Clinical trial NCT03166735
Conditions: Non-alcoholic Fatty Liver Disease
Sponsor: Boehringer Ingelheim
Start date: 2017-06-06; Completion date: 2019-06-14
Enrollment: 114 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is the proof of mechanism and support of dose finding, together with the safety evaluation in patients with clinical evidence of NASH.

To gain further insight into clinical effects of AOC3 inhibition on NASH further exploratory analyses of biomarkers related to NASH and liver fibrosis will be performed. This will include the effect of BI 1467335 on reduction of secondary biomarker endpoints (ALT, AST, AP, γ-GT and CK18 fragments). Safety will be assessed throughout the study to provide key information regarding the use of BI 1467335 in patients with NASH.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: BI 1467335 intervention 2: Placebo
Intervention descriptions: intervention 1: once daily intervention 2: once daily

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c08980589-06
EudraCT No.:
EU Trial No:
2016-000499-83
BI Trial No.:
1386-0004
BI Investigational 
Product(s):
BI 1467335
Title:
A multi-centre, double-blind, parallel-group, randomised, placebo 
controlled phase II a study to investigate safety, tolerability, 
pharmacodynamics, and pharmacokinetics of different doses of orally 
administered BI 1467335 during a 12-week treatment period compared 
to placebo in patients with clinical evidence of NASH.
Lay Title:
Different doses of BI 1467335 compared to placebo in patients with 
clinical evidence of NASH
Clinical Phase:
IIa
Trial Clinical Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment 5)
Version and Date:
Version 6.0
Date: 12 Sep 2018
Page 1 of 101
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:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 1467335
Protocol date:
02 Dec 2016
Trial number:
1386-0004
Revision date:
12 Sep 2018
Title of trial:
A multi-centre, double-blind, parallel-group, randomised, placebo 
controlled phase II a study to investigate safety, tolerability, 
pharmacodynamics, and pharmacokinetics of different doses of orally 
administered BI 1467335 during a 12-week treatment period 
compared to placebo in patients with clinical evidence of NASH.
Coordinating
Investigator:
Phone: 
Fax: 
Trial site(s):
Multicentre Trial conducted in approximately 8 countries / 50 sites
Clinical phase:
IIa
Objective(s):
The primary objective of this study is the proof of mechanism and 
support of dose finding, together with the safety evaluation in patients 
with clinical evidence of NASH over different doses of BI 1467335 
compared to placebo.
Methodology:
Placebo-controlled, double blind, randomised, parallel design 
comparison of 5 groups over 12 weeks of treatment.
No. of patients: 
total entered:
Approximately 108
each treatment:
Placebo n1=28; 1mg BI 1467335 n2=14; 3mg BI 1467335 n3=14; 6mg 
BI 1467335 n4=14; 10mg BI 1467335 n5=28
Diagnosis :
Patients with clinical evidence for non-alcoholic-steato-hepatitis 
based on a) histological evidence or b) hepatic steatosis in 
combination with hepatic fibrosis.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 1467335
Protocol date:
02 Dec 2016
Trial number:
1386-0004
Revision date:
12 Sep 2018
Main criteria
for inclusion:
The population will include male and female patients over 18 years of 
age with clinical evidence for NASH and ALT > 1.5 upper limit 
normal. Patients with a history of significant alcohol consumption or 
other forms of chronic liver disease (including liver cirrhosis) will be 
excluded.
Test product(s):
BI 1467335
dose:
1mg QD, 3mg QD, 6mg QD, 10mg QD
mode of administration:
Tablet, p.o.
Comparator products:
Placebo
dose:
Not applicable
mode of administration:
Tablet, p.o.
Duration of treatment:
12 weeks


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 1467335
Protocol date:
02 Dec 2016
Trial number:
1386-0004
Revision date:
12 Sep 2018
Endpoints
Primary Endpoint: Plasma  AOC3 activity relative to baseline in %, at 
24 h post dose, after 12 weeks of treatment
Secondary endpoints:

number (%) of subjects with adverse reactions

Relative ALT change from baseline after 12 weeks of 
treatment

Relative AST change from baseline after 12 weeks of 
treatment

Relative AP change from baseline after 12 weeks of treatment

Relative -GT change from baseline after 12 weeks of 
treatment

Relative caspase cleaved cytokeratin 18 (M30) change from 
baseline after 12 weeks of treatment

Relative total cytokeratin 18 (M65) change from baseline 
after 12 weeks of treatment
Safety criteria:
Adverse event reporting, vital signs and standard laboratory tests
Statistical methods:
For dose-response relationship analysis a non-linear 3-parametric 
model is used to fit the primary endpoint AOC3 activity relative to
baseline, at 24 h post dose, after 12 weeks of treatment with either BI 
1467335 or placebo. The dose will be estimated where the fitted 
mean curve drops below 10%. The secondary biomarker endpoints
including ALT, AST, AP, -GT, caspase cleaved and total CK18 are 
evaluated using a mixed effect model for repeated measurements 
(MMRM). The estimated dose effects at week 12 will then be 
analysed using the MCPMod approach to test if there is a non-flat 
dose response relationship between the different doses of BI 1467335 
and placebo.


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FLOW CHART 1
Trial Period
Screening2
Treatment Period
Follow-up
Visit or phone call ()
1
2
Baseline
3

3A
4
5
6

6A
EOT/
ED6
FU
Study-Day
-28 to  -7 
1
15
27
29 
43
57
83
85
EOT
+28
Week
-4 to -1
2
4
6
8
12
16
Time window (in days)
±3
-2
±3
±3
±3
-2
+3
±3
Patient information &  
informed consent signed 
(including informed consent 
for biobanking1)
X
Register Patient in IRT
X
Randomisation (via IRT)
X
Demographics
X
Medical history / baseline 
conditions
X
In-/exclusion criteria, incl. 
quantification of alcohol 
consumption
X
X13
Clinical imaging (optional)21
X21
Concomitant medications
X
X
X
X
X
X
X
X
Height (screening only) /
weight / waist and hip
circumference17
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Physical examination
X
X
X14
X14
X14
X14
X
X
Resting ECG 12
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
Pregnancy testing10, 15
Xs
Xu
Xu
Xu
Xu
Xu
Xu
Xu
IRT call3 
X
X
X
X
Dispense trial medication
X
X
X
Collect study drug
X
X
X
Check of medication 
compliance and dispense/ 
collect study drug diary 11
X
X
X
X
X
X
Telephone contact16
X
X
Infection testing19
X
Safety laboratory tests15,
biomarkers (except screening)
X20
X9
X
X9
X
X
X9
X9
Biomarker urine collection 22
X
X
X
X
X
X
X 
Sodium citrate coagulation 
collection23
X
X
X
X
X
X
PK sampling4
X
X
X
X
X
X
PG sampling5
X
X
PD sampling8 
X
X
X
X
X
X
X18
Blood samples Biobanking
X
X
1 Prior to any study related procedure, may also be done at an extra visit up to 2 weeks before V1. 
2 Screening visit to be performed -28 to -7 days before randomisation visit (V2).


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3 At visits 2, 4 and 6, the respective IMP kit number has to be allocated to the patient via IRT. At Visit EOT/ED the IRT call 
is performed to close out the patient (Termination of medication).
 
 
 
 
or 
DNA banking, blood samples will be collected at visit 2 and EOT/ED (for details please refer to section 5.5.4).
6 Also to be completed for patients who are withdrawn or who have discontinued the trial early: in case of early termination,
the EOT/ED Visit will be completed instead of the planned treatment period visit. This early discontinuation (ED)
visit will include the same procedures as the normal EOT visit except PK, PG and PD sampling. Visit FU should be 
performed 28 days after the last study drug intake.
For patients who discontinue IMP but are willing to attend scheduled trial visits, only one PK sample and one PD 
blood sample for measurement of AOC3 activity should be taken and the actual time of the blood draw recorded. 
Please refer to section 6.2.2.
8 PD blood samples for measurement of AOC3 activity and concentration. Please see Flow Charts 2, 3, 4 and table 10.1:1 for 
timing.
For patients who discontinue IMP but are willing to attend scheduled trial visits, only one PD blood sample for 
measurement of AOC3 activity should be taken and the actual time of the blood draw recorded. Please refer to section 
6.2.2.
 
10 Pregnancy Testing: Xs =serum testing; Xu= onsite urine testing; Serum pregnancy is done at screening and as a reflex 
when urine testing is positive.
11 All patients will complete a study drug diary during the treatment phase to document drug intake and treatment 
compliance. The diary will be dispensed to the patients at Visit 2 and regularly checked by site-staff at the following 
visits. Please refer to section 6.2.2
12 12-lead ECGs will be recorded at the visits outlined in the flowchart for all patients approximately 90 min after study drug 
intake. At visits without drug administration ECGs should preferentially be performed prior blood sampling. For 
detailed timing please refer to Flow Charts 2, 3, 4. ECGs will be recorded after the patients have rested for at least 5 
minutes in a supine position. The ECG at the screening visit is regarded as baseline. Please refer to section 5.3.4
13 Confirm eligibility from Screening visit.
14 Only symptom-derived physical examination required.
15 At dosing visits: The respective procedure is to be performed and completed prior to study drug administration.
 
 
17 Waist and hip circumference only at screening and EOT/ED. For detailed instruction how to measure waist and hip
circumference see Section 5.3.1.1.
18 For the timing of this blood sample please refer to table 10.1:1. Not applicable in case of early discontinuation.
 
20If the historic ALT > 1.25 ULN value is older than 3 months prior to screening, the ALT > 1.5xULN  must be confirmed 
via two measurements at least 1 week apart within the screening period. Please refer to sections 3.3.2 and 6.2.1
21Clinical imaging (optional): only applicable for patients who don’t have the required clinical imaging results suggestive of 
NASH yet (no more than 3 years prior to screening, according to Inclusion criterion #1). Not required if histological 
 
23 One additional blood sample (sodium citrate coagulation tube) will be taken for platelet-rich plasma (PRP). Please refer to 
section 5.5.2.


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FLOW CHART 2: TIMING OF PROCEDURES*: VISIT 2 AND 4 (DAYS 
1 AND 29): 
Time 
relative to 
drug 
administra
tion (h)4
-24
-0.5
0
0.25
0.5
1
1.5
2
3
6
8
Administer  
trial 
medication1
X
PK blood 
sampling
X
X
X
X
X3
X
X
X
X
PK urine 
collection2
<-
->
AOC 3 PD 
blood 
sampling4
X4
X
X
X
X
X
X
1 To be done at the clinical site
2 PK urine collection only to be done on days 28-29. Container should be given to the patient on day 1 (or day 15). Site to 
call patient on day 27 to remind of 24 h urine collection and study drug intake. Collected urine to be returned to the site 
on the next morning.
3 ECG measurement to be performed directly prior to the PK blood sampling at 1.5h.
4 AOC3 activity measurements at all indicated time points; in addition AOC3 concentration measurement at -0.5h only
FLOW CHART 3: TIMING OF PROCEDURES*: VISIT 3, 5 AND 6 
(DAYS 15, 43 AND 57): 
Time relative 
to drug 
administration
(h) 
-0.5
0
1
1.5
Administer  
trial 
medication1
X
PK blood 
sampling
X
X
X2
AOC 3 PD 
blood sampling
X3
1 To be done at the clinical site.
2 ECG measurement to be performed directly prior to the PK blood sampling at 1.5 h.
3 AOC3 activity and concentration measurement.


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FLOW CHART 4: TIMING OF PROCEDURES*: EOT (DAY 85): 
Time 
relative to 
drug 
administra
tion (h) 5
-0.5
0
0.25
0.5
1 
1.5
2 
3 
6
8
24
Administer  
trial 
medication1
X
PK blood 
sampling
X
X
X
X
X3
X
X
X
X
X
PK urine 
collection2
<-
-
-
-
-
-
-
-
-> <-
->
AOC 3 PD 
blood 
sampling4
X4
X
X
X
X
X
X
X
1 To be done at the clinical site
2 24 h urine collection Collection of 0-8 h urine to be performed at the site; collection of 8-24 h urine to be performed by 
patients and to be returned to the site in the next morning; no overnight stay is required.
3 ECG measurement to be performed directly prior to the PK blood sampling at 1.5h.
4 AOC3 activity measurements at all indicated time points; in addition AOC3 concentration measurement at -0.5h only.
5 Site to call patient on day 83 to remind of study drug intake on day 84.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART 1.....................................................................................................................5
FLOW CHART 2: TIMING OF PROCEDURES*: VISIT 2 AND 4 (DAYS 1 AND 29):7
FLOW CHART 3: TIMING OF PROCEDURES*: VISIT 3, 5 AND 6 (DAYS 15, 43 
AND 57): ................................................................................................................7
FLOW CHART 4: TIMING OF PROCEDURES*: EOT (DAY 85): ................................8
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................12
INTRODUCTION...............................................................................................15
1.
MEDICAL BACKGROUND.............................................................................15
1.1
DRUG PROFILE................................................................................................16
1.2
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....19
2.
RATIONALE FOR PERFORMING THE TRIAL.........................................19
2.1
TRIAL OBJECTIVES........................................................................................19
2.2
BENEFIT - RISK ASSESSMENT.....................................................................20
2.3
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
3.
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.1
3.1.1
Administrative structure of the trial .................................................................23
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................23
SELECTION OF TRIAL POPULATION .......................................................23
3.3
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................24
3.3.3
Exclusion criteria ................................................................................................25
3.3.4
Removal of patients from therapy or assessments...........................................27
Removal of individual patients .............................................................................27
3.3.4.1
3.3.4.1.1
Removal of individual patients in case of increased liver enzymes .....................27
3.3.4.1.2
Further criteria for removal of individual patients................................................29
Discontinuation of the trial by the sponsor...........................................................29
3.3.4.2
TREATMENTS...................................................................................................30
4.
INVESTIGATIONAL TREATMENTS ...........................................................30
4.1
4.1.1
Identity of the Investigational Medicinal Products..........................................30
4.1.3
Method of assigning patients to treatment groups...........................................32
4.1.4
Drug assignment and administration of doses for each patient......................32


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4.1.5
Blinding and procedures for unblinding...........................................................33
Blinding.................................................................................................................33
4.1.5.1
Unblinding and breaking the code ........................................................................33
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................33
4.1.7
Storage conditions...............................................................................................34
4.1.8
Drug accountability.............................................................................................34
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................35
4.2.1
Other treatments and emergency procedures..................................................35
4.2.2
Restrictions, warnings and precautions............................................................35
TREATMENT COMPLIANCE........................................................................37
4.3
VARIABLES AND THEIR ASSESSMENT ....................................................38
5.
TRIAL ENDPOINTS..........................................................................................38
5.1
5.1.1
Primary Endpoint(s)...........................................................................................38
5.1.2
Secondary Endpoint(s) .......................................................................................38
...........................................................................................38
ASSESSMENT OF EFFICACY........................................................................38
5.2
ASSESSMENT OF SAFETY.............................................................................39
5.3
5.3.1
Physical examination ..........................................................................................39
Waist and hip circumference.................................................................................39
5.3.1.1
Body weight ..........................................................................................................39
5.3.1.2
5.3.2
Vital Signs............................................................................................................39
5.3.3
Safety laboratory parameters. ...........................................................................40
5.3.4
Electrocardiogram ..............................................................................................42
5.3.5
Assessment of adverse events.............................................................................43
Definitions of AEs ................................................................................................43
5.3.5.1
Adverse event collection and reporting ................................................................46
5.3.5.2
 
ASSESSMENT OF BIOMARKER(S) ..............................................................50
5.5
5.5.2
Biochemical and cellular biomarkers................................................................51
5.5.3
Methods of sample collection .............................................................................52
5.5.5
Appropriateness of Measurements....................................................................54


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INVESTIGATIONAL PLAN.............................................................................55
6.
VISIT SCHEDULE.............................................................................................55
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................55
6.2
6.2.1
Screening..............................................................................................................55
6.2.2
Treatment period ................................................................................................56
6.2.3
Follow Up Period and Trial Completion...........................................................58
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
7.
...............................................................................................................................59
STATISTICAL DESIGN - MODEL.................................................................59
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................59
7.2
PLANNED ANALYSES.....................................................................................60
7.3
7.3.1
Primary endpoint analyses.................................................................................60
7.3.2
Secondary endpoint analyses .............................................................................62
..................................................................................63
7.3.4
Safety analyses.....................................................................................................64
INTERIM ANALYSES ......................................................................................65
7.4
HANDLING OF MISSING DATA ...................................................................65
7.5
RANDOMISATION ...........................................................................................65
7.6
DETERMINATION OF SAMPLE SIZE .........................................................66
7.7
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
8.
PUBLICATION POLICY..................................................................................69
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................69
DATA QUALITY ASSURANCE ......................................................................70
8.2
RECORDS...........................................................................................................70
8.3
8.3.1
Source documents ...............................................................................................70
8.3.2
Direct access to source data and documents.....................................................71
8.3.3
Storage period of records ...................................................................................72
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................72
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........72
8.5
TRIAL MILESTONES.......................................................................................72
8.6
REFERENCES....................................................................................................74
9.
PUBLISHED REFERENCES............................................................................74
9.1
APPENDICES.....................................................................................................78
10.
PHARMACOKINETIC AND BIOMARKER SAMPLING TIME POINTS78
10.1
INCREASED LIVER ENZYMES PROCEDURE ..........................................82
10.3


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ABBREVIATIONS
%AUCtz-∞
λz
Aet1-t2
A1At 
AE
the percentage of AUC0-∞obtained by extrapolation
terminal rate constant in plasma
amount of analyte that is eliminated in urine from the time interval t1 to t2
Alpha-1 Antitrypsin
Adverse Event
AESI
AOC3
Adverse Event of Special Interest
amine oxidase copper-containing 3
AUC
AUC0-24
AUC0-∞
AUC0-tz
AUCt1-t2
Area under the Curve
area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours after administration
area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
b.i.d.
bis in die (twice daily dosing)
BIRDS
BMI
Cpre
C0.5
C1
Cmax
Boehringer Ingelheim Regulatory Documents for Submission
Body Mass Index
predose concentration of the analyte in plasma immediately before 
administration
concentration of the analyte in plasma 0.5 hours after administration
concentration of the analyte in plasma 1 hour after administration
maximum measured concentration of the analyte in plasma after 
administration
CCDS
Company Core Data Sheet
CI
CLR, t1-t2
CL/F
Confidence Interval
renal clearance of the analyte in plasma from the time point t1 to t2
apparent clearance of the analyte in the plasma after extravascular 
administration
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
D10
Smallest dose where 10 % AOC3 activity is reached
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ED
Early discontinuation
EDC
eGFR
Electronic Data Capture
Estimated Glomerular Filtration Rate
EOT
End of treatment
ePRO
Electronic Patient Reported Outcome


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EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
fet1-t2
Flow Chart
fraction of administered drug excreted unchanged in urine from time point 
t1 to t2
FFA
Free Fatty Acids
GCP
HOMA
Good Clinical Practice
Homeostasis Model Assessment
HPC
Human Pharmacology Center
hsCRP
High sensitive C-reactive protein
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
LoEE
List of Essential Element 
MedDRA
Medical Dictionary for Drug Regulatory Activities
MCPMod
MMRM
MRE
MRI-PDFF
MRTex
MST
NASH
Multiple Comparison Procedures – Modelling
mixed effect model for repeated measurements
Magnetic Resonance Elastography 
Magnetic Resonance Imaging of Proton Density Fat Fraction
mean residence time of the analyte in the body after extravascular 
administration
Medical Sub team
Non-alcoholic steatohepatitis
OPU
Operative Unit
PD
Pharmacodynamics
PK
Pharmacokinetics
p.o.
per os (oral)
PCC
PRP
Protocol Challenge Committee
platelet-rich plasma
q.d.
RA,Cmax
RA,AUCt1-t2
quaque die (once a day)
accumulation ratio based on Cmax after multiple doses versus Cmax after the 
first dose
accumulation ratio based on AUCt1-t2 after multiple doses versus AUCt1-t2
after the first dose
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
s.c.
SOC
Subcutaneous
System Organ Class
SPC
SSAO
tmax
Summary of Product Characteristics
semi-carbazide-sensitive amine oxidase
time from dosing to maximum measured concentration of the analyte in 
plasma


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t1/2
terminal half-life of the analyte in plasma
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TMW
Trial Medical Writer
TSAP
US
Vz/F
Trial Statistical Analysis Plan
Ultrasound
apparent volume of distribution during the terminal phase after 
extravascular administration


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INTRODUCTION
1.
MEDICAL BACKGROUND
1.1
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) and amine oxidase copper-containing 3 (AOC3) for 
the indication non-alcoholic steatohepatitis (NASH).
NASH is characterized histologically by a high level of steatosis, ballooning of hepatocytes, 
and necroinflammation. AOC3 in liver sinusoidal endothelial cells is responsible for the firm 
adhesion and transmigration of leukocytes 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. Recent findings with AOC3 
knockout mice or animals treated with anti-AOC3 antibody displayed reduced hepatic 
inflammation and fibrosis development in several disease-related models of liver injury [R15 
5365] and are supportive of this therapeutic concept. Therefore, targeting inhibiting 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 40% of patients with NASH progress [R16-5301].As the disease progresses, 
significant fibrosis develops in 37-41% of 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 in the US, according to the National Institute 
of Health [R15-6057]. Patients with NASH are also at increased risk of hepatocellular 
carcinoma (HCC), 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 EU5, 5 million in China). 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. 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 therefore only affects a minor proportion of the patients [R15-6044].
Persistent inflammation in response to liver injury is the critical factor that drives progression 
to fibrosis, cirrhosis, and hepatocellular carcinoma [R15-5365]. Inflammation at any site, 
including the liver, is the result of an accumulation of leukocytes organized into an 
inflammatory infiltrate. For this to occur, leukocytes must be recruited from the circulation 
by interactions with the endothelium and positioned within the tissue [R15-6046]. A key 
protein in promoting the recruitment of leukocytes in liver tissue is AOC3, which is 
constitutively expressed on human hepatic endothelium. BI 1467335 is an irreversible AOC3 
inhibitor with anti-inflammatory and anti-oxidative stress activities that is currently under 


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development for the treatment of chronic liver disease secondary to Non-alcoholic 
Steatohepatitis (NASH). 
DRUG PROFILE
1.2
BI 1467335 is an AOC3 inhibitor that is being developed for symptomatic treatment of 
NASH. In humans, NASH is characterized by steatohepatitis, lipotoxicity, necroinflammation, 
stellate cell differentiation, myofibroblast activation and fibrosis. The potential role of AOC3 
in NASH warrants the development of the irreversible AOC3 inhibitor BI1467335 for the 
treatment of patients with NASH.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
2.
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Increased plasma levels of ALT in NASH patients are a consequence of the lipotoxicity-
induced necroinflammation of the parenchymal liver tissue. Soluble plasma AOC3 (sAOC3) 
activity is positively correlated with a variety of diseases including atherosclerosis, liver and 
kidney fibrosis, and septic shock, thereby indicating a potential pivotal role in various forms 
of inflammation (R15-5801, R15-5774, R15-5773, R15-5766, R15-5767, P15-12198, R15-
5771, R15-5772, R15-5802). Inhibition of AOC3, therefore, has the potential to reduce 
oxidative stress and hepatic inflammation in steatohepatitis, and to improve fibrosis 
resolution in patients with NASH and ultimately resulting in reduced liver cell damage, 
thereby reducing elevated plasma ALT levels. This first study in NASH patients is performed
to support the proof of mechanism and to allow further insights into the dose-response
relationship of BI 1467335.
TRIAL OBJECTIVES
2.2
The primary objective of this study is the proof of mechanism and support of dose finding, 
together with the safety evaluation in patients with clinical evidence of NASH.
This proof of mechanism study will explore the inhibition of AOC3 activity (% of baseline) 
after 12 weeks treatment as the primary endpoint. 
 
. This will 
include the effect of BI 1467335 on reduction of secondary biomarker endpoints (ALT, AST, 
AP, -GT and CK18 fragments).
Safety will be assessed throughout the study to provide key information regarding the use of
BI 1467335 in patients with NASH. 
The proof of clinical mechanism will be achieved through primary endpoint comparison 
(inhibition of AOC3 activity (% of baseline)) of the four BI 1467335 doses (1mg QD, 3mg 
QD, 6mg QD, 10mg QD) and placebo. To this end, the dose-response relationship of the 
primary endpoint will be analysed by means of non-linear regression. 
For the secondary endpoints ALT, AST, -GT, AP, caspase cleaved cytokeratin 18 and total 
cytokeratin 18 a non-flat dose response relationship between the BI doses and placebo will be 
tested using the multiple comparison procedures and modelling (MCPmod) approach [R10-
1424]. 
 


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BENEFIT - RISK ASSESSMENT
2.3


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DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a 12-week, multi-centre, randomised, double blind, placebo-controlled, parallel-group 
comparison in patients with NASH. In total, 108 patients who meet the entry criteria are 
planned to be randomised in this trial. All eligible patients will be instructed at every visit 
(including screening) to adhere to their normal dietary and exercise regimen from screening 
until safety follow-up visit (see inclusion criterion #5 for details). Eligible patients will be 
randomised to the 12 week double-blind treatment period at Visit 2 and will be assigned to 
one of the 5 treatment groups (placebo QD, BI 1467335 1 mg QD, BI 1467335 3 mg QD, BI 
1467335 6 mg QD or BI 1467335 10 mg QD; each patient will receive one active treatment 
and/or placebos to match the alternative active treatment). The randomised treatment will be 
double blind. After the end of the double-blind treatment period, patients will be followed up 
for additional 4 weeks without study medication. Safety will be evaluated at each visit until 
end of the observational period which is 28 days after end of treatment or for an appropriately 
longer time in case of unresolved adverse events.
Figure 3.1: 1 Trial Design


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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in ISF.
Boehringer Ingelheim 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 Investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and internal SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
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.
Details of the trial supplies including responsible institutions are given in Section 4 of this
protocol.
A central laboratory service and vendors for ECG and IRT (Interactive Response
Technology) will be used in this trial. Details will be provided in the applicable manuals, 
available in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
A randomised, double blind, placebo- controlled design is chosen for this trial in order to 
evaluate safety, pharmacodynamics, and PK of BI 1467335 in patients with clinical evidence 
of NASH.
A placebo control arm was chosen to be included in order to evaluate the absolute effects of 
BI 1467335 on safety and tolerability. This is acceptable as no standard treatment is 
available. 
SELECTION OF TRIAL POPULATION
3.3
In total, 108 patients with clinical evidence of NASH will be randomised to one of the five 
treatment arms. Approximately 50 sites in multiple countries are planned. Recruitment will 
be competitive. Patients who discontinue following randomisation will not be replaced and 


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may not be re-enrolled at a later date. A record is kept of all patients failing to complete all 
trial visits and their reasons for discontinuation. Permission to randomise more than 20 
patients per site must be obtained from the TCM at Boehringer Ingelheim. This will only be 
allowed after a careful review of the enrolment status.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) at the investigational site irrespective of 
whether they have been treated with investigational drug or not.
3.3.1
Main diagnosis for trial entry
The study will include patients with clinical evidence of NASH. This is defined as increase in 
ALT and diagnosis of NASH (histological evidence of NASH or presence of hepatic steatosis 
in combination with liver fibrosis (see inclusion criterion #1 for details) within 3 years prior 
to screening).
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Clinical evidence of NASH defined as 
a. histological evidence of NASH (no more than 3 years prior to screening)
OR
b. clinical imaging results suggestive of NASH (no more than 3 years prior to 
screening OR within the screening phase, imaging procedures performed as per local 
standard)
i.
evidence of hepatic steatosis >5% measured by the MRI-PDFF or assessed as 
steatosis (raised echogenicity of the liver parenchyma) by ultrasound
AND
ii.
evidence of liver fibrosis defined as mean stiffness > 3.64 kPa as measured by 
the MRE protocol or mean stiffness > 7.2 kPa as measured by ultrasound based 
transient elastography (Fibroscan®)
2. Increased ALT defined as
a.  ALT >1.5 ULN at screening and ALT >1.25 ULN in a local lab within 1 week to 3 
months prior screening
OR
b. Historic ALT > 1.25 ULN more than 3 months prior to screening and two 
consecutive ALT > 1.5xULN must be confirmed at least 1 week apart within the 
screening period


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3. Age ≥ 18 and ≤75 years at screening
4. BMI ≥25kg/m2 and <45kg/m2 at screening
5. Stable body weight defined as less than 5% change in body weight in the 3 months 
prior to screening while being treated with the standard of care and not treated with 
anti-obesity medication at screening.
6. Treatment with Antidiabetic concomitant medication including any insulin regimen
needs to be stable for 3 months, and treatment with vitamin E needs to be stable for 6 
months prior to informed consent and expected to be stable throughout the trial. All 
other concomitant medication has to be stable for at least 4 weeks prior screening.
Concomitant medications taken to treat acute conditions (e.g. headache, sinusitis) for 
a short period (< 7 days) are permissible, if not otherwise prohibited. For restricted 
medications please refer to section 4.2.2.1.
7. For female patients: Women of childbearing potential* can be randomized after a 
negative pregnancy test and under adequate contraception with two methods, of which 
at least one is highly effective, during the trial.
* A woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
8. Signed and dated written informed consent in accordance with GCP and local 
legislation prior to admission to the trial.
3.3.3
Exclusion criteria
1. Current or history of significant alcohol consumption (defined as intake of 
>210g/week in males and >140g/week in females on average over a consecutive 
period of more than 3 months) or inability to reliably quantify alcohol consumption 
based on investigator judgement.
2. Prior participation in an interventional NASH trial 6 months before baseline or 5 
times halflife of the investigational drug, whichever is longer.
3. Prior or planned bariatric surgery during study conduct, except gastric-band surgery 
more than 2 years prior to screening (including adjustments) with a stable body 
weight within the last 12 months.
4. Use of drugs historically associated with liver injury, hepatic steatosis or 
steatohepatitis in the 4 weeks prior to screening; please refer to section 4.2.2.


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5. History of liver cirrhosis (fibrosis stage 4), or hepatic decompensation (e.g. ascites, 
hepatic encephalopathy, variceal bleeding, etc.) or history of other forms of chronic 
liver disease (for example Hepatitis B, Hepatitis C, autoimmune liver disease, primary 
biliary sclerosis, primary sclerosing cholangitis, Wilsons disease, hemochromatosis, 
A1At deficiency, history of liver transplantation).
6. Active known chronic or relevant acute infections, such as HIV (Human 
Immunodeficiency Virus), \viral hepatitis, or tuberculosis. QuantiFERON® TB test 
and HBs Ag test will be performed during screening. Patients with a positive test 
result may participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that the patient has no evidence of active 
infection.
7. Solid liver lesions other than haemangiomas.
a.
Suspicion or diagnosis or history of hepatocellular carcinoma (HCC)
8. eGFR <60ml/min/1.73m2 at screening (CKD-EPI formula).
9. ALT >5.0 ULN at screening.
10. Platelet count < 150.000/µL
11. Bilirubin level > ULN (except for known Gilbert´s disease with a conjugated bilirubin 
of < 0.3 mg/dL))
12. Uncontrolled diabetes defined as an HbA1c ≥9.5% in the 3 months prior to or at 
screening.
13. Diagnosis of a serious or unstable disease including hepatic (other than NASH), renal, 
gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), 
endocrinologic, neurologic , psychiatric, immunologic, or hematologic disease and 
other conditions that, in the clinical judgment of the investigator, are likely to 
interfere with the analyses of safety and efficacy in this study. Patients with an 
expected life expectancy of less than 2 years are also excluded.
14. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to randomisation or planned during study conduct, e.g. hip replacement.
15. Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal cell carcinoma of the skin 
or in situ carcinoma of uterine cervix.
16. Patients who must or wish to continue the intake of restricted medications (see section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
17. Previous randomisation in this trial.


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18. Currently enrolled in another investigational device or drug study, or less than 30 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s).
19. Chronic drug abuse or any condition that, in the investigator’s opinion, makes them 
an unreliable study subject or unlikely to complete the trial.
20. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
21. Patients with Wolff-Parkinson-White Syndrome, baseline QTc > 450 ms, family 
history of long QT, or on medication prolonging QT time at screening or planned 
initiation during the trial.
22. Any other clinical condition that, in the opinion of the investigator, would jeopardize 
patient safety while participating in this clinical trial.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 
careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal.
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for trial treatment or trial participation, without 
the need to justify the decision.

The patient needs to take concomitant drugs that interfere with the 
investigational product or other trial medication 4.2.2,

The patient can no longer be treated with trial medication for other medical 
reasons (such as surgery, adverse events, other diseases, or pregnancy)

The patient has repeatedly shown to be non-compliant with important trial 
procedures and, in the opinion of both, the investigator and sponsor 
representative, is not willing or able to stick to the trial requirements in the 
future.
3.3.4.1.1
Removal of individual patients in case of increased liver enzymes
In addition, study-specific procedures have been defined in case of increased liver enzymes
(AST, ALT and total bilirubin) after randomisation as outlined below [R16-5309].
Please also refer to section 10.3.


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Treatment should be temporarily interrupted and the increased laboratory values need to be 
confirmed by a second measurement (i.e. the patient is informed to stop IMP and to come for 
an additional unscheduled visit within 48 hours of initial laboratory hepatic injury alert / 
notification or as soon as possible if timelines cannot be met). Other causes for liver injury 
should be excluded. 
1) If the values are confirmed or even further increased, IMP will be 
permanently stopped and the patient is withdrawn from treatment and 
will be monitored closely on a weekly basis until resolution or stabilization 
in the following cases:
AST is normal at baseline and:

If AST is more than 8x ULN

If AST is 5-8x ULN for more than 2 weeks
ALT and/or AST are abnormal at baseline and:

If ALT or AST is more than 8x baseline OR > 500 U/L absolute value, 
whichever is lower.
After resolution or stabilization the patient is encouraged to continue in the 
study and complete all visits. If the patient is not willing to continue in the 
study, the patient should complete the withdrawal- and follow-up protocol 
study procedures.
2) If the values are confirmed, IMP will stay interrupted and the patient 
will be monitored closely until resolution or stabilization in the following 
cases:
AST is normal at baseline and:

If AST is 3x – 8x ULN AND total bilirubin is > 2 mg/dL

If AST is 3x – 8x ULN OR total bilirubin is > 2 mg/dL 
AND the patient is presenting clinical symptoms of hepatic injury as e.g. 
encephalopathy, nausea, vomiting, pruritus, severe fatigue, etc.
ALT and AST are abnormal at baseline and:

If ALT or AST is 5x – 8x baseline OR > 300 U/L absolute value (whichever is 
lower)
AND total bilirubin is > 2 mg/dL 

If ALT or AST is 5x – 8x baseline OR > 300 U/L absolute value (whichever is 
lower) OR total bilirubin is > 2 mg/dL 
AND the patient is presenting clinical symptoms of hepatic injury as e.g. 
encephalopathy, nausea, vomiting, pruritus, severe fatigue, etc.
If the values return to the baseline value (Visit 2), a re-start of the IMP 
can be considered after discussion with the sponsor. After re-start of 
IMP the patient should be monitored on a weekly basis until EOT. In 
the case the initially elevated liver enzyme, which lead to interruption,


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increases again more than 2x baseline, the IMP has to be discontinued 
permanently.
Given the patient’s agreement, the patient will continue the study, or 
otherwise should be encouraged to undergo the procedures for early 
treatment discontinuation and follow up as outlined in the Flow Chart (FC)
and section 6.2.3.
3.3.4.1.2
Further criteria for removal of individual patients
If a patient becomes pregnant during the trial, the study medication needs to be discontinued, 
and the patient will complete EOT- and Follow-up Visit procedures. The patient will be 
followed up until birth or otherwise termination of the pregnancy.
If a patient develops QTc > 500 ms during the trial, the study medication needs to be 
discontinued, and the patient will complete EOT- and Follow-up Visit procedures.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the CRF. 
These data will be included in the trial database and reported.
Patients who discontinue the trial after receiving the first dose of study medication at visit 2
will not be replaced.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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TREATMENTS
4.
INVESTIGATIONAL TREATMENTS 
4.1
Multiple doses of BI 1467335 and/or Placebo to match BI 1467335 will be administered. 
All products will be supplied by Boehringer Ingelheim.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
BI 1467335, 1 mg:
Substance:
BI 1467335
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Strasse 65
D-88397 Biberach a.d. Riss
Unit strength:
1 mg
Posology
QD
Route of administration:
Per os
Table 4.1.1: 2
BI 1467335, 5 mg:
Substance:
BI 1467335
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Strasse 65
D-88397 Biberach a.d. Riss
Unit strength:
5 mg
Posology
QD
Route of administration:
Per os


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Table 4.1.1: 3
Placebo matching BI 1467335, 1 mg:
Substance:
BI 1467335
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Strasse 65
D-88397 Biberach a.d. Riss
Unit strength:
n.a.
Posology
n.a.
Route of administration:
Per os
Table 4.1.1: 4
Placebo matching BI 1467335, 5 mg:
Substance:
BI 1467335
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Strasse 65
D-88397 Biberach a.d. Riss
Unit strength:
n.a.
Posology
n.a.
Route of administration:
Per os


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4.1.3
Method of assigning patients to treatment groups
All treatments will be double-blind as to be indistinguishable for the patient as well as for the 
investigator. Patients are randomised to treatment groups at Visit 2. Note that the medication 
number is different from the patient number (the latter is assigned directly after informed 
consent was obtained). Site personnel will enter the medication number on the case report 
form/in the CRF.
During visit 2 eligible patients will be randomised to receive a 2:1:1:1:2 ratio according to a 
randomisation plan (see figure 3.1: 1 for details). The assignment will occur in a blinded 
fashion via Interactive Response Technology (IRT).
4.1.4
Drug assignment and administration of doses for each patient
IRT will allocate medication kit numbers at Visit 2, 4, and 6. The amount of trial medication 
dispensed and returned will be recorded on drug accountability forms.
For blinding reasons all treatments will consist of five tablets verum or placebo to be taken 
within 10-15 minutes in the morning depending on the treatment arm. This will not be 
changed during the entire study treatment period (V2-EOT). 
For days without site visits, patients should be instructed to take the tablets orally with water 
in the morning before breakfast at approximately the same time every day without food
(defined as no food intake until 60 mins after dosing). If a dose is missed by more than 8hrs, 
that dose should be skipped and the next dose should be taken as scheduled. No double doses 
should be taken and dose reductions are not permitted. Patients should be instructed to bring 
all unused drug and empty study blister to the study site.
Patients should be instructed NOT to take their study medication on the morning of scheduled 
trial visits. The first dose of study medication will be taken at the visit 2 under supervision of 
the investigator or site staff. At all site visits the morning dose of the investigational drug will 
be taken during the visit under supervision of the investigator or relevant site staff. The actual 
visit date and time of study drug administration at the trial visit will be recorded in the eCRF 
at each visit. Patients should be fasted at the beginning of the study visit. Patients who 
erroneously take the morning dose of study medication before coming to the clinic at a visit 
with scheduled PK samples should have the visit rescheduled as soon as possible, ideally on 
the following day. Patients will record the administration dates and times of all doses with the 
help of a diary as outlined in the Flow Chart and in Section 6.2.2.


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4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Patients, investigators and everyone involved in trial conduct or analysis or with any other 
interest in this double-blinded trial will remain blinded with regard to the randomized 
treatment assignments until after database lock. Please refer to Section 4.1.5.2 for rules of 
breaking the code for patients in emergency situations.
The randomization code will be kept secret by Clinical Trial Support up to database lock. The 
randomization codes will be provided to bioanalytics prior to last patient out to allow for the 
exclusion from the analyses of PK samples taken from placebo patients and to a member of 
the unblinded team in preparation of a possible interim PK/PD analysis. Bioanalytics will not 
disclose the randomization code or the results of their measurements until the trial is 
officially unblinded.
A possible interim PK/PD analysis will be performed by an unblinded team independent from 
the trial and project teams to maintain the blinded conduct of the study. Results of the interim 
analysis will only be presented as aggregated data and not on subject level to maintain 
blinding. The logistical aspects of conducting the interim PK / PD analysis, and the plan to 
access of interim results will be described in the Interim Analysis Logistics Plan and Results 
Access Plan.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’ s
Pharmacovigilance group to access the randomisation  code for individual patients during 
trial conduct. The access to the code will only be given to authorised Pharmacovigilance 
representatives and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.


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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 on the medication label. IMP needs to 
be shipped and stored under refrigerated conditions (2-8°C / 36-46°F). A temperature log 
must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The Investigator, Pharmacist or 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 investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the principal Investigator

Availability of Form 1572
The Investigator, Pharmacist or 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 patient, and 
the return to the sponsor or warehouse / drug distribution centre or alternative disposal of 
unused products. If applicable, the sponsor or warehouse / drug distribution centre will 
maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor< and/or >appointed CRO, the Investigator / Pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.


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OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.2.2
Restrictions, warnings and precautions


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TREATMENT COMPLIANCE
4.3
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as the number of tablets
taken, divided by the number of tablets which should have been taken according to the 
scheduled period, multiplied by 100. Compliance will be verified by the on-site monitor 
authorised by the sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
Number of tablets which should have been taken
If the number of doses taken is not between 80-120%, site staff will explain the patient the 
importance of treatment compliance.


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VARIABLES AND THEIR ASSESSMENT
5.
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint(s)
The primary endpoint is the plasma amine oxidase copper-containing 3 (AOC3) activity 
relative to baseline in %, 24 h post dose, after 12 weeks of treatment. The baseline is defined 
as the last AOC3 activity measurement prior to administration of any randomised study 
medication.
5.1.2
Secondary Endpoint(s)
Safety and tolerability will be assessed based on the number (%) of subjects with adverse 
reactions.
The secondary biomarker endpoints will be assessed based on the
relative ALT change from baseline after 12 weeks of treatment
relative AST change from baseline after 12 weeks of treatment
relative AP change from baseline after 12 weeks of treatment
relative -GT change from baseline after 12 weeks of treatment
relative caspase cleaved cytokeratin 18 (M30) change from baseline after 12 weeks of 
treatment
relative total cytokeratin 18 (M65) change from baseline after 12 weeks of treatment
ASSESSMENT OF EFFICACY
5.2
Not Applicable


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ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A full physical examination will be performed at the visits indicated in the Flow Chart. This 
should be performed according to medical standards and usually includes (but is not 
necessarily limited to) a review of the following organ systems: General appearance 
(including Skin), Head-Eyes-Ears-Nose-Throat (HEENT), Chest (including Pulmonary and 
Heart), Abdomen, Extremities, Urogenital  and neurological assessment (basic mental status, 
cranial nerves, motor system, sensation, cerebellum/coordination). Clinically relevant 
abnormal findings noticed after randomisation will be reported as (S)AEs. At all other visits 
according to the Flow Chart a symptom-derived physical examination should be performed.
This includes vital sign assessment as well as an evaluation of the organ systems associated 
with AE(s) symptoms or laboratory abnormalities.
Clinically significant abnormal findings will be reported as baseline conditions or AE’s.
Waist and hip circumference
5.3.1.1
Waist and hip circumference will be measured at screening and EOT/ED visit. 
Waist circumference measurements should be made around a patient’s bare midriff, after the 
patient exhales while standing without shoes and with both feet touching and arms hanging 
freely. The measuring tape should be placed perpendicular to the long axis of the body and 
horizontal to the floor and applied with sufficient tension to conform to the measurement 
surface. Waist circumference should be determined by measuring the midpoint between the 
lowest rib and the iliac crest.
Hip circumference measurement should be taken around the widest portion of the buttocks.
Body weight
5.3.1.2
The scale used to capture body weight for each patient should remain consistent during the 
trial. In order to get comparable body weight values, it should be performed in the following 
way:
- Fasting (except for the screening visit);
- After the urine sampling (body weight after bladder voiding);
- Shoes and coat/jackets should be taken off; and
- Pockets should be emptied of heavy objects (i.e. keys, coins etc.)
5.3.2
Vital Signs
Systolic and diastolic blood pressure (BP), respiratory frequency (RF) and pulse rate (PR) 
will be measured after the patient has rested for at least 5 min in the sitting position. 


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Measurement of vital signs should precede blood sampling to avoid the impact of blood 
sampling on the vital measurements. The measured vital signs will be documented in the 
source documents and recorded in the eCRF.
5.3.3
Safety laboratory parameters.
Parameters that will be determined during the trial conduct are listed in Table 5.3.3: 1 and 
will be collected by the trial site at the time points indicated in the Flow Chart. All analyses 
will be performed by a central laboratory. Patients have to be fasted (except for the screening 
visit) for at least 8 h before the blood sampling for the safety laboratory. The respective 
reference ranges and details about sample handling shipment and results reporting will be 
provided in the ISF (Lab Manual).
Clinically significant abnormal findings will be reported as baseline conditions or AE’s.


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Table 5.3.3: 1
Safety laboratory parameters – whole blood, serum or plasma
Hematology
Haematocrit
Haemoglobin
MCV, MCH, RDW, MCHC
Red Blood Cells (RBC) / Erythrocytes
WBC / Leukocytes
Platelet Count / Thrombocytes
Differential Automatic (relative and absolute 
count): 
Neutrophils, Eosinophils, Basophils, 
Monocytes,  Lymphocytes
Coagulation
Activated Partial Thromboplastin Time 
(aPTT)
Prothrombin Time (INR)
Fibrinogen
Clinical chemistry
Albumin 
Alkaline phosphatase
-GT (gamma-glutamyl transferase)
ALT (alanine aminotransaminase, SGPT)
AST (aspartate aminotransaminase, 
SGOT) 
Bicarbonate
Bilirubin Total
Bilirubin Direct
Bilirubin Indirect 
Calcium 
Chloride 
Creatinine 
hsC-reactive protein
Creatine kinase (CK)
CK-MB, troponin I (reflex tests if CK is 
elevated)
eGFR*
Fasting Plasma Glucose
Ferritin
Plasma Insulin
Serum Free fatty acids
Lactate dehydrogenase (LDH)
Lipase
Magnesium 
Phosphate 
Potassium
Protein total 
Sodium
Urea (BUN)
LDL/HDL and total cholesterol
Triglycerides
TSH
* Estimated Glomerular filtration rate as assessed by the CKD-EPI formula (2009).


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Urine chemistry
Urine creatinine (for urine biomarker assessment, please see section 5.5.2)
Pregnancy Test

Urine Pregnancy test1

Serum Pregnancy test2
1 Urine pregnancy test performed on-site at all dosing visits (pre-dose) as well as EOT and 
FU (only for female patients of childbearing potential).
2 Serum pregnancy test at screening as well as confirmation of positive urine pregnancy test 
(only for female patients of child bearing potential at screening as well as reflex for positive 
urine pregnancy test).
5.3.4
Electrocardiogram
Printed paper traces from 12-lead ECGs in triplicate will be recorded at the visits outlined in 
the flowchart for all patients approximately 90 min after study drug intake. At visits without 
drug administration ECGs should preferentially be performed prior blood sampling. Please 
refer to the Flow Charts 1, 2, 3 and 4 for exact timing. ECGs will be recorded after the 
patients have rested for at least 5 minutes in a supine position. Six limb leads, as specified by 
Einthoven (I, II and III) and Goldberger (aVR, aVL, aVF), and six pre-cordial leads (V1–
V6), according to Wilson, will be used. ECGs may be repeated for quality reasons and the 
repeated recording used for analysis.
In the event of any clinical cardiac symptoms (e.g. suspicion of heart rhythm disorders or 
cardiac ischaemia), an additional ECG will be recorded at the investigator´s discretion.
At screening visit all triplet ECGs will be printed and evaluated (signed, dated and 
commented upon) by the treating physician/ investigator and will be filed in the patient’s
source documents. This will be used as baseline before the first drug administration.
At all other visits, only the first of the three replicate ECGs at a single assessment time will 
be evaluated by the treating physician/ investigator and stored locally. The remaining second 
and third replicate ECGs will be printed and kept together with other medical records of the 
patient for additional analyses if required at a later time point.
All ECGs recorded during trial conduct including the baseline ECG will also be transmitted 
to a vendor for central evaluation and stored at an external central ECG database. Only the 
first of the three replicate ECGs at a single assessment time will be centrally evaluated and 
transferred to the sponsor. The results of the centralized evaluation will be sent from the ECG 
core lab to the sponsor according to a pre-specified data transmission agreement. The 
remaining second and third replicate ECGs will only be stored at the ECG vendor for 
additional analyses if required at a later time point. The central reader’s evaluation of the 
tracing is considered the official reading for the trial.


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In case of discrepancies between investigator and central reading, the central evaluation will 
be valid.
Clinically significant abnormal findings will be reported either as baseline condition (if
identified at the screening visit) or otherwise as adverse events and will be followed up
and/or treated locally until normal or stable condition.
Information about the details of ECG collection will be provided in the ISF.
5.3.5
Assessment of adverse events
Definitions of AEs 
5.3.5.1
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:
-
results in death,
-
is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalisation or 
-
prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 


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development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in 5.3.5.2, subsections “AE Collection” and AE reporting to sponsor and 
timelines”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the EDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESI need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory and clinical 
parameters as defined by the removal and stopping criteria in section 3.3.4.1.1 and section
10.3.
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 (e.g. encephalopathy, nausea, vomiting, 
pruritus, severe fatigue, icterus, etc.) without lab results (ALT, AST, total bilirubin) available, 
the Investigator should make sure these parameters are analysed, if necessary in an 
unscheduled blood test. Should the results meet the criteria of hepatic injury alert, the
procedures described in the DILI checklist should be followed.


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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
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
1. The event is consistent with the known pharmacology of the drug 
2. The event is known to be caused by or attributed to the drug class.
3. A plausible time to onset of the event relative to the time of drug exposure.
4. Evidence that the event is reproducible when the drug is re-introduced
5. No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).
6. The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).
7. 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:
1. 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)
2. 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.
3. 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).
4. Disappearance of the event even though the study drug treatment continues or remains 
unchanged.


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Adverse event collection and reporting
5.3.5.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:

From signing the informed consent onwards through the Residual Effect Period 
(REP), until individual patient’s end of trial:
o
all AEs (serious and non-serious) and all AESIs.
However, if an individual patient discontinues trial medication prematurely but stays 
in the trial (i.e. if further visits incl. telephone visits, or vital status assessments are 
planned) from then on and until the individual patient’s end of the trial the 
Investigator must report related SAEs and related AESIs.

After the individual patient’s end of trial: 
the Investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the Investigator may become 
aware of.
As the REP is to be explored in this trial, it is considered as the entire FU period from last 
dose administration of trial medication until individual patient’s end of trial. 
All AEs which occurred through the treatment phase until entire Follow-up period will be 
considered as on treatment, please see section 7.3.4. 
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.


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Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. 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 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 trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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ASSESSMENT OF BIOMARKER(S) 
5.5


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5.5.2
Biochemical and cellular biomarkers
Concentration and activity of AOC3 in plasma will be measured at the time points indicated 
in the Flow Charts 1, 2, 3, 4 and in Section 10.1. The values determined prior to the first 
dosing of BI 1467335 will be defined as baseline.
AOC3 activity per time point will be presented relative to baseline. AOC3 concentration will 
be presented as absolute values and relative to baseline.
The following parameters will be determined for plasma AOC3 activity relative to baseline, if 
feasible; after multiple dosing the parameters will be denoted with the index ‘N’, where N is 
the number of doses administered.
Emax (maximum plasma AOC3 activity relative to baseline within the dosing interval)
Emin (minimum plasma AOC3 activity relative to baseline within the dosing interval)
tmax (time from dosing to reach Emax)
tmin (time from dosing to reach Emin)
Epre,N (plasma AOC3 activity relative to baseline prior to the Nth dose of BI 1467335)
.
For the secondary endpoints ALT, AST, ALP, -GT, caspase cleaved cytokeratin 18 (M30) 
and total cytokeratin 18 (M65) samples will be collected as described in the Flow Chart 1.
Relative changes from baseline in ALT, AST, AP,-GT and Cytokeratine18 fragments after 
2, 4, 8, 12 weeks of treatment and 4 weeks after last dose will be determined.
 
 
 
 
 
For the endpoints and exploratory biomarkers clear endpoint definitions and further details on 
evaluation will be provided in the TSAP.


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5.5.3
Methods of sample collection
For the measurement of the activity and the concentrations of AOC3 4.0 ml of blood will be 
taken from an antecubital or forearm vein into a K2-EDTA anticoagulant blood drawing tube 
at the time points indicated in the Flow Chart. 2 x 4.0 ml will be taken at Visit 2 to have a 
back-up sample for the pre-dose value.  
Blood will be withdrawn by means of either an indwelling venous catheter or by 
venepuncture with a metal needle.
For the secondary endpoints and the exploratory biomarkers evaluation approximately 23 ml 
of blood (10 ml for K2-EDTA blood and 10 ml for serum and 3ml for sodium citrate 
coagulation tube) will be taken at the time points indicated in the Flow Chart 1. Blood will be 
withdrawn by means of either an indwelling venous catheter or by venepuncture with a metal 
needle.
Further details on collection, handling, storage and processing of the blood sample will be
provided in a separate laboratory instruction manual.
All left over samples will be stored and used for not yet specified explorative investigations. 
These samples will be stored for up to three years after the end of the clinical trial and may be 
used for not yet specified biomarker analyses to enable further characterization of metabolic 
diseases and their progress, as well as method development and evaluation. Results of these 
assessments will not be part of the Clinical Trial Report.


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5.5.5
Appropriateness of Measurements
All measurements performed during this trial are standard measurements and will be
performed in order to monitor subjects’safety and to determine pharmacokinetic and
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that
might occur as a result of administration of trial medication. The safety assessments are
standard, are accepted for evaluation of safety and tolerability of an orally administered drug,
and are widely used in clinical trials. The pharmacokinetic parameters and measurements
outlined in Section 5.4 are generally used assessments of drug exposure.


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INVESTIGATIONAL PLAN
6.
VISIT SCHEDULE
6.1
All patient visits should be scheduled according to the Flow Chart. Each visit date
(with its window) is to be counted from Day 1. If any visit has to be rescheduled, subsequent 
visits should follow the original visit schedule. The trial medication packs contain sufficient 
medication to allow for these time windows.
All trial visits should be initiated preferentially in the morning starting before 9:00 AM. 
Patients should be instructed to avoid intake of the morning dose of the study medication at 
home at scheduled visit days as they will be dosed whilst at the study site.
Study measurements and assessments according to the Flow Chart scheduled to occur before 
study drug administration on Day 1, 15, 29, 43, 57 and 85 are to be performed and completed 
within a 2 h-period prior to the study drug administration.
Unscheduled visits will be possible at the discretion of the investigator at any time in order to 
check the safety of the patient.
If the reason for removal of a patient from the treatment is an adverse event or an abnormal 
laboratory test result, the patient must be followed until complete resolution or stabilization 
of the event or until follow-up is agreed adequate by the Investigator and BI Clinical Monitor.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening 
Screening Period
All patients must sign an Informed Consent consistent with ICH-GCP guidelines and the 
local legislation prior to any study specific procedures. Once they have consented, the patient 
is considered to be enrolled in the trial and have started screening. The patient should be 
recorded on the enrolment log and be registered in IRT as a screened patient. Patients will be 
assigned a patient number and enrolment must be recorded in eCRF pages. The Screening 
period is defined as the period from the Screening visit to Randomisation (first study drug 
administration). The screening period should be no longer than 28 days and no less than 7 
days and will be used to assess eligibility of the patients. Thus patients will not be 
randomized until all screening procedures are completed and results are reviewed to verify 
study eligibility. Please refer to Section 8.1. 
For the comprehensive list of the trial procedures required at the Screening Visit (Visit 1) 
please refer to the Flow Chart.
Patients are allowed to repeat lab testing once during the screening period.
For those patients with historic ALT > 1.25 ULN value more than 3 months prior to 
screening, the ALT > 1.5x ULN  must be confirmed via two measurements at least 1 week 
apart within the screening period.


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Patients without required clinical imaging results suggestive of NASH (no more than 3 years 
prior to screening, according to inclusion criterion #1), clinical imaging can be performed as 
optional procedure during the screening period. The imaging procedures will be performed 
according to local standards. Please refer to Flow Chart 1.
No imaging is required if histological evidence of NASH (no more than 3 years prior to 
screening) is available. Please refer to section 3.3.2
Demographics
Information on race will be collected because this is required for the calculation of eGFR 
(CKD-EPI formula).
Re-screening
Patients who screen-fail the study after Visit 1 should be registered in the IRT as a screen 
failure within the protocol defined screening period.
Re-screening of not yet randomised patients can be allowed in exceptional cases but should 
be discussed on a case-by-case basis between the study site, Monitor staff and with the TCM.
IRT
All patients that are screened must be registered with IRT. If the patient results in a screen 
failure, IRT should be notified as soon as possible and within the 28- day screening period.
Details of IRT procedures can be found in the IRT manual located in the ISF
6.2.2
Treatment period
Visits 2, 3, 4, 5, 6 and EOT
The treatment period consists of a maximum of 6 visits (visits 2 - EOT). Visit 2 is the 
randomisation visit and visit EOT is the end of treatment visit, where the last dose of 
medication will be administered. Procedures are to be performed according to the flowcharts 
1, 2, 3, 4, section 10.1 and the respective protocol sections.
Safety laboratory testing
Patients should be fasted (no food and only water) for at least 8 hours prior to the start of 
procedures until 60 mins after drug intake. If a patient comes in non-fasted where a fasting 
condition is required, the visit should be performed, the non-fasted condition documented on 
the laboratory requisition, and the patient reminded about the expected condition. 
Pregnancy testing
Urine pregnancy testing for all women of childbearing potential will be conducted on-site 
prior to every dosing and must be negative to further treat the patient. A positive urine test 
must be confirmed with a serum pregnancy test.
Randomisation (Visit 2)
Randomisation via IRT and administration of the first dose of study medication will occur at 
Visit 2.


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Study drug diary 
The study patients will be instructed to complete a study drug diary during the treatment 
phase to document drug intake (date and time) and number of the tablet row indicating the 
day of intake between the on-site visits.
The diary will be dispensed to the patients at Visit 2 and the patient´s entries will be checked 
by site-staff during the consecutive treatment visits. Selected entries (drug administration date 
and time 3 days prior to each visit) will be entered by site-staff into the CRF.
Pharmacokinetic and biomarker blood sampling
The blood sampling times given in Section 10.1 are the recommended sampling times relative 
to the drug administration and should be adhered to as closely as possible. The actual times of 
drug administration and blood samplings will be recorded in the CRF.
Please refer to the Flow Charts 1, 2, 3 and 4 for exact timing.
 
 
 
 
Telephone contacts
Day 27/ Phone Call 3A: 
The site staff should call the patients on day 27 to remind them of the urine collection starting
directly after the drug administration at day 28 (24h prior to planned visit 4/ day 29 drug 
administration) and study drug intake.
Day 83/ Phone Call 6A: 
The site staff should call the patients on day 83 to remind them of study drug intake on day 
84. Please refer to section PK urine collection above and Flow Charts 1, 4 and section 10.1.
End of Treatment (EOT) Visit/ Early Discontinuation (ED):
If the regular end of the treatment period at week 12 is reached, the EOT Visit will be 
completed. The time interval for the regularly scheduled EOT Visit is 4 days, i.e. Day 85+3. 
The overall duration of the treatment period (randomisation to EOT) should not be less than 
85 days.
If the patient refuses to continue the treatment in the trial or must stop treatment the early 
discontinuation (ED) Visit will be completed instead of the planned treatment period visit. 
This early discontinuation visit will include the same procedures as the normal EOT visit 
except drug administration, PK, PG and PD sampling. Visit FU should be performed no later 
than four weeks after the last study drug intake.


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It is important to distinguish between premature study drug discontinuation and complete 
withdrawal of consent to participate in further study procedures. Patients not willing to 
continue study drug intake should be asked to further attend scheduled trial visits, follow-up 
visits and assessments until the end of the trial unless they withdraw consent to participate in 
the study. For patients who discontinue IMP but are willing to attend scheduled trial visits,
the early discontinuation (ED) Visit will be completed according to FlowChart instead of the 
next planned treatment period visit. All following visits should be performed according to the 
initial study schedule (without study drug administration). In addition to the safety sampling,
only one PK sample and one PD blood sample for measurement of AOC3 activity should be 
taken at each visit on which PK and/or PD sampling was originally planned and the actual 
time of the blood draw recorded. One of these remaining visits should be performed no later 
than four weeks after the last study drug intake.
Should it not be possible to attend all visits, at least phone contacts should occur at the 
scheduled visits time points. It is vital to explain to these patients the importance to continue 
trial participation.
All unused study medication will be collected and the study drug diary will be checked by the 
site. Procedures are to be performed according to the Flow Chart.
6.2.3
Follow Up Period and Trial Completion
Follow-up (FU):
This visit will be performed 28±3 days after EOT (see Flow Chart 1 and Section 10.1 for 
procedures to be performed).
In case of early discontinuation this visit will include the same procedures as the normal FU
visit except PG and PD sampling.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. Adverse events persisting after trial completion must be 
monitored until they have normalised or have been sufficiently characterised.
Trial completion:
Trial completion is defined as patients completing the FU visit within the specified window 
per the flow chart and who have not discontinued drug prematurely. 


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STATISTICAL METHODS AND DETERMINATION OF
7.
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
See Section 3.1 for details on the design of the study.
See Section 2.2 for details on the objective of the study.
Primary endpoint is the plasma AOC3 activity relative to baseline in %, 24 hours post dose,
after 12 weeks of treatment. Baseline is defined as the last measured plasma AOC3 activity 
prior to administration of any randomised study medication.
The dose-response relationship of the primary endpoint will be analysed using a nonlinear 
regression model applied to the AOC3 activity at week 12. The fitted regression model will 
be used to derive the smallest dose where the mean plasma AOC3 activity curve drops below 
10% (D10). This corresponds to:
D10 = min { ∈[0,10]| ()
 ≤10%}
where d is the dose and ()
 is the fitted dose-response curve described in Section 7.3.1.
The analyses of the secondary biomarker endpoints ALT AST, AP, -GT and CK18 
fragments will follow the MCPmod approach allowing for the simultaneous evaluation of 
different potential dose response patterns, whilst protecting the overall probability of type I 
error (one-sided alpha of 0.05).
NULL AND ALTERNATIVE HYPOTHESES
7.2
In this trial it is not planned to test any statistical hypotheses in a confirmatory sense. Where 
statistical testing is used it will have to be interpreted in the perspective of the exploratory 
character of the study.
No hypothesis testing will be used for the primary analysis of the primary endpoint.
The analyses of the secondary biomarker endpoints ALT, AST, AP, -GT and CK18 
fragments contain hypotheses testing. The null hypothesis is that there is a flat dose response 
pattern across placebo and any dose of BI 1467335 within the tested dose range (0-10mg).
The alternative hypothesis is that there is a non-flat dose response pattern indicating a benefit 
of BI 1467335 compared to placebo.


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PLANNED ANALYSES
7.3
The following patient analysis sets are defined for this trial:

Treated Set (TS): includes all patients who signed informed consent and were treated 
with at least one dose of the trial medication. Patients in TS are analyzed under the 
actual trial medication received at randomisation. The TS is used for safety analyses
as well as demographics and baseline characteristics.

Full Analysis Set (FAS): includes all patients in treated set who had non-missing 
baseline and at least one non-missing post-baseline and on-treatment measurement on 
any biomarker endpoint. Patients in FAS are analyzed according to the intent-to-treat 
principle, i.e., patients in FAS are analyzed under the randomized trial medication. 

Per protocol set (PPS): includes all patients from the FAS without important protocol 
violations (IPV) leading to exclusion. This includes:
Compliance to randomised treatment within 80% -120% (inclusive)
At least 80% treatment compliance within 4 weeks before last visit
 
Data from subjects who are screened but not randomised will be listed but not included in any 
summary statistics or inferential statistics. Specifications of important protocol violations 
leading to exclusion will be provided in the TSAP.
Further Analysis sets will be defined in the TSAP.
7.3.1
Primary endpoint analyses
The primary analysis of the primary endpoint will be based on the PPS. 
The subject specific plasma AOC3 activity at time t relative to baseline in % is calculated via
%3 ∶=  !3 − 3,#$%&' !3#$() −3#$(),#$%&'
*
+ ∗100
Where 3 is the AOC3 activity measured at time t, 3,#$%& is the background 
noise at time t, 3#$() is the AOC3 activity measured at baseline and 3#$(),#$%& is 
the background noise at baseline.
As the primary endpoint should show a reduction in AOC3 activity with higher doses, a 
decreasing 3-Parameter regression curve will be used of the form
%3-.,/ =
01 ∗2/
3
42503 + 2/
3 + 7/


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where
%3-.,/
is the response value of patient i, 24h after drug 
administration at week 12 (EOT visit),
01
is the highest AOC3 activity,
2/
is the administered drug amount to patient i
4250
is the dose, which produces half of TOP
8
is the slope factor determining the steepness of the dose-
response curve,
7/
is the random error term of patient i.
Note that the dose-response relationship is assumed to asymptotically approach 0% at high 
doses. 
As it is expected to see a higher variability in AOC3 activity measurements in placebo treated 
patients then in patients treated with BI 1467335 the model fit will use power of mean 
variance estimates (POM) to account for heterogeneity.
In case of the 24h value after drug administration at week 12 is missed, the -0:30 values at 
week 12 can be used instead. In case of other missing AOC3 activity values, except of 
missing baseline where no imputation is done, multiple imputation will be used. After 
exploring the missing data mechanism and observed measurements on the blinded data the 
variable AOC3 activity relative to baseline in % will be included in the imputation model.
If the data is monotone missing, a regression model will be used for imputation including
baseline AOC3 activity, and AOC3 activity relative to baseline measurements predose (-
0:30h relative to drug administration) at Visit 4 and 6 and 24h relative to drug administration 
at visit 3,5 and EOT by treatment.
In the case of non-monotone missing, a Markov chain Monte Carlo (MCMC) step will be 
used to create monotone missing data in multiple datasets. The regression method will then 
be used to complete the imputation in each dataset. For each imputed complete dataset, the 
decreasing 3-parameter curve model will be used for the analysis. The results will be pooled 
following the standard multiple imputation procedure.
The dose where the model fit drops below 10% and the 95% confidence interval will be 
determined (D10). The fitted curve will be graphically displayed.


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7.3.2
Secondary endpoint analyses
The number (%) subjects with adverse reactions will be evaluated descriptively on the TS. 
For more details see Section 7.3.4.
The primary analysis of the secondary biomarker endpoints will be first analysed using a 
repeated measurement analysis (MMRM) on the PPS. The relative ALT (AST, AP, -GT and 
CK18 fragments respectively) changes from baseline at visit 3,4,5,6 and EOT will be 
evaluated on log scale using an MMRM accounting for the following sources of variation: 
‘baseline’, ‘visit’, ‘treatment’, ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effect 
as well as the random ‘subject’ effect. The unstructured covariance structure will be used to 
model the within patient measurements. To estimate denominator degrees of freedom the 
Kenward-Roger approximation will be used.
The dose-response relationship of the week 12 estimates from MMRM will then be analysed 
using MCPMod. A set of plausible dose response patterns is considered with pre-specified 
parameters define:
The following model assumptions have been selected to cover a plausible and diverse range 
of dose response patterns when having matching Placebo and active BI 1467335 doses of 1 
mg, 3 mg, 6 mg and 10 mg:

Linear: no assumptions needed

Linear logistic no assumptions needed

Quadratic: 90 % of the maximum effect is achieved at 7 mg

Exponential: 90 % of the maximum effect is achieved at 7 mg

Emax: 90 % of the maximum effect is achieved at 7 mg

Sigmoidal Emax: 30 % of the maximum effect is achieved at 3 mg and 90 % of 
the maximum effect is achieved at 7 mg

Logistic: 30 % of the maximum effect is achieved at 3 mg and 90 % of the 
maximum effect is achieved at 7 mg

Betamod: 90 % of the maximum effect is achieved at 5 mg, maximum effect is 
achieved at 4 mg and maximal dose is 10 mg


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Figure 7.3.2: 1 Defined MCPMod shapes to be used.
If there is a at least one significant model, the null hypothesis of a flat dose-response 
relationship for the secondary endpoint ALT ( for AST, AP, -GT and CK18 fragments 
respectively) jointly for each of the candidate dose-response models with a contrast test 
controlled for the family-wise error rate (α = 0.05 1-sided) will be rejected.
When the null hypothesis is rechecked, the best-fitting model from the above set of eight
models can be refitted to the data without any parameter assumptions to generate new 
estimates of the model parameters from the data. The target dose will be obtained via model 
averaging across the significant models based on Akaike Information Criterion (AIC) (the 
smaller the AIC value the better the model fit). The target dose(s) can then be determined 
from that model by incorporating information on the minimum clinically relevant effect as 
well as safety information. 
Further details on the primary analysis, 
 will be 
provided in the TSAP.


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and individual patient’s end of trial
will be assigned to the treatment period for evaluation.
The analysis will be done by ‘treatment at onset’.
All treated patients will be included in the safety analysis (analysis on TS). In general, safety 
analyses will be descriptive in nature and will be based on BI standards. No hypothesis 
testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and 
individual patient’s end of trial will be considered ‘treatment-emergent’. Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA). Frequency tables for all adverse 
events, protocol-specified AESI, serious adverse event (SAE), adverse event leading to death, 
adverse event leading to discontinuation, investigator assessed drug-related adverse event and 
serious adverse event will be generated for treatment-emergent adverse events.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, 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.


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INTERIM ANALYSES
7.4
An interim PK/PD analysis may be performed for model development purposes of the 
population PK and PK/PD analysis and to support dose decision for future trials. The interim 
analysis will focus on PK and AOC3 inhibition; other secondary biomarker endpoints may be 
evaluated in addition. The exact time point for data cut-off will be aligned with other studies 
investigating BI 1467335 and general project planning. Details of this analysis will be 
defined in the interim PK/PD analysis plan.
The result of the interim analysis will not be used to make any adaptions of the trial like 
sample size adjustments.
For steps to maintain blinding during the interim analysis see Section 4.1.5.1.  
HANDLING OF MISSING DATA
7.5
Primary and secondary biomarker endpoints
Every effort will be made to collect complete data at the specified time points.
If missing values still occur they will be handled as described in the corresponding section.
Safety
With respect to safety evaluations, it is not planned to impute missing values.
 
RANDOMISATION
7.6
Patients will be randomised in blocks to double-blind treatment in a 2:1:1:1:2 ratio (Placebo, 
1 mg, 3 mg, 6mg and 10 mg respectively). The randomisation of patients to the treatment 
groups will be performed via an interactive response technology (IRT). 
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the CTR. Access to the codes will be 
controlled and documented.


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DETERMINATION OF SAMPLE SIZE
7.7
The sample size calculation is based on both, plasma AOC3 activity relative to baseline and 
ALT change from baseline, the latter being the biomarker with the least favorable ratio of 
anticipated effect size to variance.
Under the assumptions given in detail below, a sample size of 98 with an allocation ratio of 
2:1:1:1:2 for Placebo, 1 mg, 3 mg, 6mg and 10 mg respectively is appropriate for both the 
estimation of D10 of plasma AOC3 activity relative to baseline and the MCPMod analysis of 
biomarkers. This assumes 98 evaluable patients for the primary and secondary endpoints and 
thus around 108 will need to be randomized. For the dose assessment the lowest (Placebo) 
and highest (10 mg BI 1467335) dose groups will have the highest impact on the analysis. 
Due to the nature of the dose- response-relationship, the biggest difference is anticipated 
between Placebo and the 10 mg group. The power analysis and simulation via MCPMod 
supported the 2:1:1:1:2 allocation ratio instead of equal allocations (see also Table 7.7:1).
ALT
Sample size is based on four assumptions:

an assumed maximum effect size of BI 1467335 vs. placebo of 30% for relative 
change from baseline in ALT after 12 weeks of treatment

a target dose of 20% difference to placebo can be estimated

the target dose lies within the tested dose range

MCPMod shapes and guesstimates as described below
The defined response patterns and model assumptions from section 7.3.2 are used.
Further assumptions are a mean baseline ALT of 80 U/L, a placebo effect at week 12 of -10 
U/L and an effect of active treatment at week 12 of -34 U/L, i.e. the true difference between 
the relative change from baseline between placebo and active treatment at week 12 is 
assumed to be 30%. Further on, it is assumed to have a constant coefficient of variation over 
the whole ALT range of 40/80 = 0.5. This assumption is based on external data from 
CENTAUER, GOLDEN and ARAMCHOL (R16-5489; R18-2779; R18-2781; mean baseline 
ALT of 63-78 and respective SD of 31-44) and on blinded estimated SD for baseline ALT 
from 61 patients from this study.
On log scale this corresponds to a change from baseline in the placebo group of -0.14 and in 
the active treatment group of -0.56, i.e. a difference of 0.42. 
An autoregressive correlation structure is assumed with constant variability of ALT on log 
scale regardless of visit and exponentially declining correlation with distance. The correlation 
between measurements at visits four weeks apart are assumed to be 0.7. Consequently, 
correlation between baseline and week 12 is 0.34 


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MCMod will be applied to change from baseline of ALT at week 12 on log scale. It is 
investigated if (i) the MCPMod testing step rejects the null hypothesis of no dose-response 
relationship at one-sided alpha = 0.05, and (ii) a target dose of 20% difference to placebo, 
corresponding to a Delta on log-scale of 0.26, can be estimated and lies within the tested dose 
range.
Simulations show that under the assumptions given above and assuming a true effect of 30% 
(Situation 3), the probability to fulfil the two conditions is approx. 84% with a sample size 
of 98 using an allocation ratio of 2:1:1:1:2 for doses Placebo, 1 mg, 3 mg, 6mg and 10 mg 
respectively..
Table 7.7:1 Possible scenarios to fulfil the two conditions using the assumptions define 
above.
SD
N per arm (total)
True assumed effect
probability to fulfil the 
two conditions
40
28 : 14 : 14 : 14 : 28 (98)
Situation 1 with true 
assumed effect of 0.001%
5.3%
Situation 2 with true 
assumed effect of 20%
50.4%
Situation 3 with true 
assumed effect of 30%
84.8%
Using these parameter estimates, datasets with 98
patients in a 2:1:1:1:2 ratio were simulated (1000 repeats). The D10 of the fitted nonlinear 
curves using simulated data was between 3.95 mg and 5.1 mg, the 5% and 95% quantiles of 
the distribution being 4.2 mg and 4.8 mg, respectively. This precision is considered to be 
sufficient for the purpose of the trial.


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Figure 7.7:1: Boxplot of estimated D10 using 1000 simulated datasets.
Simulation shows that a 10% drop out rate does not decrease the precision of D10 estimation 
to an unacceptable degree.
The calculations have been performed using R version 3.3.2 as well as SAS Version 9.4. The 
R and SAS codes for the sample size calculations will be documented in a separate file and 
stored in the TMF.


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INFORMED CONSENT, TRIAL RECORDS, DATA 
8.
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP*.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
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 patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’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 patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The Investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the contents. 
The Investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms (CRF) for individual patients will be provided by the sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure patient confidentiality.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date 
patient was informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if 
applicable)

Medication history


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
Adverse events and outcome events (onset date (mandatory), and end date (if 
available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, 
with proper documented medical evaluation (in validated electronic format, if 
available)

Completion of Patient’s Participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial 
participant meets all inclusion criteria and does not meet any exclusion criteria.
The absence of records (either medical records, verbal documented feedback of 
the patient or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical 
trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). The CRA and auditor may review all CRFs and informed consents. The accuracy 
of the data will be verified by direct comparison with the source documents described in 
section 8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.
An adaptive approach to clinical trial monitoring will be utilised. The sponsor will perform a 
risk assessment of the trial to determine the extent and nature of monitoring required in order 
to ensure the reliability and robustness of the results. Regular review of risk reports will 
provide sponsor oversight during trial conduct and direct monitoring activities to the areas of 
greatest risk which have the most potential impact to subject safety and data quality.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results. 
The CRA and auditor may review all CRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in section 8.3.1. 
The sponsor will also monitor compliance with the protocol and ICH GCP.


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8.3.3
Storage period of records
Trial site(s):
The trial site(s) 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.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below and in 5.5.4. Patient 
privacy will be ensured by using patient 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 given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’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.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent. The end of the trial is defined as the date of the last visit of the last 
patient in the whole trial (“Last Patient Out”). The “Last Patient Drug Discontinuation”
(LPDD) date is defined as the date on which the last patient at an individual trial site ends 
trial medication (as scheduled per protocol or prematurely). Individual Investigators will be 
notified of SUSARs occurring with the trial medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.


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The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).


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REFERENCES
9.
PUBLISHED REFERENCES
9.1
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studies combining multiple companrisons and modelling procedures. J
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Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment 
of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012. 10(8): 
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(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
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14_QuickReference_8.5x11.pdf. 2010.
R15-1863 
Inoue T, Morita M, Tojo T, Nagashima A, Moritomo A, Miyake H. 
Novel1H-imidazol-2-amine derivatives as potent and orally active vascular 
adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema 
treatment. Bioorg Med Chem. 2013. 21(13): 3873-3881.
R15-1868 
Foot JS, Deodhar M, Turner CI, et al. The discovery and development of 
selective 3-fluoro-4-aryloxyallylamine inhibitors of the amine oxidase 
activity of semicarbazide-sensitive amine oxidase/vascular adhesion 
protein-1 (SSAO/VAP-1). Bioorg Med Chem Lett. 2012. 22(12): 3935-
3940.
R15-2803 
Stolen CM, Marttila-Ichihara F, Koskinen K, et al. Absence of the 
endothelial oxidase AOC3 leads to abnormal leukocyte traffic in vivo. 
Immunity. 2005. 22(1): 105-115.
R15-5365 
Weston CJ, Shepherd EL, Claridge LC et al. Vascular adhesion protein-1 
promotes liver inflammation and drives hepatic fibrosis. J Clin Invest. 2015. 
125(2): 501-520.
R15-5652 
Bonder CS, Norman MU, Swain MG, et al. Rules of recruitment for Th1 
and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and 
vascular adhesion protein-1. Immunity. 2005. 23: 153-163.
R15-5654 
Koskinen K, Vainio PJ, Smith DJ, et al. Granulocyte transmigration 
through the endothelium is regulated by the oxidase activity of vascular 
adhesion protein-1 (VAP-1). Blood. 2004. 103(9): 3388-3395.


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R15-5697 
Karim S, Liaskou E, Fear J, Garg A, Reynolds G, Claridge L, et al.
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.
R15-6056 
O’Rourke AM, Wang EY, Miller A, Podar EM, et al. Anti-inflammatory 
effects of LJP 1586 [Z-3-fluoro-2-(4-methoxybenzyl)allylamine 
hydrochloride], an amine-based inhibitor of semicarbazide-sensitive amine 
oxidase activity. J Pharmacol Exp Ther. 2008. 324(2): 867-875.
R15-6057 
Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Nat Vital Stat 
Rep. 2013. 61(4): 1-117.
R15-6058 
Merinen M, Irjala H, Salmi M, Jaakkola I, Hanninen A, Jalkanen S.
Vascular adhesion protein-1 is involved in both acute and chronic
inflammation in the mouse. Am J Pathol. 2005. 166(3): 793-800.
R15-6059 
Lee WY, Salmi M, Kelly MM, Jalkanen S, Kubes P. Therapeutic advantage 
of anti-VAP-1over anti-α4 integrin antibody in concanavalin A-induced 
hepatitis. Hepatology. 2013. 58(4): 1413-1423.
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(6): 2005-2023.
R15-6045 
Marttila-Ichihara F, Smith DJ, Stolen C, et al. Vascular amine oxidases are 
needed for leukocyte extravasation into inflamed joints in vivo. Arthritis 
Rheum. 2006. 54(9): 2852-2862.
R15-6046 
Lalor PF, Edwards S, McNab G, et al. Vascular adhesion protein-1 
mediates adhesion and transmigration of lymphocytes on human hepatic 
endothelial cells. J Immunol. 2002. 169(2): 983-992.
R15-6047 
Salter-Cid LM, Wang E, O’Rourke AM, et al. Anti-inflammatory effects of 
inhibiting the amine oxidase activity of semicarbazide-sensitive amine 
oxidase. J Pharmacol Exp Ther. 2005. 315(2): 553-562.
R15-6048 
Xu HL, Salter-Cid L, Linnik MD, Wang EY, Paisansathan C, Pelligrino 
DA. Vascular adhesion protein-1 plays an important role in postischemic 
inflammation and neuropathology in diabetic, estrogen-treated 
ovariectomized female rats subjected to transient forebrain ischemia. J 
Pharmacol Exp Ther. 2006. 317(1):19-29.


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R15-6070 
Dharel N, Fuchs M. Nonalcoholic fatty liver disease – a major public health 
challenge for the 21st century. JSM Gastroenterol Hepatol. 2014. 2(2):
1018.
R15-5801 
Aalto K, Maksimow M, Juonala M, et al. Soluble vascular adhesion 
protein- 1 correlates with cardiovascular risk factors and early 
atherosclerotic manifestations. Arterioscler Thromb Vasc. Biol. 2012. 32:
523-532.
R15-5774
Li HY, Jiang YD, Chang TJ, et al. Serum vascular adhesion protein-1 
predicts 10-year cardiovascular and cancer mortality in individuals with 
type 2 diabetes. Diabetes. 2011. 60(3): 993-999.
R15-5773
Li HY, Wei JN, Lin MS, et al. Serum vascular adhesion protein-1 is 
increased in acute and chronic hyperglycemia. Clinica Chimica Acta. 2009.
404: 149-153.
R15-5766 
Lin MS, Li HY, Wei JN, et al. Serum vascular adhesion protein-1 is higher 
in subjects with early stages of chronic kidney disease. Clin Biochem. 2008. 
41: 1362-1367.
R15-5767 
Madej A, Reich A, Orda A, Szepietowski JC. Expression of Vascular 
Adhesion Protein-1 in Atopic Eczema. Int Arch Allergy Immunol. 2006. 
139(2): 114-121.
P15-12198 
Kurkijärvi R, Yegutkin GG, Gunson BK, Jalkanen S, Salmi M, Adams DH. 
Circulating soluble vascular adhesion protein-1 accounts for the increased 
serum monoamine oxidase activity in chronic liver disease.
Gastroenterology. 2000. 119(4): 1096-1103.
R15-5771 
Kurkijärvi R, Adams DH, Leino R, Mottonen T, Jalkanen S, Salmi M. 
Circulating form of human vascular adhesion protein-1 (VAP-1): increased 
serum levels in inflammatory liver diseases. J. Immunol. 1998. 161: 1549-
1557.
R15-5772 
Kurkijärvi R, Jalkanen S, Isoniemi H, Salmi M. Vascular adhesion protein-
1 (VAP-1) mediates lymphocyte-endothelial interactions in chronic kidney 
rejection. Eur J Immunol. 2001. 31: 2876-2884.
R15-5802
Boomsma F, van den Meiracker AH, Winkel S, et al. Circulating 
semicarbazide-sensitive amine oxidase is raised both in type I 
(insulindependent), in type II (non-insulin-dependent) diabetes mellitus and 
even in childhood type I diabetes at first clinical diagnosis. Diabetologia. 
1999. 42: 233-237.


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R16-5301
McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM.
Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis 
using paired biopsies: implications for prognosis and clinical management. 
J Hepatol. 2015. 62: 1148-1155.
R16-5309
Chalasani N, Regev A. Drug induced liver injury in patients with 
preexisting chronic liver disease in drug development – how to identify and 
manage? Gastroenterology. 2016.
R16-5489
Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al, 
GOLDEN-505 Investigator Study Group
Elafibranor, an agonist of the peroxisome proliferator-activated receptor-
alpha and -delta, induces resolution of nonalcoholic steatohepatitis without 
fibrosis worsening.
Gastroenterology 150 (5), 1147 - 1159 (2016)
R18-2779
Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, et 
al, FLORA Group
The fatty acid-bile acid conjugate Aramchol reduces liver fat content in 
patients with nonalcoholic fatty liver disease.
Clin Gastroenterol Hepatol 12 (12), 2085 - 2091 (2014)
R18-2781
Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, 
Caballeria J, et al
A randomized, placebo-controlled trial of cenicriviroc for treatment of 
nonalcoholic steatohepatitis with fibrosis.
Hepatology 67 (5), 1754 - 1767 (2018)


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APPENDICES
10.
PHARMACOKINETIC AND BIOMARKER SAMPLING TIME POINTS
10.1
Table 10.1:1
Blood sampling scheme for pharmacokinetic and 
pharmacodynamic/biomarker blood samples
Visit 
No.
Day
Time point
Time 
rel. to 
drug 
admin. 
[h]
CRF Time 
/ planned 
time
[h:min]
PK 
samples
AOC3 activity / 
concentration
2
1
Prior to first BI 
1467335 dose 
(baseline)
-0.5
-0:30
X
X
BI 1467335 
administration
0
0:00
0.25
0:15
X
0.5
0:30
X
X
1
1:00
X
X
1.5
1:30
X
2
2:00
X
X
3
3:00
X
X
6
6:00
X
X
8
8:00
X
X
3
15
-0.5
335:30
X
X
BI 1467335 
administration
0
336:00
1
337:00
X
1.5
337:30
X


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Table 10.1:1
continued Blood sampling scheme for pharmacokinetic and 
pharmacodynamic/biomarker blood samples
Visit 
No.
Day
Time point
Time 
rel. to 
drug 
admin. 
[h]
CRF Time 
/ planned 
time
[h:min]
PK 
samples
AOC3 
activity / 
concentratio
n
4
29
-0.5
671:30
X
X
BI 1467335 
administration
0
672:00
0.25
672:15
X
0.5
672:30
X
X
1
673:00
X
X
1.5
673:30
X
2
674:00
X
X
3
675:00
X
X
6
678:00
X
X
8
680:00
X
X
5
43
-0.5
1007:30
X
X
BI 1467335 
administration
0
1008:00
1
1009:00
X
1.5
1009:30
X
6
57
-0.5
1343:30
X
X
BI 1467335 
administration
0
1344:00
1
1345:00
X
1.5
1345:30
X


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Table 10.1:1
continued Blood sampling scheme for pharmacokinetic and 
pharmacodynamic/biomarker blood samples
Visit 
No.
Day
Time point
Time 
rel. to 
drug 
admin. 
[h]
CRF Time 
/ planned 
time
[h:min]
PK 
samples
AOC3 
activity / 
concentratio
n
EOT
85
-0.5
2015:30
X
X
BI 1467335 
administration
0
2016:00
0.25
2016:15
X
0.5
2016:30
X
X
1
2017:00
X
X
1.5
2017:30
X
2
2018:00
X
X
3
2019:00
X
X
6
2022:00
X
X
8
2024:00
X
X
24
2040:00
X
X
EOT 
+ 28
113
672
2688:00
X


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INCREASED LIVER ENZYMES PROCEDURE
10.3
Please also refer to section 3.3.4.1.1.
Figure 10.3: 1 study- specific procedures in case of further increased liver enzymes after 
randomisation.


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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c15128276-02
BI Trial No.:
1386-0004
Title:
A multi-centre, double-blind, parallel-group, randomised, placebo
controlled phase II a study to investigate safety, tolerability,
pharmacodynamics, and pharmacokinetics of different doses of
orally administered BI 1467335 during a 12-week treatment period
compared to placebo in patients with clinical evidence of NASH.
Including Protocol Amendment 1 [c08980589-01], amendment 2
[c08980589-03-02], amendment 3 [c08980589-03], amendment 4
[c08980589-04]
Investigational
Product(s):
BI 1467335
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
10 AUG SIGNED
Version:
FINAL
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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...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT .....................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoint .....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
5.3.2
Safety endpoints ..................................................................................................11
5.4
OTHER VARIABLES........................................................................................15
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................16
6.1
TREATMENTS...................................................................................................16
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................17
6.3
PATIENT SETS ANALYSED...........................................................................20
...............................................................22
6.5
POOLING OF CENTRES .................................................................................23
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................23
6.6.1
Definition of criteria for censoring....................................................................23
6.6.2
Endpoint specific handling of missing data......................................................23
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................24
7.
PLANNED ANALYSIS......................................................................................29
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........30
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................30
7.3
TREATMENT COMPLIANCE........................................................................30
7.4
PRIMARY ENDPOINT .....................................................................................31
7.4.1
Primary analysis..................................................................................................31
7.5
SECONDARY ENDPOINTS.............................................................................32
7.5.1
Key secondary endpoint .....................................................................................32
7.5.2
Secondary endpoints...........................................................................................32
.....................................................................34
.....................................................................34
.....................................................................36


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..........................36
..........................37
..........................37
7.7
EXTENT OF EXPOSURE.................................................................................38
7.8
SAFETY ANALYSIS..........................................................................................38
7.8.1
Adverse events.....................................................................................................38
7.8.2
Laboratory data ..................................................................................................39
7.8.3
Vital signs.............................................................................................................40
7.8.4
ECG......................................................................................................................40
8.
REFERENCES....................................................................................................43
....45
....45
....45
....46
....46
....48
....48
....48
....48
....48
....49
10.
HISTORY TABLE..............................................................................................50


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LIST OF TABLES
Table 6.1: 1
Treatment descriptions.....................................................................................16
Table 6.1: 2
Analysing periods (same for all treatment groups) ..........................................16
Table 6.2: 1
Important protocol violations...........................................................................17
Table 6.3: 1
Patient sets analysed.........................................................................................21
Table 6.7: 1
Time schedule of 12-lead ECG recordings ......................................................25
Table 6.7: 2
Visit window for centralized ECG endpoints ..................................................25
Table 6.7: 3
Visit window for AOC3...................................................................................26
Table 6.7: 4
Time window for AOC3 ..................................................................................26
Table 6.7: 5
Visit window for secondary and further biomarker endpoints*.......................27
Table 6.7: 6
Visit window for safety endpoints ...................................................................27
Table 7.5.2: 1 Contrast coefficients.........................................................................................33
Table 10: 1
History table .....................................................................................................50


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
γ-GT
Gamma-Glutamyltransferase
AE
Adverse event
ALT
Alanine Aminotransferase
 
AOC3
Amine oxidase copper-containing 3
AP
Alkaline Phosphatase
AST
Aspartate Aminotransferase
BP 
Blood pressure
BRPM
Blinded report planning meeting
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV [%] 
Arithmetic coefficient of variation in %
DBLM
Data base lock meeting
DBP
Diastolic blood pressure
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DRA
Drug Regulatory Affairs
DMG
Dictionary Maintenance Group
ECG
Electrocardiogram
ECGS
ECG analysis set
ELF
Enhanced Liver Fibrosis
EMEA
European Agency for the Evaluation of Medicinal Products
FAS
Full Analysis Set
HDL
High Density Lipoprotein
HR 
[beats/min]
Heart rate in beats per minute


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Term
Definition / description
HV
Healthy volunteer
ICH
International Conference on Harmonisation
IPV
Important Protocol Violation
LDL
Low Density Lipoprotein
MCPMod
Multiple Comparison Procedure Modelling
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Effect Model Repeated Measurement
MQRM
Medical Quality Review Meeting
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
PK
Pharmacokinetics
PKECGS
PK ECG set
PPS
Per protocol set
PR interval
ECG interval from the onset of P wave to the beginning of the QRS
PSTAT
Project Statistician
PT
Preferred term
PV
Protocol violation
QD
quaque die (once a day)
QRS complex
Combination of the Q, R, and S waves
QT interval
ECG interval from the beginning of the QRS complex to the end of the T 
wave
QTcB [msec]
QT interval, heart rate corrected according to Bazetts formula
QTcF [msec]
QT interval, heart rate corrected according to Fridericias
formula
QTcN [msec]
QT interval, heart rate corrected according to study
population formula
REP
Residual effect period
RR interval
ECG interval from the peak of the R wave to the peak of the subsequent R 
wave
RPM
Report Planning Meeting


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Term
Definition / description
RS
Randomised set
SA
Statistical analysis
SBP
Systolic blood pressure
SD
Standard deviation
SMQ
Standardised MedDRA query
SOC
System organ class
TCM
Trial Clinical Monitor
 
ToC
Table of contents
TMW
Trial Medical Writer
TS
Treated set
TSAP
Trial statistical analysis plan


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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 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 medidata RAVE (BRAVE) system.
The statistical analyses will be performed within the validated working environment CARE
(Clinical data Analysis and Reporting Environment), including SASTM (current Version 9.4,
by SAS Institute Inc., Cary, NC, USA), and a number of SASTM-based tools (e.g., macros for 
the analyses of adverse event (AE) data or laboratory data; Report Appendix Generator
system (RAGe) for compilation/formatting of the clinical trial report (CTR) appendices). R 
version 3.3.2 or later with “DoseFinding” package [R15-2001] will be used for analysis based 
on MCPMod.
 


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
No changes to the planned analysis according to the CTP have been made.


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5.
ENDPOINTS
General remarks with regard to naming convention and its derivation:

Absolute value: 	

 or 


Absolute change from baseline: 	

 −


Change from baseline in %: 
 

∗100

Relative to baseline in %:  


∗100
5.1
PRIMARY ENDPOINT
CTP Section 5.1.1:
The primary endpoint is the plasma amine oxidase copper-containing 3 (AOC3) activity 
relative to baseline in %, 24 h post dose, after 12 weeks of treatment. The baseline is defined 
as the last AOC3 activity measurement prior to administration of any randomised study 
medication.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
There are no key secondary endpoints in this trial.
5.2.2
Secondary endpoints
CTP Section 5.1.2:
Safety and tolerability will be assessed based on the number (%) of subjects with adverse
reactions[displayed as drug-related adverse events].
The secondary biomarker endpoints will be assessed based on the

relative ALT change from baseline after 12 weeks of treatment

relative AST change from baseline after 12 weeks of treatment

relative AP change from baseline after 12 weeks of treatment

relative γ-GT change from baseline after 12 weeks of treatment (GGT)

relative caspase cleaved cytokeratin 18 (M30) change from baseline after 12 weeks of
treatment (CK-18 Caspase)

relative total cytokeratin 18 (M65) change from baseline after 12 weeks of treatment
(CK-18 Total)
The relative change from baseline in % will be described as “relative to baseline in %” or in 
short as “R2Base %”.


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5.3.2
Safety endpoints
12-lead ECG endpoints
For the definition of baseline and a summary of time points please refer to Section 6.7.
Quantitative ECG endpoints:
The following quantitative ECG endpoints will be determined for the ECG variables QTcF, 
QT, HR, PR, QRS, RR and QTcB derived as described in Additional Section 9.1:

absolute values (per time point)

changes from baseline (per time point) 

percent changes from baseline (per time point; for HR, PR, QRS)
Categorical ECG endpoints
The following categorical ECG endpoints will be determined based on the quantitative ECG 
endpoints:
New onset (meaning that this or a higher category was not present any time at baseline) of 
maximum QTcF interval > 450 to 480 msec, > 480 to 500 msec, or > 500 msec on 
treatment. For assignment of a particular patient to one of the above categories, all time 
points on-treatment (refer to Table 6.7: 1) will be considered. 

Maximum change from baseline in QT interval ≤ 60 msec, or > 60 msec on treatment

Maximum change from baseline in QTcF interval ≤ 30 msec, > 30 to ≤ 60 msec, or 
> 60 msec on treatment
The occurrence of any of the following will be viewed as “notable findings”:

New onset (not present any time at baseline) of uncorrected QT interval > 500 msec at 
any time on treatment


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If baseline is missing, any occurrence of QT interval > 500 msec at any time on treatment 
will be a notable finding

New onset of QTcF interval > 500 msec at any time on treatment
If baseline is missing, any occurrence of QTcF interval > 500 msec at any time on 
treatment will be a notable finding

Increase in QTcF interval from baseline by > 60 msec at any time on treatment

Increase in HR from baseline by ≥ 25%, when corresponding on-treatment value of HR is 
> 100 bpm, or decrease in HR by ≥ 25%, when corresponding on-treatment value of HR 
is < 50 bpm, at any time on treatment

Increase in the PR interval from baseline by ≥ 25%, when corresponding on-treatment 
value of PR interval is > 200 msec, at any time on treatment

Increase in the QRS complex from baseline by ≥ 10%, when corresponding on-treatment 
value of QRS complex is > 110 msec, at any time on treatment
Categorical endpoints will also include morphological (i.e. qualitative) findings that might be 
attributable to treatment. In particular, new onset of findings not present at baseline with 
regard to e.g. rhythm, conduction, ST segment changes, T and U wave abnormalities and 
myocardial infarction will be explored.
Vital signs and body weight
For the Vital Signs variables:

Systolic blood pressure

Diastolic blood pressure

Pulse rate

Respiratory rate
And the body weight variables:

BMI

Body weight

Waist circumference

Hip circumference

Hip/Waist ratio
The following quantitative vital signs and body weight endpoints will be determined

absolute values (per time point)

changes from baseline (per time point)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic trial information on treatments to be administered, assignment of a dose group, and 
selection of doses, see CTP Section 4.
Table 6.1: 1
Treatment descriptions
Long Name
Short Name
Placebo
Placebo
BI 1467335 1 mg QD
1 mg QD
BI 1467335 3 mg QD
3 mg QD
BI 1467335 6 mg QD
6 mg QD
BI 1467335 10 mg QD
10 mg QD
Patients will be analysed as randomised for safety and efficacy analyses. 
Table 6.1: 2
Analysing periods (same for all treatment groups)
Analysing Treatment 
Period
Start time
Stop time
Screening
0:00 h on day of informed 
consent
first treatment administration
On-treatment
first treatment administration
Individual trial termination date
Displays of AEs, laboratory tests and vital signs will be presented separately for the
following treatments during the “On-treatment” phase:

Placebo

BI 1467335 1 mg QD

BI 1467335 3 mg QD

BI 1467335 6 mg QD

BI 1467335 10 mg QD
AEs:
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 only) of the 
CTR displays:
In these displays, the on-treatment phase will be analysed (labelled with the name of the 
study treatment (short name)). Screening period will not be included in this analysis. 


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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 (labelled “Screening”)

On-treatment (labelled with the name of the study treatment (label with short name))
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all active treatments during on-treatment ("Total BI")
Laboratory tests:
Laboratory values are displayed for

Baseline

On-treatment
Vital signs:
Vital signs and 12-lead ECG values are displayed for

Baseline

On-treatment
For more details refer to Section 6.7.
More details on the technical implementation of these analyses are provided in the Analysis
Data Set Plan (ADS Plan) of this TSAP.
6.2
IMPORTANT PROTOCOL VIOLATIONS
A protocol violation (PV) is important if it affects the rights or safety of the study patients, or
if it can potentially influence the primary outcome measurement(s) in a non-negligible way.
A list of important PVs (IPVs) is given in Table 6.2: 1. Important PVs will be reviewed at
Medical Quality Review Meetings (MQRMs) conducted periodically during the trial. A list
of protocol deviations will be discussed at the Blinded Report Planning Meetings (BRPMs).
If the data show other important PVs, this table will be supplemented accordingly at MQRMs
or BRPMs or through team review of the manual PV log. The decision whether a patient will
be excluded from the analysis will be made at the final BRPM prior to Database Lock (DBL).
Table 6.2: 1
Important protocol violations
Category / 
Code
Description
Comment
Excluded 
from
A
Entrance criteria not met
A1
Target indication not met
A1.01
Clinical evidence of NASH
Inclusion criterion checked
PPS
A2
Inclusion criteria not met


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Comment
Excluded 
from
A2.01
ALT >1.5 ULN at screening and ALT >1.25 
ULN in a local lab within 1 week to 3 months 
prior screening
Inclusion criterion checked
PPS
A2.02
Age ≥ 18 and ≤75 years at screening
Inclusion criterion checked
None
A2.03
BMI ≥25kg/m2 and <45kg/m2 at screening
Inclusion criterion checked
None
A2.04
Stable body weight
Inclusion criterion checked
None
A2.05
Stable concomitant medication (Antidiabetic, 
anti-obesity, Vitamine E)
Inclusion criterion checked
PPS
A2.06
Stable concomitant medication (All other)
Inclusion criterion checked
None
A2.07
For females: use of double barrier 
contraception
Inclusion criterion checked
None
A3
Exclusion criteria met
A3.01
Current or history of significant alcohol 
consumption 
Exclusion criterion checked
PPS
A3.02
Prior participation in an interventional NASH 
trial 
Exclusion criterion checked
PPS
A3.03
Prior or planned bariatric surgery
Exclusion criterion checked
PPS
A3.04
Drugs associated with liver injury, hepatic 
steatosis or steatohepatitis prior screening
Exclusion criterion checked
PPS
A3.05
History of liver cirrhosis or other forms of 
liver disease
Exclusion criterion checked
PPS
A3.06
active infection
Exclusion criterion checked
None
A3.07
Solid liver lesions other than haemangiomas
Exclusion criterion checked
PPS
A3.08
eGFR <60ml/min/1.73m2 at screening (or 
Renal insufficiency or renal impairment 
(assessed by eGFR))
Exclusion criterion checked
None
A3.09
ALT >5.0 ULN at screening
Exclusion criterion checked
PPS
A3.10
Platelet count < 150.000/µL
Exclusion criterion checked
PPS
A3.11
Bilirubin level > 1.25xULN 
Exclusion criterion checked
PPS
A3.12
Uncontrolled diabetes 
Exclusion criterion checked
PPS
A3.13
Diagnosis of a serious or unstable disease 
Exclusion criterion checked
PPS
A3.14
Prior or planned major surgery 
Exclusion criterion checked
PPS
A3.15
Active, suspected or history of Malignancy
Exclusion criterion checked
None
A3.16
Use of restricted medication
Exclusion criterion checked
PPS
A3.17
Previous randomisation in this trial
Exclusion criterion checked
PPS
A3.18
Currently enrolled in another investigational 
study
Exclusion criterion checked
PPS
A3.19
Chronic drug abuse or any condition 
unsuitable for trial participation
Exclusion criterion checked
PPS
A3.20
Pregnant, nursing or who plan to become 
pregnant women
Exclusion criterion checked
None
A3.21
baseline QT issue or WPW syndrome
Exclusion criterion checked
None
A3.22
Use of MAO-B inhibitors at screening or 
planned during study*
Exclusion criterion checked
PPS
A3.23
Safety concerns by investigator opinion
Exclusion criterion checked
None
B
Informed consent
B1
Informed consent not available
Date or signatory missing
All


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Comment
Excluded 
from
B2
Informed consent too late
Date of informed consent 
not obtained prior to any 
study related procedure
None
B5
Informed consent obtained with error
None
C
Trial medication and randomisation
C1
Incorrect trial medication
C1.01
No study medication taken
Patient randomised but no 
study medication taken
TS, FAS, 
PPS, 
C1.02
Incorrect trial medication taken
Wrong medication taken 
for more 
than 20% of the overall 
treatment duration or for 
more than 20% of the last 
visit interval before the 
primary endpoint 
assessment (different 
medication than the patient 
was randomised to taken 
i.e. drug kit recorded in 
eCRF from different 
treatment group than drug 
kit assigned by IVRS 
[automated check PV])
PPS
C3
Non-compliance
C3.01
Non-compliance with study drug intake
Overall study treatment 
compliance outside 80% 
and 120% (exclusive) or 
study treatment compliance 
below 80% in the last visit 
interval before primary 
endpoint assessment.
PPS
C4
Medication code broken
C4.01
Medication code broken at site without just 
cause
Medication code was 
broken for no valid reason.
Final decision at the DBL 
meeting based on medical 
judgement
None
Final 
decision at 
the DBL 
meeting.
D1
Concomitant medication
D1.01
Non stable concomitant medication during 
treatment (Amiodarone, methotrexate, 
systemic glucocorticoids, tetracyclines, 
tamoxifen, estrogens (excluding oral 
contraception), anabolic steroids, valproic 
acid, Pioglitazone and GLP1-Agonists as well 
as the initiation of insulin)
Review of eCRF for 
concomitant medication 
use.
Final decision at the DBL 
meeting based on medical 
judgement.
PPS
Final 
decision at 
the DBL 
meeting


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Comment
Excluded
from
D2
Prohibited medication use
D2.01
Use of prohibited medication during 
treatment period
Review of eCRF for 
prohibited medication.
Final decision at the DBL 
meeting based on medical 
judgement.
PPS
Final 
decision at 
the DBL 
meeting. 
E
Missing data**
E1.01
No baseline biomarker value (for all of AOC3 
activity, ALT, AST, AP, γ-GT, CK-18 
caspase and CK-18 total)
No valid baseline 
biomarker value
FAS, PPS
E1.02
No on-treatment biomarker value (for all of 
AOC3 activity, ALT, AST, AP, γ-GT, CK-18 
caspase and CK-18 total)
No valid on-treatment 
biomarker value
FAS, PPS
G
Trial specific
G1.01
Too short treatment duration
at least 8 weeks on 
treatment
PPS
G1.02
Pregnant female during trial
None
* Exclusion criteria was deleted in CTP Version 3 (16 March 2018).
**Further missing data beyond the explicitly described in E will not be considered as IPV.
The IPV category B5, D1 and D2 will be a manual IPV and need to be identified at a site 
level on the manual PV log. All remaining IPVs are programmed automatically.
6.3
PATIENT SETS ANALYSED
The following patient analysis sets are defined for this trial:

Screened Set (SCR): includes all patients who signed informed consent.

Randomised Set (RS): includes all patients who were screened for the trial and were 
randomised to trial treatment, regardless of whether any trial treatment was 
administered.

Treated Set (TS): includes all patients who signed informed consent and were treated 
with at least one dose of the trial medication. The TS is used for safety analyses as 
well as demographics and baseline characteristics.

Full Analysis Set (FAS): includes all patients in treated set who had non-missing
baseline and at least one non-missing post-baseline and on-treatment measurement on
any primary, secondary or further biomarker endpoint. Patients in FAS are analysed 
according to the intent-to-treat principle.

Per Protocol Set (PPS): includes all patients from the FAS without IPVs leading to 
exclusion. 

 


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
ECG Set (ECGS): This patient set includes all patients in the TS who do not have 
artificial cardiac pacemakers and have at least one on-treatment value for at least one 
ECG endpoint, which is not excluded due to ECG relevant protocol violations. 
Relevant protocol violations may be e.g. the use of pro-arrhythmic medications.
Exclusion of single ECG values due to relevant PVs is to be decided no later than in 
the BRPM before data base lock and will be documented in the CTR.

ECG Pharmacokinetic Concentration Set (ECGPCS): This patient set includes all 
patients from the ECGS who provide at least one pair of a valid drug plasma 
concentration and a corresponding (i.e. time-matched) ECG endpoint on-treatment to 
be used in the exposure-response analysis. Since placebo patients will be included in 
the exposure response analyses with plasma concentrations set to 0, a plasma 
concentration BLQ is considered a valid drug plasma concentration for placebo 
patients. The decision about concentration value validity needs to be assessed within 
the Clinical Pharmacology group. The decision whether a time deviation between PK 
blood sampling and ECG recording is acceptable (and thus whether the pair of values 
will be used) is to be made no later than at the BRPM before data base lock.
Table 6.3: 1
Patient sets analysed
Patient set
Class of endpoint
SCR
TS
FAS
PPS
ECGS
ECGPCS
Primary and secondary 
endpoints 
x
 
 
Safety endpoints
x
ECG endpoints
x
x**
Demographic/baselin
e endpoints
x
Important protocol 
violations
x
Disposition
x
; ** only for exposure response analysis


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Based on the different reasons of patients’ data missing for different endpoints, various
methods will be used to assess the impact of missing data on the efficacy endpoints of this
trial, depending upon the type of the endpoint:
6.6.1
Definition of criteria for censoring
The new introduction or change of concomitant therapies can influence certain study 
endpoints of interest. To allow the assessment of the impact of such changes, specific 
efficacy endpoint values after changes of concomitant medication will be set to missing. I.e. 
there may be the case that there is a an IPV with regard to D1 or D2 which only leads to 
exclusion of certain measurements within a certain time frame, but not to exclusion of the 
patient from the analysis set. This will be decided and documented before DBL.
6.6.2
Endpoint specific handling of missing data
Primary endpoint:
Handling of missing AOC3 activity values is covered by using multiple imputation described 
in more detail in Section 7.3.1 of the CTP. Sensitivity analyses with other methods how to 
handle missing values are described in Section 7.4.2.
Secondary biomarker endpoints:
Missing values of the secondary biomarker endpoints are directly handled within the applied 
MMRM model based on the likelihood method under the “missing at random” assumption.
 
 
Safety endpoints and other variables:
As already described in the CTP Section 7.5 it is not planned to impute missing values. The 
only exceptions where imputation might be necessary for safety evaluation are AE dates. 


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Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (3)).
ECG variables:
If single cardiac cycles of an ECG (out of the three) are missing, the arithmetic mean for this 
single ECG will be computed with the reduced (1 or 2) number of cardiac cycles.
For the classification of the on-treatment QTc/QT intervals into ‘no new onset’ / ‘new onset’ 
categories, a missing value is obtained only in case that 
i.
all on-treatment values are missing and 
ii.
the baseline value is less than or equal to 500 msec, or missing. 
If condition (i) is fulfilled but the baseline value is greater than 500 msec, this case will be 
categorized as ‘no new onset’. If baseline is missing and the maximum on-treatment QTc 
interval is greater than 450 msec (or 500 msec for QT interval, respectively), this is classified 
as a ‘new onset’ in the respective category. If baseline is missing and the maximum QTc 
interval is less than or equal to 450 msec (or 500 msec for QT interval, respectively), this will 
be categorized as ‘no new onset’. If baseline is missing, a QTc/QT interval > 500 msec at any 
time on treatment will be a notable finding.
For patients on active drug, missing plasma concentration values with ‘BLQ’ in the comment 
field will be replaced by ½ LLOQ.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Unless a different definition is provided below, baseline values are the last measurements 
taken prior to the first administration of trial treatment. If this value is not available, the 
measurement at the screening visit is used.
Centralized 12-lead ECG
There will be a centralised evaluation of all 12-lead ECG recordings at the time points 
specified in the Table 6.7: 1 below for the first of the three replicate ECGs at a single 
assessment time, except for baseline where triplicates are used. The baseline value of an ECG 
variable is then defined as the mean of the triple ECG measurements prior to drug 
administration:


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Table 6.7: 1
Time schedule of 12-lead ECG recordings
Visit
Planned Day
Planned time relative to 
drug administration
[hh:mm]
Study phase
1
Within -28 to-7 days 
before drug 
administration
Baseline
2
1
1.5
On-treatment
3
15
1.5
4
29
1.5
5
43
1.5
6
57
1.5
EOT/
ED
85
1.5
FU
EOT+28
-
For the exposure response analyses, pair of ECG variables and corresponding plasma 
concentrations will be built using the same planned time points, e.g. HR change from 
baseline and plasma sample taken at planned time 0:30 will build one pair. Whether a time 
deviation between PK sample and corresponding ECG extraction is too big and the pair has 
to be excluded or matched to another time point will be decided no later than at the 
BRPM/DBLM.
For quantitative analysis except exposure response analysis, data will be presented according 
to visit window described below.
Table 6.7: 2
Visit window for centralized ECG endpoints
Interval Definition
Visi
t
Planned 
day
From day
To day
Visit description
1
-28 to -7
-28
-1
Baseline
2
1
1
1
Day 1
3
15
2
22
Day 15 (week 2)
4
29
23
36
Day 29 (week 4)
5
43
37
50
Day 43 (week 6)
6
57
51
71
Day 57 (week 8)
EOT
85
72
Date of drug intake in 
EOT visit+1
Day 85 (week 12)
FU
113
Date of drug intake in 
EOT visit+2
Last assessment date
Day 113 (FU)


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Primary endpoint:
Table 6.7: 3
Visit window for AOC3
Interval Definition
Visit
Planned 
day
From day
To day
Visit description
2
1
1
1
Baseline*
1
1
7
Day 1*
3
15
8
22
Day 15 (week 2)
4
29
23
36
Day 29 (week 4)
5
43
37
50
Day 43 (week 6)
6
57
51
71
Day 57 (week 8)
EOT
85
72
Date of drug intake in 
EOT visit+1
Day 85 (week 12)
FU
113
Date of drug intake 
in EOT visit+2
Last assessment date
Day 113 (FU)
*before drug admin its baseline, afterwards its Day 1
In addition to the visit window, a time window for planned time should be used for AOC3 as
defined in the table below.
Table 6.7: 4
Time window for AOC3
Planned time
Interval definition (in minutes after
treatment administration in that visit)
Planned Day
hour
minute
from
to
1, 29
-0.5
-30
-150
0
0.5
30
1
45
1
60
46
90
2
120
91
150
3
180
151
270
6
360
271
420
8
480
421
540
15, 43, 57
-0.5
-30
-150
0
85
-0.5
-30
-150
0
0.5
30
1
45
1
60
46
90
2
120
91
150
3
180
151
270
6
360
271
420
8
480
421
960
24
1440
961
1620
113*
672
40320
Sample taken on follow up visit
* For follow-up visit time from treatment administration in EOT visit is considered. 


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Secondary biomarker endpoints:
Table 6.7: 5
Visit window for secondary and further biomarker endpoints*
Interval Definition
Visit
Planned 
day
From day
To day
Visit description
1
-28 to -7
NA
0
Screening
2
1
1
1
Baseline**
3
15
8
22
Day 15 (week 2)
4
29
23
36
Day 29 (week 4)
5
43
37
50
Day 43 (week 6)
6
57
51
71
Day 57 (week 8)
EOT
85
72
Date of drug intake in 
EOT visit +1
Day 85 (week 12)
FU
113
Date of drug intake in 
EOT visit +2
Last assessment date
Day 113 (FU)
*Measurements that are within some definition gaps will be assigned to the later window but will not be valid 
for the analysis of the window
**last value before drug admin is baseline, all previous measurements are called screening, when the
measurement before first drug administration was done more than 8 weeks before first drug admin, this value 
will not be used as baseline.
For parameters which are not measured at each visit, still the defined windowing from Table 
6.7:5 for the respective visit applies.
Safety endpoints including vital signs and lab parameters
Table 6.7: 6
Visit window for safety endpoints
Interval Definition
Visit
Planned day
from
to
Visit description
1
-28- -7
NA
0
Screening
2
1
1
1
Baseline*
3
15
2
22
Day 15 (week 2)
4
29
23
36
Day 29 (week 4)
5
43
37
50
Day 43 (week 6)
6
57
51
71
Day 57 (week 8)
EOT
85
72
Date of drug intake 
in EOT visit +14
Day 85 (week 12)
FU
113
Date of drug intake in 
EOT visit +15
Last assessment date
Day 113 (FU)
*last value before drug admin is baseline, all previous measurements are called screening, when the baseline 
measurement was done more than 8 weeks before first drug admin, this value will not be used anymore.


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Screening visits will only be shown in listings. If there is no measurement at the baseline 
visit, the screening measurement which is closest to the drug administration will be taken.
Repeated and unscheduled efficacy measurements will be listed in SDL according to visit 
window described below. Only one observation per time window will be selected for analysis 
at an on-treatment visit. 
For efficacy measurements, the value will be selected which is closest to the protocol planned 
visit day.
For safety analysis except vital signs, worst value will be selected for analysis in case of 
multiple values within one visit window (see guidance for Handling, Display and Analysis of 
Laboratory Data (6)). For vital signs measurements, the value will be selected which is 
closest to the protocol planned visit day.


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7.
PLANNED ANALYSIS
In general the display format of the analysis results follows BI guideline and standards as
much as possible.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min
minimum
Median 
median
Max 
maximum
Biomarker and safety lab values will show in addition Q1 (25th percentile) and Q3 (75th 
percentile).
For plasma concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10
10th percentile 
Q1
25th percentile 
Q3
75th percentile 
P90
90th percentile 
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient
set whether they have non-missing values or not). 
The precision for percentages should be one decimal point, unless the denominator is smaller 
than 100 (in all treatment columns), in which case percentages are given in integer numbers.
The category missing will be displayed only if there are actually missing values.


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The individual values of all patients will be listed, sorted by treatment group, centre
(investigator site), patient number and visit, with ascending doses starting with placebo. The
source data listings (SDL) will be contained in Appendix 16.2 of the CTR.
The tables and graphs will be contained in CTR in-text and Section 15.1-7 or in Appendix 
16.1.9.13.
 
Analysis of biomarkers will be presented in 15.7 of the CTR and in Appendix 16.1.9.13.6
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. The evaluation of 
demographics and baseline characteristics will be based on the TS. The data will be 
summarized separately for each treatment and in total. Additionally the demographics and 
baseline biomarker parameters will be summarized for the defined subgroups in Section 6.4.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report using the treated set.
Concomitant therapies (CTs) are coded according to WHO DD. CTs will be classified
according to the Anatomical, Therapeutic, Chemical (ATC) classification system. The third
ATC level will be used to categorise CTs by therapy type. In situations where a medical
product may be used for more than one equally important indication, there are often several
classification alternatives. As appropriate, patients receiving CTs with more than one possible 
ATC level-three category will be counted more than once; a footnote will clarify this possible 
double counting in tables. Summaries will be presented for new concomitant therapies added 
during randomised treatment phase and those taken at baseline. Therapies will be considered 
new if the added therapy is coded to a preferred name, where the patient did not report any 
medication that was coded to the same preferred name at baseline, except if the medication 
was stopped for more than one week.
Concomitant diseases are coded similarly as AEs based on the most current MedDRA®
version. A summary of concomitant diseases will be provided by treatment group, system
organ class (SOC), and preferred term (PT) and sorted alphabetically.
The coding version number will be displayed as a footnote in the respective output.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The number and
percentage of patients with overall compliance will be reported. Overall compliance will be
calculated as a weighted average of reported compliance. The sum of all reported compliance


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over the observed visits 2 to EOT visit will be multiplied by their duration and then divided 
by 100.
Example:
70% compliance between visit 2-3 (2 weeks)
90% compliance between visit 3-4 (2 weeks)
95% compliance between visit 4-5 (2 weeks)
100% compliance between visit 5-6 (2 weeks)
75% compliance between visit 6-EOT (4 weeks)
Overall compliance = (70*2+90*2+95*2+100*2+75*4)/12= 84%
This patient would be overall compliant, but he didn’t reach 80% compliance within the last 4 
weeks of treatment, so he will be excluded from PPS.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis
The primary analysis of the primary endpoint will be performed as described in the CTP 
Section 7.3.1.
Relevant time points are:
predose (-0:30h relative to drug administration) at visit 2,3,4,5,6 and 24h at EOT. In case of 
missing 24h value at EOT, predose value planned -0.5h relative to drug administration can be 
used.
To account for heterogeneity between active and placebo treatment the power of mean 
variance estimates (POM) according to the paper (R17-1924) will be used.
 
 
 
 
 
 
 
 
 
 
 


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
Primary analysis
The number (%) patients with adverse reactions will be evaluated descriptively based on the 
TS. For more details see Section 7.8.1.
The primary analysis of the secondary biomarker endpoints defined in Section 5.2.2 is a 
MCPMod analysis with a previous applied MMRM model.
First a Mixed effects Model for Repeated Measurements (MMRM) over time is applied to the 
log transformed data (natural logarithms). The model will include the fixed effects 'base', 
'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. The covariance 
model for the repeated effect 'time' will be unstructured (i.e. TYPE=UN or UNR). For each 
dose group and each time point, the contrast of the means for ‘treatment-placebo’ will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means); two-
sided 90% CIs based on the t-distribution will also be computed. Baseline and all on-
treatment time points will be used within the analysis. In case of convergence problem step 1-
4 from Section 9.1.3 can be applied. The time profiles of the mean differences to placebo of 
the relative ALT (AST, AP, -GT, CK-18 caspase and CK-18 total respectively) change from 
baseline and the corresponding 90% CIs will be presented in a figure (back transformed on 
original scale using delta-delta method to calculate approximate SE and CIs). The dose-
response relationship of the week 12 estimates from MMRM will then be analysed using 
MCPMod.
The Multiple Comparison Procedures and Modelling (MCP-Mod) approach (R10-1424, R15-
4293) is implemented in two main steps: (1) trial design stage; (2) trial analysis stage. The 
procedures for the trial design stage, including the selection of candidate models covering a 
suitable range of dose-response shapes and sample size and power calculations, are provided 
in the CTP Section 7.3.2 and 7.7. The procedures for the trial analysis stage are specified 
below.
The treatment difference estimates over placebo for each active dose group, as well as their 
estimated variance-covariance matrix estimate from the MMRM are used in the trial analysis 
stage. Multiple comparison procedure will be implemented using optimal contrast tests which 
control the family-wise type I error rate at one-sided α = 0.05. The optimal contrasts 


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corresponding to the candidate models are calculated as in the trial design stage and are 
shown in Table 7.5.2: 1. They will be updated using the expected model means from 
candidate set and the estimated variance-covariance matrix from the data.
Table 7.5.2: 1 Contrast coefficients
Contrast coefficients for dose
Model
Dose
0 mg
Dose 
1 mg
Dose 
3 mg
Dose 
6 mg
Dose 
10 mg
Linear
0.492
0.369
0.123
-0.246
-0.739
Linear in log
0.797
0.141
-0.143
-0.328
-0.466
Quadratic
0.598
0.377
0.003
-0.388
-0.591
Exponential
0.387
0.336
0.204
-0.099
-0.828
Emax
0.831
0.094
-0.210
-0.329
-0.385
Sigmoid Emax
0.462
0.453
0.135
-0.453
-0.597
Logistic
0.468
0.418
0.168
-0.422
-0.632
Beta model
0.449
0.280
-0.452
-0.627
0.350
If at least one dose-response model is statistically significant, rejecting the null hypothesis of 
a flat dose-response curve is indicating a benefit of BI 1467335 over placebo.
When the null hypothesis is rechecked, the best-fitting model from the above set of eight 
models can be refitted to the data without any parameter assumptions to generate new 
estimates of the model parameters from the data. The target dose will be obtained via model 
averaging across the significant models based on Akaike Information Criterion (AIC) (the 
smaller the AIC value the better the model fit).
 
 
 
 


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7.7
EXTENT OF EXPOSURE
Basis for the assessment of the treatment exposure will be the amount of trial medication 
intake and the duration of exposure counted in days. Standard statistical parameters will be 
displayed by treatment.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and NOT on the number of AEs. The 
reporting and analyses of AEs will follow the BI guideline (4).


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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 (LLT, intensity according to CTCAE Version 4.03, 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 
2 occurrences is given if the second occurrence started on the same day or on the day after 
the end of the first occurrence) 
For further details on summarization of AE data, please refer to guidelines (3, 4).
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake until trial 
termination date will be assigned to the treatment they were randomised to. All adverse 
events occurring before first drug intake will be assigned to ‘screening’. For details on the 
treatment definition, see Section 6.1.
According to ICH E3 (5), 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 a Medical Quality Review 
Meeting.
An overall summary of adverse events for BI 1467335 will be presented. For further details 
on which summaries will be provided see Section 6.1.
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class and preferred term. Separate tables will be provided for patients with 
other significant adverse events according to ICH E3 (5), for patients with adverse events of 
special interest and for patients with serious adverse events.
The system organ classes will be sorted alphabetically; preferred terms will be sorted 
alphabetically as well (within system organ class).
7.8.2
Laboratory data
The analyses of safety laboratory data will be descriptive in nature and will be based on BI 
standards (6).
For continuous safety laboratory parameters standardised and normalised values will be
derived as well as the differences to baseline. The process of standardisation and
normalisation as well as standard analyses for safety laboratory data are described in the BI
guidance for the Display and Analysis of Laboratory Data (6).
Laboratory values will be compared to their reference ranges and frequency tables will be
provided for the number of patients within and outside the reference range at baseline and 
with 12 weeks of treatment and with the follow up visit 4 weeks after last drug 
administration. Descriptive statistics will be provided by treatment group for baseline, on-


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treatment values and for changes from baseline. Frequency tables will summarise the number 
of patients with potentially clinically significant abnormalities as defined for the new XLAB 
macro.
Clinically relevant findings in laboratory data will be reported as AEs and will be analysed as
part of AE analysis.
The Estimated Glomerular filtration rate as assessed by the CKD-EPI formula:
eGFR (ml/min/1.73 m²) = 141 *min(SCr/κ, 1)α *max(SCr/κ, 1)-1.209 *0.993Age *1.018 [if 
female] * 1.159 [if black]
where SCr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicates the minimum of SCr/κ or 1, and max indicates the 
maximum of SCr/κ or 1. The process of standardisation and normalisation as described in the 
guidance document (6) does not apply. Additionally the shift tables for eGFR will use the 
following categories (similar to the staging of renal impairment): eGFR ≥ 90; 60-<90; 30-
<60; and<30.
7.8.3
Vital signs
Descriptive statistics of absolute values, changes from baseline and compared to placebo of 
the exploratory vital signs endpoints defined in Section 5.3.2 over time will be provided.
Clinically relevant findings in vital signs data will be reported as AEs and will be analysed as
part of AE analysis.
7.8.4
ECG
All evaluation of ECG data except of exposure response analysis will be based on the ECGS. 
The exposure-response analysis will then be done on the ECGPCS.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. 
Occurrences of notable findings will be flagged.
For all patients with any notable finding in quantitative ECG recordings, a separate listing 
will be created as end-of-text display (based on the same display template as in Appendix 
16.2), and the corresponding time profiles will be shown.
Comments regarding the ECGs will be listed.
Analyses categorical Endpoints
For the categorical endpoints, frequency tables will be provided.


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The findings (ECG abnormalities) resulting from morphological analyses of the ECGs will also 
analysed as categorical endpoints. 
Analyses of quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the absolute 
values as well as the changes from baseline over time for QTcF, HR, QT, PR and QRS. Time 
profiles of mean and SD for the changes from baseline on treatment will be displayed 
graphically by treatment.
For QTcF and HR changes from baseline the relationship to the corresponding plasma 
concentration is evaluated using an exposure response model.
For the following analyses, all time points with available ECG endpoints and corresponding 
plasma concentrations will be included. For patients on active drug, in case of BLQ values 
they will be replaced by ½ LLOQ for analysis.
The changes from baseline in QTcF (QTcF) can be investigated as response variable. The 
placebo patients in the analysis will be included, with zero plasma concentrations. 
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to 
metabolites) effect of the drug on QTcF. A general visual impression will be provided by 
overlaying time profiles of plasma concentrations and QTcF changes from baseline 
(QTcF).All figures will be generated for each patient (presented in Appendix 16.1.13.1.9.1
of the CTR), as well as for means per active treatment (presented in Section 15.3 of the CTR).
The relationship between BI 1467335 plasma concentrations and QTcF changes from 
baseline will be investigated in an exploratory manner using a random coefficient model to 
estimate the difference in means between BI 1467335 and placebo of QTcF change from 
baseline and its 90% confidence interval at the geometric mean of Cmax for each dose. 
Additionally, the estimated overall slope with its 90% confidence interval will be provided. 
The used random coefficient model is based on a white paper from Garnett et. al. (R18-0143)
with QTcF as response variable, centered baseline QTc and plasma concentration as 
continuous covariates, treatment and day as fixed categorical effects, and a random intercept 
and slope for each patient. For more details refer to Section 9.1.2.
For visualization, a scatterplot of the BI 1467335 plasma concentration against the following 
individual QTcF values will be provided: For each patient on active treatment and each time 
point, subtract the mean value of all individual observed ΔQTcF values from the placebo 
group for this time point from the individual observed ΔQTcF value for this patient and time 
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used 
for plotting purposes. The corresponding regression line and its pointwise confidence bands 
as well as and the geometric mean of Cmax for each dose will additionally be displayed in the 
plot.
To check model assumptions, the conditional residuals will be plotted and presented in 
Appendix 16.1.13.1.9.1 of the CTR. In case of non-linearity or if there is evidence for a 


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delayed effect, further models will be explored in order to better characterise the PK-ECG 
relationship (e.g. effect compartment models, non-linear models, etc.).
All of the above described graphical and statistical analyses will be also performed for HR in 
place of QTcF.
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval (values log-transformed using the natural 
logarithm) will be estimated by applying the random coefficient model described in Section 
9.1.1 using all time points. A scatterplot of QTcF vs RR including the overall regression line 
will be included in the Statistical Appendix of the CTR. The resulting (fixed effect) slope 
together with two-sided 95% confidence intervals will be included in the footnote for this 
plot. 


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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.
 
 
 
5.
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
 
7.
R18-0143: Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al; Scientific 
white paper on concentration-QTc modeling. J Pharmacokin Pharmacodyn (2017)
8.
R05-0788: Hoffman D, Kringle R, Lockwood G, Turpault S, Yow E, Mathieu G. 
Nonlinear mixed effects modelling for estimation of steady state attainment. Pharm Stat. 
2005.
9.
R17-1924: Giltinan, D.M. & Ruppert, D. Fitting Heteroscedastic Regression Models to 
Individual Pharmacokinetic Data Using Standard Statistical Software. Journal of 
Pharmacokinetics and Biopharmaceutics (1989) 17: 601.
10. R10-1424: Pinheiro J, Bornkamp B, Bretz F; Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures.; J Biopharm Stat 16 (5), 639 
- 656 (2006)
11. R15-4293: Pinheiro J, Bornkamp B, Glimm E, Bretz F; Model-based dose finding under 
model uncertainty using general parametric models.; Stat Med 33 (10), 1646 - 1661 
(2014)
12. R17-3207: P. Angulo, Jason M, G Machesini, et al. The NAFLD Fibrosis Score: A 
Noninvasive System That Identifies Liver Fibrosis in Patients with NAFLD. Hepatology 
2007; 45;846-854
13. R17-3206: Sterling RK, Lissen E, Clumeck N, et. al. Development of a simple 
noninvasive index to predict significant fibrosis patients with HIV/HCV co-infection. 
Hepatology 2006;43:1317-1325.
14. R17-3205: Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate 
aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an 
updated meta-analysis. Hepatology. 2011;53:726-36.
 


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17. R10-2920: Ring A; Statistical models for heart rate correction of the QT interval; Stat 
Med 29, 786-796 (2010)
18. R15-2001: Bornkamp B; Pinheiro J; Bretz F, Package 'DoseFinding' (February 19, 
2015). http://cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf (access  
date: 28 April 2015) ; Comprehensive R Archive Network; 2015.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
03-APR-2017
None
This is the initial TSAP with necessary 
information for trial conduct
FINAL
10-AUG-2017
All
This is the final TSAP version. All 
missing information from initial TSAP 
version was added.