Conditions: Renal Insufficiency Healthy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: yes

Brief summary:
The primary objective of the current study is to investigate the influence of moderate renal impairment on the pharmacokinetics of multiple doses in comparison to a matched control group with normal renal function.

Detailed description:

Arms:
arm 1: Participants with normal renal function. arm 2: Participants with moderate renal impairment.

Interventions: intervention 1: BI 1467335
Intervention descriptions: intervention 1: 28 day treatment period

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c17401132-03
EudraCT No.:
BI Trial No.:
2017-002180-18
1386-0002
BI Investigational
Product:
BI 1467335
Title:
Pharmacokinetics, safety and tolerability after multiple dose
administration of BI 1467335 in subjects with moderate renal 
impairment and subjects with normal renal function (a mono-centric,
open-label study in matched-group design)
Lay Title:
This study tests how BI 1467335 is taken up in the body of people 
with normal kidney function and people with reduced kidney function. 
The study also looks at how well the participants tolerate BI 1467335.
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:    
Principal Investigator:
Phone: 
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0 
Date: 15 March 2018
Page 1 of 65
Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1467335
Protocol date:
Trial number:
Revision date:
15 March 2018
21 July 2017
1386-0002
Title of trial:
Pharmacokinetics, safety and tolerability after multiple dose administration of  BI 
1467335 in subjects with moderate renal impairment and subjects with normal renal 
function (a mono-centric, open-label study in matched-group design)
Principal Investigator:
Trial site:
Clinical phase:
I
Objective:
To investigate the effect of moderate renal impairment on the pharmacokinetics of 
BI 1467335
Methodology:
Multiple-dose, open-label in matched-group design
No. of subjects: 
total entered:
20
each treatment:
10
Diagnosis:
Male and female subjects (at least 25% of each gender) with moderate renal 
impairment based on assessment of eGFR (30 – 59 mL/min/1.73m2); healthy subjects 
will be matched by gender, race, smoking status and within ±10% of age and BMI to 
renal impaired subjects
Main criteria
for inclusion:
Male and female subjects age 18 to 79 years, body mass index (BMI) 18.5 to 34 kg/m2
Glomerular filtration rate (GFR), based on CKD-EPI formula:
-
30 to 59 mL/min/1.73m2 for moderate renal impairment (group 1) with at least 
5 subjects with an eGFR between 30 and 45 ml/min/1.73m2
-
≥ 90 mL/min/1.73m2 for healthy subjects (group 2)
Test product:
BI 1467335 film-coated tablet formulation
dose:
10 mg (2 x 5 mg)
mode of admin.:
Oral with 240 mL of water
Comparator product:
Not applicable
Duration of treatment: 28 days with multiple doses of  BI 1467335 q.d.
Criteria for
pharmacokinetics:
Primary endpoints: AUC0-24 and Cmax (Day 1); AUCτ,28 and Cmax,28 (Day 28) of 
BI 1467335 
Secondary endpoints: AUCτ,14 and Cmax,14 (Day 14) of BI 1467335
Further parameters of interest as appropriate


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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:
15 March 2018
21 July 2017
1386-0002
Criteria for safety:
Adverse events (AEs), safety laboratory tests, 12-lead electrocardiogram (ECG), vital
signs (blood pressure [BP], pulse rate [PR]), and physical examination
Statistical methods:
Descriptive statistics for primary and all other parameters will be calculated. To assess 
the effect of moderate renal impairment on the pharmacokinetics of BI 1467335, point 
estimates (geometric means) of the intra-subject ratios (moderate renal impaired 
subjects compared to their matched healthy volunteer controls) of BI 1467335 and the 
two-sided 90% confidence intervals will be calculated for the primary and secondary 
PK endpoints mentioned above. The statistical model will be an ANOVA on log-
transformed parameters including the fixed effect "degree of renal impairment" and 
subject pair as a random effect.


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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 
PK urine
9
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -3
Screening (SCR)1
x
x
x
215
-2
-48:00
08:00
Ambulatory visit7
x
x
x
x
-1
-12:00
20:00
Admission to trial site5
1
-2:00
06:00
x11,2
x12
x
x2,3
x2
x2
0:00
08:00
First drug administration10, 13
▲
0:15
08:15
x
│
0:30
08:30
x
│
x3
x
0:45
08:45
x
│
1:00
09:00
x
│
x3
x
x
1:30
09:30
x
│
2:00
10:00
240 mL fluid intake and light breakfast3
x
│
x
x
3:00
11:00
x
│
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
┼
x
x
6:00
14:00
x
│
8:00
16:00
Snack (optional)3
x
┼
x3
x
x
10:00
18:00
Dinner3
x
│
12:00
20:00
x
┼
x3
x
x 
2
23:55
07:55
x
│
x2,3
x2
x2
24:00
08:00
Drug administration, dispense of study 
medication10,13
▼
25:00
09:00
x
26:00
10:00
Discharge from trial site (confirmation 
of fitness)14, optional light breakfast
x
x3
x
x
4
71:55
07:55
x
x2
x2
72:00
08:00
Drug administration10,13
73:00
09:00
x
74:00
10:00
Discharge from trial site, optional light 
breakfast
x
x
x
7
143:55
07:55
x
x2,3
x2
x2
144:00
08:00
Drug administration, dispense of study 
medication10,13
145:00
09:00
x
146:00
10:00
Discharge from trial site, optional light 
breakfast
x
x3
x
x
10
215:55
07:55
x
x2
x2
216:00
08:00
Drug administration10,13
217:00
09:00
x
218:00
10:00
Discharge from trial site, optional light 
breakfast
x
x
x
13
300:00
20:00
Admission to trial site5
x


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Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
PK urine
9
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
215
14
311:55
07:55
x2
x
x2,3
x2
x2
312:00
08:00
Drug administration10, 13
▲
312:15
08:15
x
│
312:30
08:30
x
│
x3
x
312:45
08:45
x
│
313:00
09:00
x
│
x3
x
x
313:30
09:30
x
│
314:00
10:00
240 mL fluid intake and light breakfast3
x
│
x
x
315:00
11:00
x
│
316:00
12:00
240 mL fluid intake, thereafter lunch3
x
┼
x
x
318:00
14:00
x
│
320:00
16:00
Snack (optional)3
x
┼
x
x
x
322:00
18:00
Dinner3
x
│
324:00
20:00
x
┼
x
x
x 
15
335:55
07:55
x
│
x2,3
x2
x2
336:00
08:00
Drug administration, dispense of study 
medication10,13
▼
337:00
09:00
x
338:00
10:00
Discharge from trial site (confirmation 
of fitness)14, optional light breakfast
x
x3
x
x
17
383:55
07:55
x
x2
x2
384:00
08:00
Drug administration10,13
385:00
09:00
x
386:00
10:00
Discharge from trial site, optional light 
breakfast
x
x
X
21
479:55
07:55
x
x2,3
x2
x2
480:00
08:00
Drug administration, dispense of study 
medication10,13
481:00
09:00
x
482:00
10:00
Discharge from trial site, optional light 
breakfast
x
x3
x
x
25
575:55
07:55
x
x2
576:00
08:00
Drug administration, discharge from 
trial site
26
599:55
07:55
x
x2
600:00
08:00
Drug administration, discharge from 
trial site
27
636:00
20:00
Admission to trial site5
x


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Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
PK urine
9
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
215
28
647:55
07:55
x2
x
x2,3
x2
x2
648:00
08:00
Last drug administration10, 13
▲
648:15
08:15
x
│
x
648:30
08:30
x
│
x
x
648:45
08:45
x
│
x
x
649:00
09:00
x
│
│
x
x
x
649:30
09:30
x
│
x
650:00
10:00
240 mL fluid intake and light 
breakfast3
x
│
│
x
x
x
651:00
11:00
x
│
652:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
┼
│
x
x
x
654:00
14:00
x
│
656:00
16:00
Snack (optional)3
x
┼
x
x
x
658:00
18:00
Dinner3
x
│
660:00
20:00
x
┼
x
x
x 
29
672:00
08:00
x
▼
x
x
x
673:00
09:00
Discharge from trial site 
(confirmation of fitness)14
x
x
x
x
x
30
696:00
08:00
Ambulatory visit
x
x
31
720:00
08:00
Ambulatory visit
x
x
33
768:00
08:00
Ambulatory visit
x
x
35
816:00
08:00
Ambulatory visit
x
x
3
38 to 41
9999:00
08:00
End of trial (EOT) examination4, 5, 8
x
x
x
x
x


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1.
Screening includes subject information, informed consent, physical examination, check of vital signs, ECG, safety 
laboratory (including drug screening, pregnancy test and assessment of eGFR), 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.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action. ECG recording must be 
conducted before any blood sampling is performed.
4.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of
AEs and concomitant therapies.
5.
Urine drug screening and alcohol breath test as well as pregnancy test in all women of childbearing potential 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 -5, -4 or -3.
8.
At End of Trial Examination the time of 9999:00 is only a dummy time for PK sampling.
9.
A blank urine sample (x) is to be obtained prior to the administration of trial medication on Day 1. On Day 1, 14 and 28 
fractionated urine sampling 0-4, 4-8, 8-12, and 12-24 h will be conducted.
10. Administration under fasting conditions.
11. Includes a blood sample for pharmacogenetic analysis.
12. Samples to be drawn immediately (within 30 minutes) prior to drug administration.
13. On Day 1, 2, 4, 7, 10, 14, 15, 17, 21, 25, 26 and 28 dose to be taken at study site.
14. Confirmation of fitness includes physical examination.
15. On Day 3, Days 5 to 6, Days 8 to 9, Days 11 to 13, Day 16, Days 18 to 20, Days 22 to 24 and Day 27 subjects are 
allowed to take their study medication at home if deemed appropriate by the investigator. Compliance of medication 
intake will be monitored by phone call.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................15
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 20
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................20
2.2
TRIAL OBJECTIVES.......................................................................................20
2.3
BENEFIT - RISK ASSESSMENT ...................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 23
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................23
3.1.1
Administrative structure of the trial...................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................24
3.3.1
Main diagnosis for study entry............................................................25
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................26
3.3.4
Removal of subjects from therapy or assessments.............................28
3.3.4.1
Removal of individual subjects................................................28
3.3.4.2
Discontinuation of the trial by the sponsor..............................28
3.3.5
Replacement of subjects .......................................................................29
4.
TREATMENTS........................................................................................ 30
4.1
TREATMENTS TO BE ADMINISTERED....................................................30
4.1.1
Identity of BI investigational product and comparator product......30
4.1.2
Method of assigning subjects to treatment groups ............................30
4.1.3
Selection of doses in the trial................................................................30
4.1.4
Drug assignment and administration of doses for each subject .......30
4.1.5
Blinding and procedures for unblinding ............................................31
4.1.6
Packaging, labelling, and re-supply ....................................................31
4.1.7
Storage conditions.................................................................................32
4.1.8
Drug accountability ..............................................................................32
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................33


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4.2.1
Other treatments and emergency procedures....................................33
4.2.2
Restrictions............................................................................................33
4.2.2.1
Restrictions regarding concomitant treatment .........................33
4.2.2.2
Restrictions on diet and life style.............................................34
4.3
TREATMENT COMPLIANCE.......................................................................34
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 35
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................35
5.1.1
Endpoints of efficacy.............................................................................35
5.1.2
Assessment of efficacy...........................................................................35
5.2
SAFETY..............................................................................................................35
5.2.1
Endpoints of safety................................................................................35
5.2.2
Assessment of adverse events...............................................................35
5.2.2.1
Definitions of adverse events...................................................35
5.2.2.2
Adverse event collection and reporting ...................................38
5.2.3
Assessment of safety laboratory parameters......................................40
5.2.4
Electrocardiogram................................................................................43
5.2.5
Assessment of other safety parameters...............................................43
5.2.5.1
Vital signs ................................................................................43
5.2.5.2
Medical examinations..............................................................43
5.3
OTHER...............................................................................................................44
5.3.1
Pharmacogenomic evaluation..............................................................44
5.3.1.1
Methods and timing of sample collection................................44
5.3.1.2
Analytical determinations........................................................44
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................44
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................45
5.5.1
Pharmacokinetic endpoints..................................................................45
5.5.1.1
Primary endpoints....................................................................45
5.5.1.2
Secondary endpoints................................................................45
5.5.1.3
Further parameters of interest..................................................45
5.5.2
Methods of sample collection...............................................................47
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................47
5.5.2.2
Plasma sampling for drug metabolism analysis.......................47
5.5.2.3
Urine sampling for pharmacokinetic analysis..........................48
5.5.3
Analytical determinations ....................................................................48
5.5.3.1
Analytical determination of analyte plasma concentration......48
5.5.3.2
Analytical determination of analyte urine concentration.........49
5.6
BIOMARKER(S) ...............................................................................................49
6.
INVESTIGATIONAL PLAN.................................................................. 50
6.1
VISIT SCHEDULE............................................................................................50
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................50
6.2.1
Screening period....................................................................................50


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6.2.2
Treatment period ..................................................................................50
6.2.3
End of trial period.................................................................................51
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 52
7.1
STATISTICAL DESIGN – MODEL ...............................................................52
7.1.1
Objectives...............................................................................................52
7.1.2
Endpoints...............................................................................................52
7.1.3
Model......................................................................................................52
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................53
7.3
PLANNED ANALYSES....................................................................................53
7.3.1
Primary analyses...................................................................................54
7.3.2
Secondary analyses ...............................................................................54
7.3.3
Safety analyses.......................................................................................55
7.3.4
Interim analyses ....................................................................................56
7.3.5
Pharmacokinetic analyses ....................................................................56
7.4
HANDLING OF MISSING DATA ..................................................................56
7.4.1
Safety......................................................................................................56
7.4.2
Plasma/urine drug concentration - time profiles ...............................56
7.4.3
Pharmacokinetic parameters...............................................................57
7.5
RANDOMISATION ..........................................................................................57
7.6
DETERMINATION OF SAMPLE SIZE ........................................................57
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 58
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................58
8.2
DATA QUALITY ASSURANCE .....................................................................58
8.3
RECORDS..........................................................................................................59
8.3.1
Source documents .................................................................................59
8.3.2
Direct access to source data and documents.......................................59
8.3.3
Storage period of records.....................................................................59
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................59
8.5
STATEMENT OF CONFIDENTIALITY.......................................................59
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................60
8.6
SAMPLES AND DATA ARE USED ONLY IF AN APPROPRIATE 
INFORMED CONSENT IS AVAILABLE.COMPLETION OF TRIAL ....60
9.
REFERENCES......................................................................................... 61
9.1
PUBLISHED REFERENCES...........................................................................61
9.2
UNPUBLISHED REFERENCES.....................................................................62
10. APPENDICES .......................................................................................... 63
10.1
CKD-EPI FORMULA.......................................................................................63


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11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 64


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
amount of analyte that is eliminated in urine from the time interval t1 to t2
ALT
Alanine amino transferase
AST
Aspartate amino transferase
AOC3
Amine oxidase copper-containing 3
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-24
area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours after administration
AUCτ,14
area under the concentration-time curve of the analyte in plasma over the 
dosing interval after administration of the 14th dose
AUCτ,28
area under the concentration-time curve of the analyte in plasma over the 
dosing interval after administration of the 28th dose
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CLR, t1-t2
renal clearance of the analyte in plasma from the time point t1 to t2
Cmax 
Maximum measured concentration of the analyte in plasma 
Cmax,14
maximum measured concentration of the analyte in plasma following 
administration of the 14th dose
Cmax,28
maximum measured concentration of the analyte in plasma following 
administration of the 28th dose
CML
Clinical Monitor Local
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
CTCAE
Clinical Research Organisation
Common Terminology Criteria for Adverse Events
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supplies Unit
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
eGFR
Estimated glomerular filtration rate
EOT
End of trial
FDA
Food and Drug Administration


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fet1-t2
fraction of administered drug excreted unchanged in urine from time point 
t1 to t2
λz
terminal elimination rate constant in plasma
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GLP
gMEAN
Good Laboratory Practice
Geometric mean
HCL
Hydrochloride
HR
Heart rate
HV
Healthy Volunteers
IB
Investigator’s brochure
IEC
IPV
Independent Ethics Committee
Important protocol violations
IRB
Institutional Review Board
ISF
Investigator site file
FSH
Follicle Stimulating Hormone
LC-MS/MS
Liquid chromatography tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
NCE
New chemical entity
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set
PP
Polypropylene
PR
PTM
Pulse rate
Planned time of the measurement
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)
QTcF
Intervalo QT corregido para la frecuencia cardiaca mediante la fórmula de 
Fridericia
QTcV
Heart-rate corrected QT interval using Van de Water’s formula
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


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SAE
Serious adverse event
SCR
Screening
SOP
Standard Operating Procedure
SRD
Single-rising dose
SSAO
Semi-carbazide-sensitive amine oxidase
T
Test product or treatment
TDMAP
TEAE
Trial Data Management and Analysis Plan
Treatment-emergent adverse event
tmax
time from dosing to maximum measured concentration of the analyte in 
plasma
TMF
Trial master file
TS
Treated Set
TSAP
Trial statistical analysis plan
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
VAP-1
Vascular adhesion protein-1
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Boehringer Ingelheim (BI) is developing BI 1467335 (formerly Pharmaxis PXS-4728A), an 
oral, small-molecule inhibitor of semi-carbazide-sensitive amine oxidase (SSAO), also 
known as vascular adhesion protein-1 (VAP-1) or amine oxidase copper-containing 3 
(AOC3), in the indication of non-alcoholic steatohepatitis (NASH).
NASH is characterised histologically by steatosis, ballooning of hepatocytes, and 
necroinflammation. NASH can lead to fibrosis which can progress to cirrhosis with a high 
risk of liver failure. AOC3 in liver sinusoidal endothelial cells is responsible for the firm 
adhesion and transmigration of leukocytes into the tissue and for the propagation of the 
inflammatory environment in steatohepatitis. Fibrotic regions of NASH liver sections are 
strongly positive for AOC3 immune reactivity [R15-5697]. The associated generation of 
peroxide during the course of amine oxidation is known to activate quiescent stellate cells 
supporting the differentiation into myofibroblasts, and fibrotic tissue generation. Therefore, 
targeting the inhibition of AOC3 enzymatic activity might be beneficial for patients with 
steatohepatitis and fibrosis in order to reduce the recruitment of leukocytes into the liver and 
reduce cytokine and oxygen stress dependent hepatocyte damage and activation of hepatic 
stellate cells.
With a prevalence of about 20 - 30% in the general population of Western countries, non-
alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease 
worldwide [R15-5365]. While simple hepatic steatosis can have a benign, non-progressive 
course, about 20-30% of patients with NAFLD progress to NASH. As the disease progresses, 
significant fibrosis develops in 37 - 41% of these subjects within 15 years. In the United 
States, NASH is believed to be the most common cause of liver cirrhosis [R15-6070] which 
is estimated to be the 12th leading cause of death [R15-6057]. Patients with NASH are also at 
increased risk of hepatocellular carcinoma, even in the absence of cirrhosis [R15-5365]. By 
2023, about 13 million patients are projected to have NASH with advanced stages (i.e. ≥ 
stage 3) of fibrosis (of those, 2.9 million in the US, 3.5 million in EU, 5 million in China). 
Individuals with advanced fibrosis are estimated to progress with a 4% annual event rate to 
cirrhosis. The risk of liver-related death in Western patients with NASH ranges from 10% 
over 13.7 years to 18% over 18.5 years [P13-02280].
To date, no approved therapy for liver fibrosis or effective disease modifying regimen for 
NASH is available, despite the strong interface with metabolic syndrome, obesity and Type 2 
diabetes mellitus. The current standard of care for NASH is weight loss through diet and 
exercise to improve insulin resistance and lower fat mass which is a clinically challenging 
goal to achieve and shows minimal impact on disease progression [R15-6044].
1.2
DRUG PROFILE
BI 1467335 is a small molecule irreversible AOC3 inhibitor that exhibits both anti-
inflammatory and anti-fibrotic characteristics in various animal models. AOC3 is a 
membrane bound adhesion protein that facilitates the binding of leukocytes to endothelial 


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cells and the subsequent transmigration to sites of inflammation. The target indication of the 
compound will be NASH.
For a more detailed description of the BI 1467335 profile please refer to the current
Investigator’s Brochure (IB) [c04751792].
Non-clinical findings
Nonclinical pharmacology
In several disease related rodent models, resembling different aspects of NASH, BI 1467335 
showed reduced steatosis, inflammatory cell infiltrates and fibrotic area compared to control 
animals (Stelic Animal ModelTM mouse model), a reduction of stellate cell activation 
(Methionine-Choline deficient Diet model), and an (inconsistent) reduction of biomarkers for 
inflammation and fibrosis (carbon tetrachloride induced fibrosis model in mice and rats). 
However, the overall conclusion from these studies was that BI 1467335 demonstrated 
beneficial signals for main NASH-related pathologies, including myofibroblast activation, 
necro-inflammation, and fibrogenesis, supported by literature data on the potential role of 
AOC3 in NASH.
In a cardiovascular safety pharmacology study, male dogs received BI 1467335 single oral 
doses of 0, 6, 15 and 45 mg/kg with adequate recovery period between dose levels. While no 
effects were observed with single doses of 6 mg/kg, significant increases in QTc intervals 
were seen at doses ≥15 mg/kg. All other safety pharmacology studies showed no BI 1467335 
related changes.
Toxicology
The NOAEL in rats orally exposed to BI 1467335 for 13 weeks was 12.5 mg/kg. This dose
corresponded to mean C(max) and AUC(0-24h) levels of 8430 nM and 65700 nM.h,
respectively, in rat. The NOAEL in dogs orally exposed to BI 1467335 for 13 weeks was
3 mg/kg. This dose corresponded to mean Cmax and AUC(0-24h) levels of 3000 nM and
25900 nM.h, respectively, taken from the sex with the lower plasma exposure at the NOAEL.
This provides an adequate safety window between clinical exposure and exposure at NOAEL 
levels in animals. For further details, please refer to the current ‘Investigator’s Brochure (IB)’ 
[c04751792].
These findings are consistent with results of the 4 weeks toxicology studies in rats and dogs 
[n00244592] [n00247850].
BI 1467335 does not present a genotoxic hazard. 
In the study on embryo-fetal development in rabbits with BI 1467335 treatment from day 6-
18 of gestation, abortion was noted in one doe treated at 10 mg/kg (with marked maternal
toxicity) and in three does at 45 mg/kg. Due to these findings Women of childbearing
potential must be willing and able to use a double-barrier contraception (barrier in the
meaning of method) with at least one highly effective method of birth control per ICH M3
(R2) that result in a low failure rate of less than 1% per year when used consistently and
correctly in this study (1386-0002).
The pharmacokinetic behavior of BI 1467335 in rats and dogs was characterised by rapid 
absorption, a low to moderate half-life and a predominantly over proportional increase of 


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plasma exposure with an increase in dose. The in vitro plasma protein binding was low in all 
investigated species, with ≤25% bound in human plasma. In vitro studies in cryopreserved 
human hepatocytes indicated a prevalence of oxidative O-dealkylation as primary metabolic 
pathway.
BI 1467335 inhibited MAO-B catalyzed kynuramine deamination with an IC50 of 1.04 μM 
and MAO-A catalyzed kynuramine deamination with an IC50 of 74.4 μM (n00257993). Time 
dependent inhibition of MAO-B catalyzed kynuramine deamination by BI 1467335 was 
observed indicating an irreversible inhibition mechanism. Inhibition constants for irreversible 
enzyme inhibition were determined and resulted in an inhibition constant (KI) of 2.01 μM and 
an inactivation rate constant (kinact) of 0.087 min-1 (n00259383).
Clinical experience
To date one combined SRD and MRD study (c09036683) investigating single doses of 1-20 
mg BI 1467335 (HCl, corresponding to 0.885 – 17.7 mg free base) and multiple doses of 3 to 
10 mg BI 1467335 HCl q.d. (corresponding to 2.66 to 8.85 mg free base) for 14 days have 
been completed. An additional phase I study (c08854973) just recently finished investigated
multiple doses of 10 mg, 15 mg and 20 mg q.d. for 28 days (doses refer to free base). 
Preliminary data of this ongoing study have recently become available (c16567028).
Clinical safety in healthy subjects
To date, all doses of BI 1467335 (provided as powder for oral solution) have been well 
tolerated up to 20 mg q.d.for 28 days. Frequencies of reported AEs were similar between 
active drug and placebo groups. All reported treatment-emergent adverse events (TEAEs) 
were of mild or moderate intensity and all subjects recovered. There were no SAEs. Based on 
an interim analysis (c16567028), all subjects of the 10 mg dose group and 7 of 8 subjects of 
the 15 mg dose group completed the study per protocol (one subject assigned to 15 mg q.d.
discontinued after the 5th dose because of a common cold). In addition there were no 
noteworthy changes in vital signs or laboratory parameters. A centralized ECG evaluation
(based on completed 10 mg dose group and incomplete 15 mg dose group) did not show any 
relevant individual QT prolongation, i.e. QTcF increase of greater 60 ms from baseline or an 
absolute QT or QTc value greater than 500 ms. Explorative systemic BI 14567335 exposure 
versus QTcF, QTcN, and HR analyses did not show any relevant signals (c16567028).
In the completed Phase I SRD/MRD Study PXS-4728A-101, investigating single doses up to 
20 mg (HCl salt) and multiple dosing for 14 days up to 10 mg q.d. (HCL salt), there were no 
changes in ECG parameters or changes that were assessed as clinically significant. There was 
no relevant individual QT prolongation, i.e. no QTcF increase of greater 60 ms from baseline 
or an absolute QT value greater than 500 ms. There were no apparent trends in ECG 
parameters over time. One subject treated with 6 mg q.d. (HCL salt) showed an isolated 
episode of extra systoles on Day 14, mild in severity, which resolved 3.8 hours after onset. 
No similar finding was observed in the ongoing MRD study 1386.8.
Pharmacokinetics in healthy subjects
Following both single and multiple doses of 10 and 15 mg, BI 1467335 Cmax and AUC0-24 
increased in a more than dose proportional manner on Days 1, 14 and 28 (Figure 1.2: 1).
Resulting from the accumulation of BI 1467335 following repeat oral dosing, quantifiable BI 


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1467335 concentrations could be measured up to 4 h and 8 h postdose for 10 and 15 mg 
respectively on Day 1; and up to 24 h postdose on Days 14, and Day 28.  Resulting from the 
limited time period over which quantifiable BI 1467335 concentrations could be measured on 
Day 1; the resulting AUC0-24 values on Day 1 need to be regarded with caution, as they may 
be underestimates, due to the large number of concentrations below the assays lower limit of 
quantification
The observed apparent elimination half-life (gMean) for BI 1467335 is significantly shorter 
on Day 1 (<1 h) compared to Days 14 and 28, (<4 h following 10 mg and < 9 h following 
15 mg on Day 28). Despite the short apparent elimination half-lives, BI 1467335 significantly 
accumulates following q.d. dosing. For 10 mg q.d., Cmax increased by approximately 26-fold 
on Day 14 and 40-fold on Day 28, and AUC0-24 increased by approximately 58-fold on Day 
14 and 159-fold on Day 28.  For 15 mg q.d. dosing, Cmax increased by approximately 14-fold 
on Day 14 and 16-fold on Day 28, and AUC0-24 increased by approximately 72-fold on Day 
14 and 82-fold on Day 28.  
Taking all the BI 1467335 data together, including trough concentrations, 1 h postdose 
samples along with AUC0-24 values, they suggest that steady state may be attained close to 
Day 14 following 15 mg q.d., whereas it was not attained by Day 14 following 10 mg q.d..
Following 10 mg q.d., Cmax and AUC0-24 are approximately 54% and 180% higher 
respectively on Day 28 compared to that on Day 14, whereas following 15 mg q.d., Cmax and 
AUC0-24 are approximately 13 and 15 % higher respectively on Day 28 compared to that on 
Day 14. For further details, please refer to the current ‘Investigator’s Brochure (IB)’ 
[c04751792].  
Thus, BI 1467335 appears to display both dose and time dependent kinetics, where BI 
1467335 Cmax and AUC0-24 values on Days 14 and 28 are greater than predicted from Day 1 
data. BI 1467335 accumulation may in part be due to irreversible binding to AOC3 enzymes 
which are present in many different tissues within the body (Target Mediated Drug 
Disposition). This may explain the observation that steady state appears to be attained earlier 
following 15 versus 10 mg q.d. the highest dose tested to date.


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Figure 1.2: 1
Geometric Mean BI 1467335 concentration-time profiles following 
single and multiple BI 1467335 dosing, 10 mg q.d. (left graph) and 
15 mg q.d. (right graph), to healthy subjects on Days 1, 14 and 28 (up 
to 24 h postdose, semi-log scale)
Pharmacodynamics in healthy subjects
AOC3 activities and their change from baseline were determined throughout study PXS-
4728A-101 [c09036683]. During the SRD part of the study, a strong, dose related response 
to AOC3 activity inhibition could be demonstrated with increasing numbers of subjects 
achieving a reduction of 90% with increasing doses. At the highest single dose of 20 mg, 
AOC3 inhibition of greater than 90% was reported up to 12 hours post-dose in 5 of 6 
subjects, with the mean SSAO inhibition at 24 hours being greater than 80%. The maximum 
inhibition was observed within 2 hours of single dose administration for most subjects across 
all dose groups.
During the MRD part of the study, inhibition of AOC3 activity at 24 hours post-dose on 
Day 14 remained greater than 90% for all subjects receiving a daily dose of 6 or 10 mg 
BI 1467335. At the lowest repeat dose level of 3 mg BI 1467335 per day, the AOC3 
inhibition was greater than 80% at 24 hours post-dose on Day 14 in all subjects.
For further details, please refer to the current ‘Investigator’s Brochure (IB)’ [c04751792].
10 mg BI 1467335
15 mg BI 1467335


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
An association between NAFLD/NASH and impaired renal function was consistently shown 
in numerous epidemiological studies [P16-05590] and may be due to common underlying 
inflammatory pathways in liver and kidney. BI 1467335 is going to enter phase IIb in a 
NASH population. Taking the published epidemiological data into consideration this may be 
associated in up to 20% of NASH patients with a reduced GFR < 60 ml/min i.e. at least 
moderate renal impairment. 
Based on both the preclinical and ongoing clinical phase I study 1386.8, renal clearance is 
considered to be involved in the elimination of BI 1467335, especially following multiple 
dosing. The study is conducted to support the safe inclusion of NASH patients who may have 
moderate renal impairment in Phase IIb/III studies.
The PK will be investigated during a 4 week treatment with 10 mg of BI 1467335 q.d. which 
has already been shown to be well tolerated in healthy subjects. A dose of 10 mg is the 
planned maximum therapeutic dose in a NASH population. Currently 20 mg q.d. is being 
investigated in HVs. Preliminary 15 mg q.d. in HVs on Day 28 resulted in gMean Cmax and 
AUC0-24 values approximately 2.6 and 4.7-fold higher than those observed on Day 28 
following 10 mg q.d..
2.2
TRIAL OBJECTIVES
The primary objective of the current study is to investigate the influence of moderate renal 
impairment on the pharmacokinetics of multiple doses in comparison to a matched control 
group with normal renal function.
The assessment of safety and tolerability will be an additional objective of this trial.
A description of the endpoints to be determined, and the observations along with specific
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects or subjects 
with moderate renal impairment. Their participation in the study, however, is of major 
importance to the clinical development of BI 1467335. The subjects are exposed to the risks 
of the study procedures and the risks related to the exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to veinipuncture for blood sampling.


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The total volume of blood withdrawn during the entire study period of 6 weeks will not 
exceed about 300 mL per subject. This is less than the volume of a normal blood donation 
(500 mL). No health-related risk to the subjects is expected from this blood withdrawal.
Drug-related risks and safety measures
Assessment of drug related risks is mainly based on data of an ongoing phase I study 
investigating safety, tolerability and pharmacokinetics of 10 mg, 15 mg and 20 mg q.d. of BI 
1467335 for 28 days in healthy subjects. Data have been obtained for the complete 10 mg 
dose group (9 on active and 3 on placebo) and 7 subjects (5 on active and 2 on placebo) who 
completed the 15 mg q.d. treatment. The 20 mg q.d. dose group has recently completed 
treatment as well, however data evaluation is still ongoing. Regarding the 10 mg and 15 mg 
dose group and as already observed in a preceding 2 week study [c09036683] there were no 
SAEs and no AEs considered to be dose limiting. Nearly all of the AEs were of mild 
intensity. One subject assigned to 15 mg q.d. discontinued after receiving the 5th dose 
because of a common cold. There were no changes in safety labs, vital signs or ECGs 
readings considered to be clinically relevant. While the evaluation of the 20 mg dose group is 
ongoing there were no SAEs and no AEs considered being dose limiting as well. These 
findings are consistent with results of a preceding SRD/MRD study investigating a dose 
range of up to 10 mg of BI 1467335 administered for 14 days.
Following both single and multiple doses of 10 and 15 mg of BI 1467335 Cmax and AUC0-24 
increased in a more than dose proportional manner on Days 1, 14 and 28 [c04751792].
Despite the short apparent elimination half-lives, BI 1467335 significantly accumulates 
following q.d. dosing. For 10 mg q.d., Cmax increased by approximately 26-fold on Day 14 
and 40-fold on Day 28, and AUC0-24 increased by approximately 58-fold on Day 14 and 159-
fold on Day 28. For 15 mg q.d. dosing, Cmax increased by approximately 14-fold on Day 14 
and 16-fold on Day 28, and AUC0-24 increased by approximately 72-fold on Day 14 and 82-
fold on Day 28.
The exposure ratio (AUC0-24) between the 10 mg and 15 mg dose group is in a range of about
4.7 fold. This should provide a sufficient safety margin in renally impaired subjects receiving 
a dose of 10 mg q.d., taking into consideration that a 4.7 fold higher exposure was also well 
tolerated in healthy subjects.
Taken together no specific drug-related risks are anticipated. Still, the following safety
measures will be applied in this study in order to minimize the risk for the participating
subjects:

There will be a staggered inclusion of renal impaired subjects starting with a cohort of 
3 subjects. The remaining subjects with renal impairment will enter the trial at least 
14 days apart after the principal investigator and sponsor have evaluated safety and 
PK data up to 1 week after start of treatment from this initial cohort.

Over the entire period the subjects will be under close medical observation either 
during the hospitalization and ambulatory phase (see Flow Chart).

Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 


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evaluation, and follow-up of laboratory alterations in selected liver laboratory 
parameters to ensure subjects´ safety, see also Section 5.2.2.1.
Healthy subjects and subjects with moderate renal impairment are not expected to have direct 
medical benefit from participation in this MRD trial with BI 1467335. However, it is 
considered that all subjects participating in the study will not be exposed to undue risks and 
adverse events in relation to the information expected from this trial. Considering the medical 
need of the development of an effective and well tolerated drug for the therapy of NASH, the 
benefit of this trial is considered to outweigh the potential risks and justifies the exposure of 
healthy and renally impaired subjects at the intended dose levels and treatment duration.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed open-label, in a multiple-dose, matched group design with 
moderate renal impaired and healthy male and female subjects. In this exploratory study it is 
considered reasonable to aim for at least 25% of either gender.
It is planned to include altogether 20 participants in the trial, of which up to 10 subjects with 
moderate renal impairment. All subjects will receive over 4 weeks 10 mg of BI 1467335 once 
daily, the maximum therapeutic target dose in the upcoming phase II studies in a NASH 
population. Each renally impaired subject will have a healthy subject matched for gender, 
race, smoking status, age (within ±10%) and BMI (within ±10%). They will build a pair for 
later evaluation.
Renal impaired subjects will receive a subject number starting with 
 while healthy 
subjects will receive a subject number starting with 
The study will follow a staggered inclusion starting with a subcohort of 3 renally impaired 
subjects. For this initial subcohort there will be a safety review meeting between sponsor and 
investigator to decide whether the study can proceed as planned. Matched healthy subjects 
will be only included if the corresponding renally impaired subjects have completed the 
study.
Additional safety reviews may be conducted at any time if deemed necessary by the 
investigator or sponsor. 
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
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,
-
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.


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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.
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
The study will be conducted according to a multiple-dose, open-label design with matched-
groups.
BI 1467335 displays non-linear, time dependent kinetics with a 40-fold higher Cmax and 159-
fold higher AUC0-24 on Day 28 compared to Day 1 (see Section 1.2, refers to 10 mg of BI 
14673335 q.d., the dose selected for the planned study). Since steady state PK is not 
predicted by single dose data, multiple doses are required to assess the clinically relevant data 
as BI 14673335 is being developed for chronic dosing. Based on preliminary evaluation, 
treatment duration of 4 weeks, the currently maximum treatment duration in healthy subjects, 
and a dose regimen of 10 mg q.d. should provide close to steady state conditions. This should 
also reliably exclude any transient effects. 
The resulting group sizes (see Section 7.1) are considered to be sufficient for the exploratory
evaluation of pharmacokinetics. The assignment of matched healthy volunteers is a useful
method to control for other factors which may influence the pharmacokinetics of BI 1467335
in a renal impaired population.
The open-label treatment is not expected to bias results, since the primary endpoints are
derived from measurement of plasma concentrations of the analytes provided by a
bioanalytical laboratory. It is also considered sufficiently accurate as the trial observations are
objective (PK, laboratory) and over-reporting of AEs is unlikely.
3.3
SELECTION OF TRIAL POPULATION
It is planned that up to 20 male and female subjects will enter the study (10 in each of two 
groups). Subjects with moderate renal impairment (estimated GFR based on the CKD-EPI 
formula 30 to 59 mL/min/1.73m2) will be assigned to Group 1, while healthy subjects (eGFR 
≥90 mL/min/1.73m2) matched individually by gender, race, smoking status, age (within 
±10%) and BMI (within ±10%) to a renal impaired subjects will be assigned to Group 2. 


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Group 1 should include at least 25% of either gender and 5 subjects with an estimated GFR 
between 30 and 45 mL/min/1.73m2. 
The estimated glomerular filtration rate (eGFR) will be determined at the screening 
examination and on Day -2 of Visit 2 if screening was more than 10 days ago.
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 moderate renally impaired subjects as well as healthy 
subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Despite of moderate renal impairment (Group 1) healthy male or female subjects
according to the assessment of the investigator, based on a complete medical history 
including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical 
laboratory tests
2. eGFR based on CKD-EPI formula for Group 1 between 30 and 59 mL/min/1.73m2 and 
for Group 2 ≥90 mL/min/1.73m2
3. Age of 18 to 79 years (incl.)
4. BMI of 18.5 to 34 kg/m2 (incl.)
5. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
6. Male subjects, or female subjects who meet any of the following criteria (according to the 
CTFG Recommendations related to contraception and pregnancy testing in clinical trials, 
methods with a failure rate of less than 1% per year) starting from at least 30 days before 
the first administration of trial medication and until 30 days after trial completion, e.g.:
-
Use of adequate contraception, e.g. any of the following methods plus condom:
implants, injectables, combined oral or vaginal contraceptives (inhibition of 
ovulation)
-
Hormonal intrauterine device
-
Sexually abstinent (defined as refraining from heterosexual intercourse during the 
entire period of risk)
-
A vasectomised sexual partner (provided that vasectomy was performed at least 1 year 
prior to enrolment and the vasectomised partner has received medical assessment of 
the surgical success)
-
Surgically sterilised (including bilateral tubal occlusion, hysterectomy)


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-
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)
3.3.3
Exclusion criteria
Subjects who meet any of the following criteria will not enter into this trial:
Healthy subjects
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. eGRF calculated by CKD-EPI formula < 90 mL/min/1.73m2
Subjects with moderate renal impairment
7. Subject with significant diseases other than moderate renal impairment. 
A significant disease is defined as a disease which in the opinion of the investigator:
- puts the subjects at risk because of participation in the study
- may influence the results of the study
- may influence the subject’s ability to participate in the study
- is not in a stable condition
Diabetic or hypertensive subjects can be entered in this trial if the disease is not 
significant according to these criteria.
8. Any finding of the medical examination (including BP, PR and ECG) of clinical 
relevance
9. Moderate and severe concurrent liver function impairment (e.g. due to hepatorenal 
syndrome) or biliary obstruction
10. Clinically relevant laboratory abnormalities (except for renal function tests or deviation of 
clinical laboratory values that are related to renal impairment)
11. eGRF calculated by CKD-EPI formula ≥60 mL/min/1.73m2 and < 30 mL/min/1.73m2
For all subjects
12. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
13. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
14. History of relevant orthostatic hypotension, fainting spells, or blackouts


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15. Chronic or relevant acute infections
16. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
17. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
18. Participation in another trial where an investigational drug has been administered within 
30 days prior to planned administration of trial medication or longer if required by local 
regulation, or within 5-half-lives of the investigational agent taken (whichever is longer), 
or current participation in another trial involving administration of investigational drug
19. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
20. Inability to refrain from smoking on specified trial days
21. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for
males)
22. Drug abuse or positive drug screening
23. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
24. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
25. Inability to comply with dietary regimen of trial site
26. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or 
any other relevant ECG finding at screening
27. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
28. 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 
Female subjects will not be allowed to participate if any of the following applies:
29. Positive pregnancy test, pregnancy or plans to become pregnant within 30 days after 
study completion
30. Lactation period
Male subjects will not be allowed to participate if any of the following applies:
31. Male subjects with WOCBP partner who are unwilling to use male contraception
(condom or sexual abstinence) from the first administration of trial medication until 30 
days after last administration of trial medication
For study restrictions, refer to Section 4.2.2.


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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. 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.
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 events refer to 
Section 5.2.2.2.
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% 


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of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP, 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.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number.


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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, dosage and treatment schedule are given below. 
Substance:
BI 1467335 
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology:
2-0-0
Route of administration:
Per os
Duration of use:
28 days
4.1.2
Method of assigning subjects to treatment groups
This is an open-label trial with one treatment. As all study participants will receive the same
treatment, randomisation is not applicable in this trial. The subjects will be assigned to  group
1 or group 2 according to the estimated glomerular filtration rate as outlined in Section 3.3.2. 
At screening the subjects will be allocated to a unique subject identification code. Once a 
subject is eligible, they will be allocated to a study subject number. Due to the matching 
criteria, the subjects for the renally impaired Group 1 (eGFR 30 - 59 mL/min/1.73m2) will be 
included first in the trial and matched subjects in Group 2 (eGFR ≥90 mL/min/1.73m2) will 
be subsequently included. 
4.1.3
Selection of doses in the trial
The dose of 10 mg q.d. selected for this trial reflects the maximum planned therapeutic dose 
of Phase II studies in NASH patients (see Section 1.2).
4.1.4
Drug assignment and administration of doses for each subject
This trial is an open-label study, with a matched-parallel group design. All subjects will 
receive the same treatment, 10 mg q.d. over 28 days. The inclusion of matched subjects of
Group 2 will be done on an individual basis after corresponding renal impaired subjects of 
Group 1 have completed the treatment period.
If intake of study medication occurs at study site, 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.


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In case of ambulatory intake subjects are required to contact the site by phone to confirm the 
intake of study medication.
In principal, for both hospitalized and ambulatory conditions intake of study medication 
should be performed following an overnight fast, which is to start no later than 10 h before 
the scheduled dosing. During ambulatory conditions subjects may have breakfast about 1 h 
after drug intake. If a subject misses his morning dose by 6 h, the subject should omit drug 
intake on this specific day.
To ensure a dosing interval close to 24 h, the administration or intake (during ambulatory 
periods) of trial medication should take place at a similar time every day.
Subjects will be kept under close medical surveillance from the evening of Day -1 to the 
morning of Day 2, from the evening of Day 13 to the morning of Day 15, and from the 
evening of Day 27 to the morning of Day 29. During the first 2 h after drug administration, 
subjects should not 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
This Phase I trial will be handled in an open fashion throughout (i.e. during the conduct, 
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, since all subjects receive the same dose and study 
is an open label design.
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. Each subject receives on a weekly basis one small box which 
contains two blisters. The subject number, study week, dispensing date and name of 
investigator need to be written in the corresponding empty fields on the box label. On the 
blister labels the subject number need to be included as well.
The required information according to the German Drug Law as well as Annex 13/EU GMP 
Guideline will be provided on the small boxes and they 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


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
Placeholder to include Subject  number 

Batch number

Tick box to include study week

Placeholder to include dispensing date

Placeholder to include name of investigator
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.
Re-supply may be required.
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 storage conditions. Where necessary, a temperature log 
must be maintained to make certain that the drug supplies are stored at the correct 
temperature. This applies only to the investigational site and not for storage conditions at 
subjects home. If the storage conditions at the investigational site are found to be outside the 
specified range, the local clinical monitor (as provided in the list of contacts) is to be 
immediately contacted.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol

Availability of the Form 1572
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator / 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 disposal of unused products. 


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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 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 must verify 
that all unused or partially used drug supplies have been returned by the clinical trial subject
and that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In healthy subjects, no concomitant therapy is allowed except for hormonal contraceptives or 
ovary hormone replacement. All concomitant or rescue therapies will be recorded (including 
time of intake on study days) on the appropriate pages of the CRF.
Concomitant medication is allowed for treatment of concomitant or underlying disease in 
subjects with renal impairment (group 1). A case-by-case decision may be made after 
consultation with the sponsor if drug-drug interactions are likely to occur. 
Since BI 1467335 demonstrated in vitro to be an irreversible inhibitor of monoamine oxidase 
B (MAO-B), patients should be advised to avoid medications that interact with MAO-B 
inhibitors. These include for example medications prohibited 2 weeks prior to BI 1467335 
dosing and during study participation (Meperidine, Tramadol, Methadone, Propoxyphene, 
Dextromethorphan, Cyclobenzaprine, Sympathomimetic medications including nasal, oral 
and ophthalmic decongestants and cold remedies) and medications prohibited 5 weeks prior 
to BI 1467335 dosing, during study participation, and up to 14 days after last intake of 
BI 1467335, such as MAO Inhibitors and antidepressants (SSRIs, SNRIs, triazolopyridine, 
tricyclic or tetracyclic antidepressants).
Any newly introduced medication should be only used after consultation and approval of the 
medical investigator.
In the case of AEs the volunteers will be treated as necessary and kept under constant 
supervision at the trial centre or transferred to hospital until such time that all the results of 
the evaluations have returned to a medically acceptable level.


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4.2.2.2
Restrictions on diet and life style
All subjects should be requested to refrain from meat (and creatin containing products used 
for bodybuilding) for at least 12 hours before blood sampling for serum creatinine is to be 
done. All subjects should refrain from heavy exercise for 24 hours before blood sampling for 
serum creatinine is to be done. 
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.
On Day 1, Day 14 and Day 28, fluid intake from breakfast until 22 hours post-dose should be 
within about 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.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed at days of inhouse confinement. 
Patients should be advised to avoid foods containing a very large amount of tyramine 
(especially found in fermented food) while taking BI 1467335. These include for example 
aged cheese, aged meats, soybean products (soy sauce), red wine, tap (draft) beer, St John’s 
Wort, pickled herring, sauerkraut (fermented cabbage), and tryptophan supplements. 
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.
If female subjects of child bearing potential are included, adequate contraception, double 
barrier method, is to be maintained throughout the course of the trial (see Section 3.3.2 for 
adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be monitored by either administration of all trial medication in the study 
centre under supervision of the investigating physician or a designee or during ambulatory 
period subjects confirm drug intake by phone contact with the study site. The measured 
plasma concentrations will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety and tolerability of the investigational drug will be assessed based on: 

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3). 
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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 

is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 


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
requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, or 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.2.2, subsections ‘AE collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system. 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. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
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 


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make sure these parameters are analysed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described in 
the DILI checklist should be followed.
Intensity of AEs
The intensity (severity) 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].
Causal relationship of AEs
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).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 


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5.2.2.2
Adverse event collection and reporting
AE 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  until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs. 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers (in this trial including renal impaired 
volunteers), when subjects discontinue from the trial due to screening failures 
prior to administration of any trial medication. In these cases, the subjects’ 
data must be collected at trial site but will not be entered in the CRF or trial 
database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report related SAEs and related AESIs of which the investigator 
may become aware of by any means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.


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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 for this clinical trial. Therefore, all AEs 
reported until the end of trial examination (last per protocol contact) will be considered on 
treatment (please see Section 7.3.3). 
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF 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 BI SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been  assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.


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Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the Investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male
trial participant becomes pregnant. This requires a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
As 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 an abnormality in the automatic blood cell count or in the urinalysis,
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit 
Haemoglobin 
Red blood cell count (RBC) 
Reticulocyte count
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 abnormal and 
considered by the investigator 
clinically relevant )
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
Substrates1
Plasma glucose
Creatinine (+ calculation of eGFR by CKD-EPI)
Cystatin
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


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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 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.
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 and as 
part of the end of trial examination in plasma and on Days -1, 13 and 27 in urine. Drug 
screening will be performed at screening and on Days -1, 13, 27 and end of trial examination.
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 C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (ACE Alcoscan 
III) will be performed at screening and prior to each PK profiling day, 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.


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The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
 
with the exception of the drug screening and pregnancy tests. 
These tests will be performed at the trial site using hcG meditrol, medichem and 10TC, nal 
von minden, respectively.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a
computerised electrocardiograph (MAC 5500 GE Medical Systems) at the time points given 
in the Flow Chart.
All ECGs will be recorded for a 10-sec duration after the subjects have rested for at least 5
min in a supine position. 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. 
Electrode placement will be performed according to the method of Wilson, Goldberger and 
Einthoven modified by Mason and Likar (hips and shoulders instead of ankles and wrists). 
Precise electrode placement will be marked with an indelible mark on the skin to allow 
reproducible placement throughout the study.
All locally printed ECGs will be evaluated by the investigator or a designee. ECGs may be 
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the repeated ECG will be used for analysis. Additional (unscheduled) ECGs 
may be collected by the investigator for safety reasons. 
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.
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) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap ProCare Monitor DPC220X-GE, GE Healthcare Mock) at the times indicated in 
the Flow Chart, after subjects have rested for at least 5 min in a supine position. All 
recordings should be made using the same type of blood pressure recording instrument on the 
same arm if possible.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 


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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.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Pharmacogenomics investigates genetic variations to explain and to predict an individual’s 
response to drugs. Therefore, a blood sample for pharmacogenomic testing will be taken from 
each subject. In case of unexplainable variability in pharmacokinetic parameters, DNA might 
be extracted from these samples and used for exploratory analysis of variants of genes 
involved in Absorption, Distribution, Metabolism and Excretion (ADME) of drugs. It is not 
intended to include these data in the final report. However, the data may be part of the report 
if necessary. All remaining samples will be destroyed no later than three years after the end 
of the trial.
5.3.1.1
Methods and timing of sample collection
One blood sample of at approximately 3 mL will be taken from an arm vein into an EDTA 
drawing tube at Visit 2. If not feasible at Visit 2, the sample may also be drawn at any later 
visit.
After drawing, the tube needs to be gently inverted about 10 times. The blood sample has to 
be stored at a temperature of approximately -20°C or below. Once frozen, thawing of the 
samples should be avoided.
Frozen blood samples should be shipped on dry ice to:
Boehringer Ingelheim Pharma GmbH & Co. KG
Zentrale Logistik Biberach E147
Pharmacogenomics; Attn: 
 or representative
Hubertus-Liebrecht-Straße 32
88400 Biberach/Riß, Germany
5.3.1.2
Analytical determinations
Genomic DNA may be extracted from blood samples according to standard molecular 
genetics methods and analysed by DMET analysis or other standard genotyping technologies.
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.


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs. 
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Primary endpoints
After the first dose (Day 1), for BI 1467335 :

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), for BI 1467335:

AUCτ,28 (area under the concentration-time curve of the analyte in plasma over the 
dosing interval after administration of the 28th dose)

Cmax,28 (maximum measured concentration of the analyte in plasma following 
administration of the 28th dose)
5.5.1.2
Secondary endpoints
After the 14th dose (Day 14), for BI 1467335:

AUCτ,14 (area under the concentration-time curve of the analyte in plasma over the 
dosing interval after administration of the 14th dose)

Cmax,14 (maximum measured concentration of the analyte in plasma following 
administration of the 14th dose)
5.5.1.3
Further parameters of interest
Further pharmacokinetic parameters will be calculated as feasible and may include (but are 
not limited to):
For DI 629956 and CD 6652 (major metabolites of BI 1467335):

Same parameters as mentioned in 5.5.1.1 and 5.5.1.2 for BI 1467335

RAUCx,M/P (ratio of the AUC value of the metabolite versus AUC value of the parent 
compound). To be calculated for AUCs on Day 1, 14 and 28, if feasible. 

RCmax, M/P (ratio of the Cmax value of the metabolite versus Cmax value of the parent 
compound).


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For BI 1467335, DI 629956 and CD 6652
After the first dose (Day 1) if the data allows:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

%AUCtz-∞(the percentage of AUC0-∞obtained by extrapolation)

AUCt1-t2 (area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2)

tmax (time from dosing to maximum measured concentration of the analyte in plasma)

λz (terminal elimination rate constant in plasma)

t1/2 (terminal elimination half-life of the analyte in plasma)

MRTex (mean residence time of the analyte in the body after oral administration)

(apparent clearance of the analyte in the plasma after extravascular administration), 
for BI 1467335 only

Vz/F (apparent volume of distribution during the terminal phase after extravascular 
administration), for BI 1467335 only

Aet1-t2 (amount of analyte that is eliminated in urine from the time interval t1 to t2)

fet1-t2 (fraction of administered drug excreted unchanged in urine from time point t1 to 
t2) 

CLR, t1-t2 (renal clearance of the analyte in plasma from the time point t1 to t2) 
After the 14th dose (Day 14) and the 28th dose (Day 28):

AUCt1-t2,N (area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2 following N doses)

(time from the Nth dosing to maximum concentration of the analyte in plasma
following N doses)

λz,N (terminal rate constant in plasma following N doses)

t1/2,N (terminal half-life of the analyte in plasma following N doses)

MRTex,N (mean residence time of the analyte in the body following N orally 
administered doses)

CL,N/F (apparent clearance of the analyte in the plasma following N doses of 
extravascular administration; calculated as Dose/AUC0-24,N), for BI 1467335 only

Vz,N/F (apparent volume of distribution during the terminal phase λz following N 
doses of extravascular administration; calculated as CL,N/F/λz,N), for BI 1467335 only

RA,Cmax,N (accumulation ratio based on Cmax after N doses)

RA,AUC,N (accumulation ratio based on AUCτ after N doses)

Aet1-t2,N (amount of analyte that is eliminated in urine following N doses from the time 
point t1 to time point t2)

fet1-t2,N (fraction of analyte eliminated in urine following N doses from time point t1 to 
time point t2)

CLR,t1-t2,N (renal clearance of the analyte in plasma from the time point t1 to time point 
t2 following N doses)


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On days 2, 4, 7, 10, 14, 15, 17, 21, 25, 26 and 28:

Cpre,N (predose concentration of the analyte in plasma immediately within 30 minutes 
before administration of the Nth dose)
Further pharmacokinetic parameters might be calculated as appropriate.
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.
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 0.5 mL plasma which was pretreated with 10
µL phenelzine solution (approx. 25 mM/L). 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.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as matrix and 
analyte may also be provided. 
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
No additional plasma samples for the quantification of drug metabolites will be collected. For 
quantification of metabolites backup samples collected for the pharmacokinetic analysis will 
be used (see Section 5.5.2.1).
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


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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 on days 1) 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 
3 L polyethylene (PE) containers and stored at room temperature. Subjects will be told to 
empty their bladders prior to start of urine sampling interval (this urine will be discarded) and 
at the end of each sampling interval (this urine will be collected).
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 including lid 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.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
BI 1467335, DI 629956 and CD 6652 concentrations in plasma will be determined by a
validated LC-MS/MS (liquid chromatography tandem mass spectrometry) assay.


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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, DI 629956 and CD 6652 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
5.6
BIOMARKER(S) 
Not applicable.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration (only on Day 1 this includes blank values for PK in urine and 
plasma).
On Day 14 and 28, same time windows apply except of the plasma PK sample which will be 
collected 5 minutes before drug administration. 
The acceptable deviation from the scheduled time for vital signs and ECG will be ± 30 min 
for the first 4 h after trial drug administration and ± 60 min thereafter when not already stated 
otherwise in the Flow Chart.
If scheduled in the Flow Chart at the same time as a meal, 12-lead ECG recordings followed 
by vital signs 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 prior to meal due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned individual plasma concentration sampling times and urine collection intervals 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Pharmacogenomic genotyping will be performed in all volunteers (for details see
Section 5.3).
6.2.2
Treatment period
Each subject will receive a single dose of BI 1467335 from Day 1 to Day 28.


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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 drug administration. The 
subjects will be kept hospitalized from the evening of Day -1 to the morning of Day 2, the 
evening of Day 13 to the morning Day 15 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.
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. 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.
6.2.3
End of trial period
For AE assessment, laboratory tests, PK sampling, recording of ECG and vital signs, and 
physical examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the effect of moderate renal impairment 
(test, T) on the pharmacokinetics and safety of BI 1467335 in comparison to a control group 
with normal renal function (reference, R) after single 10 mg BI 1467335 treatment for 28 
days. The trial is designed to allow intra-subject comparisons (via pairs of renal impaired 
subjects and their matching healthy controls) and will be evaluated statistically by use of an 
appropriate linear model which is further described in Section 7.1.3. 
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between subject groups (moderate renal impaired and normal renal function). The 
secondary objectives will be assessed by descriptive statistics.
The assessment of safety and tolerability will be an additional objective of this trial, and will 
be evaluated by descriptive statistics.
7.1.2
Endpoints
The effect of moderate renal impairment is to be determined on the basis of the primary 
endpoints Cmax, AUC0-24 of BI 1467335 on Day 1, and Cmax,28 and AUCτ,28 of BI 1467335 on 
Day 28 (see Section 5.5.1) as well as the secondary pharmacokinetic endpoints Cmax,14 and 
AUCτ,14 of BI 1467335 on Day 14 (see Section 5.5.2)
Safety and tolerability will be determined on the basis of the parameters specified in 
Section 5.2.1.
7.1.3
Model
The statistical model used for the analysis will be an ANOVA (analysis of variance) model 
on the logarithmic scale including the effect "degree of renal impairment" as a fixed effect as 
well as subject pair as a random effect. The model is described by the following equation:
 =  + 
 +  + ,where

logarithm of response (endpoint for relative bioavailability evaluation, (see in 
Section 7.1.3) measured on the degree of renal impairment k for subject pair i,

the overall mean,

the ith subject pair (each renal impaired subject has his own matching healthy 
control), i=1,…,10


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
the kth degree of renal impairment, k = 1 for normal and k=2 for moderate 
renal impaired
,
the random error associated with the kth degree of renal impairment for 
subject pair i.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The effect of renal impairment on the pharmacokinetics of BI 1467335 will be evaluated via 
comparing moderate renal impaired subjects to their matched subjects with normal renal 
function. This will be estimated by the ratios of the geometric means (test/reference) for the 
PK endpoints mentioned in Section 7.1.2. Additionally, their two-sided 90% confidence 
intervals (CIs) will be provided. This method corresponds to the two one-sided t-tests 
procedure, each at the 5% significance level. Since the main focus is on estimation and not 
testing, an acceptance range was not specified, that is, no hypothesis will be tested.
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 will be identified no later than in the Report Planning Meeting and 
provided in the Trial Statistical Analysis Plan (TSAP).
The following analysis sets will be defined for this trial:
Further analysis sets will be defined in the TSAP, if needed.

Randomised set (RS):
This subject set includes all subjects who were randomized, i.e., who have been 
assigned a study subject number, whether treated or not.

Treated set (TS):
This subject set includes all subjects in the RS who were documented to have 
receivedone dose of study drug. This is the full analysis set population in the sense of 
ICH-E9.

PK analysis set (PKS):
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.


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Relevant protocol violations may be
o
Incorrect dose of trial medication taken
o
Use of restricted medications.
Plasma and urine concentrations and/or parameters will be considered as non-
evaluable, if for example
o
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),
o
missing samples/concentration data at important phases of PK disposition 
curve.
The PK analysis set (PKS) includes all subjects in the TS who provide at least one PK 
parameter that was defined as primary or secondary endpoint and was not excluded 
according to the description above. Thus, a subject will be included in the PKS, even 
if he/she contributes only one PK parameter value to the statistical assessment.

PK statistical analysis set (PKS-stat):
This subject set includes all subjects from the PKS who built a subject pair of renal 
impaired subject and his matching healthy volunteer control and provide at least one 
PK parameter that was defined as primary or secondary endpoint and was not 
excluded according to the description above.
7.3.1
Primary analyses
The primary analyses of the primary endpoint will be based on the PKS-stat (cf. Section 7.3).
Point estimates of the ratios of the geometric means (T/R) for the endpoints described in 
Section 7.1.2 and their two-sided 90% confidence intervals (CIs) will be provided.
To this end, the PK endpoints will be log-transformed (natural logarithm) prior to fitting the
ANOVA model (cf. Section 7.1.3). For each endpoint, the difference between the expected
means for log(T)-log(R) will be estimated by the difference in the corresponding adjusted
means (Least Squares Means), and a two-sided 90% confidence interval based on the t-
distribution will be computed. These quantities will then be back-transformed to the original
scale to provide the point estimate and 90% CIs for each endpoint.
7.3.2
Secondary analyses
Pharmacokinetic endpoints defined in Section 5.5.1 will be compared between subject groups 
(moderate renal impaired and normal renal function) by means of descriptive evaluations, as 
described in Section 7.3.5 based on the PKS. In addition, the same pharmacokinetic 
parameters that will be evaluated with inferential statistics for BI 1467335, will be evaluated 


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in the same manner for the 2 major metabolites, DI 629956 and CD 6652 and the ratios of 
parent to CD6652 and parent to DI 629956.
Additionally the relationship of estimated renal function and the primary and secondary PK 
endpoints will be investigated using a regression model, if the data allows. In case of too 
narrow renal function range only a scatterplot will be provided.
Safety and tolerability will be evaluated by descriptive evaluations, as described in 
Section 7.3.3.
7.3.3
Safety analyses
Safety will be assessed for the further parameters 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 analysis (TS). Safety analyses will be descriptive in nature and will be 
based on BI standards. No hypothesis testing is planned.
The analyses will be done by ‘treatment at onset’.
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used for the evaluation of categorical (qualitative) data, and tabulations of descriptive 
statistics will be used to analyse continuous (quantitative) data.
Measurements (such as 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' and those between first trial medication intake until the trial 
completion date will be assigned to the treatment period. These assignments including the 
corresponding time intervals will be defined in detail in the TSAP.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and post-study intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
Relevant ECG findings will be reported as AEs.


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7.3.4
Interim analyses
No interim analysis is planned. However, as mentioned in Section 2.3 a staggered inclusion 
of renally impaired subjects will be applied, where based on the safety and PK data of the 
first 3 subjects up to one week after start of dosing, it will be decided whether the remaining 
subjects can be dosed. For this purpose exploratory evaluation of safety and PK data will be 
performed.
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 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.
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 profiles
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


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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 pre-dose values).
7.4.3
Pharmacokinetic parameters
No imputation of missing PK parameters will be performed
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 as the period between time zero and 
the first time point with a concentration above the quantification limit.
7.5
RANDOMISATION
Not applicable.
7.6
DETERMINATION OF SAMPLE SIZE
It is planned that 20 volunteers will take part in this study, 10 of them within each subject 
group (moderate renal impaired and normal renal function). The planned sample size is not 
based on a power calculation, but is judged to be adequate to get reliable results that meet the 
objectives of this study.


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


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8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
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.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation  in accordance with
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY
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.
Data protection and data security measures are implemented for the collection, storage and
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP
handbook. Treatment data may be provided to the subject’s personal physician or to other 


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appropriate medical personnel responsible for the subject’s welfare. Data generated as a 
result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB/IEC and the regulatory authorities, i.e. 
the CA.
8.5.1
Collection, storage and future use of biological samples and corresponding
data
Measures are in place to comply with the applicable rules for the collection, storage and
future use of biological samples from clinical trial participants and the corresponding data, in
particular

A Quality Management System has been implemented to ensure the adherence with
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from
clinical trial participants as well as the laboratories' activities for clinical trials
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and
the banking facility are therefore assessed to be qualified for the storage and use of
biological samples and data collected in clinical trials.
8.6
SAMPLES AND DATA ARE USED ONLY IF AN APPROPRIATE 
INFORMED CONSENT IS AVAILABLE.COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P13-02280
Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment 
of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012; 
10:837-58.
P16-05590
Marcuccilli M, Chonchol M. NAFLD and chronic kidney disease. Int J Mol 
Sci 2016;17(4):562
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 IIIAF, Feldman HI, 
et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 
2009;150(9):604-12.
R13-4387
KDIGO. Clinical Practice Guideline for the Evaluation and Management of 
Chronic Kidney Disease. Kidney inter, Suppl 2012 3:1-150.
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.
R15-5697
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.
R15-6044
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.
R15-6057
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).
R15-6070
Dharel N, Fuchs M. Nonalcoholic Fatty Liver Disease – A Major Public 
Health Challenge for the 21st Century. JSM Gastroenterology and 
Hepatology. 2014; 1018.


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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.
c08854973
. 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). 1386.8. 05 Oct 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.
c16567028
. 8 07 other preliminary analysis
10+15mg appendix2. 1386.8. 28 Mar 2017.
n00244592
BI 1467335: 4-week oral (gavage) supplementary toxicity study in Sprague 
Dawley rats. 15B108.
n00247850
 A Four-Week Oral Repeat Dose Toxicity and Toxicokinetic Study 
of PXS-4728A in Beagle Dogs  53703-13-825  04 Nov 2014.
n00257993
  In vitro inhibition of MAO-A and MAO-B 
catalyzed kynuramine deamination by BI 1467335  A437/17LU  B6034  
31 Aug 2017.
n00259383
  Irreversible in vitro inhibition of MAO-B 
catalyzed kynuramine deamination by BI 1467335  A442/17LU  B6114  
01 Dec 2017.


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BI Trial No.: 1386-0002
c17401132-03
Trial Protocol
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10.
APPENDICES
10.1
CKD-EPI FORMULA
eGFR = 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 
[if Black]
SCr (standardized serum creatinine) = mg/dL
κ = 0.7 (females) or 0.9 (males)
α = -0.329 (females) or -0.411 (males)
min = indicates the minimum of SCr/κ or 1
max = indicates the maximum of SCr/κ or 1
age = years
See reference [R12-1392] and [R13-4387].


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
11 September 2017
EudraCT number
2017-002180-18
BI Trial number
1386-0002
BI Investigational Product(s)
BI 1467335
Title of protocol
Pharmacokinetics, safety and tolerability after 
multiple dose administration of  BI 1467335 in 
subjects with moderate renal impairment and 
subjects with normal renal function (a mono-
centric, open-label study in matched-group 
design)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Section 3.3.2, Inclusion criteria
Description of change
Contraceptive measures were further detailed. In 
addition it was particularly mentioned that only 
contraceptive methods with a failure rate of less 
than 1% per year are acceptable.
Rationale for change
To be compliant with recommendations by 
regulatory bodies.


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Number of global amendment
2
Date of CTP revision
15 March 2018
EudraCT number
2017-002180-18
BI Trial number
1386-0002
BI Investigational Product(s)
BI 1467335
Title of protocol
Pharmacokinetics, safety and tolerability after 
multiple dose administration of  BI 1467335 in 
subjects with moderate renal impairment and 
subjects with normal renal function (a mono-
centric, open-label study in matched-group 
design)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.2 Drug profile
4.2.2 Restrictions
Description of change
Section 1.2: Implementation of new in vitro data 
classifying BI 1467335 as potential irreversible 
MAO-B inhibitor.
Section 4.2.2: Addition of prohibited foods and 
drugs to mitigate the risk of relevant adverse 
reactions.
Rationale for change
Time dependent inhibition of MAO-B catalyzed 
kynuramine deamination by BI 1467335 was 
observed indicating an irreversible inhibition 
mechanism.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17401132
3.0
clinical-trial-protocol-revision-02
Pharmacokinetics, safety and tolerability after multiple dose administration of  BI
1467335 in subjects with moderate renal impairment and subjects with normal renal
function (a mono-centric, open-label study in matched-group design)
Approval-Team Member Medicine
19 Mar 2018 08:24 CET
Author-Trial Clinical
Pharmacokineticist
19 Mar 2018 08:28 CET
Approval-Therapeutic Area 
19 Mar 2018 08:32 CET
Author-Trial Clinical Monitor
19 Mar 2018 08:52 CET
Author-Trial Statistician
19 Mar 2018 10:53 CET
Verification-Paper Signature
Completion
21 Mar 2018 08:44 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17401132
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c25432470-01
BI Trial No.:
1386-0002
Title:
Pharmacokinetics, safety and tolerability after multiple dose 
administration of BI 1467335 in subjects with moderate renal 
impairment and subjects with normal renal function (a mono-
centric, open-label study in matched-group design)
Including Protocol Amendment 1 and 2 [c17401132-03]
Investigational
Product:
BI 1467335
Responsible trial 
statisticians:
Phone:
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
10 OCT 2018 SIGNED 
Version:
Final
Page 1 of 27
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINTS.....................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoints......................................................................................8
5.2.2
Secondary endpoints.............................................................................................8
....................................................................................9
..................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................14
.....................................................................................................15
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................19
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINTS...................................................................................19
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoints....................................................................................20
7.5.2
Secondary endpoints...........................................................................................20
.................................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................22
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24
8.
REFERENCES....................................................................................................25
...............................................................................26
10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................11
Table 6.2: 1
Important protocol deviations ..........................................................................13
Table 6.3: 1
Analysis sets for endpoints/data description ....................................................15
Table 10: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis Dataset
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANOVA
Analysis of Variance
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
AUCτ,14
Area under the concentration-time curve of the analyte in plasma following 
administration of the 14th dose
AUCτ,28
Area under the concentration-time curve of the analyte in plasma following 
administration of the 28th dose
BI
Boehringer Ingelheim
BWU
Bioavailability/Bioequivalence, Within-Subject Design, uncontrolled
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,14
Maximum measured concentration of the analyte in plasma following
administration of the 14th dose
Cmax,28
maximum measured concentration of the analyte in plasma following
administration of the 28th dose
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation
DB
Dose Proportionality, Between-Subject Design
DBLM
Database Lock Meeting
ECG
Electrocardiogram
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
ICH
International Conference On Harmonisation
LLT
Lower Level Term


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Term
Definition / description
iPD
Important Protocol Deviation
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
O*C
Oracle Clinical
PK
Pharmacokinetic(s)
PKS
PK analysis set
PKS-stat
PK statistical analysis set
PO
Per Os (oral)
PT
Preferred Term
qd
Quaque die, once daily
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. The following change compared to the protocol will be made:
No ‘Randomised set’ will be defined in the TSAP as data of subjects randomised but 
discontinued before first administration of trial medication will not be entered in the case 
report form. A correct display of the ‘Randomised set’ would not be possible. 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 5.5.1.1 of the CTP:
After the first dose (Day 1), for BI 1467335:

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), for BI 1467335:

AUCτ,28 (area under the concentration-time curve of the analyte in plasma over the 
dosing interval after administration of the 28th dose)

Cmax,28 (maximum measured concentration of the analyte in plasma following 
administration of the 28th dose)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 5.5.1.2 of the CTP: 
After the 14th dose (Day 14), for BI 1467335:

AUCτ,14 (area under the concentration-time curve of the analyte in plasma over the
dosing interval after administration of the 14th dose)

Cmax,14 (maximum measured concentration of the analyte in plasma following 
administration of the 14th dose)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Section 3.1 of the CTP: It is planned to include altogether 20 participants in the trial, of 
which up to 10 subjects with moderate renal impairment. All subjects will receive over 4 
weeks 10 mg of BI 1467335 once daily […]. Each renally impaired subject will have a 
healthy subject matched for gender, race, smoking status, age (within ±10%) and BMI 
(within ±10%). They will build a pair for later evaluation.
For details of dosage and formulation, see Table 6.1:1 below.
Table 6.1: 1
Labels for treatments for use in the CTR 
Treatment
Short label
A
BI 1467335, 2*5mg tablet, po, qd, renal
impaired
Moderate
B
BI 1467335, 2*5mg tablet, po, qd, healthy
volunteer
Normal 
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00 h on day of informed consent until first administration 
time of study drug (BI 1467335))

On treatment
o
Normal (ranging from the time of first administration of BI until 0:00h on the 
day after the trial termination date for subjects with normal renal function)
o
Moderate (ranging from the time of first administration of BI until 0:00h on the 
day after the trial termination date for subjects with moderate renal impaired 
function)
Please note that all AEs reported between start of trial drug administration and the last per-
protocol contact will be considered on treatment (i.e. no follow-up period is considered in this 
trial).
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT) of the CTR 
displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening will not be included in this analysis. 
The following totals will be provided in addition:

a total over all on treatment phases included in this analysis ("Total on treatment") 
(Section 15.3 only)


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B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all study phases ("Total")
Tables of vital signs and laboratory values will present results by the above mentioned on 
treatment phase.
For detailed information on the handling of the treatments in the O*C views refer to 
Technical TSAP ADS (analysis data set) plan and Data Reviewers guide. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects.
Consistency check listings (for identification of deviations 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 combined report planning and database lock meeting 
(RPM/DBLM). At this meeting, all manual deviations identifyed at the sites by the CRAs and 
deviations too complex to program will be reviewed by the trial team to decide which are 
considered important. For definition of important protocol deviations (iPD), and for the 
process of identification of these, refer to the Boehringer Ingelheim (BI) SOP "Identify and 
Manage Important Protocol Deviations (iPD)" (3).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM minutes via an accompanying Excel spreadsheet (2). The following table 6.2: 1
contains the categories which are considered to be iPDs in this trial. If the data show other 
iPDs, this table will be supplemented accordingly by the time of the RPM/DBLM at the 
latest.


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Table 6.2: 1
Important protocol deviations 
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
Non-compliance
C3
Incorrect intake of trial medication
D
Concomitant medication
D1
Concomitant medication with the potential to affect the assessment of the 
trial medication
E
Missing data 
E1
Certain deviations of procedures used to measure primary or secondary data
F
Incorrect timing1
F1
Certain deviations of time schedule used to measure primary or secondary 
data
G
Other trial specific important deviations
G1
Appropriate fasting condition not met prior to study drug administration
G2
Protocol deviations affecting safety and rights
1 Time deviations will only be flagged as iPD, when leading to exclusion of the entire subject from an analysis set


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6.3
SUBJECT SETS ANALYSED

Treated set (TS):
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for safety 
analyses.
Plasma and urine concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol deviation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be:

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.

PK analysis set (PKS):
The PK analysis set (PKS) includes all subjects in the TS who provide at least one PK 
parameter that was defined as primary or secondary endpoint and was not excluded 
according to the description above. Thus, a subject will be included in the PKS, even if 
he/she contributes only one PK parameter value to the statistical assessment.

PK statistical analysis set (PKS-stat):
This subject set includes all subjects from the PKS who built a subject pair of renal
impaired subject and his matching healthy volunteer control and provide at least one PK 
parameter that was defined as primary or secondary endpoint and was not excluded 
according to the description above.
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.


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Table 6.3: 1
Analysis sets for endpoints/data description
Analysis set
Endpoint/data description
TS
PKS
PKS-stat
Safety assessments
X
Primary and secondary analyses of primary, secondary and 
further PK endpoints 
X
Further analyses of primary and secondary PK endpoints
X
Descriptive evaluations of primary, secondary and further PK 
endpoints
X
Demographic/baseline data
X
Important Protocol Deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.4.
The only 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 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before first administration of 
BI 1467335.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and end of trial examination 
are given in the CTP Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration on Day 1 are to be performed and completed within a 2 h-period prior to the
trial drug administration (only on Day 1 this includes blank values for PK in urine and
plasma).
On Day 14 and 28, same time windows apply except of the plasma PK sample which will be 
collected 5 minutes before drug administration.
The acceptable deviation from the scheduled time for vital signs […] will be ± 30 min for the 
first 4 h after trial drug administration and ± 60 min thereafter when not already stated
otherwise in the CTP Flow Chart.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Sections 7.4 and 7.5.2) will also be 
performed by 
 and will be presented in Section 15.5 of the CTR 
and in Appendix 16.1.13.3.
Descriptive data analysis of PK parameters and concentrations will be performed by the 
department Translational Medicine and Clin. Pharmacology at BI and will be presented in 
Section 15.6 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations.
The individual values of all subjects will be listed, sorted by renal function group, subject
number, and visit. 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.


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Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each renal 
function group. Percentages will be rounded to one decimal place and will be based on all 
subjects in the respective subject set, whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The ADS ADPP (PK parameters) contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’, the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’, the value can be used for further analyses based on actual times. If ACEXCO 
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (7).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by renal function group and in total. 


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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be monitored by either administration of all trial 
medication in the study centre under supervision of the investigating physician or a designee 
or during ambulatory period subjects confirm drug intake by phone contact with the study 
site. The measured plasma concentrations will provide additional confirmation of
compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
The effect of moderate renal impairment is to be determined on the basis of the primary
endpoints Cmax, AUC0-24 of BI 1467335 on Day 1, and Cmax,28 and AUCτ,28 of BI 1467335 on
Day 28 as well as the secondary pharmacokinetic endpoints Cmax,14 and AUCτ,14 of 
BI 1467335 on Day 14.
These analyses will be based on the PKS-stat.
Section 7.1.3 of the CTP:
The statistical model used for the analysis will be an ANOVA (analysis of variance) model on 
the logarithmic scale including the effect "degree of renal impairment" as a fixed effect as
well as subject pair as a random effect. The model is described by the following equation:
yik = µ + τk + si + ɛik, where
yik
logarithm of response (endpoint for relative bioavailability evaluation, 
measured on the degree of renal impairment k for subject pair i),


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µ
the overall mean,
si
the ith subject pair (each renal impaired subject has his own matching healthy
control), i=1,…,10,
τk
the kth degree of renal impairment, k = 1 for normal and k=2 for moderate
renal impaired,
ɛik
the random error associated with the kth degree of renal impairment for
subject pair i.
Point estimates of the ratios of the geometric means (T/R) for the endpoints and their two-
sided 90% confidence intervals (CIs) will be provided.
To this end, the PK endpoints will be log-transformed (natural logarithm) prior to fitting the 
ANOVA model. For each endpoint, the difference between the expected means for log(T)-
log(R) will be estimated by the difference in the corresponding adjusted means (Least 
Squares Means), and a two-sided 90% confidence interval based on the t-distribution will be 
computed. These quantities will then be back-transformed to the original scale to provide the 
point estimate and 90% CIs for each endpoint.
The analysis will be accomplished by using the XPKISTAT macro, based on PKS-stat
(design BWU).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
7.5.2
Secondary endpoints
The same analyses as for the primary endpoints will be performed for the secondary 
endpoints Cmax,14 and AUCτ,14 of BI 1467335 on Day 14 (refer to Section 7.4).


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.


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If not stated otherwise, the safety results will be sorted by renal function group.
The safety data for treated subjects who failed to complete the study (dropouts or
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (9).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
The intensity (severity) of adverse events will be performed according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (12).
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence)
For further details on summarization of AE data, please refer to [001-MCG-156] (9).
Section 5.2.2.1 of the CTP: The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters
o
an elevation of AST and/ or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/ or AST) elevations ≥10 fold ULN
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. 
Section 5.2.2.2 of the CTP: 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 for this clinical 
trial. Therefore, all AEs reported until the end of trial examination (last per protocol contact) 
will be considered on treatment […].


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According to ICH E3 (10), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at the Report Planning Meeting.
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarized by treatment, primary system organ 
class (SOC) and preferred term (PT). This table will also be shown by maximum CTCAE 
grade. Separate tables will be provided for subjects with other significant AEs according to 
ICH E3 (10), for subjects with serious AEs, for subjects with drug-related AEs, for subjects 
with drug related serious adverse events and for subjects with AESIs.
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards [001-MCG-157] (11). Differences from baseline will be evaluated descriptively.
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible 
clinically significant will be highlighted in the data listings.
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM/DBLM at the latest). 
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate).
Body weight at screening and post examination will be listed only.


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7.8.4
ECG
12-lead ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment).
7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED
3.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, BIRDS
4.
001-MCG-156_RD-01: "Handling of Missing and Incomplete AE Dates", current 
version; IDEA for CON.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
7.
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
8.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
9.
001-MCG-156: “Analysis and Presentation of Adverse Event Data from Clinical Trials”, 
current version; IDEA for CON.
10. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version
11. 001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
12. 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.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf; 2010. [R10-4848]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
10-OCT-18
None
This is the final TSAP without any 
modification