Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 39
Healthy volunteers: yes

Brief summary:
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics (PK) of BI 706321 in healthy male and female subjects following oral administration of multiple rising doses for 14 days.

Detailed description:

Arms:
arm 1: Subjects were orally administered a single daily dose of 2 x 1 capsule of 1 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. The trial medication was administered with about 240 millilitres (mL) of water after an overnight fast of at least 10 hours (h). arm 2: Subjects were orally administered a single daily dose of 1 capsule of 5 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. The trial medication was administered with about 240 millilitres (mL) of water after an overnight fast of at least 10 hours (h). arm 3: Subjects were orally administered a single daily dose of 1 capsule of 5 milligrams (mg) and 3 capsules of 1 mg of BI 706321 on Day 1 and from Day 6 to 19. Subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 mL of water after an overnight fast of at least 10 hours (h). arm 4: Subjects were orally administered a single daily dose of 2 capsules of 5 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. Subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 mL of water after an overnight fast of at least 10 hours (h). arm 5: Subjects were orally administered a single daily dose of matching placebo to BI 706321 capsules on Day 1 and from Day 6 to 19. Three out of the seven subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 millilitres (mL) of water after an overnight fast of at least 10 hours (h).

Interventions: intervention 1: BI 703621 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: BI 703621 intervention 2: Placebo intervention 3: Midazolam

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c29586669-04
EudraCT No.
2019-004351-36
BI Trial No.
1425-0002
BI Investigational
Medicinal Product
BI 706321
Title
Safety, tolerability, and pharmacokinetics of multiple rising oral 
doses of BI 706321 in healthy male and female subjects (double-
blind, randomised, placebo-controlled, parallel group design)
Lay Title
A study to test how well healthy men and women tolerate 
different doses of BI 706321.
Clinical Phase
I
Clinical Trial 
Leader
Tel.:
Fax:
Principal 
Investigator
Phone: 
Fax:
Status
Final Protocol (Revised Protocol (based on global amendment 3))
Version and Date
Version: 4.0
Date: 02 June 2020
Page 1 of 101
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
03 December 2019
Revision date
02 Jun 2020
BI trial number
1425-0002
Title of trial
Safety, tolerability, and pharmacokinetics, of multiple rising oral doses of BI 
706321 in healthy male and female subjects (double-blind, randomised, placebo-
controlled, parallel group design)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
Effects of multiple rising doses of BI 706321 on safety, tolerability, and 
pharmacokinetics will be assessed in healthy volunteers.
Trial objectives
To investigate safety, tolerability, and pharmacokinetics following multiple rising 
doses of BI 706321; 
Trial endpoints
Primary endpoint to assess safety and tolerability of BI 706321 is the percentage 
of subjects with drug-related adverse events
Secondary endpoints:
After the last dose, 
AUCτ,ss and Cmax,ss, Cmin,ss, RA,AUC, and RA,Cmax of BI 706321
Trial design
Double-blind, randomised within dose groups, placebo-controlled parallel-group 
design
Number of subjects 
total entered
40*
each treatment
10 per dose group (8 on BI 706321 and 2 on placebo) 
* Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 40, but is not to exceed 60.
Diagnosis
Not applicable


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Trial Protocol
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Main criteria
for inclusion
Healthy male/female* subjects, age of 18 to 55 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive) 
* Female subjects of non-childbearing potential
Test product
BI 706321 Capsules (strengths: 1 mg, 5 mg)
dose
BI 706321 2 mg, once daily 
BI 706321 5 mg, once daily
BI 706321 8 mg, once daily
BI 706321 10 mg, once daily
mode of admin.
Probe drug
dose
Oral with 240 mL of water after an overnight fast of at least 10 h
Midazolam for injection used as oral solution
75 µg, once daily
Oral with 240 mL of water after an overnight fast of at least 10 h
Comparator product
Matching placebo to BI 706321
dose
Not applicable
mode of admin.
Oral, once daily with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
BI 706321 or Placebo: Single dose on day 1 followed by 14 days with once daily
multiple doses from day 6;
 
Statistical methods
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 706321 will be explored using a regression model. A 
90% confidence interval (CI) for the slope will be computed. Linearity index will 
be estimated using a linear model providing a two-sided 90% CI. Attainment of 
steady state will be analysed by a repeated measures linear model for trough 
concentrations of BI 706321 with dose as an additional covariate, if permissible.


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BI Trial No.: 1425-0002
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Trial Protocol
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FLOW CHART DOSE GROUPS 2 AND 5 MG
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment7
Safety laboratory
Biobanking
PK blood 
8, 10
PK urine
10, 11
 
12-lead ECG
Vital signs (BP, PR, T)
Questioning for AEs and 
concomitant therapy 6
1
-28 to -3
Screening (SCR)1
x
x
x
2
-1
Admission to trial site14
x
x
1
-1:00
07:30
Allocation to treatment2
x5
x
x2
x2
x2
x2,9,12
x2
x2
0:00
08:00
First drug administration
▲
0:30
08:30
x
│
1:00
09:00
x
│
x9
x
2:00
10:00
240 mL fluid intake
x
│
x2
x9
x
x
3:00
11:00
x
│
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
┼
x9
x
x
5:00
13:00
x
│
6:00
14:00
x
x
│
x2
8:00
16:00
Snack3
x
┼
x9
x
x
10:00
18:00
Dinner3
x
│
12:00
20:00
Snack3
x
┼
x9
x
x 
2
24:00
08:00
Breakfast3
x
x
x
┼
x2
x9
x
x
36:00
20:00
x
│
x9
x
3
48:00
08:00
Discharge from trial site
x
┼
x9
x
4
72:00
08:00
Ambulatory visit
x
▼13
5
96:00
08:00
Ambulatory visit
x
▼
x
x
5
Admission to trial site14
6
120:00
08:00
Drug administration
x2
x
x2
x2
x2
x2
x2
7
144:00
08:00
Drug administration
x2
x2
x2
8
168:00
08:00
Drug administration
x2
x
x2
x2
x2
9
192:00
08:00
Drug administration
x2
x2
x2
x2
10
216:00
08:00
Drug administration
x2
x2
x2
x2
11
240:00
08:00
Drug administration
x2
x,2
x2
x2
12
264:00
08:00
Drug administration
x2
x
x2
x2
x2
13
288:00
08:00
Drug administration
x2
x2
x2
x2
14
312:00
08:00
Drug administration
x2
x2
x2
x2
15
336:00
08:00
Drug administration
x2
x2
x2
x2
16
360:00
08:00
Drug administration
x2
x2
x2
17
384:00
08:00
Drug administration
x2
x2
x2
x2
18
408:00
08:00
Drug administration 
x2
x
x2
x2
x2
19
431:45
07:45
x8,2
x2
x9,2
x2
x2
432:00
08:00
Last drug administration
▲
432:30
08:30
x8
│
433:00
09:00
x8
│
x9
x
434:00
10:00
240 mL fluid intake 
x8
│
x
x9
x
x
435:00
11:00
x8
│
436:00
12:00
240 mL fluid intake, thereafter 
lunch3
x8
┼
x9
x
x
437:00
13:00
x8
│


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Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment7
Safety laboratory
Biobanking
PK blood 
8, 10
PK urine
10, 11
 
12-lead ECG
Vital signs (BP, PR, T)
Questioning for AEs and 
concomitant therapy 6
438:00
14:00
x8
│
x
440:00
16:00
Snack 3
x8
┼
x9
x
x
442:00
18:00
Dinner3
x8
│
444:00
20:00
Snack3
x8
┼
x9
x
x 
446:00
22:00
x8
│
20
456:00
08:00
Light breakfast
x
x
x8
┼
x
x9
x
x
21
480:00
08:00
Discharge from trial site
x8
┼
x9
x
x
22
504:00
08:00
Ambulatory visit 
x
x8
▼13
x
x
x
23
528:00
08:00
Ambulatory visit
x8
▼
x
24
552:00
08:00
Ambulatory visit
x8
x
x
x
x
25
576:00
08:00
Ambulatory visit
x8
x
26
600:00
08:00
Ambulatory visit
x
x8
x
x
3
27
624:00
08:00
End of trial (EoTrial) 
examination4
x
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the procedures are to be performed and completed within the 3 h prior to drug administration
on day 1. On all other days the 3h window only applies to safety assessments. 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 fluid and meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs, and concomitant therapies. 
5.
Only Pharmacogenetic samples will be collected.
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.
On all non intensive PK days, standard light breakfast will be served approx. 1 h after the dose. On all study days 
standard meals (lunch, snack, dinner, snack) will be given approx. 4, 8, 10 and 12 hours post dose.
8.
9.
The ECG recording has to be performed in triplicate at this time.
10. Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK 
data) including addition of samples and visits as long as the total blood volume drawn does not exceed 500 mL per 
subject.
11. 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, 24-48, 48-72 and 72-96 h on days 1 
and 19 for all doses above 2mg.
12. At baseline (i.e. Day 1, prior to drug administration) 3 triplicate ECGs are recorded within approximately one hour. The 
recordings should be separated by at least 15 minutes. 
13. Urine samples are to be collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24, 24-48, and 
48-72 on days 1 and 19 for 2mg dose group.
14. SARS-CoV-2 PCR test will be performed shortly (within 72 hours) before admission to the site.


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FLOW CHART DOSE GROUPS 8 AND 10 MG
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment7
Safety laboratory
Biobanking
PK blood 
9
PK urine
10
 
12-lead ECG
Vital signs (BP, PR, T)
Questioning for AEs and 
concomitant therapy 6
1
-28 to -3
Screening (SCR)1
x
x
x
-2
Admission to trial site12
x
x
-1
-24:30
7:30
x
-24:00
8:00
Administration of Midazolam
-23:45
8:15
x
-23:30
8:30
x
-23:00
9:00
x
-22:30
9:30
x
-22:00
10:00
240 mL fluid intake
x
-21:30
10:30
x
-21:00
11:00
x
-20:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
-18:00
14:00
x
-16:00
16:00
Snack 3
x
1
-1:00
07:30
Allocation to treatment2
x5
x
x2
x2
x2
x2,8,11
x2
x2
0:00
08:00
First drug administration
▲
0:30
08:30
x
│
1:00
09:00
x
│
x8
x
2:00
10:00
240 mL fluid intake
x
│
x
x8
x
x
3:00
11:00
x
│
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
┼
x8
x
x
5:00
13:00
x
│
6:00
14:00
x
x
│
x
8:00
16:00
Snack3
x
┼
x8
x
x
10:00
18:00
Dinner3
x
│
12:00
20:00
Snack3
x
┼
x8
x
x 
2
24:00
08:00
Breakfast3
x
x
x
┼
x
x8
x
x
36:00
20:00
x
│
x8
x
3
48:00
08:00
Discharge from trial site
x
┼
x8
x
4
72:00
08:00
Ambulatory visit
x
┼
5
96:00
08:00
Ambulatory visit
x
▼
x
x
5
Admission to trial site12
6
120:00
08:00
Drug administration
x2
x
x2
x2
x2
x2
x2
7
144:00
08:00
Drug administration
x2
x2
x2
8
168:00
08:00
Drug administration
x2
x
x2
x2
x2
9
192:00
08:00
Drug administration
x2
x2
x2
x2
10
216:00
08:00
Drug administration
x2
x2
x2
x2
11
240:00
08:00
Drug administration
x2
x,2
x2
x2
12
264:00
08:00
Drug administration
x2
x
x2
x,2
x2
13
288:00
08:00
Drug administration
x2
x2
x2
x2
14
312:00
08:00
Drug administration
x2
x2
x2
x2
15
336:00
08:00
Drug administration
x2
x2
x2
x2


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Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment7
Safety laboratory
Biobanking
PK blood 
9
PK urine
10
 
12-lead ECG
Vital signs (BP, PR, T)
Questioning for AEs and 
concomitant therapy 6
16
360:00
08:00
Drug administration
x2
x2
x2
17
384:00
08:00
Drug administration
x2
x2
x2
x2
18
408:00
08:00
Drug administration 
x2
x
x2
x
x2
19
431:45
07:45
x2
x
x2
x8,2
x2
x2
432:00
08:00
Last drug administration and 
Administration of Midazolam
▲
│
432:15
08:15
x
│
432:30
08:30
x
x
│
433:00
09:00
x
x
│
x8
x
433:30
09:30
x
│
434:00
10:00
240 mL fluid intake 
x
x
│
x
x8
x
x
434:30
10:30
x
│
435:00
11:00
x
x
│
436:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
┼
x8
x
x
437:00
13:00
x
│
438:00
14:00
x
x
│
x
440:00
16:00
Snack 3
x
x
┼
x8
x
x
442:00
18:00
Dinner3
x
│
444:00
20:00
Snack3
x
┼
x8
x
x 
446:00
22:00
x
│
20
456:00
08:00
Light breakfast
x
x
x
┼
x
x8
x
x
21
480:00
08:00
Discharge from trial site
x
┼
x8
x
x
22
504:00
08:00
Ambulatory visit 
x
x
┼
x
x
x
23
528:00
08:00
Ambulatory visit
x
▼
x
24
552:00
08:00
Ambulatory visit
x
x
x
x
x
25
576:00
08:00
Ambulatory visit
x
x
26
600:00
08:00
Ambulatory visit
x
x
x
x
3
27
624:00
08:00
End of trial (EoTrial) 
examination4
x
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the procedures are to be performed and completed within the 3 h prior to drug administration
on day 1. On all other days the 3h window only applies to safety assessments. 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 fluid and meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs, and concomitant therapies. 
5.
Only Pharmacogenetic samples will be collected.
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.
On all non intensive PK days, standard light breakfast will be served approx. 1 h after the dose. On all study days 
standard meals (lunch, snack, dinner, snack) will be given approx. 4, 8, 10 and 12 hours post dose.
8.
The ECG recording has to be performed in triplicate at this time.


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9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK 
data) including addition of samples and visits as long as the total blood volume drawn does not exceed 600 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, 12-24, 24-48, 48-72 and 72-96 h on days 1 
and 19.
11. At baseline (i.e. Day 1, prior to drug administration) 3 triplicate ECGs are recorded within approximately one hour. The 
recordings should be separated by at least 15 minutes. 
12.
SARS-CoV-2 PCR test will be performed shortly (within 72 hours) before admission to the site.


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BI Trial No.: 1425-0002
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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART DOSE GROUPS 2 AND 5 MG..............................................4
FLOW CHART DOSE GROUPS 8 AND 10 MG............................................6
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................17
Clinical experience in humans.............................................................19
1.2.5
Residual Effect Period..........................................................................21
1.2.6
Drug product.........................................................................................22
1.2.7
Midazolam .............................................................................................22
1.2.8
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.4
BENEFIT - RISK ASSESSMENT ...................................................................23
Summary of safety measures ...............................................................30
1.4.1
Overall benefit-risk assessment ...........................................................32
1.4.2
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 33
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......33
Main objectives......................................................................................33
2.1.1
Primary endpoint..................................................................................33
2.1.2
Secondary endpoint ..............................................................................33
2.1.3
Safety and tolerability..............................................................33
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..........................................................................................39
3.3
SELECTION OF TRIAL POPULATION ......................................................39


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Main diagnosis for trial entry..............................................................39
3.3.1
Inclusion criteria...................................................................................39
3.3.2
Exclusion criteria ..................................................................................40
3.3.3
Withdrawal of subjects from treatment or assessments ...................42
3.3.4
Discontinuation of trial treatment............................................42
3.3.4.1
Withdrawal of consent to trial participation ............................43
3.3.4.2
Discontinuation of the trial by the sponsor..............................43
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................................................................46
4.1.2
Method of assigning subjects to treatment groups ............................46
4.1.3
Drug assignment and administration of doses for each subject .......47
4.1.4
Blinding and procedures for unblinding ............................................48
4.1.5
Blinding48
4.1.5.1
Unblinding and breaking the code...........................................49
4.1.5.2
Packaging, labelling, and re-supply ....................................................49
4.1.6
Storage conditions.................................................................................50
4.1.7
Drug accountability ..............................................................................50
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................50
Other treatments and emergency procedures....................................50
4.2.1
Restrictions............................................................................................51
4.2.2
Restrictions regarding concomitant treatment .........................51
4.2.2.1
Restrictions on diet and life style.............................................51
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................51
5.
ASSESSMENTS....................................................................................... 53
5.1
ASSESSMENT OF EFFICACY.......................................................................53
5.2
ASSESSMENT OF SAFETY............................................................................53
Physical examination ............................................................................53
5.2.1
Vital signs...............................................................................................53
5.2.2
Safety laboratory parameters..............................................................53
5.2.3
Electrocardiogram................................................................................57
5.2.4
12-lead resting ECG.................................................................57
5.2.4.1
Assessment of adverse events...............................................................59
5.2.5
Definitions of adverse events...................................................59
5.2.5.1


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Adverse event ............................................................59
5.2.5.1.1
Serious adverse event ................................................59
5.2.5.1.2
AEs considered ‘Always Serious’.............................60
5.2.5.1.3
Adverse events of special interest .............................60
5.2.5.1.4
Intensity (severity) of AEs.........................................61
5.2.5.1.5
Causal relationship of AEs ........................................61
5.2.5.1.6
Adverse event collection and reporting ...................................62
5.2.5.2
AE collection.............................................................62
5.2.5.2.1
AE reporting to the sponsor and timelines ................62
5.2.5.2.2
Information required..................................................63
5.2.5.2.3
Pregnancy ..................................................................63
5.2.5.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................63
Assessment of pharmacokinetics .........................................................63
5.3.1
Methods of sample collection...............................................................63
5.3.2
Blood sampling for pharmacokinetic analysis.........................63
5.3.2.1
Urine sampling for pharmacokinetic analysis..........................65
5.3.2.3
5.5
BIOBANKING ...................................................................................................67
5.6
OTHER ASSESSMENTS .................................................................................67
Pharmacogenomic evaluation..............................................................67
5.6.1
Methods and timing of sample collection............................................68
5.6.2
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................68
6.
INVESTIGATIONAL PLAN.................................................................. 69
6.1
VISIT SCHEDULE............................................................................................69
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................69
Screening period....................................................................................69
6.2.1
Treatment periods.................................................................................69
6.2.2
Follow-up period and trial completion ...............................................70
6.2.3
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 71
7.1
STATISTICAL DESIGN – MODEL ...............................................................71
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................71
7.3
PLANNED ANALYSES....................................................................................71


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Primary endpoint analyses...................................................................72
7.3.1
Secondary endpoint analyses ...............................................................73
7.3.2
Safety analyses.......................................................................................76
7.3.4
Pharmacokinetic - pharmacodynamic analysis..................................77
7.3.5
7.4
INTERIM ANALYSES .....................................................................................77
7.5
HANDLING OF MISSING DATA ..................................................................77
Safety......................................................................................................77
7.5.1
Pharmacokinetics..................................................................................78
7.5.2
7.6
RANDOMISATION ..........................................................................................78
7.7
DETERMINATION OF SAMPLE SIZE ........................................................78
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 79
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................79
8.2
DATA QUALITY ASSURANCE .....................................................................80
8.3
RECORDS..........................................................................................................80
Source documents .................................................................................80
8.3.1
Direct access to source data and documents.......................................81
8.3.2
Storage period of records.....................................................................81
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................82
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......82
Collection, storage and future use of biological samples and 
8.5.1
corresponding data ...............................................................................82
8.6
TRIAL MILESTONES .....................................................................................82
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................83
9.
REFERENCES......................................................................................... 85
9.1
PUBLISHED REFERENCES...........................................................................85
9.2
UNPUBLISHED REFERENCES.....................................................................86
10. APPENDICES .......................................................................................... 87
10.1
ADVERSE EVENTS FROM FIRST-IN-HUMAN TRIAL 1425-0001.........87
10.2
DRUG SUPPLIES USED FOR DILUTION AND DOSING.........................91
Drug supplies overview.........................................................................91
10.2.1
Required equipment and dosing aids – overview...............................91
10.2.2
Dilution procedure................................................................................92
10.2.3
In-use stability.......................................................................................92
10.2.4
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 93


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11.1
GLOBAL AMENDMENT 1 .............................................................................93
11.2
GLOBAL AMENDMENT 2 .............................................................................94
11.3
GLOBAL AMENDMENT 3 ...........................................................................101


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
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
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’)
CTL
Clinical Trial Leader
CTM
Clinical Trial Monitor  
CTP
Clinical trial protocol
CTR
Clinical trial report
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 


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EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
GCP
Good Clinical Practice
GLP
Good laboratory Practice
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
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
NOD
Nucleotide Oligomerization Domain
PD
Pharmacodynamic
PE
Polyethylene
PK
Pharmacokinetic
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)


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RA,AUC
accumulation ratio based on AUC0-τ
RA,Cmax
accumulation ratio based on Cmax,ss
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
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


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1.
INTRODUCTION
BI 706321 is a Receptor-Interacting Protein Kinase-2 (RIPK2) inhibitor candidate, in an early 
clinical development for the indication of Crohn’s disease. In this study, multiple rising doses 
of BI 706321 will be given for the first time to humans. Safety, tolerability, and 
pharmacokinetics of multiple 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. 


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Clinical experience in humans
1.2.5
At the time of the submission of this Trial 1425-0002, preliminary results are available from
the Phase Ia first-in-human Trial 1425-0001, conducted in Germany. This was a partially -
randomised, single-blind, placebo-controlled parallel group trial to investigate safety, 
tolerability, and pharmacokinetics (PK) single rising doses (SRD) of BI 706321 administered 
as oral solution, reconstituted from 20 mg capsules (0.3, 0.6 and 1.2 mg dose groups) and 
capsules (2, 4, 8, 15 and 25 mg dose groups) to 46 healthy male adult subjects as compared to 
placebo (n=15).


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Residual Effect Period
1.2.6
 
This is the period after the last dose 
with measurable drug levels and/or pharmacodynamic effects still likely to be present.


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Drug product
1.2.7
For a more detailed description of the BI 706321 profile, please refer to the current 
Investigator’s Brochure (IB) [c26475781].
Midazolam
1.2.8
Midazolam is a sensitive substrate of CYP3A4, used both in vitro and in vivo as a probe drug 
for CYP3A4 drug interactions. Absorption is rapid, with maximum concentrations reached 
around 15 to 30 min. Clearance is also rapid, with an elimination half-life of 1.5 to 2.5 hours. 
The PK of midazolam is dose proportional over a range of at least 0.1 µg to 3 mg 
[R17-3022]. A microdose is typically defined as 1% of the pharmacologically active dose or 
100 µg, whichever is less. Therapeutic dose of oral midazolam is 7.5 - 15 mg in adults; 
division of the lower dose by 100 would result in 75 µg. For further information, refer to the 
summary of product characteristics [R20-0572].
1.3
RATIONALE FOR PERFORMING THE TRIAL
Crohn’s Disease patients not responding to conventional therapy of orally administered 
aminosalicylates (e.g. 5-ASA), glucocorticoids and immunomodulatory agents (azathioprine 
or 6-MP), are usually treated with biologic TNFα inhibitors (TNFi). Induction therapy with a 
TNFi results in clinical remission in fewer than 50% of patients, and only about 25% of 
patients achieve mucosal healing. Other biologics (vedolizumab, ustekinumab) offer 
alternative additional treatments options for patients who fail TNFi, but response rates to 
these agents do not exceed those associated with TNFi treatment. Medical treatment options 
for fistulizing and fibrotic disease remain limited. Thus, a substantial unmet need remains for 
oral agents with greater efficacy than current therapies, either as a standalone therapy or in 
combination with existing therapies.
As described in Section 1.1, 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. 
Following favorable safety, tolerability and PK demonstrated after single dose administration 
to healthy male volunteers in first-in-human Trial 1425.0001, BI 706321 is now being
advanced to the next step of clinical development. 
The aim of Trial 1425-0002 is to investigate the safety, tolerability and pharmacokinetics of 
BI 706321 in healthy male and female volunteers. Within each dose group, all actively 
treated individuals will receive the same doses of BI 706321 once daily for 14 days. The next 
higher dose level will only be administered if the treatment in the preceding dose group 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.


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In order to be able to address future scientific questions, subjects will be asked to voluntarily 
donate biospecimens for banking (please see Section 5.5). If the patient agrees, banked 
samples may be used for future biomarker research and drug development projects, e.g. to 
identify patients that are more likely to benefit from a treatment or experience an adverse 
event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby 
better match patients with therapies.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 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. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising and, in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
ECG electrodes may cause local and typically transient skin reactions.
The total volume of blood withdrawn per subject during the entire study in the 2 and 5 mg 
dose groups will not exceed the volume of a normal blood donation (500 mL). The total 
volume of blood withdrawn per subject in the 8 and 10 mg dose groups slightly exceeds the 


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volume of a normal blood donation (500 mL) and is estimated to be approximately 550 mL. 
However, no health-related risk to healthy subjects is expected from withdrawal of this
volume of blood over the entire study duration of about 1.5 months.
Selection of doses in this trial
Repeat dose studies in cynomolgus monkeys (most sensitive species) resulted in adverse 
effects to the hematopoietic system (decreases to peripheral blood platelets and non-
regenerative/ poorly regenerative erythroid responses, observed as decreases in circulating 
red blood cell parameters and reticulocytes and decreased bone marrow erythroid cellularity). 
Therefore, the maximum acceptable systemic exposure of BI 706321 (exposure cap) for this 
trial is defined as follows and is similar to the exposure cap implemented in the preceding 
singe rising dose trial:
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. That means, a dose level 
will only be administered if expected gMean values for Cmax,ss and AUCss do not exceed these 
exposure values.
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).
Based on exposure caps, preliminary safety, tolerability and PK data from Trial 1425-0001 
and PK modelling the following 4 dose groups have been selected for this Trial 1425-0002: 2, 
5, 8 and 10 mg once daily. Table 1.4: 1 presents the predicted BI 706321 geometric mean 
exposure values based on PK modelling. The probability of exceeding the exposure cap for 
Cmax,ss in an individual subject is 0% for all dose groups. The probability of exceeding the 
exposure cap for AUCss in an individual subject is 0% for 2 and 5 mg dose groups, 0.3% for 8 
mg and 2.3% for 10 mg dose group. These low probabilities for exceeding the exposure caps 
set by NOAEL are considered acceptable for the current trial with customary safety and 
tolerability monitoring procedures.
Table 1.4: 1
Predicted BI 706321 exposure values
Dose group
2 mg qd
5 mg qd
8 mg qd
10 mg qd
Escalation factor from
previous dose level


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Modelling of the exploratory target engagement biomarker (MDP induced TNF-α) data from 
Trial 1425-0001 was conducted to predict the TNF-α reduction from baseline under current 
dose groups.
 
Considering the novelty of the target, exploratory 
nature of the target engagement biomarker, and low probability of exceeding the exposure 
caps, selection of 10 mg as a high dose is justified. Even if the future dose ranging studies in 
Crohn’s disease patients confirm the accuracy of efficacy prediction of this target 
engagement assay and demonstrate efficacy plateau in 8-10 mg qd range, the safety and 
tolerability of future studies with renal and hepatic impairment patients. 
Drug-related risks and safety measures
Specific RIPK2 inhibition is a novel mechanism of action for which there is no precedent
clinical data for multiple dose administration in humans. Single doses of 0.3 – 25 mg BI 
706321 were well tolerated by healthy subjects in the first-in-human Trial 1425-0001 (refer 
to Section 1.2.5 for details). Below are the theoretical risk considerations based on literature 
and pre-clinical studies.
Increased susceptibility to infection
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
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 
signalling pathways (i.e. Toll-like receptor signalling) intact.
In Trial 1425-0001, two subjects reported nasopharyngitis and one subject reported rhinitis 
on active treatment, but there was no dose dependency. Considering the prevalence of these 
infections in general population and lower number of placebo subjects in that trial, observed 
infections are not considered as safety signal. One subject in 25 mg dose group reported a 
generalized sensation of cold about 10 hours after dosing that lasted for 15 min (see details in 
Section 1.2.5).


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Risk mitigation:

Subjects with immunological disorder (who might be more susceptible to infection),
as well as subjects tested positive for HIV, HBV, HCV and TB at screening are 
excluded from trial participation (see Section 3.3.3). 

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 by 
exposure caps (see Section 1.4 Selection of doses in this trial).

Oral body temperature is measured at select time points (see Flow Chart).
Gastrointestinal function
In Trial 1425-0001, two subjects reported loose stool and watery stool on active treatment (at 
8 and 25 mg, both assessed as drug related). Considering the prevalence of diarrhea in 
general population and lower number of placebo subjects in that trial, there is no sufficient 
evidence that for diarrhea to be considered as safety signal.
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)

Subjects will be asked at pre-defined time points for AEs (see Flow Chart) and will be 
instructed to report AEs spontaneously.
Central nervous system function
In Trial 1425-0001, an episode of mild dizziness has been observed in one subject in the 
15 mg dose group which spontaneously resolved without sequelae. 
Risk mitigation: 

Subjects will be in-house at the trial site under close medical observation for the 
whole treatment duration until 48 hours after last drug administration (see 
Flow Chart). They will only be allowed to leave the trial site after formal assessment 


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and confirmation of their fitness by the investigator or 
 designee. If required, in-
house observation period may be prolonged.

Subjects will be asked at pre-defined time points for AEs (see Flow Chart) and will be 
instructed to report AEs spontaneously. 
Cardiovascular system
Clinical monitoring did not show any relevant changes of ECG-parameters, BP and PR vital 
signs in Trial 1425-0001. Centralized QTc measurement evaluation is still ongoing.
Risk mitigation:

Subjects with relevant findings in BP, PR or ECG at Screening, cardiovascular 
disorders, history of relevant orthostatic hypotension, fainting spells or blackouts, use 
of drugs that might prolong the QT/QTc interval, marked (Section 3.3.3), or subjects 
with additional risk factors for Torsade de Pointes arrhythmia (Section 3.3.3) are 
excluded from trial participation.

A dose escalation stopping criterion based on QT/QTc increase has been defined 
(Section 3.3.4.3,).

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 the 
whole duration of the treatment until 48 hours after drug administration (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.


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Effects to hematopoietic system
Risk mitigation:

For definition of maximum acceptable exposure based on NOAEL in the 4-week GLP 
monkey study see Section 1.2.3, 1.2.5.

For safety margins see Section 1.2.5

Subjects with Hb, platelets and neutrophils values below lower limit of normal range 
at screening will be excluded from trial participation

Oral body temperature is measured at select time points (see Flow Chart)

Potential changes to hematology parameters (red blood cell parameters, reticulocytes, 
platelets, and leukocytes) will be monitored (see Flow Chart and Section 5.2.3).
Effects to the liver


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Based on preliminary evaluation, no relevant changes in liver function laboratory assessments 
were noted in Trial 1425-0001.
Risk mitigation: 

Subjects with liver enzymes (ALT, AST) exceeding upper limit of normal will be 
excluded from trial participation (Section 3.3.3). 

Liver enzymes (ALT, AST) will be measured before, during 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.
Other toxicity at very high plasma exposures in animals
In Trial 1425-0001, one subject in 25 mg dose group (No. 
) reported a generalized 
sensation of cold and had concurrent transient increase in CRP (see details in Section 1.2.5).
Risk mitigation:

Subjects are protected from these findings by safety margins (see Sections 1.2.3, 
1.2.5)

White blood cell count and differential will be monitored (see Section 5.2.3)

Subjects will be in-house at the trial site under close medical observation for the 
whole duration of the treatment until at least 48 hours after drug administration (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.

Frequent ECG and vital signs including body temperature measurements during the 
time of expected relevant exposure (see Flow Chart).

CRP values will be monitored.

Subjects will be asked at pre-defined time points for AEs (see Flow Chart) and will be 
instructed to report AEs spontaneously. 
Genotoxicity, reproductive and developmental toxicity


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Risk mitigation:

Only female subjects of non childbearing potential and male subjects will participate 
in this study.

Concerning the embryo-fetal risk posed from treatment of male subjects with BI 
706321, where it is theoretically possible that relevant systemic concentrations may 
be achieved in women of child-bearing potential (WOCBP) from exposure to seminal
fluid, male subjects need to use barrier contraception (condom) or abstinence (see 
Section 3.3.3).
Phototoxicity
BI 706321 is not likely to be phototoxic at clinically relevant doses. 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.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.5.1.4, adverse events of special interest.
Drug-drug interactions
Summary of safety measures
1.4.1
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 


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preclinical studies. Escalation factors between dose steps decrease at higher doses. For 
details see Sections 1.2.3, 1.2.4, and 1.2.5 including subsections. 
o
A maximum acceptable human exposure has been defined based on toxicity findings 
(see Section 1.4). Dose escalation is guided by preliminary analysis of BI 706321 
single dose PK (Cmax and AUC0-24). 
-
A dose level will only be administered if estimated (predicted) gMean values 
for Cmax,ss and AUCtau,,ss do not exceed the maximum acceptable human 
exposure (see Sections 1.4 and 7.4 and Section 3.3.4.3, dose escalation 
stopping criterion 7). 
-
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 6).
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 the last drug 
administration of a dose group and dosing of the subsequent dose group is 7 days for 
escalation 
o
Stringent inclusion 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 8 days after last drug administration. These examinations include 
extensive standard safety laboratory examinations (see Flow Chart (time points) and 
Section 5.2.3 (test details). 
o
Frequent 12-lead ECG and vital signs measurements at time points as described in the 
Flow Chart are planned.
o
Subjects in the 2 and 5 mg dose groups will be confined to the trial site starting from 
day -1, and subjects in the 8 and 10 mg dose group will be confined to the trial site 
starting from day -2 (treatment with oral microdose of midazolam) for the whole 
duration of the drug administration phase until at least 48 hours after the last drug 
administration (see Flow Chart). 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
Male subjects with WOCBP partner have to use barrier contraception (condom) or 
abstinence as detailed in Section 3.3.3.
o
WOCBP will be excluded from this study.


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Overall benefit-risk assessment
1.4.2
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 in early 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 and women non child bearing potential.
 
 
 (see also Section 1.2.2, 1.2.3).
Clinical data from the first-in-man study evaluating the single doses of BI 706321 up to 
25 mg, did not reveal any unexpected safety signals.
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


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics
(PK) of BI 706321 in healthy male and female subjects following oral administration of 
multiple rising doses for 14 days.
Primary endpoint
2.1.2
The primary endpoint for assessment of safety and tolerability of BI 706321 is the percentage 
of subjects with drug-related adverse events.
Secondary endpoint
2.1.3
The following pharmacokinetic parameters will be determined if feasible:
After the last dose of the multiple dose segment:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)

Cmin,ss (minimum concentration of the analyte in plasma at steady state over a uniform 
dosing interval τ)

RA,Cmax (accumulation ratio based on Cmax,ss)

RA,AUC (accumulation ratio based on AUC0-τ)
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)


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
Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate, body temperature)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This multiple-rising dose phase I trial is designed as double-blind, randomised (within dose 
groups), placebo-controlled, parallel group comparison.
It is planned to include a total of 40 healthy male and female subjects in the trial. The 
subjects will be assigned to 4 groups consisting of 10 subjects per group; the groups will be 
dosed sequentially (see Table 3.1: 1). The investigator (after consultation with the sponsor) 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 40 but is not to exceed 60. Such changes may be 
implemented via non-substantial CTP amendments.
Within each dose group, 8 subjects will receive BI 706321 and 2 will receive placebo. Only 
one dose is tested within each dose group. 
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
Daily dose (mg)
2
5
8
10
Number of subjects
10
10
10
10
Subjects receiving placebo
2
2
2
2
Subjects receiving BI 706321
8
8
8
8
The groups will be dosed consecutively in ascending order, and a time interval of at least 7 
days will be maintained between the last drug administration to subjects in the previous dose 
group and the first multiple drug administration to subjects in the subsequent dose group. The 
decision to treat the next dose group will be based upon safety, tolerability, and 
pharmacokinetic data of all the preceding dose groups. The next dose group will only be 
implemented 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 3.3.4.2).


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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 3.3.4.2).
At minimum, data from 6 subjects on active drug need to be available for escalation to a 
higher dose. The minimum data set for review consists of the following:

AEs in the current and preceding dose groups up to at least 48 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 in the current and preceding dose groups up to at least 48 h 
post dosing

Vital signs in the current and preceding dose groups up to at least 48 h post dosing

Clinical laboratory tests in the current and preceding dose groups up to at least 72 h 
post dosing

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.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For multiple-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.
Double-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 level
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 multiple rising dose trials involving healthy volunteers to include a placebo 
group to control for safety and tolerability effects of the trial medication. Each dose group 
consists of 10 subjects, with 8 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. Eight subjects per active treatment group are generally considered to be sufficient 
for the exploratory evaluation of safety, tolerability and pharmacokinetics. 
After the first dose (single dose segment), a sufficient wash-out period will be included 
before the second dose (first dose of the multiple dose segment) is administered. This will 
allow for appropriate calculation of pharmacokinetic parameters after a single dose 
administration and for inter-subject comparison with pharmacokinetic parameters at steady 
state.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 40 healthy male and female subjects will enter the study. The actual number 
of subjects entered may exceed the total of 40 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 and postmenopausal or surgically sterilised female subjects will be 
included in the trial because no data on reproductive toxicology are available at this time.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
Main diagnosis for trial entry 
3.3.1
The study will be performed in healthy subjects.
Inclusion criteria
3.3.2
Subjects will only be included in the trial if they meet the following criteria:


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1. Healthy male or female subjects according to the assessment of the investigator, as based 
on a complete medical history including a physical examination, vital signs (BP, PR, 
temperature), 12-lead ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive, at screening) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive, at screening) 
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, 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 45 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract 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 30 days (or 5 half-lives 
(whichever longer)) 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 of more than 10 cigarettes or 3 cigars or 3 pipes per day
14. Inability to refrain from smoking while in-house stay
15. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for
males), and unwillingness/inability to refrain from intake of alcoholic beverages from 48 
hours prior to the trial medication administration and until Day 7 post trial medication 
administration.


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16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or 
any other relevant ECG finding at screening
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. ALT (alanine transaminase), AST (aspartate transaminase), or creatinine exceed upper 
limit of normal range at screening, confirmed by a repeat test
24. Hb, platelets and neutrophils below lower limit of normal range at screening, confirmed 
by a repeat test
25. Positive result for HIV, HBV, and HCV infection at screening.
26. History of TB or positive finding in IGRA.
Female subjects will not be allowed to participate, if any of the following apply:
27. Not surgically sterilised⃰or not postmenopausal, defined as at least 1 year of spontaneous 
amenorrhea without an alternative medical cause (in questionable cases a blood sample 
with simultaneous levels of FSH above 30 U/L and estradiol below 20 ng/L is 
confirmatory)
28. Positive pregnancy test
29. Lactation
⃰Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
Male subjects will not be allowed to participate, if any of the following apply:
30. 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.
For study restrictions, refer to Section 4.2.2.


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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. If the discontinuation occurs 
before the end of the REP (see Section 1.2.6), the discontinued subject should if possible be 
questioned for AEs and concomitant therapies at or after the end of the REP in order to 
ensure collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject.
WOCBP are excluded in this trial. In very unlikely case of pregnancy in this clinical trial the 
following procedures are to be followed. If it is known that a subject becomes pregnant 
during the trial, administration of the trial medication is to be stopped immediately, and the 
subject is to be removed from the trial. The subject is to be followed until she has given birth 
or until the end of the pregnancy. The subject’s data are to be collected until the end of the 
trial (last visit of last subject) and reported in the CTR. For reporting of pregnancy and 
associated events, refer to Section 5.2.5.2.4.
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. An AE or clinically significant laboratory change or abnormality occurs that the 
investigator assesses as warranting discontinuation of treatment. This may include cases 
of: 

sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP 
>180/100 mmHg),

clinically relevant changes in ECG requiring intervention,

moderate to severe acute infection, 


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
fever lasting longer than 24 hours, or

unexplained clinically relevant hepatic enzyme or CRP elevation, or decrease 
in red blood cell count, reticulocytes, or thrombocytes at any time during the 
trial. These respective laboratory tests need to be repeated and drug 
administration continued only if the repeat test is within normal range and in 
the opinion of the investigator it is safe to continue the drug administration.  
6. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
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
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. Dose escalation will be terminated if 50% of 
the subjects at one dose level show drug-related and clinically relevant adverse events of 
moderate or severe intensity, or if at least one drug-related serious adverse event is 
reported.
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. a QTc increase of greater than 60 ms from 
baseline in connection with absolute QTc greater than 500 ms, as confirmed by a repeat 
ECG recording
6. Dose escalation will be stopped, if the measured Cmax,ss or AUCtau,ss of at least 1 subject  
exceeds the exposure thresholds of 


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7. Dose escalation will be stopped if the estimated gMean exposure of the next higher dose 
group is expected to exceed a 
 
In this case, additional dose level 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).
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
Replacement of subjects
3.3.5
If some subjects do not complete the trial, the Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. A replacement subject will be assigned a unique trial subject number, and will be 
assigned to the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products will be supplied by BI Pharma GmbH & Co. KG
Identity of the Investigational Medicinal Products
4.1.1
The characteristics of the test product are given below:
BI 706321 Capsules 1 mg
Substance:
BI 706321
Pharmaceutical formulation: Capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
1 mg
Posology:
2-0-0 (DG 1), 
3 (1mg) +1 (5mg) – 0 – 0 (DG 3)
Route of administration:
oral
Duration of use:
1 day single dose and 14 days q.d. dosing
BI 706321 Capsules 5 mg
Substance:
BI 706321 
Pharmaceutical formulation: Capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology:
1-0-0 (DG 2), 2-0-0 (DG 4),
3 (1mg) +1 (5mg) – 0 – 0 (DG 3)
Route of administration:
oral
Duration of use:
1 day single dose and 14 days q.d. dosing
The characteristics of the reference product (placebo) are given below:
Placebo to BI 706321 Capsules
Substance:
not applicable*
Pharmaceutical formulation: Capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
not applicable 
Posology:
2-0-0 (DG 1), 1-0-0 (DG 2), 4-0-0 (DG 3), 2-0-0 (DG 4)


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Route of administration:
oral
Duration of use:
1 day single dose and 14 days q.d. dosing
For the matching placebo, the drug substance is replaced by cellulose microcrystalline.
Probe drug:
Substance:
Midazolam 
 1 mg/mL
Pharmaceutical formulation: Solution for injection or infusion, to be used as oral solution
Source:
Unit strength:
5 mg/ 5 mL diluted to 50 µg/mL*1.5 mL (75 µg)
Posology:
1-0-0
Route of administration:
oral
Duration of use:
single doses on Days -1 and 19
Selection of doses in the trial
4.1.2
The doses of BI 706321 selected for this trial cover the subtherapeutic as well as the 
estimated therapeutic range and include a safety margin (see Sections 1.2, 1.4).
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
according to their temporal availability. As soon as enough subjects are allocated to 1 of the 
4 dose groups, the following subjects will be allocated to one of the other dose groups. 


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Therefore, the allocation of subjects to dose groups 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.
The randomisation procedure is described in Section 7.6.
Drug assignment and administration of doses for each subject
4.1.4
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of units for 
placebo corresponds to the number of units of the corresponding dose level.
Table 4.1.4: 1
BI 706321 and placebo treatments, oral administration
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Number of units / 
per administration
Total daily
dose
1
BI 706321
capsule
1 mg
2 capsules
2 mg
2
BI 706321
capsule
5 mg
1 capsule
5 mg
3
BI 706321
capsule
1 and 5 mg
3+1 capsules
8 mg
4
BI 706321
capsule
5 mg
2 capsules
10 mg
Table 4.1.4: 2
Midazolam treatment, oral administration
Dose
groups
Substance
Pharmaceutical 
form
Unit strength
Number of units / 
per administration
Total daily dose
The trial will be divided into two segments (single dose and multiple dose). During the single 
dose segment (Days 1 to 6), subjects will receive one single dose of BI 706321 (or placebo) 
on Day 1. The multiple dose segment starts on Day 6 and subjects will receive repeat doses of 
BI 706321 (or placebo) once daily for 14 days (Days 6 to 19).
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, 


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the so-called four-eye principle (two-person rule) should be applied. For this, 1 authorised 
employee of the trial site should witness the administration of trial medication. To ensure a 
dosing interval of 24 h, the administration of trial medication should take place at 
approximately the same time every day.
On Day 19 in dose groups 3 and 4, BI 706321 will be administered immediately prior to 
midazolam.
Subjects will be kept under close medical surveillance from the morning of Day -1 to the 
morning of Day 3 and again from the evening of Day 5 to the morning of Day 21. During the 
first 2 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. 
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
The trial is designed double-blind. The treatments administered (active or placebo) will be 
blinded to the subjects and the investigators (outcome assessors) in order to limit the 
occurrence of any bias which the knowledge of treatment may have.
At the trial site, access to the randomisation schedule is only granted to unblinded 
pharmacists, pharmacy staff members or staff who will prepare the subject specific study 
medication for the administration at the clinical unit. 
At the sponsor’s site, access to the randomisation schedule is restricted to the randomisation 
operators, the Clinical Trial Support group and the Pharmaceutics Department.
Prior to unblinding of the trial data, the randomisation codes may be provided to bioanalytical 
staff to allow them to exclude PK samples taken from placebo-treated subjects from the 
bioanalytical analyses. The Trial Bioanalyst will sign a statement confirming that the codes 
will be treated confidentially and that all unblinding information is restricted to the laboratory 
staff involved in sample analysis.
In addition, the trial pharmacokineticist may receive the randomisation codes prior to official 
unblinding to perform the preliminary PK analysis. He or she will confirm in writing that the 
codes will be treated confidentially.
Furthermore, the drug metabolism scientist may receive the randomisation codes prior to 
official unblinding to perform metabolites in safety testing (MIST) analysis. He or she will 
confirm in writing that the codes will be treated confidentially.
Regarding the sponsor, the data base of this trial will be handled open label. This means that 
trial functions of the sponsor are unblinded (including data manager, statistician, bioanalyst, 
pharmacokineticist, pharmacometrician, drug metabolism scientist as well as dedicated 
pharmacy personnel of the trial site). This is acceptable because they are neither in contact 
with subjects nor with site staff. CTL, who is in contact with the clinical site, will remain 
blinded during the whole trial duration until data base lock (or snapshot for fast track 
analysis).


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The trial may be unblinded prior to database lock for fast track analysis and expedited 
reporting. However, the trial site will only be unblinded after locking of the database. The 
dates of unblinding and database lock will be included in the CTR.
Within the central ECG lab, the staff involved with interval measurements and if needed in 
morphological analyses 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.
If an interim safety analysis of ECG data is required, a part of the staff of the central ECG lab 
may be unblinded. This part of the staff will be strictly separated from the blinded staff 
members who are involved with ECG interval measurements and assessments of ECGs.
Access to the randomisation schedule will be controlled and documented by a signed 
confidentiality statement, which will be stored in the TMF. 
Unblinding and breaking the code
4.1.5.2
The investigator or designee will be supplied with a set of sealed envelopes containing the 
medication codes for each subject according to the randomisation scheme. The envelopes will 
be kept unopened at the trial site until the end of data collection. An envelope may only be 
opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or otherwise assure safety of 
trial participants. If the envelope for a subject is opened, the sponsor must be informed 
immediately. The reason for breaking the code must be documented on the envelope and/or 
appropriate CRF page along with the date and the initials of the person who broke the code.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
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. 
Midazolam will be ordered locally by the trial site.
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.


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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 
local clinical monitor (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

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that all unused or partially used drug supplies have been 
returned by the clinical trial subject and that no remaining supplies are in the investigator’s 
possession.
All unused trial medication will be disposed of locally by the trial site upon written 
authorisation of the trial clinical monitor. Receipt, usage, and disposal of trial medication
must be documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
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 authorize


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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 except for ovary hormone replacement. All 
concomitant or rescue therapies will be recorded (including time of intake on study days) on 
the appropriate pages of the CRF.
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 the first and last drug 
intake (Days 1 and 19) as well as on Day -1 for midazolam administration. On all other 
dosing days (Days 6 to 18), food is not allowed 10 hour before and approx. 1 hour after drug 
intake. On all non intensive PK study days standard meals (light breakfast, lunch, snack, 
dinner, snack) will be served approx. 1, 4, 8, 10 and 12 hours after drug administration, and 
200 mL of fluid will be served to the light breakfast on all non-intensive PK days.
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 on Day -1, 1 and 19 at 2 h and 4 h 
post-dose (mandatory for all subjects).
During the days of urine collection, total fluid intake should be at least 1.5 litres and should 
not exceed 3.5 litres.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each study period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks) are not 
allowed from day -1 in dose groups 1 and 2, and from day -2 in dose groups 3 and 4 for the 
whole duration of the trial.
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 first administration of trial medication until the end of trial examination. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 


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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). 


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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 (results not mandatory to be entered into CRF), relevant medical 
history and concomitant therapy, review of inclusion and exclusion criteria, review of vital 
signs (BP, PR, temperature), 12-lead ECG, laboratory tests, and a physical examination. At 
the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, and a physical examination including determination of weight.
Vital signs
5.2.2
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap V 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.
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. 
Manual differential white blood cell count or urine sediment examinations will be performed 
parallel to the automatic blood cell count or the urinalysis, respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
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/ 
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.
X
X
X
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
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
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
X
Hormones
Thyroid Stimulating Hormone
X
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined on Day -1, 6, 12, 20 and 27 (for time points refer to Flow Chart)
C: parameters to be determined on Days 2, 8, 10, 14, 16, 18 and 22 (for time points refer to Flow Chart)


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab 
group
BI test name [comment/abbreviation]
A
B
C
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin (protein electrophoresis)
Alpha-1-globulin (protein electrophoresis)
Alpha-2-globulin (protein electrophoresis)
Beta-globulin (protein electrophoresis)
Gamma-globulin (protein electrophoresis)
C-Reactive Protein (Quant)
Uric Acid 
Cholesterol, total 
Triglyceride
Haptoglobin
Ferritin
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
X
X
Electrolytes
Sodium
Potassium
Calcium
Phosphate (as Phosphorus, Inorganic)
X
X
X
X 
X
X
X
X 
Urinalysis1 (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 sediment1
(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)
X
X
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined on Day -1, 6, 12, 20 and 27 (for time points refer to Flow Chart)
C: parameters to be determined on Days 2, 8, 10, 14, 16, 18 and 22 (for time points refer to Flow Chart)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy tests and drug screening, it is planned to perform these tests at 
screening only. Pregnancy testing in women will be performed at screening, prior to each 
treatment period, and as part of the end of trial examination. Drug screening will be 
performed at screening and prior to each treatment period.


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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)
TB test (IGRA: QuantiFERON® Gold assay/T-SPOT®.TB)
COVID 19 infection1
SARS-CoV-2 virus PCR test
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
1 will be performed shortly (within 72 hours) before admission to the site as per Flow Chart.
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
6510, 
) will be performed prior to each treatment period, and 
may be repeated at any time during the study at the discretion of an investigator or designee. 
The results will not be included in the CTR
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of drug screening 
and pregnancy tests. These tests will be performed at the trial site using Triage® TOX Drug 
Screen,
and TestPack+Plus with hCG-Urine,
, respectively, or comparable test 
systems. SARS-CoV-2 virus PCR test will be performed either by 
 or the trial site.
Laboratory data will be transmitted electronically from the laboratory to the trial site.


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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 (
device, 
) 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 should be marked 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 or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) 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. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. 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
ECGs will be stored at the site and ECG core lab.
Data transfer
Triplicate ECGs will be transferred electronically to the central ECG lab
 
.
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).
Evaluation
a) Central ECG lab


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Central ECG lab evaluation will be performed post-study for the first of three 
replicate ECGs per time point on Days 1 and 19 at relevant time points before and up 
to 48 h after the first and last drug administration. 
Central ECG lab evaluation will be performed for all time points with triplicate ECGs. 
Only the first ECG will be evaluated. This will include the determination of the QRS-
axis as measured automatically by the ECG machines algorithm, and RR, QT, PR, and 
QRS intervals evaluated 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.
If the either the ECGs analysis described above, or clinical evaluation performed by 
investigator/designee described below will reveal any relevant findings, the extended 
ECG evaluation (including morphological analyses, and semi-automatically 
measurements of intervals described above for all 3 ECGs) might be implemented 
retrospectively.
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.


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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. 
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 

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 


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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 Section 5.2.5.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ might be provided upon request. 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.


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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


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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 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 immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions the 
Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.


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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
WOCBP are excluded in this trial. In very unlikely case of pregnancy in this clinical trial the 
following procedures are to be followed. 
Once a subject has been enrolled in the clinical trial and has taken trial medication, the 
investigator must report any drug exposure during pregnancy in a trial participant 
immediately (within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the 
sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires 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
in the CRFs.
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 
600 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, approx. 3 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 


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the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
For quantification of midazolam plasma concentrations, approximately 4 mL of blood will be 
taken from an antecubital or forearm vein into a K-EDTA-anticoagulant blood drawing tube 
at the times indicated in the Flow Chart for dose groups 8 and 10 mg.
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 90 minutes with 
interim storage of blood samples and aliquots at room temperature. The time each aliquot was 
placed in the freezer will be documented. Until transfer on dry ice to the analytical 
laboratory, the aliquots will be stored upright at approximately -20°C or below at the trial 
site. The second aliquot will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory, the plasma 
samples will be stored at approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 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.


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Urine sampling for pharmacokinetic analysis
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.


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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 
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.


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5.5
BIOBANKING
Blood samples will be drawn and biobanked at various timepoints as listed in the Flow Chart. 
These samples may be analyzed for exploratory biomarker analysis.
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements.
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see Flow Chart. Approximately 4 mL 
blood will be drawn for Plasma, for banking purposes.
5.6
OTHER ASSESSMENTS
Pharmacogenomic evaluation 
5.6.1
Pharmacogenomics investigates genetic variations to explain and to predict an individual’s
response to drugs. Therefore, a blood sample for pharmacogenomic testing will be taken from


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each randomized subject. In case of unexplainable variability of PK, DNA may be extracted 
from these samples and used for exploratory analysis genes involved in Absorption, 
Distribution, Metabolism and Excretion (ADME) of drugs.
It is not intended to include these data in the final report. However, the data may be part of
the report if necessary. All remaining samples will be destroyed no later than until the CTR
has been signed.
Detailed instructions for pharmacogenomics sampling, including handling and shipment of
samples will be provided in the laboratory manual in the ISF.
Methods and timing of sample collection
5.6.2
One blood sample of 8.5 mL will be taken from an arm vein in a PAXgene blood DNA
drawing tube on day 1.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an orally administered drug, 
and are widely used in clinical trials. The pharmacokinetic parameters and measurements 
outlined in Section 5.4 are generally used assessments of drug exposure. The biomarkers and 
pharmacodynamic parameters and measurements outlined in Sections 5.5 and 5.6 are of 
exploratory nature.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (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.
The tolerance for drug administration will be ± 1 min on Days 1 and 19 and ± 10 min on all 
other treatment days.
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.
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.
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 5.2.3 to 5.2.5.
Treatment periods
6.2.2
Each subject will receive a single dose of BI 706321 or placebo on Day 1 and then daily 
multiple daily doses of BI 706321 or placebo for 14 days from Day 6 onwards.


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Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
Subjects in dose groups 1 and 2 will be admitted to the trial site on Day -1.
All subjects will be kept under close medical surveillance for 48 h following the first 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 
 designee. For the 
multiple dose segment, study participants will be admitted to the trial site on Day 5 and kept 
under close medical surveillance for at least 48 h following the last drug administration 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 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
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 5.2.2 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 characterized, or no further 
information can be obtainedd. 
If a subject discontinues from the trial, the subject will be followed until the investigator or 
sub-investigator is convinced of the subject’s safety. If follow-up is not possible or comes to 
an end, follow-up should be formally completed after discussion with the sponsor. If a subject 
stops attending trial assessments, the investigator should assess the subject’s status as 
comprehensively as possible and the well-being of the subject should be monitored. 
However, if the subject withdraws from the trial, it is the subject’s choice whether or not to 
participate in further assessments; he or she cannot be compelled.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The primary objective of this trial is to investigate the safety and tolerability of BI 706321
by using descriptive statistics for all endpoints comparing active dose groups to placebo. The
primary endpoint is defined in Section 2.1.2. Inferential statistics are not planned (as
explained in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) of BI 706321. 
Endpoints as specified in Section 2.1.3 and 2.2.2.2 will be analysed by descriptive statistics. 
The secondary endpoints AUCτ,ss and Cmax,ss  as defined in Section 2.1.3 will be subjected to 
analysis of dose proportionality by use of the power model.
Trough concentration values will be analysed regarding attainment of steady state as a
prerequisite for calculation of steady state parameters. Additionally, the linearity index will 
be estimated, if feasible.
7.2
NULL AND ALTERNATIVE HYPOTHESES
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.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The 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 deviation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 


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included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be specified in the integrated quality and risk management plan 
(IQRMP). IPDs will be identified no later than in the Report Planning Meeting, and the IPD
categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2 for 706321will be calculated 
according to the relevant SOP of the Sponsor [001-MCS-36-472]. 
Plasma and urine concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol deviation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviationss 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 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.
Plasma/urine 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.
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
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.


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Secondary endpoint analyses
7.3.2
Primary analyses
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively. Analyses will 
be performed for the parent drug.


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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. 
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 first intake of trial medication will 
be assigned to the screening period, those between the first trial medication intake and end of 
REP (see Section 1.2.6) will be assigned to the treatment period. Events occurring after the 


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REP but prior to trial termination date 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. 
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.
Pharmacokinetic - pharmacodynamic analysis
7.3.5
An association of BI 706321 plasma concentrations and the exploratory biomarker 
(Section 2.2.2.3) may be investigated in an exploratory manner. 
7.4
INTERIM ANALYSES
No formal interim analysis is planned.
Instead, a “Fast track” analysis for the primary and secondary endpoints might be performed 
after completion of the dose group 3. After all selected primary and secondary endpoints data 
are available and cleaned, a snapshot of the database will be taken. This snapshot will be used 
for performing the Fast track analysis. Details regarding statistical analysis will be outlined in 
the TSAP. On-site monitors, site personnel and subjects will remain blinded until the final 
database lock.
7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.


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Pharmacokinetics
7.5.2
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure [001-MCS-36-472].
Subjects who are not included in the PKS will be reported with their individual plasma/ urine 
concentrations and individual PK parameters. However, they will not be included in 
descriptive statistics for plasma/ urine concentrations, PK parameters or other statistical 
assessment.
7.6
RANDOMISATION
Subjects will be randomised within each dose group in a 4:1 ratio (test treatment to placebo).
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 40 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 10 subjects per dose group (8 on active treatment, and 2
on placebo) is commonly used in multiple-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics.
Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 40, but will not exceed 60 subjects entered.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract.
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 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.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
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. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
Clinspark:
In the 
Phase I unit – the validated Clinspark system is used for processing information 
and controlling data collected in clinical studies. 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.


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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 Clinspark (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 Clinspark 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 must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).


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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, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking 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.


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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
, 
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 Trial Clinical Monitor, 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 local clinical monitors (CTM), Clinical 
Research Associates, and investigators of participating trial sites
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany.
Midazolam 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 
.


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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 according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P14-08681
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions: final 
(21 June 2012, CPMP/EWP/560/95/Rev. 1 Corr). (this guideline replaces 
guideline CPMP/EWP/560/95). London: European Medicines Agency 
(EMA) 2012.
P19-01288
Ministry of Health, Labour and Welfare. Guideline on drug interaction for 
drug development and appropriate provision of information. 
https://www.mhlw.go.jp/hourei/doc/tsuchi/T190212I0040.pdf (access date: 
12 February 2019) ; Ministry of Health, Labour and Welfare; 2019.
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).
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).website: 
ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E1 
4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016) ; Geneva: 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (2015).
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.
R17-3022
Halama B, Hohmann N, Burhenne J, Weiss J, Mikus G, Haefeli WE, et al. 
A nanogram dose of the CYP3A probe substrate midazolam to evaluate 
drug interactions. Clin Pharmacol Ther 2013;93(6):564-571.
R17-3023
Hohmann N, Kocheise F, Carls A, Burhenne J, Haefeli WE, Mikus G. 
Midazolam microdose to determine systemic and pre-systemic metabolic 
CYP3A activity in humans. Br J Clin Pharmacol 2014;79(2):278-285.
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.


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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.
R20-0261
Guidance for industry: in vitro drug interaction studies - cytochrome P450 
enzyme- and transporter-mediated drug interactions (January 2020, clinical 
pharmacology). https://www.fda.gov/media/134582/download (access date: 
28 January 2020) ; Silver Spring: U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER) (2020).
R20-0572
Midazolam 1 mg/ml Solution for Injection or Infusion; Summary of 
Product Characteristics Updated 02-Jul-2018  Accord Healthcare Limited.
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. Current 
version.
n00274674
. Evaluation of cytochrome P450 isoform induction 
potential by BI 706321 in cultured human hepatocytes. Draft report 
available.


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10.
APPENDICES
10.1
ADVERSE EVENTS FROM FIRST-IN-HUMAN TRIAL 1425-0001
Table 10.1: 1
Frequency [N (%)] of patients with adverse events by treatment, 
primary system organ class and preferred term - Treated set
           BI 0.3mg os
       BI 0.6mg os
BI 1.2mg os
System organ class/
Preferred term
           N
%
     N
  %             N
   %
Number of patients
6
100.0
6
100.0
5
100.0
Total with adverse 
events
3
50.0
2
33.3
1
20.0
Gastrointestinal 
disorders
1
16.7
0
0.0
0
0.0
Diarrhoea
0
0.0
0
0.0
0
0.0
Abdominal pain
0
0.0
0
0.0
0
0.0
Abdominal pain upper
0
0.0
0
0.0
0
0.0
Lip dry
1
16.7
0
0.0
0
0.0
Musculoskeletal and 
connective tissue 
disorders
2
33.3
0
0.0
0
0.0
Back pain
0
0.0
0
0.0
0
0.0
Myalgia
0
0.0
0
0.0
0
0.0
Myosclerosis
1
16.7
0
0.0
0
0.0
Pain in extremity
1
16.7
0
0.0
0
0.0
General disorders and 
administration site 
conditions
0
0.0
0
0.0
1
20.0
Catheter site pain
0
0.0
0
0.0
0
0.0
Feeling cold
0
0.0
0
0.0
0
0.0
Puncture site reaction
0
0.0
0
0.0
1
20.0
Infections and 
infestations
0
0.0
1
16.7
0
0.0
Nasopharyngitis
0
0.0
1
16.7
0
0.0
Rhinitis
0
0.0
0
0.0
0
0.0
Injury, poisoning and 
procedural 
complications
1
16.7
0
0.0
0
0.0
Contusion
1
16.7
0
0.0
0
0.0
Skin abrasion
0
0.0
0
0.0
0
0.0


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Table 10.1: 1
Frequency [N (%)] of patients with adverse events by treatment, 
primary system organ class and preferred term - Treated set (cont.)
BI 0.3mg os
BI 0.6mg os
          BI 1.2mg os
System organ class/
Preferred term
N
%
N
   %
           N
       %
Nervous system 
disorders
0
0.0
0
0.0
0
0.0
Headache
0
0.0
0
0.0
0
0.0
Dizziness
0
0.0
0
0.0
0
0.0
Respiratory, thoracic 
and mediastinal 
disorders
0
0.0
1
16.7
0
0.0
Nasal congestion
0
0.0
0
0.0
0
0.0
Oropharyngeal pain
0
0.0
1
16.7
0
0.0
Eye disorders
0
0.0
0
0.0
0
0.0
Photokeratitis
0
0.0
0
0.0
0
0.0
Vascular disorders
0
0.0
0
0.0
0
0.0
Haematoma
0
0.0
0
0.0
0
0.0


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Table 10.1: 1
Frequency [N (%)] of patients with adverse events by treatment, 
primary system organ class and preferred term - Treated set (cont.)
BI 2mg cap
BI 4mg cap
BI 8mg cap
BI 15mg cap
BI 25mg cap
System organ class/
Preferred term
N
%
N
%
N
%
N
%
N
%
Number of patients
6
100.0
6
100.0
6
100.0
5
100.0
6
100.0
Total with adverse 
events
0
0.0
3
50.0
1
16.7
3
60.0
2
33.3
Gastrointestinal 
disorders
0
0.0
0
0.0
1
16.7
0
0.0
1
16.7
Diarrhoea
0
0.0
0
0.0
1
16.7
0
0.0
1
16.7
Abdominal pain
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
Abdominal pain upper 0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
Lip dry
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
Musculoskeletal and 
connective tissue 
disorders
0
0.0
1
16.7
0
0.0
0
0.0
0
0.0
Back pain
0
0.0
1
16.7
0
0.0
0
0.0
0
0.0
Myalgia
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
Myosclerosis
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
Pain in extremity
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
General disorders and 
administration site 
conditions
0
0.0
1
16.7
0
0.0
0
0.0
1
16.7
Catheter site pain
0
0.0
1
16.7
0
0.0
0
0.0
0
0.0
Feeling cold
0
0.0
0
0.0
0
0.0
0
0.0
1
16.7
Puncture site reaction
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
Infections and 
infestations
0
0.0
0
0.0
0
0.0
1
20.0
1
16.7
Nasopharyngitis
0
0.0
0
0.0
0
0.0
1
20.0
0
0.0
Rhinitis
0
0.0
0
0.0
0
0.0
0
0.0
1
16.7
Injury, poisoning and 
procedural 
complications
0
0.0
1
16.7
0
0.0
0
0.0
0
0.0
Contusion
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
Skin abrasion
0
0.0
1
16.7
0
0.0
0
0.0
0
0.0
Nervous system 
disorders
0
0.0
0
0.0
0
0.0
1
20.0
0
0.0
Headache
0
0.0
0
0.0
0
0.0
1
20.0
0
0.0
Dizziness
0
0.0
0
0.0
0
0.0
1
20.0
0
0.0
Respiratory, thoracic 
and mediastinal 
disorders
0
0.0
1
16.7
0
0.0
0
0.0
0
0.0
Nasal congestion
0
0.0
1
16.7
0
0.0
0
0.0
0
0.0
Oropharyngeal pain
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
Eye disorders
0
0.0
0
0.0
0
0.0
1
20.0
0
0.0
Photokeratitis
0
0.0
0
0.0
0
0.0
1
20.0
0
0.0
Vascular disorders
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
Haematoma
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0


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Table 10.1: 1
Frequency [N (%)] of patients with adverse events by treatment, 
primary system organ class and preferred term - Treated set (cont.)
Placebo Total on
treatment
BI Total on
treatment
System organ class/
Preferred term
N
%
N
%
Number of patients
15
100.0
46
100.0
Total with adverse events
6
40.0
15
32.6
Gastrointestinal disorders
2
13.3
3
6.5
Diarrhoea
0
0.0
2
4.3
Abdominal pain
1
6.7
0
0.0
Abdominal pain upper
1
6.7
0
0.0
Lip dry
0
0.0
1
2.2
Musculoskeletal and connective 
tissue disorders
2
13.3
3
6.5
Back pain
1
6.7
1
2.2
Myalgia
1
6.7
0
0.0
Myosclerosis
0
0.0
1
2.2
Pain in extremity
0
0.0
1
2.2
General disorders and administration 
site conditions
0
0.0
3
6.5
Catheter site pain
0
0.0
1
2.2
Feeling cold
0
0.0
1
2.2
Puncture site reaction
0
0.0
1
2.2
Infections and infestations
0
0.0
3
6.5
Nasopharyngitis
0
0.0
2
4.3
Rhinitis
0
0.0
1
2.2
Injury, poisoning and procedural 
complications
0
0.0
2
4.3
Contusion
0
0.0
1
2.2
Skin abrasion
0
0.0
1
2.2
Nervous system disorders
1
6.7
1
2.2
Headache
1
6.7
1
2.2
Dizziness
0
0.0
1
2.2
Respiratory, thoracic and mediastinal 
disorders
0
0.0
2
4.3
Nasal congestion
0
0.0
1
2.2
Oropharyngeal pain
0
0.0
1
2.2
Eye disorders
0
0.0
1
2.2
Photokeratitis
0
0.0
1
2.2
Vascular disorders
1
6.7
0
0.0
Haematoma
1
6.7
0
0.0
Source: Tables 15.3.1: 1, from tgl\ae-t.sas 29OCT2019
Percentages are calculated using total number of patients per treatment as the denominator. 
MedDRA version used for reporting: 22.0 
AEs occurring up to last per-protocol contact were assigned to treatment. 


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10.2
DRUG SUPPLIES USED FOR DILUTION AND DOSING
Drug supplies overview
10.2.1
a) Midazolam
 1 mg/mL solution for injection or infusion 5 mg/5 mL, 
5 mL ampoules
b) Isotonic Sodium Chloride Solution 0.9%, 100 ml bottles 
c) Empty, appropriately labelled glass container, preferably with lid 
Required equipment and dosing aids – overview
10.2.2
Dosing and diluting syringes:

2-part disposable
NORM-JECT® Syringes 2 mL

2-part disposable
NORM-JECT® Syringes 20 mL

Blunt, non-bevelled needle tip

Combi-Stopper®
Only CE certified syringes WITHOUT rubber stoppers are to be used!


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Dilution procedure
10.2.3
Solution preparation for oral use 
Step 1: 
Open the commercial isotonic saline solution (0.9% NaCl).
Step 2: 
Attach a needle tip to the 2 mL syringe and withdraw a bit more than 1 mL of 
the midazolam solution [concentration: 1 mg/mL] from the originator 
ampoule using a 2 mL syringe.
Step 3:
Remove any air bubbles in syringe (turn upside down and gently push out air 
by depressing the plunger); ensure that exactly 1 mL midazolam solution 
remains in the 2 mL syringe.
Step 4:
Remove and dispose of needle tip; transfer the full 1 mL of midazolam 
solution into an appropriate glass container (with cap) by completely
depressing the plunger on the 2 mL syringe.
Step 5: 
Attach a needle tip to the 20 mL syringe and withdraw a bit more than 19 mL 
isotonic saline solution into the 20 mL syringe; remove air bubbles (see 
Step 3) and ensure exactly 19 mL isotonic saline solution remains in the 20 ml 
syringe.
Step 6:
Remove and dispose of needle tip; transfer the full 19 mL of isotonic saline 
solution into the same glass container with the midazolam solution by 
completely depressing the plunger on the 20 mL syringe.
Step 7:
Following addition of the midazolam and saline solutions into the glass 
container, ensure the glass container is closed using the corresponding cap. 
The content of the glass container should be mixed thoroughly by swirling 
gently for approximately 1 minute.
Step 8:
Extract a little more than 1.5 mL of the dilution solution using a needle tip 
and a new 2mL syringe; remove bubbles (see Step 3) and ensure that exactly 
1.5 mL of the diluted midazolam solution (final concentration: 50 µg/mL) 
remains in the 2 mL syringe. Remove and dispose of the needle tip and close 
the syringe with a cap; the solution is now ready for oral administration. 
The final midazolam microdose Oral Solution concentration is 50 µg/mL, for 
administration of 1.5 mL (75 µg), which will be administered per os directly from the 
syringe.
In-use stability
10.2.4
The chemical in-use stability of the dilution solution is 24 h after its preparation, incl. storage 
at room temperature (15-25°C) in
2-part disposable
 NORM-JECT®
syringes until administration.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1 
Date of amendment
23 Dec 2019
EudraCT number
EU number
2019-004351-36
BI Trial number
1425-0002
BI Investigational Medicinal 
Product
BI 706321
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 706321 in healthy 
male and female subjects (double-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
Flow Chart, page 4-5; 
3.3.4.1 Discontinuation of trial treatment;
5.2.3 Safety laboratory parameters
Description of change
Additional monitoring of the safety laboratory 
parameters (CRP, red blood cell parameters, 
reticulocytes, platelets, liver enzymes) was added.
Stopping rules were updated for red blood cells/ 
reticulocytes/ platelets parameters decrease and CRP 
increase.
Rationale for change
To intensify the safety monitoring strongly 
recommended by the RA.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
24 Feb 2020
EudraCT number
EU number
2019-004351-36
BI Trial number
1425-0002
BI Investigational Medicinal 
Product
BI 706321
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 706321 in healthy 
male and female subjects (double-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 (probe drug and treatment duration for 
probe drug)
Description of change
Updated for Midazolam microdose to be additionally 
tested in the highest dose groups
Section to be changed
Flow Chart dose groups 8 and 10 mg (page 6, 7)
Description of change
Additional Flow Chart has been developed for 8 and 
10 mg dose groups 4 with midazolam microdosing
Section to be changed
1.2.8 Midazolam (Drug product, page 22)
Description of change


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Section to be changed
1.3 Rationale for performing the trial (page 23)
Description of change
The following texts have been added:
Section to be changed
1.4 Benefit - risk assessment (page 23, 30, 31)
Description of change
The following texts have been added:
The total volume of blood withdrawn per subject 
during the entire study in the 2 and 5 mg dose groups 
will not exceed the volume of a normal blood 
donation (500 mL). The total volume of blood 
withdrawn per subject in the 8 and 10 mg dose 
groups slightly exceeds the volume of a normal 
blood donation (500 mL) and is estimated to be 
approximately 550 mL. However, no health-related 
risk to healthy subjects is expected from withdrawal 
of this volume of blood over the entire study 
duration of about 1.5 months.


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Drug-drug interactions
Section to be changed
Description of change


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Section to be changed
3.1 Overall trial design and plan (page 37)
Description of change
The following text has been added:
Section to be changed
3.2 Discussion of trial design, including the choice 
of control group (page 39)
Description of change
The following text has been added:
Section to be changed
4.1.1 Identity of the Investigational Medicinal 
Products (page 46)
Description of change
Probe drug (Midazolam) information has been 
added.
Section to be changed
4.1.2 Selection of doses in the trial (page 46) 
Description of change
The following text has been added:


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contains midazolam in isotonic saline solution, 
while the oral solution has added excipients, 
making it less than ideal for such a dilution. Finally, 
the IV solution has been successfully diluted and 
administered orally as a microdose in previous 
clinical studies without any reports of AEs [R17-
3022, R17-3023].
Section to be changed
4.1.4 Drug assignment and administration of doses 
for each subject (page 47, 48)
Description of change
Table 4.1.4: 2 Midazolam treatment, oral 
administration table and the following texts have 
been added:
The oral solutions for dosing midazolam will be 
prepared according to the instruction given in 
Appendix 10.2. Trial medication 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.
On Day 19 in dose groups 3 and 4, BI 706321 will 
be administered immediately prior to midazolam.
Section to be changed
4.1.5 Blinding and procedures for unblinding 
(page 49)
Description of change
The following text has been added:
Midazolam treatment will be handled in an open 
fashion throughout (that is, during the conduct, 
including data cleaning and preparation of the 
analysis).
Midazolam will be purchased locally by the trial 
site.
Section to be changed
4.2.2.2 Restrictions on diet and life style (page 51)
Description of change
Has been updated for meal on day -1, and fluid and 
drinks intake
Section to be changed
5.3 Drug concentration measurements and 
pharmacokinetics (page 63, 66) 
Description of change
The following texts have been added:


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K-EDTA-anticoagulant blood drawing tube at the 
times indicated in the Flow Chart.
or by a specialised contract 
research organisation appointed by BI. All details 
of the analytical methods will be available prior to 
the start of sample analysis.
Section to be changed
6.2.2 Treatment periods (page 70)
Description of change
The following text has been updated:
Subjects of the dose groups 1 and 2 will be 
admitted to the trial site on Day -1. All subjects will 
be kept under close medical surveillance for 48 h 
following the first drug administration.
Section to be changed
7.1 Statistical design – model (page 71)
7.7 Determination of the sample size (page 78)
Description of change
1. The following text has been added on page 71:
Section to be changed
8.7 Administrative structure of the trial (page 83)


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Description of change
Provider for the Midazolam supply midazolam has
been added.
Section to be changed
9. References (page 85, 86)
Description of change
Published and unpublished reference documents 
have been added.
Section to be changed
Appendix 10.2 Drug supplies used for dilution and 
Dosing (page 91, 92)
Description of change
Microdose Midazolam solution preparation for oral 
use has been added.
Rationale for changes


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BI Trial No.: 1425-0002
c29586669-04
Trial Protocol
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11.3
GLOBAL AMENDMENT 3
Date of amendment
02 Jun 2020
EudraCT number
EU number
2019-004351-36
BI Trial number
1425-0002
BI Investigational Medicinal 
Product
BI 706321
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 706321 in healthy 
male and female subjects (double-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.) Flow Charts (pages 4 - 7)
2.) Table 5.2.3: 2 Exclusionary laboratory tests
3.) Section 5.4.1
Description of change
1.) Foot note 14 has been added to the Flow 
Chart dose groups 2 and 5 mg, and Foot note 
12 has been added to the Flow Chart dose 
groups 8 and 10 mg.
2.) SARS-CoV-2 virus PCR test has been added 
to the exclusionary laboratory, and the foot 
note 1 explaining the time points
3.) Freezer-temperature changed from -20° C to 
-70°C
Rationale for changes
Due to the recent COVID-19 outbreak, and given 
infected individuals may be clinically asymptomatic, 
SARS-CoV-2 virus PCR tests are being 
implemented shortly before admission to the
research site for two clinical confinement periods. 
Implementation of these tests should safeguard the 
subject’s safety, and exclude infected volunteers 
from study participation.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29586669
4.0
clinical-trial-protocol-version-04
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 706321
in healthy male and female subjects (double-blind, randomised, placebo-controlled,
parallel group design)
Author-Clinical Trial Leader
02 Jun 2020 12:24 CEST
Author-Trial Statistician
02 Jun 2020 13:07 CEST
Verification-Paper Signature
Completion
02 Jun 2020 13:18 CEST
Author-Trial Clinical
Pharmacokineticist
02 Jun 2020 14:08 CEST
Approval-Team Member Medicine
02 Jun 2020 14:11 CEST
Approval-
 Medicine
02 Jun 2020 19:01 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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c29586669
4.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c34166601-01
BI Trial No.:
1425-0002
Title:
Safety, tolerability, and pharmacokinetics of multiple rising oral 
doses of BI 706321 in healthy male and female subjects (double-
blind, randomised, placebo-controlled, parallel group design)
  Including Protocol Amendment 1 [c29586669- 02]
  Including Protocol Amendment 2 [c29586669- 03]
  Including Protocol Amendment 3 [c29586669- 04]
Investigational
Product(s):
BI 706321
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
12-JAN-2021 SIGNED
Version:
1
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3.1
Safety parameters .................................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................19
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINT .....................................................................................19
7.4.1
Primary analysis of the primary endpoint........................................................19
7.5
SECONDARY ENDPOINTS.............................................................................19
7.5.1
Key secondary endpoint .....................................................................................19
7.5.2
Secondary endpoints...........................................................................................20
7.6.1
Safety parameters ...............................................................................................21


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7.7
EXTENT OF EXPOSURE.................................................................................24
7.8
SAFETY ANALYSIS..........................................................................................24
7.8.1
Adverse Events ....................................................................................................24
7.8.2
Laboratory data ..................................................................................................26
7.8.3
Vital signs.............................................................................................................26
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................29
8.
REFERENCES....................................................................................................30
10.
HISTORY TABLE..............................................................................................37


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs for dose groups 
1 to 4.................................................................................................................12
Table 6.2: 1
Handling of iPDs..............................................................................................14
Table 6.3: 1
Subject sets analysed........................................................................................15
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation ..........17
Table 10: 1
History table .....................................................................................................37


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%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
BI
Boehringer Ingelheim
BMS
Biomarker analysis set
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
Cmin
Minimum measured concentration of the analyte in plasma
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Council for Harmonisation
IPD
Important Protocol Deviation
z
Terminal rate constant of the analyte in plasma
MIST
Metabolites in Safety Testing
MMRM
Mixed-Effect Model for Repeated Measure
PKS
Pharmacokinetic parameter analysis set
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram


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Term
Definition / description
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) or 
Bazett (QTcB)
RA,AUC
Accumulation ratio based on AUC0-τ 
RA,Cmax
Accumulation ratio based on Cmax,ss
REP
Residual Effect Period
SD
Standard Deviation
ss
(At) steady state
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
tmax,ss
Time from last dosing to maximum concentration of the analyte in plasma at 
steady state
tz
Time of last measurable concentration of the analyte in plasma
TS
Treated set
ULN
Upper limit of normal range
Vss
Apparent volume of distribution at steady state after intravascular 
administration


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP and to 
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its amendments. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 ‘Statistical Methods 
and Determination of Sample Size’. Therefore, TSAP readers may consult the revised CTP 
for more background information on the study, e.g., on study objectives, study design and 
population, treatments, definition of measurements and variables, planning of sample size, 
randomisation.
Study data will be stored in a trial database within the RAVE EDC system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods planned in 
the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint for assessment of safety and tolerability of BI 706321 is the percentage 
of subjects with drug-related adverse events, as defined in Section 2.1.2 of the CTP.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable
5.2.2
Secondary endpoints
Secondary PK endpoints will be as defined in Section 2.1.3 of the CTP.
These endpoints are AUCτ,ss, Cmax,ss, Cmin,ss, RA,Cmax and RA,AUC of BI 706321 after the last 
dose of the multiple dose segment.
5.3.1
Safety parameters
Further safety parameters of interest will be as defined in Section 2.2.2.1 of the CTP:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate, body temperature)
12-lead ECG endpoints
For the MRD part, ECG data will be analysed centrally. For the definition of baseline and a 
summary of time points please refer to Section 6.7.
Quantitative ECG endpoints:
The following quantitative ECG endpoints will be determined for the ECG variables QTcF, 
QT, HR, PR, QRS, RR and QTcB, derived as described in Additional Section 9.1:

absolute values (per time point)

changes and placebo-corrected changes from baseline (per time point)
Categorical ECG endpoints
The following categorical ECG endpoints will be determined based on the quantitative ECG 
endpoints:


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
New onset (meaning that this or a higher category was not present at baseline) of 
maximum QTcF interval > 450 to 480 msec, > 480 to 500 msec, or > 500 msec on 
treatment.
For assignment of a particular subject to one of the above categories, all time points on-
treatment (refer to Table 6.7: 1) will be considered. If baseline is missing, but the 
maximum absolute QTcF interval falls in a category other than normal (i.e. when 
QTcF > 450 msec), then this is categorized as a new onset in the respective category. If 
baseline is missing, but the maximum absolute QTcF interval is normal, then it is 
categorized as "No new onset".

Maximum change from baseline in QT interval ≤ 60 msec, or > 60 msec on treatment

Maximum change from baseline in QTcF interval ≤ 30 msec, > 30 to ≤ 60 msec, or 
> 60 msec on treatment
The occurrence of any of the following will be viewed as "notable findings":

New onset (not present any time at baseline) of uncorrected QT interval > 500 msec at 
any time on treatment
If baseline is missing, any occurrence of QT interval > 500 msec at any time on treatment 
will be a notable finding

New onset of QTcF interval > 500 msec at any time on treatment 
If baseline is missing, any occurrence of QTcF interval > 500 msec at any time on 
treatment will be a notable finding

Change from baseline of QTcF > 60 msec at any time on treatment

Percent change from baseline of HR ≥ 25%, when corresponding on-treatment value of 
HR is > 100 beats/min, or percent change from baseline of HR - 25%, when 
corresponding on-treatment value of HR is < 50 beats/min, at any time on treatment

Percent change from baseline of PR ≥ 25%, when corresponding on-treatment value of 
PR interval is > 200 msec, at any time on treatment 

Percent change from baseline of QRS ≥ 10%, when corresponding on-treatment value of 
QRS complex is > 110 msec, at any time on treatment
For a detailed description of ‘new onset’, refer to Additional Section 9.4.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment 
groups, and selection of doses, cf. Section 4 of the CTP.
In this study, subjects will receive a single dose of 2 mg, 5 mg, 8 mg or 10 mg of BI 706321
or placebo (orally as capsules) on Day 1 followed by 14 days with once daily multiple doses 
from Day 6 to Day 19. 
 
no 
separate phases will be defined for the safety analysis of dose groups 3 and 4.
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).
For statistical analysis of AEs, the following analysis phases are defined for each subject:
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs for dose groups 1
to 4
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first administration 
of BI 706321 /Placebo
On-treatment
Placebo,
2 mg BI,
5 mg BI,
8 mg BI,
or 10 mg BI,
respectively
Date/time of first administration 
of BI 706321 /Placebo
8 days after last administration 
of BI 706321 /Placebo
Follow-up *
F/U Placebo,
F/U 2 mg BI,
F/U 5 mg BI,
F/U 8 mg BI,
or F/U 10 mg BI,
respectively
8 days after last administration 
of BI 706321 /Placebo
12:00 a.m. on day after subject's 
trial completion date
* If a subject completes the study in accordance with the CTP, no follow-up (F/U) phase exists for this subject.
Analysis phases for statistical analysis of AEs are defined for each subject as described in the 
Table 6.1: 1 for dose groups 1,2, 3 and 4.
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only.
In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 
AE tables), the following totals will be provided in addition:


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
"Total BI", defined as the total over all on-treatment phases involving BI (this includes 
BI plus 
)

"Total on-trt", defined as the total over all on-treatment phases, involving BI (this 
includes BI plus 
) and placebo
Safety laboratory data, vital signs and ECG will be analysed based on dose groups (Placebo, 
2 mg, 5 mg, 8 mg and 10 mg of BI 706321). ECG measurements are considered to be on-
treatment if they were measured between the first administration of BI 706321 /Placebo and 8 
days after the last administration of BI 706321 /Placebo.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important protocol deviation (IPD). For definition of IPDs, and for the 
process of identification of these, refer to the BI reference document "Identify and Manage 
Important Protocol Deviations (IPD)" (2).
If any IPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. Categories which are considered to be IPDs in this trial are defined in the 
integrated quality and risk management plan (IQRMP). If the data show other IPDs, the 
definition in the IQRMP will be supplemented accordingly by the time of the Report 
Planning Meeting.
IPDs will be summarized and listed. Table 6.2: 1 below specifies which kind of IPDs could 
potentially lead to exclusion from which analysis set. The decision on exclusion of subjects
from analysis sets will be made at the latest at the Report Planning Meeting, after discussion 
of exceptional cases and implications for analyses. If the data show other IPDs, this table will 
be supplemented accordingly by the time of the Report Planning Meeting.
Important and non-important Covid-19 related PDs will only be listed (12).


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Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Excluded from which 
analysis set
A1
Inclusion Criteria Not Met
PKS, BMS
A2
Exclusion Criteria Violated
PKS, BMS
B1
Informed consent not available/not done
TS, PKS, BMS
B2
Informed consent too late
None
C1
Non-compliance
PKS, BMS
C2
Incorrect intake of trial medication
PKS, BMS
C3
Randomization not followed
PKS, BMS
C4
Accidental Unblinding
PKS, BMS
D1
Prohibited medication use
PKS, BMS
D2
Improper washout of concomitant medication
PKS, BMS
E1
Certain violations of procedures used to measure 
primary or secondary data
PKS
F1
Certain violations of time schedule used to measure 
primary or secondary data
PKS
G1
Intake of meal not according to CTP
PKS
6.3
SUBJECT SETS ANALYSED
Subject sets will be used as defined in the Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The 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 deviation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.
In addition, the following subject sets for a certain analysis of ECG and biomarker data 
will be used.
All ECG analyses are performed on the TS, except for the exposure-response analyses, 
which are performed on the ECGPCS defined below.


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
ECG plasma concentration set (ECGPCS): This subject set includes all subjects from 
the TS who provide at least one pair of a valid drug plasma concentration and a 
corresponding (i.e. time-matched) ECG endpoint to be used in the exposure-response 
analyses. For placebo subjects, the plasma concentration is set to zero and hence 
always considered as valid. The decision whether a time deviation between PK blood 
sampling and ECG recording is acceptable (and thus whether the pair of values will 
be used) is to be made no later than at the RPM before data base lock. For subjects 
treated with active drug, the decision about concentration value validity needs to be 
made within the Clinical Pharmacology Group.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
ECGPCS
Disposition
X
IPDs
X
Primary endpoint 
X
Secondary endpoints
X
Safety parameters
X
Demographic/baseline 
conditions 
X
Exposure
X
Exposure-response analyses
of ECG data
X
ECG except from exposure-
response analyses
X
6.5
POOLING OF CENTRES
This section is not applicable because the trial is performed in only one center.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of subjects who received the first administration of trial medication but failed to 
complete all periods of the study (dropouts or withdrawals) will be reported in the CTR as far 
as their data are available. Subjects who removed or withdraw from trial prior to the first 
administration of BI 706321 will not be entered in the CRF and thus will not be reported in 
the CTR. All withdrawals will be documented and the reason for withdrawal reported in the 
CTR.
CTP Section 7.5.1: It is not planned to impute missing values for safety parameters.
One exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
Missing data and outliers of PK data are handled according to BI standards (4) and (5). 
If replicate ECG recordings are missing, the arithmetic means per time point will be 
computed with the reduced number (1 or 2) of recordings.
For the classification of the on-treatment QTc/QT intervals into ‘no new onset’ / ‘new onset’ 
categories, the handling of missing value is described in Additional Section 9.4. For subjects 
on active drug, missing plasma concentration values with ‘BLQ’ in the comment field will be 
replaced by ½ LLOQ.
For placebo subjects, the missing plasma concentration values will be replaced by 0 for the 
exposure-response analyses.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For all parameters, except for ECG, the last non-missing value determined prior to first 
dosing of BI 706321 or placebo will be defined as baseline. 
There will be a centralised evaluation of 12-lead ECG recordings at the time points and for 
the ECG recordings specified in Table 6.7: 1.
Three triplicate ECGs will be recorded as the baseline before the first drug administration.
Triple ECGs (3 single ECGs recorded within 180 sec) will be recorded on on-treatment time 
points defined in the protocol with centralised ECG evaluation. 
The baseline value of an ECG variable is defined as the mean of the 3 single ECGs of the 
first of the 3 triplicates prior to first study drug administration. For all on-treatment 
assessments, only the first of the three replicate ECG at a single assessment time will be 
centrally evaluated.


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Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation
Visit
Day
Planned time [hh:mm]
- relative to respective 
drug administration
Study phase
Central evaluation
2
1
-1:00
Baseline
Mean of the 3 single ECGs of the 
first of the 3 triplicates prior to 
first study drug administration
1:00
On-treatment
First single ECG of the triplicate
2:00
4:00
8:00
12:00
2
24:00
36:00
3
48:00
19
431:45
433:00
434:00
436:00
440:00
444:00
20
456:00
21
480:00
For the exposure response analyses, pairs of ECG variables and corresponding plasma 
concentrations will be built using the same planned time points, e.g., the HR change from 
baseline and the plasma concentration measured at planned time 01:00 will build one pair. 
Whether a time deviation between PK blood sampling time and corresponding ECG 
recording is too big for a reliable assessment and the pair has to be excluded from the 
analysis will be decided no later than at the RPM.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
clinical trials and project summaries" (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment group 
subject number and visit (if visit is applicable in the respective listing). AE listings will be 
sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subjects set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
A medication will be considered concomitant, if it

is ongoing at the time of first study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
Only descriptive statistics are planned for this section of the CTR.
CTP Section 7.3.4: Previous and concomitant therapies will be presented per treatment 
group without consideration of time intervals and treatment periods.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analyzed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (RPM) (cf. Section 6.2) 
and described in the CTR.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis 
of the percentage of subjects with drug related AEs, which is the primary endpoint of this 
trial.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Not applicable.


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7.5.2
Secondary endpoints
Primary analyses
The secondary endpoints will be analysed descriptively based on the PKS and will be 
performed for the parent drug. The analysis of standard PK parameters is performed 
according to BI standards (4).


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Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma and urine concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the 
value will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies"(4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (5).
7.6.1
Safety parameters
Safety and tolerability will be analysed as described in Section 7.8 of this TSAP.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
CTP Section 7.3.5:  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 DG 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.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
The analysis of AEs will be based on the concept of treatment-emergent AEs. That means 
that all AEs will be assigned to screening or on-treatment phases as defined in Section 6.1. 


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AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
AEs occurring after the REP but prior to trial termination date will be assigned to ’follow-
up’.
An overall summary of AEs will be presented. This overall summary will also comprise 
summary statistics for the class of AESIs.
CTP Section 5.2.5.1.4: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
○
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 
○
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted), meaning AEs
(i) which are marked hematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs and
subjects with AESIs (according to ICH E3 (8)). AEs will be additionally summarized by 
maximum intensity.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5% (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5% (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards "Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which mean transforming to a standard unit and 
a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of absolute values and change from baseline from laboratory parameters
over time (see Section 6.7) will be provided. Frequency tables of changes between baseline 
and last value on treatment with respect to the reference range will be presented.
Unscheduled measurements of laboratory data will be assumed to be repeat measurements of 
the most recent scheduled measurement (e.g. for follow-up or confirmation of a particular 
value). Therefore, unscheduled measurements will be assigned to the planned time point of 
the previous scheduled measurement. Descriptive statistics will be calculated by planned time 
point based on the worst value of the subject at that planned time point (or assigned to that 
planned time point).
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the Report Planning Meeting (RPM) at the latest. It is the 
Investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values in an 
automated manner will not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
Line plots presenting individual values and means of c-reactive protein by treatment group 
over time as well as a scatter plot including AUCτ,ss and maximum c-reactive protein (during 
multiple dosing period) by treatment group will be displayed.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate and body temperature) will be 
descriptive in nature. Descriptive statistics of absolute values and (possible on-treatment 
relevant) changes from baseline from vital signs over time (see Section 6.7) will be provided.
Unscheduled measurements of vital signs will be assigned to planned time points in the same 
way as described above for laboratory data. However, for vital signs, descriptive statistics 
will be calculated by planned time point based on the last value of the subject at that planned 
time point (or assigned to that planned time point).
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment)
if judged clinically relevant by the investigator, and will be analyzed as such.


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A graph of body temperature by actual time will also be presented.
7.8.4
ECG
Abnormal findings will be reported as baseline conditions (prior to first study drug 
administration) or as AEs (from first study drug administration onwards ) if judged clinically 
relevant by the investigator (applies to all post-baseline ECG measurements). No separate 
listing or analysis of safety ECG findings will be prepared.
Centralized ECG
Descriptive analysis of ECG endpoints will be based on the TS. 
The evaluation of the relationship between plasma concentration and change in ECG 
endpoints (exposure-response analysis) will be based on the ECGPCS.
Generally, ECG measurements will not be included in the statistical analysis if one of the 
following applies:

No date or time available for ECG measurement

Pre-dose measurement done after first drug administration

On-treatment measurement done before first drug administration

Measurement is a repeated measurement

More than 3 single ECGs (i.e., measurements from 4th single ECG onwards will not 
be included)

Unscheduled measurements
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR, only listings will be provided. Occurrences of notable findings as well as 
measurements which are excluded from the statistical analysis will be flagged. In case of 
excluded measurements the reason for exclusion will be displayed.
CTP Section 5.2.4.1: Additional (unscheduled) ECGs may be recorded for safety reasons. 
These ECGs are assigned to the prior scheduled time point in the sponsor’s database. […]
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.
The above mentioned unscheduled ECGs will be listed separately.
Additionally comments regarding the ECGs will be listed.


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Categorical endpoints
CTP Section 7.3.4: 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.
For the categorical endpoints, frequency tables will be provided.
For all subjects with any notable finding in quantitative ECG recordings, a separate listing 
will be created as end-of-text display (based on the same display template as in 
Appendix 16.2), and the corresponding time profiles will be shown.
For subjects with notable findings, the individual time courses of QTcF, QT, HR, PR and 
QRS of these subjects will be presented in figures. Additionally a corresponding listing will 
be provided.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the absolute 
values and changes from baseline over time of QTcF, HR, QT, PR and QRS. The time 
profiles of mean and SD for the changes from baseline on treatment will be displayed 
graphically by treatment for PR, QT and QRS. Similar plots (not showing SD) are defined for 
QTcF and HR below, in context of the exposure-response analysis. 


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7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of 
Clinical Trials, current version
2
001-MCS-40-413_2.0: "Identify and Manage Important Protocol Deviations 
(iPD)", current version; IDEA for CON
3
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE 
dates", current version; KMED
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON
5
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", current version; IDEA for CON
6
KM Asset BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials 
and Project Summaries", current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0066: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED
8
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
9
KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED
10 Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white 
paper on concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 
2018;45(3):383-397 [R18-0143]
11 BI Statistical Position Paper: "Statistical Methods for PK", current version; KMED
12 KM Asset BI-KMED-COPS-HTG-0141: "CTR writing guidance for trial impacted 
by the COVID-19 pandemic", current version; KMED


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
12-JAN-21
None
This is the final TSAP