Flow Chart.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 15 min for the first 6 h after trial drug administration and ± 30 min thereafter. 
Starting from 72 h post administration a deviation from the scheduled time for vital signs, 
ECG and laboratory tests of ±70 min is acceptable.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
For the SRD part, there will be a centralised evaluation of all 12-lead ECG recordings at the 
time points specified in the Table 6.7: 1 below:


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Table 6.7: 1
Time schedule of 12-lead ECG recordings (SRD part)
Visit
Day
Planned time 
[hh:mm]
(relative to drug 
administration)
Study phase
2/3*
1
-02:00
Baseline
00:30
On-treatment
01:00
02:00
03:00
04:00
05:00
06:00
08:00
10:00
12:00
2
24:00
34:00
3
48:00
*Visit 3 only applicable for subjects in DG 8 and 9.
Triple ECGs (3 single ECGs of 10 sec duration each, recorded within 180 sec) will be 
recorded at the baseline before the first drug administration and at all time points on-
treatment.
The baseline value of an ECG variable is defined as the mean of the triple ECG measurements 
prior to drug administration.
CTP: With the exception of the first triple ECG (used as baseline before the first drug 
administration), only the first of the three replicate ECG at a single assessment time will be 
evaluated.


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7.
PLANNED ANALYSIS
The SRD and BA part will be evaluated separately.
Safety analysis (refer to Section 7.8) will be performed by M.A.R.C.O. GmbH & CO. KG and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2.
Inferential statistical analyses of PK endpoints (refer to Section 7.5.2) as well as the PK-ECG 
analysis will also be performed by M.A.R.C.O. GmbH & CO. KG and will be presented in 
Section 15.5 of the CTR and in Appendix 16.1.9.3.
Descriptive data analysis of PK endpoints will be performed by Translational Medicine and 
Clin. Pharmacology at BI and will be presented in Section 15.6 of the CTR.
Descriptive data analysis of PD endpoints (refer to Section 7.6) will be performed by 
M.A.R.C.O GmbH & Co. KG and will be presented in Section 15.7 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of clinical trials and project summaries” [001-MCG-159] (6) with the 
exception of those generated for PK calculations.
The individual values of all subjects will be listed, sorted by treatment group (SRD part) or by 
treatment sequence (BA part), subject number, visit, study day and actual treatment (BA part, 
if appropriate). The listings will be included in Appendix 16.2 of the CTR.
DG 8 (400 mg/placebo with continental breakfast) and DG 9 (400 mg/placebo with high-fat 
breakfast) will be listed and tabulated as if they consist of different individuals, but will be 
counted only once to get subjects in total.
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 as well as for all PK parameters, the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The data format for descriptive statistics of concentrations will be identical with 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 


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evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment group. Percentages will be rounded to one decimal place and will be based on all 
subjects in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The ADS ADPP 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 or 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 only; the value is 
included for all other analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (7).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
In the SRD part, the data will be summarised by treatment group (joined DG 8 and DG 9) and 
in total.
In the BA part, the data will be summarised in total only.


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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/DBLM.  
7.3
TREATMENT COMPLIANCE
CTP: Compliance will be assured by administration of all trial medication in the study centre 
under supervision of the investigating physician or a designee. The measured plasma 
concentrations and/or urinary excretion 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/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 730357.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoints
Assessment of dose proportionality (SRD part, tablet application under fasting conditions)
Dose proportionality of the PK endpoints AUC 0-∞and Cmax in plasma of BI 730357 tablets 
under fasting conditions (dose groups C, D, E, F, and G) will be explored as a secondary 
analysis using the power model that describes the functional relationship between dose and 
PK endpoints. The basic model consists of a regression model applied to log-transformed data
under fasting conditions. The corresponding ANCOVA (Analysis of Covariance) model 
includes the logarithm of the dose as a covariate.


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The model is described by the following equation:
CTP: 
Yij = α + β*Xi + εij
where
Yij
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, …,5 j = 1, 2, …, 6, 
α
intercept parameter;
β 
slope parameter;
Xi
logarithm of dose i;
εij
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model. Based on the estimate for slope 
parameter (β), a 2-sided 95% CI for the slope will be computed. Perfect dose proportionality 
would correspond to a slope of 1. The assumption of a linear relationship between the log-
transformed pharmacokinetic endpoint and the log-transformed dose will be checked.
If dose proportionality over the entire dose range under fasting conditions investigated 
cannot be shown, an attempt will be made to identify dose range(s), where dose 
proportionality can be assumed. 
This analysis will be accomplished by using the XPKISTAT macro (design DB), based on the 
PKS.
Intra-individual comparison of fed conditions (SRD part, DG 8 and 9 only)
The intra-individual comparison of fed conditions is primarily to be determined on the basis 
of the parameters AUC0-∞and Cmax. Those parameters will be ln-transformed (natural 
logarithm) prior to fitting the model.
The statistical model used for the analysis of AUC0-∞ and Cmax will be an ANOVA (analysis of 
variance) model on the logarithmic scale. This model will include effects accounting for the 
following sources of variation: ‘subjects’ and ‘treatment’. The effect ‘subjects’ will be 
considered as random, whereas the ‘treatment’ effect will be considered as fixed. The model 
is described by the following equation
ykm = µ+ sm + τk + ekm, 
where
ykm 
logarithm of response measured on subject m receiving treatment k,
µ
the overall mean,
sm 
the effect associated with the mth subject, m =1, 2, ..., n


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τk
the kth treatment effect, k = 1, 2
ekm
the random error associated with the mthsubject who received treatment k.
The difference between the expected means for test treatment (400mg high-fat breakfast) and 
reference treatment (400mg continental breakfast), ln(400mg high-fat breakfast)-ln(400mg 
continental breakfast), will be estimated by the difference in the corresponding Least Square 
Means (point estimate). Two-sided 90% confidence intervals based on the t-distribution will 
be computed. These quantities will then be back-transformed to the original scale to give the 
point estimator (geometric mean) and interval estimates for the ratio between response under 
test and response under reference.
The analysis will be accomplished by using the XPKISTAT macro, based on PKS (design
BWU).
Investigation of relative bioavailability (BA part)
CTP: Relative bioavailability is primarily to be determined on the basis of the parameters 
AUC0-∞and Cmax […]. Those parameters will be ln-transformed (natural logarithm) prior to 
fitting the model.
The statistical model used for the analysis of AUC0-∞ and Cmax will be an ANOVA (analysis of 
variance) model on the logarithmic scale. This model will include effects accounting for the 
following sources of variation: ‘sequence’, ‘subjects within sequences’, ‘period’ and 
‘treatment’. The effect ‘subjects within sequences’ will be considered as random, whereas the 
other effects will be considered as fixed. For tests on subject, period, and treatment effects, 
the denominator sum of squares will be the sum of squares for error; while for tests on 
sequence effects, the denominator will be the sum of squares for subjects. The model is 
described by the following equation
yijkm = µ+ ζi + sim + πj + τk + eijkm, 
where
yijkm 
logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,
µ
the overall mean,
ζi
the ith sequence effect, i = 1, 2, …, 6
sim 
the effect associated with the mth subject in the ith sequence, m =1, 2, ..., ni
πj
the jth period effect, j = 1, 2, 3
τk
the kth treatment effect, k = 1, 2  (Note: Separate models will be used to assess 
the difference between R and T1 and R and T2.)
eijkm
the random error associated with the mthsubject in sequence i who received 
treatment k in period j.


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The difference between the expected means for test treatments and reference treatment
log(Ti)-log(R), i=1,2, will be estimated by the difference in the corresponding Least Square 
Means (point estimate) and two-sided 90% confidence intervals based on the t-distribution 
will be computed. These quantities will then be back-transformed to the original scale to give 
the point estimator (geometric mean) and interval estimates for the ratio between response 
under test and response under reference.
Pairwise comparisons will be done for:
• Oral solution (PfOS) fasted (Test 1/T1) vs tablet fasted (Reference)
• Tablet fed (Test 2/T2) vs tablet fasted (Reference)
The analysis will be accomplished by using the XPKISTAT macro, based on PKS (design
BWC).
In addition, a sensitivity analysis will be performed by fitting the model described above, but 
using all effects as fixed. This analysis will be done using PROC GLM.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by actual treatment, applicable to SRD 
part and to BA part.
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
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and presentation of adverse event data from 
clinical trials” [001-MCG-156], version 6 (9).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, therapy
required, seriousness, reason for seriousness, relationship, outcome, AE of special 
interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started within the same hour)
For further details on summarization of AE data, please refer to (4, 9).
CTP: The following are considered as adverse event of special interest (AESI) in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory
parameters:


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o
an elevation of AST and/or ALT ≥3-fold upper limit of normal (ULN) combined 
with an elevation of total bilirubin ≥2-fold ULN measured in the same blood 
sample, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. 
CTP: The residual effect period (REP) for BI 730357, when measurable drug levels or PD 
effects are still likely to be present after the last administration, is not known for this first-in-
human trial. Therefore, all AEs reported until the end of trial examination (last per protocol 
contact) will be considered on treatment […].
According to ICH E3 (10), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting.
An overall summary of adverse events will be presented.
The frequency of subjects with adverse events will be summarised by treatment, primary 
system organ class (SOC) and preferred term (PT). Separate tables will be provided for 
subjects with other significant AEs according to ICH E3 (10), for subjects with serious AEs, 
for subjects with drug-related AEs, for subjects with drug related serious adverse events and
for subjects with AESIs.
The SOC and PTs will be sorted by frequency. The MedDRA version number will be 
displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[001-MCG-157] (11).


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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 clinically 
relevant will be highlighted in the data listings.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the electronic case report form (eCRF) or at the RPM/DBLM 
at the latest. It is the investigator's responsibility to decide whether a lab value is clinically 
significant abnormal or not. Standard or project-specific rules for flagging clinically 
significant values will not be applied in this study.
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate).
7.8.4
ECG
The ECG analyses will only be performed in the SRD part.
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.
12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator. 
All evaluation of ECG data except of exposure response analysis will be based on the TS. The 
exposure-response analysis will then be done on the ECGPK set.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. 
Occurrences of notable findings will be flagged.
For all subjects with any notable finding in quantitative ECG recordings, a separate listing 
will be created as end-of-text display (based on the same display template as in Appendix 
16.2), and the corresponding time profiles will be shown.
Comments regarding the ECGs will be listed.
Analysis of central tendency
Descriptive statistics (SRD part):


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Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time in all ECG variables.


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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.
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-50-413_RD-02: “Important Manual Protocol Violations Spreadsheet”, current 
version, IDEA for CON.
3.
001-MCS-50-413_RD-01: “Protocol Violation Handling Definitions”, current version, 
IDEA for CON.
4.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
001-MCG-159: “Reporting of clinical trials and project summaries”, current version; 
IDEA for CON.
7.
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
8.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
9.
001-MCG-156: “Analysis and presentation of adverse event data from clinical trials”, 
Version 6; IDEA for CON.
10. 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
11. 001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
12. R08-0437: Garnett, Christine E. et al.: “Concentration-QT relationships play a key role in 
the evaluation of proarrhythmic risk during regulatory review”, J Clin Pharmacol 48, 13 -
18 (2008))


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
22-SEP-2017
None
This is the final TSAP