Clinical trial NCT02733627
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2016-07-07; Completion date: 2017-07-12
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the safety and tolerability of BI 1467335 in healthy male and female subjects following oral administration of multiple rising doses over 28 days.

Secondary objectives are the exploration of the pharmacokinetics (PK) and target engagement biomarkers of BI 1467335 after multiple dosing.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: BI 1467335 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08854973-04
EudraCT No.:
BI Trial No.:
2015-005049-29
1386.8
BI Investigational
Product:
BI 1467335
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
multiple rising oral doses of BI 1467335 in healthy male and female 
subjects (double-blind, randomised, placebo-controlled within dose 
groups)
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:     
Principal Investigator:
Phone: 
Fax:     
Status:
Final Protocol (Revised Protocol (based on global amendment 3))
Version and Date:
Version: 4.0
Date: 05 OCT 2016
Page 1 of 101
Proprietary confidential information
© 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 2 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1467335
Protocol date:
Trial number:
Revision date:
05 OCT 2016
09 March 2016
1386.8
Title of trial:
Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising oral 
doses of BI 1467335 in healthy male and female subjects (double-blind, randomised, 
placebo-controlled within dose groups)
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability, pharmacokinetics and pharmacodynamics following 
multiple rising doses of BI 1467335
Methodology:
Double-blind, randomised, placebo-controlled within dose groups, parallel-group 
design
No. of subjects: 
total entered:
36*
each treatment:
12 per dose group (9 on active drug and 3 on placebo) 
* Additional subjects may be entered to allow testing of an additional dose within the 
approved dose range on the basis of experience gained during trial conduct (e.g. 
preliminary PK, ECG and safety data),. In this case up to 48 subjects may be included.
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male/female of non-childbearing potential subjects, age of 18 to 50 years, 
body mass index (BMI) of 18.5 to 29.9 kg/m²
Test product:
BI 1467335, Powder for oral solution (PfOS)
dose:
Dose group 1:
10 mg BI 1467335, q.d.
Dose group 2:
15 mg BI 1467335, q.d.
Dose group 3:
20 mg BI 1467335, q.d.
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
Comparator product:
Solvent for Oral Solution (Sucralose 4 mg/ml + Menthol 2 mg/ml) as placebo 
dose:
Not applicable
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment: 28 days with multiple doses of BI 1467335 q.d.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 3 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1467335
Protocol date:
Trial number:
Revision date:
05 OCT 2016
09 March 2016
1386.8
Criteria for
pharmacokinetics:
Secondary endpoints:
After the first dose:
AUC0-24 and Cmax
After the last dose:
AUC0-24,28 and Cmax,28
Further PK parameters of interest will be calculated as appropriate
Criteria for 
pharmacodynamics:
 
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 1467335 is the number 
[N (%)] of subjects with drug-related adverse events (AEs).
 
 
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 1467335 will be explored using a regression model. A 
95% confidence interval (CI) for the slope will be computed.
Linearity index will be estimated using a linear model providing a two-sided 95% CI, 
if AUC0-∞is possible to determine and steady state is achieved.
 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 4 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
FLOW CHART
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9
PK urine
10
PD blood 
17
12-lead ECG 8
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -3
Screening (SCR)1, 12
x
x
x
2
-2
-48:007
08:00
Ambulatory visit
x
x
x
x
-1
-12:00
20:00
Admission to trial site
x5
x
1
-2:00
06:00
Allocation to treatment2
x13
x2
x2
x2
x2
x2
0:00
08:00
First drug administration
x14
▲
x2
0:15
08:15
x
│
x
x
0:30
08:30
x
│
x
x
x
0:45
08:45
x
│
x
x
x
1:00
09:00
x15
│
x
x
x
x
1:30
09:30
x
│
x
x
2:00
10:00
240 mL fluid intake and light breakfast3
x
│
x
x
x
x
3:00
11:00
x
│
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
┼
x
x
x
x
6:00
14:00
x
│
x
8:00
16:00
Snack (voluntary)3
x
┼
x
x
x
x
10:00
18:00
Dinner3
x
│
x
12:00
20:00
x
┼
x
x
x
x 
2
24:00
08:00
Drug administration11
x14
▼
x14
x2
x2
x2
3
48:00
08:00
Drug administration11
x
x2
x2
x2
4
72:00
08:00
Drug administration11
x14
x2
x2
73:00
09:00
Discharge from trial site (confirmation of 
fitness)4
x
x
x
x
5
96:00
08:00
Ambulatory visit,  Drug administration11
x2
x2
x2
6
120:00
08:00
Ambulatory visit,  Drug administration11
x2
7
144:00
08:00
Ambulatory visit,  Drug administration11
x
x14
▲
x14
x2
x2
x2
145:00
09:00
Discharge
x
│
x
x
8
168:00
08:00
Ambulatory visit,  Drug administration11
▼
x²
x2
9
192:00
08:00
Ambulatory visit,  Drug administration11
x²
x2
10
216:00
08:00
Ambulatory visit,  Drug administration11
x²
x2
11
240:00
08:00
Ambulatory visit,  Drug administration11
x2
x2
x2
12
264:00
08:00
Ambulatory visit,  Drug administration11
x
x14
x2
x2
x2
265:00
09:00
Discharge
x
x
x
x
13
288:00
08:00
Ambulatory visit,  Drug administration11
x14
x2
x2
x2
289:00
09:00
Discharge
x
x
x
x
300:00
20:00
Admission to trial site
x5
x


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 5 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9
PK urine
10
PD blood
17
12-lead ECG 8
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
2
14
310:00
06:00
x2
x2
x2
x2
312:00
08:00
Drug administration
x14
▲
x14
312:15
08:15
x
│
x
312:30
08:30
x
│
x
x
312:45
8:45
x
│
x
x
313:00
09:00
x15
│
x
x
x
313:30
09:30
x
│
x
314:00
10:00
240 mL fluid intake and light breakfast3
x
│
x
x
x
315:00
11:00
x
│
316:00
12:00
240 mL fluid intake, thereafter lunch3
x
┼
x
x
x
318:00
14:00
x
│
320:00
16:00
Snack (voluntary)3
x
┼
x
x
x
322:00
18:00
Dinner3
x
│
324:00
20:00
x
┼
x
x
x 
15
336:00
08:00
Drug administration11, 12
x14
▼
x2
x2
x2
16
360:00
08:00
Drug administration11
x14
x2
x2
x2
17
384:00
08:00
Drug administration11
x14
x2
x2
x2
385:00
09:00
Discharge from trial site (confirmation 
of fitness)4
x
x
x
x
18
408:00
08:00
Ambulatory visit,  Drug 
administration11
x²
x2
19
432:00
08:00
Ambulatory visit,  Drug 
administration11
x²
x2
20
456:00
08:00
Ambulatory visit,  Drug 
administration11
x²
x2
21
480:00
08:00
Ambulatory visit,  Drug 
administration11
x2
x14
▲
│
x14
x2
x2
x2
481:00
09:00
Discharge
x
│
x
x
x
22
504:00
08:00
Ambulatory visit,  Drug 
administration11
▼
x²
x2
23
528:00
08:00
Ambulatory visit,  Drug 
administration11
x²
x2
24
552:00
08:00
Ambulatory visit,  Drug 
administration11
x²
x2
25
576:00
08:00
Ambulatory visit,  Drug 
administration11
x14
x2
x2
x2
577:00
09:00
Discharge
x
x
x
x
26
600:00
08:00
Ambulatory visit,  Drug 
administration11
x14
▲
│
x2
x2
x2
601:00
09:00
Discharge
x
│
x
x
x
27
624:00
08:00
Ambulatory visit,  Drug 
administration11
x14
▼
▲
x2
x2
x2
625:00
09:00
Discharge
x
│
x
x
x
636:00
20:00
Admission to trial site
x5
│
x


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 6 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood
9
PK urine
10
PD blood
17
12-lead ECG 8
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
2
28
646:00
6:00
x2
│
x2
x2
x2
648:00
08:00
Last drug administration
x14,
16
▼
▲
x14
648:15
08:15
x16
│
x
x
648:30
08:30
x16
│
x
x
x
648:45
08:45
x16
│
x
x
x
649:00
09:00
x15,
16
│
│
x
x
x
x
649:30
09:30
x16
│
x
x
650:00
10:00
240 mL fluid intake and light breakfast3
x16
│
x
x
x
x
651:00
11:00
x16
│
x
652:00
12:00
240 mL fluid intake, thereafter lunch3
x16
┼
x
x
x
x
654:00
14:00
x16
│
x
656:00
16:00
Snack (voluntary)3
x16
┼
x
x
x
x
658:00
18:00
Dinner3
x16
│
x
660:00
20:00
x16
┼
x
x
x
x 
29
672:00
08:00
Ophthalmological investigation12
x16
▼
x
x
x
x
673:00
09:00
Discharge from trial site (confirmation 
of fitness)4
30
696:00
08:00
Ambulatory visit
x
x
x
x
x
x
31
720:00
08:00
Ambulatory visit
x
x
32
744:00
08:00
Ambulatory visit
x
x
x
34
792:00
08:00
Ambulatory visit
x
x
x
36
840:00
08:00
Ambulatory visit
x
x
38
888:00
08:00
Ambulatory visit
x
x
40
936:00
08:00
Ambulatory visit
x
x
3
42 to 48
End of trial (EOT) examination4, 5, 12
x
x
x
x
x
1.
Screening includes subject information, informed consent, physical examination, check of vital signs, ECG, safety 
laboratory (including drug screening), demographics (including determination of body height and weight, smoking status 
and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the respective procedure is to be performed and completed within 2 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to (first) drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies. Confirmation of fitness includes physical examination.
5.
Urine drug screening and alcohol breath test as well as pregnancy test in women will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Safety laboratory, ECG, blood pressure assessment and AE questioning to be done and medically evaluated within 
3 days prior to first administration of study drug; this visit can be omitted, if the screening examination is performed on 
Days -3, -2 or -1.
8.
The ECG recording has to be performed as triple on Day 1 and Day 2, Day 14 and Day 15, Day 21, Day 28 and Day 29.
All other ECG recordings will be single ECGs.
9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 510 mL per subject.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 7 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
10. A blank urine sample (x) is to be obtained prior to the first administration of trial medication. Other urine samples are to 
be collected over the stated post-dose intervals (◄––│––│––►) [on Day 1, Day 14 and Day 28 fractionated sampling 
0-4, 4-8, 8-12, and 12-24 h, otherwise 0-24 hour collection].
11. Administration under fasting conditions, light breakfast (or snack) 2 h p.a.
12. Ophthalmological examinations (exclusion of cataract).
13. Includes a blood sample for pharmacogenetic analysis.
14. Samples to be drawn immediately (within 30 minutes) prior to drug administration.
15. Additional blood samples for stability testing in the 10 mg and 15 mg dose group.
16. Additional blood samples for metabolite analysis.
17. Analysis of selected PD samples may be omitted based on information obtained during the trial. 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 8 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
TABLE OF CONTENTS
TITLE PAGE ........................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 29
2.2
TRIAL OBJECTIVES.......................................................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 35
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................35
3.1.1
Administrative structure of the trial...................................................36
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................37
3.3
SELECTION OF TRIAL POPULATION ......................................................38
3.3.1
Main diagnosis for study entry............................................................38
3.3.2
Inclusion criteria...................................................................................38
3.3.3
Exclusion criteria ..................................................................................39
3.3.4
Removal of subjects from therapy or assessments.............................40
3.3.4.1
Removal of individual subjects................................................40
3.3.4.2
Discontinuation of the trial by the sponsor..............................42
4.
TREATMENTS........................................................................................ 43
4.1
TREATMENTS TO BE ADMINISTERED....................................................43
4.1.1
Identity of BI investigational product and comparator product......43
4.1.2
Method of assigning subjects to treatment groups ............................44


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 9 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
4.1.3
Selection of doses in the trial................................................................44
4.1.4
Drug assignment and administration of doses for each subject .......44
4.1.5
Blinding and procedures for unblinding ............................................45
4.1.5.1
Blinding....................................................................................45
4.1.5.2
Procedures for emergency unblinding .....................................46
4.1.6
Packaging, labelling, and re-supply ....................................................46
4.1.7
Storage conditions.................................................................................46
4.1.8
Drug accountability ..............................................................................47
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................47
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................47
4.2.2
Restrictions............................................................................................48
4.2.2.1
Restrictions regarding concomitant treatment .........................48
4.2.2.2
Restrictions on diet and life style.............................................48
4.3
TREATMENT COMPLIANCE.......................................................................48
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 49
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................49
5.1.1
Endpoints of efficacy.............................................................................49
5.1.2
Assessment of efficacy...........................................................................49
5.2
SAFETY..............................................................................................................49
5.2.1
Endpoints of safety................................................................................49
5.2.2
Assessment of adverse events...............................................................49
5.2.2.1
Definitions of adverse events...................................................49
5.2.2.2
Adverse event collection and reporting ...................................52
5.2.3
Assessment of safety laboratory parameters......................................54
5.2.4
Electrocardiogram................................................................................57
5.2.4.1
12-lead resting ECG.................................................................57
5.2.5
Assessment of other safety parameters...............................................58
5.2.5.1
Vital signs ................................................................................58
5.2.5.2
Medical examinations..............................................................58
5.2.5.3
Ophtalmological examination..................................................59
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................60
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................60
5.5.1
Pharmacokinetic endpoints..................................................................60


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 10 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
5.5.1.1
Secondary endpoints................................................................60
5.5.2
Methods of sample collection...............................................................62
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................62
5.5.2.2
Plasma sampling for drug metabolism analysis.......................62
5.5.2.3
Urine sampling for pharmacokinetic analysis..........................63
5.5.2.4
Additional blood sample for stability-testing ..........................64
5.5.3
Analytical determinations ....................................................................64
5.5.3.1 Analytical determination of BI 1467335 plasma concentration
..................................................................................................64
5.5.3.2
Analytical determination of analyte urine concentration.........65
6.
INVESTIGATIONAL PLAN.................................................................. 68
6.1
VISIT SCHEDULE............................................................................................68
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................68
6.2.1
Screening................................................................................................68
6.2.2
Treatment period ..................................................................................68
6.2.3
End of trial and follow-up period........................................................69
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 70
7.1
STATISTICAL DESIGN – MODEL ...............................................................70
7.1.1
Objectives...............................................................................................70
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................70
7.3
PLANNED ANALYSES....................................................................................70
7.3.1
Primary analyses...................................................................................70
7.3.3
Safety analyses.......................................................................................75
7.3.4
Preliminary PK analyses......................................................................76
7.3.5
Pharmacokinetic analyses ....................................................................77
7.4
HANDLING OF MISSING DATA ..................................................................78
7.4.1
Safety......................................................................................................78
7.4.2
Plasma/urine drug concentration - time profile.................................78
7.4.3
Pharmacokinetic parameters...............................................................78


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 11 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
7.5
RANDOMISATION ..........................................................................................78
7.6
DETERMINATION OF SAMPLE SIZE ........................................................79
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 80
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................80
8.2
DATA QUALITY ASSURANCE .....................................................................80
8.3
RECORDS..........................................................................................................81
8.3.1
Source documents .................................................................................81
8.3.2
Direct access to source data and documents.......................................81
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................81
8.5
STATEMENT OF CONFIDENTIALITY.......................................................81
8.6
COMPLETION OF TRIAL..............................................................................82
9.
REFERENCES......................................................................................... 83
9.1
PUBLISHED REFERENCES...........................................................................83
9.2
UNPUBLISHED REFERENCES.....................................................................85
10. APPENDICES .......................................................................................... 87
10.1
RECONSTITUTION INSTRUCTION............................................................87
10.1.1 Drug supplies overview.........................................................................87
10.1.2 Required equipment and dosing aids - overview ...............................87
10.1.3 Reconstitution procedure.....................................................................88
10.1.3.1 Reconstitution procedure for the preparation of the active 
BI 1467335 oral solution 0.5 mg/mL.......................................88
10.1.3.2 Preparation of the solvent for oral solution for use as placebo 
solution.....................................................................................89
10.1.4 Illustration of reconstitution procedure..............................................90
10.1.5 In-use stability.......................................................................................91
10.1.6 Mode of application ..............................................................................91
10.1.7 General remarks - important! .............................................................92
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 93


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 12 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
ABBREVIATIONS
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2(,N)
Amount of analyte eliminated in urine over the time interval t1 to t2 (after 
the Nth dose)
ANOVA
Analysis of variance
APC
Absolute platelet count
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-24(,N)
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to 24h (after the Nth dose)
AUCt1-t2(,N)
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2 (after the Nth dose)
AUC0-tz(,N)
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point (after the Nth dose)
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
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
CCl4
Carbon tetrachloride
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F(,N)
Apparent clearance of the analyte in plasma after extravascular 
administration (after the Nth dose)
Cmax(,N)
Maximum measured concentration of the analyte in plasma (after the Nth
dose)
CML
Clinical Monitor Local
CNS
Central nervous system
Cpre,N
Predose concentration of the analyte in plasma immediately before 
administration of the Nth dose after N-1 doses were administered
CRA
Clinical Research Associate
CRF
Case report form
CRO
Clinical Research Organisation
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supplies Unit
CV
Arithmetic coefficient of variation
DEDP
Drug exposure during pregnancy
DILI
Drug induced liver injury


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 13 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
F
Absolute bioavailability factor
FDA
Food and Drug Administration
fet1-t2(,N)
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2 (after the Nth dose)
FIH
First in human
FOB
Functional observational battery
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GFR
Glomerular filtration rate
GI
Gastro-intestinal
GLP
Good Laboratory Practice
gMean
Geometric mean
GMP
Good Manufacturing Practice
HCC
Hepatocellular carcinoma
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
z(,N)
Terminal rate constant of the analyte in plasma (after the Nth dose)
LC-MS/MS
Liquid chromatography tandem mass spectrometry
LLOQ
Lower limit of quantification
LOX
Lysyl Oxidase
LSD
Lysergic acid diethylamide
MAD
Multiple ascending dose
MAO
Mono Amine Oxidase
MCD
Methionine-Choline deficient Diet
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in safety testing
MRD
Multiple-rising dose
MRT
Mean residence time of the analyte in the body after intravenous bolus 
administration
MRTpo(,N)
Mean residence time of the analyte in the body after oral administration
(after the Nth dose)
NBE
New biological entity
NC
Not calculated
NCE
New chemical entity
NOA
Not analysed


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 14 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PE
Polyethylene
PfOS
Powder for oral solution
PIB
Powder in the bottle
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
q.d.
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
RA
Accumulation ratio of the analyte in plasma after multiple dose 
administration over a uniform dosing interval τ
RDC
Remote Data Capture
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SfOS
Solvent for Oral Solution
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SRD
Single-rising dose
ss
(at) steady state
SSAO
Semi-carbazide-sensitive amine oxidase
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test product or treatment
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
Ter in die, three times daily
tz,start(end)
Lower (upper) limit on time for values to be included in the calculation of 
z
t1/2(,N)
Terminal half-life of the analyte in plasma (after the Nth dose)
tmax(,N)
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma (after the Nth dose)
TMF
Trial master file
TS
Treated Set
TSAP
Trial statistical analysis plan
TSH
Thyroid stimulating hormone
tz(,N)
Time of last measurable concentration of the analyte in plasma (after the 
Nth dose)
ULN
Upper limit of normal
VAP-1
Vascular adhesion protein-1


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 15 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz/F(,N)
Apparent volume of distribution during the terminal phase after
extravascular administration (after the Nth dose)


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 16 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 17 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 18 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 19 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 20 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 21 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 22 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 23 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 24 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 25 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 26 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 27 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 28 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 29 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 1467335 
in healthy male and female subjects following oral administration of multiple rising doses of 
10 mg, 15 mg, 20 mg, of BI 1467335 q.d. over 28 days. Based on the experience gained 
during the study, intermediatedoses within the approved dose range may be optionally tested.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 30 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Secondary objectives are the exploration of the pharmacokinetics (PK) and target 
engagement biomarkers of BI 1467335 after multiple dosing.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 31 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 32 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 33 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 34 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 35 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This multiple-rising dose trial is designed as double-blind, randomised, and placebo-
controlled within parallel dose groups.
A total of 36 healthy male and female subjects is planned to participate in the trial, according 
to at least 3 sequential groups comprising 12 subjects per group. However, additional subjects 
may be entered to allow testing of intermediate doses within the approved dose range on the 
basis of experience gained during trial conduct (as described in Section 2.3), i.e. the actual 
number of subjects entered may exceed 36 but no more than 48. Such changes may be 
implemented via non-substantial CTP Amendments.
Within each dose group, 9 subjects will receive the active drug and 3 will receive placebo. 
Only one dose is tested within each dose group.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
Daily dose (mg)
10
15
20
Number of subjects
12
12
12
Subjects receiving placebo
3
3
3
Subjects receiving active drug
9
9
9
Subject number 
Subject replacement number
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 14 days between last dosing of the previous dose group and the first 
drug administration of the subsequent dose group. The decision to proceed to the next cohort 
at the same dose level or the next higher dose group will be based upon the safety, tolerability 
and PK of the preceding cohort or dose groups as described in Section 2.3, Section 3.1 and in 
Section 3.3.4.1. The inclusion of the second cohort of the 10 mg dose group will be based 
exclusively on safety and tolerability including checking for individual stopping rules (see 
Section 3.3.4.1), but not on PK data.
A documented Safety Review must take place prior to inclusion of any new cohort and 
between dose groups. Furthermore, an unscheduled safety review meeting can be requested 
anytime for any reasonable cause by the Principal Investigator (or an authorised deputy) or 
the sponsor of the study, e.g. because of any unforeseen adverse events, etc. Dose escalation 
will only be permitted if no safety concerns exist in the opinion of the Principal Investigator 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 36 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
(or an authorised deputy) and the trial clinical monitor (or an authorised deputy) as described 
in Section 2.3.
The minimum data set for review consists of the following data:

AEs in the current and, if applicable, preceding dose groups (including clinically 
relevant findings from ancillary safety testing listed below) (Note: AEs may be 
ongoing at the time of Safety Reviews and AE information may be subject to change 
prior to Database Lock)

Results from 12-lead EGG in the current and preceding dose groups.

Vital signs in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Check of criteria for stopping subject treatment as per Section 3.3.4.1

PK data including extrapolation to support conclusions about safety margins (not 
required for inclusion of second cohort of the 10 mg dose group since based on the 
results from the previous SRD/MRD study (see Section 1.2.5) exposure is not 
expected to exceed Cmax and 1/2 of the AUC of the 4-week rat toxicology study at 
NOAEL.
The decision to continue with the next cohort at the same dose level or the next higher dose 
level will be made jointly by the Principal Investigator (or an authorised deputy) and the trial 
clinical monitor (or an authorised deputy) based on the criteria described in Section 2.3. 
In-depth analysis includes preliminary PK data, if possible extrapolations of exposure for the 
current and any new cohorts, all available safety data, especially SAEs (if occurred), AEs 
fulfilling stopping criteria, other AEs and out-of-range laboratory results (if considered 
clinically significant) and ECG results. Safety Reviews can be conducted face-to-face or by 
video/telephone conference. The trial clinical monitor is responsible for organizing and 
minuting the reviews. Minutes will be signed off by the Principal Investigator (or an 
authorised deputy) and filed in the ISF and TMF.
To proceed to the next higher dose level at least data up to Day 28 from 10 evaluable subjects 
of the preceding dose level (with at least 7 subjects on active treatment) are required. 
The investigator (after consultation with the sponsor) is allowed to alter the scheduled dose
levels within the planned dose range on the basis of experience gained during the study.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 37 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany.
The trial will be conducted at 
 
 under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
.
The analyses of BI 1467335 (and its metabolites and stability) concentrations in plasma will 
be performed at the Department of Drug Metabolism and Pharmacokinetics, BI Pharma 
GmbH & Co. KG, Biberach, Germany.
The analysis of the concentration 
 will be performed by the 
.
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for central evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For multiple-rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 1467335.
With the rising dose design, double -blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to the dose-depending effects as well as time effects, but it has the 
virtue of minimizing subject risk by sequentially studying ascending doses. As time-effects 
are expected to be small relative to the differences between the doses in the broad range 
investigated, unbiased comparisons between treatments can still be expected.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 38 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety, tolerability and pharmacodynamic effects. Each dose group consists 
of 12 subjects with 9 on active treatment, and 3 on placebo. The placebo control group 
includes all subjects of all dose groups treated with placebo. At the 10 mg dose level there 
will be a staggered inclusion of 2 cohorts of 6 subjects. At any higher dose level there will be 
a staggered inclusion of 3 cohorts each consisting of 4 subjects with 3 subjects randomized to 
active treatment and 1 subject randomized to placebo. The criteria to proceed with any new 
cohort are provided in Section 2.3 and Section 3.1.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 36 healthy male and female subjects will enter the study. The actual number 
of subjects entered may exceed the total of 36 if intermediate doses will be tested (see Section 
3.1). Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects and postmenopausal or surgically sterilised female subjects will be 
included into the study because hitherto no data on reproductive toxicology are available.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male or female subjects according to the investigator’s assessment, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory 
2. Age of 18 to 50 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5. Male subjects, or female subjects who meet any of the following criteria starting from at 
least 30 days before the first administration of trial medication and until 30 days after trial 
completion:
-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in
questionable cases a blood sample with simultaneous levels of FSH above 40 U/L and 
estradiol below 30 ng/L is confirmatory)


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 39 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-
lives of the respective drug prior to administration of trial medication
12. Within 10 days prior to administration of trial medication, use of drugs that might 
reasonably influence the results of the trial or that might prolong the QT/QTc interval
13. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication
14. Used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 
6 weeks before screening and unable to abstain from using these products until study 
completion
15. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for
males)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTcB interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or 
any other relevant ECG finding at screening


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 40 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
23. Detection of cataract in slit lamp examination
24. GFR according to CKD-EPI-Formula < 90 mL/min at screening [R12-1392]
Female subjects will not be allowed to participate if any of the following applies:
25. Females who are not surgically sterilised or who are not postmenopausal, defined as at 
least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with 
simultaneous levels of FSH above 40 U/L and estradiol below 30 ng/L is confirmatory)
26. Positive pregnancy test
27. Lactation period
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as pregnancy,
surgery, adverse events, or diseases)
4. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP 
>180/100 mmHg) or of clinically relevant changes in ECG requiring intervention as well 
as unexplained liver enzyme elevations at any time during the trial.
5. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
6. Relevant individual QT prolongation, i.e. a QTcB increase of greater 60 ms from baseline 
in connection with absolute QT or QTc greater than 500 ms, which has been confirmed 
by a repeat ECG recording.
7. eGFR calculated with the CKD-EPI formula is determined to be below 80 ml/min on 
2 consecutive assessments 24 h apart
8. If a patient develops symptoms of muscle or tissue injury (e.g., muscle aches, dark urine 
or other signs of rhabdomyolysis), in line with clinically significant increased CK levels.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 41 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
9. Neutropenia will lead to individual discontinuation from trial medication if any of the 
following applies: 
- Febrile Neutropenia at any time, i.e. absolute neutrophil count (ANC) below lower limit 
of normal with concomitant body temperature greater or equal 38 degrees C
- ANC below 1000/microliter at any time
- ANC below 1500/microliter (but greater 1000/microliter) if still present after 1 week
10. Leukopenia will lead to individual discontinuation from trial medication if any of the 
following applies:
- Febrile leukopenia at any time, i.e. absolute lymphocyte count (ALC) below lower limit 
of normal with concomitant body temperature greater or equal 38 degrees C 
- ALC below 2500/microliter at any time
- ALC below 3000/microliter (but greater 2500/microliter) if still present after 1 week
11. Thrombocytopenia will lead to individual discontinuation from trial medication if any of 
the following applies:
- Thrombocytopenia, i.e. absolute platelet count (APC) below lower limit of normal at 
any time if associated with clinical signs or symptoms of bleeding
- APC below 80,000/microliter at any time
- APC below 100,000/microliter (but greater 80,000/microliter) if still present after 
1 week
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication has to be stopped immediately, and the subject has to be removed from the trial. 
The subject is to be followed until she has given birth or until the end of pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the clinical trial report. For reporting of pregnancy and all related events refer to 
Section 5.2.2.2.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 42 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported that is
considered to be unacceptable.
2. The expected enrolment goals overall or at a particular trial site are not met.
3. Violation of GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial.
4. The sponsor decides to discontinue the further development of the investigational 
product.
5. Inclusion of any new cohort, and the treatment of current cohorts will be stopped as soon 
as at least 2 subjects at one dose level on active drug showed relevant individual QT 
prolongation, i.e. a QTc increase of greater 60 ms from baseline in connection with 
absolute QT or QTc greater than 500 ms, which has been confirmed by a repeat ECG 
recording.
6. Inclusion of any new cohort, and the treatment of current cohorts will be stopped as soon 
as at least 2 subjects at one dose level on active drug shows AEs fulfilling stopping 
criteria (Section 3.1).
7. This multiple dose study is planned not to exceed the Cmax or 1/10th of the AUC observed 
at NOAEL in the 4-week rat toxicity study as stated in Section 1.2.3. For this reason 
preliminary PK assessments will be performed at each dose level before starting with the 
next cohort (not applicable at the 10 mg dose level).
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of
trial termination (except in case of the third reason).


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 43 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are given below:
Substance:
BI 1467335
Pharmaceutical formulation: Powder for oral solution (PfOS)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
40 mg (target solution concentration BI 1467335: 0.5 mg/ml)
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
28 days q.d. dosing
BI 1467335 will be provided as a powder for oral solution in 100 mL amber glass bottles.
Solvent for reconstitution is Sucralose (4 mg/mL) and Menthol (2 mg/mL) solution provided 
in 100 mL clear glass vials. 
Solvent for reconstitution will be used as placebo.
At the time of use, the oral solution for dosing will be prepared as detailed in the instruction
given in Appendix 10.1 using the PfOS and co-supplied Solvent for Oral Solution (SfOS).
The solvent for reconstitution will be transferred to an empty 100 mL amber glass bottle, 
which will be appropriately labeled:
Substance:
Matching placebo
Pharmaceutical formulation: Solvent for oral solution (SfOS)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
28 days q.d. dosing
Solvent is Sucralose (4 mg/mL) and Menthol (2 mg/mL) solution provided in 100 mL clear 
glass vials.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 44 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects have been allocated to 
the first dose group, the following subjects will be allocated to the next dose level. Therefore, 
the allocation of subjects to dose cohorts is not influenced by trial personnel, but only by the 
subjects’ temporal availability. As the study includes healthy subjects from a homogenous 
population, relevant imbalances between the dose groups are not expected.
The list of subject and medication numbers will be provided to the trial site in advance. The
allocation of subjects to study subject numbers will be performed prior to the first 
administration of trial medication. For this purpose, the subjects will be allocated to a study 
subject number by the method ‘first come-first served’. Once a subject number has been 
assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
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).
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of dose 
volume for placebo corresponds to the number of dose volume of the respective dose level.
Table 4.1.4: 1
BI 1467335 and placebo treatments, oral administration 
Dose
Substance
Pharmaceutical 
form
Unit strength**
Dose volume 
per administration
Total daily
dose**
1
BI 1467335
oral solution
0.5 mg/mL
20 mL (10 mg) q.d. for 28 days
10 mg
2
BI 1467335
oral solution
0.5 mg/mL
30 mL (15 mg) q.d. for 28 days
15 mg
3
BI 1467335
oral solution
0.5 mg/mL
40 mL (20 mg) q.d. for 28 days
20 mg
1-3
Placebo*
oral solution
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
** Unit strength and dose refer to free base of BI 1467355
The oral solutions for dosing (active drug and placebo) will be prepared according to the 
instruction given in Appendix 10.1 by pharmacists or qualified pharmacy staff members or 
qualified medical study personnel at the trial site under the responsibility of the investigator.
The trial medication will be administered to the subjects, while in a sitting position, as an oral 
dose together with about 240 mL of water under supervision of the investigating physician or 
an authorised designee. The so-called four-eye principle (two-person rule) should be applied 
for administration of trial medication and – if applicable – its preparation (e.g. reconstitution), 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 45 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
if correct dosage cannot be ensured otherwise. Administration will be performed following an 
overnight fast, which is to start no later than 10 h before the scheduled dosing.
To ensure a dosing interval of 24 h, the administration of trial medication should take place at 
the same time every day.
Subjects will be kept under close medical surveillance from the evening of Day -1 to the 
morning of Day 4, from the evening of Day 13 to the morning of Day 17, and from the 
evening of Day 27 to the morning of Day 29. 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. For restrictions 
with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The trial is designed double-blind with regard to the subjects and the investigators (as well as 
the research staff at the trial site) in order to eliminate observer or performance bias. This 
means avoiding systematic differences in assessments regarding the subject’s treatment 
(active or placebo). According to the rising dose design, the current dose level will be known 
to subjects and investigators.
At the trial site, access to the randomisation schedule is restricted to unblinded pharmacists. 
Access to the codes will be controlled and documented by a signed confidentiality statement, 
which will be stored in the TMF. Persons directly involved in the clinical conduct of the trial 
will not have access to the treatment allocation prior to database lock.
At the ECG laboratory all staff will be blinded with respect to treatment. Within the ECG 
laboratory, the staff involved with interval measurements and assessments will also be 
blinded with regard to the recording date and time as well as time points of the ECGs. Semi-
automatic interval measurements for a given subject will be performed in random and blinded 
sequence by a single technician.
In addition, the trial bioanalyst, will receive the randomisation codes prior to official 
unblinding to perform the interim / preliminary PK analysis. He or she will confirm in writing 
that the codes will be treated confidentially.
In addition, the drug metabolism scientist will receive the randomisation codes prior to 
official unblinding to perform metabolites in safety testing analysis (MIST). He or she will 
confirm in writing that the codes will be treated confidentially.
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical monitor, data manager, 
statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug metabolism scientist, 
clinical research associate as well as dedicated CRO personnel). The objective of the trial is
not expected to be affected.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 46 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
4.1.5.2
Procedures for emergency unblinding
For blinded trials, the investigator will be supplied with a set of sealed envelopes containing 
the medication codes for each subject according to the randomisation scheme. The envelopes 
will be kept unopened at the trial site until the end of data collection. An envelope may only 
be opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or to assure safety of trial 
participants. If the envelope for a subject is opened, the sponsor must be informed 
immediately. The reason for opening the code break must be documented on the envelope or 
appropriate CRF page along with the date and the initials of the person who broke the code. 
At the close-out visit all envelopes are collected.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Smaller boxes and 
bottles within the clinical trial supply containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Subject or medication number

Batch number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 47 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the study protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre

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 or immediately imminent 
signing of the clinical trial protocol 
Only authorised personnel as documented in the form ‘Site Delegation Log’ may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorization by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies.
The investigator / pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each subject, and 
the return to the sponsor or alternative disposal of unused products.
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the subjects were provided the doses specified by the CTP, and that 
reconcile all investigational products received from the sponsor. At the time of disposal, the 
investigator / pharmacist / investigational drug storage manager must verify that no remaining 
supplies are in the investigator’s possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency 
procedures are to be followed. No additional treatment is planned. However, in case of 
adverse events in need of treatment, the investigator can authorise symptomatic therapy. In 
those cases, subjects will be treated as necessary and, if required, kept under supervision at 
the trial site or transferred to a hospital until all medical evaluation results have returned to an 
acceptable level.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 48 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. From Day 1 to Day 28, no food is allowed for at least 10 h 
before and 2 h after administration of the study drug.
From Day 1 to Day 28, starting from 1 hour before drug administration until 2 h after drug 
intake fluid intake is not allowed except from the 240 mL water administered with the drug 
intake. From breakfast until 22 hours post-dose water intake will be within 1000 to 3000 mL.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and
dietary supplements and products including St. John's wort (Hypericum perforatum) are not
permitted starting 7 days before the first administration of trial medication until after the last
PK sample is collected.
 nicotine-containing 
products (e.g., cigarettes, cigars, chewing tobacco, snuff) should be stopped at least 6 weeks 
before screening and abstained from using these products until study completion.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and
chocolate) are not allowed at days of inhouse confinement. On the ambulatory days, it is
restricted up to max 200 ml (coffee, tea, cola, red bull, energy drinks), or 50 g (chocolate and
chocolate products).
Excessive physical activity (such as competitive sport) should be avoided starting 7 days
before the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study center under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and urinary excretion will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 49 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 1467335 is the number [N (%)] of 
subjects with drug-related AEs.
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 50 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death, 

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 
or 

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as given 
above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system. A copy of the latest 
list of ‘Always Serious AEs’ will be provided upon request. These events should always be 
reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs in this trial:


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 51 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Hepatic injury, as defined by the following alterations of hepatic laboratory parameters:
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
AESIs are also those AEs fulfilling individual stopping rules as described in Section 3.3.4.1.
Intensity of AEs
The intensity of adverse events should be classified and recorded in the (e) CRF according to 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 dated 
14 June 2010 [R10-4848] in the (e)CRF.
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 52 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards through the residual effect period (REP), 
until 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.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 53 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report relevant SAEs and relevant AESIs of which he may 
become aware of.
The REP for BI 1467335, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known at this early stage of development. 
Therefore, all AEs reported until the trial termination date will be considered on treatment;
please see Section 7.3.3.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours of 
awareness) to the sponsor’s unique entry point (country specific contact details will be 
provided in the ISF). This immediate report is required irrespective of whether the 
investigational product has been administered or not and irrespective of causal relationship. 
In specific occasions the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (if applicable). The investigator should determine the causal 
relationship to the trial medication. The following should also be recorded as an (S)AE in the 
CRF and on the SAE form (if applicable):

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.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 54 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into 
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is a clinically relevant abnormality in the automatic blood cell count or in 
the urinalysis, respectively.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 55 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
White blood cell count (WBC)
Platelet count
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic
differential WBC is clinically relevant 
abnormal)
Polymorphnuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Glutamate dehydrogenase (GLDH)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
Hormones1
Thyroid stimulating hormone (TSH)
fT3, fT4
FSH2
Substrates1
Plasma glucose
Creatinine 
eGFR (derived from creatinine using CKD-EPI formula)
Cystatine
Total bilirubin 
Direct bilirubin
Total protein
Protein electrophoresis (only at screening examination)
Albumin 
Alpha-1-Globulin
Alpha-2-Globulin
Beta-Globulin
Gamma-Globulin 
C-Reactive Protein (CRP)
Uric acid 
Total cholesterol 
Triglycerides
Electrolytes
Sodium
Potassium
Chloride
Calcium
Inorganic phosphate


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 56 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
Test name 
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment (microscopic
examination if erythrocytes, leukocytes 
nitrite or protein are clinically relevant 
abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1
Protein electrophoresis only at screening. Hormones only at screening and end of trial.
2
Only if confirmation of postmenopausal stage is needed
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy test and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, Day -1, 
Day 13, Day 27, and as part of the end of trial examination. Drug screening will be performed 
at screening, Day -1, Day 13, Day 27and end of treatment.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV 1+2-antibody/p24-antigen Combitest
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed at screening and prior to each treatment
period, and may be repeated at any time during the study at the discretion of an investigator 
or designee. The results will not be included in the CTR.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 57 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
 with the exception 
of the urinalysis (stix), drug screening and pregnancy tests. These tests will be performed at 
the trial site using, Combur 9 Test, MAHSAN® –Kombi/DOA10 rapid test and 
TestPack+Plus hCG Urin respectively.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart. Electrode placement will be performed 
according to the method of Wilson, and modified Goldberger and Einthoven (Mason-Likar). 
The same electrode positions on a specific subject should be used for all ECG recordings 
throughout the study.
Triple ECGs (recorded within 180 sec) will be recorded on all time points on Day 1, Day 2, 
Day 14, Day 15, Day 21, Day 28 and Day 29. On all other visits/time points single ECGs will 
be obtained. ECGs may be repeated for quality reasons (like alternating current artefacts, 
muscle movements, electrode dislocation). For time points with triple ECGs, all three single 
ECGs will be repeated.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for 10-sec duration after the subjects 
have rested for at least 5 min in a supine position. The site personnel will be instructed to 
assure a relaxed and quiet environment so that all subjects are at complete rest during the 
recordings. ECG assessment will always precede all other study procedures of the same time 
point (except blood drawing from an intravenous cannula which is already in place) to avoid 
impact of sampling on the ECG quality.
All locally printed ECGs will be evaluated by the investigator or a designee. Additional 
(unscheduled) ECGs may be collected by the investigator for safety reasons. These ECGs are 
assigned to the prior scheduled time point. Unscheduled ECGs will not be included into the 
statistical analysis of interval lengths.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of cardiac 
safety during the study, the QT and QTcB values generated by the ECG machines or their 
manual corrections by the investigators will be used. In doubtful cases, ECGs may be sent 
upfront for centralized evaluation (see below). In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
All recorded ECGs will be sent electronically to an independent ECG core lab. The
centralised evaluation of all 12-lead ECGs recorded on Day 1 to Day 4, Day 7, Day 14 to 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 58 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Day 17, Day 21, and Day 28 to Day 29 will be performed by an independent ECG laboratory. 
In case it is needed ECGs recorded at other visits/time points may also undergo centralized 
evaluation.
For this analysis, all cardiac intervals (PR, QRS, RR and and QT intervals) will be 
determined semi-automatically, whereas PR and QRS intervals are determined by a validated 
GE 12-SL-algorithm or equivalent. Other parameters (e.g. cardiac axis) are determined by a 
validated GE 12-SL-algorithm or equivalent but do not undergo semiautomatic evaluation. 
All interval measurements for each subject will be performed on the same lead. The intervals 
will be measured from four cardiac cycles (beats) in lead II. If lead II shows a flat T wave or 
is not measurable for any reason, lead V5 will be used, or if that lead is not measurable, then 
lead I will be used. The lead actually used will be reported in the CTR.
For blinding status see Section 4.1.5.1. No more than two different blinded readers will 
evaluate all ECGs of the study. 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 with respect to the overall variance of the measured intervals, in order to detect 
accidentally switching of leads and/or false subject assignments of the ECGs. After the 
quality control the fiducial point markings will be reviewed by the cardiologist assigned to 
the study. Abnormalities detected during centralized ECG evaluation will not necessarily 
qualify as AE.
The results of the centralized evaluation will be sent from the ECG core lab to the data 
management of BI according to a pre-specified data transmission agreement.
Assessed ECGs will comply with the ICH E14 guidance document and supplements [R05-
2311, R13-0801, R13-4095] as well as the FDA requirements for annotated digital ECGs 
[R09-4830].
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap, GE Medical Systems, Freiburg, Germany) at the times 
indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine position
and after ECG recording was taken. All recordings should be made using the same type of 
blood pressure recording instrument on the same arm if possible.
5.2.5.2
Medical examinations
At the screening visit, the medical examination will include documentation of subject 
information, informed consent, demographics including height and body weight, smoking 
and alcohol history, relevant medical history and concomitant therapy, review of inclusion
and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 
12-lead ECG, laboratory tests, and a physical examination with determination of weight.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 59 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
5.2.5.3
Ophtalmological examination
A slit lamp examination (Carl Zeiss Jena RSL 110) will be conducted by an ophthalmologist 
at screening, Day 15, Day 29 and EOT to exclude findings suspicious for signs of cataract.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 60 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an orally administered drug, 
and are widely used in clinical trials. The pharmacokinetic parameters and measurements 
outlined in Section 5.5 are generally used assessments of drug exposure. The biomarker 
measurements outlined in Section 5.6 are of exploratory nature only.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and exact time points of blood sampling will be 
documented in the CRFs by the medical personnel. The actual sampling times will be used 
for determination of pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per subject does not exceed 510 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints
After the first dose (Day 1):

AUC0-24 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma after administration 
of the first dose)
After the last dose (Day 28):

AUC0-24,28 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours after administration of the 28th dose)

Cmax,28 (maximum measured concentration of the analyte in plasma following
administration of the 28th dose)


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 61 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 62 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 1467335 plasma concentrations, approx. 2.7 mL of blood will be 
taken from an antecubital or forearm vein into a K3-EDTA (tripotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
30 µL phenelzine solution (approx. 50 mM/L) will be added to all blood samples before
withdrawal. All blood samples will be centrifuged using a cooled centrifuge at about 2000 x g 
to 4000 x g and at a temperature of 4 - 8°C for at least 10 minutes (intermittent storage on 
ice). The obtained K3-EDTA plasma will be split into two cryotubes (e.g. Nunc tubes) which 
will be frozen immediately and not later than 60 min after blood sampling with interim 
storage on ice. One of the aliquots should contain at least 0.7 mL plasma. The second aliquot 
containing the remaining plasma will be used as analytical back-up sample. Until transfer on 
dry ice to the analytical laboratory, the plasma samples will be stored frozen and in upright 
position at about –20°C or below at the clinical site and at the analytical laboratory until 
analysis.
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) will be generated by these additional investigations. 
The study samples will be discarded after completion of the additional investigations but not 
later than 5 years upon the final study report has been signed.
5.5.2.2
Plasma sampling for drug metabolism analysis
Additional K3-EDTA plasma samples for the identification of drug metabolites will be 
investigated in all dose groups. The blood samples will be drawn in parallel to the PK 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 63 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
samples on Day 28 to 29 (see Flow Chart). At each of these time points, 2.7 ml blood will be 
needed for metabolite analysis. The blood samples will be centrifuged using a cooled 
centrifuge at about 2000 x g to 4000 x g and at a temperature of 4 - 8°C for at least 10 
minutes (intermittent storage on ice). The obtained K3-EDTA plasma (approximately 1 mL) 
will be transferred into a single polypropylene tube. Samples will be stored at about -70°C or 
below until transfer to the metabolism laboratory.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time and ‘MetID’. Further information such as 
matrix and analyte may also be provided. 
Metabolite analysis will be performed under non-GxP conditions in the laboratory of 
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics
Birkendorfer Straße 65
88397 Biberach/Riß, Germany
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
the drug metabolism will be reported separately but not included in the CTR of this trial. The 
study samples will be discarded after completion of the experiments but not later than 3 years 
after the final study report has been signed.
5.5.2.3
Urine sampling for pharmacokinetic analysis
A blank urine sample will be collected before administration of trial medication (within 2 h 
before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical 
interference by concomitant or rescue medication.
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
2 L polyethylene (PE) containers and stored at room temperature. Subjects will be told to 
empty their bladders at the end of each sampling interval.
The urine weight/volume (weight will be set equal to volume, i.e. 1 kg = 1 L, without 
correction for specific gravity of urine) for each collection interval will be documented and 
two 2 mL aliquots (e.g. Nunc tubes) will be stored for bioanalytical measurement. The weight 
of the empty container will be determined and the weight of the container at the end of each 
sampling interval will be determined.
Until transfer to the analytical laboratory, the urine samples will be stored at about -20C or 
below at the clinical site and stored at the analytical laboratory at –20C or below until 
analysis. The back-up aliquots will be transferred to the analytical laboratory after the 
bioanalyst has acknowledged safe arrival of the first aliquot.
After completion of the trial the urine samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) will be generated by these additional investigations. 
The study samples will be discarded after completion of the additional investigations but not 
later than 5 years upon the final study report has been signed.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 64 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
5.5.2.4
Additional blood sample for stability-testing
In order to assess the stability of the analyte in whole blood, one additional blood sample 
each on days 1, 14 and 28 will be taken from all subjects of dose group 10 mg and 15 mg.
Approximately 3.6 mL blood will be taken from an antecubital or forearm vein using three 
1.2 mL K3 EDTA-blood drawing tubes at the time indicated in the Flow Chart (immediately 
after the drawing of a regular blood PK sample, which is to say that no additional venous 
puncture will be necessary).
To the first two 1.2 mL K3 EDTA-blood drawing tubes 10µL phenelzine solution (approx. 
50 mM/L) will be added before taken from all subjects of dose group 1 and 2 at the time 
indicated in the Flow Chart.
Approx. 0.5 mL of plasma will be generated out of each blood sample:

Sample handling for stability samples of dose group 2, procedures will be provided in 
a separate lab manual.Blood sample one (‘stability reference’) will be centrifuged 
within 10 min after collection. Centrifugation will last for about 10 min (at about 2000 
g to 4000 g and 4 to 8 °C), plasma will be separated and transferred into a freezer.

Blood sample two and three (‘stability test’) will be stored for about 4 h at room 
temperature and ambient light conditions (documentation of storage time necessary) 
and will then be centrifuged and stored according to the first sample. To the plasma 
sample from blood sample three 5µL phenelzine solution (approx. 50 mM/L) will be 
added before freezing.
At a minimum, the aliquots should be labelled with the following information: BI trial 
number, administered drug, subject number, planned sampling time, ‘stability reference’ or 
‘stability test’.
Until transfer to the analytical laboratory, all aliquots will be stored at about -20 °C or below 
at the clinical site. All aliquots will be provided to the responsible bioanalyst together with 
the information about sample handling (i.e. storage time of ‘test sample’ at room 
temperature). After receipt, the aliquots will be stored at the bioanalytical laboratory at about 
-20°C or below until analysis.
The results of the analysis of these samples will not be reported within this clinical trial but 
will be used for bioanalytical assay validation and therefore included in the corresponding 
method validation report. The remaining sample volume will be discarded upon completion 
of the method validation report at the latest.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 1467335 plasma concentration
BI 1467335 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 65 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
The analysis will be performed at:
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics
Birkendorfer Straße 65
88397 Biberach/Riß, Germany
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.
5.5.3.2
Analytical determination of analyte urine concentration
BI 1467335 concentrations in urine will be determined by a validated LC-MS/MS assay 
The analysis will be performed at:
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics
Birkendorfer Straße 65
88397 Biberach/Riß, Germany


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 66 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 67 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 68 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1, Day 14, and Day 28 are to be performed and completed within a 
2 h-period prior to the trial drug administration (including blank values for PK and 
biomarkers collected predose on Day 1).
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 min for the first 4 h after trial drug administration and ± 30 min thereafter when 
not already stated otherwise in the flowchart.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned individual plasma concentration sampling times and urine collection intervals 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Before first dosing on day 1 pharmacogenomic genotyping will be performed in all subjects 
(for details see Section 5.3).
6.2.2
Treatment period
Each subject will receive a single dose of BI 1467335 or placebo from Day 1 to Day 28.
Study participants will be admitted to the trial site in the evening of day -1 and kept under 
close medical surveillance for at least 24 h following the first /last drug administration. The 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 69 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
subjects will be kept hospitalized from the evening of Day -1 to the morning of Day 4, the 
evening of Day 13 to the morning Day 17 and from the evening of Day 27 to the morning of 
Day 29.On all other time periods the study will be performed in an ambulatory fashion
provided there are no medical reasons preventing the discharge from the unit.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2. 
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial and follow-up period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. Adverse events persisting after trial completion must be 
monitored until they have normalised or have been sufficiently characterised. 
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.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 70 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 1467335
by using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in Section 5.2.1. Inferential statistics is not planned (as explained 
in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) 
) of BI 1467335. Endpoints as specified in 5.5.1 and 5.7.1 will be 
analysed by descriptive statistics. Secondary endpoints as defined in Section 5.5.1.1 will be 
subjected to analysis of dose proportionality by use of the power model. 
 
 
 
 
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 3 different dose groups of BI 1467335 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have 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
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
All treated subjects (that is, all subjects who received at least one dose of study drug), will be 
included in the treated set.
The primary endpoint will be analysed only descriptively on the treated set. For more details 
see Section 7.3.3.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 71 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
The secondary endpoints (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472].
Plasma and urine concentration data and parameters of a subject will be included in the
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol violation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma and urine 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.
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one PK parameter that was not excluded according to the description above.
All statistical evaluations of PK parameters will be based on the PKS.
Excluded subjects will be listed with their individual plasma concentrations and individual 
pharmacokinetic parameters, however, will not be included in descriptive statistics for plasma 
concentrations, pharmacokinetic parameters or other statistical assessment.
Assessment of dose proportionality
Dose proportionality will be assessed using the pharmacokinetic endpoints AUC0-24, Cmax, 
AUC0-24,28 and Cmax,28 as specified in 5.5.1.1.
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints.
The model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate.
ij
i
ij
ε
)
X
exp(
)
exp(Y









Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 72 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Together with 
and 
, taking natural logarithms converts this model 
to a linear form as follows:
where
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, 3, j = 1, 2, …, N;

intercept parameter;
slope parameter;
logarithm of dose i;
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model.
Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
When steady state is already reached after 14 days of treatment, dose proportionality will be 
also investigated for AUC0-24,14 and AUC0-24,28 together (Cmax,14 and Cmax,28 respectively) 
using the following model accounting for the repeated measurement per subject:
 = 	 +  ∗ +  + 
where

logarithm of the pharmacokinetic endpoint for subject j at dose 
level I on day k; where i = 1, 2, 3, j = 1, 2, …, N;

intercept parameter;
slope parameter;
logarithm of dose i;

Categorical day variable where  = 0 when PK parameter is from 
day 14 and  = 1 when PK parameter is from day 28

random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
Linearity index
Linearity will be explored if data allow using the linearity index (LI) that will be computed as 
follows:



0
,
AUC
AUC
LI
ss

)
exp(


)
exp(
ε
ij
ij



ij
i
ij
ε
X
β
α
Y




ij
Y
β
i
X
ij
ε
β
i
X


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 73 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
The AUC, can be AUC,  and/or AUC,! depending on when the steady state is 
reached. If steady state is not reached within the 28 days, no linearity index will be evaluated.
In order to construct a confidence interval for LI, a statistical model using AUCτ,ss and 
AUC0-∞will be set up: A linear model on the logarithmic scale including effects for 'subject' 
and 'AUC type' can be applied, where 'subject' is a random and 'AUC type' a fixed effect.
[1]
 = " + # + s% + e'% , where

logarithm of the response (AUC after first dose and at steady state) for subject j
and AUC type i; where i = 1 (after first dose) or 2 (at steady state) and j=1, 2,…, n
"
the overall mean
#
the AUC type i
s%
the effect associated with subject j (random effect)
e'%
random error associated with subject j at AUC type i (assumed to be independent 
and identically normally distributed).
A pairwise comparison of both areas via the log transformed difference
log(
()*+,,,
()*-./) = log(0123,44) - log(0125)
will then be performed including calculation of a 2-sided 95% CI. The back transformed 
point estimate then represents the estimate of  LI. Perfect linearity holds true if this index 
equals unity.
Generally, this model will be applied to each dose level separately. If there is evidence that 
the areas are comparable across dose levels, they can be analysed simultaneously. The 
corresponding model will then include the log transformed dose as (additional) covariate


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 74 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Graphical displays
To support the analyses of dose proportionality, linearity and 
 
graphical representations of the data might be created. These might include (but are not 
limited to) individual time-courses of trough and 1 h post-dose plasma concentrations and the 
(geometric) mean plasma concentration time profiles.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 75 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
 
 
 
 
7.3.3
Safety analyses
Safety will be assessed for the primary endpoint and parameter of interest listed in Section 
5.2.1. All treated subjects (that is, all subjects who received at least one dose of study drug), 
will be included in the safety evaluation. Safety analyses will be descriptive in nature and will 
be based on BI standards.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the trial 
termination date will be assigned to the treatment period, and those after the trial termination 
date will be assigned to ‘post-study’. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, intensity according to CTCAE grading and causal relationship of 
AEs will be tabulated by treatment, primary system organ class and preferred term. SAEs, 
AESIs (see Section 5.2.2.1) and other significant AEs (according to ICH E3) will be listed 
separately.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be flagged. Additionally, differences from baseline will be evaluated.
For vital signs, the differences from baseline will be evaluated.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 76 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the derivation of further ECG parameters based on the ECG variables QT, HR, QTcF, 
QTcB, PR, QRS, and RR. The baseline value of an ECG variable is defined as the mean of 
the triple ECG measurements prior to drug administration. It is planned to evaluate the 
difference to placebo of change from baseline for QTcF, QT and HR over time via a repeated 
measurements model as well as the exposure response relationship of change from baseline 
for QTcF, QT and HR. More details on this and further analysis as well as the derivation of 
the quantitative and qualitative ECG endpoints are given in the TSAP.
7.3.4
Preliminary PK analyses
At least 7 preliminary analyses of plasma PK parameters (Cpre, C1, AUC0-24 and Cmax) are 
planned to be performed to ensure that assessed or extrapolated systemic exposure to 
BI 1467335 will not exceed predefined margins (see Section 2.3). Additional preliminary PK 
analyses may be performed based on the request of the Trial Clinical Monitor, the 
Investigator, or Trial Clinical Pharmacokineticist if deemed necessary based on the results of 
available preliminary PK analyses, tolerability and safety of the compound, or changes of 
dosing schedule (e.g. additional intermediate doses).
1st analysis:
after both cohorts of the first dose group (10 mg) have been treated for 
28 days. All plasma samples collected up to this time point will be analysed, and the data (if 
possible, together with data from a previous multiple rising dose study [c09036683-01]) will 
be used for extrapolation of Cmax and AUC0-24 on days 14 and 28 with higher doses of 
BI 1467335, to support the decision to start with the first cohort of the second dose group 
(planned: 15 mg).
2nd analysis: after the first cohort of the second dose group (15 mg) has been treated for 
7 days. All plasma samples collected up to this time point will be analysed and the data will 
support the decisions to continue with the treatment of the first cohort and to start with 
treatment of second cohort.
3rd analysis: 
after the second cohort of the second dose group (15 mg) has been treated for 
14 days. All plasma samples collected up to this time point will be analysed and the data will 
support the decisions to continue with the treatment of the first and second cohort and to start 
with treatment of the third cohort.
4th analysis:
after all three cohorts of the second dose group (15 mg) have been treated for 
28 days. All plasma samples collected up to this time point will be analysed, and the data 
(together with those from the previous preliminary analyses) will be used for extrapolation of 
Cmax and AUC0-24 on days 1, 14 and 28 with higher doses of BI 1467335, to support the 
decision to start with the first cohort of the third dose group (20 mg).
5th analysis: 
after the first cohort of the third dose group (20 mg) has been treated for 
7 days. All plasma samples collected up to this time point will be analysed and the data will 
support the decisions to continue with the treatment of the first cohort and to start with 
treatment of second cohort.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 77 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
6th analysis: 
after the second cohort of the third dose group (20 mg) has been treated for 
14 days. All plasma samples collected up to this time point will be analysed and the data will 
support the decisions to continue with the treatment of the first and second cohort and to start 
with treatment of the third cohort.
7th analysis: 
after all three cohorts of the third dose group (20 mg) have been treated for 
28 days. All plasma samples collected up to this time point will be analysed, and data 
(together with those from the previous preliminary analyses) will be used for extrapolation of 
Cmax and AUC0-24 on days 1, 14 and 28 with higher doses of BI 1467335, to support the 
decision whether to include further dose groups into the study.
In contrast to the final PK calculations, the preliminary analyses will be based on planned 
sampling times rather than on actual times. Therefore, minor deviations of preliminary and
final results may occur. The preliminary analyses will provide individual concentration-time 
data and PK parameters (without subject identification) and descriptive statistics thereof.
The preliminary results will be distributed to the Investigator and the trial team. The PK data 
together with safety and tolerability results will be used for decisions to continue with 
treatments as described above. No formal preliminary PK report will be written.
No inferential statistical interim analysis is planned. 
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1467335 will be 
calculated according to the BI SOP ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472].
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma / urine concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for, pharmacokinetic parameters or 
other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
Descriptive evaluations of PK parameters listed in 5.5.1.2 are based on PKS.
The following descriptive statistics will be calculated for analyte concentrations as well as for
all pharmacokinetic parameters: N, geometric mean, geometric coefficient of variation, 
arithmetic mean, arithmetic coefficient of variation, standard deviation, minimum, median, 
and maximum. The data format for descriptive statistics of concentrations will be identical 
with the data format of the respective concentrations. The descriptive statistics of 
pharmacokinetic 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 clinical trial 
report.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 78 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
In addition, the PK data from this study may be included in a population PK analysis at the 
project level. This analysis will not be part of the CTR, but will be reported separately.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma/urine drug concentration - time profile
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
[001-MCS-36-472].
For tabulation and graphical displays, drug concentration data identified with NOS (no 
sample available), NOR (no valid result), NOA (not analysed), or BLQ (below the lower 
limit of quantification) will be displayed as such and not replaced by zero at any time point 
(this rule also applies also to the lag phase, including the predose values).
For the calculation of PK parameters by non-compartmental analysis, concentration data 
identified with NOS, NOR or NOA will generally not be considered. Concentration values in 
the lag phase identified as BLQ will be set to zero. All other BLQ values of the profile will be 
ignored. The lag phase is defined as the period between time zero and the first time point with 
a concentration above the quantification limit.
7.4.3
Pharmacokinetic parameters
No imputation of missing PK parameters will be performed.
 
7.5
RANDOMISATION
Subjects will be randomised within each dose group in a 3:1 ratio, which reflects the ratio of 
subjects receiving active drug to placebo.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 79 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 36 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 12 subjects per dose group (9 on active treatment, and 3
on placebo) is commonly used in multiple-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics [R95-0013].
Additional subjects may be entered to allow testing of additional doses within the planned 
dose range on the basis of experience gained during trial conduct (e.g. preliminary PK data), 
i.e. the actual number of subjects entered may exceed 36.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 80 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 81 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP. Furthermore the U.S. Food and Drug Administration 
(FDA) will also receive all SAEs and AESIs expedited.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 82 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 83 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P13-02280
Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment 
of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012; 
10:837-58.
R95-0013
Broom C. Design of first-administration studies in healthy man. Early
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R05-2311
ICH E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonised 
tripartite guideline, recommended for adoption at step 4 of the ICH process 
on 12 May 2005 by the ICH Steering Committee). www.emea.eu.int 
2005:1-14.
R05-0788
Hoffman D, Kringle R, Lockwood G, Turpault S, Yow E, Mathieu G. 
Nonlinear mixed effects modelling for estimation of steady state attainment. 
Pharm Stat. 2005.
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010). http://evs.nci.ni 
h.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf; 2010.
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI). A new equation to 
estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-612.
R13-0801
E14 Clinical Evaluation of QT/QTc Interval Prolongation and
Proarrhythmic Potential for Non-Antiarrhythmic Drugs - Questions and 
Answers (R1). October 2012. 
website.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/ucm323656.htm
R13-4095
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): ICH guideline E14 - questions and answers: step 
5 (May 2012, EMA/CHMP/ICH/310133/2008). 
website.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2009/09/WC500002878.pdf
R15-1863
Inoue T, Morita M, Tojo T, Nagashima A, Moritomo A, Miyake H. Novel 
1H-imidazol-2-amine derivatives as potent and orally active vascular 
adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema 
treatment. Bioorg. Med. Chem. 2013; 21:3873-3881.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 84 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
R15-1868
Foot JS, Deodhar M, Turner CI, et al. The discovery and development of 
selective 3-fluoro-4-aryloxyallylamine inhibitors of the amine oxidase 
activity of semicarbazide-sensitive amine oxidase/vascular adhesion 
protein-1 (SSAO/VAP-1). Bioorg. Med. Chem. Lett. 2012; 22:3935.
R15-2803
Stolen CM, Marttila-Ichihara F, Koskinen K, et al. Absence of the 
endothelial oxidase AOC3 leads to abnormal leukocyte traffic in vivo. 
Immunity. 2005; 22:105-115.
R15-5365
Weston CJ, Shepherd EL, Claridge LC et al. Vascular adhesion protein-1 
promotes liver inflammation and drives hepatic fibrosis. Journal of Clinical 
Investigation. 2015; 125:501-520.
R15-5652
Bonder CS, Norman MU, Swain MG, et al. Rules of recruitment for Th1 
and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and 
vascular adhesion protein-1. Immunity 2005; 23:153-163.
R15-5654
Koskinen K, Vainio PJ, Smith DJ, et al. Granulocyte transmigration
through the endothelium is regulated by the oxidase activity of vascular 
adhesion protein-1 (VAP-1). Blood. 2004; 103: 3388-3395.
R15-5697
Karim S, Liaskou E, Fear J, Garg A, Reynolds G, Claridge L, Adams DH, 
Newsome PN, Lalor PF. Dysregulated hepatic expression of glucose 
transporters in chronic disease: contribution of semicarbazide-sensitive 
amine oxidase to hepatic glucose uptake. Am J Physiol 2014; 307 (12): 
G1180 - G1190.
R15-5770
Vainio PJ, Kortekangas-Savolainen O, Mikkola JH, Jaakkola K, et al. 
Safety of blocking vascular adhesion protein-1 in patients with contact 
dermatitis. Basic Clin. Pharmacol. Toxicol. 2005; 96: 429-435.
R15-5803
Jaakkola K, Nikula T, Holopainen R, et al. In vivo detection of vascular 
adhesion protein-1 in experimental inflammation. Am. J. Pathol. 2000; 157: 
463471.
R15-5804
Jalkanen S, Salmi M. VAP-1 and CD73, endothelial cell surface enzymes in 
leukocyte extravasation. Arterioscler. Thromb. Vasc. Biol. 2008; 28:18-26.
R15-6044
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management 
of non-alcoholic fatty liver disease: practice guideline by the American 
Association for the Study of Liver Diseases, American College of 
Gastroenterology, and the American Gastroenterological Association 
Hepatology. 2012; 55:2005-2023.
R15-6045
Marttila-Ichihara F, Smith DJ, Stolen C, et al. Vascular amine oxidases are 
needed for leukocyte extravasation into inflamed joints in vivo. Arthritis 
Rheum. 2006; 54:2852.
R15-6046
Lalor PF, Edwards S, McNab G, et al. Vascular adhesion protein-1 
mediates adhesion and transmigration of lymphocytes on human hepatic 
endothelial cells. J. Immunol. 2002; 169: 983.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 85 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
R15-6047
Salter-Cid LM, Wang E, O’Rourke AM, et al. Anti-inflammatory effects of 
inhibiting the amine oxidase activity of semicarbazide-sensitive amine 
oxidase. J. Pharmacol. Exp. Ther. 2005; 315: 553.
R15-6048
Xu HL, Salter-Cid L, Linnik MD, Wang EY, Paisansathan C and Pelligrino 
DA. Vascular adhesion protein-1 plays an important role in post ischemic 
inflammation and neuropathology in diabetic, estrogen-treated 
ovariectomized female rats subjected to transient forebrain ischemia. J. 
Pharmacol. Exp. Ther. 2006; 317:19.
R15-6056
O’Rourke AM, Wang EY, Miller A, Podar EM, et al. Anti-inflammatory 
effects of LJP 1586 [Z-3-fluoro-2-(4-methoxybenzyl)allylamine 
hydrochloride], an amine-based inhibitor of semicarbazide-sensitive amine 
oxidase activity. J. Pharmacol. Exp. Ther. 2008; 324: 867.
R15-6057
Murphy SL, Xu J and Kochanek KD. Deaths: final data for 2010. Centers 
for Disease Control and Prevention website: 
www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_04.pdf (Updated May 8, 2013. 
Accessed February 6, 2014).
R15-6058
Merinen M, Irjala H, Salmi M, Jaakkola I, Hanninen A, Jalkanen S. 
Vascular adhesion protein-1 is involved in both acute and chronic 
inflammation in the mouse. Am J Pathol. 2005;166:793-800.
R15-6059
Lee WY, Salmi M, Kelly MM, Jalkanen S and Kubes P (2013) Therapeutic 
advantage of anti-VAP-1over anti-α4 integrin antibody in concanavalin 
Ainduced hepatitis. Hepatology 2013; 58:1413.
R15-6070
Dharel N, Fuchs M. Nonalcoholic Fatty Liver Disease – A Major Public 
Health Challenge for the 21st Century. JSM Gastroenterology and 
Hepatology. 2014; 1018.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c04751792
  Investigator's 
Brochure: BI 1467335 in NASH  09 Feb 2016.
c09036683
Single ascending dose and multiple ascending dose Phase 1 study of PXS-
4728A administered orally in healthy adult males. PXS-4728A-101. 
13 Nov 2015.
n00244592
BI 1467335: 4-week oral (gavage) supplementary toxicity study in Sprague 
Dawley rats. 15B108.
n00244640
PART: FORMULATION ANALYSIS REPORT  
15B108.
n00246522
  Study to investigate the protein binding of the test compound, 
4728A, in human and rat plasma  CYP0526 R1, R3, R3A  12 Oct 2015.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 86 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
n00247448
PXS-4728A: 7-day Oral Dose Range Toxicity Study in Beagle Dog. 
VPT1073. 25 Sep 2013.
n00247807
Functional Observational Battery (FOB) Study of PXS-4728A in Sprague 
Dawley Rats. 53702-14-001. 30 Oct 2014.
n00247816
A Cardiovascular Safety Pharmacology Study of PXS-4728A in Beagle 
Dogs. 53702-14-005. 07 Nov 2014.
n00247850
  A Four-Week Oral Repeat Dose Toxicity and Toxicokinetic Study 
of PXS-4728A in Beagle Dogs  53703-13-825  04 Nov 2014.
n00247851
A 4-Week Oral Dose Toxicity and Toxicokinetic Study of PXS-4728A in 
Sprague-Dawley Rats. 53703-13-828. 27 Feb 2014.
n00248307
In Vitro Investigation of Effects on hERG Tail Currents recorded from 
Stably transfected HEK293 Cells. VPT2417. 29 Aug 2014.
n00248308
A Respiratory Safety Pharmacology Study of PXS-4728A in Sprague 
Dawley Rats. Study No. 53702-14-999. 30 Oct 2014.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 87 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
10.
APPENDICES
10.1
RECONSTITUTION INSTRUCTION
10.1.1
Drug supplies overview
a)
BI 1467335 Powder for Oral Solution 40 mg (target solution concentration 
BI 1467335: 0.5 mg/mL), provided in 100 mL amber glass bottles with plastic screw 
cap
b)
Solvent for Oral Solution 80 mL (Sucralose 4 mg/ml +Menthol 2 mg/ml) provided in 
100 ml glass vials with tear-off caps
c)
Empty appropriately labeled amber glass bottle, 100ml with plastic screw-cap
10.1.2
Required equipment and dosing aids - overview
a)
Mechanical (reciprocal) shaker for bottles (e.g. Bühler Type KL2)
b)
Dosing dispensers/syringes and bottle adapters
For the withdrawal of respective volume aliquots from the final oral solution to be 
administered amber BAXA ExactaMed oral dispensers/ syringes should be used in a 
size as close as possible to the required dose volume. For this purpose a range of 
syringe sizes from 1 mL up to 60 mL should be stocked in the trial sites.
In order to ease the withdrawal of the oral solution from the glass bottles with the 
amber BAXA ExactaMed syringes BAXA bottle adapters and dispenser tip caps (e.g. 
Order No 50300) should be used and stocked in the trial sites, preferably BAXA 
Press-In Bottle Adapters (PIBATM) – e.g. Order No. H9382001or BAXA AdaptaCap 
Bottle Adapters (E-28 mm) –e.g. Order No. 5105. 
Possible amber BAXA ExactaMed dispensers/ syringes 
•
BAXA ExactaMed amber oral dispenser 1 mL – e.g. Order No – 1601
•
BAXA ExactaMed amber oral dispenser 3 mL – e.g. Order No – 1602
•
BAXA ExactaMed amber oral dispenser 5 mL – e.g. Order No – 1605
•
BAXA ExactaMed amber oral dispenser 10 mL – e.g. Order No – 1610
•
BAXA ExactaMed amber oral dispenser 20 mL – e.g. Order No – 1620
•
BAXA ExactaMed amber oral dispenser 35 mL – e.g. Order No – 1635
•
BAXA ExactaMed amber oral dispenser 60 mL – e.g. Order No – 1650
Only CE certified syringes are to be used!


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 88 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
10.1.3
Reconstitution procedure
2 bottle concept, see also Chapter 10.1.4.
10.1.3.1
Reconstitution procedure for the preparation of the active BI 1467335 oral 
solution 0.5 mg/mL
Necessary materials
a)
BI 1467335 Powder for Oral Solution 40 mg (target solution concentration 
BI 1467335: 0.5 mg/mL), provided in 100 mL amber glass bottles with plastic screw 
cap.
b)
Solvent for Oral Solution 80 mL (Sucralose 4 mg/ml + Menthol 2 mg/ml) provided in 
100 mL glass vials with tear-off caps.
Reconstitution procedure
Step 1:
Open the vial containing the Solvent for Oral Solution 80 mL (Sucralose 
4 mg/mL + Menthol 2 mg/ml)
Step 2:
Transfer the content of the Solvent for Oral Solution 80 mL (Sucralose 4 mg/mL 
+ Menthol 2 mg/ml) completely and carefully into the bottle containing the 
BI 1467335 Powder for Oral Solution 40 mg
Step 3:
Close the bottle with the plastic screw cap and shake the bottle manually until the 
BI 1467335 powder is wetted. Mount the bottle in a horizontal recumbent 
position on a mechanical shaker (e.g. Bühler Type KL2) 
Step 4:
Let the bottle shake for 30 min at 350 rpm in its horizontal recumbent position.
Visually control that the powder is dissolved (clear to almost clear solution). 
After dissolution the solution is ready to use 
The final BI 1467335 Oral Solution concentration is 0.5 mg/mL.
The allowable dose range is from 0.1 mg - 40 mg.
lowest possible dose in mg = C1 * V1
highest possible dose in mg = C1 * V2
C1 = oral solution concentration = 0.5 mg/mL 
V1 = 0.2 mL corr. to the minimum volume to be withdrawn from the oral solution 
         (assumption: use of 1 mL syringe)
V2 = 80 mL, corr. to the maximum allowable administration volume per dose


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 89 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
10.1.3.2
Preparation of the solvent for oral solution for use as placebo solution
Necessary materials
a)
Solvent for Oral Solution 80 mL (Sucralose 4 mg/ml + Menthol 2 mg/ml)) provided 
in 100 mL glass vials with tear-off caps.
b)
Empty appropriately labeled amber glass bottle, 100ml with plastic screw cap
Solution transfer procedure
Step 1:
Open the vial containing the Solvent for Oral Solution 80 mL (Sucralose 4 mg/ml 
+ Menthol 2 mg/ml)
Step 2:
After removing the screw cap, transfer the content of the Solvent for Oral 
Solution 80 mL (Sucralose 4 mg/ml + Menthol 2 mg/ml) completely and 
carefully into the empty labeled amber bottle, and reclose as appropriate with the 
plastic screw cap.
Step 3:
From the transferred solution volume aliquots can be withdrawn with the Baxa 
Adaptacap bottle adapter and the Baxa dispenser (as outlined in section 10.1.2) 
according to the clinical trial protocol dose escalation step.
The Placebo Solution is the Solvent for Oral Solution 80 ml (Sucralose 4 mg/ml +
Menthol 2 mg/ml).


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 90 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
10.1.4
Illustration of reconstitution procedure
The following scheme on the principle followed for the present PfOS formulation incl. 
placebo, 2-bottle concept, should serve as an additional illustration to clarify, how the 
reconstitution has to be performed.
PfOS reconstitution procedure
2-bottle concept: SfOS + PfOS (API)
Component
g/Vial
Function
Sucralose
0.3200
Sweetener
Citric acid monohydrate
0.1600
pH-
adjustment
Menthol L spray-dried
0.1600
Flavor
Water
79.4560
Solvent
80.096
Component
g/Vial
Function
BI 1467335
0.040
Active 
ingredient
1
2
Transfer  the complete SfOS
SfOS
Solvent for Oral Solution
API powder in bottle
Powder for Oral Solution PfOS
Final solution for
administration
0.5mg/ml
2
Empty amber bottle
in case of placebo


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 91 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
The following picture shows the original powder and solvent bottles needed for the 
preparation of the final oral solution for administration.
10.1.5
In-use stability
The in-use stability of the reconstituted solution is 6 hours after its preparation, incl. storage 
in BAXA dispensers/syringes until administration. Further details are given on the CTS 
labels.
10.1.6
Mode of application
Withdraw the required volume aliquot with amber BAXA ExactaMed dispensers/syringes to 
obtain the required doses. In case the complete content of a bottle is to be used, it can be 
administered directly out of the bottle.
Use BAXA ExactaMed syringes at a volume size as close as possible to the volume to be 
withdrawn.
Please note that it is the responsibility of the investigator to assure that appropriate supplies 
are used for administration of a dose, based on guidance in the clinical trial protocol, and 
dosing is limited to the allowed dosing range for a specific dose formulation as stated in this 
Reconstitution Instruction.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 92 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
10.1.7
General remarks - important!
Because of lacking analytical coverage beyond the instructed preparation procedure of the 
different dose formulations no further (external) dilutions of the reconstituted solutions are 
allowed!
The present reconstitution instruction does not contain any advice how to withdraw a specific 
dose from the reconstituted solutions. The specific dose volumes to be withdrawn from the 
described dose formulations in order to obtain a required dose will be calculated and 
documented by TransMed in the Clinical Trial Protocol (CTP) and subsequent documents 
(e.g. work sheets)!


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 93 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
04 May 2016
EudraCT number
2015-005049-29
BI Trial number
1386.8
BI Investigational Product(s)
BI 147335
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses 
of BI 1467335 in healthy male and female 
subjects (double-blind, randomised, placebo-
controlled within dose groups)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Synopsis and Flowchart
2. Section 1.2.5, Clinical experience in humans
3. Section 2, Rationale, objectives and benefit-
risk assessment
4. Section 3.1, Overall trial design and plan
5. Section 3.3.2, Exclusion criteria
6. Section 3.3.4.1, Removal of individual 
subjects
7. Section 3.3.4.2. Discontinuation by the 
Sponsor
8. Section 4.1, Treatment
9. Section 5.2.2, Assessment of adverse events
10. Section 5.2.3, Assessment of safety laboratory 
parameters
11. Section 5.2.4.1, 12-lead resting ECG
12. Section 5.6.3, Methods of sample collection


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 94 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
1
13. Section 7.3.4, Pharmacokinetic analysis
14. Section 8.4,  Listedness and expedited 
reporting of adverse events
15. Section 10.1, Reconstitution instruction
Description of change
The amended protocol includes major changes. 
Since most of the changes apply to several 
sections throughout the protocol, the changes may 
be described only once and not repeated for each 
section: 
1. Synopsis, Flowchart
-
Change of placebo (removal of quinine)
-
Dose escalation steps modified to 10 mg, 
15 mg and 20 mg, additional dose groups 
> 20 mg may be included taking into 
account predefined stopping criteria. 
- Additional ECG recordings (including an 
ECG recording 15 minutes after dosing)
- 2 predose PD samples instead of only one 
sample
2. Section 1.2.5
- Correction of maximum individual Tmax to 
1.1 h (instead of 1.3 h)
3. Section 2
- Deferred inclusion of subjects and 
implementation of more cohorts per dose 
group taking into account safety, 
tolerability and preliminary PK data
- Prespecified stopping criteria based on 
extrapolated PK data in the ongoing study 
(Cmax or 1/10th AUC at NOAEL of 4 week 
rat study should not be exceeded)
4. Section 3.1
- Modified to comply with previous sections 
(Synopsis, Section 2)
5. Section 3.3.3.2
- Additional exclusion criterion GFR based 
on CKD-EPI > 90 ml/min 
6. Section 3.3.4.1
- Additional stopping rules based on safety 
(such as eGFR calculated with the CKD-
EPI formula < 80 ml/min; signs of 
rhabdomyolysis; threshold for 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 95 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
1
thrombocytopenia, leukopenia, 
neutropenia)
7. Section 3.3.4.2
- Discontinuation criteria by the Sponsor 
modified to comply with previous sections
8. Section 4.1 
- Description of treatment modified 
9. Section 5.2.2 
-
Implementation of CTCAE grading
10. Section 5.2.3 
- Additional renal safety marker (serum 
cystatine)
11. Section 5.2.3 
- ECG schedule updated
12. Section 5.6.3 
- Blood loss during the study (overall 
duration 6 to 7 weeks) will be 510 mL and 
thus in the range of a normal blood 
donation (500 mL)
13. Section 7.3.4
- Modification of statistical section to further 
specify the interim PK assessments
14. Section 8.4
- Expedited reporting of SAEs and AEs is to 
FDA
15. Section 10.1
- Reconstitution instruction updated due to 
change of placebo (removal of quinine)
In connection with this amendment, minor 
inconsistencies such as discrepancies between 
text and flow chart or typing errors were 
corrected.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 96 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
1
Rationale for change
Based on the feedback by FDA, BfArM and 
Ethics Committee, the respective 
recommendations were included in a revised 
protocol. This applies for all major changes as 
summarized in ‘Sections to be changed’, in 
particular for the revised selection of doses, dose 
escalation procedures, the further deferred 
inclusion of subjects in the study, the withdrawal 
of quinidine as placebo, the implementation of 
additional stopping rules and the expedited 
reporting of (S)AEs.


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 97 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
2
Date of CTP revision
13 July 2016
EudraCT number
2015-005049-29
BI Trial number
1386.8
BI Investigational Product(s)
BI 147335
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses 
of BI 1467335 in healthy male and female 
subjects (double-blind, randomised, placebo-
controlled within dose groups)
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. Abbreviations
2. Section 3.1, Overall trial design
3. Section 4.1.1, Identity of BI investigational 
product and comparator product
4. Section 4.1.5.1, Blinding
5. Section 5.2.3, Assessment of safety laboratory 
parameters
6. Section 5.5.2, Methods of sample collection
7. Section 6.2.1, Screening
Description of change
1. Abbreviations
-
Added GFR
2. Section 3.1
-
Correction of random numbers for 
replacement subjects
3. Section 4.1.1
-
Powder for placebo solution deleted
4. Section 4.1.5.1
-
Addition of CRA as unblinded sponsor 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 98 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
2
function
5. Section 5.2.3
-
Minor modifications in the table section to 
be consistent with flow chart and text
6. Section 5.5.2
-
In all PK sample tubes, replacement of the 
stabilizing agent semicarbazide by 
phenelzine
7. Section 6.2.1
-
Pharmagonemic genotyping in all subjects 
as indicated in the flow chart
Rationale for change
Pharmacokinetic sample handling was modified 
to consider most recent findings in which the 
stabilizing agent phenelzine was superior to 
semicarbazide. In context with these changes a 
few remaining inconsistencies were also 
corrected. 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 99 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
3
Date of CTP revision
05 OCT 2016
EudraCT number
2015-005049-29
BI Trial number
1386.8
BI Investigational Product(s)
BI 147335
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses 
of BI 1467335 in healthy male and female 
subjects (double-blind, randomised, placebo-
controlled within dose groups)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Synopsis
2. Section 2, Rationale, objectives and benefit-
risk assessment
3. Section 3.1, Overall trial design
4. Section 3.3, Selection of trial population
5. Section 5.5.2, Methods of sample collection
6. Section 7.3.1 and 7.3.2 Attainment of steady 
state
Description of change
Changes apply to several sections throughout the 
protocol and are described only once and not 
repeated for each section:
1. Deletion of dose groups > 20 mg QD. 
2. Increase of the individual AUC threshold, 
which must not be exceeded by subjects, from 
1/10th to 1/2 of the NOAEL in the 4 week rat 
study.
3.  Additional Stability samples for the 15 mg 
Dose Group will be taken to assess more data 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 100 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
3
of the stability of the analyte in whole blood.
4. Attainment of steady state analysis via 
MMRM model changes to secondary analysis 
and nonlinear mixed model analysis added as 
primary analysis.
Rationale for change
The 10 mg dose group in this ongoing study 
1386.8 has recently completed the 4 week 
treatment period. The evaluation is ongoing, 
preliminary data have become available. Overall, 
BI 1467355 was well tolerated. There were in 
particular no AEs considered to be dose limiting 
and no SAEs, all subjects completed the treatment 
period per protocol. There were no clinically 
relevant abnormalities with respect to safety 
laboratory, vital signs, or ECG. In particular there 
were no ECG findings suggesting adverse effects 
on the QT interval. Preliminary PK data obtained
for the 10 mg dose level shows in all subjects an
AUC exposure below Cmax and 1/10th of the 
AUC at NOAEL in the 1 month rats study, the 
initially defined exposure threshold not to be 
exceeded by subjects. Extrapolations based on the 
clinical PK data derived from the completed 10 
mg dose group and the data obtained with the 
completed 2 week Phase I study suggest that with 
the next planned dose of 15 mg QD over 4 weeks 
some subjects may exceed the 1/10th AUC 
margin at the end of the 4 week treatment period. 
The estimated mean and the 95% prediction 
interval of Cmax extrapolation to 15 mg are still 
well below the Cmax at NOAEL. As steady state 
was not reached after 4 weeks of treatment with 
10 mg BI 1467355 it is considered to be more 
appropriate to use a nonlinear fit for 
determination of the attainment of steady state.
Additional data obtained with the 15 mg dose 
group are considered crucial to provide a safety 
margin regarding the assumed maximum 
efficacious dose of 10 mg QD in NASH patients. 
Since in the completed 10 mg dose group there 
were no safety signals precluding the continuation 
with the next higher dose it is considered to be 
justified to increase the initial exposure threshold 
from 1/10th AUC to ½ AUC at NOAEL obtained 
in the 4 week toxicology study in rats. It should 


Boehringer Ingelheim
05 OCT 2016
BI Trial No.: 1386.8
c08854973-04
Trial Protocol
Page 101 of 101
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
3
be highlighted that all remaining stopping rules 
(individual discontinuation criteria or stopping 
rules for the whole study) will remain unchanged. 
In addition the study is conducted under close 
clinical monitoring (including central ECG 
reading) to early identify adverse safety signals.
In context with the changes required for 
Amendment 3 a few remaining inconsistencies 
were also corrected. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08854973
4.0
clinical-trial-protocol-revision-03
Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising oral
doses of BI 1467335 in healthy male and female subjects (double-blind, randomised,
placebo-controlled within dose groups)
Author-Trial Statistician
06 Oct 2016 10:41 CEST
Author-Trial Clinical Monitor
06 Oct 2016 10:51 CEST
Author-Clinical Pharmacokineticist
06 Oct 2016 11:53 CEST
Approval-Therapeutic Area 
06 Oct 2016 14:40 CEST
Approval-Team Member Medicine
07 Oct 2016 08:29 CEST
Verification-Paper Signature
Completion
10 Oct 2016 07:10 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08854973
4.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c17305575-01
BI Trial No.:
1386.8
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
multiple rising oral doses of BI 1467335 in healthy male and 
female subjects (double-blind, randomised, placebo-controlled 
within dose groups)
(Including protocol amendment 1 (c08854973-02), amendment 2 
(c08854973-03) and amendment 3 (c08854973-04) )
Investigational
Product:
BI 1467335
Responsible trial 
statisticians:
Phone: 
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
29 Aug 2017 SIGNED
Version:
Final
Page 1 of 34
Proprietary confidential information
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 2 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINTS...................................................................................10
5.2
SECONDARY ENDPOINT ...............................................................................10
5.2.1
Key secondary endpoint .....................................................................................10
5.2.2
Secondary endpoint.............................................................................................10
5.3.2
Safety parameters ...............................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................14
6.1
TREATMENTS...................................................................................................14
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................15
6.3
SUBJECT SETS ANALYSED...........................................................................16
6.5
POOLING OF CENTRES .................................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................18
7.
PLANNED ANALYSIS......................................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........21
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................22
7.3
TREATMENT COMPLIANCE........................................................................22
7.4
PRIMARY ENDPOINTS...................................................................................22
7.5
SECONDARY ENDPOINT ...............................................................................22
7.5.1
Key secondary endpoint .....................................................................................22
7.5.2
Secondary endpoints...........................................................................................22
7.6.2
Safety parameters ...............................................................................................23
7.7
EXTENT OF EXPOSURE.................................................................................24


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 3 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8
SAFETY ANALYSIS..........................................................................................25
7.8.1
Adverse events.....................................................................................................25
7.8.2
Laboratory data ..................................................................................................26
7.8.3
Vital signs.............................................................................................................26
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................29
8.
REFERENCES....................................................................................................30
9.
ADDITIONAL SECTIONS ...............................................................................31
9.1
DETAILED DESCRIPTION OF ENDPOINTS FOR ECG...........................31
9.2
STEPS IN CASE OF CONVERGENCE PROBLEMS FOR REPEATED 
MEASURES MODEL IN ECG .........................................................................32
10.
HISTORY TABLE..............................................................................................34


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 4 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data, vital signs and ECG................................................................14
Table 6.2: 1
Important protocol violations ...........................................................................15
Table 6.3: 1
Subject sets analysed ........................................................................................17
Table 6.7: 1
Time schedule of 12-lead ECG recordings.......................................................18
Table 10: 1
History table .....................................................................................................34


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 5 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADME
Absorption, distribution, metabolism, and excretion
ADS
Analysis dataset
AE
Adverse event
Ae0-24,N
Amount of analyte eliminated in urine over 24 h after administration 
of the Nth dose
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to 24 hours after administration of the first 
dose
AUC0-24,28
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to 24 hours after administration of the 28th
dose
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
BMS
Biomarker set
C1,N
Concentration of the analyte in plasma 1 hour after administration of 
the Nth dose
CARE
Clinical data analysis and reporting environment
Cmax
Maximum measured concentration of the analyte in plasma after 
administration of the first dose
Cmax,28
Maximum measured concentration of the analyte in plasma following
administration of the 28th dose
Cpre,N
Predose concentration of the analyte in plasma immediately before 
administration of the Nth dose after N-1 doses were administered
CRF
Case report form
CTCAE
Common terminology criteria for adverse events
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 6 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Term
Definition / description
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECGPCS
Electrocardiogram plasma concentration set
eCRF
Electronic case report form
EMA
European Medicines Agency
EudraCT
European union drug regulating authorities clinical trials
gCV
Geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IPV
Important protocol violation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analysed
NOR
No valid result
NOS
No sample available
on-trt
on-treatment
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set
PR interval
ECG interval from the onset of P wave to the beginning of the QRS
PV
Protocol violation
QRS complex
Combination of the Q, R, and S waves
QT interval
ECG interval from the beginning of the QRS complex to the end of the 
T wave
QTcB
QT interval, heart rate corrected according to Bazett's formula
QTcF
QT interval, heart rate corrected according to Fridericia's formula
QTcN
QT interval, heart rate corrected according to study population formula
R
Reference treatment
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


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 7 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Term
Definition / description
RS
Randomised set
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SOC
System organ class
T
Test treatment
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 8 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to 
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its amendments. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 "Statistical Methods 
and Determination of Sample Size". Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version 6.3, Certara 
USA Inc., Princeton, NJ, USA).


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 9 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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 revised CTP.
 
 
 
 
 
 
QTcN correction was added as additional further ECG parameter to be evaluated.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 10 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoint is the number [N (%)] of subjects with drug-related AEs, as defined in 
Section 5.2.1 of the CTP.
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoint
Secondary endpoints are AUC0-24, Cmax, AUC0-24,28 and Cmax,28 of BI 1467335 in plasma, as 
defined in Section 5.5.1.1 of the CTP.
5.3.2
Safety parameters
CTP: Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Exclusion of cataract formation


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 11 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
12-lead ECG endpoints
For the definition of baseline and a summary of time points please refer to Section 6.7.
Quantitative ECG endpoints:
The following quantitative ECG endpoints will be determined for the ECG variables QTcN, 
QTcF, QT, HR, PR, QRS, RR 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)
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 QTcN interval > 450 to 480 msec, > 480 to 500 msec, or > 500 msec on 
treatment (and similar for QTcF).
For assignment of a particular subject to one of the above categories, all time points on-
treatment (refer to Table 6.7: 1) will be considered. If baseline is missing, but the 
maximum absolute QTcN interval falls in a category other than normal (i.e. when QTcN > 
450 msec), then this is categorized as a new onset in the respective category. If baseline is 
missing, but the maximum absolute QTcN interval is normal, then it is categorized as "No 
new onset" (similar for QTcF).

Maximum change from baseline in QT interval ≤ 60 msec, or > 60 msec on treatment

Maximum change from baseline in QTcN interval ≤ 30 msec, > 30 to ≤ 60 msec, or 
> 60 msec on treatment (similar for QTcF)
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
If baseline is missing, any occurrence of QT interval > 500 msec at any time on treatment 
will be a notable finding

New onset of QTcN interval > 500 msec at any time on treatment (and similar for QTcF)
If baseline is missing, any occurrence of QTcN interval > 500 msec at any time on 
treatment will be a notable finding (similar for QTcF)

Increase in QTcN interval from baseline by > 60 msec at any time on treatment (similar 
for QTcF)

Increase in HR from baseline by ≥ 25%, when corresponding on-treatment value of HR is 
> 100 beats/min, or decrease in HR by ≥ 25%, when corresponding on-treatment value of 
HR is < 50 beats/min, at any time on treatment

Increase in the PR interval from baseline by ≥ 25%, when corresponding on-treatment 
value of PR interval is > 200 msec, at any time on treatment 

Increase in the QRS complex from baseline by ≥ 10%, when corresponding on-treatment 
value of QRS complex is > 110 msec, at any time on treatment


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 12 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 13 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 14 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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 will be treated with 10 mg, 15 mg or 20 mg of BI 1467335 (test treatment, T) or 
placebo (reference treatment, R) once daily over 28 days. All placebo subjects will be 
analysed in one pooled placebo group (i.e. no distinction between dose groups will be made
for placebo subjects).
For statistical analysis of AEs, safety laboratory data, vital signs and ECG, the following 
analysis phases are defined for each subject:
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data, vital signs and ECG
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
Placebo,
10 mg BI,
15 mg BI,
or 20 mg BI,
respectively
Date/time of first 
administration of study drug
12:00 AM on day after 
subject's trial termination 
date
CTR Section 15, Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 AE displays will present 
results for the on-treatment phase only.
In CTR Section 15 AE tables (but not in Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 AE 
tables), the following totals will be provided in addition:

"Total BI", defined as the total over all on-treatment phases involving BI, i.e., "10 mg 
BI" + "15 mg BI" + "20 mg BI"

"Total on-trt", defined as the total over all on-treatment phases, i.e., "Placebo" + "10 
mg BI" + "15 mg BI" + "20 mg BI"
CTR Appendix 16.1.9.2.8.1 displays will present results for the screening and on-treatment
phases.
Additionally to the totals defined above, the following total will be provided in CTR Section 
16.1.9.2.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment)


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 15 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL VIOLATIONS
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/DBLM. 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 IPV. For 
definition of IPVs, and for the process of identification of these, refer to the BI reference 
document "Protocol Violation Handling Definitions" (1).
If any IPVs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet (2). The following table 
contains the categories which are considered to be IPVs in this trial. If the data show other 
IPVs, this table will be supplemented accordingly by the time of the RPM/DBLM.
IPVs will be summarised and listed.
Table 6.2: 1
Important protocol violations
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C3
Non-compliance
C4
Medication code broken inappropriately
C5
Incorrect intake of trial medication
D
Concomitant medication
D1
Prohibited medication use
E
Missing data
Certain violations of procedures used to measure primary or secondary data
Violations C1, C2, C4, and C5 can only be detected at the trial site.
Source: BI reference document "Protocol Violation Handling Definitions" [001-MCS-50-413_RD-01] (1).


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 16 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.3
SUBJECT SETS ANALYSED
The following subject sets will be defined for statistical analysis:

Randomised set (RS): 
This subject set includes all subjects who were randomised, i.e., who have been 
assigned a subject number, whether treated or not.

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug, as 
defined in Section 7.3.1 of the CTP. This is the full analysis set population in the sense 
of ICH-E9.

Pharmacokinetic parameter analysis set (PKS):
This subject set includes all subjects of the TS who provide at least one PK parameter 
that was not excluded due to relevant PVs or due to PK non-evaluability, as defined in 
Section 7.3.1 of the CTP.
 
 
All ECG analyses are performed on the TS, except for the exposure-response analyses, which 
are performed on the ECGPCS defined below.

ECG PC set (ECGPCS):
This subject set consists of all subjects in the TS who provide a baseline value and at 
least one post-baseline value for at least one ECG variable used in the exposure-
response analysis, and a corresponding (i.e. time-matched) valid drug plasma 
concentration. Since placebo subjects will be included in the exposure-response 
analyses with plasma concentration set to 0, a plasma concentration BLQ is considered 
a valid drug plasma concentration for placebo subjects.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 17 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
RS
TS
PKS
BMS
ECGPCS
Disposition
X
X
Exposure
X
IPVs
X
Demographic/baseline endpoints
X
Primary endpoint
X
ECG endpoints and plasma 
concentrations used in exposure-
response analysis
X
ECG endpoints in other analyses
X
Other safety parameters
X
Secondary PK endpoints
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
CTP: If a subject is removed from or withdraws from the trial prior to first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) or 
trial database and will not be reported in the clinical trial report (CTR). If a subject is 
removed from or withdraws from the trial after first administration of trial medication, this 
will be documented and the reason for discontinuation must be recorded in the CRF. In this 
case, the data will be included in the CRF/trial database and will be reported in the CTR.
CTP: With respect to safety evaluations, it is not planned to impute missing values.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (3)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-36-
472_RD-01) (4). CTP: For tabulation and graphical displays, drug concentration data 
identified with NOS (no sample available), NOR (no valid result), NOA (not analysed), or 


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 18 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BLQ (below the lower limit of quantification) will be displayed as such and not replaced by 
zero at any time point (this rule also applies also to the lag phase, including the predose 
values).
CTP: For the calculation of PK parameters by non-compartmental analysis, concentration 
data identified with NOS, NOR or NOA will generally not be considered. Concentration 
values in the lag phase identified as BLQ will be set to zero. All other BLQ values of the 
profile will be ignored. The lag phase is defined as the period between time zero and the first 
time point with a concentration above the quantification limit.
CTP: No imputation of missing PK parameters will be performed.
CTP: 
 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
There will be a centralised evaluation of all 12-lead ECG recordings at the time points 
specified in Table 6.7: 1 below:
Table 6.7: 1
Time schedule of 12-lead ECG recordings
Visit
Day
Planned time 
[hh:mm]
(relative to drug 
administration)
Study phase
2
1
-02:00
Baseline
00:15
On-treatment
00:30
00:45
01:00
01:30
02:00
04:00
08:00
12:00
2
24:00
3
48:00
4
72:00
73:00
Table 6.7: 1
Time schedule of 12-lead ECG recordings (continued)
Visit
Day
Planned time 
Study phase


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 19 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
[hh:mm]
(relative to drug 
administration)
2
7
144:00
On-treatment
145:00
14
310:00
312:15
312:30
312:45
313:00
313:30
314:00
316:00
320:00
324:00
15
336:00
16
360:00
17
384:00
385:00
21
480:00
481:00
28
646:00
648:15
648:30
648:45
649:00
649:30
650:00
652:00
656:00
660:00
29
672:00
Triple ECGs (3 single ECGs recorded within 180 sec) will be recorded on all time points on 
Day 1, Day 2, Day 14, Day 15, Day 21, Day 28 and Day 29. On all other time points, single 
ECGs will be recorded.
The value of an ECG variable at each of the time points with triple ECG is defined as the 
arithmetic mean of the 3 single ECG measurements. In particular, the baseline value of an 


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 20 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ECG variable is defined as the mean of the triple ECG measurements prior to first drug 
administration.
In all other analyses (except for analyses of ECG variables), the last non-missing value 
determined prior to the first dosing of BI 1467335 will be defined as baseline. 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 21 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (001-MCG-159) (9).
The individual values of all subjects will be listed. Listings will generally be sorted by dose 
group, subject number and visit (if visit is applicable in the respective listing). AE listings will 
be sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
Inferential statistical analyses of secondary and further PK endpoints will be performed by 
 and will be presented in Section 15.5 of the CTR and in Appendix 
16.1.9.3
 
 
Descriptive data analysis of PK 
 will be performed by BI and 
presented in Sections 15.6 and 15.7 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 and biomarker parameters, the 
following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if there actually are missing values. Percentages will be based on 
all subjects in the respective 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 CTR.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 22 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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 CTR.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of first administration of the respective treatment or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM/DBLM (cf. Section 6.2) and described in the 
CTR.
7.4
PRIMARY ENDPOINTS
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis of 
the frequency of subjects with drug related AEs, which is the primary endpoint of this trial.
7.5
SECONDARY ENDPOINT
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.
Dose proportionality of secondary endpoints will be evaluated as defined in the CTP, 
Section 7.3.1, by use of the power model. If steady state will already be reached after 14 days 
of treatment, dose proportionality will also be investigated for AUC0-24,14 and AUC0-24,28
together (and for Cmax,14 and Cmax,28 together, respectively) by use of a repeated measurements 
model, as described in Section 7.3.1 of the CTP.
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma concentrations


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 23 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses.
Further details are given in 001-MCS-36-472_RD-01 "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies" (4) and 001-MCS-36-472_RD-03 
"Description of Analytical Transfer Files and PK/PD Data Files" (5).
7.6.2
Safety parameters
Safety and tolerability will be analysed as described in Section 7.8 of this TSAP.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 24 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 25 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
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 eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity [CTCAE grade Version 4.03], 
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 "Handling and summarization 
of adverse event data for clinical trial reports and integrated summaries" (6) [001-MCG-156] 
and "Handling of missing and incomplete AE dates" (3) [001-MCG-156_RD-01]. 
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 phase or on-treatment phase as defined in 
Section 6.1.
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 and for the class of 
AESIs.
CTP: The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory parameters: 
○
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or
○
marked peak 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 SOC and 
preferred term. AEs which were considered by the investigator to be drug related (primary 
endpoint) will be summarised separately. Separate tables will also be provided for subjects 


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 26 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
with SAEs, subjects with AESIs and subjects with other significant AEs (according to ICH E3 
(8)). The frequency of subjects with AEs and the frequency of subjects with AEs considered 
by the investigator to be drug related will also be summarised by maximum grade of CTCAE 
(version 4.03), primary SOC and preferred term.
The SOCs will be sorted according to the standard sort order specified by the EMA, preferred 
terms will be sorted by total frequency (within SOC).
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(7). Due to inclusion of male and female subjects, laboratory analyses will be based on 
normalised values, i.e., for a given laboratory parameter, values will be transformed to a 
standard unit and a standard reference range before statistical analysis.
CTP: Laboratory data will be compared to their reference ranges. Values outside the 
reference range will be flagged. Additionally, differences from baseline will be evaluated.
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 or at the RPM/DBLM at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. Standard 
or project-specific rules for flagging clinically significant values in an automated manner will 
not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
The analyses 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 (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 27 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8.4
ECG
12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator. 
All evaluation of ECG data except of exposure response analysis will be based on the TS. The 
exposure-response analysis will then be done on the ECGPCS.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. 
Occurrences of notable findings will be flagged.
For all subjects with any notable finding in quantitative ECG recordings, a separate listing 
will be created as end-of-text display (based on the same display template as in Appendix 
16.2), and the corresponding time profiles will be shown.
Comments regarding the ECGs will be listed.
Analysis of central tendency
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time in all ECG variables.
For QTcN, QTcF, QT and HR, a repeated measurements analysis of the changes from 
baseline with baseline as a covariate will be performed. The model will include the fixed 
effects "baseline", "treatment", "time", "baseline*time" interaction, and "treatment*time"
interaction. The covariance model for the repeated effect "time" will be unstructured (i.e. 
TYPE=UN or UNR); in case of convergence problems refer to Additional Section 9.2. For 
each dose group and each time point, the contrast of the means for "treatment-placebo" will 
be estimated by the difference in the corresponding adjusted means (Least Squares Means); 
two-sided 90% CIs based on the t-distribution will also be computed. For each of the above 
ECG variables, the time profiles of the mean differences to placebo in the changes from 
baseline and the corresponding 90% CIs will be presented in a figure.
The following SAS code can be used to fit the model:
PROC MIXED DATA=indata CL METHOD=REML;
CLASS subject treat time;
MODEL ECGep = treat time base treat*time base*time / DDFM=KR CL ALPHA=0.1;
REPEATED time / TYPE=UN SUBJECT=subject;
LSMEANS treat*time / DIFF CL ALPHA=0.1;
SLICE treat*time / SLICEBY=time DIFF CL ALPHA=0.1 NOF PLOT=none;
RUN;
For PR, QRS, RR as well as QTcB, the time profiles of mean and SD for the changes from 
baseline on treatment will be displayed graphically by treatment.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 28 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Plasma concentrations and relationship to QTcN, QTcF, QT interval and HR change from 
baseline
For the following analyses, all time points with available ECG endpoints, which were derived 
from triple ECG measurements (Days 1, 2, 14, 15, 21, 28, 29), and corresponding plasma 
concentrations will be included.
The changes from baseline in QTcN (QTcN) will be investigated as response variable. The 
placebo subjects will be included in the analysis, with zero plasma concentrations. Time 
points with plasma concentrations "BLQ" in subjects in active dose groups will be ignored in 
this analysis.
As a first step, it will be investigated if there is a potential delayed or accelerated (e.g. 
metabolites) effects of the drug on QTcN. A general visual impression of the PK-QT 
relationship is provided by overlaying time profiles of plasma concentrations and QTcN 
changes from baseline (QTcN). All figures will be generated for each subject (presented in 
Appendix 16.1.9.2 of the CTR), as well as for means per active treatment (presented in 
Section 15.3 of the CTR).
In case of non-linearity or if there is evidence for a delayed effect, further models will be 
explored that better characterise the PK/ECG relationship (effect compartment, non-linear 
model etc.).
If there is no non-linearity or delayed effect seen, the relationship between BI 1467335 
plasma concentrations and QTcN changes from baseline will be investigated in an exploratory 
manner using a random coefficient model approach to estimate the QTcN change from 
baseline and its 90% confidence interval at the geometric mean of the Cmax for each dose. 
Additionally, the estimated slope with its 90% confidence interval will be provided. The used 
random coefficient model is based on Garnett et al. 2016 [R17-0553] (10):
PROC MIXED DATA=myDATA METHOD=REML;
CLASS subject active(ref=FIRST) time;
MODEL ECGep = conc active time / NOINT CL ALPHA=0.1 ALPHAP=0.1 DDFM=KR
OUTPREDM=pred;
RANDOM INT conc / TYPE=UN SUBJECT=subject;
ESTIMATE 'Pred. value at conc. xx.xx' conc xx.xx active 1 -1 / CL
ALPHA=0.1;
ESTIMATE 'Slope estimate' conc 1 / CL ALPHA=0.1;
RUN;
Here "ECGep" is the QTcN change from baseline, "active" is a dummy 0/1 variable indicating 
the active treatment (1=active, 0=placebo), "conc" is the corresponding plasma concentration 
value of the drug, and "xx.xx" is the given concentration value (usually the value of the 
geometric mean Cmax of a given dose group). The "TYPE=UN" option causes the two 
specified random coefficients to have a bivariate normal distribution. In case of convergence 
problems see Section 9.2 for possible improvements (option "TYPE=FA0(2)" may also be 
used as a potential solution, it requests a G matrix estimate that is constrained to be 
nonnegative definite). If the note "estimated G matrix is not positive definite" occurs in the 
SAS log file, the random slope "conc" might be removed from the "RANDOM" statement. 


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 29 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
When the plasma concentrations are not normally distributed, the exposure-response model 
can be applied to log(conc) instead of the raw concentration.
For visualization, the BI 1467335 plasma concentration against the response will be plotted as 
well as the (fixed effect) regression line, its 90% confidence interval and the geometric mean 
of Cmax for each dose. For each subject and each time point, subtract the mean value of all 
individual observed ΔQTc values from the placebo group for this time point from the 
individual observed ΔQTc value for this subject and time point. This results in estimates for 
"individual ΔΔQTc" values. These estimates should only be used for plotting purposes.
All of the above described graphical and statistical analyses will be also performed for QTcF, 
HR and QT in place of QTcN.
Categorical Endpoints
For the categorical endpoints, frequency tables will be provided.
For subjects with notable findings, the individual time courses of QTcN, QTcF, QT, HR, PR 
and QRS of these subjects will be presented in figures.
7.8.5
Others
Physical examination findings and ophthalmological examination findings (exclusion of 
cataract) will be reported as relevant medical history/baseline condition (i.e., a condition 
already existent before intake of study drug) or as AE and will be summarised as such. No 
separate listing or analysis of physical examination or ophthalmological examination findings 
will be prepared.


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 30 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.
REFERENCES
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


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 31 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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 with centralised evaluation, measurements of QT, PR, QRS and 
preceding RR interval of four cardiac cycles will be determined and stored in the database as 
raw data.
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/min) will be 
calculated as
/0 [234/67] = 60 000
00
::::
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
QTcF [msec] = B1000
RR
::::
D
QT
:::: ,
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
QTcB [msec] = B1000
RR
::::
F
QT
:::: .
In addition, data dependent population heart rate correction QTcN will be derived for a given 
pair of QT and RR values as
QTcN [msec] = I1000
00 J
	K
∗LM[642],
(RR and QT are given in msec). A common slope will be estimated for the whole population 
(all subjects in the TS) based on the random coefficient model described below. The RR and 
QT intervals used for this slope estimation will be the arithmetic means of the four cardiac 
cycles from each single ECG on baseline and on placebo. Hence, the evaluation will be based 
on 1098 pairs (36 subjects * 1 central baseline ECG with triple measurement * 
3 measurements + 9 placebo subjects * [34 central post-baseline ECGs with triple 


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 32 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
measurement * 3 measurements + 8 central post-baseline ECGs with single measurement]) of 
RR and QT interval measurements for each subject. If there is a missing baseline or placebo 
value, no imputed values will be used in the analysis described in the following:
A random coefficient model with covariate "log-transformed RR interval" is fit (natural log), 
which accounts for subject effects (Ring [R10-2920] (11)):
NO = PQ + 4QO + (TU + 4UO)WO + XO ,
where
Yik
log-transformed QT interval of the ith ECG of subject k;
μ0
the overall intercept;
s0k
the random intercept associated with subject k;
δ1
the regression effect of the covariate, i.e. the common slope associated with the 
relationship between the log-transformed QT and RR intervals;
s1k
the random slope associated with subject k;
xik
log-transformed RR interval of the ith ECG of subject k;
εik
the random error associated with the ith ECG of subject k.
The slope is then calculated as δ1.
The following SAS code will be used to fit the model:
PROC MIXED DATA=xxxx CL METHOD=REML; 
CLASS subject; 
MODEL lnQT = lnRR / DDFM= KENWARDROGER ALPHA=0.05 CL; 
RANDOM INT lnRR / TYPE=UN SUBJECT=subject; 
ESTIMATE 'Population slope' lnRR 1 / ALPHA=0.05 CL; 
RUN;
The PR and QRS values for a single ECG are derived as the means of the PR and QRS values, 
respectively, of the four cardiac cycles for this ECG. 
In case of triple ECGs at a time point, the respective ECG variable will be averaged over the 
triple ECG measurements at this time point (arithmetic mean). Note that in case of missing 
values the averaging is simply done for the available values.
9.2
STEPS IN CASE OF CONVERGENCE PROBLEMS FOR REPEATED 
MEASURES MODEL IN ECG
In case of convergence problems one may try one (or more) of the following steps:
1.) Set MAXITER=100 (or even higher for PROC GLIMMIX) and/or MAXFUNC=200 (for 
PROC GLIMMIX, these options are available within the NLOPTIONS statement)
2.) Set SINGULAR=1E-10 as option (for PROC MIXED: in the model statement)
3.) Use option SCORING=4 in the final run to request a Fisher scoring algorithm to be used 
for the first 4 iterations
4.)
Include the additional statement in the PROC MIXED call:
PERFORMANCE NOTHREAD;


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 33 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.) Perform an initial run including the statement
ODS OUTPUT COVPARMS=covstart;
followed by a final run using
PARMS / PARMSDATA=covstart;
In the special case with the note "Convergence criteria met but final hessian is not positive 
definite" try instead/in addition
PARMS / OLS;
to request ordinary least squares starting values.
6.) One may also use estimates from a simpler model (e.g. using AR(1)) as starting values 
for the run with TYPE=UN or UNR
In case an unstructured covariance matrix (i.e. TYPE=UN or UNR) does not work, also in 
conjunction with all steps from 1)-6) mentioned above, the following covariance structures 
will be chosen, in the pre-defined order:

Toeplitz structure with heterogeneous variances (TOEPH) for the REPEATED effect

heterogeneous first-order autoregressive structure (ARH(1)) for the REPEATED effect

TOEPH for both the RANDOM and the REPEATED effect

ARH(1) for both the RANDOM and the REPEATED effect, but with the additional 
random statement  RANDOM INT / SUBJECT=subject;


Boehringer Ingelheim
TSAP for BI Trial No: 1386.8
Page 34 of 34
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
29-Aug-2017
 
None
This is the final TSAP without any 
modification