Safety, Tolerability, and Pharmacokinetics of Single Rising Oral Doses of BI 706321 in Healthy Male Subjects (Single-blind, Randomised, Placebo-controlled, Parallel Group Design)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26547838-07
EudraCT No.
2019-000888-25
BI Trial No.
1425-0001
BI Investigational
Medicinal Product
BI 706321
Title
Safety, tolerability, and pharmacokinetics of single rising oral 
doses of BI 706321 in healthy male subjects (single-blind, 
randomised, placebo-controlled, parallel group design)
Lay Title
A study to test how well healthy men tolerate different doses of 
BI 706321
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal 
Investigator
Phone:
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 6))
Version and Date
Version: 7.0
Date: 07 July 2020
Page 1 of 102
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 2 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
09 Apr 2019
Revision date
07 July 2020
BI trial number
1425-0001
Title of trial
Safety, tolerability, and pharmacokinetics of single rising oral doses of BI 706321 
in healthy male subjects (single-blind, randomised, placebo-controlled, parallel 
group design)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
Part I: This trial starts the clinical development of BI 706321. Effects of single 
rising doses of BI 706321 on safety, tolerability, and pharmacokinetics will be 
assessed in healthy male volunteers.
Part II: to define dose and dosing conditions for the upcoming patient trial
Trial objectives
The main objectives of Part I of this trial are to investigate safety, tolerability, and 
pharmacokinetics (PK) of BI 706321 in healthy male subjects following oral 
administration of single rising doses.
In Part II of this trial the relative bioavailability of BI 706321 after administration 
of capsules (fasted) and tablets (fasted and fed) should be determined.
Trial endpoints
Part I:
Primary endpoint to assess safety and tolerability of BI 706321 is the percentage of 
subjects with drug-related adverse events
Secondary endpoints: AUC0-∞, Cmax, and tmax of BI 706321
Part II:
Primary endpoints: AUC0-tz and Cmax of BI 706321
Secondary endpoints: AUC0-of BI 706321
Trial design
Part I: Single-blind, randomised within dose groups, placebo-controlled parallel-
group design
Part II: open, randomised, 3-way cross-over

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 3 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Number of subjects 
total entered
80 
each treatment
Part I: 8 subjects per dose group (6 on BI 706321 and 2 on placebo)
Part II: 12 subjects (in addition up to 4 replacement subjects may be included)
Diagnosis
Not applicable
Main criteria
for inclusion
Part I: Healthy male subjects, age of 18 to 45 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Part II: Healthy male subjects, age of 18 to 55 years (inclusive), BMI of 18.5 to 
29.9 kg/m2 (inclusive)
Test products

BI 706321 Capsules (strength: 20 mg) for reconstitution of an Oral Solution
(solvent: Tartaric Acid 5 mg/mL)

BI 706321 Capsules (strengths: 1, 5, or 20 mg)

BI 706321 Tablet, strength 2 mg (in Part II only)
dose

Part I: BI 706321 Oral Solution: 0.3 mg, 0.6 mg, 1.2 mg

Part I: BI 706321 Capsules: 2 mg, 4 mg, 8 mg, 15 mg ,  25 mg,

Part II: BI 706321 Capsules, 4 mg (Reference)

Part II: BI 706321 Tablets, 4 mg (Test 1 and Test 2)
mode of admin.
Part I: Oral with 240 mL of water after an overnight fast of at least 10 h
Part II: oral with 240 mL of water after an overnight fast of at least 10 h (Reference, 
Test 1) and after a high fat, high calorie breakfast (Test 2)
Comparator products
Part I only: Matching placebo (for capsules or for oral solution)
dose
Not applicable
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 4 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Treatments
Part I:
Dose group 1: 0.3 mg BI 706321 or placebo, given as oral solution
Dose group 9: 0.6 mg BI 706321 or placebo, given as oral solution
Dose group 2: 1.2 mg BI 706321 or placebo, given as oral solution
Dose group 11: 2 mg BI 706321 or placebo, given as capsule
Dose group 3: 4 mg BI 706321 or placebo, given as capsule
Dose group 4: 8 mg BI 706321 or placebo, given as capsule
Dose group 5: 15 mg BI 706321 or placebo, given as capsule
Dose group 6: 25 mg BI 706321 or placebo, given as capsule
Part II:
Reference: 4 capsules BI 706321 (strength: 1 mg) under fasted conditions
Test 1: 2 tablets BI 706321 (strength: 2 mg) under fasted conditions
Test 2: 2 tablets BI 706321 (strength: 2 mg) under fed conditions
The treatments in Part II will be separated by a wash-out phase of at least 12 days.
Statistical methods
Descriptive statistics will be calculated for all endpoints.
Part II only: Relative bioavailability of tablets (A) and the effect of food (B) will be 
estimated by the ratios of the geometric means (A: Test 1/Reference; B: Test 2/Test 
1) for the primary and secondary endpoints. Additionally, their two-sided 90% 
confidence intervals (CIs) will be provided. This method corresponds to the two 
one-sided t-test procedure, each at a 5% significance level. Since the main focus is 
on estimation and not testing, a formal hypothesis test and associated acceptance 
range is not specified. The statistical model will be an analysis of variance 
(ANOVA) on the logarithmic scale including effects for sequence, subjects nested 
within sequences, period and treatment. CIs will be calculated based on the residual 
error from the ANOVA.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 5 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
FLOW CHART DOSE GROUPS 1, 2, 9, 11 (< 4 MG)
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 
9
PK urine
9,10
PD blood TNFα assay 9
PD blood RNA assay 9
12-lead ECG
Continuous ECG monitoring
Vital signs (BP, PR)
Questioning for AEs and
concomitant therapy 6
1
-21 to -1
Screening (SCR) 1
A
x
x12
2
-3 to -1
-72:00
08:00
Ambulatory visit7
B7
x7
1
-2:00
06:00
Admission to site2
x5
x2,8,11
x2
x2,12
x2
-1:45
06:15
x2,8,11
-1:30
06:30
Treatment allocation2
C2
x2
x2
x2
x2
x2,8,11
0:00
08:00
Drug administration
▲
▲
0:30
08:30
x
│
x8
│
x
1:00
09:00
x
│
x8
│
x
x
1:30
09:30
x
│
x8
│
x
2:00
10:00
240 mL fluid intake
x
│
x
x
x8
│
x
x
2:30
10:30
x
│
x8
│
x
3:00
11:00
x
│
x8
│
x
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
B
x
┼
│
x
x
x8
▼
x12
x
6:00
14:00
x
│
x
x
x
8:00
16:00
Snack (voluntary)3
x
┼
x8
x
x
10:00
18:00
x
│
11:00
19:00
Dinner
│
12:00
20:00
x
┼
x8
x12
x 
2
24:00
08:00
Breakfast3 (voluntary),
discharge from site
C
x
▼
x
x
x8
x12
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
B
x
x
x
x
x
x
8
168:00
08:00
Ambulatory visit
C
x
x
x
x
5
15 to 22
End of trial (EoTrial) 
examination4
C
x
x12
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs (including oral body temperature), ECG (12-lead ECG 
and rhythm strip over at least 15 min), 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; procedures are to be performed and completed within the 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, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs, and concomitant therapies.
5.
Only urine drug screening and alcohol breath test.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 6 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
7.
Safety laboratory to be taken and to be medically evaluated within 3 days (within 76 h) prior to administration of study 
drug; this safety laboratory assessment (including AE&CT questioning) can be omitted if the screening examination is 
performed on Days -3, -2 or -1. 
8.
For central ECG lab analysis (see Section 5.2.4.1)
9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK
or PD data) including addition of samples and visits as long as the total blood volume removed does not exceed 500 mL 
per subject
10. 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, and 12-24 h.
11. At baseline (i.e. Day 1, prior to drug administration) 3 ECGs are recorded within approximately one hour. The 
recordings should be separated by at least 15 minutes.
12. Including oral body temperature

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 7 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
FLOW CHART DOSE GROUPS 3 - 6 (≥4 MG)
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
PD blood TNFα assay 10
PD blood RNA assay 10
12-lead ECG
Continuous ECG monitoring
Vital signs (BP, PR)
Questioning for AEs and
concomitant therapy 6
1
-21 to -1
Screening (SCR) 1
A
x
x14
2
-3 to -1
-72:00
08:00
Ambulatory visit7
B7
x7
1
-2:00
06:00
Admission to site2
x5
x2,9,13
x2
x2,14
x2
-1:45
06:15
x2,9,13
-1:30
06:30
Treatment allocation2
C2
x2
x2
x2
x2
x2,9,13
0:00
08:00
Drug administration
▲
▲
0:30
08:30
x
│
x9
│
x
1:00
09:00
x
│
x9
│
x
x
1:30
09:30
x
│
x9
│
x
2:00
10:00
240 mL fluid intake
x8
│
x
x
x9
│
x
x
2:30
10:30
x
│
x9
│
x
3:00
11:00
x
│
x9
│
x
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
B
x
┼
│
x
x
x9
▼
x14
x
6:00
14:00
x
│
x
x
x
8:00
16:00
Snack (voluntary)3
x
┼
x9
x
x
10:00
18:00
x
│
11:00
19:00
Dinner
│
12:00
20:00
x
┼
x9
x14
x 
2
24:00
08:00
Breakfast3
C
x
┼
x
x
x9
x14
x
28:00
12:00
Lunch3
│
x
32:00
16:00
Snack (voluntary)
│
34:00
18:00
x
│
x9
x
x
35:00
19:00
Dinner
│
3
48:00
08:00
Breakfast3 (voluntary),
discharge from site
B
x
▼
x
x
x9
x
x
4
72:00
08:00
Ambulatory visit
x
x
8
168:00
08:00
Ambulatory visit
C
x
x
x
x
5
15 to 22
End of trial (EoTrial) 
examination4
C
x
x14
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs (including oral body temperature), ECG (12-lead ECG 
and rhythm strip over at least 15 min), 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; procedures are to be performed and completed within the 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, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs, and concomitant therapies.
5.
Only urine drug screening and alcohol breath test.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 8 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days (within 76 h) prior to administration of study 
drug; this safety laboratory assessment (including AE/CT questioning) can be omitted if the screening examination is 
performed on Days -3, -2 or -1. 
8.
One blood sample for stability testing will be taken at this time (refer to Section 5.3.2.4) 
9.
For central ECG lab analysis (see Section 5.2.4.1)
10. Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK
or PD data) including addition of samples and visits as long as the total blood volume removed does not exceed 500 mL 
per subject
11. Including blood sample for metabolite identification at select dose level (refer to Section 5.3.2.2)
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. At baseline (i.e. Day 1, prior to drug administration) 3 ECGs are recorded within approximately one hour. The 
recordings should be separated by at least 15 minutes.
14. Including oral body temperature

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 9 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
FLOW CHART (PART II)
Period
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory 5
PK blood
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
A
x
x
1/2/3 (periods separated by a wash-out interval of at least 12 days)
2/3/4
1
-2:00
06:00
Allocation to treatment2 (visit 2 only), 
drug screen, alcohol breath test
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast (in 
treatment Test 2 only)
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
x
2:30
10:30
x
3:00
11:00
x
x
3:30
11:30
x
4:00
12:00
240 mL fluid intake
x
x
4:30
12:30
x
5:00
13:00
lunch3
x
x
x
x
5:30
13:30
x
6:00
14:00
x
7:00
15:00
x
8:00
16:00
Snack (voluntary)3
x
x
10:00
18:00
x
11:00
19:00
Dinner3
12:00
20:00
x
x
2
24:00
08:00
Discharge from trial site, breakfast 
(voluntary)3
B
x
x
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
x
x
6
120:00
08:00
Ambulatory visit
x
x
FU
5
8 to 22
End of trial (EoTrial) examination4
C
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial (EoTrial) visit, the EoTrial examination includes physical examination, vital signs, ECG, safety 
laboratory, recording of AEs and concomitant therapies. 
5.
Letters A, B, and C define different sets of safety laboratory examinations (see Section 5.2.3)
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 10 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART DOSE GROUPS 1, 2, 9, 11 (< 4 MG) ...................................5
FLOW CHART DOSE GROUPS 3 - 6 (≥4 MG)............................................7
FLOW CHART (PART II) ................................................................................9
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 15
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE...............................................................................................18
Prediction of human pharmacokinetics..............................................18
1.2.1
Residual Effect Period..........................................................................19
1.2.2
Clinical experience with BI 706321 .....................................................19
1.2.3
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................20
Selection of starting dose for this trial ................................................21
1.3.1
Derivation of safe starting dose ...............................................21
1.3.1.1
Safety margins of starting dose to the NOAEL in rat and 
1.3.1.2
monkey GLP toxicity studies...................................................21
Maximum exposure and maximum dose for this trial ......................22
1.3.2
Maximum exposure .................................................................22
1.3.2.1
Maximum dose.........................................................................23
1.3.2.2
Safety margins of maximum acceptable systemic exposure....23
1.3.2.3
Escalation scheme (guided by preliminary PK analysis) ..................26
1.3.3
Escalation scheme....................................................................26
1.3.3.1
Justification for dose groups 7 and 8 .......................................26
1.3.3.2
Preliminary PK analysis...........................................................27
1.3.3.3
1.4
BENEFIT - RISK ASSESSMENT ...................................................................28
Expected benefit for the target population.........................................28
1.4.1
Procedure-related risks ........................................................................28
1.4.2
Drug-related risks and safety measures (Part I)................................28
1.4.3
Summary of safety measures (Part I)..................................................33
1.4.4
Benefit risk assessment for Part II ......................................................34
1.4.5
Overall benefit-risk assessment ...........................................................34
1.4.6
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 35
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......35
Main objectives......................................................................................35
2.1.1
Primary endpoint..................................................................................35
2.1.2

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 11 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Secondary endpoint ..............................................................................35
2.1.3
Safety and tolerability..............................................................36
2.2.2.1
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 37
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................37
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................40
3.3
SELECTION OF TRIAL POPULATION ......................................................41
Main diagnosis for trial entry..............................................................41
3.3.1
Inclusion criteria...................................................................................41
3.3.2
Exclusion criteria ..................................................................................41
3.3.3
Withdrawal of subjects from treatment or assessments ...................43
3.3.4
Discontinuation of trial treatment............................................43
3.3.4.1
Withdrawal of consent to trial participation ............................43
3.3.4.2
Discontinuation of the trial by the sponsor..............................44
3.3.4.3
Replacement of subjects .......................................................................44
3.3.5
4.
TREATMENTS........................................................................................ 45
4.1
INVESTIGATIONAL TREATMENTS ..........................................................45
Identity of the Investigational Medicinal Products ...........................45
4.1.1
Selection of doses in the trial................................................................47
4.1.2
Method of assigning subjects to treatment groups ............................47
4.1.3
Drug assignment and administration of doses for each subject .......48
4.1.4
Blinding and procedures for unblinding ............................................51
4.1.5
Blinding51
4.1.5.1
Unblinding and breaking the code...........................................52
4.1.5.2
Packaging, labelling, and re-supply ....................................................52
4.1.6
Storage conditions.................................................................................52
4.1.7
Drug accountability ..............................................................................52
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................53
Other treatments and emergency procedures....................................53
4.2.1
Restrictions............................................................................................53
4.2.2
Restrictions regarding concomitant treatment .........................53
4.2.2.1
Restrictions on diet and life style.............................................53
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................54
5.
ASSESSMENTS....................................................................................... 55
5.1
ASSESSMENT OF EFFICACY.......................................................................55

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 12 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
5.2
ASSESSMENT OF SAFETY............................................................................55
Physical examination ............................................................................55
5.2.1
Vital signs...............................................................................................55
5.2.2
Safety laboratory parameters..............................................................55
5.2.3
Electrocardiogram................................................................................58
5.2.4
12-lead resting ECG.................................................................58
5.2.4.1
Continuous ECG monitoring (Part I only)...............................60
5.2.4.2
Assessment of adverse events...............................................................60
5.2.5
Definitions of adverse events...................................................60
5.2.5.1
Adverse event ............................................................60
5.2.5.1.1
Serious adverse event ................................................60
5.2.5.1.2
AEs considered ‘Always Serious’.............................61
5.2.5.1.3
Adverse events of special interest .............................61
5.2.5.1.4
Intensity (severity) of AEs.........................................62
5.2.5.1.5
Causal relationship of AEs ........................................62
5.2.5.1.6
Adverse event collection and reporting ...................................63
5.2.5.2
AE collection.............................................................63
5.2.5.2.1
AE reporting to the sponsor and timelines ................63
5.2.5.2.2
Information required..................................................64
5.2.5.2.3
Pregnancy ..................................................................64
5.2.5.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................64
Assessment of pharmacokinetics .........................................................64
5.3.1
Methods of sample collection...............................................................64
5.3.2
Blood sampling for pharmacokinetic analysis.........................64
5.3.2.1
Blood sampling for metabolism analysis (Part I only) ............65
5.3.2.2
Urine sampling for pharmacokinetic analysis (Part I only).....66
5.3.2.3
Additional blood sample for stability-testing (Part I only)......67
5.3.2.4
Pharmacokinetic - pharmacodynamic relationship...........................68
5.3.4
5.5
BIOBANKING ...................................................................................................69
5.6
OTHER ASSESSMENTS .................................................................................70
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................70
6.
INVESTIGATIONAL PLAN.................................................................. 71
6.1
VISIT SCHEDULE............................................................................................71
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................71
Screening period....................................................................................71
6.2.1

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 13 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Treatment period ..................................................................................71
6.2.2
Follow-up period and trial completion ...............................................72
6.2.3
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 73
7.1
STATISTICAL DESIGN – MODEL ...............................................................73
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................73
7.3
PLANNED ANALYSES....................................................................................73
Primary endpoint analyses...................................................................75
7.3.1
Secondary endpoint analyses ...............................................................76
7.3.2
Safety analyses.......................................................................................77
7.3.4
7.4
PRELIMINARY ANALYSES..........................................................................79
7.5
HANDLING OF MISSING DATA ..................................................................79
Safety......................................................................................................79
7.5.1
Pharmacokinetics..................................................................................80
7.5.2
7.6
RANDOMISATION ..........................................................................................80
7.7
DETERMINATION OF SAMPLE SIZE ........................................................80
8.
THE CALCULATION WAS PERFORMED AS 
DESCRIBED BY JULIOUS [R11-5230] USING R VERSION 
3.4.2.INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 82
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................82
8.2
DATA QUALITY ASSURANCE .....................................................................83
8.3
RECORDS..........................................................................................................83
Source documents .................................................................................83
8.3.1
Direct access to source data and documents.......................................84
8.3.2
Storage period of records.....................................................................84
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................85
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......85
Collection, storage and future use of biological samples and 
8.5.1
corresponding data ...............................................................................85
8.6
TRIAL MILESTONES .....................................................................................85
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................86
9.
REFERENCES......................................................................................... 88
9.1
PUBLISHED REFERENCES...........................................................................88
9.2
UNPUBLISHED REFERENCES.....................................................................89

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 14 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
10. APPENDICES .......................................................................................... 90
10.1
RECONSTITUTION INSTRUCTION(S).......................................................90
Drug supplies overview.........................................................................90
10.1.1
Required equipment and dosing aids - overview ...............................90
10.1.2
Reconstitution procedure.....................................................................91
10.1.3
Reconstitution procedure for the preparation of the active BI 
10.1.3.1
706321 oral solution 0.25 mg/mL............................................91
Necessary materials...............................................91
10.1.3.1.1
Reconstitution procedure ......................................91
10.1.3.1.2
Preparation of the solvent for oral solution for use as placebo 
10.1.3.2
solution 91
Necessary materials...............................................91
10.1.3.2.1
Procedure ..............................................................91
10.1.3.2.2
Withdrawal of oral solution.................................................................92
10.1.4
Withdrawal procedure of the BI 706321 oral solution ............92
10.1.4.1
Withdrawal of placebo oral solution...................................................94
10.1.5
Withdrawal procedure of the placebo oral solution.................94
10.1.5.1
In-use stability.......................................................................................95
10.1.6
Mode of application ..............................................................................95
10.1.7
General remarks – important..............................................................95
10.1.8
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 96
11.1
GLOBAL AMENDMENT 1 .............................................................................96
11.2
GLOBAL AMENDMENT 2 .............................................................................98
11.3
GLOBAL AMENDMENT 3 .............................................................................99
11.4
GLOBAL AMENDMENT 4 ...........................................................................100
11.5
GLOBAL AMENDMENT 5 ...........................................................................101
11.6
GLOBAL AMENDMENT 6 ...........................................................................102

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 15 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
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 h after administration
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
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
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
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, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
fet1-t2
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2
GCP
Good Clinical Practice

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 16 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
GI
Gastro-intestinal
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in Safety Testing
MRT,ex
Mean residence time of the analyte in the body, extravascular
NOD
Nucleotide Oligomerization Domain
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual effect period
RIPK2
Receptor-Interacting Protein Kinase-2
RR
Respiratory rate
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
ss
(at) steady state
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
t1/2,eff 
Effective half-life
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

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 17 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
XTC
Ecstasy

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 18 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
1.
INTRODUCTION
BI 706321 is a Receptor-Interacting Protein Kinase-2 (RIPK2) inhibitor candidate, entering 
clinical development for the indication of Crohn’s disease. In this first-in-man study, 
BI 706321 will be given for the first time to humans. Safety, tolerability, pharmacokinetics, 
and pharmacodynamics (biomarkers) of single rising oral doses of BI 706321 will be 
investigated.
1.1
MEDICAL BACKGROUND
Crohn’s disease is characterized by transmural inflammation with ulcerative lesions affecting 
any site within the gastrointestinal tract, with most frequent involvement of terminal ileum, 
often combined with inflammation in colon. 
In Crohn’s disease, mucosal inflammation is driven by dysbiosis of the microbial flora, which 
leads to aberrant stimulation of immune and non-immune cells in the gut. Microbial 
stimulation of somatic cells is partially mediated by Nucleotide Oligomerization Domain 
(NOD) pattern recognition receptors through RIPK2 at the earliest stage in the development 
of the immuno-inflammatory cascade. RIPK2 inhibition is postulated to blunt the dominant 
NOD1/2-driven inflammatory response to the microbiome in the gut, while sparing other 
microbial sensing pathways to prevent broad immunosuppression. This will result in reduced 
levels of inflammatory cells and inflammatory mediators in intestinal tissue, and improved 
epithelial barrier function, which is expected to lead to mucosal healing and clinical response 
in Crohn’s disease. 
For more details on medical background refer to the Investigator’s Brochure (c26475781).
1.2
DRUG PROFILE
BI 706321 is a potent and specific inhibitor of the human RIPK2 kinase. 
Nonclinical pharmacology, pharmacokinetics in animals and toxicology results are described 
in the IB (c26475781).  
Prediction of human pharmacokinetics
1.2.1
Table 1.2.1: 1 shows predicted human PK parameters, and Table 1.2.1: 2 shows predicted
human therapeutic dose and exposure for BI 706321 (n00266137). For prediction of 
exposures following single doses planned in the current trial please refer to Section 1.3.3.1.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 19 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Table 1.2.1: 1 Predicted human pharmacokinetic parameters
Parameter
Prediction
ka [h-1]
0.47
F [%]
45
Vss [L/kg]
5.1
CL [mL/min/kg]
8.6
tmax [h]
2.0
t1/2,eff [h]
6.8
Table 1.2.1: 2 Predicted human therapeutic dose and systemic exposure at steady state (once 
daily [q.d.] dosing)
Parameter
Prediction
AUCss [nM*h]
79
Cmax,ss [nM]
7.5
Cmin,ss [nM]
1.0
Therapeutic dose [mg]
3.3
Residual Effect Period
1.2.2
The Residual Effect Period (REP) is the period after the last dose with measurable drug levels 
and/or pharmacodynamic effects still likely to be present. For BI 706321, a residual effect 
period has been determined at 8 days based on Part I. In Part 1, the conservatively, a 
minimum observation period of 2 weeks has been selected, i.e. the individual subject’s end of 
trial is on day 15 following dosing at the earliest (see Flow Chart).  In Part II it is at 8 days. 
All AEs reported between administration of BI 706321 and the individual subject’s end of 
trial will be counted as on-treatment AEs.  
Clinical experience with BI 706321
1.2.3
In Part I of this study single rising doses up to 25 mg BI 706321 have been well tolerated by 
healthy subjects. The observed AEs did not follow any specific pattern of distribution and no 
dose dependency was observed. Neither SAE nor severe AE were observed. AEs reported in 
>1 subject on active treatment were coded as diarrhea (n=2, loose stool (8 mg) and watery 
stool (25 mg)) and nasopharyngitis (n=2, 0.6 and 15 mg). A total of 5 drug related AEs have 
been observed on active treatment: dry lips (0.3 mg), loose stool (8 mg), dizziness (15 mg), 
watery stool (25 mg) and generalized sensation of cold (25 mg). All these AEs were of mild 
intensity. 
The “generalized sensation of cold” was accompanied by a slightly increased body 
temperature (37.4°C) and an increased CRP-value (35.4 mg/l). Beyond this no specific 
changes of laboratory parameters have been observed in the tested dose groups. Clinical 
monitoring did not show any relevant changes of ECG-parameters and vital signs.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 20 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Human pharmacokinetics was characterized by a slow absorption, a late tmax, a long 
elimination phase and a nearly dose proportional kinetics. Preliminary PK-data of dose 
groups tested in Part I of this study are displayed in the table below: 
Table 1.2.3: 1 Preliminary PK Parameter given as gMean  (tmax is given as median) after 
single oral doses of BI 706321 (Part I)
Dose (mg)
terminal t1/2(h)
tmax (h)
Cmax (nmol/l)
AUC0-24 (nM*h)
0.3
8.53
6
0.388
5.17
0.6
17.7
6
0.781
11.5
1.2
24.0
6
1.02
15.2
2
22.8
6
2.27
34.8
4
35.8
5
5.19
69.8
8
37.5
4.5
11.8
166
15
37.8
4
24.6
320
25
13.1
3.5
41.1
559
Higher doses have not been tested in Part I of this study, because 2 subjects of the 25 mg dose 
group reached an AUC-value (741 and 759 nM*h) that exceeded the maximum acceptable 
systemic exposure of this trial (693 nM*h), meeting a defined stopping criterion (see Section 
3.3.4.3).
1.3
RATIONALE FOR PERFORMING THE TRIAL
This first-in-man trial is intended to start the clinical development of BI 706321 for the 
treatment of Crohn’s disease.
Part I: Effects of single rising doses of BI 706321 on safety, tolerability, pharmacokinetics, 
and pharmacodynamics will be assessed in healthy male volunteers. Within each dose group, 
all actively treated individuals will receive the same dose of BI 706321. The next higher dose 
will only be administered if the treatment in the preceding dose group(s) was safe and 
showed acceptable tolerability, and if the estimated systemic exposure of the next dose 
(guided by preliminary PK analyses) does not exceed the upper limit of exposure (for details 
see Sections 1.3.2 (including subsections), 1.3.3.3, 3.3.4.3 (criteria 6 and 7) and 7.4).
Part II: In the upcoming trial 1425-0003 BI 706321 will be administered to patients with 
Crohn’s Disease. In that first patient trial BI 706321 tablets will be used. Therefore, Part II of 
this study (1425-0001) is designed to investigate the relative bioavailability of tablets 
compared to the capsule formulation tested in Part I, and the effect of food on tablet 
bioavailability to define the respective dose(s) and dosing conditions. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 21 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Selection of starting dose for this trial
1.3.1
Derivation of safe starting dose
1.3.1.1
Maximum recommended starting dose was estimated following FDA Guidance for Industry 
“Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers” (R06-1037). In short, the cynomolgus monkey was selected as 
more sensitive species. Using the NOAEL in the 4-week GLP toxicity study in monkey, 
converting it into a human equivalent dose and applying a standard safety factor of 10 
resulted in a safe starting dose based on toxicity data of 1.9 mg. Secondly, a safety factor of 
11 was applied to the estimated human therapeutic dose of 3.3 mg q.d. and resulted in a safe 
starting dose of 0.3 mg. The more conservative starting dose of 0.3 mg was selected for this 
study. 
A detailed description of the derivation of the maximum safe starting dose can be found in 
the IB (c26475781).
Maximum recommended safe starting dose: 0.3 mg
This dose is selected as starting dose for this clinical trial.
Safety margins of starting dose to the NOAEL in rat and monkey GLP toxicity 
1.3.1.2
studies
Administration of an oral single dose of 0.3 mg BI 706321 is expected to result in exposure 
values of 0.57 nM for Cmax and 6 nM*h for AUC0-24 (see Table 1.3.3.1: 1). This provides the 
following expected safety margins (exposure at NOAEL divided by predicted systemic 
exposure after a single dose of 0.3 mg):
-
1,772x (Cmax) and 1,433x (AUC0-24) to the male Day 29 exposure at NOAEL in the rat 
4 week GLP study. In that study, NOAEL in male* animals was observed at 
10 mg/kg/day corresponding to Day 29 Cmax of 1,010 nM and AUC0-24 of 
8,600 nM*h.    
-
151x (Cmax) and 116x (AUC0-24) to the combined* male and female Day 28 exposure 
at NOAEL in the monkey 4 week GLP study. In that study, NOAEL was observed at 
1 mg/kg/day corresponding to Day 28 Cmax of 86.1 nM and AUC0-24 of 693 nM*h.    
These safety margins of expected exposure at the starting dose to the relevant exposures at 
NOAEL are considered sufficient.
* In preclinical studies, BI 706321 plasma exposure in female rats was higher than in male rats, therefore 
exposure in male rats was used for safety margin calculations. In monkeys, there was no evidence for a sex-
based difference in exposure, therefore the combined exposure values were used for safety margin calculations.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 22 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Maximum exposure and maximum dose for this trial
1.3.2
Maximum exposure
1.3.2.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For a complete report of toxicity findings refer to the IB (c26475781).
 
 
 
Therefore, the following maximum acceptable systemic exposure of BI 706321 (exposure 
cap) for this trial is defined as follows:
Maximum acceptable systemic exposure of BI 706321 (exposure cap) for this trial:
o
Cmax:
86.1 nM
o
AUC0-24: 
693 nM*h

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 23 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
This exposure cap is defined for the expected (predicted) gMean values of a dose level as 
estimated based on preliminary PK data of preceding dose group(s). That means, a dose level 
will only be administered if expected gMean values for Cmax and AUC0-24 do not exceed these 
exposure values (see dose escalation stopping criterion 6 in Section 3.3.4.3).
In addition, due to inter-individual variability, actual systemic exposure in individual subjects 
may exceed these values. However, as soon as the actual observed exposure in one subject 
exceeds the maximum acceptable exposure, dose escalation will be stopped (see dose 
escalation stopping criterion 7 in Section 3.3.4.3). 
Maximum dose
1.3.2.2
Maximum dose is described in Section 1.3.3.1, and this dose will not be exceeded in this 
trial. Dose escalation will be guided by preliminary PK analysis (see Section 1.3.3).
Safety margins of maximum acceptable systemic exposure
1.3.2.3
Safety margins of the maximum acceptable systemic exposure to relevant NOAELs / relevant 
further toxicity findings are as follows (animal exposure at NOAEL divided by maximum 
acceptable systemic exposure in humans or animal exposure at dose level of toxicity finding 
divided by maximum acceptable systemic exposure):
Studies in rats: (for details regarding the findings refer to the IB (c26475781))
Safety margins to NOAEL of the 4-week rat GLP toxicity study (n00259952)
o
NOAEL for male* animals was observed at 10 mg/kg/day corresponding to Day 29 
Cmax of 1,010 nM and AUC0-24 of 8,600 nM*h. Safety margins to the maximum 
acceptable exposure are 12x for both Cmax and AUC0-24.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 24 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Studies in monkeys: (for details regarding the findings refer to the IB (c26475781))
 
 
 
hemophagocytes) observed at this lowest dose 
level administered to monkeys.
Safety margins to the single dose exposure levels in the GLP cardiovascular function 
study in monkeys (n00262560)
o
At 1 mg/kg, no effects on cardiovascular function were seen. Mean plasma exposure 
at 1 mg/kg was Cmax of 172 nM and AUC0-24 of 1,430 nM*h. Safety margins to the 
exposure at this dose level are 2x for both Cmax and AUC0-24.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 25 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
o
At 8 mg/kg, QT/QTc prolongation (up to +18 ms for QT and up to +8 ms for QTc) 
and lower diastolic (up to -3 mmHg) and mean arterial pressures (up to -3 mmHg) 
were observed. Mean plasma exposure at 8 mg/kg was Cmax of 1,060 nM and AUC0-24
of 8,010 nM*h. Safety margins to this exposure are 12x for both Cmax and AUC0-24.
o
At 40 mg/kg, QT and QTc were prolonged by up to 43 ms and 30 ms, respectively. 
Moreover, lower heart rate (up to -12 bpm), lower systolic, diastolic and mean arterial 
pressure (up to -6, -7, and -7 mmHg, respectively), higher inotropic state (increased 
LVdP/dtmax; up to +371 mmHg/sec), and lower lusitropic state (decreased 
LVdP/dtmin; up to -389 mmHg) were observed. Mean plasma exposure at 40 mg/kg 
was Cmax of 4,420 nM and AUC0-24 of 46,100 nM*h. Safety margins to this exposure 
are 51x for Cmax and 67x for AUC0-24.
These safety margins are considered sufficient to minimize risk to volunteers participating in 
this trial. The definition of the maximum acceptable systemic exposure is assessed as 
conservative and adequate for investigation of BI 706321 in healthy volunteers without 
benefit from trial participation. 
* In preclinical studies BI 706321 plasma exposure in female rats was higher than in male rats, therefore 
exposure in male rats was used for safety margin calculations. In monkeys, there was no evidence for a sex-
based difference in exposure, therefore the combined exposure values were used for safety margin calculations.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 26 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Escalation scheme (guided by preliminary PK analysis)
1.3.3
Escalation scheme
1.3.3.1
Escalation scheme has been chosen such that escalation factors are decreasing with increasing 
doses. Table 1.3.3.1: 1 shows the planned dose escalation, the escalation factors, and the 
predicted systemic exposures. 
Predictions are from simulations performed in R (version 3.4.3) and are based on preclinical 
data. Concentration profiles were predicted after a single oral administration, from a 2-
compartment model with first-order absorption and first-order elimination, where parameter 
values originated from animal species fits. The model is described in (n00266137)..
Table 1.3.3.1: 1
Dose escalation scheme, escalation factors and BI 706321 exposure in 
plasma predicted based on preclinical data
Dose level 
[#]*
Dose of 
BI 706321 [mg]
Escalation factor from 
previous dose level**
Predicted 
Cmax [nM]
Predicted AUC0-24
[nM*h]
1
0.3
0.57
6
9***
0.6
2.0
1.13
12
2
1.2
2.0
2.27
23
11***
2
1.7
3.78
38
3
4
2.0
7.56
77
4
8
2.0
15.12
154
5
15
1.9
28.35
288
6
25
1.7
47.24
480
7
40
1.6
75.59
768
8
60
1.5
113.39
1152
* A dose level (= dose group) will only be administered if the treatment in the preceding dose 
group(s) was safe and showed acceptable tolerability and if the systemic exposure of the next 
dose (gMean values for AUC0-24 and Cmax, guided by preliminary PK analysis) is expected to 
not exceed the maximum acceptable exposure (see Section 1.3.2.1). Moreover, dose 
escalation will be stopped in case individual observed exposure values in one subject exceed 
the maximum acceptable exposure. For escalations up to 4 mg (inclusive), preliminary PK 
data are not needed (see also Section 7.4).
** Rounded to one decimal place.
*** added with global amendment n 1; dose group numbering follows logistical reasons 
(alignment with other trial documentation)
Justification for dose groups 7 and 8
1.3.3.2
Dose groups 7 (40 mg) and 8 (60 mg) will only be administered after approval of a 
substantial amendment to the CTP.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 27 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Dose levels 7 and 8 are predicted to result in systemic exposure values of BI 706321 that 
exceed the maximum acceptable exposure. However, there is uncertainty in predictions from 
preclinical data to human, and actual PK parameters may deviate from predicted values. Dose 
groups 7 and 8 are planned for the case that actual systemic exposure is lower than predicted, 
e.g., due to lower-than-predicted F or higher CL. Preliminary PK analysis will be performed 
during the trial to inform dose escalation meetings including the decision whether dose 
groups 7 and 8 can be given.
Table 1.3.3.2: 1 Dose escalation scheme, preliminary PK-data (of DG 1, 9 and 2) and 
predicted (a) / estimated (b) BI 706321 plasma exposure 
Dose 
level [#]*
Dose of 
BI 706321 
[mg]
Predicted / 
estimated
Cmax [nM]
Measured
Cmax [nM]
Predicted / 
estimated
AUC0-24 [nM*h]
Measured 
AUC0-24
[nM*h]
1
0.3
0.57a
0.388
6 a
5.17
9**
0.6
1.13 a
0.781
12 a
11.5
2
1.2
2.27 a
1.02
23 a
15.2
11**
2
1.7 b
n.a.
25 b
n.a.
3
4
3.4 b
n.a.
50 b
n.a.
4
8
6.8 b
n.a.
100 b
n.a.
13***
20
17 b
n.a.
250 b
n.a.
7
40
34 b
n.a.
500 b
n.a.
* A dose level (= dose group) will only be administered if the treatment in the preceding dose 
group(s) was safe and showed acceptable tolerability and if the systemic exposure of the next 
dose (gMean values for AUC0-24 and Cmax, guided by preliminary PK analysis) is expected to 
not exceed the maximum acceptable exposure (see Section 1.3.2.1). Moreover, dose 
escalation will be stopped in case individual observed exposure values in one subject exceed 
the maximum acceptable exposure. Escalation from 8 to 20 mg will be performed only, if the 
expected increase of exposure (based on preliminary PK-data) does not exceed factor 2. 
Otherwise (if the expected increase of exposure exceeds factor 2) the escalation would follow 
the original dosing schedule (with DG 5 = 15 mg and DG 6 = 25 mg), which will be 
implemented via non-substantial amendment. 
** added with global amendment No. 1; dose group numbering follows logistical reasons 
(alignment with other trial documentation)
*** added with global CTP amendment 3; dose group numbering follows logistical reasons
a predictions are based on pre-clinical data
b estimations are based on linear extrapolation of 1.2 mg preliminary PK data
Preliminary PK analysis
1.3.3.3
Dose escalation will be guided by preliminary PK analysis with the following aims:
-
Ascertaining that adequate exposures are reached in this trial as a basis for further 
development of BI 706321, 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 28 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
-
Ascertaining that the expected gMean exposure values of the next dose group do not 
exceed the maximum acceptable exposure in order to protect subject’s safety, and
-
Ascertaining that dose escalation is stopped in case observed exposure values of a 
single subject exceed the maximum acceptable exposure.
For details, see Sections 3.3.4.3 and 7.4.
1.4
BENEFIT - RISK ASSESSMENT
Expected benefit for the target population
1.4.1
Healthy volunteer subjects participating in this clinical trial are not expected to have any 
individual (therapeutic) benefit. Their participation, however, is of major importance for the 
development of BI 706321, which represents a novel approach for treating patients with
Crohn’s disease. Because of significant unmet medical need in Crohn’s disease, oral 
medicines with a novel mode of action that include regulation of the complex interaction 
between microbiome and intestinal tissue would be particularly attractive. 
Procedure-related risks
1.4.2
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising and, in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
ECG electrodes may cause local and typically transient skin reactions.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures (Part I)
1.4.3
Specific RIPK2 inhibition is a novel mechanism of action for which there is no precedent
clinical data, and BI 706321 has not yet been tested in humans. There are no known side
effects or tolerability concerns for humans. Gefitinib and erlotinib, epidermal growth factor
receptor tyrosine kinase inhibitors, have been approved for oncology indications and are
believed to inhibit RIPK2 in addition to main target of tyrosine kinase (R16-5289, R19-
0652), suggesting that RIPK2 inhibition, albeit in the context of other kinase inhibition, can
be tolerated in humans.
Increased susceptibility to infection (IB (c26475781))
Based on the role of RIPK2 in the innate arm of the immune system, there is a potential
theoretical concern with increased susceptibility to infection with selective RIPK2 inhibition.
Pre-clinical literature reports suggest that RIPK2 null mice are more susceptible to infection
after intravenous administration of Listeria monocytogenes (R17-1239) and intranasal
administration of H1N1 influenza virus (R19-0610). Genetic associations between human
NOD2 and RIPK2 polymorphisms and susceptibility to Mycobacterium leprae suggest a role
for RIPK2 in the clearance of intracellular pathogens (R19-0611). However, the

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 29 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
translatability between genetic loss of function and pharmacologic inhibition of RIPK2
kinase activity is unknown. It is important to note that RIPK2 inhibition will selectively block
the NOD-RIPK2 pathway, leaving the remaining innate pattern recognition receptor signaling
pathways (i.e. Toll-like receptor signaling) intact. 
Risk mitigation:

Subjects with immunological disorder (who might be more susceptible to infection) 
are excluded from trial participation (see Section 3.3.3, criterion 5).

Subjects will be asked at pre-defined time points for adverse events (AEs; see Flow 
Chart) and will be instructed to report AEs spontaneously. 

Safety laboratory includes white blood cells (WBC) and differential as well as 
C-reactive protein (CRP; see Section 5.2.3).

Subjects are protected from findings in cynomolgus monkey toxicity studies at
≥40 mg/kg/day by a safety margin (see Section 1.3.2.3). 
Gastrointestinal function (IB (c26475781))
A single dose resulted in an increased rate of gastric emptying and intestinal transit, and
liquid accumulation to intestinal contents in rats. Repeat dosing resulted in soft, loose, wet, or
liquid stool in rats and monkeys. This may suggest a risk for loose stool or diarrhea; any such 
effects would however be expected to be of transient nature. 
Risk mitigation: 

Subjects with gastrointestinal disorders (who might be more susceptible to 
gastrointestinal side effects and whose baseline condition could confound the safety 
assessment with regards to gastrointestinal effects) are excluded from trial 
participation (see Section 3.3.3, criterion 5)

Subjects will be asked at pre-defined time points for AEs (see Flow Chart) and will be 
instructed to report AEs spontaneously. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 30 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Cardiovascular system (IB (c26475781))
In cynomolgus monkeys, a single dose resulted in prolongation of QT/QTc intervals, lower
diastolic, systolic, and mean arterial pressures, lower heart rate, higher inotropic state, and
lower lusitropic state. A single dose to dogs resulted in an increase in inotropic state. For 
safety margins between maximum exposure in this trial and findings in the GLP 
cardiovascular function study in monkeys see Section 1.3.2.3. There is low risk for relevant 
cardiovascular effects such as QT prolongation, decreased heart rate, and decreased blood 
pressure at the exposures expected in this trial. 
Non-adverse slight myocardial mononuclear infiltrates were seen in rats at the lowest dose in
2 weeks study and did not repeat at any or higher doses in 4 weeks study. Because of the
minimal nature of these non-consistent findings, observed myocardial mononuclear infiltrates
are not considered a relevant risk in humans.
Risk mitigation:

Subjects with relevant findings in BP, PR or ECG at Screening (Section 3.3.3, criteria 
1,2,20), cardiovascular disorders (Section 3.3.3, criterion 5), history of relevant 
orthostatic hypotension, fainting spells or blackouts (Section 3.3.3, criterion 8), use of 
drugs that might prolong the QT/QTc interval (Section 3.3.3, criterion 11), marked 
baseline prolongation of QT/QTc interval at screening (Section 3.3.3, criterion 20), or 
subjects with additional risk factors for Torsade de Pointes arrhythmia (Section 3.3.3, 
criterion 21) are excluded from trial participation.

A dose escalation stopping criterion based on QT/QTc increase has been defined 
(Section 3.3.4.3, criterion 5).

Frequent ECG and vital signs measurements during the time of expected relevant 
exposure (see Flow Chart).

Subjects will be in-house at the trial site under close medical observation for 24 hours 
after drug administration (dose groups < 4 mg) or 48 hours after drug administration 
(dose groups ≥ 4 mg; see Flow Chart). They will only be allowed to leave the trial site 
after formal assessment and confirmation of their fitness by the investigator or
designee. If required, in-house observation period may be prolonged.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 31 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Effects to the liver (IB (c26475781))
In rats, there were non-adverse infiltrates/aggregates of mononuclear cells/histiocytes to the
liver, mesenteric lymph node, spleen and heart (for heart see also above). Infiltrates/
aggregates to the liver and mesenteric lymph nodes were observed at the lowest dose tested in
the rats. Infiltrates to spleen had high multiple of exposure. In rats, there were increases in 
serum AST and ALT that did not consistently correlate with the liver infiltrates. Liver 
infiltrates did not progress when evaluated in a 13 week exploratory study in rats. In 
monkeys, there were non-adverse effects to the liver (hypertrophy of sinusoidal (Kupffer) 
cells) that also were observed at the lowest dose tested and not associated with increases to 
AST or ALT. Because of the nature of the findings these tissue changes are not considered a 
relevant risk in humans.
Risk mitigation: 

Subjects with liver enzymes (ALT, AST) exceeding upper limit of normal will be 
excluded from trial participation (Section 3.3.3, criterion 24). 

Liver enzymes (ALT, AST) will be measured before and after dosing. 

Standard drug-induced liver injury (DILI) criteria (Section 5.2.5.1.4, adverse events 
of special interests) are defined, and this trial requires timely detection, evaluation, 
and follow-up of laboratory alterations in selected liver laboratory parameters to 
ensure subjects’ safety. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 32 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Genotoxicity, reproductive and developmental toxicity (IB (c26475781))
In vitro and in vivo genetic toxicology studies indicated that BI 706321 is free of any 
genotoxic potential.
Developmental and reproductive toxicity studies have not been conducted.
Phototoxicity
BI 706321 is not likely to be phototoxic at clinically relevant doses (see IB (c26475781)). 
Subjects will be advised to avoid direct exposure to sun and UV light during the entire study 
(see Section 4.2.2.2). Further measures are not necessary.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 33 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Summary of safety measures (Part I)
1.4.4
The following precautionary measures will be taken in this study in order to minimise the risk 
for healthy volunteers:
o
Dose selection is based on the expected pharmacologically active dose, expected 
systemic exposures after single-dose administration, and toxicity findings in 
preclinical studies. Escalation factors between dose steps decrease at higher doses. 
For details see Sections 1.3.1, 1.3.2, and 1.3.3 including subsections. 
o
A maximum acceptable human exposure has been defined based on toxicity findings 
(see Section 1.3.2.1). Dose escalation is guided by preliminary analysis of BI 706321 
PK (Cmax and AUC0-24). 
-
A dose level will only be administered if estimated (predicted) gMean values 
for Cmax and AUC0-24 do not exceed the maximum acceptable human exposure 
(see Sections 1.3.2.1, 1.3.3.3, and 7.4 and Section 3.3.4.3, dose escalation 
stopping criterion 6).
-
Moreover, dose escalation will be stopped in case observed exposure in one 
subject who has been dosed with BI 706321 has exceeded the maximum 
acceptable exposure (see Section 3.3.4.3, dose escalation stopping criterion 7).
o
For safety reasons, each dose group of 8 subjects (6 on active and 2 on placebo) will 
be divided into two cohorts of 2 subjects each (1st and 2nd cohort) and one cohort of 4 
subjects (3rd cohort). The first 2 cohorts will be dosed in a single blinded, fixed-
sequence fashion (1st cohort: ‘active – placebo’; 2nd cohort: ‘active-active’). Order of 
dosing in the 3rd cohort (3 active, 1 placebo) will be randomized. The first drug 
administration of cohort 1 and the first drug administration of cohort 2 will be 
separated by at least 22 hours. The first drug administration of cohort 2 and the first 
drug administration of cohort 3 will be separated by at least 22 hours. Within each 
cohort, drug administrations will be separated by at least 10 min. This design ensures 
that between first and second active dose of each dose level there is a time interval of 
at least 22 hours. This time interval is expected to be sufficient to detect relevant first 
acute effects of BI 706321.
o
A documented Safety Review takes place prior to each dose escalation. Dose 
escalation is only permitted if there are no safety concerns and if none of the pre-
specified stopping criteria are met. The minimum time interval between dosing of the 
last subject of a dose group and dosing of the first subject of the subsequent dose 
group is 3 days for escalation up to a dose level of 4 mg (inclusive) and 10 days for 
escalation up to dose levels higher than 4 mg. For details see Section 3.1.
o
Stringent in- and exclusion criteria define a relatively homogenous population and
exclude subjects that might be at increased risk for side effects (see Section 3.3).
o
Safety laboratory examinations will be performed at pre-defined time points before 
and for at least two weeks after drug administration. These examinations include 
extensive standard safety laboratory examinations (see Flow Chart (time points) and
Section 5.2.3 (test details). 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 34 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
o
A thorough ECG and heart rate monitoring including continuous ECG monitoring for 
4 h post dose and in addition frequent 12-lead ECG and vital signs measurements at 
time points as described in the Flow Chart are planned.
o
Subjects will be confined for at least 24 h after study drug administration (dose groups
< 4 mg; see Flow Chart) or for at least 48 h after study drug administration (dose 
groups ≥ 4 mg; see Flow Chart) to the trial site. During in-house confinement the 
subjects are under medical observation and are monitored for both expected and 
unexpected adverse events. They will only be allowed to leave the trial site after 
formal assessment and confirmation of their fitness by the investigator or
designee. If required, in-house observation period may be prolonged.
o
Subjects will be advised to avoid direct exposure to sun and UV light during the entire 
study (see Section 4.2.2.2).
o
Subjects with WOCBP partner have to use barrier contraception (condom) or 
abstinence as detailed in Section 3.3.3.
Benefit risk assessment for Part II
1.4.5
In Part I (single-rising dose part) of this study, BI 706321 has been well tolerated up to a 
single dose of 25 mg, which resulted in a mean exposure of 41.1 nM (Cmax) and 559 nM*h 
(AUC0-24) (see section 1.2.3). In Part II of this trial single doses of 4 mg BI 706321 will be 
administered. In Part I of this trial a single dose of 4 mg resulted in a mean exposure of 5 nM 
(Cmax) and 70 nM*h (AUC0-24) thus providing a safety margin of 8 to the highest exposure 
tested. This safety margin is regarded as sufficient to cover a potential food effect and a 
possibly higher bioavailability of the tablet compared to the capsule. Therefore, no undue risk 
for healthy subjects is expected from participation in Part II of this trial. 
Overall benefit-risk assessment
1.4.6
A substantial unmet need remains for agents with greater efficacy than current therapies in 
the treatment of Crohn’s disease. Oral medicines with a novel mode of action that include 
regulation of the complex interaction between microbiome and intestinal tissue would be 
particularly attractive for the current unmet need in Crohn’s disease. 
BI 706321 is a potent and specific RIPK2 inhibitor that has been adequately characterised in 
preclinical studies and is now entering clinical development for the indication of Crohn’s 
disease. The non-clinical safety package supports administration of BI 706321 for up to 4 
weeks duration to men. In rats and monkeys, toxicities were identified. These were both 
monitorable and reversible, or subjects are protected by adequate safety margins (see also 
Section 1.3.2.3).
Transition from preclinical investigations to clinical development requires assessment of 
safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of BI 706321 in 
healthy volunteers. Considering the medical need for an effective and safe treatment of 
Crohn’s disease, the benefit of this trial is assessed to outweigh the potential risks.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 35 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
Part I: The main objectives of Part I of this trial are to investigate safety, tolerability, and 
pharmacokinetics (PK) of BI 706321 in healthy male subjects following oral administration 
of single rising doses.
Part II: The relative bioavailability of BI 706321 after administration of tablets and capsules
under fasted conditions will be compared with each other (comparison A: Test 1 = tablets, 
fasted / Reference = capsules, fasted). Furthermore, the effect of food (Test 2 = tablets, fed) 
on the tablet bioavailability will be investigated (comparison B: Test 2 / Test 1).
Primary endpoint
2.1.2
Part I: The primary endpoint for assessment of safety and tolerability of BI 706321 is the 
percentage of subjects with drug-related adverse events.
Part II: The following pharmacokinetic parameters will be determined for BI 706321:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
Secondary endpoint
2.1.3
Part I: The following pharmacokinetic parameters will be determined for BI 706321 if 
feasible:

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)

tmax (time from dosing to the maximum measured concentration of the analyte in 
plasma)
Part II: The following pharmacokinetic parameter will be determined for BI 706321:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 36 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Safety and tolerability
2.2.2.1
Safety and tolerability of BI 706321 will be assessed based on:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring (Part I only)

Vital signs (blood pressure, pulse rate; oral body temperature in Part I)

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 37 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
Part I:
This single-rising dose trial is designed as single-blind, randomised, and placebo-controlled 
within parallel dose groups.
It is planned to include a total of 64 healthy male subjects in the trial. The subjects will be 
assigned to 8 groups consisting of 8 subjects per group; the groups will be dosed sequentially
(see Table 3.1: 1). The investigator is allowed to alter the scheduled dose groups (e.g., add 
low and/or intermediate dose groups) on the basis of experience gained during the study (for 
instance, based on preliminary PK data), provided the planned and approved highest dose is 
not exceeded. Thus, the actual number of subjects entered may be more than 64, but is not to 
exceed 80. Such changes may be implemented via non-substantial CTP amendments.
Within each dose group, 6 subjects will receive BI 706321 and 2 will receive placebo. Only 
one dose is tested within each dose group. For safety reasons, each dose group will consist of 
3 cohorts. The trial medication will be administered in the following order: 

Cohort 1: 1 subject on active treatment and 1 subject on placebo (in total 2 subjects)

Cohort 2: 2 subjects on active treatment (in total 2 subjects) 

Cohort 3: randomised 3 subjects on active treatment and 1 subject on placebo (in total 
4 subjects)
There will be at least 10 min between treatment of the sentinel subject, i.e. the first subject of 
cohort 1 (BI 706321) and the second subject of cohort 1 (placebo).
Cohort 2 will be treated not earlier than 22 hours later (minimum time interval between 1st
subject of cohort 1 [sentinel subject] and 1st subject of cohort 2). This is expected to be 
sufficient to detect relevant acute effects of BI 706321 in the sentinel subject prior to 
exposing more volunteers to BI 706321 at the respective dose level. In cohort 2, a time 
interval of at least 10 min will be maintained between dosings of individual subjects (both 
treated with BI 706321).
Cohort 3 will be treated not earlier than 22 hours later (minimum time interval between 1st
subject of cohort 2 and 1st subject of cohort 3). In cohort 3, a time interval of at least 10 min 
will be maintained between dosings of individual subjects (3 treated with BI 706321, 1 
treated with placebo; randomized order).
At each dose level cohort 3 may be started only after at least 2 subjects have been treated 
with BI 706321 in the preceding cohorts 1 and 2.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 38 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Table 3.1: 1
Dose groups
Dose Group
1
9**
2
11**
3
4
5
6
7*
8*
Dose (mg)
0.3
0.6
1.2
2
4
8
15
25
40
60
Number of subjects
8
8
8
8
8
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
2
2
2
2
2
Subjects receiving BI 706321
6
6
6
6
6
6
6
6
6
6
* Dose groups 40 mg and 60 mg will only be dosed after approval of a substantial amendment.
** Added with global CTP amendment 1. Dose group numbering follows logistical reasons 
(alignment with other trial documentation).
Table 3.1: 1
Dose groups
Dose Group
1
9*
2
11*
3
4
13**
7
Dose (mg)
0.3
0.6
1.2
2
4
8
20
40
Number of subjects
8
8
8
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
2
2
2
Subjects receiving BI 706321
6
6
6
6
6
6
6
6
* Added with global CTP amendment 1. Dose group numbering follows logistical reasons (alignment 
with other trial documentation).
** Added with global CTP amendment 3. Dose group numbering follows logistical reasons.
The groups will be dosed consecutively in ascending order, and a time interval of at least 3
days (escalation to dose groups up to 4 mg (inclusive)) or of at least 10 days (escalation to all 
dose groups higher than 4 mg) will be maintained between the last drug administration to
subjects in the previous dose group and the first drug administration to subjects in the 
subsequent dose group. The decision to treat the next dose group will be based upon safety, 
tolerability, and, starting from escalation to dose group 4 (8 mg) (see Section 7.4),
pharmacokinetic data of preceding dose group(s). The next dose group will only be treated if, 
in the opinion of the investigator, no safety concerns have arisen in the preceding dose groups
(i.e. no dose-limiting events occurred), and if none of the pre-specified trial-specific stopping 
criteria have been met (refer to Section 3.3.4.3).
A documented safety review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime by the Principal Investigator (or 
an authorised deputy) or the sponsor of the study (for instance, due to the occurrence of any 
unforeseen adverse events). 
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 
absence of any safety concern (i.e. no dose-limiting events occurred) and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4.3).

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 39 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
At minimum, data from 5 subjects on active drug need to be available for escalation to a 
higher dose. For the minimum dataset with regards to preliminary PK data, see Section 7.4.
The minimum data set for review consists of the following:

AEs in the current and preceding dose groups up to at least 24 h 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 ECG and the assessment of the continuous ECG monitoring in 
the current and preceding dose groups up to at least 24 h post dosing

Vital signs in the current and preceding dose groups up to at least 24 h post dosing

Clinical laboratory tests in the current and preceding dose groups up to at least 24 h 
post dosing (for escalation to dose groups up to 4 mg [inclusive]) or up to at least 
Visit 2 Day 8 (for escalation to dose groups higher than 4 mg).

Preliminary PK data for the selected time as per Section 7.4

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 Clinical Trial Leader (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). In addition and depending on the 
results and findings, suitable experts from the sponsor or external institutions may be 
consulted on an as needed basis. In these cases expert recommendations will be documented 
in the minutes of the Safety Review and considered for the decision making. Dose escalation 
will only be permitted if no safety concerns exist neither in the opinion of the Principal 
Investigator (or an authorised deputy) nor the Clinical Trial Leader (or an authorised deputy). 
Safety Reviews can be conducted face-to-face or by video/telephone conference. The Clinical 
Trial Leader is responsible for the organisation and minutes of the reviews. Minutes will be 
signed off by the Principal Investigator (or an authorised deputy) and Clinical Trial Leader
(or an authorised deputy), and will be filed in the ISF and TMF.
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.
Procedure for additional lower dose groups
As described above, the investigator is allowed to alter the scheduled dose groups (e.g., add 
low and/or intermediate dose groups) on the basis of experience gained during the study (for 
instance, based on preliminary PK data), provided the planned and approved highest dose is 
not exceeded. Such changes may be implemented by non-substantial amendment to the 
clinical trial protocol. 
In case a dose group is added that is lower than a dose level that has already been tested in 
this trial, this needs to be discussed and decided in a Safety Review meeting as described 
above and documented in the minutes of the meeting. All subjects of the additional lower 
dose group may be dosed on the same calendar day (i.e. within a single cohort), and no 
minimal time interval between dosings is defined. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 40 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Part II:
Part II of this trial will be performed following a randomised, open-label, three-way 
crossover design to compare the  treatments T1 and R (comparison A) and T2 and T1 
(comparison B):
R: 
4 capsules à 1 mg BI 706321 under fasted conditions
T1:
2 tablets à 2 mg BI 706321 under fasted conditions
T2:  
2 tablets à 2 mg BI 706321 after a standardised breakfast
The subjects will be randomly allocated to one of the 3 treatment sequences R-T1-T2, T1-T2-
R or T2-R-T1. For details, refer to Section 4.1. There will be a washout period of at least 12
days between the treatments.
An overview of all relevant trial activities is provided in the Flow Chart (Part II). For visit 
schedule and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, 
respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
Part I:
For single-rising dose trials, the sequential rising dose design described in Section 3.1 is 
viewed favourably under the provision not to expose the subjects involved to undue risks.
Treatment in the first two cohorts of each dose level is fixed for safety reasons (see Section 
3.1). Treatment in the third cohort is randomized (3 subjects with BI 706321, 1 with placebo) 
to partially balance experimental groups (treated with different doses of BI 706321) and 
control group (placebo group) on confounders.
Single-blind conditions regarding the subject’s treatment (active or placebo) are maintained 
within each dose group. However, subjects and investigators will be aware of the dose of 
drug administered. The disadvantage of the trial design is a possible observer bias with regard 
to the dose-dependent effects; in addition, the sequential dosing of groups could potentially 
result in time-related effects. However, as such 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 single-rising dose trials involving healthy volunteers to include a placebo 
group to control for safety, tolerability, and pharmacodynamic effects of the trial medication. 
Each dose group consists of 8 subjects, with 6 on active treatment, and 2 on placebo. For data 
analysis purposes, the placebo control group will include all subjects of all dose groups 
treated with placebo. Six subjects per active treatment group are generally considered to be 
sufficient for the exploratory evaluation of pharmacokinetics. 
Part II:
For investigation of relative bioavailability, the cross-over design is preferred because of its 
efficiency: since each subject serves as his own control, the comparison between treatments is 
based on an intra-subject comparison, thus removing inter-subject variability from the 
comparison between treatments [R94-1529].

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 41 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte, which are not expected to be 
influenced by the knowledge of treatment received.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 80 healthy male subjects will enter the study. The actual number of subjects 
entered may exceed the total of 80 if additional intermediate doses are tested (see Section 
3.1). Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included in the trial because no data on embryofetal toxicology 
are available at this time.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
Main diagnosis for trial entry 
3.3.1
The study will be performed in healthy male subjects.
Inclusion criteria
3.3.2
Subjects will only be included in the trial if they meet all of the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR, oral body 
temperature), 12-lead ECG, and clinical laboratory tests
2. Age of 18 to 45 years (inclusive) in Part I and of 18 to 55 years (inclusive) in Part II
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
Exclusion criteria
3.3.3
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, oral body temperature, or
ECG) deviating from normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 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 assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 42 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 24 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or
has a condition that would not allow safe participation in the study 
23. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from time point of administration of trial medication until 
30 days thereafter. Sperm donation is not allowed from the time point of drug 
administration until 30 days thereafter.
24. ALT (alanine transaminase), AST (aspartate transaminase), or creatinine exceed upper 
limit of normal range at screening, confirmed by a repeat test.
25. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
For study restrictions, refer to Section 4.2.2.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 43 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Withdrawal of subjects from treatment or assessments
3.3.4
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR.
At the time of discontinuation, a complete end of trial examination will be performed, if 
possible, and the information will be recorded in the CRF. 
Discontinuation of trial treatment
3.3.4.1
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future 
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and section 6.2.3.
Withdrawal of consent to trial participation
3.3.4.2
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see section 3.3.4.1 above

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 44 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Discontinuation of the trial by the sponsor
3.3.4.3
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk assessment. 
3. Violation of GCP or the CTP impairing the appropriate conduct of the trial.
4. The sponsor decides to discontinue the further development of the investigational product
5. Dose escalation will be stopped if at least 2 subjects on active treatment at one dose level 
have relevant individual QT prolongations, i.e. absolute QTc greater than 500 ms, as 
confirmed by a repeat ECG recording, or a QTc increase of greater than 60 ms from 
baseline mean, as confirmed by a repeat ECG recording
6. Dose escalation will be stopped if the estimated gMean exposure of the next higher dose 
level is expected to exceed a Cmax of 86.1 nM or an AUC0-24 of 693 nM*h. In this case, 
one or two additional dose levels lower than the planned next dose level may be given, as 
long as the expected gMean exposure values of the interim dose do not exceed these 
exposure thresholds. Estimation will be done based on preliminary PK results of 
preceding dose groups (see Section 7.4)
7. Dose escalation will be stopped if the observed Cmax or AUC0-24 of at least 1 subject of 
one dose group exceeds the exposure thresholds defined in dose escalation stopping 
criterion 6 above. 
8. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in 2 subjects of the same dose group or occurrence of at least one drug-
related serious adverse event. Moreover, dose escalation will be terminated if more than 3 
of the actively dosed subjects at one dose level show drug-related and clinically relevant 
adverse events of at least moderate intensity.
Replacement of subjects
3.3.5
Part I: In case that one dose group is completed by less than 5 subjects on active treatment 
(due to e.g. drop-outs or recruitment reasons), the Clinical Trial Leader together with the 
Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects 
will be replaced. A replacement subject will be assigned a unique trial subject number, and 
will be assigned to the same treatment as the subject he replaces.
Part II: In case that Part II is completed by less than 12 subjects, the Clinical Trial Leader
together with the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how 
many subjects will be replaced. However, the maximum number of replacement subjects is 4. 
A replacement subject will be assigned a unique trial subject number, and will be assigned to 
the same treatment sequence as the subject he replaces.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 45 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products will be supplied by BI Pharma GmbH & Co. KG.
Identity of the Investigational Medicinal Products
4.1.1
The characteristics of the test products are given below:
BI 706321 Capsules 20 mg for Reconstitution of an Oral Solution (Part I only)
Substance:
BI 706321
Pharmaceutical formulation: Capsule 
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
20 mg (1 capsule to be dissolved in 80 mL solvent [see below]; 
concentration of reconstituted oral solution: 0.25 mg/mL)
Posology:
1.2 mL (0.3 mg) -0-0 (DG 1), 2.4 mL (0.6 mg) -0-0 (DG 9), 
4.8 mL (1.2 mg) -0-0 (DG 2)
Route of administration:
oral
Duration of use:
Single dose 
Reconstitution of BI 706321 Oral Solution:
Prior to administration, BI 706321 Oral Solution is reconstituted as follows: 1 capsule 
containing 20 mg BI 706321 is added to 80 mL of solvent (tartaric acid 0.5%) and dissolved. 
After complete dissolution, appropriate volume aliquots (see Section 4.1.4) of the solution are 
withdrawn by use of oral dispensers. 
Detailed reconstitution instructions are given in Appendix 10.1.
BI 706321 Capsules 1 mg (Part I and II)
Substance:
BI 706321
Pharmaceutical formulation: Capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
1 mg
Posology:
2-0-0 (DG 11), 4-0-0 (DG 3), 8-0-0 (DG 4)
4-0-0 (Treatment R in Part II)
Route of administration:
oral
Duration of use:
Single dose 
BI 706321 Capsules 5 mg (Part I only)
Substance:
BI 706321
Pharmaceutical formulation: Capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology:
3-0-0 (DG 5), 5-0-0 (DG 6) 
Route of administration:
oral
Duration of use:
Single dose 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 46 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
BI 706321 Capsules 20 mg (Part I only)
Substance:
BI 706321
Pharmaceutical formulation: Capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
20 mg
Posology:
2-0-0 (DG 7), 3-0-0 (DG 8)
Route of administration:
oral
Duration of use:
Single dose
BI 706321 Film-coated tablets 2 mg (Part II only)
Substance:
BI 706321
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
2 mg
Posology:
2-0-0 (Treatment T1 and T2 in Part II)
Route of administration:
oral
Duration of use:
Single dose
The characteristics of the reference products (placebo) are given below:
Placebo for BI 706321 Oral Solution (Part I only)
Substance:
Tartaric acid
Pharmaceutical formulation: Solvent for oral solution
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg/mL
Posology:
1.2 mL -0-0 (DG 1), 2.4 mL –0-0 (DG 9), 4.8 mL -0-0 (DG 2)
Route of administration:
oral
Duration of use:
Single dose 
The solvent for oral solution will directly be used as placebo solution. Appropriate volume 
aliquots (see Section 4.1.4) of the solution are withdrawn into oral dispensers. For more 
details see Appendix 10.1.
Placebo for BI 706321 Capsules (Part I only)
Substance:
not applicable*
Pharmaceutical formulation: Capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
not applicable 
Posology:
2-0-0 (DG 11), 4-0-0 (DG 3), 8-0-0 (DG 4), 3-0-0 (DG 5), 5-0-0 
(DG 6), 2-0-0 (DG 7), 3-0-0 (DG 8) 
Route of administration:
oral
Duration of use:
Single dose
* For the matching placebo capsule, the drug substance is replaced by cellulose 
microcrystalline. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 47 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Selection of doses in the trial
4.1.2
Part I: The doses selected for this trial cover the subtherapeutic as well as the estimated 
therapeutic range and include a safety margin (see Sections 1.2.1, 1.3.1, 1.3.2, and 1.3.3).
Part II: The dose of 4 mg has been chosen for safety reasons (see Section 1.4.5).
Method of assigning subjects to treatment groups
4.1.3
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups (3 
cohorts per dose group) according to their temporal availability. As soon as enough subjects 
are allocated to one of the dose cohorts, 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. Because the study includes 
healthy subjects from a homogenous population, relevant imbalances between the dose 
groups are not expected.
Subjects will be assigned to treatments (active treatment or placebo) prior to the first 
administration of trial medication. For this purpose, the randomisation list will be provided to 
the trial site in advance. Numbers of the randomization list will be allocated to subjects by 
drawing lots. Subjects are then assigned to treatment according to the randomisation list.
Note: Treatment allocation in cohorts 1 and 2 is fixed, treatment allocation in cohort 3 is 
randomised (see Section 3.1).
The randomisation procedure is described in Section 7.6.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 48 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Drug assignment and administration of doses for each subject
4.1.4
Part I:
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of units / 
dose volume for placebo corresponds to the number of units / dose volume of the
corresponding dose level.
Table 4.1.4: 1
BI 706321 and placebo treatments, oral administration 
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Dose volume / number of 
units per administration
Total dose of 
BI 706321
1
BI 706321
oral solution
0.25 mg/mL
1.2 mL 
0.3 mg
9
BI 706321
oral solution
0.25 mg/mL
2.4 mL
0.6 mg
2
BI 706321
oral solution
0.25 mg/mL
4.8 mL 
1.2 mg
11
BI 706321
capsule
1 mg
2 capsules
2 mg
3
BI 706321
capsule
1 mg
4 capsules
4 mg
4
BI 706321
capsule
1 mg
8 capsules
8 mg
5
BI 706321
capsule
5 mg
3 capsules
15 mg
6
BI 706321
capsule
5 mg
5 capsules
25 mg
7**
BI 706321
capsule
20 mg
2 capsules
40 mg
8**
BI 706321
capsule
20 mg
3 capsules
60 mg
1, 2, 9
Placebo*
oral solution
--
volume identical to active 
treatment
--
3-8, 11
Placebo*
capsule
--
number identical to active 
treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
** Dose groups 7 and 8 may only be dosed after approval of a substantial amendment.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 49 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Table 4.1.4: 1
BI 706321 and placebo treatments, oral administration 
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Dose volume / number of 
units per administration
Total dose of 
BI 706321
1
BI 706321
oral solution
0.25 mg/mL
1.2 mL 
0.3 mg
9
BI 706321
oral solution
0.25 mg/mL
2.4 mL
0.6 mg
2
BI 706321
oral solution
0.25 mg/mL
4.8 mL 
1.2 mg
11
BI 706321
capsule
1 mg
2 capsules
2 mg
3
BI 706321
capsule
1 mg
4 capsules
4 mg
4
BI 706321
capsule
1 mg
8 capsules
8 mg
13
BI 706321
capsule
5 mg
4 capsules
20 mg
7
BI 706321
capsule
20 mg
2 capsules
40 mg
1, 2, 9
Placebo*
oral solution
--
volume identical to active 
treatment
--
3, 4, 7, 
11,13
Placebo*
capsule
--
number identical to active 
treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
The oral solutions for dosing (active treatment and placebo) will be prepared by pharmacists 
or qualified pharmacy staff members or qualified medical study personnel at the trial site 
under the responsibility of the investigator according to the instructions provided in Appendix
10.1.
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. The investigator (or 
authorised designee) will administer the trial medication as an oral dose together with about 
240 mL of water to subjects who are in a sitting or standing position. For drug administration, 
the so-called four-eye principle (two-person rule) should be applied. For this, one authorised 
employee of the trial site should witness the administration of trial medication by the 
investigator (or authorised designee). In addition, two-person rule will be applied for solution 
reconstitution / preparation. 
Subjects will be kept under close medical surveillance until 24 h (dose groups < 4 mg) or 
until 48 h (dose groups ≥4 mg) after drug administration. During the first 4 h after drug 
administration, subjects are not allowed to lie down (i.e. no declination of the upper body of 
more than 45 degrees from upright posture except for medical examination) or to sleep. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 50 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Part II:
Part II of this trial will be performed following a 3-way cross-over design. All subjects will 
receive the 3 treatments in a randomised order. The treatments to be evaluated are outlined in 
Table 4.1.4: 2 below. 
Table 4.1.4: 2
Dosage and treatment schedule
Treatment
Substance
Formulation Unit strength
Dosage
Total  dose
T1 (Test 1)
BI 706321
Tablet
2 mg
2 tablets as one single dose on Day 
1 in the fasting state
4 mg
T2 (Test 2)
BI 706321
Tablet
2 mg
2 tablets as one single dose on Day 
1 following a high-fat, high-calorie 
breakfast
4 mg
R (Reference)
BI 706321
Capsule
1 mg
4 capsules as one single dose on 
Day 1 in the fasting state
4 mg
Administration of investigational medicinal product: The investigator (or authorised 
designee) will administer the trial medication as an oral dose together with about 240 mL of 
water to subjects who are in a sitting or standing position. For drug administration, the so-
called four-eye principle (two-person rule) should be applied. For this, one authorised 
employee of the trial site should witness the administration of trial medication.
Treatments R and T1: Administration of trial medication will be performed after subjects 
have fasted overnight; fasting is to start no later than 10 h before the scheduled dosing. 
Treatment T2: A high-fat, high-calorie meal will be served 30 min before drug 
administration. The subjects must completely consume the meal prior to drug intake. The 
composition of the standard high-fat, high-calorie meal is detailed in Table 4.1.4: 3; this meal 
is in compliance with the FDA guidance ‘Food-Effect Bioavailability and Fed 
Bioequivalence Studies’ [R03-2269]. For restrictions with regard to diet, see Section 4.2.2.2.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 51 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Table 4.1.4: 3
Composition of the high-fat, high-calorie meal (breakfast)
Ingredients
kcal
2 chicken eggs (whole content) for scrambled eggs1
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum2
984
1
Whole eggs or liquid egg may be used
2
The total caloric content is supplied approximately as following: 150 kcal as protein, 250 kcal as 
carbohydrate, and 500 to 600 kcal as fat. 
All treatments: Subjects will be kept under close medical surveillance until 24 h after drug 
administration. During the first 4 h after drug administration, subjects are not allowed to lie 
down (i.e. no declination of the upper body of more than 45 degrees from upright posture).
The treatments will be separated by a wash-out phase of at least 12 days.
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
Part I:
The trial is designed single-blind. The treatments administered (active or placebo) will be 
blinded to subjects, but will be known to the investigators (outcome assessors). Only the 
current dose level will be known to the subjects due to the rising dose design.
A single-blind design is considered acceptable because the potential bias in this type of study 
seems to be low and according to study procedures it is assured that the investigator's 
knowledge of the next treatment does not influence the decision to enter a subject.
All trial data will be handled open label. This means that trial functions of the sponsor are 
unblinded (including clinical trial leader, clinical trial manager, clinical research associate, 
data manager, statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug 
metabolism scientist as well as dedicated personnel of the trial site). 
Within the central ECG laboratory, the staff involved with interval measurements will be 
blinded with respect to the treatment and also with regard to the recording date and time as 
well as planned time points of the ECGs. The interval measurements for a given subject will 
be performed in a random and blinded sequence by a single technician.
Access to the randomisation schedule will be controlled and documented by a signed 
confidentiality statement, which will be stored in the TMF. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 52 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Part II:
Part II of this trial will be handled in an open-label fashion throughout (that is, during the 
conduct, including data cleaning and preparation of the analysis). This is considered 
acceptable because the potential for bias seems to be low and does not outweigh practical 
considerations.
Unblinding and breaking the code
4.1.5.2
As this trial will be conducted single-blind (Part I) and open (Part II), subjects’ treatment 
assignments will be known to investigators. Therefore, no emergency envelopes will be 
provided.
Packaging, labelling, and re-supply
4.1.6
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
Storage conditions
4.1.7
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
clinical trial manager (as provided in the list of contacts) is to be contacted immediately.
Drug accountability
4.1.8
The investigator or designee will receive the investigational drugs from the sponsor when the 
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority,  e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 53 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused trial medication will be disposed of locally by the trial site upon written 
authorisation of the Clinical Trial Leader. Receipt, usage, and disposal of trial medication 
must be documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES, 
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
Restrictions
4.2.2
Restrictions regarding concomitant treatment
4.2.2.1
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.
Paracetamol, diclofenac or other drugs with relevant hepatotoxicity should be avoided during 
the entire study.
Restrictions on diet and life style
4.2.2.2
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
Part I: From 1 h before drug intake until lunch, fluid intake is restricted to the water 
administered with the drug and an additional 240 mL of water served at 2 h and 4 h post-dose 
(mandatory for all subjects). From lunch on Day 1 until 24 hours post dose, fluid intake is 
restricted to 3000 mL. 
Part II: From 1 h before drug intake until lunch, fluid intake is restricted to the milk served 
with the breakfast (Treatment Test 2 only), 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 on Day 1 until 24 hours post dose, fluid intake is restricted to 3000 mL. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 54 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the administration of trial medication until after the last PK 
sample is collected.
Alcoholic beverages and poppy seeds containing products are not allowed from 3 days before 
the administration of trial medication until after the Day 8 ambulatory visit.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before administration of trial medication until discharge 
from the trial site.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the administration of trial medication until the end of trial examination. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion of trial medication will provide additional confirmation of 
compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 55 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
Physical examination
5.2.1
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history results not mandatory to be entered into CRF or 
to be reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR; oral body temperature in Part I only), 12-
lead ECG ( including rhythm strip of at least 15 minutes in Part I only), 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.
Vital signs
5.2.2
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap Pro 100,
 at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm, if possible. Oral body temperature will be measured at select 
time points (see Flow Chart).
Safety laboratory parameters
5.2.3
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. 
Reference ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 56 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Table 5.2.3: 1
Routine laboratory tests
Functional lab 
group
BI test name [comment/abbreviation]
A1
B1
C1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
Reticulocytes/Erythrocyte
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
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 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, 
absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands; Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
X
X
X
X
X
X
X
X
--
--
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
Haptoglobin
Ferritin
Uric Acid 
Cholesterol, total 
Triglyceride
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
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)
X
X
X
X
X
X
X
--
X
--
X
X
X
X
X
1 A, B, and C are different sets of laboratory values. The Flow Chart defines at which time point which set is to 
be investigated.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 57 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1 A, B, and C are different sets of laboratory values. The Flow Chart defines at which time point which set is to 
be investigated.
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests at screening only. Drug 
screening will be performed at screening and prior to dosing at Visit 2.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410,
 will be performed prior to each treatment period, and 
may be repeated at any time during the study at the discretion of an investigator or designee. 
The results will not be included in the CTR.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 58 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of 
drug screening tests. These tests will be performed at the trial site using M-10/14-PDT 
multiline test, or a comparable test system.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
Electrocardiogram
5.2.4
12-lead resting ECG
5.2.4.1
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System,
) at the time points given in the Flow Chart. Electrode placement will be performed 
according to the method of 
and
modified by
and
(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.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. The repeat ECGs are assigned to the respective 
scheduled time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database.
Storing
All ECGs will be stored electronically on the Muse Cardiology Information System (
 
.
Data transfer
For time points specified in the Flow Chart, ECGs will be transferred electronically to the 
central ECG lab 
) for evaluation.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 59 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Evaluation
a) Central ECG lab
Central ECG lab evaluation will be performed post-study per time point indicated in 
the Flow Chart. For baseline, all 3 ECGs will be evaluated.
This will include the determination of cardiac QRS-axis as assessed by the ECG 
machine’s algorithm as well as the intervals RR, PR, QRS and QT measured semi-
automatically.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will 
be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements no lead will be provided. After quality control, 
the fiducial point markings will be reviewed by the cardiologist assigned to the study.
For blinding arrangements see Section 4.1.5. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. For quality assurance and control of the measurements, all ECGs of a 
subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect 
accidental switching of leads and/or false subject assignments of the ECGs. After 
quality control, the fiducial point markings will be reviewed by the cardiologist 
assigned to the study. 
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
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 
computerised ECG system or their manual corrections by the investigators will be 
used. 
In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data transfer) for
cardiologic assessment by the central lab. In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
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. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 60 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Continuous ECG monitoring (Part I only)
5.2.4.2
Cardiac rhythm (including heart rate) will be monitored by means of continuous 3-lead ECG 
recording using the CARESCAPE Monitor B450
) for at 
least 15 min before drug administration (for baseline assessment) and for 4 h following drug 
administration). This continuous ECG monitoring supports the early detection of adverse 
events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the trial site. 
Beyond this clinical evaluation at the trial site, no further data collection or analyses are 
performed based on continuous ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial 
database. Abnormal findings during continuous ECG recording will be recorded as AEs if 
judged clinically relevant by the Investigator.
Assessment of adverse events
5.2.5
Definitions of adverse events
5.2.5.1
Adverse event
5.2.5.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.2.5.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 61 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.5.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.5.2.1, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.5.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.5.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are 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.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 62 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Intensity (severity) of AEs
5.2.5.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
5.2.5.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 63 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Adverse event collection and reporting
5.2.5.2
AE collection
5.2.5.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial:
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related AESIs 
of which the investigator may become aware of by any means of communication, 
e.g. phone call. Those AEs should, however, not be reported in the CRF
AE reporting to the sponsor and timelines
5.2.5.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 64 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Information required
5.2.5.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
Pregnancy
5.2.5.2.4
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.3.1
Date and clock times of drug administration and pharmacokinetic sampling will be recorded.
Exact times 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. as a result of 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.
Methods of sample collection
5.3.2
Blood sampling for pharmacokinetic analysis
5.3.2.1
For quantification of BI 706321 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venepuncture with a 
metal needle.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 65 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
second aliquot should contain the remaining plasma. The process from blood collection until 
transfer of plasma aliquots into the freezer should be completed in less than 60 min, with 
interim storage of blood samples in ice water or on ice. The time each aliquot was placed in 
the freezer will be documented. Until transfer on dry ice to the analytical laboratory, the 
aliquots will be stored upright at approximately -20°C or below at the trial site. The second 
aliquot will be transferred to the analytical laboratory after the bioanalyst has acknowledged 
safe arrival of the first aliquot. At the analytical laboratory, the plasma samples will be stored 
at approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 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 or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the CTR is 
archived.
Blood sampling for metabolism analysis (Part I only)
5.3.2.2
Additional K2-EDTA plasma samples for the identification of drug metabolites will be 
investigated in the 4 mg dose group. Based on the knowledge gained during the trial conduct, 
e.g. from preliminary PK results, the dose group may be modified to a different one. The 
change will be implemented via a non-substantial CTP amendment.
The blood samples will be drawn at the same time points as PK samples at Visit 2 (see Flow 
Chart). At each of these times, 2.7 mL blood will be needed for metabolite analysis. The 
blood samples will be processed in the same way as the PK samples (see Section 5.3.2.1)
Two plasma aliquots will be obtained and stored in polypropylene (PP) tubes. The first
aliquot (labelled as MIST-1 samples), should contain at least 0.5 mL plasma. The remaining
plasma will be the second aliquot (labelled as MIST-2 samples). 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 or below. 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 or below 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 a matrix and analyte may also be provided.
Plasma samples dedicated to metabolism investigation are transferred to:

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 66 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Phone: 
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
drug metabolism will be reported separately and will not be included in the CTR. The study 
samples will be discarded after completion of the experiments but not later than 5 years after 
the CTR has been archived. 
Urine sampling for pharmacokinetic analysis (Part I only)
5.3.2.3
A blank urine sample will be collected before administration of trial medication (within 3 h 
before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical 
interference by concomitant or rescue medication. 
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
2 L polyethylene (PE) containers and stored at room temperature. Subjects are told to empty 
their bladders at the end of each sampling interval. 
To avoid adsorption of the drug (its metabolites) to the container wall, 2 mL of 10% Tween 
20 solution will be added to each 2 L PE collection container prior to the start of urine 
sampling. The weight of the empty container will be determined, 2 mL of 10% Tween 20 will 
be added, and the weight of the container at the end of each sampling interval will be 
determined.
The urine weight/volume for each collection interval will be documented (however, no
correction for the specific gravity of urine is done, i.e. 1 L is defined to be equal to 1 kg).
Two 0.5 mL aliquots will be stored in polypropylene (PP) tubes for bioanalytical 
measurements. If more than one collection container is used in a sampling interval, the 
contents of all containers have to be mixed before aliquots are prepared. Mixing should be 
done by transferring the entire content of all collection containers into a single PE/PP or glass 
container, and stirring the mixed fractions for about 1 min (manually or using a stir bar or 
other stirring device made of PE, PP, Teflon or glass). Generally, the collection container 
should be shaken upon addition of every urine fraction to ensure proper distribution of Tween 
and urine.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned collection time. Further information, such as matrix and analyte may also be 
provided. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
approximately -20°C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the 
urine samples will be stored at approximately -20°C or below until analysis. 
After completion of the trial, the urine samples may be used for further methodological 
investigations (e.g., for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 67 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the CTR has been archived.
Additional blood sample for stability-testing (Part I only)
5.3.2.4
In order to assess the stability of the analyte in whole blood, one additional blood sample will 
be obtained from all subjects of dose group 4 mg. Based on the knowledge gained during the 
trial conduct, e.g. from preliminary PK results, the chosen timing or dose group may be 
changed to a different one. The change will be implemented via a non-substantial CTP 
amendment.
Approximately 2.4 mL blood will be drawn from an antecubital or forearm vein into two 
1.2 mL K2-EDTA-blood drawing tubes at the time indicated in the Flow Chart (immediately 
after the drawing of a regular blood PK sample, which means that no additional venous 
puncture will be necessary).
From each K2-EDTA tube, one aliquot will be generated:

One aliquot (‘stability reference’) will be centrifuged within 10 min after collection. 
Centrifugation will last for approximately 10 min (at approximately 2000 g to 4000 g 
and 4 to 8 °C), plasma will be separated and transferred into a freezer

The second aliquot (‘stability test’) will be stored for about 4 h at room temperature 
and ambient light conditions (storage time must be documented) and will then be 
centrifuged and stored as for the first aliquot. 
At a minimum, the aliquots should be labelled with BI trial number, administered drug, 
subject number, planned sampling time, and whether the sample is the ‘stability reference’ or 
‘stability test’ sample.
Until transfer to the analytical laboratory, both aliquots will be stored at 
approximately -20 °C or below at the trial site. Both aliquots will be provided to the 
responsible bioanalyst together with the information about sample handling (i.e., storage time 
of stability test sample at room temperature). After receipt, the aliquots will be stored at the 
bioanalytical laboratory at approximately -20°C or below until analysis.
The results of the analysis of these samples will not be reported in the CTR but will be used
for bioanalytical assay validation and therefore included in the corresponding method 
validation report. The remaining sample volume will be discarded at latest upon completion
of the method validation report.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 68 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Pharmacokinetic - pharmacodynamic relationship
5.3.4
An analysis of the relationship between pharmacokinetic and pharmacodynamic parameters
may be investigated in an exploratory manner, see Sections 7.3.4 and 7.3.5.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 69 of 102
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
5.5
BIOBANKING
Not applicable.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 70 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
5.6
OTHER ASSESSMENTS
5.7
APPROPRIATENESS OF MEASUREMENTS
Safety and pharmacokinetic measurements performed during this trial are standard 
measurements. The scheduled safety measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Sections 2.1.3, 
2.2.2.2, and 5.3 are generally used assessments of drug exposure. The biomarkers outlined in 
Section 5.4 are of exploratory nature.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 71 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests 
will be ± 15 min for the first 4 h after trial drug administration, ± 30 min thereafter on Day 1, 
± 60 min on Day 2, and ± 120 min from 48 h post administration onwards.
If several activities are scheduled at the same time point in the Flow Chart, ECG should be 
the first and meal the last activity. 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. In part II subjects may have there dinner together at 07.00 pm.
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 the determination of 
pharmacokinetic parameters.
Starting from 48 h post administration a deviation from the scheduled time for PK and 
biomarker sampling of ± 120 min is acceptable.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Screening period
6.2.1
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study. For information 
regarding laboratory tests (including drug and virus screening), ECG, vital signs, and 
physical examination, refer to Sections 5.2.1 to 5.2.4. Genotyping will be performed in those 
volunteers whose genotypes have not been previously determined (for details, see Section 
5.6.1). 
Treatment period
6.2.2
Part I:
Each subject will receive one dose of trial medication (BI 706321 or placebo) at Visit 2.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 72 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Trial medication will be taken orally by each subject under direct supervision of the 
investigator or his designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
Study participants will be admitted to the trial site in the morning of Day 1 and kept under 
close medical surveillance for at least 24 h (dose groups < 4 mg) or for at least 48 h (dose 
groups ≥4 mg) following drug administration. The subjects will then be allowed to leave the 
trial site after formal assessment and confirmation of their fitness by the investigator or his 
designee. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, refer to Flow Chart and Section 5.3.2. 
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
Part II:
Each subject is expected to participate in 3 treatment periods, which will be separated by a 
wash-out period of at least 12 days. 
On Day 1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2. 
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart (Part II). For details on times of all other trial 
procedures, refer to the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from screening until the end of trial examination.
Follow-up period and trial completion
6.2.3
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.1 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 73 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
Part I:The main objectives of this trial will be assessed by calculating descriptive statistics for 
safety and tolerability as well as for PK parameters, which will be compared between the 
treatment groups. Further analyses of these endpoints comprise the power model for 
assessment of dose proportionality. 
Part II: The relative bioavailability of BI 706321 after administration of tablets and capsules 
under fasted conditions will be compared with each other (comparison A: Test 1 / Reference). 
Furthermore the effect of food (Test 2) on the tablet bioavailability will be investigated 
(comparison B: Test 2 / Test 1).
7.2
NULL AND ALTERNATIVE HYPOTHESES
Part I: 
It is not planned to test any statistical hypotheses in this study.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the study; i.e., confidence intervals are considered as interval estimates for 
effects.
Part II: 
The relative bioavailability of BI 706321 tablets compared with BI 706321 capsules will be 
estimated by the ratios of the geometric means (Test 1/Reference; Test 2/Test 1), and their
corresponding 2-sided 90% confidence intervals (CIs) will be provided. This method
corresponds to the two one-sided t-test procedure, each at the 5% significance level. Since the
main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
For both tial parts, statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the subjects received. The treated set will be 
used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol violation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 74 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Adherence to the protocol will be assessed by the trial team. Important protocol violation
(IPV) categories will be specified in the TSAP, IPVs will be identified no later than in the 
Report Planning Meeting, and the IPV categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 706321 will be calculated 
according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma and urine (in part I of the trial) concentration data and parameters of a subject will be 
included in the statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion 
due to a protocol violation relevant to the evaluation of PK (to be decided no later than in the 
Report Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, 
based on the criteria specified below). Exclusion of a subject’s data will be documented in the 
CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine (in part I) concentrations and/or parameters of a subject will be considered 
as non-evaluable, if for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
In addition, plasma concentrations and/or parameters of a subject will be considered as 
nonevaluable in the BA part of the trial, if for example

The subject experiences emesis at any time during the labelled dosing interval.

A predose concentration is >5% Cmax value of that subject.
Plasma and urine (in part I) concentration data and parameters of a subject which is flagged 
for exclusion will be reported with its individual values but will not be included in the 
statistical analyses. Descriptive and inferential statistics of PK parameters will be based on 
the PKS.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 75 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
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 as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report). 
Primary endpoint analyses
7.3.1
Primary analyses 
Part I
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards.
The analysis will be based on the treated set (TS) and will be descriptive in nature.
Part II
The primary endpoints (refer to Section 2.1.2) will be calculated according to the BI Standard 
Operating Procedure (SOP) ‘Standards and processes for analyses performed within Clinical
Pharmacokinetics/ Pharmacodynamics’ (001-MCS-36-472).
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include
effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect ‘subject within sequences’ will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 76 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
where s ~ N(0, σ
) i. i. d. , e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the
residual error from the ANOVA and quantiles from the t-distribution. These quantities will
then be back-transformed to the original scale to provide the point estimate and 90% CIs for
each endpoint.
 
 
Secondary endpoint analyses
7.3.2
Primary analyses
Part I:
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively. Analyses will 
be performed for the parent drug.
Part II:
The PK endpoint AUC0-∞will be assessed statistically using the same methods as described
for the primary endpoint in part II.
 
 
 
 
 
 
 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 77 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Safety analyses
7.3.4
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2 based on 
the treated set (TS). Safety analyses will be descriptive in nature and will be based on BI 
standards. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 78 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
For all analyses the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. The placebo group in the safety evaluation 
will consist of all subjects treated with placebo, regardless of the dose group in which they 
were treated. The test 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.
Measurements (such as ECGs, 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 intake of trial medication (part I) 
or prior to first intake of trial medication (part II) will be assigned to the screening period, 
those between the (first) trial medication intake and end of REP (see Section 1.2.2) will be 
assigned to the treatment period. Events occurring after the REP but prior to trial termination
date (part I and II) or prior to second or third treatment period (part II) will be assigned to
’follow-up’. These assignments including the corresponding time intervals will be defined in 
detail in the TSAP. Note that AEs occurring after the last per protocol contact but entered 
before database lock will be reported to Pharmacovigilance only and will not be captured in 
the trial database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the 
TSAP in order to provide summary statistics for other than above periods, 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 5.2.5.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as possibly clinically significant values will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline. 
Part I only: The ECG variables QT, HR, QTcF, QTcB, PR, QRS, and RR obtained from the 
centralised evaluation of 12-lead ECG recordings will be the basis for the derivation of 
quantitative and categorical ECG endpoints. These endpoints and their analyses will be 
described in the TSAP.
 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 79 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
7.4
PRELIMINARY ANALYSES
Part I:
A preliminary analysis of PK parameters (AUC0-24 and Cmax of BI 706321), provided as 
individual values and geometric means, will be performed for each dose level prior to 
proceeding to the next higher level, with the exceptions described below under “Notes”. 
Notes: 
-
Data from at least 4 subjects on active treatment need to be available at the respective 
dose levels.
-
For escalations up to Dose Group 3 (4 mg), preliminary PK data are not required. This 
is acceptable because the predicted plasma exposure parameters up to a dose of 4 mg 
(see Section 1.3.3.1) are sufficiently below the maximum acceptable exposure.
In contrast to the final PK
 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. Therefore, minor deviations may occur between preliminary and final results. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification information. The 
preliminary results will be distributed to the investigator and the trial team. 
Depending on the results of available preliminary PK analyses and the tolerability and safety 
of the compound, changes to the dosing schedule (e.g., additional low or intermediate doses) 
and additional PK preliminary analysis may be performed if requested by the Clinical Trial 
Leader, the investigator, or Trial Clinical Pharmacokineticist. Preliminary PK results will not 
be reported in the CTR.
No inferential statistical interim analysis is planned. However, after completion of each dose 
group the investigator (or his or her deputy) is allowed to postpone further dose progression 
until a preliminary analysis of the data has been performed.
Part II:
No preliminary or interim analysis is planned.
7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 80 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Pharmacokinetics
7.5.2
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
In part I of the trial, the first 4 subjects of each dose level will not be randomised to maintain 
a treatment sequence of active-placebo (Cohort 1) active-active (Cohort 2) due to safety 
reasons. The remaining 4 subjects of each dose level (i.e., Cohort 3) will be randomised in a 
3:1 ratio (test treatment to placebo). More details to the cohorts can be found in Section 3.1.
In part II of the trial, subjects will be randomised to one of the 3 treatment sequences R-T1-
T2, T1-T2-R or T2-R-T1 in a 1:1:1 ratio. The block size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
Part I: It is planned to include a total of 64 subjects in this trial. 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.
Part II: It is planned to enter a total of 12 subjects in Part II of the trial. The planned sample 
size is not based on a power calculation but is considered sufficient to achieve the aims of 
this exploratory trial part. With this sample size, the following precision in estimating the 
ratio of geometric means (test/reference) can be expected with 95% probability. Precision is 
defined as the ratio of upper CI limit to the relative BA estimate. Note that the precision is 
independent of the actual ratio of geometric means.
For this First-in-Man trial, no information on intra-subject variability is available. Therefore,
Table 7.7: 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 mean ratios T/R in the three-period three-sequence crossover design.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 81 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Table 7.7: 1
Precision that can be expected with 95% tolerance probability and
illustrative two-sided 90% confidence intervals around the ratios of
geometric means (T/R) for different gCVs in a 3x3 crossover trial 
(N=12)
gCV [%]
Precision upper CI
/ relative BA
estimate
Ratio [%]*
Lower CI [%]
Upper CI [%]
20
1.191
80
67.17
95.28
1.191
100
83.97
119.10
1.191
125
104.96
148.87
1.191
150
125.95
178.64
1.191
200
167.93
238.19
25
1.243
80
64.38
99.41
1.243
100
80.47
124.27
1.243
125
100.59
155.33
1.243
150
120.71
186.40
1.243
200
160.94
248.53
30
1.296
80
61.74
103.65
1.296
100
77.18
129.57
1.296
125
96.47
161.96
1.296
150
115.77
194.35
1.296
200
154.36
259.14
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(µT)/exp(µR).
The expected 90% confidence interval limits in the table were derived by
CI limit.//01,23401 = 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.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 82 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
8.
THE CALCULATION WAS PERFORMED AS DESCRIBED
BY JULIOUS [R11-5230] USING R VERSION 
3.4.2.INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the responsible Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) and competent authority (CA) according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or his delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 83 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the
Phase I unit – the 
validated ClinBaseTM system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
Source documents
8.3.1
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number,
and social security number) have properly been removed or redacted to ensure subject
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 84 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
Direct access to source data and documents
8.3.2
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
Storage period of records
8.3.3
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 85 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
Collection, storage and future use of biological samples and corresponding 
8.5.1
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g., biomarker proposal, analysis plan and 
report) ensures compliant usage

If applicable, a fit for purpose approach will be used for assay/equipment validation 
depending on the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 86 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state.
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 of 
 
under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of clinical trial managers (CTM), Clinical 
Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
Analyses of BI 706321 concentrations in plasma and urine will be performed at
 
 
 analyses will be performed at the Department of

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 87 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Biomarker investigations will be performed at the Department of 
or at a laboratory 
appointed by BI. 
The digitally recorded 12-lead ECGs 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 or a contract research 
organization appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 88 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
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.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval   
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.   
Rockville: 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); 2005.
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005). 
2005.
R16-0366
E14 Implementation Working Group. ICH E14 guideline: the clinical 
evaluation of QT/QTc interval prolongation and proarrhythmic potential for   
non-antiarrhythmic drugs: questions & answers (R3) (current version dated 
10 December 2015). 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/
Guidelines/Efficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 
29 January 2015) ; Geneva: International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use; 2015.
R16-5289 
Tigno-Aranjuez JT, Benderitter P, Rombouts F, Deroose F, Bai X, Mattioli 
B, et al. In vivo inhibition of RIPK2 kinase alleviates inflammatory disease. 
J Biol Chem 2014;289(43):29651-29664.
R17-1239
Chin AI, Dempsey PW, Bruhn K, Miller JF, Xu Y, Cheng G. Involvement 
of receptor-interacting protein 2 in innate and adaptive immune responses.   
Nature 2002;416:190-194.
R19-0610
Lupfer C, Thomas PG, Anand PK, Vogel P, Milasta S, Martinez J, et al. 
Receptor interacting protein kinase 2-mediated mitophagy regulates 
inflammasome activation during virus infection. Nature Immunol 
2013;14(5):480-488.
R19-0611
Marcinek P, Jha AN, Shinde V, Sundaramoorthy A, Rajkumar R, 
Suryadevara NC, et al. LRRK2 and RIPK2 variants in the NOD 2-mediated 
signaling pathway are associated with susceptibility to Mycobacterium 
leprae in Indian populations. Plos One 2013;8(8):e73103.
R19-0652 
Conradt L, Godl K, Schaab S, Tebbe A, Eser S, Diersch S, et al. Disclosure 
of erlotinib as a multikinase inhibitor in pancreatic ductal adenocarcinoma.   
Neoplasia (New York) 2011;13(11):1026-1034.
R94-1529
Chow SC, Liu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 89 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
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.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c26475781 
 Investigator’s Brochure BI 706321 Crohn’s Disease.
n00253840
 Two-week oral (gavage) toxicity and toxicokinetics 
study in the rat.
n00259952
 BI 706321: Four-Week Oral (Gavage) Toxicity and Toxicokinetics 
Study in the Rat Followed by an Eight-Week Recovery Period.
n00262560
 BI 706321: Cardiovascular Safety Pharmacology Evaluation by 
Oral Gavage to Male Telemetry-Instrumented Conscious Monkeys.
n00266137
 Prediction of BI 706321 Pharmacokinetics and 
Therapeutic Dose in Human.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 90 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
10.
APPENDICES
10.1
RECONSTITUTION INSTRUCTION(S)
Drug supplies overview
10.1.1
a) BI 706321 capsules for oral solution 20 mg packed in 10-count polypropylene bottles 
(80 mL) closed with polypropylene screw cap with desiccant
b) Solvent for Oral Solution 80 mL (Tartaric acid 0.5%) provided in 100 mL amber glass 
bottles
Required equipment and dosing aids - overview
10.1.2
a) Mechanical (orbital) shaker for bottles (e.g. Bühler Type KL2)
b) Dosing dispensers/syringes and bottle adapters 
For the withdrawal of respective volume aliquots from the oral solution, amber 
BAXA/BAXTER ExactaMed Syringe dispensers and BAXA/BAXTER bottle 
Adapters should be stocked at the trial site. 
The syringe size should be as close as possible to the required dose volume.
ExactaMed Oral Dispenser Tip Caps are to be used to close the filled syringes prior to 
administration.
Possible syringes: 

BAXA/BAXTER ExactaMed Oral amber dispenser 1 mL

BAXA/BAXTER ExactaMed Oral amber dispenser 3 mL 

BAXA/BAXTER ExactaMed Oral amber dispenser 5 mL

BAXA/BAXTER ExactaMed Oral amber dispenser 10 mL 

BAXA/BAXTER ExactaMed Oral amber dispenser 20 mL 
Only CE certified syringes are to be used.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 91 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Reconstitution procedure
10.1.3
Reconstitution procedure for the preparation of the active BI 706321 oral solution 
10.1.3.1
0.25 mg/mL
Necessary materials
10.1.3.1.1
a) BI 706321 capsules for oral solution 20 mg packed in 10-count polypropylene bottles 
(80 mL) closed with polypropylene screw cap with desiccant.
b) Solvent for Oral Solution 80 mL (Tartaric acid 0.5%) provided in 100 mL amber glass 
bottles.
Reconstitution procedure
10.1.3.1.2
Step 1: 
Take the amber glass bottle containing Solvent for Oral Solution (Tartaric 
acid 0.5%) and remove the white screw cap from the bottle. 
Step 2:
Open the 10-count propylene bottle containing BI 706321 capsules for oral 
solution 20 mg and transfer one single capsule into the bottle with Solvent for 
Oral Solution (Tartaric acid 0.5%). Only one capsule 20 mg will be used out 
of one propylene bottle.
Step 3:
Close the amber glass bottle containing Solvent for Oral Solution (Tartaric 
acid 0.5%) and one BI 706321 capsule for oral solution 20 mg with its white 
screw cap.
Step 4:
Mount the amber glass bottle in a horizontal recumbent position on a 
mechanical shaker (e.g. Bühler Typ KL2).
Step 5:
Let the bottle shake orbitally for 20 min at 350 rpm. Control visually that the 
capsule and the powder are completely dissolved (clear to almost clear 
solution). After dissolution, the bottle contains the drug product BI 706321 
Oral Solution 0.25 mg/ml.
Preparation of the solvent for oral solution for use as placebo solution
10.1.3.2
Necessary materials
10.1.3.2.1
a) Solvent for Oral Solution 80 mL (Tartaric acid 0.5%) provided in 100 mL amber glass 
bottles.
Procedure
10.1.3.2.2
The Solvent for Oral Solution will directly be used as placebo solution. Due to the 
amber color of the dispenser, sufficient blinding is obtained if the procedure is carried 
out separated from the healthy volunteer. 

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 92 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Withdrawal of oral solution
10.1.4
Withdrawal procedure of the BI 706321 oral solution
10.1.4.1
Step 1:
Take the 100 mL amber glass bottle containing reconstituted BI 706321 Oral 
Solution 0.25 mg/mL. Remove the white screw cap of the bottle and mount the 
blue bottle adapter on the bottle. 
Step 2:
Take the respective BAXA/BAXTER dispenser, connect the dispenser with the 
bottle adapter and turn the bottle upside down. Withdraw the desired volume of 
BI 706321 Oral Solution 0.25 mg/mL.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 93 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Step 3:
Close the BAXA/BAXTER dispenser with an ExactaMed Oral Dispenser Tip 
Cap. 
The allowable dose range is 0.1 mg – 5 mg resulting in a filling volume of 0.4 mL to 20 mL.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 94 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Withdrawal of placebo oral solution
10.1.5
Withdrawal procedure of the placebo oral solution
10.1.5.1
Step 1:
Take the 100 mL amber glass bottle with Solvent for Oral Solution 80 mL
(Tartaric acid 0.5%). Remove the white screw cap of the bottle and mount the 
blue bottle adapter on the bottle. 
Step 2:
Take the respective BAXA/BAXTER dispenser, connect the dispenser with the 
bottle adapter and turn the bottle upside down. Withdraw the desired volume of 
Solvent for Oral Solution to be used as placebo.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 95 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Step 3:
Close the BAXA/BAXTER dispenser with an ExactaMed Oral Dispenser Tip 
Cap. 
The allowable filling volume is 0.4 mL to 20 mL.
In-use stability
10.1.6
The in-use stability of the reconstituted solution and for the placebo solution is 24 hours after 
its preparation, incl. storage in BAXA/BAXTER dispensers until administration. Further 
details are provided on the CTS labels.
Mode of application
10.1.7
Withdraw the required volume aliquot to obtain the required doses. Use BAXA/BAXTER 
dispensers for dose withdrawal/administration at a volume size as close as possible to the 
volume to be withdrawn.
Please note that it is the responsibility of the Clinical Trial Leader to assure that appropriate 
supplies are used for administration of a dose, based on guidance in the clinical trial protocol, 
and dosing is limited to the allowed dosing range for a specific dose formulation as stated in 
this reconstitution instruction.
General remarks – important
10.1.8
Because of lacking analytical coverage beyond the instructed preparation procedure of the 
different dose formulations, no further (external) dilutions of the reconstituted solutions are 
allowed.
The present reconstitution instruction does not contain any advice how to withdraw a specific 
dose from the reconstituted solutions. The specific dose volumes to be withdrawn from the 
described dose formulations in order to obtain a required dose will be calculated and 
documented by TMCP in the Clinical Trial Protocol (CTP) and subsequent documents (e.g. 
work sheets).

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 96 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1 
Date of amendment
15 May 2019
EudraCT number
EU number
2019-000888-25
BI Trial number
1425-0001
BI Investigational Medicinal 
Product(s)
BI 706321
Title of protocol
Safety, tolerability, and pharmacokinetics of single 
rising oral doses of BI 706321 in healthy male 
subjects (single-blind, randomised, placebo-
controlled, parallel group design)
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, Flow Chart, Sections 1.3.3.1, 1.4.4, 3.1, 
3.3, 4.1.1, 4.1.4, 7.3.2, 7.7
2) Flow Chart, Sections 3.3.4.3, 5.2.4.1, 
3) Flow Chart, Sections 1.4.3, 2.2.2.1, 3.3.2, 3.3.3, 
5.2.1, 5.2.2, 
4) Sections 3.1, 3.3.5
5) Sections 1.3.3.2, 3.1, 4.1.4
6) Flow Chart
7) Section 5.4
Description of change
1) Addition of dose groups 0.6 mg and 2 mg. 
-
For logistical reasons (agreement with other 
trial documentation), these additional dose 
groups receive dose group numbers 9 and 11. 
-
Number of subjects planned to be entered into 
the trial adjusted to 80 (maximal 96 in case of 
additional dose groups)
2) Change of dose escalation stopping criterion 5 in 
Section 3.3.4.3: Escalation will now be stopped if 
at least 2 subjects on active treatment at one dose 
level demonstrate a confirmed QTc increase from 
baseline mean of greater than 60 ms.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 97 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
-
For facilitation of implementation, all ECGs 
are done as single ECGs and not as triplicates.
3) Addition of oral body temperature to vital signs at 
select time points. Consideration of body 
temperature in inclusion criterion 1 and exclusion 
criterion 1.
4) At minimum, safety and tolerability data of 5 
instead of 4 actively dosed subjects at the current 
dose level are needed for dose escalation to the 
next higher dose level
5) Dose groups 40 mg and 60 mg will only be dosed 
after approval of a substantial amendment. 
6) Minor change of planned times of pre-dose 
procedures on Day 1: Drug/alcohol screening 
at -2 h instead of at -1:30 h; urine PK pre-dose 
value at -1:30 h instead of at -2 h.
7) First paragraph: mRNA may be analysed instead 
of “will”
Rationale for change
1) Request from competent authority / IEC
2) Request from competent authority / IEC
3) Request from competent authority / IEC
4) Request from competent authority / IEC
5) Request from competent authority / IEC
6) Logistical reasons (This allows that random 
number is allocated after drug / alcohol test and 
before urine PK)
7) Alignment of wording with the second-last 
paragraph of the same Section (“[…] depending 
on these results a decision will be made […]”)

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 98 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
11.2
GLOBAL AMENDMENT 2
Date of amendment
12 June 2019
EudraCT number
EU number
2019-000888-25
BI Trial number
1425-0001
BI Investigational Medicinal 
Product(s)
BI 706321
Title of protocol
Safety, tolerability, and pharmacokinetics of single 
rising oral doses of BI 706321 in healthy male 
subjects (single-blind, randomised, placebo-
controlled, parallel group design)
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) 5.3.2.3
2) 5.4.1
Description of change
1) Change of 10% Tween 20 volume per urine 
container from 10 mL to 2 mL
2) Specification of transport conditions and time 
window.
Rationale for change
1) According to validation results, 2 mL 10% 
Tween 20 solution is needed
2) Information is needed for organisational 
reasons.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 99 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
11.3
GLOBAL AMENDMENT 3 
Date of amendment
07 Aug 2019
EudraCT number
EU number
2019-000888-25
BI Trial number
1425-0001
BI Investigational Medicinal 
Product(s)
BI 706321
Title of protocol
Safety, tolerability, and pharmacokinetics of single 
rising oral doses of BI 706321 in healthy male 
subjects (single-blind, randomised, placebo-
controlled, parallel group design)
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
Synopsis, 1.3.3.1, 3.1, 4.1.1, 4.1.4, 7.7
Description of change
Escalation of dose levels will be changed :
Old: 0.3 - 0.6 - 1.2 - 2 - 4 – 8 – 15 – 25 – 40 – 60 mg
New: 0.3 - 0.6 - 1.2 - 2 - 4 – 8 – 20 – 40 mg
Rationale for change
-
Bioavailability is worse than expected
-
After escalation from 0.6 mg to 1.2 mg 
exposure increased less than 35%

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 100 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
11.4
GLOBAL AMENDMENT 4 
Date of amendment
06 Sep 2019
EudraCT number
EU number
2019-000888-25
BI Trial number
1425-0001
BI Investigational Medicinal 
Product(s)
BI 706321
Title of protocol
Safety, tolerability, and pharmacokinetics of single 
rising oral doses of BI 706321 in healthy male 
subjects (single-blind, randomised, placebo-
controlled, parallel group design)
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
Synopsis, 1.3.3.1, 3.1, 4.1.1., 4.1.4
Description of change
With the exception of the total number of dose 
groups all changes from Amendment 3 have been 
removed in this Amendment 4. Thus the original
dose escalation schedule of CTP Version 3.0 will be 
valid again: 0.3 - 0.6 - 1.2 - 2 - 4 - 8 - 15 - 25 - 40 -
60 mg 
Rationale for change
Global Amendment 3 specified conditions for 
changing the escalation schedule. These conditions 
are not given. Based on preliminary PK-data, dose 
escalating from 8 mg to 20 mg would increase the 
exposure of BI 706321 more than factor 2.Therefore,
the Global Amendment 4 is written to return to the 
original dose escalation schedule (given in CTP 3.0).
The return to the original escalation schedule via 
Non-Substantial Amendment under the given 
conditions has been described in Amendment 3.

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 101 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
11.5
GLOBAL AMENDMENT 5 
Date of amendment
16 Dec 2019 
EudraCT number
EU number
2019-000888-25
BI Trial number
1425-0001
BI Investigational Medicinal 
Product(s)
BI 706321
Title of protocol
Safety, tolerability, and pharmacokinetics of single 
rising oral doses of BI 706321 in healthy male 
subjects (single-blind, randomised, placebo-
controlled, parallel group design)
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, Flow chart, Sections 1.2.3, 1.3, 1.4.3, 
1.4.4. 1.4.5, 2.1.1, 2.1.2,  2.1.3, 2.2.2, 3.1, 3.2, 3.3.2, 
3.3.5, 4.1.1, 4.1.2, 4.1.4, 4.1.5, 4.2.2.2, 5.2.1, 5.2.4.2, 
5.3.2, 5.4, 6.1, 6.2.2, 7.1, 7.2, 7.3, 7.4, 7.6, and 7.7
3.) Section 1.2.2
Description of change
1.) To implement Part II to the study protocol. 
3.) Residual effect period is reduced to 8 days
Rationale for change
1.) Global Amendment 5 has been written to add a 
Part II to the trial protocol. In Part II the relative 
bioavailability of a tablet (compared to the capsule 
tested in Part I) and the effect of food on tablet 
bioavailability should be investigated to prepare 
upcoming trials in patients (e.g. to advise a suitable 
dosing regimen).
3.) Based on safety and PK-data obtained in Part I

Boehringer Ingelheim
07 July 2020
BI Trial No.: 1425-0001
c26547838-07
Trial Protocol
Page 102 of 102
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
11.6
GLOBAL AMENDMENT 6 
Date of amendment
07 July 2020 
EudraCT number
EU number
2019-000888-25
BI Trial number
1425-0001
BI Investigational Medicinal 
Product(s)
BI 706321
Title of protocol
Safety, tolerability, and pharmacokinetics of single 
rising oral doses of BI 706321 in healthy male 
subjects (single-blind, randomised, placebo-
controlled, parallel group design)
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
Section 3.3.3
Description of change
A new exclusion criterion has been added to cover 
pandemic COVID-19.
Rationale for change
Request of competent authority.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26547838
7.0
clinical-trial-protocol-version-7
Safety, tolerability, and pharmacokinetics of single rising oral doses of BI 706321 in
healthy male subjects (single-blind, randomised, placebo-controlled, parallel group
design) 
Author-Clinical Trial Leader
08 Jul 2020 13:28 CEST
Author-Trial Clinical
Pharmacokineticist
08 Jul 2020 13:44 CEST
Approval-Team Member Medicine
08 Jul 2020 14:41 CEST
Author-Trial Statistician
08 Jul 2020 17:40 CEST
Approval-
Medicine
09 Jul 2020 15:36 CEST
Verification-Paper Signature
Completion
13 Jul 2020 08:39 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26547838
7.0