Clinical trial NCT03794323
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2019-01-30; Completion date: 2019-08-12
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics (PK) of BI 764122 in healthy male subjects following oral administration of single rising doses.

The objective of the food effect (FE) part is to investigate the relative bioavailability of BI 764122 under fed and fasted conditions.

Detailed description:

Arms: arm 1: 4 uncoated tablets of 1 milligram (mg) BI 764122 (total: 4 mg) were administered as single oral dose with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). Single rising dose (SRD) part. arm 2: 1 film-coated tablet of 10 mg and 2 uncoated tablets of 1 mg BI 764122 (total: 12 mg) were administered as single oral dose with 240 mL of water after an overnight fast of at least 10 h. SRD part. arm 3: 2 film-coated tablets of 10 mg and 5 uncoated tablets of 1 mg BI 764122 (total: 25 mg) were administered as single oral dose with 240 mL of water after an overnight fast of at least 10 h. SRD part. arm 4: 5 film-coated tablets of 10 mg BI 764122 (total 50 mg) were administered as single oral dose with 240 mL of water after an overnight fast of at least 10 h. SRD part. arm 5: 1 film-coated tablet of 100 mg BI 764122 (total: 100 mg) was administered as single oral dose with 240 mL of water after an overnight fast of at least 10 h. SRD part. arm 6: 2 film-coated tablets of 100 mg BI 764122 (total: 200 mg) were administered as single oral dose with 240 mL of water after an overnight fast of at least 10 h. SRD part. arm 7: 3 film-coated tablets of 100 mg BI 764122 (total: 300 mg) were administered as single oral dose with 240 mL of water after an overnight fast of at least 10 h. SRD part. arm 8: 4 film-coated tablets of 100 mg BI 764122 (total: 400 mg) were administered as single oral dose with 240 mL of water after an overnight fast of at least 10 h. SRD part. arm 9: 5 film-coated tablets of 10 mg BI 764122 (total: 50 mg) were administered as single oral dose with 240 mL water after an overnight fast of at least 10 h, followed by wash-out period of at least 7 days followed by 5 film-coated tablets of 10 mg BI 764122 (total: 50 mg) administered as single oral dose with 240 mL water after a standardized high-fat, high-calorie breakfast. Food effect (FE) part. arm 10: 5 film-coated tablets of 10 mg BI 764122 (total: 50 mg) were administered as single oral dose with 240 mL water after a standardized high-fat, high-calorie breakfast, followed by wash-out period of at least 7 days followed by 5 film-coated tablets of 10 mg BI 764122 (total: 50 mg) administered as single oral dose with 240 mL water after an overnight fast of at least 10 h. FE part. arm 11: placebo matching in size and weight to corresponding uncoated or film-coated BI 764122 tablets were administered as single oral dose with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). Single rising dose (SRD) part.
Interventions: intervention 1: BI 764122 intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c25602783-02
EudraCT No.
2018-003604-39
BI Trial No.
1430-0001
BI Investigational
Medicinal Product
BI 764122
Title
Safety, tolerability and pharmacokinetics of single rising oral 
doses of BI 764122 (single-blind, partially randomised, placebo-
controlled, parallel (sequential) group design) and the effect of 
food on BI 764122 (open-label, randomised, single-dose, two-
period, two-sequence crossover design) in healthy male subjects
Lay Title
A study in healthy men to find out how well different doses of 
BI 764122 are tolerated and whether food affects the amount of 
BI 764122 in the blood
Clinical Phase
I
Clinical Trial Lead
Phone:
Fax:
Principal 
Investigator
Phone:
Fax:
Status
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date
Version: 2.0
Date: 10 January 2019
Page 1 of 89
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
26 November 2018
Revision date
10 January 2019
BI trial number
1430-0001
Title of trial
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 764122 
(single-blind, partially randomised, placebo-controlled, parallel (sequential) group 
design) and the effect of food on BI 764122 (open-label, randomised, single-dose, 
two-period, two-sequence crossover design) in healthy male subjects
Principal Investigator
Trial site
 
Clinical phase
I
Trial rationale
As a transition from non-clinical investigations to clinical development, in this first-
in-man trial, safety, tolerability and pharmacokinetics of BI 764122 will be assessed 
in healthy male volunteers using single rising oral doses in order to provide the 
basis for a clinical development in the indication of Crohn’s disease.
The effect of food on the exposure of BI 764122 will be evaluated in healthy male 
volunteers using single oral doses under fasted and fed conditions in order to inform 
upcoming clinical studies in terms of improved trial-designs and optimized trial-
formulations.
Trial objectives
To investigate safety, tolerability and pharmacokinetics following single rising 
doses of BI 764122
To investigate the relative bioavailability of BI 764122 under fed and fasted 
conditions
Trial endpoints
Primary endpoint: the percentage of subjects with drug-related adverse events after 
single doses of BI 764122
Secondary endpoints: AUC0-∞and Cmax of BI 764122 after single doses
Trial design
Single rising dose (SRD) part: single-blind, partially randomised within DGs, 
placebo-controlled, parallel (sequential) group design
Food effect (FE) part: open-label, randomised, single-dose, two-period, two-
sequence crossover design


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Number of subjects 
total entered
76*
each treatment
SRD: 64
8 per DG (DG - 6 on BI 764122 and 2 on placebo)
FE: 12 (all on BI 764122)
* 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 is not exceeded. Thus, the actual number of subjects entered may 
exceed 76, but is not to exceed 92.
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product
BI 764122 as tablets (tablet strength 1 mg, 10 mg and 100 mg)
dose
SRD: 4 mg, 12 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg
FE: 50 mg (tentatively*)
* Dose selection based on the assumption to include the potential therapeutic dose. Dose may 
be decreased or increased based on the knowledge gained during trial conduct (e.g. safety, 
exploratory PK 
). In any case, the selected dose must be at least 2-fold lower 
than the last safely tested dose in the SRD part, and must not exceed the maximum 
acceptable thresholds of Cmax and AUC0-24 per protocol.
mode of admin.
SRD: Oral with 240 mL of water after an overnight fast of at least 10 h.
FE: Oral with 240 mL of water after an overnight fast of at least 10 h (fasted) or 
after a standardized high-fat, high-calorie breakfast (fed)
Comparator product
Matching placebo as tablets
dose
Not applicable
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
SRD: single dose
FE: 2 single doses separated by a washout period of at least 7 days


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Statistical methods
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Single rising dose (SRD) part:
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
10, 11
12-lead ECG
Continuous ECG monitoring
Vital signs (BP, PR)
Questioning for AEs and
concomitant therapy 6
1
-28 to -1
Screening (SCR)1
x
x
x
2
-3 to -1
-72:00 to 
-24:00
08:00
Ambulatory visit
x7
x
1
-1:30
06:30
Admission to trial site
-0:30
07:30
Allocation to treatment2
x2,5
x2
x2,8
x2
x2
0:00
08:00
Drug administration
▲
0:10
08:10
x
x9
│
x
0:20
08:20
x
│
0:30
08:30
x
x9
│
x
0:45
08:45
x
x9
│
x
1:00
09:00
x13
x9
│
x
x
1:30
09:30
x
x9
│
x
2:00
10:00
240 mL fluid intake
x
x9
│
x
x
3:00
11:00
x
x9
│
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x9
│
▼
x
x
6:00
14:00
x
x9
x
x
8:00
16:00
Snack (voluntary)3
x
x9
x
x
10:00
18:00
Dinner3
x
x9
x
x
12:00
20:00
x
x9
x
x 
2
24:00
08:00
x
x
x9
x
x
34:00
18:00
x
x
x
x
3
48:00
08:00
Breakfast (voluntary)3,
discharge from trial site
x
x
x
x
x
4
72:00
08:00
Ambulatory visit
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
x
6
120:00
08:00
Ambulatory visit
x
x
x
x
3
7 to 11
End of trial (EoT) examination4
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; procedures are to be performed and completed within the 3 h prior to drug administration. 
Allocation to treatment may be performed at any time following enrolment but must be completed prior to (first) drug 
administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoT examination includes physical examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs, and concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time.


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6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
ambulatory visit can be omitted if the screening examination is performed on Days -3, -2 or -1.
8.
At baseline (i.e. Day 1, prior to drug administration) 3 triplicate ECGs are recorded within approximately one hour. 
Each triplicate recording should be separated by at least 15 minutes.
9.
The ECG recording has to be performed in triplicate ECGs within 180 sec 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 removed does not exceed 500 mL per 
subject.
11. Including blood samples for metabolite identification only in DG 4 (50 mg). See Section 5.3.2.2.
13. Only in DG 4 (50 mg) one additional blood sample for stability testing will be taken at this time (see Section 5.3.2.4).


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Food effect (FE) part:
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and
concomitant therapy 6
1
-28 to -1
Screening (SCR)1
x
x
x
2 or 38
-3 to -1
-72:00 to 
-24:00
08:00
Ambulatory visit
x7
x
(separated by a washout period of at least 7 days)
1
-1:30
06:30
Admission to trial site,
allocation to treatment2
x5
x2
x2
x2
x2
-0:30
07:30
Standardized breakfast (only in fed 
state arm)
0:00
08:00
Drug administration
0:10
08:10
x
x
x
0:20
08:20
x
x
x
0:30
08:30
x
x
x
0:45
08:45
x
x
x
1:00
09:00
x
x
x
x
1:30
09:30
x
x
x
2:00
10:00
240 mL fluid intake
x
x
x
x
3:00
11:00
x
x
x
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
x
x
x
6:00
14:00
x
x
x
x
8:00
16:00
Snack (voluntary)3
x
x
x
x
10:00
18:00
Dinner3
x
x
x
x
12:00
20:00
x
x
x
x
2
24:00
08:00
Breakfast (voluntary),
discharge from trial site
x
x
x
x
x
34:00
18:00
Ambulatory visit
x
x
x
x
3
48:00
08:00
Ambulatory visit
x
x
x
x
x
4
72:00
08:00
Ambulatory visit
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
x
6
120:00
08:00
Ambulatory visit
x
x
x
x
4
7 to 11
End of trial (EoT) examination4
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; procedures are to be performed and completed within the 3 h prior to drug administration. 
Allocation to treatment may be performed at any time following enrolment but must be completed prior to (first) drug 
administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoT examination includes physical examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs, and concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time.
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. 
Only for Visit 2: if safety laboratory is taken and medically evaluated within 3 days prior to administration of study drug 
(i.e. if the screening examination is performed on Days -3, -2 or -1) this ambulatory visit can be omitted.


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8.
Two identical treatment periods, separated by a washout period of at least 7 days between drug administrations; based 
on sequence intake of study drug under fasted or fed conditions. The duration of washout period may be revised based 
on the PK exploratory analysis in SRD part of the study.
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 removed does not exceed 500 mL per 
subject.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 13
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.2
DRUG PROFILE...............................................................................................16
Nonclinical pharmacology....................................................................17
1.2.1
Toxicology..............................................................................................20
1.2.2
Nonclinical pharmacokinetics..............................................................22
1.2.3
Prediction of human pharmacokinetics..............................................25
1.2.4
Clinical experience in humans.............................................................25
1.2.5
Residual Effect Period..........................................................................25
1.2.6
Drug product.........................................................................................25
1.2.7
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................26
Starting dose..........................................................................................27
1.3.1
Maximum dose and dose escalation ....................................................27
1.3.2
1.4
BENEFIT - RISK ASSESSMENT ...................................................................28
Expected benefit for the target indication ..........................................28
1.4.1
Procedure-related risks ........................................................................29
1.4.2
Drug-related risks and safety measures..............................................29
1.4.3
Mode of action and nature of the target...................................29
1.4.3.1
Relevance of animal models....................................................29
1.4.3.2
Findings in non-clinical safety studies.....................................30
1.4.3.3
Drug induced liver injury.........................................................30
1.4.3.4
Risk minimization (safety precautions and stopping rules).....30
1.4.3.5
Overall assessment................................................................................31
1.4.4
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


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 35
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................35
Single rising dose (SRD) part...............................................................35
3.1.1
Food effect (FE) part ............................................................................37
3.1.2
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................37
3.3
SELECTION OF TRIAL POPULATION ......................................................38
Main diagnosis for trial entry..............................................................38
3.3.1
Inclusion criteria...................................................................................38
3.3.2
Exclusion criteria ..................................................................................39
3.3.3
Withdrawal of subjects from treatment or assessments ...................40
3.3.4
Discontinuation of trial treatment............................................41
3.3.4.1
Withdrawal of consent to trial participation ............................41
3.3.4.2
Discontinuation of the trial by the sponsor..............................42
3.3.4.3
Replacement of subjects (only FE part)..............................................42
3.3.5
4.
TREATMENTS........................................................................................ 43
4.1
INVESTIGATIONAL TREATMENTS ..........................................................43
Identity of the Investigational Medicinal Products ...........................43
4.1.1
Selection of doses in the trial and dose modification .........................44
4.1.2
Method of assigning subjects to treatment groups ............................45
4.1.3
Drug assignment and administration of doses for each subject .......45
4.1.4
Blinding and procedures for unblinding ............................................47
4.1.5
Blinding ...................................................................................47
4.1.5.1
Unblinding and breaking the code...........................................48
4.1.5.2
Packaging, labelling, and re-supply ....................................................48
4.1.6
Storage conditions.................................................................................48
4.1.7
Drug accountability ..............................................................................48
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................49
Other treatments and emergency procedures....................................49
4.2.1
Restrictions............................................................................................49
4.2.2
Restrictions regarding concomitant treatment .........................49
4.2.2.1
Restrictions on diet and life style.............................................49
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................50
5.
ASSESSMENTS....................................................................................... 51
5.1
ASSESSMENT OF EFFICACY.......................................................................51
5.2
ASSESSMENT OF SAFETY............................................................................51
Physical examination ............................................................................51
5.2.1
Vital signs...............................................................................................51
5.2.2
Safety laboratory parameters..............................................................51
5.2.3
Electrocardiogram................................................................................54
5.2.4
12-lead resting ECG.................................................................54
5.2.4.1


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Continuous ECG monitoring (SRD part only) ........................56
5.2.4.2
Other safety parameters.......................................................................56
5.2.5
Assessment of adverse events...............................................................56
5.2.6
Definitions of adverse events...................................................56
5.2.6.1
Adverse event ............................................................56
5.2.6.1.1
Serious adverse event ................................................57
5.2.6.1.2
AEs considered ‘Always Serious’.............................57
5.2.6.1.3
Adverse events of special interest .............................58
5.2.6.1.4
Intensity (severity) of AEs.........................................58
5.2.6.1.5
Causal relationship of AEs ........................................58
5.2.6.1.6
Adverse event collection and reporting ...................................59
5.2.6.2
AE collection.............................................................59
5.2.6.2.1
AE reporting to the sponsor and timelines ................60
5.2.6.2.2
Information required..................................................60
5.2.6.2.3
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................60
Assessment of pharmacokinetics .........................................................60
5.3.1
Methods of sample collection...............................................................61
5.3.2
Blood sampling for pharmacokinetic analysis.........................61
5.3.2.1
Blood sampling for metabolism analysis.................................61
5.3.2.2
Analytical determinations ....................................................................64
5.3.3
Analytical determination of BI 764122 plasma concentration 64
5.3.3.1
5.4
ASSESSMENT OF BIOMARKERS................................................................64
Methods of sample collection...............................................................64
5.4.1
Analytical determinations ....................................................................65
5.4.2
5.5
BIOBANKING ...................................................................................................65
5.6
OTHER ASSESSMENTS .................................................................................65
Pharmacogenomic evaluation..............................................................65
5.6.1
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................65
6.
INVESTIGATIONAL PLAN.................................................................. 66
6.1
VISIT SCHEDULE............................................................................................66
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................66
Screening period....................................................................................66
6.2.1
Treatment periods.................................................................................66
6.2.2
Follow-up period and trial completion ...............................................67
6.2.3
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 69
7.1
STATISTICAL DESIGN – MODEL ...............................................................69


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7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................69
7.3
PLANNED ANALYSES....................................................................................69
Primary endpoint analyses...................................................................71
7.3.1
Secondary endpoint analyses ...............................................................71
7.3.2
Safety analyses.......................................................................................73
7.3.4
7.4
INTERIM ANALYSES .....................................................................................75
7.5
HANDLING OF MISSING DATA ..................................................................75
Safety......................................................................................................75
7.5.1
Pharmacokinetics..................................................................................76
7.5.2
7.6
RANDOMISATION ..........................................................................................76
7.7
DETERMINATION OF SAMPLE SIZE ........................................................76
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 78
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................78
8.2
DATA QUALITY ASSURANCE .....................................................................79
8.3
RECORDS..........................................................................................................79
Source documents .................................................................................79
8.3.1
Direct access to source data and documents.......................................80
8.3.2
Storage period of records.....................................................................80
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................80
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......81
Collection, storage and future use of biological samples and 
8.5.1
corresponding data ...............................................................................81
8.6
TRIAL MILESTONES .....................................................................................81
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................82
9.
REFERENCES......................................................................................... 84
9.1
PUBLISHED REFERENCES...........................................................................84
9.2
UNPUBLISHED REFERENCES.....................................................................86
10. APPENDICES .......................................................................................... 88
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 89
11.1
GLOBAL AMENDMENT 1 .............................................................................89


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CD
Crohn’s disease
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTM
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
DG
Dose group
DILI
Drug induced liver injury
ECG
Electrocardiogram
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid


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EoT
End of trial
EU
European Union
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FDA
Food and Drug Administration
FE
Food effect
FIM
First-in-man
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GLP
Good laboratory practice
gMean
Geometric mean
HED
Human Equivalent Dose
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
iPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
IV
Intravenous
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MCT
Melanin-containing tissues
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in Safety Testing
NC
Not calculated
NOAEL
No observed adverse effect level
NOEL
No observed effect level
PAD
Pharmacologically Active Dose
PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set


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PO
oral
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
RR
Respiratory rate
SAE
Serious adverse event
SCR
Screening
SNP
Single nucleotide polymorphism
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or treatment
TMDD
Target mediated drug disposition
TMF
Trial master file
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
XTC
Ecstasy


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Crohn’s disease (CD) is characterized by a 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. CD incidence and prevalence have been 
rising in all ethnic groups. The recent incidence and prevalence have been reported to range 
from 7.9 to 20.2 and from 161 to 319 per 100,000, respectively [R13-2231]. CD typically 
follows a relapsing and remitting course, and causes substantial acute and long-term 
morbidity and increased mortality. Patients often develop local complications (e.g. fistulas, 
abscesses, strictures, or perforation), systemic complications (e.g. uveitis, arthritis), or side 
effects of treatment, and may require major surgery. Roughly a third of patients fall into each 
of the categories of mild, moderate, and severe disease.
Unmet medical need in CD is highest in patients with moderate to severe disease. Patients, 
not responding to conventional therapy of orally administered aminosalicylates (e.g. 5-ASA), 
glucocorticoids and immunomodulator agents (azathioprine or 6-MP), are 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. 
Another 30-40% of patients, receiving TNFi, have only a limited response, or lose their 
response over time (maintenance therapy). Additionally, there remain concerns over 
infection- and lymphoma risks with these agents. Biologic options (vedolizumab, 
ustekinumab) offer alternative additional treatment 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 
medical need remains for agents with greater efficacy than current therapies, either as a 
stand-alone therapy or in combination with existing therapies.
In CD, vanin enzymes are dysregulated and are linked to development of epithelial barrier 
injury through their product cysteamine [R18-3167, R17-3322, R17-3323]. By reducing 
cysteamine levels, a vanin inhibitor is expected to provide the epithelial barrier with a broad 
protective effect against diverse disease-driving stimuli, leading to direct epithelial barrier 
repair and resulting in mucosal healing. In addition, vanin inhibitor is expected to attenuate 
chronic inflammation that is underlying the disease. Oral medicines with a novel mode of 
action that includes repair of epithelial barrier would address the unmet medical need in CD. 
Therefore, BI 764122, a first-in-class vanin inhibitor, will be developed in CD.
1.2
DRUG PROFILE
Vanin-1 and -2 (Vascular Non-Inflammatory molecules 1 and 2) are extracellular enzymes 
expressed in humans on epithelial cells (lung, kidney, and intestinal tract), liver, dendritic 
cells macrophages, monocytes, B- & T-lymphocytes, neutrophils and platelets, shed in 
significant amounts into the extracellular milieu, and are found in most extracellular 
compartments across tissues.
Inflammatory mediators and bacterial endotoxins drive expression Vanin-1 and 2 enzymes 
whose common function is to convert pantetheine into pantothenic acid and cysteamine 


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[R18-3178, R18-3176]. It is through production of cysteamine that Vanin enzymes directly 
impact extracellular metabolic homeostasis of tissues by chemically reducing and depleting 
cystine in tissues through reducing it to cysteine [R18-3175, R18-3178, R18-3176]. Cystine 
depletion is understood to alter the intracellular redox balance of tissues, resulting in 
increased oxidative stress, endoplasmic reticular stress, and disruption and eventual 
destruction of tissue. In addition, cystine depletion results in increased extracellular cysteine 
levels, enhancing adaptive immune response, increasing T-lymphocyte proliferation and the 
production of pro-inflammatory cytokines IFNγ, IL-4, IL-5 and IL-13.
Therefore, it is expected that inhibition of Vanin enzyme function will directly restore tissue 
metabolite homeostasis and redox balance leading to tissue repair, while curbing chronic 
inflammation which could prove beneficial in diseases characterized by tissue lesions and 
ulceration as well as the presence of chronic inflammation.
For consistency of nomenclature, Vanin-1 and Vanin-2 isoforms, unless referenced 
otherwise, will be referred to as Vanin.
Nonclinical pharmacology
1.2.1
Primary pharmacodynamics
In vitro primary pharmacodynamics
In a human recombinant human vanin-1 enzymatic activity assay [n00264301], pantothenic 
acid production (as a measurement of vanin-1 activity) was inhibited with an IC50 of 0.08 nM 
(CI 95%: 0.06; 0.12 nM).
In human whole blood, BI 764122 inhibited vanin activity [n00264300], measured by a 
decrease in pantothenic acid formation, with a mean IC50 value of 3.01 nM (CI 95%: 1.6, 
5.8 nM).
In non-diseased human colon tissue explants, BI 764122 inhibited vanin activity 
[n00264303], measured by a decrease in cysteamine formation with a mean IC50 of 3.7 nM 
(CI 95%: 1.5 and 9.4 nM).
In a human small intestinal barrier model, trans-epithelial electrical resistance was used to 
assess the intestinal barrier function [n00259752]. After a TNFα-mediated epithelial barrier 
injury, a protection of epithelial barrier function could be demonstrated with an IC50 of 
3.4 nM (CI 95%: 1.6; 6.9 nM) applying BI 764122 at 10 nM.
In an ex vivo colon tissue assay [n00259751], using resected, non-inflammatory bowel 
disease human colon explants (n= 6), 5 μM of BI 764122 reduced the formation of an 
apoptotic neoepitope of Cytokeratin-18 (CK-18), detected by immunohistochemistry in 
colonic crypt epithelial cells. This was interpreted as a signal of epithelial healing and crypt 
preservation. 
Tissue biopsies taken from ileal (n=8) and colonic (n=2) lesions from active CD patients 
(n=10) were profiled for the expression of 186 genes, including key markers of epithelial 
injury, repair, tissue remodeling and inflammation in the presence or absence of BI 764122 
[n00259750]. Markers associated with epithelial repair, such as KRT18 (CK-18 transcript) 
and EPCAM were significantly elevated and calprotectin (S100A8/9) levels were reduced 
under 5μM of BI 764122.


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The effect of BI 764122 on T-lymphocyte activity was tested in CD3/28 stimulated CD4+ 
T-cells [n00259748], obtained from healthy volunteers (n=8) and CD patients (n=7). 
Proliferation of CD4+ T-cells were examining by flow cytometry and by assessing secretion 
of IFNγ, IL-4, IL-5 and IL-13. Vanin activity significantly enhanced T-cell proliferation and 
cytokine production. These effects were reversed by 1μM of BI 764122, resulting in a 
reduction of both, T-cell proliferation and inflammatory mediator production.
In a cross-species comparison, vanin-1 expression is well-conserved and aligned between 
human and rodent species. However, as rodents lack vanin-2, there is a considerable 
discrepancy between species. In dogs, vanin-1 mRNA levels are high in the lung, liver, 
spleen and kidney. Comparative expression in tissues is generally lower in the rat, although 
tissue distribution is comparable. While dogs possess a vanin-2 gene, its expression in dog 
tissues is not characterized. In cynomolgus monkey, tissue distribution of both Vanin-1 and -
2 isoforms are broadly comparable to human.
Vanin activity is present in the blood of humans, mouse, rat, dog and cynomolgus monkey. 
Potency of BI 764122 was determined in human whole blood with IC50 = 3 nM [n00264300] 
and in mice with IC50 = 22 nM [n00264302].
BI 00764122 does not inhibit any targets included in the Eurofins panel of assays 
[n00264294], and does not inhibit any of the 281 kinases included in the Invitrogen kinase 
panel [n00264299].
In vivo primary pharmacodynamics
In a model of dextran sodium sulfate (DSS) mediated intestinal injury [n00259753], female 
C57Bl/6 mice received 30 mg/kg of BI 764122 orally, twice daily over 7 days. The animals 
showed reduced epithelial damage and improved barrier integrity, as well as a decrease in the 
formation of inflammatory infiltrates. BI 764122 treatment also reduced intestinal 
permeability (assessed by a reduction of sucralose uptake through the colon) and 
demonstrated target engagement, as measured by decreased levels of the vanin product, 
cysteamine, in plasma and colon tissue.
Safety pharmacology
General and safety pharmacology studies have been conducted with BI 764122 to assess 
possible effects on cardiovascular, CNS, respiratory, renal and liver function.
Cardiovascular system
BI 764122 was tested twice for blocking hERG-mediated potassium current in HEK293 cells 
[n00261485]. Since no inhibition at highest concentrations was seen, the IC50 for hERG 
inhibition was not calculated.
In a GLP-study, cardiovascular function of BI 764122 was assessed in conscious, telemetry 
instrumented Beagle dogs (3m/ 3f) at oral doses of 30, 100, and 300 mg/kg [n00261087]. 
Heart rate, systemic blood pressure parameters (diastolic, pulse and mean arterial pressures), 
left ventricular parameters (left ventricular systolic pressure, left ventricular end diastolic 
pressure, left ventricular contractility and relaxation), electrocardiographic duration/intervals 
(PR, RR, QRS, QT, and QTcv), qualitative ECG parameters and body temperature were 
measured up to 24 hours post dose. With the exception of (1) a mild increase in heart rate 
from 1 to 6 hours post dose at 100 mg/kg (Cmax of 227,000 nM and AUC of 1,260,000 nM•h 


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based on combined sex ) and (2) a slight decrease in systolic and diastolic pressure with a 
concurrent increase in heart rate at 300 mg/kg up to 12 hours post dose, no biologically 
significant changes were noted.
Respiratory function
In a GLP-study, BI 764122 at oral dose up to 1000 mg/kg had no effect on the respiratory 
system of male Wistar Han rats up to 24 hours post dose [n00261089].
Central nervous system effects
In a GLP study, BI 764122 had no effect on the central nervous system of male Wistar Han 
rats at oral doses of up to 300 mg/kg. The administration of 1000 mg/kg resulted in 
autonomic changes (decreases in body temperature) at 1 and 6 hours post dose and behavioral 
changes (reduction in alertness) at 6 hours post dose, as well as sensorimotor changes 
(minimal response to tail pinch, tactile reflex and auricular startle) and neuromuscular 
changes (flaccid body tone and flaccid extensor thrust) at 6 hours post dose. Effects were 
transient and had reverted by 24 hours post dose.
Gastrointestinal function
In a non-GLP study, BI 764122 did not affect gastric emptying and intestinal transit in 
conscious male rats after a single oral dose of up to 10 mg/kg [n00262543].
Renal and hepatic function
In non-GLP examinations, following the administration of 10 mg/kg (highest dose) in male 
Wistar Han rats [n00262545], BI 764122 did not affect urine- and serum-derived parameters 
as well as the calculated clearance of urea and creatinine, with the exception of a slight 
increase of conjugated bilirubin levels.
Further considerations on safety pharmacology
In a vanin-1 knock-out/NOD diabetic mouse model, vanin deficiency aggravated islet cell 
death and diabetes, whereas treatment with super-physiological levels of cysteamine reduced 
pancreatic islet cell death and thus might play a role in islet cell protection [R17-3327]. Other 
findings suggest that elevated expression of vanin-1 in pancreatic ductal adenocarcinoma 
cells aggravated loss of pancreatic islet function and was associated with the onset of 
pancreatic cancer-associated new onset diabetes [R18-2866]. However, further studies, 
assessing the metabolic impact of vanin-1 deficiency, absence of vanin-1 either in knock-out 
mice or by pharmacological inhibition, did not impact glycemic control [R18-2867]. 
Pharmacological inhibition of vanin-1 in diabetic rats for 8 days using RR6, a small molecule 
vanin-1 inhibitor, was well tolerated and showed no significant effects on hepatic steatosis in 
diabetic rats [R18-2867]. These diverse data suggest that BI 764122 might impact islet cell 
survival and glycemic control although the findings of different studies are contradictory. 
Thus far conducted safety pharmacology, genetic toxicology and general toxicology studies 
did not indicate any toxicity of BI 764122 related to glycemic control. 
A human missense single nucleotide polymorphism (SNP) (rs2272996) in the gene encoding 
vanin-1 is associated with decreased blood pressure, with the SNP causing faster degradation 
of vanin-1 and significant reduction of vanin-1 plasma levels [R18-2692].


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Pharmacodynamic interactions
No pharmacodynamics interaction studies have been carried.
Conflicting literature exists regarding effect of Vanin inhibition on acetaminophen 
(paracetamol) toxicity. An earlier study [R18-2954] suggested that Vanin-1 deficiency (in 
knock-out mice) might protect mice against acetaminophen-induced liver toxicity. In another 
[R17-3326], acetaminophen-induced liver toxicity was exacerbated in Vanin-1 knock-out 
mice compared to wild type littermates.
In conclusions, there is evidence from in vitro, ex- and in vivo models of mucosal barrier 
disruption that the vanin inhibitor BI 764122 is contributing to epithelial healing and crypt 
preservation as well as to T-lymphocyte attenuation. General and safety pharmacology was 
addressed in a core battery of CNS (GLP), cardiovascular (GLP), respiratory (GLP) as well 
as renal and hepatic function (non-GLP). BI 764122 has a low risk for QT prolongation. The 
observed decrease in blood pressure with compensatory increases in heart rate in the GLP 
dog telemetry study at 300 mg/kg may be related to the pharmacological inhibition of Vanin. 
Genetic mutations in humans, resulting in a lower vanin-1 expression, were associated with a 
decrease in blood pressure [R18-2692]. Autonomic, behavioral, sensorimotor and 
neuromuscular changes at 6 hours post dose were seen after the administration of 1000 mg/kg 
to rats. These effects were transient and had reverted by 24 hours post dose.
Toxicology
1.2.2
Single dose toxicity
Acute toxicity was not studied.
Repeat dose toxicity
In a 4-week GLP-study in Wistar Han rats, BI 764122 was administered for 4 weeks at oral 
doses of 100, 300 and 1000 mg/kg/day, followed by a 4-week recovery period [n00261387]. 
No mortality was observed. No BI 764122-related effects on clinical signs, body weight, food 
consumption, ophthalmology, or immunophenotyping was seen at any dose level. At doses of 
≥100 mg/kg/day, a (reversible) increase in kidney and liver weight was observed. 
Microscopically, no correlating changes were identified. At doses of ≥300 mg/kg/day, a 
(reversible) increase in mean relative/ absolute reticulocytes and red cell distribution width 
was observed. A (reversible) decrease in mean potassium, chloride and globulin was noted. In 
one of 10 animals, debris in epididymal ducts was seen. At doses of 1000 mg/kg/day, an 
increase in mean white blood cell counts was observed, attributed to an increase in mean 
absolute neutrophils and monocytes. Also, a decrease in mean absolute eosinophils was 
noted. A (reversible) increase in mean alanine aminotransferase, urinary protein (reversible) 
and urinary mixed crystals was seen. In addition, a decrease in mean total protein and 
albumin was observed. A (reversible) decrease in mean chloride and (reversible) increase of 
mean phosphorus was noted. A (reversible) decrease in thymic weight was seen in male 
animals without macroscopic and microscopic correlation. Microscopic effects on the testes 
and epididymides (minimal retention of spermatids, abnormal spermatogenesis) were 
observed. This finding is considered adverse because it may indicate disruption of the normal 
spermatogenic cycle that could result in effects on fertility [R18-2864]. The NOAEL was 


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considered to be 300 mg/kg/day which corresponded to a Cmax of 394,000 nM and AUC0-24 of 
1,750,000 nM•h in males and Cmax of 423000 nM and AUC0-24 of 1,400,000 nM•h in females.
In a 4-week GLP-study in male and female Beagle dogs, BI 764122 was administered for at 
least 4 weeks at oral doses of 30, 100 or 300 mg/kg/day, followed by a 4-week recovery 
period [n00261263]. No mortality was observed. There were no BI 764122-related effects on 
clinical signs, ophthalmology, physical examinations, electrocardiograms, urinalysis, or 
immunophenotyping observed at any dose level. At doses of ≥ 100 mg/kg/day, an increase in 
mean alanine aminotransferase (ALT) was noted without any microscopic liver changes. 
Also, a (reversible) decrease in thymus size with a corresponding decrease in lymphocytic 
cellularity was seen. At doses of 300 mg/kg/day, a decrease in mean body weight was noted, 
corresponding with a decrease in food consumption. Due to the magnitude of the change, it 
was considered adverse. Also, an increase in aspartate aminotransferase (AST) levels was 
observed. In addition, a (reversible) decrease in mean phosphorus levels was seen. The 
NOAEL was considered to be 100 mg/kg/day which corresponded to a Cmax of 159,000 nM 
and AUC0-24 of 1,070,000 nM•h (male and female combined!). The NOEL was at 30 
mg/kg/day which corresponded to a Cmax of 32,900 nM and AUC0-24 of 157,000 nM•h 
(male).
Genotoxicity
BI 764122 was not mutagenic in the bacterial reverse gene mutation (Ames) test [n00261507]
up to 5000 μg/ plate and in the in vitro micronucleus assay [n00261509] up to the dose limit 
of 1 mM. In the in vivo rat bone marrow micronucleus assay [n00261378] no increase in the 
incidence of micronuclei in polychromatic erythrocyte (MnPCEs) was observed up to an oral 
dose of 2000 mg/kg/day. BI 764122 was concluded to be negative in the rat bone marrow 
micronucleus assay.
Carcinogenicity
Carcinogenicity studies have not yet been conducted.
Reproductive and developmental toxicity
In the 4-week rat study [n00261387], there were adverse microscopic effects on the testis and 
epididymis at 1000 mg/kg/day. No adverse effects on the reproductive tract were seen at 
300 mg/kg/day. No effects on the reproductive tract were noted in the 4-week dog study 
[n00261263].
Local tolerance
No local tolerance studies have been conducted.
Other toxicity studies
BI 764122 exhibits an absorption band in the spectral region of 290-700 nm with a maximum 
absorbance at 310 nm (molar extinction coefficient of 9745 L mol-1 cm-1) [n00260689]. In an 
in vitro assay, using BALB/c 3T3 mouse fibroblasts, BI 764122 did not demonstrate any 
phototoxic potential up to 100 μg/mL [n00261538].
In conclusion, toxicological data of BI 764122 support clinical studies in men with daily oral 
administration for up to 28 days. Results from 4-week GLP studies suggest a NOAEL of 
300 mg/kg/day in rat (corresponding to Cmax of 394,000 nM and AUC0-24 of 1,750,000 nM•h 


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in male, as well as Cmax of 423,000 nM and AUC0-24 of 1,400,000 nM•h in female) and 
100 mg/kg/day in dog (corresponded to Cmax of 159,000 nM and AUC0-24 of 1,070,000 nM•h 
in male and female combined). The risk of genotoxicity and phototoxicity is low. The 
NOEL in dog was at 30 mg/kg/day (corresponded to a Cmax of 32,900 nM and AUC0-24 of 
157,000 nM•h - male). Carcinogenicity and local tolerance has not yet been examined. Signs 
of reproductive toxicity were seen in male rats at 1000 mg/kg/day (abnormal 
spermatogenesis).
Nonclinical pharmacokinetics
1.2.3
Methods of analysis
To support GLP toxicity studies, LC-MS/MS assays (GLP) were validated for quantification 
of BI 764122 in rat plasma with a lower limit of quantitation of 1000 nM [n00263794] and in 
dog plasma with a lower limit of quantitation of 50 nM [n00263812].
Absorption
The pharmacokinetics (PK) of BI 764122 following single intravenous (IV) or oral (PO) 
doses were investigated in male Wistar Han rats, male beagle dogs, and female cynomolgus 
monkeys [n00264108].
PK parameters in animals [n00264108] are summarized in Table 1.2.3: 1. The disposition of 
BI 764122 in rats and monkeys is characterized by moderate clearance (CL) and a large 
volume of distribution (Vss). In dogs, CL and Vss are moderate. The half-life (t1/2) was short 
to moderate in dogs, and moderate to long in rats and monkeys. The bioavailability (BA) in 
rats, dogs and monkeys was high.
Table 1.2.3: 1
Mean PK parameters in rats, dogs and monkeys for BI 764122 
PK Parameter
Han Wistar Rat
(mean ±SD)a
Beagle Dog
(n=3, mean ±SD)
Cynomolgus Monkey
(n=4, mean ±SD)
Route of Administration
IV b
PO
IV
PO
IV
PO
Dose (mg/kg)
1
10
0.5
1
0.5
1
Sex
male
male
male
male
female
female
CL (mL/min/kg)
26.3 ± 3.8
--
10.2 ± 0.383
--
8.25 ± 1.89
--
Vss (L/kg)
8.8 ± 2.5
--
1.19 ± 0.19
--
5.67 ± 0.917
--
t1/2 (h)
8.7 ± 3.3
7.08 ± 3.62
10.7 ± 8.12
1.04 ± 0.103
20.8 ± 2.54
26.5 ± 7.21 
tmax (h) median (range)
--
0.25 (0.25)
--
0.5 (0.25-0.5)
--
0.75 (0.5-2.0)
Cmax (nM)
--
4,980 ± 644
--
2,680 ± 337
--
1,250 ± 499
AUC0-inf (nM•h)
1,874 ± 315
8,930 ± 821
2,370 ± 89.7
5,810 ± 728
3,060 ±713
3,950 ± 754
Ae renal (%dose)
22.7 ± 2.77
--
66.4 ± 33.3
--
47.6 ± 20.7
--
Renal CL (mL/min/kg) 
6.0
--
6.87 ± 3.68
--
4.07 ± 2.06
--
BA (%) c
--
89.5 d
--
100
--
72.1
a
IV (n=5) and PO (n=3).
b
Three IV dose levels (0.01, 0.1 and 1 mg/kg) were tested in the rat. The results of the highest dose tested are represented in this table. 
The CL of BI 764122 in rats was lower at lower dose levels.
c
BA values are model based and incorporate non-linear binding to target.
d
Rat BA was calculated based on modeling of all available rat PK data.
Nonlinear PK in rats and cynomolgus monkies was expected at low doses due to the 
recognized saturable binding of BI 764122 to vanin (the pharmacologic target) which 
circulates in plasma in both species. This target mediated drug disposition (TMDD) is 
characterized by an increase in the free fraction available for clearance as vanin becomes 


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saturated at higher doses. Therefore, three IV dose levels of BI 764122 (0.01, 0.1, and 
1 mg/kg) were tested in rats. The CL and Vss increased in rats with the increase in dose which 
is consistent with the increasing fraction unbound in plasma with increasing plasma 
concentrations. As a result, the plasma exposure of BI 764122 increased less than dose 
proportionally in the dose range from 0.01 to 1 mg/kg [n00264108].
Distribution
Plasma protein binding
The binding of 3H-BI 764122 to plasma proteins was assessed in mouse, rat, dog and human 
plasma in vitro by equilibrium dialysis [n00263789]. Binding in mouse, rat, and human 
plasma was concentration dependent due to saturable binding to the target in plasma ranging 
from 10.9-58.4% bound in mouse at concentrations from 300,000 to 0.1 nM, 9.5-86.9% 
bound in rat at concentrations from 300,000 to 1 nM, and 11.8-71.3% bound in human at 
concentrations between 300,000 and 0.03 nM.
Distribution in pigmented rat
Quantitative tissue distribution of total drug-related radioactivity was investigated in male 
pigmented Long Evans rats that were administered a single oral dose of 10 mg/kg of [14C]-
BI 764122 [n00263939]. The distribution of radioactivity was followed for up to 1 week post 
dose with ocular levels of radioactivity being monitored for up to 2 weeks post dose.
As measured by autoradiography, tissue-to-plasma ratios were markedly variable, ranging 
from 0.054 to 4.2 at 1 h post dose. At 24 h post dose, tissue-to-plasma ratios ranged from not 
calculable to 41, with the highest exposure being in the liver, kidney, vesicular gland and 
melanin-containing tissues (MCT). At 168 h post dose, radioactivity was only measurable in 
the liver, kidney, adrenal glands and eyeballs. Radioactivity was detectable in CNS only at 1h 
post dose, and was present at a concentration equal to 8-9% of the concentration present in 
whole blood at this time point. These results suggest low penetration of 14C-BI 764122 into 
the CNS.
The approximate half-lives of radioactivity in total eyeball (LSC) and MCT of the ocular bulb, 
based on limited data, were 250 and 320 h, respectively. Therefore, it was concluded that 
there was a high affinity and long exposure of radioactivity in ocular tissues. In the skin, 
levels dropped below the limit of detection in the subcutis at 24 h and in all parts of the skin 
at 168 h. Due to a lack of data points, a half-life of radioactivity in the skin was not calculated.
Metabolism
Human hepatic clearance was estimated to be 0.2 mL/min/kg based on the scaling of 
metabolic stability data in human hepatocytes. Therefore, hepatic clearance is considered to 
be a minor clearance route [n00264108]. Human renal clearance was predicted to be the 
major route of elimination and was estimated to be 4.3 mL/min/kg based on non-rodent data. 
The predicted human renal clearance is higher than the glomerular filtration rate 
(1.8 mL/min/kg), indicating that BI 764122 might be actively secreted into the urine 
[n00264108]. The potential involvement of renal transporters in humans for BI 764122 has 
not yet been determined.


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Excretion
In Wistar Han rats, excretion of radioactivity was assessed after an oral dose of 10 mg/kg and 
an intravenous dose of 2 mg/kg of 14C-BI 764122 [n00263786]. After oral dosing, 58.1% of 
the total administered radioactive dose was excreted within 96 h in the urine of male, and 
65.3% in female rats. Total radioactivity recovery in feces was 33.3% in male, and 29.4% in 
female rats. The excretion after oral dosing was rapid and nearly complete, with 92.0 and 
92.2% of dosed radioactivity recovered within the first 24 h from male and female rats, 
respectively. After an intravenous dose, 55.4% of the totally administered radioactive dose 
was excreted in urine within 96 h in male, and 55.8% in female rats. In feces, 41.6% of the 
totally administered radioactive dose was recovered in male, and 40.5% in female rats within 
96 h. The total excretion after intravenous dosing was rapid and complete, with 
approximately 96 % and 93.2% of dosed radioactivity recovered within 24 h from male and 
female rats, respectively. In bile duct-cannulated rats, an administered intravenous dose of 
14C-BI 764122, the biliary excretion within 6 h was 48.5%. These data indicated no 
difference in excretion patterns between male and female rats.
Pharmacokinetic drug interactions
No pharmacokinetic drug interaction studies have been conducted.
Toxicokinetics
PK parameters were assessed in GLP-toxicological studies and are displayed in Table 1.2.3: 2:
Table 1.2.3: 2
PK parameters in GLP-toxicological studies following oral 
administration of BI 764122
Study Type 
(Study or 
Report No.)
Dose 
(mg/kg/day)
Cmax (nM)a
AUC0-24 (nM•h)a
Cmax Multipleb
AUC Multipleb
M 
F
M
F
M
F
M
F
4 Week Rat (n00264288)
100
141,000
164,000
356,000
312,000
179
208
69
61
NOAEL
300
394,000
423,000
1,750,000
1,400,000
500
537
341
273
1000
1,090,000
783,000
13,800,000
6,540,000
1383
994
2686
1273
4 Week Dog (n00264293)
NOEL
30
32,900
42,100
157,000
163,000
42
53
31
32
NOAEL
100
136,000
182,000
1,080,000
1,060,000
173
231
210
206
300
698,000
806,000
7,340,000
7,840,000
886
1023
1429
1526
Human
35 mg/day
788
5137
a
Data shown are end of study exposures
b
Multiples calculated based on estimated human therapeutic exposure
Exposures corresponding to NOAEL dose in GLP studies are listed in bold
In conclusion, validated and highly sensitive LC-MS/MS assays to quantify BI 764122 
concentrations in plasma under GLP-conditions are available for rats and dogs. The 
disposition of BI 764122 is characterized in rats, dogs and monkeys by a moderate clearance 
and a moderate to large volume of distribution. High oral bioavailability is observed across 
the preclinical species, suggesting a high bioavailability in humans. Plasma protein binding of 
BI 764122 is concentration dependent ranging from 11.8 to 71.3% bound in humans at 
concentrations between 300,000 and 0.03 nM. In a quantitative whole body autoradiography 
study, CNS and skin exposure was low. Deposition of BI 764112 into melanin-containing 
tissues of the ocular bulb was high. Excretion of BI 764122 occurred mainly into urine 


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(55.4 to 65.3% of the dose) and to a less extent in feces (29.4 to 41.6% of the dose). In bile 
duct cannulated rats, biliary excretion of BI 764122 accounted for 48.5% of the dose. Human 
hepatic clearance (0.2 mL/min/kg) is estimated to be extremely low. Human renal clearance 
of BI 764122 (4.3 mL/min/kg) is expected to be the main route of elimination. Since renal 
clearance is greater than GFR, it is assumed that BI 764122 will be actively secreted into 
urine.
Prediction of human pharmacokinetics
1.2.4
A two compartment PK/PD model was developed using in vivo data from preclinical species, 
human in vitro data regarding the binding properties of BI 764122 to vanin, and a correlation 
between target engagement in the mouse and ex vivo analysis using human intestinal tissue.
TMDD was included in this model [n00264108]. The human therapeutic dose was predicted 
based on a dose that would lead to a 75% reduction in daily cysteamine formation, 
corresponding to a Cmax of 788 nM, a Cmin of 16 nM, and an AUC0-24 of 5,137 nM•h. From 
the PK/PD model it is expected that clinical efficacy will be maintained at a BI 764122 dose 
of 35 mg once daily [n00264108].
At BI 764122 doses less than the estimated therapeutic dose of 35 mg QD, the effects of 
TMDD are predicted to result in a decrease in the fraction unbound (fu) in plasma due to 
extensive binding to circulating vanin. This would theoretically result in a decrease in both 
CL and Vss of BI 764122 at lower doses compared to higher doses. At doses of 35 mg or 
greater, the PK profile of BI 764122 is predicted to be affected by TMDD only in the 
terminal elimination   phase, i.e. when plasma concentrations are relatively low and most of 
BI 764122 in plasma remains bound to vanin. As such, due to this predicted TMDD-mediated 
effect, a less than dose proportional increase in the plasma exposure of BI 764122 in humans 
may occur as doses are escalated.
Clinical experience in humans
1.2.5
This is the first in human study with the first-in-class vanin inhibitor BI 764122. Therefore, 
clinical experience in humans is not yet available.
Residual Effect Period
1.2.6
At the projected therapeutic dose, human effective half-life of BI 764122 is predicted to be 
3.3 h [n00264108]. Due to the assumed TMDD, this value might be substantially exceeded. 
With reference to the half-life in female Cynomolgus monkey after intravenous (20.8 ± 2.5 h) 
and oral (26.5 ± 7.2 h) application (see Table 1.2.3: 1), the pharmacokinetic residual effect 
period is conservatively estimated to range from 5 to 7 days.
Drug product
1.2.7
Please refer to Section 4.1.
For a more detailed description of the BI 764112 profile, please refer to the current 
Investigator’s Brochure (IB) [c23522589].


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Overall, non-clinical evidence suggests that BI 764122 is contributing to epithelial healing 
and T-lymphocyte attenuation in models of CD. BI 764122 has a low risk for QT 
prolongation. The observed decrease in blood pressure with compensatory increases in heart 
rate in dog at 300 mg/kg may be related to the pharmacological inhibition of Vanin. Genetic 
mutations in humans, resulting in a lower vanin-1 expression, were associated with a 
decrease in blood pressure [R18-2692]. Autonomic, behavioral, sensorimotor and 
neuromuscular changes in rat at 1000 mg/kg were transient and reversible. Toxicological 
data of BI 764122 support clinical studies in men with daily oral administration for up to 
28 days. Results from 4-week GLP studies suggest a NOAEL of 300 mg/kg/day in rat 
(corresponding to Cmax of 394,000 nM and AUC0-24 of 1,750,000 nM•h in male, as well as 
Cmax of 423,000 nM and AUC0-24 of 1,400,000 nM•h in female) and 100 mg/kg/day in dog 
(corresponded to Cmax of 159,000 nM and AUC0-24 of 1,070,000 nM•h in male and female 
combined). The NOEL in dog was at 30 mg/kg/day (corresponded to a Cmax of 32,900 nM 
and AUC0-24 of 157,000 nM•h - male) The risk of genotoxicity and phototoxicity is low. 
Pharmacokinetic predictions in humans, based on non-clinical data, suggest a high 
bioavailability. The PK/ PD model predicts that BI 764122 will be mainly excreted into urine 
and to a less extent into feces. Human hepatic clearance of BI 764122 (0.2 mL/min/kg) may
be extremely low. Human renal clearance (4.3 mL/min/kg) is expected to be the main route 
of elimination, supported by a presumed active secretion. The assumed therapeutic dose in 
humans, to achieve 75%-inhibition of cysteamine production over the course of a 24-h 
dosing interval, is estimated to be 35 mg once daily, corresponding to a Cmax of 788 nM, a 
Cmin of 16 nM, and an AUC of 5,137 nM•h. Due to an assumed target mediated drug 
disposition it is expected predicted that BI 764122 exposure will be less than dose 
proportional when administered orally over a wider dosing range.
1.3
RATIONALE FOR PERFORMING THE TRIAL
As a transition from non-clinical investigations to clinical development, in this first-in-man 
trial, safety, tolerability, pharmacokinetics and pharmacodynamics of BI 764112 will be 
assessed in healthy male volunteers, using single rising oral doses in order to provide the 
basis for the clinical development of BI 764112, a first-in-class, selective vanin inhibitor, in 
the indication of CD.
Young, healthy male subjects will be recruited for this study. They (1) provide a relatively 
stable physiological, biochemical and hormonal basis for studying drug effects, (2) show no 
disease-related variation and (3) are not taking regular concomitant medications.
In the single rising dose (SRD) parts, within each DG, all actively treated individuals will 
receive the same BI 764122 dose. The next higher dose will only be administered to the next 
group, if the treatment in the preceding DG was safe and showed acceptable tolerability.
In the food effect (FE) part, BI 764112 will be administered to subjects in a randomized two-
way-crossover fashion to (1) understand the effect of food on relative bioavailability, (2) 
support upcoming clinical studies with respect to improved trial designs and (3) optimize trial 
formulations.


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Starting dose
1.3.1
Maximum recommended starting dose (MRSD)
An estimation was made on the basis of the US FDA Guidance for Industry ‘Estimating the 
Maximum Recommended Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Healthy Volunteers’ [R06-1037].
Step 1:Determination of NOAELs in the safety pharmacology and toxicity studies
Rat:
300 mg/kg/day NOAEL for general toxicology in the 4-week rat toxicity study
Dog:
100 mg/kg/day NOAEL for general toxicology in the 4-week dog toxicity 
study
Step 2:Conversion of animal NOAELs to Human Equivalent Doses (HEDs)
Rat:
NOAEL = 300 mg/kg/day
Conversion factor from rat dose to HED: 6.2
HED
= 300 mg/kg/day ÷ 6.2
= 48 mg/kg/day
i.e. 2880 mg/day in humans (assuming a body weight of 60 kg)
Dog:
NOAEL = 100 mg/kg/day
Conversion factor from dog dose to HED: 1.8
HED
= mg/kg/day ÷ 1.8
= 56 mg/kg/day
i.e. 3360 mg/day in humans (assuming a body weight of 60 kg)
Step 3:Selection of HED from the most appropriate species
The HED derived from the rat, 300 mg/day, is the more conservative HED.
Step 4:Selection of safety factor
Based on applying a safety factor of 10 to the HED of 2880 mg/day, 288 mg/day is 
considered a safe dose based on toxicity data. However, this 288 mg/day dose exceeds 
the proposed MRSD, see step 5.
Step 5: Consideration of the Pharmacologically Active Dose (PAD)
The estimated human therapeutic dose is 35 mg once daily. Applying a safety factor of 10 to 
ensure the first does in healthy volunteers is reasonably below the anticipated therapeutic 
dose, the recommended safe starting dose is 4 mg.
Maximum dose and dose escalation
1.3.2
Based on the cross-species comparison of vanin-expression (Section 1.2.1), the dog was 
chosen as the most relevant toxicological species to humans. Although the NOAEL in dog 
was determined to be 100 mg/kg/day, the NOEL of 30 mg/kg/day (corresponded to a Cmax of 
32,900 nM and AUC0-24 of 157,000 nM•h - male) was chosen to determine safety exposure 


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margins due to a not-reversible increase in mean ALT and a reversible decrease in thymus 
size at the NOAEL-level.
The maximum allowable systemic exposure of BI 764122 will be 32,900 nM for Cmax and 
157,000 nM•h for AUC0-24 in this study. It is based on findings in the 4-week dog 
toxicological study and represents a safety factor of 42 for Cmax and 31 for AUC as compared 
to the exposure at NOEL (see Table 1.2.3: 2).
To prevent exposure beyond the above predetermined safety margins in this trial, preliminary 
PK data of preceding DGs will be provided to estimate the expected mean exposure of the 
next DG (see Section 7.3.2). The next higher dose level will only be administered, if 
predicted mean values of Cmax and AUC0-24 do not exceed the predefined maximum exposure 
threshold.
In the SRD part of this trial, the following dose levels of BI 764122 are intended to be 
investigated: 4 mg, 12 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg and 400 mg.
Dose escalation will start with 4 mg (see Section 1.3.1). Decreasing escalation factors
between escalating steps will be applied: 3, up to a dose of 12 mg; thereafter about 2, up to a 
dose of 200 mg, 1.5 up to a dose of 300 mg, and about 1.33 up to a dose of 400 mg. Should at 
this dose the therapeutic window not be sufficiently characterized, a substantial amendment 
will describe further escalation steps.
In the FE part, the dose of 50 mg BI 764122 is intended to be investigated corresponding to 
an assumed (high) therapeutic dose.
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 764122, 
which represents a novel approach for the treatment of patients with Crohn’s disease.
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
Expected benefit for the target indication
1.4.1
BI 764122, a first-in-class vanin inhibitor, will be developed in CD. There is a substantial 
unmet medical need for agents with greater efficacy than current therapies, like 
aminosalicylates (e.g. 5-ASA), glucocorticoids, immunomodulator agents (azathioprine or 
6-MP), biologic TNFα inhibitors (TNFi), or other biologic options (vedolizumab, 
ustekinumab). Concerns over infection- and lymphoma risks attached to some of these 
treatmens remain. Treatment options for fistulizing and fibrotic disease are limited.
In CD, direct barrier injury is believed to be (at least partially) channeled through vanin 
enzymes and their product, cysteamine. By reducing cysteamine levels, a vanin inhibitor is 
expected to lead to direct epithelial barrier repair, resulting in mucosal healing, and to 
attenuate the chronic inflammation that is underlying the disease. Oral medicines with a novel 
mode of action that includes repair of epithelial barrier would address the unmet medical 
need in CD.


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Procedure-related risks
1.4.2
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising and, in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
1.4.3
Factors of risk may derive from particular knowledge or the lack thereof, regarding the mode 
of action, the nature of the target, the relevance of animal models and/or findings in non-
clinical safety studies.
Mode of action and nature of the target
1.4.3.1
Vanin-1 and -2 are extracellular enzymes expressed in humans on epithelial (lung, kidney, 
and intestinal tract), liver-, and immunological cells. It is shed in significant amounts into the 
extracellular milieu, and is found in most tissues. It’s function is to convert pantetheine into 
pantothenic acid and cysteamine. Through the production of cysteamine, vanin is directly 
impacting extracellular metabolic homeostasis of different tissues by chemically reducing and 
depleting cysteine, resulting in increased oxidative stress, endoplasmic reticular stress, and 
disruption and eventual destruction of tissue. Therefore, it is expected that vanin inhibition 
will directly restore tissue metabolite homeostasis and redox balance leading to tissue repair 
in CD-patients.
As described in Section 1.2.1, the human missense SNP (rs2272996) in the gene, encoding 
vanin-1, is associated with decreased blood pressure [R18-2692]. Considering this data as 
well as the findings from the dog telemetry GLP study, blood pressure and heart rate will be 
closely monitored after BI 764122 administration.
In GLP toxicology studies with BI 764122, there were no adverse histological pancreas 
findings or a lack of glycemic control. However, considering the conflicting literature,
described in Section 1.2.1 about pancreatic islet cell survival, fasting blood glucose levels 
will be closely monitored as a precautious measure.
Since there might be a relationship between vanin inhibition and acetaminophen 
(paracetamol) induced liver toxicity, in this study, acetaminophen will be strictly prohibited 
as concomitant medication.
Relevance of animal models
1.4.3.2
Vanin-1 expression is well-conserved and aligned between human and rodent species. 
However, as rodents lack vanin-2, there is a considerable discrepancy between species. In
dogs, vanin-1 mRNA levels are high in the lung, liver, spleen and kidney. Comparative 
expression in tissues is generally lower in the rat, although tissue distribution is comparable. 


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While dogs possess a vanin-2 gene, its expression in dog tissues is not characterized. In 
cynomolgus monkey, tissue distribution of both Vanin-1 and -2 isoforms are broadly 
comparable to human.
Findings in non-clinical safety studies
1.4.3.3
BI 764122 has a low risk for QT prolongation. The observed decrease in blood pressure with 
compensatory increases in heart rate in the GLP dog telemetry study at 300 mg/kg may be 
related to the pharmacological inhibition of Vanin. Autonomic, behavioral, sensorimotor and 
neuromuscular changes at 6 hours post dose were seen after the administration of 1000 mg/kg 
to rats. These effects were transient and had reverted by 24 hours post dose.
Toxicological data of BI 764122 support clinical studies in men with daily oral 
administration for up to 28 days. Results from 4-week GLP studies suggest a NOAEL of 
100 mg/kg/day in dog (corresponded to Cmax of 159,000 nM and AUC0-24 of 1,070,000 nM•h 
- male and female combined) and a NOEL of 30 mg/kg/day (corresponded to Cmax of 
32,900 nM and AUC0-24 of 157,000 nM•h - male). The risk of genotoxicity and phototoxicity 
is low. Carcinogenicity and local tolerance has not yet been examined. Signs of reproductive 
toxicity were seen in male rats at 1000 mg/kg/day (abnormal spermatogenesis).
Drug induced liver injury
1.4.3.4
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.4, adverse events of special interest.
Risk minimization (safety precautions and stopping rules)
1.4.3.5
The following risk minimization measures, including safety precautions and stopping rules, 
will be implemented in this study:

Careful selection of starting dose, as described in Section 1.3.1.

Decreasing escalation factors with increasing doses, as described in Section 1.3.2. 
Dose escalations will only be allowed after documented interim safety reviews (see 
Section 3.1.1).

Preliminary measurement of BI 764122 pharmacokinetics (Cmax, AUC0-24; see Section 
7.3.2). The expected exposure in the next higher DG will be estimated based on 
preliminary PK data of preceding DGs. The next higher dose level will only be 
administered, if estimated mean values of Cmax and AUC0-24 do not exceed the 
maximum acceptable human exposure (see Section 1.3.2).

For safety reasons, division of each DG of 8 subjects (6 on active treatment, 2 on 
placebo) into 3 staggered cohorts. On the first study day of each dose level, 2 subjects 
(Cohort 1) will be treated (one with active treatment, the other with placebo). On the 
second study day, the next 2 subjects (Cohort 2) will be treated (two with active 


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treatment). On the third study day of each dose level, the remaining 4 subjects (Cohort 
3) will be treated (three with active treatment, one with placebo). If BI 764122 was 
safe and well tolerated in Cohort 1, the study will continue with Cohort 2. If it was 
safe and well tolerated in the preceding cohorts, the study will continue with Cohort 3. 
Between the first application of BI 764122 in each cohort, there will be a time interval 
of at least 24 h which is expected to cover the peak exposure of the compound. In 
Cohort 2 and 3, subjects will be dosed at least 1 hour apart.

A monitoring of safety laboratory with specific focus on glycemic control, hepatic-
and hematological integrity (see Flow Chart).

An ECG monitoring including continuous ECG measurement over 4 hours post dose 
to cover the anticipated period of highest drug exposure and additional repeated single 
or triplicate 12-lead ECGs over 72 hours following drug administration. Dose 
escalation would be stopped as soon as at least 2 subjects at one dose level showed 
relevant QT prolongation (see Section 3.3.4.3).

Safety monitoring (including e.g. vital signs and adverse events) with a special focus 
on blood pressure and heart rate measurements.

Hospitalization of subjects at the trial site for at least 24 hours after study drug 
administration at each dose level. Based on an anticipated half-life for BI 764122 of 
about 3.3 h, this is expected to cover the period of highest risk/ peak effect. During in 
house-confinement, subjects will be under medical observation and thoroughly 
monitored for both expected and unexpected adverse events.

Application of the next higher dose, only if the respective dose of BI 764122 is safe, 
shows acceptable tolerability, and no stopping criterion is met (see Section 3.3.4.3). 
At least 7 days will be maintained between the first drug administration to subjects in 
the previous DG and the first drug administration to subjects in the subsequent DG.

Exclusion of acetaminophen as concomitant medication.

As reproductive toxicity studies have not yet been conducted, women will not be 
enrolled in this study.
Overall assessment
1.4.4
BI 764122, a first-in-class vanin inhibitor, has not yet been applied to humans. Despite the 
novelty of the target, non-clinical safety data in relevant animal species, the inhibitory mode 
of action as well as the risk assessment suggest that BI 764122 is not a high-risk compound 
and support the application of single doses of BI 764122 in this first-in-man trial. Based on 
the risk mitigation strategy, comprising of safety precautions and stopping rules, healthy 
subjects should not be exposed to undue risks by the intake of BI 764122. Healthy volunteers 
are not expected to have any direct benefit from participation in this trial, as is usually the 
case in phase 1 studies. Considering the high medical need for a novel, effective and safe 


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treatment for Crohn’s disease, it is believed that the benefit of this trial outweighs the 
potential risks and justifies exposure of healthy volunteers to BI 764122.


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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 764122 in healthy male subjects following oral administration of single rising 
doses.
The objective of the food effect (FE) part is to investigate the relative bioavailability of 
BI 764122 under fed and fasted conditions.
Primary endpoint
2.1.2
The primary endpoint for assessment of safety and tolerability of BI 764122 is the percentage 
of subjects with drug-related adverse events.
Secondary endpoint
2.1.3
The following pharmacokinetic parameters will be determined for BI 764122 if feasible:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This first-in-man (FIM) study consists of a single rising dose (SRD) and a food effect (FE) 
part. A total of 76 healthy male subjects is planned to participate in the trial, thereof 64 in the 
SRD part and 12 in the FE part. Additional subjects may be entered in the SRD part (see 
below). Thus, the actual total number of subjects may exceed 76 but not 92 subjects entered.
Single rising dose (SRD) part
3.1.1
The SRD part is designed as single-blind, partially randomised and placebo-controlled within 
parallel (sequential) DGs.
It is planned to include a total of 64 healthy male subjects in the SRD part. The subjects will 
be assigned to 8 groups consisting of 8 subjects per group; the groups will be dosed 
sequentially (see Table 3.1: 1). The investigator (after consultation with the sponsor) is 
allowed to alter the scheduled DGs (e.g., add low and/or intermediate DGs) on the basis of 
experience gained during the study (for instance, based on safety and/or preliminary PK 
data), provided the planned and approved highest dose is not exceeded. Thus, the actual 
number of subjects entered in the SRD part may be more than 64 but is not to exceed 80. 
Such changes, which are based on preliminary PK data, may be implemented via non-
substantial CTP amendments. Changes, based on safety findings, will be implemented only 
via substantial CTP amendments.
Within each DG, 6 subjects will receive BI 764122 and 2 will receive placebo. Only one dose 
is tested within each DG. For safety reasons, each DG will consist of 3 cohorts. The trial 
medication will be administered in the following order:

Cohort 1 (fixed order): the 1st subject on active treatment and the 2nd subject on 
placebo (in total 2 subjects)

Cohort 2 (fixed order): 2 subjects on active treatment (in total 2 subjects)

Cohort 3 (randomised): 3 subjects on active treatment and 1 subject on placebo (in 
total 4 subjects)
Between first drug administrations in Cohort 1 and 2, there will be a time interval of at least 
24 hours which is expected to cover the peak exposure of BI 764122. If BI 764122 was safe 
and well tolerated in Cohort 1, the study will continue with Cohort 2. The 2 subjects of 
Cohort 2 will be dosed at least 1 hour apart. If BI 764122 was still safe and well tolerated in 
all subjects of Cohort 1 and 2, the study will proceed at least 24 hours after the first drug 
administration in Cohort 2 with the 4 subjects of Cohort 3, who will be dosed at least 
15 minutes apart.
The DGs to be evaluated are outlined in Table 3.1: 1 below.


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Table 3.1: 1
Dose groups (DGs)
DG
1
2
3
4
5
6
7
8
Dose (mg)
4
12
25
50
100
200
300
400
Number of subjects
8
8
8
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
2
2
2
Subjects receiving BI 764122
6
6
6
6
6
6
6
6
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 
DG and the first drug administration to subjects in the subsequent DG. The decision to 
escalate to the next DG will be based upon safety, tolerability and pharmacokinetic data of 
all subjects of the preceding DGs. The next DG will only be treated, if, in the opinion of the 
investigator, no safety concerns have arisen in the preceding DGs (i.e. no dose-limiting 
events occurred), and if none of the pre-specified trial-specific stopping criteria have been 
met (see Section 3.3.4.1).
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested at any time 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 DG, safety will be 
continuously monitored during this trial. 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 (see Section 3.3.4.1).
At minimum, data from 4 subjects on active drug need to be available for escalation to a 
higher dose. For the minimum dataset with regards to preliminary PK data, see Section 7.4. 
The minimum data set for review consists of the following:

AEs in the current and preceding DGs 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 Review and AE information may be subject to 
change prior to Database Lock)

Results from 12-lead ECG and continuous ECG monitoring in the current and 
preceding DGs up to at least 48 h post dosing

Vital signs in the current and preceding DGs up to at least 48 h post dosing

Clinical laboratory tests in the current and preceding DGs up to at least 48 h post 
dosing

Preliminary PK data for the selected time as per Section 7.4. For escalation from DG
1 to DG 2, preliminary PK data are not required

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 Lead (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs, and out-of-range 


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laboratory results (if considered clinically relevant). 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 Lead (or an authorised deputy).
Safety Reviews can be conducted face-to-face or by video/telephone conference. The Clinical 
Trial Lead 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 Lead (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, see Sections 6.1 and 6.2, respectively.
Food effect (FE) part
3.1.2
The FE part is designed as randomised, open-label, two-way crossover, and to be conducted 
in parallel or after completion of the SRD part.
Dose selection of 50 mg of BI 764122 is based on the assumption to include a potentially
(high) therapeutic dose but it may be decreased or increased, based on the knowledge gained 
during trial conduct (e.g. safety, exploratory PK 
 analyses). In any case, the selected 
dose will be at least 2-fold lower than the last safely tested dose in the SRD part (assuming 
that the food may increase bioavailability of BI 764122), and will not exceed the maximum 
acceptable thresholds of Cmax and AUC0-24 per protocol, as described in Section 1.3.2.
Therefore, with the current assumption, the FE part may start only, if a dose of 100 mg of 
BI 764122 was safe and showed acceptable tolerability, and not earlier, than in parallel with 
DG 6 (200 mg of BI 764122).
It is planned to include a total of 12 healthy male subjects in the FE part. Within this trial 
part, subjects will be randomly allocated to the two treatment sequences (T-R or R-T). The
treatments will be 50 mg of BI 764122 in the fed state (T) and 50 mg of BI 764122 in the 
fasting state (R). For details, see Section 4.1. There will be a washout period of at least 7 days 
between treatments.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, see Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
SRD part:
For single rising dose trials, the sequential rising dose design, described in Section 3.1, is 
viewed favourably under the provision not to expose involved subjects to undue risks.
Single-blind conditions regarding the subject’s treatment (active or placebo) are maintained 
within each DG. However, subjects and investigators will be aware of the dose of drug 
administered. The disadvantage of the trial design is a possible observer bias with regard to 
the dose-dependent effects. In addition, sequential dosing of groups could potentially result in 


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time-related effects. However, as such effects are expected to be small relative to the 
differences between the doses in the broad range investigated, unbiased comparisons between 
treatments can still be expected.
It is standard in single rising dose trials involving healthy volunteers to include a placebo 
group to control for safety and tolerability of the trial medication. Each DG consists of 8
subjects, with 6 on active treatment, and 2 on placebo. For data analysis purposes, the 
placebo control group will include all subjects of all DGs treated with placebo. Six subjects 
per active treatment group are generally considered to be sufficient for the exploratory 
evaluation of pharmacokinetics.
FE part:
For relative bioavailability trials, the crossover design is preferred due to its efficiency. Since 
each subject serves as his own control, the comparison between treatments is based on a 
comparison within subjects rather than between subjects. This trial design, therefore, removes 
inter-subject variability from the comparison between treatments [R94-1529].
Blinding is not possible because the treatments are distinguishable. The open-label treatment 
is not expected to bias the results, since the PK endpoints are derived from measurement of 
plasma concentrations of the analyte which are provided by a bioanalytical laboratory that is 
blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 76 healthy male subjects will enter the study. The actual number of subjects 
entered may exceed the total of 76, if additional intermediate doses are tested (see 
Section 3.1). Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included in the trial because no data on 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:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 
12-lead ECG, and clinical laboratory tests
2. Age of 18 to 50 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)


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4. Signed and dated written informed consent prior to admission to the study, in 
accordance with GCP and local legislation
5. Male subjects who meet any of the following criteria from at least 30 days before the 
first administration of trial medication until 30 days after trial completion:
a.
Use of adequate contraception, e.g. use of condom (male subjects) plus any of 
the following methods (female partners): intrauterine device, hormonal 
contraception (e.g. implants, injectables, combined oral or vaginal 
contraceptives) that started at least 2 months prior to first drug administration
to the male subject, or barrier method (e.g. diaphragm with spermicide), or 
surgically sterilised (including bilateral tubal occlusion, hysterectomy or 
bilateral oophorectomy), or postmenopausal, defined as at least 1 year of 
spontaneous amenorrhea (in questionable cases a blood sample with FSH 
above 40 U/L and estradiol below 30 ng/L)
b. Sexually abstinent
c.
Vasectomised (vasectomy at least 1 year prior to enrolment) in combination 
with a barrier method (e.g. condom)
Unprotected sexual intercourse with a pregnant female partner and sperm donation is 
not allowed throughout the study and until 30 days after trial completion.
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 or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 
140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse 
rate outside the range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance
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


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10. History of relevant allergy or hypersensitivity (including allergy to the trial 
medication or its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc 
interval prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation 
in another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 30 g per day)
16. Drug abuse as per investigator judgment or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance,
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study
In addition, the following trial-specific exclusion criteria apply:
23. History of acute pancreatitis.
For study restrictions, see Section 4.2.2.
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.


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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.
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 relevant 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, or
unexplained hepatic enzyme elevations at any time during the trial
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 
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.


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Discontinuation of the trial by the sponsor
3.3.4.3
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. 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 more than 50% of 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, or the contract with BI 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 QT or QTc greater than 500 ms, as
confirmed by a repeat ECG recording
6. Dose escalation will be stopped, if the Cmax or AUC0-24 of at least 1 subject of one DG
increases above the following exposure thresholds or if the estimated gMean exposure 
is expected to exceed a Cmax of 32,900 nM or an AUC0-24 of 157,000 nM*h. 
Estimation will be done based on preliminary PK results of preceding DGs (see 
Section 7.4)
7. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in 2 subjects of the same dose
The investigator/ trial site will be reimbursed for reasonable expenses incurred in case of trial 
termination (except, if item 3 applies).
Replacement of subjects (only FE part)
3.3.5
If some subjects do not complete the trial, the Clinical Trial Lead 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 sequence as the subject 
 replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG. 
Identity of the Investigational Medicinal Products
4.1.1
SRD part:
The characteristics of the test product are given below:
Substance:
BI 764122
Pharmaceutical formulation:
not film-coated (1 mg) tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
1 mg
Posology:
4-0-0 (DG 1), 2-0-0 (DG 2), 5-0-0 (DG 3)
Route of administration:
oral
Duration of use:
single dose
Substance:
BI 764122
Pharmaceutical formulation:
film-coated (10 mg) tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg
Posology:
1-0-0 (DG 2), 2-0-0 (DG 3), 5-0-0 (DG 4)
Route of administration:
oral
Duration of use:
single dose
Substance:
BI 764122
Pharmaceutical formulation:
film-coated (100 mg) tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
1-0-0 (DG 5), 2-0-0 (DG 6), 3-0-0 (DG 7), 4-0-0 (DG 8)
Route of administration:
oral
Duration of use:
single dose
The characteristics of the reference product (placebo) are given below:
Substance:
placebo matching in size and weight to 1 mg not film-
coated tablet
Pharmaceutical formulation:
not film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
4-0-0 (DG 1), 2-0-0 (DG 2), 5-0-0 (DG 3)
Route of administration:
oral


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Duration of use:
single dose
Substance:
placebo matching in size and weight to 10 mg film-coated 
tablet
Pharmaceutical formulation:
film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
1-0-0 (DG 2), 2-0-0 (DG 3), 5-0-0 (DG 4)
Route of administration:
oral
Duration of use:
single dose
Substance:
placebo matching in size and weight to 100 mg film-
coated tablet
Pharmaceutical formulation:
film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
1-0-0 (DG 5), 2-0-0 (DG 6), 3-0-0 (DG 7), 4-0-0 (DG 8)
Route of administration:
oral
Duration of use:
single dose
FE part:
The characteristics of the test product are given below:
Substance:
BI 764122
Pharmaceutical formulation:
film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg
Posology:
5-0-0 (treatment T) and 5-0-0 (treatment R)
Route of administration:
oral
Duration of use:
single dose per treatment
Selection of doses in the trial and dose modification
4.1.2
The doses selected for this trial cover the subtherapeutic as well as the estimated therapeutic 
range and include a safety margin (see Section 1.2 and 1.3). It is intended to investigate the 
following dose levels of BI 764122 in the SRD part of this trial: 4 mg, 12 mg, 25 mg, 50 mg, 
100 mg, 200 mg, 300 mg and 400 mg.
In the FE part, dose selection (50 mg of BI 764122) is based on the assumption to include the 
potential therapeutic dose. Dose may be decreased or increased based on the knowledge 
gained during trial conduct (e.g. safety, exploratory PK and PD analyses). In any case, the 
selected dose in the FE part will be at least 2-fold lower than the last safely tested dose in the 
SRD part, and will not exceed the maximum acceptable thresholds of Cmax and AUC0-24 per 
protocol, as described in Section 1.3.2.


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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. Subjects willing to participate will be recruited to DGs (3 cohorts per 
DG) in the SRD part or to the FE part according to their temporal availability.
SRD part:
As soon as enough subjects are allocated to 1 of the 24 dose cohorts, the following subjects 
will be allocated to one of the other dose cohorts. Therefore, the allocation of subjects to dose 
cohorts is not influenced by trial personnel, but only by the subjects’ temporal availability. 
Because the study includes healthy subjects from a homogenous population, relevant 
imbalances between the DGs are not expected.
In Cohorts 3 of each DG, subjects will be randomly assigned to treatments (active or placebo) 
prior to the first administration of trial medication, while treatments in Cohorts 1 and 2 will 
be assigned in a fixed order for safety reasons, as described in Section 3.1.1.
FE part:
Subjects will be assigned randomly to treatment sequences (R-T or T-R) prior to the first 
administration of trial medication.
For the purpose of random assignment, the randomisation list will be provided to the trial site 
in advance. Numbers of the randomization list will be allocated to subjects by the method 
‘first come - first served’ at the time of registration. Subjects are then assigned to treatment 
according to the randomisation list. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
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 and 4.1.4: 2 below.
In the SRD part, the number of units for placebo corresponds to the number of units of the 
corresponding dose level.


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Table 4.1.4: 1
BI 764122 and placebo treatments, oral administration - SRD part
DG
Substance
Pharmaceutical 
form
Unit strength
Number of units per 
administration
Total 
daily dose
1
BI 764122
non film-coated 
tablet
1 mg
4 tablets
4 mg
2
BI 764122
non- and film-
coated tablet
1 mg and 10 mg
2 tablets of 1 mg and 1 tablet of 
10 mg
12 mg
3
BI 764122
non- and film-
coated tablet
1 mg and 10 mg
5 tablets of 1 mg and 2 tablet of 
10 mg
25 mg
4
BI 764122
film-coated 
tablet
10 mg
5 tablets of 10 mg
50 mg
5
BI 764122
film-coated 
tablet
100 mg
1 tablet of 100 mg
100 mg
6
BI 764122
film-coated 
tablet
100 mg
2 tablets of 100 mg
200 mg
7
BI 764122
film-coated 
tablet
100 mg
3 tablets of 100 mg
300 mg
8
BI 764122
film-coated 
tablet
100 mg
4 tablets of 100 mg
400 mg
1-8
Placebo*
film-coated 
tablet
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across DGs
Table 4.1.4: 2
BI 764122 treatments, oral administration - FE part
Treatment
Substance
Pharmaceutical 
form
Unit strength
Number of units per 
administration
Total daily dose
T (fed)
BI 764122
film-coated 
tablet
10 mg
5 tablets of 10 mg
50 mg
R (fasting)
BI 764122
film-coated 
tablet
10 mg
5 tablets of 10 mg
50 mg
The tablets for dosing (active treatment and placebo) will be dispensed by pharmacists or 
qualified pharmacy staff members or qualified medical study personnel at the trial site under 
the responsibility of the investigator.
Administration of trial medication will be performed after subjects have fasted overnight
(except treatment T in the FE part, see below); fasting is to start no later than 10 h before the 
scheduled dosing. The investigator (or authorised designee) will administer the trial 
medication as an oral dose together with about 240 mL of water to subjects who are in a 
sitting or standing position. For drug administration, the so-called four-eye principle (two-
person rule) should be applied. For this, one authorised employee of the trial site should 
witness the dispensing of the trial medication from bulk bottles as well as administration of 
trial medication to the subject.
In the FE part, in treatment T (in the fed state), a standard high-fat, high-calorie meal will be 
served 30 min before drug administration. The subjects must completely consume the meal 
prior to drug intake. The composition of the meal is detailed in Table 4.1.4: 3; this meal is in 
compliance with the FDA guidance 'Food-Effect Bioavailability and Fed Bioequivalence 
Studies' [R03-2269]. For restrictions with regard to diet, see Section 4.2.2.2.


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Table 4.1.4: 3
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (whole content) for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat.
Subjects will be kept under close medical surveillance until 24 h after drug administration.
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.
In the FE part, treatments T-R or R-T will be separated by a washout phase of at least 7 days 
between drug administrations.
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
The SRD part of the trial is designed single-blind. The treatments administered (active or 
placebo) will be blinded to subjects but will be known to the investigators (outcome 
assessors). Only the current dose level will be known to the subjects due to the rising dose 
design. This is considered acceptable because the potential bias in this type of study seems to 
be low, and according to study procedures, it is assured that the investigator's knowledge of 
the next treatment does not influence the decision to enter a subject.
The FE part of the trial will be handled in an open fashion throughout (that is, during the 
conduct, including data cleaning and preparation of the analysis). This is considered 
acceptable because the potential for bias seems to be low and does not outweigh practical 
considerations.
All trial data will be handled open label. This means that trial functions of the sponsor are 
unblinded (e.g. clinical trial lead, data manager, statistician, bioanalyst, pharmacokineticist, 
pharmacometrician, drug metabolism scientist as well as dedicated personnel of the trial site).
Within the central ECG lab, the staff involved with interval measurements will be blinded 
with respect to the treatment and also with regard to the recording date and time as well as 
planned time points of the ECGs. The interval measurements for a given subject will be 
performed in a random and blinded sequence by a single technician. No more than two 
different blinded readers will evaluate the ECGs of the study.
Access to the randomisation schedule will be controlled and documented by a signed 
confidentiality statement, which will be stored in the TMF.


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Unblinding and breaking the code
4.1.5.2
As this trial will be conducted single-blind (SRD part) and open-label (FE part), subjects’ 
treatment assignments will be known to investigators. Therefore, no emergency envelopes 
will be provided.
Packaging, labelling, and re-supply
4.1.6
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
Storage conditions
4.1.7
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
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 


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were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused trial medication will be disposed of locally by the trial site upon written 
authorisation of the Clinical Trial Lead. Receipt, usage, and disposal of trial medication must 
be documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES, 
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
Restrictions
4.2.2
Restrictions regarding concomitant treatment
4.2.2.1
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Acetaminophen (paracetomol) is strictly prohibited as concomitant mediation in this study. 
If necessary, short-term use of ibuprofen or acetylsalicylic acid is acceptable.
Drugs with a known hepatotoxicity profile should be avoided during the entire study.
Restrictions on diet and life style
4.2.2.2
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 3), the water administered with the drug, and an additional 
240 mL of water served on Day 1 at 2 h and 4 h post-dose (mandatory for all subjects).
During the days of urine collection, total fluid intake per day 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 administration of trial medication until after the last PK 
sample is collected.


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Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before the administration until the end of the in-house 
period at the trial site. Smoking is not allowed during in-house confinement while admitted to 
the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
If male subjects with female sexual partners are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial (see Section 3.3.2 for the definition of 
adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication at the study site under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/ or urinary excretion of trial medication will provide additional confirmation of 
compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
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 or to be reported),
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG (including rhythm strip of at least 15 minutes), 
laboratory tests, and a physical examination. The end of trial examination 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) will be measured by a 
blood pressure monitor (e.g. Dinamap Pro 100, GE Medical Systems, Germany) at the times 
indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine position. 
All recordings should be made using the same type of blood pressure recording instrument on 
the same arm, if possible.
Safety laboratory parameters
5.2.3
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. 
Reference ranges will be provided in the ISF, Section 10.
Manual differential white blood cell count will be performed if there is an abnormality 
detected with the automatic blood cell count. Urine microscopic examinations will be 
performed in addition to urinalysis (Stix) in order to correctly evaluate possible abnormalities 
detected at the urinalysis (Stix)


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Table 5.2.3: 1
Routine laboratory tests for SRD and FE part
Functional lab 
group
BI test name [comment/abbreviation]
SCR/ EoT
Day -3 to -1
Day 1, 4 h post
Day 2, 24 h post
Day 3, 48 h post
Day 5, 96 h post
Haematology
Haematocrit
Haemoglobin
Red blood cell count (erythrocytes), absol.
Reticulocytes, absol.
White blood cells (leucocytes), absol.
Platelet count (thrombocytes), absol.
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
Automatic WBC 
differential, 
relative
Neutrophils/ leukocytes; eosinophils/ leukocytes; 
basophils/ leukocytes; monocytes/ leukocytes; 
lymphocytes/ leukocytes 
X
X
X
X
X
X
Automatic WBC 
differential, 
absolute 
Neutrophil, absol.; eosinophils, absol.; basophils, 
absol.; monocytes, absol.; lymphocytes, absol.
X
X
X
X
X
X
Manual 
differential WBC 
(if automatic
differential WBC 
is abnormal)1
Neutrophils/ leukocytes; eosinophils/ leukocytes; 
basophils/ leukocytes; monocytes/ leukocytes; 
lymphocytes/ leukocytes
Neutrophil, absol.; eosinophils, absol.; basophils, 
absol.; monocytes, absol.; lymphocytes, absol.
X1
X1
X1
X1
X1
X1
Coagulation
Activated partial thromboplastin time 
Prothrombin time – INR (International 
Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
Enzymes
AST [aspartate transaminase] /GOT, SGOT
ALT [alanine transaminase] /GPT, SGPT
Alkaline phosphatase
Gamma-glutamyl transferase
Creatine kinase [CK]
Creatine kinase Isoenzyme MB [only if CK is 
elevated]
Lactic dehydrogenase
Lipase
Amylase
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
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones2
Thyroid stimulating hormone
X
--
--
--
--
--
1
if automatic differential WBC is abnormal
2
only at SCR


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab 
group
BI test name [comment/abbreviation]
SCR/ EoT
Day -3 to -1
Day 1, 4 h post
Day 2, 24 h post
Day 3, 48 h post
Day 5, 96 h post
Substrates
Glucose (Plasma)
Creatinine
Bilirubin, total
Bilirubin, direct
Protein, total
Albumin
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
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
X
--
--
--
--
--
--
--
X
X
--
--
X
X
X
X
--
--
--
--
--
--
--
X
X
--
--
Electrolytes
Sodium
Potassium
Calcium
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine nitrite, qual.
Urine protein, qual.
Urine glucose, qual.
Urine ketone, qual.
Urobilinogen, qual.
Urine bilirubin, qual.
Urine RBC/ erythrocytes, qual.
Urine WBC/ leucocytes, qual.
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)3
Only positive findings will be reported (for 
instance, the presence of sediment bacteria, casts 
in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
X
--
--
--
--
--
3
if erythrocytes, leukocytes nitrite or protein are abnormal in urine 
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. Drug screening will be performed at screening, after admission to the trial site (SRD 
part) and prior to each treatment period (FE part). Infectious serology will be performed at 
screening only.


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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, qual.
Hepatitis B core antibody, qual.
Hepatitis C antibodies, qual.
HIV-1 and HIV-2 antibody, qual.
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
6510 and Alcotest® 5510, Dräger, Belgium) 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. These tests will be performed at the trial site using e.g.Triage® TOX Drug 
Screen, Alere, or Combur9 Test®.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
Electrocardiogram
5.2.4
12-lead resting ECG
5.2.4.1
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (e.g. Cardionics SA, Brussels, Belgium at the time points 
given in the Flow Chart. Electrode placement will be performed according to the method of 
Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and shoulders instead 
of ankles and wrists). Precise electrode placement will be marked with an indelible mark on 
the skin to allow reproducible placement throughout the study.
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.


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SRD part: 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. For baseline, 3 triplicate-
ECGs will be recorded.
FE part: It is planned that single ECGs will be recorded for all time points.
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.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
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 (triplicate ECGs, SRD part only)
Triplicate ECGs recorded in the SRD part will be stored electronically on a computerised 
electrocardiograph (e.g. Cardionics SA, Brussels, Belgium).
Data transfer (triplicate ECGs, SRD part only)
For time points of triplicate ECGs in the SRD part (see the Flow Chart), ECGs will be 
transferred electronically to the central ECG lab (
for 
evaluation.
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 (only triplicate ECGs, SRD part only)
Central ECG lab evaluation will be performed post-study for the first of three 
replicate ECGs per time point on Days 1 and 2 in the Flow Chart. The remaining 
second and third replicate ECGs will be stored for additional analyses if required, e.g. 
by authorities at a later time point. For baseline, where 3 triplicate ECGs are recorded, 
only the first of each triplicate ECG (i.e. 3 single ECGs) will be evaluated.
This will include the determination of cardiac QRS-axis as assessed by the ECG 
machine’s algorithm as well as the intervals RR, PR, QRS and QT measured semi-
automatically.
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.


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Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 
computerised ECG system or their manual corrections by the investigators will be 
used. In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data 
transfer) for cardiologic assessment by the central lab. In this case, these centrally 
measured results would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening), if judged 
clinically relevant by the investigator. Any ECG abnormalities will be monitored carefully 
and, if necessary, the subject will be removed from the trial and will receive the appropriate 
medical treatment.
Continuous ECG monitoring (SRD part only)
5.2.4.2
Cardiac rhythm (including heart rate) will be monitored (only during SRD part) by means of 
continuous 5-lead ECG recording using the Monitor (e.g. GE Healthcare, Germany) for at 
least 15 min before drug administration (for baseline assessment) and for 4 h following drug 
administration). This continuous ECG monitoring supports the early detection of adverse 
events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the trial site. 
Beyond this clinical evaluation at the trial site, no further data collection or analyses are 
performed based on continuous ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial 
database. Abnormal findings during continuous ECG recording will be recorded as AEs, if 
judged clinically relevant by the Investigator.
Other safety parameters
5.2.5
Not applicable.
Assessment of adverse events
5.2.6
Definitions of adverse events
5.2.6.1
Adverse event
5.2.6.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.


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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.


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The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analyzed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
Intensity (severity) of AEs
5.2.6.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
5.2.6.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge,
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:


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
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
Adverse event collection and reporting
5.2.6.2
AE collection
5.2.6.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.


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The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial:
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.3.1
Plasma samples will be collected for the purpose of pharmacokinetic analysis. Additional 
blood samples will be collected for stability testing. Furthermore, urine samples are to be 
collected for pharmacokinetic analysis. The time points of the samples collection are 
indicated in the Flow Chart.


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Date and clock times of drug administration and pharmacokinetic sampling will be recorded
in the CRFs. The actual sampling times will be used for determination of pharmacokinetic 
parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. as a result of preliminary PK data), including addition of 
samples and visits, as long as the total blood volume taken per subject does not exceed 
500 mL. Such changes would be implemented via non-substantial CTP Amendments.
Methods of sample collection
5.3.2
Blood sampling for pharmacokinetic analysis
5.3.2.1
For quantification of BI 764122 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venepuncture with a 
metal needle.
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 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 60 min, with interim storage of blood samples and aliquots in ice 
water or on ice. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. Further information such as matrix and analyte may also be provided.
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g., for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the CTR is 
archived.
Blood sampling for metabolism analysis
5.3.2.2
Additional K2-EDTA plasma samples for the identification of drug metabolites will be 
investigated in the 50 mg DG in the SRD part of the trial. Based on the knowledge gained 
during the trial conduct, e.g. from preliminary PK results, the DG may be modified to a 
different one. The change will be implemented via a non-substantial CTP amendment.


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These blood samples will be drawn at the same time points as PK samples (see Flow Chart). 
At each of these times, 2.7 mL blood will be needed for metabolite analysis. The blood 
samples will be processed in the same way as the PK samples (see Section 5.3.2.1).
Two plasma aliquots will be obtained and stored in polypropylene (PP) cryotubes. The first 
aliquot (labelled as MIST-1 samples), should contain at least 0.5 mL plasma. The remaining 
plasma will be the second aliquot (labelled as MIST-2 samples). The process from blood 
collection to the transfer of plasma aliquots into the freezer should be completed within 
90 min, with interim storage of blood samples on crushed ice between blood collection and 
centrifugation. Until transfer on dry ice to the metabolism laboratory, the aliquots will be 
stored at the trial site.  Samples will be positioned upright and will be frozen at approximately 
-70°C. The second aliquot will be shipped to the metabolism laboratory after the metabolism 
scientist has acknowledged safe arrival of the first aliquot. At the metabolism laboratory, the 
plasma samples will be stored at about -70°C until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time and ‘MIST-1’ or ‘MIST-2’. Further information 
such a matrix and analyte may also be provided.
Plasma samples dedicated to metabolism investigation are transferred to:
Phone: 
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
drug metabolism will be reported separately and will not be included in the CTR. The study 
samples will be discarded after completion of the experiments but not later than 5 years after 
the CTR has been archived.


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Analytical determinations
5.3.3
Analytical determination of BI 764122 plasma concentration
5.3.3.1
BI 764122 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis.
The analysis will be performed at 
 
.
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.


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5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Pharmacogenomic evaluation
5.6.1
Pharmacogenomic evaluations are not considered necessary for assessment of response to 
BI 764122.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial (except biomarkers) are standard measurements 
and will be performed in order to monitor subjects’ safety and to determine pharmacokinetic 
parameters in an appropriate way. The scheduled measurements will allow monitoring of 
changes in vital signs, standard laboratory values, and ECG parameters that might occur as a 
result of administration of trial medication. The safety assessments are standard, are accepted 
for evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening 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 
).
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 and ± 30 min thereafter.
Starting from 48 h post-dose a deviation from the scheduled time for vital signs, ECG and 
laboratory tests of ±120 min is acceptable.
If several activities are scheduled at the same time point in the Flow Chart, blood sampling, 
vital signs, and 12-lead 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,
see 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, see Section 5.2.
Treatment periods
6.2.2
SRD part:
Each subject will receive one dose of trial medication (BI 764122 or placebo) at Visit 2.
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.


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Study participants will be admitted to the trial site in the morning of Day 1 and kept under 
close medical surveillance for at least 48 h following drug administration. The subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their fitness 
by the investigator or 
 designee. On all other study days, subjects will be treated in an 
ambulatory fashion.
For details on time points, and procedures for collection of plasma 
 samples for PK 
analysis, see 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, see
Flow Chart. AEs and concomitant therapy will be assessed continuously from screening until 
the end of trial examination.
FE part:
Each subject is expected to participate in two treatment periods. Treatment periods will be 
separated by at least 7 days between drug administrations.
Trial medication will be taken orally by each subject under direct supervision of the 
investigator or his/ her designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
In the morning of Day 1 of each treatment period, participants will be admitted to the trial site 
and kept under close medical surveillance for at least 24 hours following drug administration. 
Subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, the study will be performed in an ambulatory fashion.
For details on time points and procedures for collection of plasma 
 samples for PK 
analysis, see 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, see
Flow Chart. AEs and concomitant therapy will be assessed continuously from screening until 
the end of trial examination.
Follow-up period and trial completion
6.2.3
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.1 to 5.2.6.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoT 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 EoT Visit must be followed 
until they have resolved, have been sufficiently characterized, or no further information can 
be obtained.


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The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objectives of this trial will be assessed by calculating descriptive statistics for 
safety as well as for PK parameters which will be compared between the treatment groups.
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. 

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects from the 
treated set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol violation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.

ECG pharmacokinetic concentration set (ECGPCS):This subject set includes all 
subjects from the TS who participated in the SRD part and 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. The ECGPCS will be used for the exposure-
response analyses.


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Adherence to the protocol will be assessed by the trial team. Important protocol deviations 
(iPDs) categories will be specified in the IQRM plan, iPDs will be identified no later than in 
the Report Planning Meeting, and the iPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1.3 and Section 2.2.2.2 for drug 
BI 764122 will be calculated by means of non-compartmental analysis. Non-compartmental 
pharmacokinetic parameters will be calculated based on actual sampling times using a 
validated pharmacokinetic software (Phoenix® WinNonlin® 6.3). Descriptive statistics will be 
used to evaluate plasma concentration data and PK parameters. The derivation of PK 
parameters according to the relevant SOP of the Sponsor ‘Standards and processes for 
analyses performed within Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-
472).
Plasma 
 concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol deviation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below).
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma 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).
If a pre-dose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic
data will be not included in any statistical evaluations, in accordance with international


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guidances. The individual pharmacokinetic parameters of such a subject will be calculated
and listed separately. If a pre-dose concentration is above BLQ, but less than or equal to 5% 
of the subject’s Cmax value, the subject’s data without any adjustments will be included in all
pharmacokinetic measurements and calculations.
Every effort will be made to include all concentration data in an analysis. If not possible, a
case to case decision is required whether the value should only be excluded from half-life
estimation or the complete analysis.

If a concentration is only excluded from half-life determination, it will be used for all
other calculations (e.g. descriptive statistics) and for graphical presentation.

If a concentration value is excluded from all calculations, it will not be presented
graphically or used for the calculation of descriptive statistics and parameter
determination. However the excluded concentration itself will be listed in the clinical 
trial report associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual
parameter estimates of a certain parameter are available. If the actual sampling time will not
be recorded or will be missing for a certain time point, the planned time will generally be
used for this time point instead. Pharmacokinetic parameters which cannot be determined will
be identified by "not calculated" (NC).
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. See 
Section 7.3.4 for further details.
Secondary endpoint analyses
7.3.2
The pharmacokinetic parameters listed in Section 2.1.3 for drug BI 764122 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).


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Subjects who are not included in the PKS (see Section 7.3) will be reported with their 
individual plasma/ urine concentrations and individual pharmacokinetic parameters; however, 
they will not be included in descriptive statistics for plasma/ urine concentrations, 
pharmacokinetic parameters.
Primary analyses
The secondary endpoints (see Section 2.1.3) will be analyzed 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. 


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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 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.
Measurements (such as ECGs, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment-emergent AEs). 
Therefore, measurements planned or AEs recorded prior to intake of trial medication will be 
assigned to the screening period, those between the trial medication intake and end of REP 
(see Section 1.2.6) will be assigned to the treatment period. Events occurring after the 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 5.2.6.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as clinically relevant 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.


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7.4
INTERIM ANALYSES
No interim analysis is planned.
In the SRD part, a preliminary analysis of PK parameters (AUC0-24 and Cmax of BI 764122)
provided as individual values and geometric means of all available data from at least 4
subjects on active treatment per current dose level, supported by all the available data from 
subjects of preceding dose levels, will be performed before proceeding to the next higher 
dose level. For escalation from DG 1 to DG 2, and after the last DG, preliminary PK data are 
not required, see Section 3.
The pharmacokinetic parameters AUC0-24 and Cmax of BI 764122 will be calculated according 
to the BI SOP 'Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics' (001-MCS-36-472). The non-compartmental analysis 
will be performed using a validated software program such as Phoenix WinNonlinTM
software (version 6.3 or higher, Certara USA Inc., Princeton, NJ, USA). A quality check of 
the preliminary data will be performed.
In contrast to the final PK calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows. Therefore, minor deviations may occur between preliminary and final results. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification information. The 
preliminary results will be distributed to the investigator and the trial team. 
Depending on the results of available preliminary PK analyses and the tolerability and safety 
of the compound, changes to the dosing schedule (e.g., additional intermediate doses), and 
additional PK preliminary analysis may be performed if requested by the Clinical Trial Lead, 
the investigator, or Trial Clinical Pharmacokineticist. Preliminary PK results will not be 
reported in the CTR. No formal preliminary PK report will be written.
No inferential statistical interim analysis is planned. However, after completion of each DG
the investigator (or his or her deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data has been performed.
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).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
SRD part: Each DG will be divided into three cohorts. The subjects of the first 2 cohorts 
(2 subjects per cohort) will not be randomized to maintain a treatment sequence of active-
placebo (Cohort 1) and active-active (Cohort 2) due to safety reasons. In the third cohort of 
each dose level (4 subjects) the subjects will be assigned to active or placebo treatment using 
a 3:1 allocation ratio (test treatment to placebo).
FE part: Subjects will be randomized to one of the two treatment sequences R-T or T-R in a 
1:1 ratio.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system 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 (see
Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
SRD part:
It is planned to include a total of 64 subjects for the SRD assessment. The planned sample 
size is not based on a power calculation. The size of 8 subjects per DG (6 on active treatment, 
and 2 on placebo) is commonly used in single-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics.
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 
in the SRD part may exceed 64, but will not exceed 80 subjects entered.
FE part:
It is planned to enter 12 subjects in this trial part, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial.
With this sample size, the following precision of the ratio of geometric means (test/reference) 
can be expected. Precision is defined as the ratio of upper to lower confidence interval limit. 
Note that the precision is independent of the actual ratio of geometric means. For this first-in-


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man trial, no information on intra-subject variability is available. Therefore, Table 7.7: 1
provides an overview on the achievable precision for estimating the ratio of geometric means 
(test/reference) for three different gCV. For illustrative purposes, the expected 90% 
confidence intervals with 95% coverage probability are displayed for different values of 
geometric means ratios T/R in the two-period two-sequence crossover design.
Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a 2x2 crossover trial (N=12)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
20.0
1.22
80
65.61
97.54
20.0
1.22
100
82.01
121.93
20.0
1.22
125
102.52
152.41
20.0
1.22
150
123.02
182.89
20.0
1.22
200
164.03
243.86
25.0
1.28
80
62.52
102.36
25.0
1.28
100
78.15
127.95
25.0
1.28
125
97.69
159.94
25.0
1.28
150
117.23
191.93
25.0
1.28
200
156.31
255.91
30.0
1.34
80
59.63
107.33
30.0
1.34
100
74.54
134.16
30.0
1.34
125
93.17
167.71
30.0
1.34
150
111.80
201.25
30.0
1.34
200
149.07
268.33
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit%&&'(,)*+'( = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. 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 
subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the responsible Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC) and competent authority (CA) according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 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. As treatment assignments will 
be known to investigators, rules about emergency code breaks are not applicable (see 
Section 4.1.5.2). For drug accountability, see Section 4.1.8.
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.
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)


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
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.
Direct access to source data and documents
8.3.2
The investigator/ institution will allow site trial-related monitoring, audits, IRB/ IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/ data, including progress notes, copies of laboratory and medical test results, 
which must be available at all times for review by the Clinical Research Associate, auditor 
and regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
Storage period of records
8.3.3
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
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.


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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 and future use of 
biological samples and clinical data, in particular

The BI-internal facilities storing biological samples from clinical trial participants are 
qualified for the storage of biological samples collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage
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.
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.


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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 Clinical Trial Lead, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of Clinical Trial Managers (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
Analyses of BI 764122 concentrations in plasma and urine will be performed at 
 
.
Analyses of BI 764122 metabolites concentrations in plasma and urine will be performed at 
the Department of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
Biomarker analysis will be performed at the Department of Drug Metabolism and 
Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, Germany.
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 according to BI SOPs.


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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
R94-1529
Chow SC, Liu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:1-
9.
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. U.S. Department 
of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER); 2005.
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).
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R13-2231
Baumgart DC, Sandborn WJ. Crohn's disease. Lancet 2012;380:1590-1605.
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/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).
R17-3322
Berruyer C, Pouyet L, Millet V, Martin FM, LeGoffic A, Canonici A, 
Garcia S, Bagnis C, Naquet P, Galland F. Vanin-1 licenses inflammatory 
mediator production by gut epithelial cells and controls colitis by 
antagonizing peroxisome proliferator-activated receptor gamma activity. J 
Exp Med. 2006 Dec 25;203(13):2817-27.
R17-3323
Martin F, Penet MF, Malergue F, Lepidi H, Dessein A, Galland F, de Reggi 
M, Naquet P, Gharib B. Vanin-1(-/-) mice show decreased NSAID- and 
Schistosoma-induced intestinal inflammation associated with higher 
glutathione stores. J Clin Invest. 2004 Feb;113(4):591-7.


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R17-3326
Ferreira DW, Goedken MJ, Rommelaere S, Chasson L, Galland F, Naquet 
P, et al. Enhanced hepatotoxicity by acetaminophen in vanin-1 knockout 
mice is associated with deficient proliferative and immune responses. 
Biochim Biophys Acta Mol Basis Dis 2016;1862(4):662-669.
R17-3327
Roisin-Bouffay C, Castellano R, Valero R, Chasson L, Galland F, Naquet 
P. Mouse vanin-1 is cytoprotective for islet beta cells and regulates the 
development of type 1 diabetes. Diabetologia 2008;51(7):1192-1201.
R18-2692
Wang YJ, Tayo BO, Bandyopadhyay A, Wang H, Feng T, et. al. The 
association of the vanin-1 N131S variant with blood pressure is mediated 
by endoplasmic reticulum-associated degradation and loss of function. 
PLoS genetics. 2014 Sep 18;10(9):e1004641.
R18-2864
Creasy DM, Chapin RE. Testicular and epididymal toxicity: Pathogenesis 
and potential mechanisms of toxicity. Spermatogenesis. 
2014;4(2):e1005511.
R18-2866
Kang M, Qin W, Buya M, Dong X, Zheng W, Lu W, et al. VNN1, a 
potential biomarker for pancreatic cancer-associated new-onset diabetes, 
aggravates paraneoplastic islet dysfunction by increasing oxidative stress. 
Cancer Lett 2016;373:241-250.
R18-2867
Diepen JA van, Jansen PA, Ballak DB, Hijmans A, Rutjes FPJT, Tack CJ, 
et al. Genetic and pharmacological inhibvition of vanin-1 activity in animal 
models of type 2 diabetes. Sci Rep 2016;6:21906.
R18-2954
Matthews HC, Concas D, Kudo H, Anstee Q, Thomas H, Cox R, et al. Cell 
surface pantetheinase, vanin-1, increases oxidative damage in 
acetaminophen induced liver injury via a reduction in glutathione. Int Liver 
Cong 2010, 45th Ann Mtg of the European Association for the Study of the 
Liver (EASL), Vienna, 14 - 18 Apr 2010. J Hepatol 2010;52(Suppl 
1):S311-S312.
R18-3167
Gensollen T, Bourges C, Rihet P, Rostan A, Millet V, Noguchi T, Bourdon 
V, Sobol H, Dubuquoy L, Bertin B, Fumery M, Desreumaux P, Colombel 
JF, Chamaillard M, Hebuterne X, Hofman P, Naquet P, Galland F. 
Functional polymorphisms in the regulatory regions of the VNN1 gene are 
associated with susceptibility to inflammatory bowel diseases. Inflamm 
Bowel Dis. 2013 Oct;19(11):2315-25.
R18-3175
Thoene JG, Oshima RG, Crawhall JC, Olson DL, Schneider JA. Cystinosis. 
Intracellular cystine depletion by aminothiols in vitro and in vivo. J Clin 
Invest. 1976 Jul;58(1):180-9.
R18-3176
Zhang B, Lo C, Shen L, Sood R, Jones C, Cusmano-Ozog K, Park-Snyder 
S, Wong W, Jeng M, Cowan T, Engleman EG, Zehnder JL. The role of 
vanin-1 and oxidative stress-related pathways in distinguishing acute and 
chronic pediatric ITP. Blood. 2011 Apr 28;117(17):4569-79.


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R18-3178
Jansen PA, Kamsteeg M, Rodijk-Olthuis D, van Vlijmen-Willems IM, de 
Jongh GJ, Bergers M, Tjabringa GS, Zeeuwen PL, Schalkwijk J. 
Expression of the vanin gene family in normal and inflamed human skin: 
induction by proinflammatory cytokines. J Invest Dermatol. 2009 
Sep;129(9):2167-74.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c23522589
  Investigator’s Brochure BI 764122  1430.P1  Version 1  
08 Nov 2018.
n00259748
Impact of Vanin’s Inhibition on Human CD4 T Cells Effector Functions. 
02 Oct 2018.
n00259750
Human Colon Tissue-Gene Expression. 19 Oct 2018.
n00259751
In situ analysis of CD-18 and IHH expression in human colon explants. 
17 Oct 2018.
n00259752
Human Primary Cell Full Thickness Epithelium Functional assay: the effect 
on trans epithelial resistance in response to various cytokines, LPS, 
ecombinany Vanin-1 protein and TNF-alpha stimulation. Dose dependent 
rescue of barrier integrity from TNF-alpha induced damage with 
BI00764122. 15 Oct 2018.
n00259753
Pharmacodynamics of BI764122 in the dextran sulfate sodium model of 
colon injury in mice. 19 Oct 2018.
n00260689
Determination of the Molar Extinction Coefficient of BI 764122 XX . 
09 Mar 2018.
n00261087
A Pharmacological Assessment of the Effects of BI 764122 on the 
Cardiovascular System of the Beagle Dog Using Telemetry. Study 18R018.
n00261089
A Pharmacological Safety Assessment of the Effect of BI 764122 on the 
Respiratory System of Wistar Han Rats. Study 18R07.
n00261263
BI 764122: Four-Week Oral (Gavage) Toxicity and Toxicokinetics Study in 
the Dog Followed by a Four-Week Recovery Period. Study number18R068. 
Draft report available.
n00261378
BI 764122: In Vivo Mammalian Erythrocyte Micronucleus Assay in Rats. 
Study number 18R073.
n00261387
BI 764122: Four-Week Oral (Gavage) Toxicity and Toxicokinetics Study in 
the Rat Followed by a Four-Week Recovery Period. Study number18R067. 
Draft report available.
n00261485
BI 764122: Effect on hERG inactivating Tail Currents recorded from Stably 
Transfected HEK293 cells. Study 18R056.


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n00261507
BI 764122: Bacterial Reverse Mutation with an Independent Repeat Assay. 
Study number 18R071.
n00261509
BI 764122: In Vitro Mammalian Cell Micronucleus Assay in Human 
Peripheral Blood Lymphocytes (HPBL). Study 18R072.
n00261538
BI 764122: Neutral Red Uptake Phototoxicity Assay of in BALB/c 3T3 
Mouse Fibroblasts. Study number18R036.
n00262543
Effects of BI 764122 (1, 3 and 10 mg/kg p.o.) on gastrointestinal function 
in the conscious rat. Study number GP2017/0024/PH4. 19 Sep 2018.
n00262545
Effects of BI 764122 (1, 3 and 10 mg/kg p.o.) on urine and serum-derived 
parameters in conscious rats. Study number GP2017/0025/PH4. 
11 Sep 2018.
n00263786
Excretion of radioactivity in urine, faeces, and bile after oral and 
intravenous administration of [14C]BI 764122 to rats. Report in progress.
n00263789
Investigation of the concentration dependency of the in vitro protein 
binding of [3H]BI 764122 in mouse, rat, dog and human plasma. Report in 
progress.
n00263794
Validation of an LC/MS/MS Method for the Quantitation of BI 764122 in 
Rat Plasma. Report in progress.
n00263812
Validation of an LC/MS/MS Method for the Quantitation of BI 764122 in 
Dog Plasma. Report in progress.
n00263939
Quantitative whole-body autoradiography in male pigmented rats after 
single oral administration of [14C]BI 764122. Report in progress.
n00264108
Prediction of BI 764122 Pharmacokinetics and Therapeutic Dose in Human. 
Report in progress.
n00264288
  BI 764122: Four-Week Oral Gavage Toxicity and 
Toxicokinetics Study in the Rat Followed by a Four-Week Recovery Period 
Part: Toxicokinetics 18R067.
n00264293
  BI 764122: Four-Week Oral Gavage Toxicity and 
Toxicokinetics Study in the Dog Followed by a Four-Week Recovery 
Period Part: Toxicokinetics  18R068.
n00264294
  Eurofins Cerep Data Report for Pharmacology Services  n/a. 
19 Oct 2018.
n00264299
  ThermoFisher Scientific's SelectScreen (TM) Profiling Service: 
Single Point Results  n/a  26 Oct 2018.
n00264300
Vanin Inhibition in human Whole Blood. 19 Oct 2018.
n00264301
Inhibition of recombinant human Vanin-1 enzymatic activity. 15 Oct 2018.
n00264302
Vanin Inhibition in C57BL6 Mouse Blood. Draft report available.
n00264303
BI 764122 Target Engagement (TE) in Human Colon Explant Assays. 
23 Oct 2018.


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10.
APPENDICES
None


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
10 January 2019
EudraCT number
EU number
2018-003604-39
BI Trial number
1430-0001
BI Investigational Medicinal 
Product(s)
BI 764122
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 764122 (single-blind, 
partially randomised, placebo controlled, parallel 
(sequential) group design) and the effect of food on 
BI 764122 (open-label, randomised, single-dose, 
two-period, two-sequence crossover design) in 
healthy male subjects
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
- 1.2.2 Toxicology
- 3.3.2 Inclusion criteria
Description of change
- Deletion of linking emesis to a decrease of food 
consumption in a 4-week study in dog. 
- Correction of Inclusion Criterion 5: Discrepancy 
between 30 and 60 days of duration of contraception 
was reconciled to 30 days. Sperm donation 
restriction was changed from “no sperm donation is
not allowed” to “sperm donation is not allowed”.
Rationale for change
- Emesis was not observed in a 4-week study in dog.
- 30 days of adequate contraception after trial 
completion was considered as sufficient. Typo in 
sperm donation restriction was corrected.


 
 
 
 
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c25602783
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clinical-trial-protocol-revision-01
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 764122
(single-blind, partially randomised, placebocontrolled, parallel (sequential) group
design) and the effect of food on BI 764122 (open-label, randomised, single-dose,
two-period, two-sequence crossover design) in healthy male subjects
Author-Clinical Trial Leader
10 Jan 2019 09:58 CET
Author-Trial Statistician
10 Jan 2019 11:37 CET
Author-Trial Clinical
Pharmacokineticist
10 Jan 2019 13:05 CET
Approval-Team Member Medicine
10 Jan 2019 14:21 CET
Verification-Paper Signature
Completion
10 Jan 2019 14:34 CET
Approval-Therapeutic Area 
11 Jan 2019 13:47 CET


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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c28983597-01
BI Trial No.:
1430-0001
Title:
Safety, tolerability and pharmacokinetics of single rising oral doses 
of BI 764122 (single-blind, partially randomised, placebo-
controlled, parallel (sequential) group design) and the effect of food 
on BI 764122 (open-label, randomised, single-dose, two-period,
two-sequence crossover design) in healthy male subjects
Investigational
Product:
BI 764122
Responsible trial 
statisticians:
Phone: 
Fax: 
Date of statistical 
analysis plan:
13 SEP 2019 SIGNED 
Version:
“Final”
Page 1 of 31
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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
5.3.2
Safety parameters .................................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
7.
PLANNED ANALYSIS......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINT .....................................................................................20
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoint .....................................................................................20
7.5.2
Secondary endpoints...........................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse events.....................................................................................................23


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7.8.2
Laboratory data ..................................................................................................24
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................26
8.
REFERENCES....................................................................................................27
9.
ADDITIONAL SECTIONS ...............................................................................28
9.1
DETAILED DESCRIPTION OF ENDPOINTS FOR ECG...........................28
10.
HISTORY TABLE..............................................................................................31


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data, ECG and vital signs................................................................13
Table 6.2: 1
Handling of iPDs ..............................................................................................15
Table 6.3: 1
Subject sets analysed ........................................................................................16
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation ..........18
Table 10: 1
History table .....................................................................................................31


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte over the time 
interval from 0 extrapolated to infinity
BLQ
Below the lower limit of quantification
BMI
Body mass index
BI
Boehringer Ingelheim
BP
Blood pressure
CARE
Clinical data analysis and reporting environment
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
ECGPCS
Electrocardiogram plasma concentration set
eCRF
Electronic case report form
FE
Food effect
gCV
Geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
ICH
International Conference On Harmonisation
IPD
Important protocol deviation
LLT
Lower level term
MedDRA
Medical Dictionary For Regulatory Activities
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
PR
Pulse rate


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Term
Definition / description
QRS complex
Combination of the Q, R, and S waves
QT interval
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTcB
QT interval, heart rate corrected according to Bazetts formula
QTcF
QT interval, heart rate corrected according to Fridericias formula
Q1
Lower Quartile
Q3
Upper Quartile
RAGe
Report appendix generator
RPM
Report Planning Meeting
RR interval
ECG interval from the peak of the R wave to the peak of the 
subsequent R wave
SD
Standard Deviation
SRD
Single-rising dose
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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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 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 amendment. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 "Statistical Methods 
and Determination of Sample Size". Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Medidata Rave 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; RAGe
system for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version 6.3, Certara 
USA Inc., Princeton, NJ, USA).


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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 described 
in the CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint is the percentage of subjects with drug-related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints are AUC0-∞and Cmax in plasma for BI 764122.
5.3.2
Safety parameters
Further safety parameters will be used as defined in Section 2.2.2.1 of the CTP:
CTP:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring (SRD part)

Vital signs (blood pressure, pulse rate)
12-lead ECG endpoints
For the definition of baseline value and a clear presentation of measurement time points 
scheduled for ECG recording and central evaluation refer to Section 6.7.
Quantitative ECG endpoints:
The following quantitative ECG endpoints will be determined for the ECG variables QT, HR, 
PR, QRS, RR, QTcF and QTcB derived as described in Additional Section 9.1:

absolute values (per time point)

changes from baseline (per time point)

percent changes from baseline (per time point; for HR, PR, QRS)


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Categorical ECG endpoints
The following categorical ECG endpoints will be determined based on the quantitative ECG 
endpoints:

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. 

Maximum change from baseline of QT ≤ 60 msec, or > 60 msec on treatment

Maximum change from baseline of QTcF ≤ 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 at baseline) of uncorrected QT interval > 500 msec at any time on 
treatment

New onset of QTcF interval > 500 msec at any time on treatment

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


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignments of dose groups, 
and selection of doses, cf. Section 4 of the CTP.
Subjects were planned to be treated with 
SRD part:

either a single dose of 4, 12, 25, 50, 100, 200, 300 or 400 mg of BI 764122 (test 
treatments)
or

a single dose of placebo (reference treatment)
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).
FE part:

single dose of 50 mg BI 764122 in fed state (test treatment T) and in fasted state
(reference treatment R) with a wash-out period of at least 7 days between treatments
Subjects will randomly be assigned to the treatment sequence (T-R) or (R-T).
For statistical analysis of AEs, safety laboratory data, vital signs and ECG, the following 
analysis phases are defined for each subject:


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Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data, ECG and vital signs
SRD part:
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
Pbo,
4 mg BI,
12 mg BI,
25 mg BI,
50 mg BI,
100 mg BI,
200 mg BI,
300 mg BI or
400 mg BI
respectively
Date/time of first 
administration of study 
drug
Date/time of last 
administration of
study drug + 7 * 24 h (i.e., 
REP of  7 days) or 0:00 AM 
on day after subject's trial 
termination date
whatever occurs earlier
Follow-up
F/U Pbo,
F/U 4 mg BI,
F/U 12 mg BI,
F/U 25 mg BI,
F/U 50 mg BI,
F/U 100 mg BI,
F/U 200 mg BI,
F/U 300 mg BI or
F/U 400 mg BI
respectively
Date/time of last 
administration of
study drug + 7 * 24 h
0:00 AM on day after subject's 
trial completion date
FE part:
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
BI fed,
BI fasted
Date/time of first 
administration of study 
drug of respective 
treatment
Date/time of administration of
study drug in next period or
date/time of administration of
study drug + 7 * 24 h (i.e., 
REP of  7 days) or 
0:00 AM on day after subject's 
trial completion date
whatever occurs earlier
Follow-up
F/U BI
Date/time of 
administration of
study drug + 7 * 24 h
Date/time of second 
administration of study drug 
or
0:00 AM on day after subject's 
trial completion date


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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. Appendix 16.1.13.1.8.1 will present results for 
the screening, on-treatment and follow-up phase.
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:
SRD part:

"Total BI", defined as the total over all on-treatment phases involving BI

"Total on-trt SRD", defined as the total over all on-treatment phases, including 
placebo
FE part:

"Total on-trt FE", defined as the total over all on-treatment phases 
Additionally, the following total will be provided in CTR Section 16.1.13.1.8.1 AE tables:

"Total SRD", defined as the total over all study phases (incl. screening, on-treatment, 
and follow-up) of the SRD part

"Total FE", defined as the total over all study phases (incl. screening, on-treatment, 
and follow-up) of the FE part
For disclosure outputs in CTR Section 16.1.13.1 (but not for AE tables) the following total 
will be provided:

"Study Total", defined as the total over all study phases (screening, on-treatment and 
follow-up) for the SRD and FE part combined (only for disclosure outputs)
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 violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the 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  
PD (iPD). For the process of identification and managing iPDs refer to the BI reference 
document "Identify and Manage Important Protocol Deviations (iPD)" (2). For a detailed 
specification of PDs and iPDs of this trial refer to the Integrated Quality and Risk 
Management Plan (IQRMP) Section 4.1.
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the decisions 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 RPM.


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iPDs will be summarised 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 RPM, after discussion of exceptional cases 
and implications for analyses.
Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Possible exclusion from analysis 
set
A1
Inclusion Criteria Not Met
PKS,
A2
Exclusion Criteria Not Met
PKS, 
B1
Informed consent not available/not 
done
TS, PKS, 
B2
Informed consent too late
None
C2
Randomization not followed
PKS
C3
Non-compliance
PKS, 
C5
Incorrect intake of trial medication
PKS, 
C6
Improper washout between treatments
PKS
D1
Prohibited medication use
PKS, 
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
Incorrect intake of meal
PKS
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The subject sets as defined in detail in the CTP, Section 7.3 will be used. These include the 
Treated set (TS) and Pharmacokinetic parameter analysis set (PKS) for the SRD and FE part, 
and the ECG Pharmacokinetic Concentration Set (ECGPCS) and 
 
 for the SRD part.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
ECGPCS
Disposition
X
Exposure
X
IPDs
X
Demographic/baseline endpoints
X
Primary endpoint
X
Other safety parameters
X
Secondary PK endpoints
X
ECG endpoints and plasma 
concentrations used in exposure-
response analysis
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Data of treated subjects who failed to complete the study (dropouts or withdrawals) will be 
reported in the CTR as far as their data are available. All withdrawals will be documented and 
the reason for withdrawal recorded in the CTR.
CTP: It is not planned to impute missing values for safety parameters.
The only exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3) [001-MCG-
156_RD-01].
No imputation will be done for ECG endpoints. If replicate ECG recordings are missing, the 
arithmetic means per time point will be computed with the reduced (1 or 2) number of 
recordings. If single cardiac cycles (also denoted as beats or waveforms) are missing, the 


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arithmetic mean per single ECG will be computed with the reduced (1, 2 or 3) number of 
cardiac cycles.
For the classification of the on-treatment QTc/QT intervals into ‘no new onset’ / ‘new onset’ 
categories, a missing value is obtained only in case that 
(i)
all on-treatment values are missing and 
(ii)
the baseline value is less than or equal to 500 msec, or missing. 
If condition (i) is fulfilled but the baseline value is greater than 500 msec, this case will be 
categorized as ‘no new onset’. If baseline is missing and the maximum on-treatment QTc 
interval is greater than 450 msec (or 500 msec for QT interval, respectively), this is classified 
as a ‘new onset’ in the respective category. If baseline is missing and the maximum QTc 
interval is less than or equal to 450 msec (or 500 msec for QT interval, respectively), this will 
be categorized as ‘no new onset’. If baseline is missing, a QTc/QT interval > 500 msec at any 
time on treatment will be a notable finding.
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.
Missing data and outliers of PK data are handled according to BI standards (4) [001-MCS-36-
472_RD-01] and (5)
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
In all analyses (except for analyses of ECG variables), the last available off-treatment value 
determined prior to the first dosing of trial medication of the respective treatment period will 
be defined as baseline. This means that a separate baseline is defined for each study treatment 
of the FE part. Off-treatment in this context means that a value measured within an on-
treatment phase, as defined in Table 6.1: 1, will not be used as baseline for any study 
treatment. 
There will be a centralised evaluation of all 12-lead ECG recordings for the SRD part at the 
time points specified in Table 6.7: 1:


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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
2
1
-00:30
Baseline 
00:10
On-treatment
00:30
00:45
01:00
01:30
02:00
03:00
04:00
06:00
08:00
10:00
12:00
2
24:00
Three triplicate ECGs will be recorded as the baseline before the first drug administration, but 
only the first ECG of each of the 3 triplicates will be evaluated. The baseline value of an ECG 
variable is defined as the mean of the transferred baseline ECG measurements prior to drug 
administration. At all other time points, 1 triplicate ECG will be recorded, but only the first 
ECG of the triplicate will be centrally evaluated. 
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 0:30 will build one pair. 
Note, there is a time-matched PK sample planned at each planned time of ECG recordings as 
outlined in Table 6.7: 1 above, see also Flow Chart in the CTP. 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/DBLM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6)
The individual values of all subjects will be listed, sorted by treatment or sequence group, 
subject number and visit. 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 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 are actually missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. These will be based on the 
TS.


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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.
Only descriptive statistics are planned for this section of the report.
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.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint (cf. Section 5.4.2). Any 
deviations from complete intake will be addressed in the RPM (cf. Section 6.2) and described 
in the CTR.
7.4
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
This section is not applicable as no key secondary endpoint has been specified in the CTP.
7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.
The PK endpoints will be assessed descriptively. The analysis of standard PK parameters is 
performed according to BI standards (4) [001-MCS-36-472_RD-01].


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Exclusion of PK parameters
The analysis data set (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 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 CTP trial 
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)


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report, by fasting state and overall for 
the FE part. For the SRD part a listing will be sufficient.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.


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7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the electronic case report form (eCRF) will be 
collapsed into an AE event provided that all of the following applies:

All AE attributes are identical (LLT, intensity, action taken, therapy required, seriousness, 
reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended).
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 the screening or treatment phases as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (8) and for the class of 
AESIs.
CTP: 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
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological 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 system organ 
class 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, 
subjects with AESIs and subjects with other significant AEs (according to ICH E3 (8)). AEs 
will also be summarized by maximum intensity.


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The system organ classes will be sorted by total frequency, preferred terms will be sorted by 
total frequency (within system organ class).
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 system organ class 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 summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standard
"Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range.
Descriptive statistics of laboratory values over time and for the difference from baseline (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.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the eCRF or at the 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 will not be applied in this 
study.
Clinically relevant findings in laboratory data will be reported as AEs and will be analysed as 
part of AE analysis.
7.8.3
Vital signs
The analysis of vital signs will be descriptive in nature. Descriptive statistics of vital signs 
over time and for the difference from baseline (see Section 6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first study drug administration) or as AEs (during the trial) if judged clinically relevant by the 
investigator, and will be analysed as such.
7.8.4
ECG
Abnormal findings will be reported as baseline conditions (prior to first study drug 
administration) or as AEs (during the trial) if judged clinically relevant by the investigator. 


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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.
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 will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all subjects with any notable finding in ECG intervals, 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.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the 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 group.
Exposure-response analysis
To analyse the relationship between changes from baseline in QTcF and HR and the time-
matched plasma concentrations a random coefficient model will be applied to the ECGPCS, 
including placebo treated subjects. For a list of time points with scheduled ECG assessments 
and a time-matched plasma concentration, refer to Table 6.7: 1.
For the handling of missing values, see Section 6.6.
The remaining Section describes the analysis for QTcF only, however the same analysis will 
be performed for HR.
The response variable will be change from baseline in QTcF (QTcF). The placebo subjects 
will be included in the analysis, setting their plasma concentrations to zero.
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to 
metabolites) effect of the drug on QTcF. A general visual impression will be provided by 
overlaying time profiles of plasma concentrations and QTcF changes from baseline (QTcF). 
These figures will be generated for each subject (presented in the Statistical Appendix of the 
CTR), as well as for means per treatment group (presented in the End-of-Text part of the 
CTR).
The relationship between BI 764122 plasma concentrations and QTcF changes from baseline 
will be investigated in an exploratory manner using a random coefficient model to estimate 
the difference in mean QTcF change from baseline between BI 764122 and placebo and its 


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90% confidence interval at the geometric mean of Cmax for each dose. Additionally, the 
estimated overall slope with its 90% confidence interval will be provided. The used random 
coefficient model is based on a white paper from Garnett et. al. [R18-0143] (10) with QTcF 
as response variable, centred baseline QTc and plasma concentration as continuous covariates, 
treatment and time as fixed categorical effects, and a random intercept and slope for each 
subject. For more details refer to Additional Section 9.2.
For visualization, a scatterplot of the BI 764122 plasma concentration against the following 
individual QTcF values will be provided: For each subject on active treatment and each time 
point, subtract the mean value of all individual observed ΔQTcF values from the placebo 
group for this time point from the individual observed ΔQTcF value for this subject and time 
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used 
for plotting purposes. The corresponding regression line and its pointwise confidence bands 
as well as the geometric mean of Cmax for each dose will additionally be displayed in the plot.
To check model assumptions, the conditional residuals will be plotted and presented in the 
Statistical Appendix of the CTR. In case of non-linearity or if there is evidence for a delayed 
effect, further models will be explored in order to better characterise the PK-ECG relationship 
(e.g. effect compartment models, non-linear models, etc.).
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval (values log-transformed using the natural 
logarithm) will be estimated by applying the random coefficient model described in
Section 9.1 using all time points. A scatterplot of ln(QTcF) vs ln(RR) including the overall 
regression line will be included in the Statistical Appendix of the CTR. The resulting (fixed 
effect) slope together with two-sided 95% confidence intervals will be included in the 
footnote for this plot.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of first study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9; 
Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical Trials, 
current version
2
001-MCS-40-413_1.0: "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: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0041: "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]


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9.
ADDITIONAL SECTIONS
9.1
DETAILED DESCRIPTION OF ENDPOINTS FOR ECG
QT, PR, QRS and RR baseline and on-treatment measurements (see Table 6.7: 1) are included 
in the centralised ECG evaluation. 
For each single ECG, measurements of QT, PR, QRS and preceding RR interval of four 
cardiac cycles will be determined and stored in the database as raw data. Their mean values 
will be used as the QT, PR, QRS, and RR interval values, respectively, for this ECG.
QTcF, HR and QTcB will be calculated based on the derivation rules as follows:
From the four cardiac cycles of a single ECG, the HR (measured in beats per minute, 
beats/min) will be calculated as
 [	
/] = 60 000


where RR is the mean of the four RR intervals (measured in msec).
Similarly, the QT interval corrected for HR according to Fridericia’s formula (QTcF) for a 
single ECG will be derived as

 [] = 1000

 
/
∗
[],
where QT
 is the mean of the four QT intervals and RR
 is the mean of the corresponding 
preceding RR intervals of the four cardiac cycles for this ECG.
Likewise, the HR-corrected QT interval according to Bazett’s formula (QTcB) for a single 
ECG is given by
#
 [] = 1000

 
/$
∗
[].
In case of triplicate ECGs at a time point, the respective ECG variable will be averaged over 
the triplicate ECG measurements at this time point (arithmetic mean). Note that in case of 
missing values the averaging is simply done for the available values.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
13-Sep-19
None
This is the final TSAP without any 
modification