Clinical trial NCT02999191
Conditions: Healthy Volunteers
Sponsor: Boehringer Ingelheim
Start date: 2017-01-10; Completion date: 2017-04-10
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objective of this trial is to investigate the relative bioavailability of BI 1467335, given as film-coated tablet compared to BI 1467335, given as oral solution. This assessment will be performed under fasted conditions. Furthermore, the effect of food on relative bioavailability of the tablet formulation of BI 1467335 will be investigated.

Detailed description:

Arms: arm 1: Tablet under fasted conditions arm 2: Oral solution under fasted conditions arm 3: Tablet under fed conditions
Interventions: intervention 1: BI 1467335 (Treatment A) intervention 2: BI 1467335 (Treatment B) intervention 3: BI 1467335 (Treatment C)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol
TITLE PAGE
Document Number:
c09164690-01
EudraCT No.:
BI Trial No.:
2016-001534-97
1386.17
BI Investigational
Product:
BI 1467335
Title:
Relative bioavailability of a BI 1467335 tablet compared to a 
BI 1467335 oral solution and the effect of food on the bioavailability 
of the tablet following oral administration (a randomised, open-label, 
single dose, three-way crossover trial in healthy male subjects)
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version: 1.0
Date: 12 October 2016
Page 1 of 62
Proprietary confidential information
© 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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BI Trial No.: 1386.17
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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1467335
Protocol date:
Trial number:
Revision date:
Not applicable
12 October 2016
1386.17
Title of trial:
Relative bioavailability of a BI 1467335 tablet compared to a BI 1467335 oral 
solution and the effect of food on the bioavailability of the tablet following oral 
administration (a randomised, open-label, single dose, three-way crossover trial in 
healthy male subjects)
Principal Investigator:
Trial site:
Human Pharmacology Centre, Department of Translational Medicine & Clinical 
Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, 
Germany
Clinical phase:
I
Objective(s):
To investigate (1) the relative bioavailability of 10 mg BI 1467335, administered as 
2 x 5 mg film-coated tablets (Treatment A), compared to 10 mg BI 1467335 
administered as oral solution (Treatment B), and (2) the effect of food on relative 
bioavailability of the tablet formulation (Treatment C)
Methodology:
Randomised, open-label, single dose, three-way crossover trial in healthy subjects
No. of subjects: 
total entered:
18
each treatment:
18
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 55 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Test product:
BI 1467335 film-coated tablet formulation
dose:
10 mg (2 x 5 mg)
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h (Treatment A) and in 
fed state (Treatment C)
Comparator product:
BI 1467335 oral solution formulation
dose:
10 mg
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h (Treatment B)
Duration of treatment: One day for each treatment (3 single doses), separated by washout periods of at least 
21 days
Criteria for
pharmacokinetics:
Primary endpoints: AUC0-tz and Cmax of BI 1467335


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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1467335
Protocol date:
Trial number:
Revision date:
Not applicable
12 October 2016
1386.17
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead electrocardiogram (ECG), vital signs 
(blood pressure [BP], pulse rate [PR])
Statistical methods:
Relative bioavailability will be estimated by the ratios (tablet formulation fasted/oral 
solution fasted; tablet fed/tablet fasted) of the geometric means for the primary 
endpoints. Additionally, their two-sided 90% confidence intervals (CIs) will be 
provided. This method corresponds to the two one-sided t-tests procedure, each at the 
5% significance level. Since the main focus is on estimation and not testing, an 
acceptance range is not specified. The statistical model will be an ANOVA on the 
logarithmic scale including effects for ‘sequence’, ‘subjects nested within sequences’, 
‘period’ and ‘treatment’. CIs will be calculated based on the residual error from 
ANOVA. Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to 
first drug administration)
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory
PK blood
 
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
x
1/2/3 (three identical periods with a wash-out of at least 21 days)
2/3/4
-5 to -1
-123:00
Visits 3 and 4 only
x8
x8
-1
-12:00
20:00
Admission to trial site 7
x5,7
x7
1
-1:00
07:00
Allocation to treatment2 (Visit 2 
only)
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast 
(only in fed state - Treatment C)
0:00
08:00
Drug administration
0:15
08:15
x
0:30
08:30
x
x
x
0:45
08:45
x
1:00
09:00
x
x
x
x
1:15
09:15
x
1:30
09:30
x
1:45
09:45
x
2:00
10:00
240 mL fluid intake
x
x
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
Dinner 3
x
12:00
20:00
x
x
x
x
2
24:00
08:00
Discharge from trial site, breakfast3
(voluntary)
x
x
x
x
x
EOT
5
22-29
End of trial (EOT) examination4
x
x
x
x
1.
Subjects must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. 
 
2.
The time is approximate; the procedure is to be performed and completed within 3 h prior to drug administration
3.
If several actions are indicated at the same time point, the intake of meals will be the last action
4.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies
5.
Only urine drug screening and alcohol breath test
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above
7.
The time is approximate; the procedure is to be performed no later than 10 h prior to scheduled drug administration
8.
Safety laboratory to be taken within 5 days prior to administration of study drug; in visits 3 and 4, only. AE and CT 
questioning to be done at this occasion.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................12
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 16
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................16
2.2
TRIAL OBJECTIVES.......................................................................................16
2.3
BENEFIT - RISK ASSESSMENT ...................................................................16
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 19
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................19
3.1.1
Administrative structure of the trial...................................................19
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................20
3.3
SELECTION OF TRIAL POPULATION ......................................................20
3.3.1
Main diagnosis for study entry............................................................20
3.3.2
Inclusion criteria...................................................................................21
3.3.3
Exclusion criteria ..................................................................................21
3.3.4
Removal of subjects from therapy or assessment..............................22
3.3.4.1
Removal of individual subjects................................................22
3.3.4.2
Discontinuation of the trial by the sponsor..............................23
3.3.5
Replacement of subjects .......................................................................23
4.
TREATMENTS........................................................................................ 24
4.1
TREATMENTS TO BE ADMINISTERED....................................................24
4.1.1
Identity of BI investigational product and comparator product......24
4.1.2
Method of assigning subjects to treatment groups ............................24
4.1.3
Selection of doses in the trial................................................................25
4.1.4
Drug assignment and administration of doses for each subject .......25
4.1.5
Blinding and procedures for unblinding ............................................26
4.1.6
Packaging, labelling, and re-supply ....................................................26
4.1.7
Storage conditions.................................................................................27
4.1.8
Drug accountability ..............................................................................27


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4.2
OTHER TREATMENTS, EMERGENCY-PROCEDURES, 
RESTRICTIONS ...............................................................................................28
4.2.1
Other treatments and emergency procedures....................................28
4.2.2
Restrictions............................................................................................28
4.2.2.1
Restrictions regarding concomitant treatment .........................28
4.2.2.2
Restrictions on diet and life style.............................................28
4.3
TREATMENT COMPLIANCE.......................................................................29
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 30
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................30
5.1.1
Endpoints of efficacy.............................................................................30
5.1.2
Assessment of efficacy...........................................................................30
5.2
SAFETY..............................................................................................................30
5.2.1
Endpoints of safety................................................................................30
5.2.2
Assessment of adverse events...............................................................30
5.2.2.1
Definitions of adverse events...................................................30
5.2.2.2
Adverse event collection and reporting ...................................33
5.2.3
Assessment of safety laboratory parameters......................................35
5.2.4
Electrocardiogram................................................................................38
5.2.5
Assessment of other safety parameters...............................................38
5.2.5.1
Vital signs ................................................................................38
5.2.5.2
Medical examinations..............................................................38
...............................................................................................................39
..............................................................39
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................39
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................39
5.5.1
Pharmacokinetic endpoints..................................................................39
5.5.1.1
Primary endpoints....................................................................39
5.5.1.2
Key /Secondary endpoint.........................................................40
..................................................40
5.5.2
Methods of sample collection...............................................................40
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................40
5.5.3
Analytical determinations ....................................................................41
5.5.3.1
Analytical determination of BI 1467335 plasma     
concentration............................................................................41
...............42
...............42
...............42
...............42
...............43
5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....43
6.
INVESTIGATIONAL PLAN.................................................................. 44


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6.1
VISIT SCHEDULE............................................................................................44
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................44
6.2.1
Screening period....................................................................................44
6.2.2
Treatment periods.................................................................................44
6.2.3
End of trial examination.......................................................................45
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 46
7.1
STATISTICAL DESIGN – MODEL ...............................................................46
7.1.1
Objectives...............................................................................................46
7.1.2
Endpoints...............................................................................................46
7.1.3
Model......................................................................................................46
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................47
7.3
PLANNED ANALYSES....................................................................................47
7.3.1
Primary endpoint analyses...................................................................47
....................................................................................48
7.3.3
Safety analyses.......................................................................................48
7.3.4
Interim analyses ....................................................................................49
7.3.5
Pharmacokinetic analyses ....................................................................49
...............................................................................49
....................49
7.4
HANDLING OF MISSING DATA ..................................................................50
7.4.1
Safety......................................................................................................50
7.4.2
Plasma drug concentration - time profiles..........................................50
7.4.3 Pharmacokinetic parameters...............................................................50
7.5
RANDOMISATION ..........................................................................................50
7.6
DETERMINATION OF SAMPLE SIZE ........................................................50
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 53
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................53
8.2
DATA QUALITY ASSURANCE .....................................................................53
8.3
RECORDS..........................................................................................................54
8.3.1
Source documents .................................................................................54
8.3.2
Direct access to source data and documents.......................................54
8.3.3
Storage period of records.....................................................................54
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................55
8.5
STATEMENT OF CONFIDENTIALITY.......................................................55
8.6
COMPLETION OF TRIAL..............................................................................55
9.
REFERENCES......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56
9.2
UNPUBLISHED REFERENCES.....................................................................56


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10. APPENDICES .......................................................................................... 58
10.1
RECONSTITUTION INSTRUCTION............................................................58
10.1.1 Drug supplies overview.........................................................................58
10.1.2 Required equipment and dosing aids - overview ...............................58
10.1.3 Reconstitution procedure.....................................................................58
10.1.3.1 Reconstitution procedure for the preparation of the active 
BI 1467335 oral solution 0.5 mg/mL (Treatment B)...............58
10.1.4 Illustration of reconstitution procedure..............................................59
10.1.5 In-use stability.......................................................................................60
10.1.6 Mode of application ..............................................................................60
10.1.7 General remarks - important! .............................................................61
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 62


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ABBREVIATIONS
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BCS
Biopharmaceutics classification system
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
 
Cmax
Maximum measured concentration of the analyte in plasma
C(')tz
Measured (predicted) concentration of the analyte in plasma at the last time 
tz at which quantification of the analyte in plasma was still possible
CT
Concomitant treatment
CTP
Clinical trial protocol
CTR
Clinical trial report
CTS
Clinical trial supply
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDC
Electronic data capture
EOT
End of trial
F
Absolute bioavailability 
GCP
Good clinical practice
gCV
Geometric coefficient of variation


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GLP
Good laboratory practice
gMean
Geometric mean
HPC
Human Pharmacology Centre
HPLC-MS/MS
High performance liquid chromatography with tandem mass spectrometry
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
NC
Not calculated
NCE
New chemical entity
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PfoS
Powder for reconstitution of an oral solution
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
R
Reference treatment
RDC
Remote data capture
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SfOS
Solvent for oral solution
ss
(at) steady state
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test product or treatment


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TDMAP
Trial Data Management and Analysis Plan
TMF
Trial master file
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAP
Vascular adhesion protein


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Boehringer Ingelheim (BI) is developing BI 1467335
 
 
 
in the indication of non-alcoholic steatohepatitis (NASH).
NASH is characterised histologically by a high level of steatosis, ballooning of hepatocytes, 
and necro-inflammation. NASH often leads to fibrosis which can progress to cirrhosis with a 
high risk of liver failure. 
 
 
 
 
 
 
 
 
 
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 NAFLD progress to NASH. 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 [R15-6057]. Patients with NASH are also at 
increased risk of hepatocellular carcinoma, even in the absence of cirrhosis [R15-5365]. By 
2023, about 13 million patients are projected to have NASH with advanced stages 
(i.e. ≥stage 3) of fibrosis (of those, 2.9 million in the US, 3.5 million in EU, 5 million in 
China). Individuals with advanced fibrosis are estimated to progress with a 4% annual event 
rate to cirrhosis. The risk of liver-related death in Western patients with NASH ranges from 
10% over 13.7 years to 18% over 18.5 years [P13-02280].
To date, no approved therapy for liver fibrosis or effective disease modifying regimen for 
NASH is available, despite the strong interface with metabolic syndrome, obesity and Type 2 
diabetes mellitus. The current standard of care for NASH is weight loss through diet and 
exercise to improve insulin resistance and lower fat mass which is a clinically challenging 
goal to achieve and shows minimal impact on disease progression [R15-6044].
1.2
DRUG PROFILE
BI 1467335 is a 
that is expected to 
reduce oxidative stress and hepatic inflammation in steatohepatitis and prevent progression to 
fibrosis.


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Non-clinical findings
Nonclinical pharmacology
Toxicology


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Clinical experience
BI 1467335 is currently in Phase I and has been tested in one completed and one ongoing 
healthy volunteer study, the combined single rising dose (SRD)/multiple rising doses (MRD)
study 
[c09036683] and the MRD study 1386.8 [data on file]. Drug doses in 
study 
[c09036683], 
, were based on the HCL salt 
 of BI 1467335, whereas the already applied (study 1386.8
[data on file]) and further planned doses in BI studies refer to the free base
 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This study is performed to compare (1) the bioavailability between oral solution and tablets, 
and to investigate (2) the influence of food on the absorption of BI 1467335 when 
administered as tablets.
Although BI 1467335 is characterised as 
and 
‘important food effects on bioavailability are least likely for some drugs in this class, food 
can influence bioavailability, when there is a high first pass effect, extensive adsorption, 
complexation or instability of the drug substance in the gastrointestinal tract. In some cases, 
excipients or interactions between excipients and the food induced changes in the gut 
physiology can contribute to these food effects’ [R03-2269].
In future clinical studies, the preferred mode of administration of BI 1467335 will be 
‘independent of food intake’. Currently, only pharmacokinetic data under fasted conditions 
are available. The planned food interaction study will generate pharmacokinetic information
under fed conditions to support the future development in patients.
 
 
 
 
The dose of 10 mg was selected in this study, since it is intended to be used as maximum
dose in NASH-patients.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the relative bioavailability of 10 mg of 
BI 1467335, given as film-coated tablet compared to BI 1467335, given as oral solution. This 
assessment will be performed under fasted conditions. Furthermore, the effect of food on 
relative bioavailability of the tablet formulation of BI 1467335 will be investigated. 
 
.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects.


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However, their participation in the study is of major importance to the development of a new 
therapy for NASH. Subjects are exposed to risks related to (1) study procedures and (2) 
exposure to trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases, a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
Polymorph nuclear leukocytes (PMNs) migrate from the blood into areas of inflammation by 
binding to the endothelial cells of blood vessels via adhesion molecules.
 
 
 
On target effects
BI 1467335 could cause on-target toxicity as its anti-inflammatory effects may reduce the 
immune response and thus worsen infections. However, a deleterious effect relating to a 
reduction in leukocyte or lymphocyte migration was not seen in any of the preclinical models.
Nonetheless, close monitoring of clinical and laboratory signs of reduced immune response 
will be performed throughout the study.
Cardiac safety
Genotoxicity and fertility
Eye toxicity


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Human safety profile
The human safety and tolerability profile in male healthy subjects was satisfactory for single 
doses of up to 17.7 mg (
[c09036683]) and for multiple doses given over 28 consecutive days of up to 10 mg in study 
1386.8 [data on file] (see Section 1.2). There were no deaths or other serious adverse events. 
Adverse events, mostly reported as mild, had no apparent dose or exposure relationship.
Conclusion
Overall, no specific drug-related risks are anticipated. Still, the following safety 
considerations were made in order to minimize the risk for subjects in this study:

Dose selection of BI 1467335 is based on previous clinical experience 
[c09036683] and 1386.8 [data on file]) and the available preclinical package. For 
details, please refer to ‘IB’ [c04751792].

The dose of 10 mg was selected in this study, since it is intended to be used as 
maximum dose in patients of the NASH clinical development program. Good safety 
and tolerability was demonstrated for a single dose 
 
[c09036683]. Also, 14 consecutive daily 
doses of BI 1467335 were safe and well tolerated in this 
study, and resulted in about 25-fold and 45-fold higher peak (Cmax) and systemic 
(AUC) exposures, respectively, as compared to respective single doses. Even an
unlikely food effect (see above) with a 10 mg dose should result in a range of 
exposure already previously experienced. Hence, subjects should therefore not be 
exposed to an undue risk

Nonetheless, subjects will be clinically observed (e.g. for infections) and their 
laboratory, vital signs and ECG parameters will be closely monitored.

Due to the large safety margins to the NOAEL in rats and dogs, no specific 
ophthalmological examinations (lens findings in rats) seem to be warranted in this 
study.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.2.1.
Healthy subjects are not expected to have direct medical benefit from participation in this 
study. However, it is considered that healthy subjects will not be exposed to undue risks and 
adverse events in relation to the information expected from this trial. Considering the medical 
need for the development of an effective and well tolerated drug to treat NASH, the benefit of 
this trial is considered to outweigh the potential risks and justifies the exposure of healthy
human volunteers to 3 single doses of 10 mg of BI 1467335.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, single dose, three-way crossover
trial in healthy male subjects in order to compare the tablet under fasted conditions
(Treatment A) to the oral solution under fasted conditions (Treatment B) and to assess the 
food effect on the PK of BI 1467335 by comparing the tablet under fed conditions 
(Treatment C) with the tablet under fasted conditions (Treatment A).
A total of 18 healthy male subjects are planned to participate in the trial. Subjects will be 
randomly allocated to 3 treatment sequences (ABC, BCA and CAB). The treatments will be
2 x 5 mg BI 1467335 tablet in the fasted state (Treatment A), 10 mg BI 1467335 oral solution
in the fasted state (Treatment B) and 2 x 5 mg BI 1467335 tablet in fed state after a high 
caloric breakfast (Treatment C). For details, see Section 4.1.
There will be a washout period of at least 21 days between drug administrations in 
consecutive treatment periods.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating all required 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal standard
operation procedures (SOPs)

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local clinical monitors (CML), clinical 
research associates (CRAs), and participating trial sites 


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On-site monitoring, data management and statistical evaluation will be performed by BI 
according to BI SOPs or a contract research organisation appointed by BI.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For relative bioavailability trials, the crossover design is preferred due to its efficiency. Since 
each subject serves as his own control, the comparison between formulations/treatments is 
based on a comparison within subjects rather than between subjects. Therefore, this trial 
design removes intersubject variability from the comparison between formulations/treatments
[see R94-1529].
Blinding is not possible because the treatments are distinguishable.
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte provided by a bioanalytical
laboratory which is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 18 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in healthy subjects.


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3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the investigators assessment, based on a complete 
medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and 
clinical laboratory tests
2. Age of 18 to 55 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5. Willingness to comply with contraception requirements. Subjects who are sexually active, 
must use, with their female partner, adequate contraception throughout the study and until 
one month after the last administration of trial medication. Adequate methods are:
-
Sexual abstinence or
-
A vasectomy performed at least 1 year prior to screening in combination with a 
barrier method (condom or diaphragm) or
-
Surgical sterilisation (including bilateral tubal occlusion, hysterectomy or bilateral 
oophorectomy) of the subjects female partner or
-
The use of condoms, if the female partner uses in addition an adequate 
contraception method, e.g., intrauterine device (IUD), hormonal contraception 
(e.g. implants, injectables, combined oral or vaginal contraceptives) that started at 
least 2 months prior to first drug administration, or barrier method (e.g. diaphragm 
with spermicide)
Unprotected sexual intercourse with a pregnant female partner is not allowed throughout 
the study and until one month after the last administration of trial medication.
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)


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7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication, if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication or current participation in 
another trial involving administration of investigational drug
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within 7 days prior to administration of
trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a 
condition that would not allow safe participation in the study
In addition, the following trial-specific exclusion criteria apply:
23. Cataract in the medical history
For study restrictions, see Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessment
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial, if:
1. The subject withdraws consent for trial treatment or trial participation, without the 
need to justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational


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product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as 
surgery, adverse events, or diseases)
4. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with 
an elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) 
and/or needs to be followed up according to the ‘DILI checklist’ provided in the 
ISF.
A subject can also be removed from the trial, if eligibility criteria are being violated or, if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR.
At the time of discontinuation, a complete end of trial examination will be performed, if 
possible, and the information will be recorded in the CRFs. If the discontinuation occurs 
before the end of the REP (see Section 5.2.2.2), the discontinued subject should, if possible, 
be questioned for AEs and concomitant therapies at or after the end of the REP in order to 
ascertain collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated, if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity or, if at least one drug-related serious adverse event is reported that is 
considered to be unacceptable
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP by a trial site or investigator, disturbing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational product
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide, if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number, and will 
be assigned to the same treatment as the subject 
replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational products have been manufactured by BI Pharma GmbH & Co. KG.
Doses refer to the dose of the free base.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are given below. For details about dosage and 
treatment schedule, see Table 4.1.4: 1.
Substance:
BI 1467335 Treatment A (fasted) and Treatment C (fed)
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology:
2-0-0
Route of administration:
p.o.
The characteristics of the reference product are given below:
Substance:
BI 1467335 Treatment B (fasted)
Pharmaceutical formulation: Oral solution
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
0.5 mg/mL
Posology:
20 mL -0-0
Route of administration:
p.o.
A detailed description of the reconstitution instruction for the oral solution is given in Section 
10.1 of this CTP.
4.1.2
Method of assigning subjects to treatment groups
The randomisation list of study subject numbers and assigned treatment sequences will be 
provided to the trial site in advance.
According to the planned sample size, the study is planned to be performed in two cohorts. 
Prior to start of the study, subjects willing to participate will be recruited to cohorts according 
to their temporal availability.


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The allocation of subjects to study subject numbers will be performed prior to the first
administration of trial medication in the morning of Day 1 (Visit 2). For this purpose, 
subjects will be allocated to a study subject number by drawing lots. By use of the 
randomisation list subjects are then assigned to a treatment sequence.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
The dose of 10 mg selected for this trial reflects the maximal dose intended to be applied to 
patients throughout the NASH development program. For this dose, safety data in humans are 
available (see Section 1.2).
4.1.4
Drug assignment and administration of doses for each subject
This trial is a three-way crossover study. All subjects will receive the three treatments in a 
randomised order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below.
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Predose
status
Formulation
Unit
strength
Dosage
Total
dose
A
BI 1467335 
fasted
Film-coated 
tablet
5 mg/tablet
2 tablets, single dose
10 mg
B
BI 1467335 
fasted
Oral solution
0.5 mg/mL
20 mL, single dose
10 mg
C
BI 1467335 
fed
Film-coated 
tablet
5 mg/tablet
2 tablets, single dose
10 mg
The oral solution will be prepared according to the reconstitution instruction (Section 10.1) 
by qualified medical study personnel at the trial site under the responsibility of the 
investigator.
The medication will be administered as a single oral dose together with about 240 mL of 
water to a subject in the standing position under supervision of the investigating physician or 
an authorised designee. For details of drug application, please see Section 10.1.6.
The so-called four-eye principle (two-person rule) should be applied for the administration of 
trial medication and, if applicable, its preparation (e.g. reconstitution), if correct dosage 
cannot be ensured otherwise. Except for the breakfast in Treatment C, administration will be 
performed following an overnight fast starting not later than 10 h before scheduled dosing.
To evaluate the food effect on the PK of BI 1467335 tablet, in Treatment C, a high-fat, high-
caloric meal will be served within 30 min before drug administration. The meal must be 
completely consumed prior to drug administration.


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The composition of the standard high-fat, high-caloric meal will be in compliance with the 
FDA guidance ‘Food-Effect Bioavailability and Fed Bioequivalence Studies’ [R03-2269] as 
detailed in Table 4.1.4: 2.
Table 4.1.4: 2
Composition of the high-fat, high-caloric meal
Ingredients
kcal
2 chicken eggs (whole content)1 for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum2
984
1
Alternatively liquid egg (consisting of pasteurized whole chicken egg) with an amount 
corresponding to 2 chicken eggs may be used
2
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 
Subjects will be kept under close medical surveillance until 24 h following drug 
administration. During the first 4 h after drug administration, except for ECG and vital signs 
measurements and blood withdrawals or other medical reasons, they are not allowed to lie 
down (i.e. no declination of the upper body of more than 45 degrees from upright posture).
For restrictions with regard to diet, see Section 4.2.2.2.
The treatments will be separated by a wash-out phase of at least 21 days.
4.1.5
Blinding and procedures for unblinding
No blinding will be performed because treatments are distinguishable from each other.
This Phase I trial will be handled in an open fashion throughout (i.e. during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, since all subjects receive the same dose of 
different formulations in an open label design.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply


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The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification.
The required information according to the German Drug Law as well as Annex 13/EU GMP 
Guideline will be provided on the containers. Smaller boxes within the clinical trial supply 
containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Subject or medication number (for oral solution only)

Batch number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to ensure that the drug supply is stored at the correct 
temperature. If the storage conditions are found to be outside the specified range, the local 
clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:

Approval of the study protocol by the IRB / ethics committee

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol 
Only authorised personnel, as documented in the form ‘Trial Staff List’, may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 


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written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. These records will 
include dates, quantities, batch/ serial numbers, expiry (‘use-by’) dates, and the unique code 
numbers assigned to the investigational products and trial subjects. The investigator will 
maintain records that document adequately that subjects were provided the doses specified by 
the CTP, and that reconcile all investigational products received from the sponsor. At the 
time of disposal, the investigator must verify that no remaining supplies are in the 
investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY-PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy. In these cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, subjects are restricted from consuming any other food or 
drinks than those provided by the staff. Standardised meals will be served at time points 
described in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk (in Treatment C)
served with breakfast (see Table 4.1.4: 2), the water administered with the drug, and an 
additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all subjects). From lunch 
until 24 h post-dose, total fluid intake is restricted to 3000 mL.
Alcoholic beverages, green tea, grapefruits, Seville oranges (sour or bitter oranges) and their 
juices, dietary supplements and products including St. John's wort (hypericum perforatum) 
are not permitted starting 7 days before administration of trial medication until after the last 
PK sample of the respective period is collected.
Smoking is not allowed during in-house confinement at the trial site.


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Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 24 h before until 24 h after each administration of trial 
medication.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, see Section 3.3.4.1).


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety and tolerability of the investigational drug(s) will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)
These parameters will be evaluated in a descriptive way only and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3).
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

Results in death

Is life-threatening; this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death, if more severe

Requires inpatient hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly/birth defect
or

Is to be deemed serious for any other reason, if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as given 
above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system, a remote data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
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, see Section 5.5.2.2.


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The following are considered as AESIs in this trial:
Hepatic injury, as defined by the following alterations of hepatic laboratory parameters: 

An elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or

Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure that these 
parameters are analysed, if necessary in an unscheduled blood test. Should the results 
meet the criteria of hepatic injury alert, the procedures described in the DILI checklist 
should be followed.
Intensity of AEs
The intensity of the AE should be judged based on the following:

Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated

Moderate:
Enough discomfort to cause interference with usual activity

Severe:
Incapacitating or causing inability to work or to perform usual 
activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)


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
An indication of dose-response (i.e. greater effect size, if the dose is increased, 
smaller effect size, if dose is diminished)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the study drug treatment continues or remains 
unchanged
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to spontaneously report any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. 
As a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’ Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event and
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards through the residual effect period (REP), 
until individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue the trial due 
to screening failures prior to administration of any trial medication.


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In these cases, the subjects’ data must be collected at the trial site but will not 
be entered in the CRF or trial database and will not be reported in the CTR

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report relevant SAEs and relevant AESIs of which 
 may 
become aware of
The REP of BI 1467335, when measurable drug levels or PD effects are still likely to be 
present, has not been defined yet. 
 
 (see Section 2.1), a preliminary REP is defined as 
after 
administration of BI 1467335. Therefore, all AEs which will occur throughout the treatment 
phases and the preliminary REP will be considered as ‘on treatment’ (see Section 7.3.3). 
Events which occur after the preliminary REP and prior to the next drug administration will 
be considered as ‘follow-up’ events.
AE reporting to sponsor and reporting timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately, within 24 hours of 
awareness, to the sponsor’s unique entry point (country specific contact details will be 
provided in the ISF).The same timeline applies if follow-up information becomes available. 
On 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 timelines apply as for the initial 
information.
Information required
For each AE, the investigator should provide the information requested on appropriate CRF 
pages and the BI SAE form (if applicable).
The investigator should determine the causal relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and on the SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions


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
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities have already pre-existed prior to trial inclusion, they will be 
considered as baseline conditions.
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have been resolved, sufficiently characterised, or no further 
information can be obtained.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after subjects have fasted for at least 
10 h. Overnight fasting is not required at the discretion of the investigator or designee for 
retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in section 10 of the ISF.
Manual differential white blood cell counts or urine sediment examinations will only be 
performed, if there is an abnormality in the automatic blood cell count or in the urinalysis,
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit 
Haemoglobin 
Red blood cell count (RBC) 
White blood cell count (WBC)
Platelet count
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic
differential WBC is abnormal)
Polymorphnuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Glutamate dehydrogenase (GLDH)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
Hormones1
Thyroid stimulating hormone (TSH)
fT3, fT4
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Protein electrophoresis1
Albumin1
Alpha-1-Globulin1
Alpha-2-Globulin1
Beta-Globulin1
Gamma-Globulin1
C-Reactive Protein (CRP)
Uric acid 
Total cholesterol 
Triglycerides
Electrolytes
Sodium
Potassium
Chloride
Calcium


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
Test name 
Urinalysis1 (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment (microscopic
examination, if erythrocytes, leukocytes 
nitrite or protein are abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1
Only at screening and end of trial: Hormones, protein electrophoresis, and urinalysis / urine sediment
Tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only.
Drug screening will be performed at screening and prior to each treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed prior to each treatment period, and may be 
repeated at any time during the study at the discretion of the investigator or designee. The 
results will not be included in the CTR.
Laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
with the exception of 
drug screening. This test will be performed at the trial site using AccuSign® DOA 10 test.


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Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg,
Germany) at the time points given in the Flow Chart.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. The ECG assessment will always precede all other study procedures at the 
same time point (except for blood drawings from an intravenous cannula which is already in 
place) to avoid an impact of sampling on ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. ECGs may be 
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the repeated ECG will be used for analysis. Additional (unscheduled) ECGs 
may be collected by the investigator for safety reasons.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening), if judged clinically relevant by the investigator. Any ECG abnormalities will 
carefully be monitored and, if necessary, a subject will be removed from the trial and will 
receive the appropriate medical treatment.
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) at the time indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument at the same arm,
if possible.
5.2.5.2
Medical examinations
At the screening visit, the medical examination will include demographics, including height 
and body weight, smoking and alcohol history, relevant medical history and concomitant 
therapy, review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead 
ECG, laboratory tests, and a physical examination. At the end of trial examination, it will 
include review of vital signs, 12-lead ECG, laboratory tests, body weight, and a physical 
examination.


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety, and to determine pharmacokinetic and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of trial medication. Safety assessments are standard. They are 
accepted as safety and tolerability evaluation of an orally administered drug, and are widely 
used in clinical trials. The pharmacokinetic parameters and measurements, outlined in 
Section 5.5, are generally used assessments of drug exposure. Biomarkers and measurements 
outlined in Section 5.6 are of exploratory nature only.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded.
Exact time points of plasma samples will be derived from the study management system 
ClinBase™ and documented in the CRF by the medical personnel or sent as electronic files
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be determined for BI 1467335:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)


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
Cmax (maximum measured concentration of the analyte in plasma)
5.5.1.2
Key /Secondary endpoint

No secondary endpoints are defined in this study 
5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 1467335 plasma concentrations, approximately 2.7 mL of blood will 
be taken from an antecubital or forearm vein into an 
 
at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
After blood withdrawal, 
 will be centrifuged at about 
2000 g to 4000 g and at a temperature of 4 - 8°C for about 10 minutes. Two plasma aliquots 
will be obtained 


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Until transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
about -20°C or below at the trial site. At the analytical laboratory plasma samples will be 
stored at about -20°C or below until analysis.
 
 
After centrifugation, aliquots should be pipetted and frozen as soon as possible. The first 
aliquot should contain at least 0.7 mL plasma. The second aliquot that might contain 0.7°ml 
or less plasma will be used as analytical back-up sample. For each aliquot, the time when the 
sample is placed in the freezer will be documented. The second aliquot will be transferred to 
the analytical laboratory after the bioanalyst has acknowledged safe arrival of the first 
aliquot.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, period, and planned sampling time. Further information, such as matrix and 
analyte may also be provided.
After completion of the trial, plasma samples may be used for further methodological 
investigations, e.g. for stability testing or assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years upon the final study report has been signed.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 1467335 plasma concentration
BI 1467335 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis.
The analysis will be performed at:
 
During sample analysis, the bioanalyst will be blinded to treatment allocation and will have 
no access to the random code.


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5.6
BIOMARKERS


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5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening, Visits 3 and 4, and end of trial examination are given 
in the Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 min on Day 1, and ± 60 min on Day 2.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and
12-lead ECG recordings have to be done first. Furthermore, if several measurements,
including venipuncture, are scheduled at the same time, venipuncture should be the last due 
to its inconvenience to subjects and possible influence on physiological parameters.
For planned sampling times of the PK 
 blood samples, see Flow Chart. While these 
nominal times should be adhered to as closely as possible, actual sampling times will be 
recorded and used for determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled, if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, see Sections 5.2.3 to 5.2.5.
 
6.2.2
Treatment periods
Each subject is expected to participate in each of the three treatment periods (drug 
administration on Day 1 of each period, see Table 4.1.4: 1). Treatment periods will be 
separated by at least 21 days between drug administrations.
On Day -1 of each treatment period study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration on 
Day 1. Subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. Within the time window Day -5 to -1 of Visits 3 and 4, safety 
laboratory will be taken and AE/ concomitant questioning will be done.


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For details on time points and procedures for collection of plasma samples for PK 
 
analysis, refer to Flow Chart and Sections 5.5.2 and 5.6.3.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
see Flow Chart. AEs and concomitant therapy will be assessed continuously from screening 
until the end of trial examination.
6.2.3
End of trial examination
For AE assessment, laboratory tests, body weight, recordings of ECG and vital signs, and 
physical examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objectives of this trial are to investigate by means of pharmacokinetic 
parameters (1) the relative bioavailability of 10 mg BI 1467335 administered as 2 x 5 mg 
tablets compared to 10 mg BI 1467335 administered as an oral solution, and (2) the effect of 
food on the bioavailability of the tablet formulation, following oral administration. The trial 
is designed to allow intra-subject comparisons and will be evaluated statistically by use of an 
appropriate linear model.
The secondary objective is the evaluation and comparison of several further pharmacokinetic 
parameters between treatments. The secondary objective will be assessed by descriptive 
statistics.
An additional objective of the trial will be the assessment of safety and tolerability that will 
be evaluated by descriptive statistics.
7.1.2
Endpoints
Relative bioavailability and food effect is to be determined on the basis of primary 
pharmacokinetic endpoints (see Section 5.5.1.1).
Safety and tolerability will be determined on the basis of parameters specified in 
Section 5.2.1.
7.1.3
Model
The statistical model used for the analysis of primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. This model will include effects 
accounting for the following sources of variation: ‘sequence’, ‘subjects nested within 
sequences’, ‘period’ and ‘treatment’. The effect ‘subjects within sequences’ will be 
considered as random, whereas the other effects will be considered as fixed. The model is 
described by the following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response (endpoint, see Section 5.5.1) measured on subject m in
sequence i receiving treatment k in period j
= the overall mean
i = the ith sequence effect, i = 1, 2, 3
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni


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j = the jth period effect, j = 1, 2, 3
k = the kth treatment effect, k = 1, 2, 3
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 1467335 tablet formulation (Test, T1) compared to 
BI 1467335 oral solution (Reference, R1) will be estimated by the ratios of the geometric 
means (T1/R1) for the primary PK endpoints. The effect of food on the bioavailablity of 
BI 1467335 will be estimated by the ratios of the geometric means (T2/R2) of the tablet 
under fed conditions (T2) and under fasted conditions (R2) for the primary PK endpoints.
Additionally, their two-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-tests procedure, each at the 5% significance level. Since 
the main focus is on estimation (and not testing), an acceptance range was not specified, i.e.
no hypothesis will be tested.
7.3
PLANNED ANALYSES
7.3.1
Primary endpoint analyses
All treated subjects (i.e., all subjects who received at least one dose of study drug) will be 
included in the treated set.
The pharmacokinetic endpoints listed in Section 5.5.1 will be calculated according to the BI 
SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472, current version].
Plasma concentration data and parameters of a subject will be included in the statistical PK 
analyses, if they are not flagged for exclusion due to a protocol violation relevant to the 
evaluation of PK (to be decided not later than in the Report Planning Meeting) or due to PK 
non-evaluability (as revealed during data analysis, based on the criteria specified below). 
Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be:

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication to which the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications (refer to Section 4.2.2.1)
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example:


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
The subject experienced emesis at or before two times median tmax of the respective 
treatment (Median tmax is to be determined excluding subjects having experienced
emesis)

Pre-dose concentration is >5% of the Cmax value of that subject

Samples/concentration data at critical phases of PK disposition curve are missing
The PK parameter analysis set (PKS) will include all subjects in the Treated Set (TS) who 
provide at least one primary PK parameter that is not excluded according to the description 
above. Thus, a subject will be included in the PKS, even if he contributes only one PK 
parameter value for one period to the statistical assessment.
Point estimates, the ratios of the geometric means (T/R) for the primary endpoints (see 
Section 5.5.1.1), and their two-sided 90% confidence intervals (CIs) will be provided.
To this end, the PK endpoints will be log transformed (natural logarithm) prior to fitting the 
ANOVA model (see Section 7.1.3). For each endpoint, the difference between the expected 
means for log(T)-log(R) will be estimated by the difference in the corresponding adjusted 
means (Least Squares Means), and a two-sided 90% confidence interval based on the 
t-distribution will be computed. These quantities will then be back-transformed to the original 
scale to provide the point estimate and 90% CIs for each endpoint.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (i.e., all 
subjects who received at least one dose of study drug), will be included in the safety analysis. 
Safety analyses will be descriptive and will be based on BI standards. No hypothesis testing 
is planned.
The analyses will be done by ‘treatment at onset’.
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used for the evaluation of categorical (qualitative) data, and tabulations of descriptive 
statistics will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of ‘treatment emergent AEs’).


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Therefore, all AEs which will occur throughout the treatment phase and the preliminary REP 
will be considered as ‘on treatment’. Events which occurred after the preliminary REP will be 
considered as ‘follow-up’ events (refer to Section 5.2.2.2).
These assignments, including the corresponding time intervals, will be defined in detail in the 
TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, primary system organ class and preferred term. SAEs and other significant AEs 
(according to ICH E3), and AESIs will be listed separately (see Section 5.2.2.1).
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
Relevant ECG findings will be reported as AEs.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1467335 will be 
calculated according to the relevant SOP of the Sponsor (001-MCS-36-472).
Subjects who are not included in the PKS (see Section 7.3.1) will be reported with their 
individual plasma concentrations and individual pharmacokinetic parameters. However, they 
will not be included in descriptive statistics or other statistical assessments for 
pharmacokinetic parameters.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(i.e., to the same number of decimal places provided in the bioanalytical report).


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7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure of the Sponsor (001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), or BLQ (below the lower limit of quantification) will be displayed as 
such and not replaced by zero at any time point (this rule applies also to the lag phase,
including pre-dose values).
7.4.3 
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472). Missing PK parameters will not be imputed.
For the non-compartmental analysis, concentration data, identified as NOS, NOR or NOA 
will, in general, not be considered. Concentration values in the lag phase, identified as BLQ,
will be set to zero. All other BLQ values of the profile will be ignored. The lag phase is 
defined as the period between time zero and the first time point with a concentration above 
the quantification limit.
7.5
RANDOMISATION
Subjects will be randomised to one of three treatment sequences in a 1:1:1 ratio. The block 
size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication.
The randomisation list will be generated using a validated system which involves a pseudo-
random number generator and a supplied seed number so that the resulting allocation is both 
reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (see 
Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 18 subjects in the trial because this sample size is considered 
sufficient to achieve the aims of this exploratory trial.


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With this sample size, the below precision of the ratio of geometric means (test/reference)
can be expected. Precision is defined as the ratio of upper to lower confidence interval limit.
Note that the precision is independent of the actual ratio of geometric means.
The observed geometric coefficient of variation (gCV) for BI 1467335 after single oral doses 
of 10 mg 
 BI 1467335 was 104% for AUC0-tz and 94% for Cmax
, [c09036683]). The reported variability listed in this trial 
(calculated from 6 individuals) originates from a parallel group design and is an estimate of 
the total variability and not of the between-subject variability. For a crossover study, an 
estimate of the intra-individual gCV is needed. Together with the correlation between two 
responses of the same subject ρ, we can estimate the intra-individual variability out of the 
total variability. A reasonable range for ρ in PK trials based on former experience is 0.6 to 0.7, 
where ρ = 0.6 is the conservative choice. Table 7.6: 1 provides an overview of the resulting 
intra-individual gCVs.
Table 7.6: 1
Estimates of the intra-individual gCV

Endpoint
gCVT*


	

gCVw**
0.6
Cmax
94%
0.635
0. 254
53.8%
AUC0-tz
104%
0. 733
0. 293
58.4%
0.7
Cmax
94%
0. 635
0. 190
45.8%
AUC0-tz
104%
0. 733
0. 220
49.6%
*  gCVT indicates the gCV for total variability
** gCVW indicates the gCV for intra-individual variability
Assuming a gCV of 58.4% for AUC0-tz of BI 1467335 and given the chosen sample size of
18 subjects, the precision of the two-sided 90% confidence interval of the gMean ratio will be 
approximately 2.09 (upper confidence limit/lower confidence limit); for a larger correlation 
of ρ =0.7 and assumed intra-individual gCV of 49.6% for AUC0-tz of BI 1467335, the 
precision would be approximately 1. 89.
Table 7.6: 2 provides an overview of the 90% confidence intervals that are expected with 
95% probability, for possible scenarios of the ρ, gCV and intra-subject ratios (T/R).


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Table 7.6: 2
Precision and expected two-sided 90% confidence intervals around 
the ratios of geometric means for different correlations (ρ) and ratios 
in a 3x3x3 cross-over trial (N=18)
ρ
PK 
parameter
Total 
gCV(%)1
Intra-indiv. gCV 
(%)
T/R 
(%)
90% CI (%)
Precision 
(Upper CL 
/Lower 
CL)
0.6
Cmax
94%
53.8%
50
(36, 70)
1.98
100
(71, 141)
1.98
150
(107, 211)
1.98
AUC0-tz
104%
58.4%
50
(35, 72)
2.09
100
(69, 144)
2.09
150
(104, 217)
2.09
0.7
Cmax
94%
45.8%
50
(37, 67)
1.81
100
(74, 134)
1.81
150
(112, 202)
1.81
AUC0-tz
104%
49.6%
50
(36, 69)
1.89
100
(73, 137)
1.89
150
(109, 206)
1.89
1The total gCV in this table was calculated from individuals taken 10 mg 
[c09036683])
All calculations were performed as described by Kupper and Hafner [R12-0972] using R
Version 3.0.3.


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


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8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the collected data. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with source data or discrepancies must be 
explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA)/on site monitor and auditor may review all CRFs, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the competent authority.
8.6
COMPLETION OF TRIAL
The IEC / competent authority of the EU member state needs to be notified about the end of 
the trial (last subject / subject out, unless specified differently in Section 6.2.3 of the CTP) or
early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P13-02280
Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment 
of non-alcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012; 
10:837-58.
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
R03-2269
Guidance for industry: Food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER) 
2002:1-9.
R12-0972
Kupper LL, Hafner KB. How appropriate are popular sample size 
formulas? Am Stat 43 (1989) 2, 101- 105.
R15-5365
Weston CJ, Shepherd EL, Claridge LC et al. Vascular adhesion protein-1 
promotes liver inflammation and drives hepatic fibrosis. Journal of Clinical 
R15-6044
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management 
of non-alcoholic fatty liver disease: Practice guideline by the American 
Association for the Study of Liver Diseases, American College of 
Gastroenterology, and the American Gastroenterological Association 
Hepatology. 2012; 55:2005-2023.
R15-6057
Murphy SL, Xu J and Kochanek KD. Deaths: Final data for 2010. Centers 
for Disease Control and Prevention website: 
www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_04.pdf (Updated 8 May 2013. 
Accessed 6 February 2014).
R15-6070
Dharel N, Fuchs M. Nonalcoholic Fatty Liver Disease – A Major Public 
Health Challenge for the 21st Century. JSM Gastroenterology and 
Hepatology. 2014; 1018.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c04751792
Investigator's
Brochure: BI 1467335 in NASH 28 Apr 2016.


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c09036683
Single ascending dose and multiple ascending dose Phase 1 study 
administered orally in healthy adult males. 
 
13 Nov 2015.
n00244592
BI 1467335: 4-week oral (gavage) supplementary toxicity study in 
Sprague Dawley rats. 
.
n00247850
 A Four-Week Oral Repeat Dose Toxicity and Toxicokinetic Study 
of 
 in Beagle Dogs
. 4 Nov 2014.


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10.
APPENDICES
10.1
RECONSTITUTION INSTRUCTION
10.1.1
Drug supplies overview
a)
BI 1467335 Powder for Oral Solution 40 mg (target solution concentration 
BI 1467335: 0.5 mg/mL), provided in 100 mL brown glass bottles with screw cap
b)
Solvent for Oral Solution 80 mL (
 provided 
in 100 mL glass vials with tear-off caps
10.1.2
Required equipment and dosing aids - overview
a)
Mechanical (orbital) shaker for bottles (e.g. Bühler Type KL2)
b)
Dosing dispensers/syringes and bottle adapters
For the withdrawal of respective volume aliquots from the final oral solution to be 
administered, amber oral dispensers/ syringes (e.g. BAXA/ BAXTER ExactaMed) 
should be used in a size as close as possible to the required dose volume. For this 
purpose a range of syringe sizes from 1 mL up to 60 mL should be stocked at the trial 
site. In order to ease the withdrawal of the oral solution from glass bottles with the 
above syringes, bottle adapters (e.g. BAXA/ BAXTER AdaptaCap, Bottle Adapters 
(E-28 mm), Order No. H9385105) and dispenser tip caps (e.g. Order No 50300) 
should be used and stocked in the trial sites.
Possible amber BAXA ExactaMed dispensers/ syringes
•
BAXA ExactaMed amber oral dispenser 1 mL – e.g. Order No – 1601*
•
BAXA ExactaMed amber oral dispenser 3 mL – e.g. Order No – 1602*
•
BAXA ExactaMed amber oral dispenser 5 mL – e.g. Order No – 1605*
•
BAXA ExactaMed amber oral dispenser 10 mL – e.g. Order No – 1610*
•
BAXA ExactaMed amber oral dispenser 20 mL – e.g. Order No – 1620*
•
BAXA ExactaMed amber oral dispenser 35 mL – e.g. Order No – 1635*
•
BAXA ExactaMed amber oral dispenser 60 mL – e.g. Order No – 1650*
*
… or corresponding BAXTER Order-No
Only CE certified syringes are to be used!
10.1.3
Reconstitution procedure
2 bottle concept, see also Section 10.1.4.


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Step 2:
Open the vial containing the solvent for oral solution
The final BI 1467335 oral solution concentration is 0.5 mg/mL.
10.1.4
Illustration of reconstitution procedure
The following scheme on the principle followed for the present PfoS formulation, 2-bottle 
concept, should serve as an additional illustration to clarify, how the reconstitution has to be 
performed.


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The following picture shows an example of the powder and solvent bottles needed for the 
preparation of the final oral solution for administration.
10.1.5
In-use stability
The in-use stability of the reconstituted solution is 
 after its preparation, incl. storage 
in BAXA dispensers/syringes until administration. Therefore, it must be prepared in the 
morning of the administration. Further details are given on the CTS labels.
10.1.6
Mode of application
Withdraw the required volume aliquot with amber dispensers/syringes (e.g. BAXA/ 
BAXTER ExactaMed) to obtain the required doses. If the complete content of a bottle is to 
be used, it can be administered directly out of the bottle. Use syringes at a volume size as 
close as possible to the volume to be withdrawn.
Please note that it is the responsibility of the investigator to assure that appropriate supplies 
are used for administration of a dose, based on guidance in the clinical trial protocol, and 
dosing is limited to the allowed dosing range for a specific dose formulation as stated in this
Reconstitution Instruction.


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10.1.7
General remarks - important!
Because of lacking analytical coverage beyond the instructed preparation procedure of the 
different dose formulations, no further (external) dilutions of the reconstituted solutions are 
allowed!
The present Reconstitution Instruction does not contain any advice how to withdraw a 
specific dose from the reconstituted solutions. The specific dose volumes to be withdrawn 
from the described dose formulations in order to obtain a required dose will be calculated and 
documented by TransMed in the Clinical Trial Protocol (CTP) and subsequent documents 
(e.g. work sheets)!


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational product(s)
Title of protocol
To be implemented only after 
approval of the IRB / IEC /
competent authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / competent 
authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / competent 
authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09164690
1.0
clinical-trial-protocol
Relative bioavailability of a BI 1467335 tablet compared to a BI 1467335 oral
solution and the effect of food on the bioavailability of the tablet following oral
administration (a randomised, open-label, single dose, three-way crossover trial in
healthy male subjects)
Author-Trial Clinical Monitor
13 Oct 2016 15:52 CEST
Approval-Team Member Medicine
13 Oct 2016 16:51 CEST
Author-Trial Clinical
Pharmacokineticist
14 Oct 2016 16:48 CEST
Approval-Therapeutic Area 
14 Oct 2016 18:32 CEST
Author-Trial Statistician
15 Oct 2016 14:27 CEST
Verification-Paper Signature
Completion
18 Oct 2016 11:38 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09164690
1.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c14388870-01
BI Trial No.:
1386.17
Title:
Relative bioavailability of a BI 1467335 tablet compared to a
BI 1467335 oral solution and the effect of food on the bioavailability
of the tablet following oral administration (a randomised, open-label,
single dose, three-way crossover trial in healthy male subjects)
Investigational
Product(s):
BI 1467335
Responsible trial 
statistician(s):
 
 
Phone: 
Fax:     
 
Phone: 
Fax:     
Date of statistical 
analysis plan:
15MAY2017  SIGNED
Version:
Final
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2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
..................................................................................9
..................................................................................9
5.3.2
Safety endpoints ..................................................................................................10
.....................................................................................10
.............................................10
..............................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENT(S)................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................14
.....................................................................................................15
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY ENDPOINT(S) ................................................................................19
7.5
SECONDARY ENDPOINT(S) ..........................................................................20
7.5.1
Key secondary endpoint(s).................................................................................20
7.5.2
(Other) Secondary endpoint(s) ..........................................................................20
...............................................................20
...............................................................20
...............................................................20
...............................................................20
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................21
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................23


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7.8.4
ECG......................................................................................................................23
7.8.5
Others...................................................................................................................24
7.8.5.1
Physical examination ............................................................................................24
8.
REFERENCES....................................................................................................25
.............................................................................26
10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.1: 1 
Treatment regimens ..........................................................................................11
Table 6.1: 2
Study phases .....................................................................................................12
Table 6.2: 1
Important protocol violations ...........................................................................13
Table 6.3: 1
Subject sets analysed ........................................................................................15
Table 10: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
ANOVA
Analysis of variance
 
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the time of the last quantifiable data point
 
AE
Adverse Event
BI
Boehringer Ingelheim
BMI
Body mass index
CARE
Clinical data Analysis and Reporting Environment
CDR
Clinical Data Repository
CI
Confidence interval
 
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic coefficient of variation
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug induced liver injury
ECG
Electrocardiogram
EMA
European Medicines Agency
EOT
End of trial
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
ISF
Investigator site file


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Term
Definition / description
LLT
Lowest level term
log
Natural logarithm
Max
Maximum
Mean
Arithmetic mean
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
N
Number of non-missing observations
O*C
Oracle Clinical
PK
Pharmacokinetics
PKS
PK analysis set
PV
Protocol Violation
R
Reference treatment
RAGE
Report Appendix Generator system
REP
Residual effect period
RPM/DBLM
Report planning and database lock meeting
RS
Randomised set
SD
Standard Deviation
SDL
Subject data listing
T
Test treatment
 
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
 
 
WHO-DD
World Health Organisation – Drug Dictionary


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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, randomization.”
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system. 
Laboratory data will additionally be loaded and stored in the CDR.
The statistical analyses will be performed within the validated working environment CARE 
(Clinical data Analysis and Reporting Environment), including SASTM (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). 
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3, Certara USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the CTP version 1.0.


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5.
ENDPOINTS
The endpoints will be as defined in the CTP.
5.1
PRIMARY ENDPOINTS
The following primary pharmacokinetic endpoints given in the CTP in Section 5.5.1.1 will be 
determined for BI 1467335:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable as no key secondary endpoints have been specified in the protocol.
5.2.2
Secondary endpoint(s)
Not applicable as no secondary endpoints have been specified in the protocol.


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5.3.2
Safety endpoints
General
The following safety assessments will be evaluated as further endpoints (see CTP, Section
5.2.1):

AEs (including clinically relevant findings from physical examination)

Safety laboratory tests

12-lead ECG (abnormal findings documented as AEs or baseline conditions)

Vital signs (systolic and diastolic blood pressure, pulse rate)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatments to be administered, assignments of treatment 
groups, and selection of doses, see CTP Section 4. Subjects will be randomly allocated to one 
of 3 treatment sequences (ABC, BCA and CAB). The study has a single dose, randomised, 
three-way crossover, open-label design.
Subjects will be randomized to one of the 3 treatment sequences. Treatments to be evaluated 
are outlined in Table 6.1: 1 below.
Table 6.1: 1 
Treatment regimens
Description of treatment regimen
Label 
Short Label
BI 1467335, 2*5mg tablet, po, qd, 
fasted
A
BI 10 mg tab, fasted
BI 1467335, 0.5 mg/mL solution, 
10mg, po, qd, fasted
B
BI 10 mg sol, fasted
BI 1467335, 2*5mg  tablet, po, qd, 
fed
C
BI 10 mg tab, fed
tab= tablet, sol= solution
CTP (Section 6.2.2 Treatment periods): Each subject is expected to participate in each of 
the three treatment periods (drug administration on Day 1 of each period, see [CTP] Table 
4.1.4:1). Treatment periods will be separated by at least 21 days between drug 
administrations.
On Day -1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration on Day 
1. Subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. Within the time window Day -5 to -1 of Visits 3 and 4, safety
laboratory will be taken and AE/ concomitant questioning will be done.
For details on time points and procedures for collection of plasma samples for PK 
analysis, refer to Flow Chart and [CTP] Sections 5.5.2 and 5.6.3.
The safety measurements performed during the treatment period are specified in [CTP] 
Section 5.2 of this protocol and in the Flow Chart. For details on time points for all other 
trial procedures, see Flow Chart. AEs and concomitant therapy will be assessed continuously 
from screening until the end of trial examination.
For the statistical analyses of AEs, laboratory data and vital signs, the following phases of the 
study will be defined:


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Table 6.1: 2
Study phases
Label
Start 
End*
Screening
Date of informed consent 
Date/time of first drug administration
BI 10mg tab fasted or 
BI 10mg sol fasted or
BI 10mg tab fed
Date/time of BI 1467335
administration
Date/time of BI 1467335
administration 
days
F/U BI 10mg tab fasted
F/U BI 10mg sol fasted
F/U BI 10mg tab fed
Date/time of BI 1467335
administration 
days
Date/time of BI 1467335
administration in next period or End of 
trial (EOT) examination
* For all defined study phases, the end date/time itself does not belong to the study phase
Vital signs will be presented for each assessment time point.
CTP (Section 5.2.2.2 Adverse event collection and reporting): 
 
 
 
Therefore, all AEs which will occur throughout the treatment phases and the 
 REP 
will be considered as ‘on treatment’ (see [CTP] Section 7.3.3). Events which occur after the 
 REP and prior to the next drug administration will be considered as ‘follow-up’ 
events.
Based on these definitions, two types of analyses will be provided in the report, as appropriate.
A) High-level analysis (for Section 15 and Appendix 16.1.9.2.8.2 &3 displays)
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). The screening and follow-up periods will not be included.
For AE tables, a total over the active treatments (“Total BI 1467335”) will be provided.
B) Low-level analysis (for Appendix 16.1.9.2.8.1 displays)
The separate phases, as defined in the table above, will be used in this analysis.
In addition, a total over the active treatments (“Total BI 1467335) and a total over all study
phases (“Total overall”) will be provided.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all randomized subjects. 
Listings of protocol deviations and of unresolved discrepancies will be provided to be 
discussed at the combined report planning and database lock meeting (RPM/DBLM).


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It will be decided whether the discrepant data can be used as they are or whether the data have 
to be corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important protocol violation (PV).
For definition of important PVs, and for the process of identification of these, please refer to 
the Boehringer Ingelheim (BI) reference document ‘Protocol Violation Handling Definitions’ 
(7).
If any important PVs are identified, they are to be summarised into categories and will be 
captured in the RPM/DBLM minutes via an accompanying Excel spreadsheet (9). The 
following table contains the categories in which important PVs are classified. If the data show 
other important PVs, this table will be supplemented accordingly by the time of the 
RPM/DBLM.
If substantial numbers of PVs are reported at the RPM/DBLM, a decision about summarising 
the PVs in a tabular format will be made. Otherwise, only a PV listing will be provided.
Additionally, consistency checks will be prepared for identifying violations of time windows.
Table 6.2: 1
Important protocol violations
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C3
Non-compliance
C4
Medication code broken inappropriately
C5
Incorrect intake of trial medication
C6
Improper washout between treatments
D
Concomitant medication
D1
Prohibited medication use
D2
Mandatory medication not taken
D3
Improper washout of concomitant medication
E
Missing data
E1
Certain violations of procedures used to measure primary or secondary data


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Table 6.2: 1
Important protocol violations (cont’d)
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
Populations (analysis sets) and the criteria for inclusion are defined as follows:

Randomised set (RS): 
This subject set includes all randomised subjects. It will be used for disposition 
displays.

Treated set (TS): 
This subject set includes all subjects who received at least one dose of study drug. It 
will be used for analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic set (PKS):
This subject set includes all subjects in the Treated Set (TS) who provide at least one 
primary PK parameter that is not excluded due to a relevant protocol violation or non-
evaluable plasma concentrations. 
According to CTP Section 7.3.1, plasma concentrations and/or parameters of a subject 
will be considered as non-evaluable, if for example:
o
The subject experienced emesis at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding subjects 
having experienced emesis)
o
Pre-dose concentration is >5% of the Cmax value of that subject
o
Samples/concentration data at critical phases of the PK disposition curve are 
missing
A subject will be included in the PKS, even if he contributes only one PK parameter 
value for one period to the statistical assessment.
Category 
/ Code
Description
F
Incorrect timing
F1
Certain violations of time schedule used to measure primary or secondary data.
G
Other trial specific important violations
G1
Incorrect intake of meal


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The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to populations based on other data than PK, PD or Biomarkers will be made at latest 
at the RPM/DBLM. Other decisions based on  PK, PD or Biomarkers data have to be made 
once the corresponding data are assessed.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
RS
TS
PKS
Primary and further 
PK endpoints
X
Safety endpoints 
X
Demographic/baseline 
endpoints
X
Disposition
X
Note that the number of subjects with available data for an endpoint may differ. For details, 
see Section 6.6 “Handling of missing data and outliers”.
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
According to section 7.4 of the CTP:

Missing or incomplete AE times are imputed according to BI standards (see 001-
MCG-156_RD-01 (3). BI-SDTM does not contain date/time imputations, all such 
imputations are done during ADS generation.

With respect to other safety evaluations, it is not planned to impute missing values.

Missing data and outliers of PK data are handled according to BI standards (see 001-
MCS-36-472_RD-01 (2).


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
In general, the baseline value is defined as the last measurement before the first intake of 
study medication.
For laboratory data, the baseline value will be derived for each treatment to be the last value 
before intake of study medication in the respective study period. For repeated laboratory data, 
baseline will be the last repetition before intake of study medication in the respective study 
period. 
Similar for vital signs, 
the baseline value will be 
derived for each treatment.
Time windows are defined in the CTP. Adherence to time windows will be checked at the 
RPM/DBLM.
CTP (Section 6.1 Visit schedule): Exact times of measurements outside the permitted time 
windows will be documented. The acceptable time windows for screening, Visits 3 and 4 and 
end of trial examination are given in the [CTP] Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 min on Day 1, and ± 60 min on Day 2.
If scheduled in the [CTP] Flow Chart at the same time as a meal, blood sampling, vital signs 
and 12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture, are scheduled at the same time, venipuncture should be the last due 
to its inconvenience to subjects and possible influence on physiological parameters.
For planned sampling times of the PK 
 blood samples, see [CTP] Flow Chart. While 
these nominal times should be adhered to as closely as possible, actual sampling times will be
recorded and used for determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.


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7.
PLANNED ANALYSIS
Subjects will be assigned to treatment groups according to their randomised treatment.
Inferential statistical analyses of PK endpoints 
 will be presented in Section 15.5 of the CTR and in 
Appendix 16.1.9.3.
Descriptive data analysis of PK endpoints will be performed by BI ClinPK/PD group and 
presented in Section 15.6 of the CTR.
 
The format of the listings and tables will follow the BI guideline 'Reporting of clinical trials 
and project summaries' [001-MCG-159] (7).
The individual values of all subjects will be listed, sorted by sequence group, subject number 
and visit. All listings will be contained in Appendix 16.2 of the Clinical Trial Report (CTR).
Additionally, PK 
 data will be listed in Sections 15.6 
.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables: 
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For analyte concentrations as well as pharmacokinetic parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations and its descriptive statistics will be displayed 
according to SOP MCS-36-472_RD1 (8).
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actually missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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All subject data listings (SDLs), except for AE listings, will be sorted by sequence group and 
subject number.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS presented 
by sequence group and overall. The following variables will be displayed: gender, race, 
ethnicity, age, height, weight, body mass index (BMI), smoking and alcohol status. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medication will be coded 
according to the most recent version of the World Health Organisation – Drug Dictionary 
(WHO-DD).
Only descriptive statistics are planned for this section of the report.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of administration of the respective treatment or

starts within the on-treatment phase (see Section 6.1).
Hence a medication may be considered as concomitant to more than one actual treatment. In 
the listing of concomitant therapies, a record will be created for each actual treatment in 
which the therapy is present.
7.3
TREATMENT COMPLIANCE
CTP (Section 4.3 Treatment compliance): Compliance will be assured by administration of 
all trial medication in the study centre under supervision of the investigating physician or a 
designee. The measured plasma concentrations will provide additional confirmation of 
compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or
violate trial restrictions) may be removed from the trial and the CRF will be completed
accordingly.
It is not intended to list the compliance separately. Any deviations from complete intake will
be addressed and documented at the RPM/DBLM and described in the CTR.


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7.4
PRIMARY ENDPOINT(S)
To investigate the relative bioavailability of the two formulations (tablet/oral solution) and to 
investigate the effect of food on the primary PK parameters as defined in Section 5.1, the 
following comparisons will be made:
(1) T1 (tablet, fasted) vs. R1 (oral solution, fasted), to investigate the relative 
bioavailability of the tablet and solution formulations
(2) T2 (tablet fed) vs. R2 (tablet fasted) , to investigate the effect of food on the tablet 
formulation
These comparisons will be performed separately on the PKS. For further details about 
treatments see Table 6.1: 1.
The primary PK endpoints (see CTP Section 5.5.1 and TSAP Section 5.1) will be log 
transformed (natural logarithm) prior to fitting the ANOVA model. For each endpoint, the 
difference between the expected means for log(T (fasted))-log(R) and
log(T (fed))-log(T (fasted)) will be estimated by the difference in the corresponding adjusted 
means (Least Squares Means), and a two-sided 90% confidence interval based on the t-
distribution will be computed. These quantities will then be back-transformed to the original 
scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. 
Since the main focus is on estimation (and not testing), an acceptance range was not specified, 
i.e. no hypothesis will be tested.
CTP (Section 7.1.3 Model): The statistical model used for the analysis of primary endpoints 
will be an analysis of variance (ANOVA)) model on the logarithmic scale. This model will 
include effects accounting for the following sources of variation: ‘sequence’, ‘subjects nested 
within sequences’, ‘period’ and ‘treatment’. The effect ‘subjects within sequences’ will be 
considered as random, whereas the other effects will be considered as fixed. The model is 
described by the following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response (endpoint, see [CTP] Section 5.5.1) measured on 
subject m in sequence i receiving treatment k in period j
= the overall mean
i = the ith sequence effect, i = 1, 2, 3
sim = the effect associated with the mth subject in the ithsequence, 
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2, 3
k = the kth treatment effect, k = 1, 2, 3


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eijkm = the random error associated with the mth subject in sequence i who 
received treatment k in period j
The analysis will be accomplished using the XPKISTAT macro, based on PKS, and the 
option BWC (Bioavailability/Bioequivalence, within subject design, time-controlled).
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
This section is not applicable as no secondary endpoint has been specified in the protocol.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. The analyses will be done by ‘treatment at 
onset’(concept of ‘treatment emergent AEs’).
CTP (Section 7.3.3 Safety analyses): Treatments will be compared in a descriptive way. 
Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of subjects with AEs and NOT on the number of 
AEs.
Furthermore, for analysis multiple AE occurrence data on the CRF will be collapsed into an 
AE event provided that all of the following applies:

All AE attributes are identical (lowest level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest)


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
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started in the same hour in which the 
first occurrence ended)
For further details on summarization of AE data, please refer to the guideline 'Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries' (4) 
[001-MCG-156].
CTP (Section 5.2.2.1 Definitions of adverse events): The following are considered as AESIs 
in this trial:
Hepatic injury, as defined by the following alterations of hepatic laboratory parameters: 

An elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or

Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy,
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results
(ALT, AST, total bilirubin) available, the Investigator should make sure that these
parameters are analysed, if necessary in an unscheduled blood test. Should the results
meet the criteria of hepatic injury alert, the procedures described in the DILI checklist
should be followed.
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.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all adverse events occurring between first drug intake till last drug intake + residual effect 
period will be assigned to the randomised treatment. All adverse events occurring before first 
drug intake will be assigned to ‘screening’ and all adverse events occurring after the residual 
effect period will be assigned to “follow-up” (for listings only). For details on the treatments 
and the definition of study phases, see Section 6.1.
An overall summary of AEs will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class and preferred term. Separate tables will be provided for subjects with serious AEs, 
subjects with AESIs, and subjects with other significant AEs (according to ICH E3 (5)). AEs 
which were considered by the investigator to be drug related will be summarised separately. 
AEs will also be summarised by maximum intensity. The system organ classes will be sorted 


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according to the standard sort order specified by the European Medicines Agency (EMA), 
preferred terms will be sorted by frequency (within system organ class).
Separate listings will be provided for all AEs, for serious AEs, for AESIs, for other significant 
AEs (according to ICH E3), for serious AEs, AESIs or other significant AEs, and for non-
serious AEs that had an incidence of > 5% for at least one treatment.
The analysis of AEs will be based on the concept of treatment emergent AEs. For details on 
the treatments and the definition of study phases, see Section 6.1.
An overall summary of AEs will be presented.
7.8.2
Laboratory data
CTP (Section 7.3.3 Safety analyses): Laboratory data will be compared to their reference 
ranges. Values outside the reference range as well as values defined as clinically relevant will 
be highlighted in the listings. Additionally, differences from baseline will be evaluated.
The analyses of laboratory data will be based on BI standards (6). Descriptive statistics of 
laboratory values over time and for the difference from baseline will be provided. Frequency 
tables of changes between baseline and last value on treatment with respect to the reference 
range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the database or at the RPM/DBLM at the latest. It is the 
investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study. Possibly clinically significant abnormal laboratory values will only be 
presented within the scope of the listing of investigator comments.
7.8.3
Vital signs
CTP (Section 7.3.3 Safety analyses): Vital signs or other safety-relevant data observed at 
screening, baseline, during the course of the trial and at the end-of-trial evaluation will be 
assessed with regard to possible changes compared to findings before start of treatment.
Only descriptive statistic of vital signs over time and for the difference from baseline are 
planned for this section of the report.
Clinically relevant findings in vital signs data will be reported as AEs and will be analysed as 
part of the AE analysis.
7.8.4
ECG
CTP (Section 7.3.3 Safety analyses): Relevant ECG findings will be reported as AEs.
No separate listing or tables will be prepared.


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7.8.5
Others
7.8.5.1
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
3.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON.
4.
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
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
6.
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
7.
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current
version, IDEA FOR CON
8.
001-MCS-36-472_RD1: “Noncompartmental Pharmacokinetic Pharmacodynamic 
Analyses of Clinical Studies”
9.
001-MCS-50-413_RD-02: “Important Manual Protocol Violations Spreadsheet”, current 
version, BIRDS


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final 
15-MAY-2017
None
This is the final TSAP without any 
modification.