Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: yes

Brief summary:
The main objective of this trial is to investigate the pharmacodynamic effects of a single dose of BI 1358894 on CCK-4- induced anxiogenic/ panic-like symptoms using the PSS in preselected CCK-4 sensitive healthy volunteers.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 1358894 intervention 2: Placebo
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c21630258-01
EudraCT No.
2018-000057-41 
BI Trial No.
1402-0005
BI Investigational
Medicinal Product
BI 1358894
Title
A double-blind, randomised, two-way cross-over, single-dose, 
placebo-controlled trial to investigate the effects of BI 1358894 
on cholecystokinin tetrapeptide (CCK-4) induced panic 
symptoms in healthy male subjects
Lay Title
A study in healthy men to test whether BI 1358894 reduces drug-
induced panic symptoms
Clinical Phase
I
Trial Clinical Leader
Phone:
Fax:
Principal 
Investigator
Phone:
Fax: 
Status
Final Protocol
Version and Date
Version: 1.0
Date: 13 March 2019
Page 1 of 96
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
13 March 2019
Revision date
Not applicable
BI trial number
1402-0005
Title of trial
A double-blind, randomised, two-way cross-over, single-dose, placebo-controlled
trial to investigate the effects of BI 1358894 on cholecystokinin tetrapeptide (CCK-
4) induced panic symptoms in healthy male subjects 
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
Inhibition of 
 ion channels by BI 1358894 may potentially improve 
affective symptoms and emotion control in patients with affective disorders. The 
pharmacodynamic data obtained in this study will help to detect the 
pharmacological principle of the BI 1358894 compound by demonstrating indirect 
target engagement via downstream pharmacodynamic measures.
Trial objective
To investigate the pharmacodynamic effects of a single dose of BI 1358894 on 
CCK-4 induced anxiogenic/panic-like symptoms using the Panic Symptom Scale 
(PSS) in preselected CCK-4 sensitive healthy volunteers. 
Trial design
Single dose, placebo-controlled, double-blind, randomised, two-way cross-over
Trial endpoint
Primary endpoint: maximum change from baseline of PSS sum intensity score after 
CCK-4 injection
Number of subjects 
total entered
20*
*Screening may include more than 60 healthy subjects who will be exposed to 
CCK-4 to identify subjects with an anxiogenic and panic induced effect in response 
to CCK-4 as until 20 eligible subjects have been identified
each treatment
20 (all to receive both active treatment and placebo)
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male CCK-4 sensitive subjects, age of 18 to 55 years (inclusive), body 
mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive)


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Challenging agent
CCK-4 (CCK B receptor agonist)
dose
50 μg 
mode of admin.
iv bolus injection
Test product
BI 1358894 film-coated tablet, strength 25 mg (
inhibitor)
dose
100 mg (4 film-coated tablets)
mode of admin.
Oral with 240 mL of water after a standard high-fat meal
Reference product
Matching placebo as film-coated tablet
dose
Not applicable
mode of admin.
Oral with 240 mL of water after a standard high-fat meal
Duration of treatment
2 single doses of CCK-4 and BI 1358894 or placebo (separated by a washout period 
of at least 17 days between drug administrations), 1 single dose of the provoking 
agent for the preselection of CCK-4 sensitive healthy subjects
Statistical methods
Descriptive statistics will be calculated for all endpoints. The statistical model to 
assess the primary pharmacodynamic endpoint PSS sum intensity score will be a 
mixed effects model including effects for ‘treatment’, ‘period’ and ‘subject’, as well 
as covariates ‘period baseline’ and ‘subject baseline’. Two sided 90% confidence 
intervals (CIs) will be calculated based on the residual error from the mixed model.


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FLOW CHART FOR THE SINGLE DOSE CCK-4 CHALLENGE
Period
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
 
CCK-4 challenge8
12-lead ECG
Continuous ECG 
monitoring
Vital signs (BP, PR)
Suicidality assessment 7
PSS/
Questioning for AEs and 
concomitant therapy 5
SCR
1
-28 to 
-7
Screening (SCR)1
x
x
x
x
2
-6 to 
-2
-0:15
08:00
Screening CCK-4-
challenge visit8,13
x
▲
x
x
x
0:00
08:15
x
│
0:05
08:20
│
x
0:10
08:25
│
x
0:20
08:35
│
x
0:30
08:45
▼
x
x10
4:45
13:00
lunch, discharge from 
trial site14
x
x
x
x10
two identical treatment periods separated by a wash-out of at least 17days
3/
4
-1
-18:00
14:00
Admission to trial site
x
x
x
x
1
-2:00
06:00
allocation to 
treatment2
x2, 9
x2
▲
x2
x2
-0:30
07:30
Breakfast
0:00
08:00
BI 1358894 drug 
administration or 
placebo
│
x2
0:30
08:30
x
x
│
x
x
1:00
09:00
x
x
│
x
x
1:30
09:30
x
│
x
2:00
10:00
240 mL fluid intake
x
│
x
x
2:30
10:30
x
│
x
3:00
11:00
x
x
│
x
x
4:00
12:00
240 mL fluid intake3
x
x
│
│
x
x
4:30
12:30
│
4:45
12:45
x
x
x
│
x
x
x
5:00
13:00
CCK-4 challenge8
x
│
5:05
13:05
x
│
x
x10
5:10
13:10
x
│
x
x10
5:20
13:20
x
│
x
x10
5:30
13:30
x
x
│
x
x
x10
6:00
14:00
Lunch3
x
x
x
▼
x
x10
7:00
15:00
x
x
8:00
16:00
Snack (voluntary)3
x
x
x
x
10:00
18:00
Dinner3
x
x
12:00
20:00
x
x
x
2
24:00
08:00
x
x
x
x
x10
34:00
18:00
x
x
x
x
3
48:00
08:00
x
x
x
x
4
72:00
08:00
x
x
x
x


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG (including rhythm strip of at least 10 sec), safety 
laboratory (including drug screening and alcohol urine test), demographics (including determination of body height and 
weight, smoking status and alcohol history), neurological examination, relevant medical history, concomitant therapy, 
review of inclusion/exclusion criteria and suicidality assessment (C-SSRS). 
2.
The time is approximate; the respective procedure is to be performed and completed within 3 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to (first) drug administration.
3.
If several actions are indicated at the same time 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, concomitant therapies, suicidality assessment (C-SSRS), neurological examination, and PSS
5.
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.
6.
Sampling times and periods may be adapted based on information obtained during the trial 
 
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject
7.
Suicidality assessment only at screening, admission to trial site, discharge from trial site and end of trial.
8.
CCK-4 challenge test (CCK-4 injection (50 µg)) is to be performed after subjects have had a standard high-fat meal
except Visit 2, no breakfast is needed at Visit 2. Injection time must be recorded. PSS 
 assessments will be 
determined 5 ± 1, 10±1, 20±1 and 30 ±1 minutes after the injection. The CCK-4 will be administered to the subjects as a 
bolus injection over 5 seconds (maximum of 8 seconds) via a venous cannula.
9.
One additional blood sample for pharmacogenomics analyses will be taken either at Visit 3 or at Visit 4.
10. Standardized assessment of local tolerability using the criteria swelling, induration, heat, redness, pain or other findings.
11. Discharge on Day 9 includes physical examination, vital signs, ECG, safety laboratory, recording of AEs, concomitant 
therapies, suicidality assessment (C-SSRS), PSS
 and a neurological examination.
12. For ambulatory visit examinations, a time window of 3 hours is acceptable. 
13. The time is approximate and could start between 8:00 to 12:00
14. Discharge after screening CCK-4 challenge after confirmation of fitness by PI or designee
5
96:00
08:00
x
x
x
x
x
6
120:00
08:00
x
x
x
x
7
144:00
08:00
x
x
x
x
8
168:00
08:00
x
x
x
x10
9
192:00
08:00
Discharge from trial
site11
x
x
x
x
x
x
x
x
13
288:00
08:00
Ambulatory visit12
x
EOT
5
35 to 
40
End of trial (EOT) 
examination 4
x
x
x
x
x
x
x


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART FOR THE SINGLE DOSE CCK-4 
CHALLENGE .............................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................15
1.2.1
BI 1358894 .............................................................................................15
1.2.1.1
Nonclinical pharmacology.......................................................15
1.2.1.2
Safety pharmacology ...............................................................15
1.2.1.3
Toxicology...............................................................................16
1.2.1.3.1 Single dose toxicity........................................................16
1.2.1.3.2 Repeat-dose toxicity studies...........................................17
1.2.1.3.3 Genotoxicity...................................................................19
1.2.1.3.4 Reproductive and developmental toxicity......................19
1.2.1.3.5 Phototoxicity ..................................................................19
1.2.1.4
Nonclinical pharmacokinetics..................................................19
1.2.1.5
Clinical experience in humans.................................................21
1.2.1.6
Drug product ...........................................................................28
1.2.2
Cholecystokinin-tetrapeptide (CCK-4)...............................................28
1.2.3
Residual Effect Period..........................................................................30
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................30
1.4
BENEFIT - RISK ASSESSMENT ...................................................................30
1.4.1
Procedure-related risks ........................................................................31
1.4.2
Drug-related risks and safety measures..............................................31
1.4.2.1
BI 1358894...............................................................................31
1.4.2.1.1 Risks derived from observations in non-clinical studies31
1.4.2.1.2 Mode of action and nature of the target .........................31
1.4.2.1.3 Relevance of animal models ..........................................32
1.4.2.1.4 Risk minimization (safety precautions and stopping rules)
.................................................................................32
1.4.2.1.5 Drug induced liver injury...............................................33
1.4.2.2
CCK-4......................................................................................33
1.4.2.3
Overall assessment...................................................................33
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 34
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......34
2.1.1
Main objectives......................................................................................34


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2.1.2
Primary endpoint..................................................................................34
2.1.3
Secondary endpoints.............................................................................34
2.2.2.2
Safety and tolerability..............................................................35
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 37
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................37
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................37
3.3
SELECTION OF TRIAL POPULATION ......................................................37
3.3.1
Main diagnosis for trial entry..............................................................38
3.3.2
Inclusion criteria...................................................................................38
3.3.3
Exclusion criteria ..................................................................................38
3.3.4
Withdrawal of subjects from treatment or assessments ...................40
3.3.4.1
Discontinuation of trial treatment............................................40
3.3.4.2
Withdrawal of consent to trial participation ............................41
3.3.4.3
Discontinuation of the trial by the sponsor..............................41
3.3.5
Replacement of subjects .......................................................................41
4.
TREATMENTS........................................................................................ 43
4.1
INVESTIGATIONAL TREATMENTS ..........................................................43
4.1.1
Identity of the Investigational Medicinal Products ...........................43
4.1.2
Selection of doses in the trial................................................................44
4.1.3
Method of assigning subjects to treatment groups ............................45
4.1.4
Drug assignment and administration of doses for each subject .......45
4.1.5
Blinding and procedures for unblinding ............................................46
4.1.6
Packaging, labelling, and re-supply ....................................................47
4.1.6.1
BI 1358894...............................................................................47
4.1.7
Storage conditions.................................................................................47
4.1.8
Drug accountability ..............................................................................47
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................48
4.2.1
Other treatments and emergency procedures....................................48
4.2.2
Restrictions............................................................................................48
4.2.2.1
Restrictions regarding concomitant treatment .........................48
4.2.2.2
Restrictions on diet and life style.............................................48
4.3
TREATMENT COMPLIANCE.......................................................................49
5.
ASSESSMENTS....................................................................................... 50
5.1
ASSESSMENT OF EFFICACY.......................................................................50


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5.2
ASSESSMENT OF SAFETY............................................................................50
5.2.1
Physical examination ............................................................................50
5.2.2
Vital signs...............................................................................................50
5.2.3
Safety laboratory parameters..............................................................50
5.2.4
Electrocardiogram................................................................................53
5.2.4.1
Twelve-lead ECGs...................................................................53
5.2.4.2
Continuous ECG monitoring ...................................................53
5.2.5
Other safety parameters.......................................................................53
5.2.5.1
Local tolerability......................................................................53
5.2.5.2
Suicidality assessment .............................................................53
5.2.6
Assessment of adverse events...............................................................54
5.2.6.1
Definitions of adverse events...................................................54
5.2.6.1.1 Adverse event.................................................................54
5.2.6.1.2 Serious adverse event.....................................................54
5.2.6.1.3 AEs considered ‘Always Serious’..................................55
5.2.6.1.4 Detailed assessment of the adverse advent headache.....55
5.2.6.1.5 Suicidal risk assessed by the C-SSRS (paper version)...56
5.2.6.1.6 Adverse events of special interest..................................57
5.2.6.1.7 Intensity (severity) of AEs .............................................57
5.2.6.1.8 Causal relationship of AEs.............................................57
5.2.6.2
Adverse event collection and reporting ...................................58
5.2.6.2.1 AE collection..................................................................58
5.2.6.2.2 AE reporting to the sponsor and timelines.....................59
5.2.6.2.3 Information required ......................................................59
5.2.6.2.4 Pregnancy.......................................................................59
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................60
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................61
5.4
ASSESSMENT OF BIOMARKERS................................................................61
5.4.1
Methods of sample collection...............................................................61
5.4.2
Assessment of pharmacodynamic parameters...................................61
5.5
BIOBANKING ...................................................................................................61
5.6
OTHER ASSESSMENTSS ...............................................................................62
5.6.1
Pharmacogenomic evaluation..............................................................62
5.6.2
CCK-4 challenge test ............................................................................62
5.6.3
Pharmacodynamic parameters............................................................62


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5.7
APPROPRIATENESS OF MEASUREMENTS.............................................63
6.
INVESTIGATIONAL PLAN.................................................................. 65
6.1
VISIT SCHEDULE............................................................................................65
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................65
6.2.1
Screening periods..................................................................................65
6.2.2
Treatment periods.................................................................................65
6.2.3
Follow-up period and trial completion ...............................................66
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 67
7.1
STATISTICAL DESIGN – MODEL ...............................................................67
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................67
7.3
PLANNED ANALYSES....................................................................................67
7.3.1
Primary endpoint analyses...................................................................69
7.3.2
Secondary endpoint analyses ...............................................................70
7.3.4
Safety analyses.......................................................................................71
7.4
INTERIM ANALYSES .....................................................................................72
7.5
HANDLING OF MISSING DATA ..................................................................72
7.5.1
Safety......................................................................................................72
7.5.2
Pharmacokinetics..................................................................................72
7.5.3
Pharmacodynamics...............................................................................72
7.6
RANDOMISATION ..........................................................................................72
7.7
DETERMINATION OF SAMPLE SIZE ........................................................73
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 75
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................75
8.2
DATA QUALITY ASSURANCE .....................................................................76
8.3
RECORDS..........................................................................................................76
8.3.1
Source documents .................................................................................76
8.3.2
Direct access to source data and documents.......................................77
8.3.3
Storage period of records.....................................................................77
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................77
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......77


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8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................78
8.6
TRIAL MILESTONES .....................................................................................78
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................79
9.
REFERENCES......................................................................................... 80
9.1
PUBLISHED REFERENCES...........................................................................80
9.2
UNPUBLISHED REFERENCES.....................................................................82
10. APPENDICES .......................................................................................... 84
10.1
PREPARATION INSTRUCTIONS FOR CCK-4 ..........................................84
10.2
COLUMBA-SUICIDE SEVERITY RATING SCALE..................................85
10.4
PANIC SYMPTOM SCALE.............................................................................92
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 95
11.1
GLOBAL AMENDMENT 1 .............................................................................95
11.2
GLOBAL AMENDMENT 2 .............................................................................95


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine amino transferase
AST
Aspartate amino transferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC5-5.5
area under the concentration-time curve of the analyte in plasma over the
time interval 5h to 5:30h
AUC0-24
Area under the concentration-time curve of the analyte in plasma during 
24 hours
AUC0-72
Area under the concentration-time curve of the analyte in plasma during 
72 hours
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
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
borderline personality disorder
b.p.m.
Beats per minute
CA
Competent authority
CCK-4
Cholecystokinin tetrapeptide
CHO
Chinese hamster ovary
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central Nervous System
CRF
Case report form
CRO
Clinical Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CTM
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450
DILI
Drug induced liver injury


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DNA
Desoxyribonucleic acid
DRF
Dose Range Finding
ECG
Electrocardiogram
eCRF
Electronic case report form
ECT
electro-convulsive therapy
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
Emax
maximum PSS sum intensity score after CCK-4
EOT
End of trial
ES
Entered Set
ESR
Erythrocyte sedimentation rate
EU
European Union
FDA
Food and Drug Administration
FE
Food Effect
FIH
First in Human
FST
Forced Swim Test
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
hERG
human ether-a-go-go related gene
HIV
Human Immunodeficiency Virus
IB
Investigator’s brochure
ICH
International Conference of Harmonisation
IEC
IPD
Independent Ethics Committee
Important Protocol Deviation
IRB
Institutional Review Board
ISF
Investigator site file
IUD
Intrauterine device
i.v.
Intravenous
LVSP
left ventricular pressure parameters 
MDA
Methylenedioxyamphetamine
MDD
Major depressive disorder
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRTpo
Mean residence time of the analyte in the body after oral administration
NIMP
Non-investigational medicinal product
nM
Nanomolar


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NOAEL
No observed adverse effect level
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
p.o.
Oral
PR
Pulse rate
PSS
Panic Symptom Scale
q.d.
Quaque die, once daily
QD
Once Daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SRD
Single-rising dose
Ss
(at) steady state
SOP
Standard Operating Procedure
T
Test product or treatment
TMF
Trial master file
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
t1/2
Terminal half-life of the analyte in plasma
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAS
Visual Analogue Scale
WBC
White Blood Cells


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND


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1.2
DRUG PROFILE
1.2.1
BI 1358894
1.2.1.1
Nonclinical pharmacology
1.2.1.2
Safety pharmacology


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1.2.1.3
Toxicology
Single dose toxicity
1.2.1.3.1


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Repeat-dose toxicity studies 
1.2.1.3.2


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Genotoxicity
1.2.1.3.3
Reproductive and developmental toxicity
1.2.1.3.4
Phototoxicity
1.2.1.3.5
1.2.1.4
Nonclinical pharmacokinetics


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1.2.1.5
Clinical experience in humans


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Pharmacokinetics


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1.2.1.6
Drug product
For a more detailed description of the BI 1358894 profile please refer to the current 
Investigator’s Brochure (IB) [c10354149].
1.2.2
Cholecystokinin-tetrapeptide (CCK-4)
Administration of the neuropeptide cholecystokinin-tetrapeptide (CCK-4) induces panic 
attacks both in patients with panic disorder and healthy volunteers in a dose-dependent 
fashion [R19-0565]. No habituation was observed after repeated administration of CCK-4 as 
a provoking agent. It has been shown that panic disorder patients are much more sensitive to 
CCK-4 administration than healthy controls [R19-0564]. Therefore, it has been suggested 
that CCK-4 might be involved in the pathophysiology of panic disorder. 
When rechallenged without any treatment, panic disorder patients did not show any change in 
the behavioral effects of CCK-4 [R19-0625]. In contrast, it has been demonstrated that
administration of agents that are effective in the treatment of panic disorder reduce CCK-4-
induced panic. [R19-0626] investigated the effect of treatment with imipramine on CCK-4-
induced panic in panic disorder patients in an open-label design. They found a marked 
reduction in the number and intensity of panic symptoms when patients were rechallenged 
after the treatment period [R19-0626]. Similarly, Shlik [R19-0560] showed a marked
reduction of intensity and number of panic symptoms after citalopram treatment [R19-0560]. 


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In a placebo-controlled study with fluvoxamine, significant treatment effects on CCK-4-
induced panic attacks were found in panic disorder patients compared to placebo [R19-0628].
An interaction of CCK-4 with several other neurotransmitter systems has been discussed. 
Apart from the serotonergic and noradrenergic system, the gamma-amino-butyric-acid 
(GABA) system also seems to be involved in the pathophysiology of CCK-4-induced panic 
[R19-0627]; [R19-0626].
Administration of 50 μg CCK-4 was well-tolerated in numerous clinical research trials (see 
Section 4.1.2). The CCK-4 related anxiety symptoms show a rapid increase followed by a 
fast decline within a period of 5 minutes. There may be some residual anxiety symptoms after 
10 minutes, but these are usually mild and disappear without any residual symptoms within 
30 minutes. Changes in vital signs (blood pressure, pulse rate, respiratory rate) occur during 
the CCK-4 challenge test. Short lasting changes in pulse rate and blood pressure have been 
observed together with changes in anxiety-status [R18-2695].
The panic symptoms induced by CCK-4 may be expressed by the following potential 
symptoms (all symptoms are covered by the assessment of the Panic Symptom Scale (PSS), 
vital signs and will be thoroughly monitored):

Dyspnea

Dizziness

Faintness

Trembling

Sweating

Nausea

Abdominal stress

Tachycardia

Chest pain or discomfort


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
Hot flushes

Anxiety, fear or apprehension

Fear of dying, losing control, of going crazy 
1.2.3
Residual Effect Period
1.3
RATIONALE FOR PERFORMING THE TRIAL
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 1358894. 


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Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
1.4.1
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.2
Drug-related risks and safety measures
1.4.2.1
BI 1358894
Risk factors were derived from (1) observations in nonclinical studies, (2) the mode of action 
and nature of the target, and (3) the relevance of animal models. 
Risks derived from observations in non-clinical studies
1.4.2.1.1
Mode of action and nature of the target
1.4.2.1.2


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Relevance of animal models
1.4.2.1.3
Risk minimization (safety precautions and stopping rules)
1.4.2.1.4
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers: 
•
For safety reasons, each treatment period will be divided into 4 cohorts of 5 subjects. 
Each drug administration will be separated by at least 10 minutes and the dosing of 
the cohorts will be separated by at least 2 days. Adequate continuous safety 
monitoring (see below) will be performed before the subsequent cohort is dosed.
•
An extensive safety laboratory will be performed with special focus on full blood 
exam, including CRP and ESR to monitor for potential perivascular/mesenteric 
inflammation (see Flow Chart)
•
Adequate safety monitoring will be performed (e.g. vital signs (including blood 
pressure, pulse rate, respiratory rate), ECGs, safety laboratory tests including hormone 
parameters, visual analogue scales, suicidality, and assessment of adverse events) 
•
Subjects will be hospitalised throughout the study from Day -1 to Day 9 of each 
period and will be discharged only after a formal assessment and confirmation of 
fitness by an investigator or qualified designee. During the in-house stay, the subjects 
will be under medical observation and thoroughly monitored for adverse events, 
which may be reported in an expedited manner if they match the criteria for expedited 
reporting
•
As reproductive toxicity studies have not yet been conducted, only male subjects will 
be enrolled in this study 


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Drug induced liver injury
1.4.2.1.5
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.6, adverse events of special interest.
1.4.2.2
CCK-4
The CCK-4 challenge test is well-tolerated, based on numerous clinical studies (see 
Section 1.2.2). CCK-4 induced effects are transient (5 minutes) and include changes in vital 
signs (blood pressure, pulse rate, respiratory rate) and panic symptoms (increased anxiety, 
tremors, sweating, dry mouth, derealization, mild nausea, and a strange feeling in stomach). 
Safety precautions will include thorough monitoring of panic symptoms (via the PSS), vital 
signs, and continuous ECG. Subjects will be hospitalised and kept under close medical 
surveillance for at least 4 hours following CCK-4 administration.
1.4.2.3
Overall assessment
 
 Based upon 
preclinical data for BI 1358894, the preliminary clinical data from the on-going FIH study, 
the well-known safety profile of CCK-4, as well as the implemented safety measures 
described above, healthy subjects will not be exposed to undue risks from BI 1358894 or 
CCK-4 in relation to the important information expected from this trial as a basis for further 
clinical development of this compound. Healthy volunteers are not expected to have any 
direct benefit from participation in the clinical trial with BI 1358894, as is the usual case in 
such Phase I trials. Considering the medical need for the development of a safer and more 
effective treatment for patients 
 the Sponsor 
considers that the benefit outweighs the potential risks and justifies exposure of healthy 
human volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the pharmacodynamic effects of a single dose 
of BI 1358894 (4 x 25 mg film-coated tablet in the fed state) on CCK-4- induced anxiogenic/ 
panic-like symptoms using the PSS in preselected CCK-4 sensitive healthy volunteers.
2.1.2
Primary endpoint
The following pharmacodynamic parameter will be determined:
Maximum change from baseline of Panic symptom scale (PSS) sum intensity score after 
CCK-4 injection.
2.1.3
Secondary endpoints
Not applicable.


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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 1358894 will be assessed based on: 

Adverse events (including clinically relevant findings from the physical and 
neurological examinations)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS)
2.2.2.3
Local tolerability
Local tolerability of CCK-4 injections will be assessed by the investigator or designee on the 
basis of swelling, induration, heat, redness, pain, and other findings.


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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, double-blind, placebo-controlled, two-way 
crossover trial in healthy male subjects in order to compare the test treatment (T) to the 
reference treatment (R). The subjects will be randomly allocated to the two treatment 
sequences (T-R or R-T). The treatments will be 4 x 25 mg BI 1358894 film-coated tablet in 
the fed state (T) and four placebo film-coated tablets in the fed state (R) administered prior to
CCK-4 injection. For this trial CCK-4 will be used as a provoking agent. For details refer to 
Section 4.1.
There will be a washout period of at least 17 days between the treatments.
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.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
For experimental challenge studies, the crossover design is preferred due to its efficiency: 
since each subject serves as his own control, the comparison between treatments is based on a 
comparison within subjects rather than between subjects. This trial design therefore removes 
intersubjective variability from the comparison between treatments and the overall number of 
subjects enrolled can be minimized [R94-1529].
3.3
SELECTION OF TRIAL POPULATION
It is planned that 20 healthy male subjects will enter the study; a minimum of 15 subjects 
must be evaluable for the analysis of the primary endpoint (see Section 3.3.5 for replacement 
of subjects). They will be recruited from the volunteers' pool of the trial site. For the selection 
of the 20 healthy male subjects it is planned to screen up to about 60 healthy male subjects to 
identify 20 CCK-4 sensitive subjects by exposing them to a CCK-4 challenge during 
Screening. Sufficient CCK-4 sensitivity is defined as achievement of the following after a 
CCK-4 i.v. bolus injection:

A sudden onset of panic and

Presence of at least 4 symptoms in the PSS and

A score of 2 or higher on PSS item 15: “Anxiety and Fear for Apprehension” 
Or: 

Achievement of a total PSS sum intensity score > 20 after CCK-4 i.v. bolus injection.
Only male subjects will be included in the study because limited data on reproductive 
toxicology are available at this time.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.


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3.3.1
Main diagnosis for trial entry
The study will be performed in healthy male subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
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 adequate contraception with their female partner 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 (with medical assessment 
of the surgical success) or

Surgical sterilisation (including bilateral tubal occlusion, hysterectomy or bilateral 
oophorectomy) of the subject's female partner or

Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in 
questionable cases a blood sample with FSH above 40 U/L and estradiol below 30 
ng/L is confirmatory) or

The use of condoms, if the female partner uses an adequate contraception method 
in addition, 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 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) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. C-Reactive Protein >ULN, erythrocyte sedimentation rate (ESR) ≥15 millimeters/h, liver 
or kidney parameter above ULN, 


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4. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
5. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
6. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
7. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
8. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
9. History of relevant orthostatic hypotension, fainting spells, or blackouts
10. Chronic or relevant acute infections
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication, 
CCK-4 or its excipients) 
12. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
13. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14. Smoker (more than 5 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Average intake of more than 21 units of alcohol per week (1 unit of alcohol equals 
approximately 250 mL of beer, 100 mL of wine, or 35 mL of spirits)
17. Drug abuse or positive drug screening
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
19. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. 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
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
24. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)


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25. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
26. Insufficient response to the CCK-4 challenge in Screening Visit 2 (see Section 3.3
above).
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.3), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg) or of clinically relevant changes in ECG requiring intervention as well as 
unexplained liver enzyme elevations at any time during the trial


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6. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
7. The subject shows a raised CRP level of >3.00 mg/dL or an ESR of ≥20 millimeters/hour
if these results are confirmed by a second sample.
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals 
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported
3. Violation of GCP, or the CTP, or the contract with BI, impairing the appropriate conduct 
of the trial
4. The sponsor decides to discontinue the further development of the investigational product
5. The trial will be stopped if at least 2 subjects show relevant individual QT prolongation 
(absolute QT or QTc greater than 500 ms), which has been confirmed by a repeat ECG 
recording
6. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in 2 subjects of the same dose group
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the Clinical Trial Leader together with the 
Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects 


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will be replaced. A replacement subject will be assigned a unique trial subject number, and 
will be assigned to the same treatment as the subject he replaces. A minimum of 15 subjects 
evaluable for the analysis of the primary endpoint have to be enrolled.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product BI 1358894 was manufactured by 
 
The provoking agent solution containing 50 µg CCK-4 acetate is manufactured by 
 
.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 1358894
Pharmaceutical formulation: Film-coated tablet
Source:
Unit strength:
25 mg
Posology:
4-0-0
Route of administration:
p.o.
Duration of use:
1 single dose
The characteristics of the reference product are given below:
Substance:
Placebo
Pharmaceutical formulation: Film-coated tablet
Source:
Unit strength:
n.a.
Posology:
4-0-0
Route of administration:
p.o.
Duration of use:
1 single dose
The characteristics of the provoking agent (NIMP) are given below:
Substance:
CCK-4 (cholecystokinin tetrapeptide)
Pharmaceutical formulation: injection solution


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Source:
Unit strength:
50 μg
Posology:
1-0-0
Route of administration:
i.v. bolus injection
Duration of use:
3 single dose
4.1.2
Selection of doses in the trial
The CCK-4 dose selected for this trial reflects standard doses for clinical trials (see 
Section 1.2). The administration of 50 μg CCK-4 has been performed in numerous clinical 
research trials in healthy subjects, elderly subjects, and patients with anxiety disorders. It has 
proven to be well-tolerated, even in patients with anxiety disorders who are highly sensitive 
to such challenges [P98-0035], [R18-2694], [R18-2695], [R18-2696].
In this single dose CCK-4 challenge study a higher inhibition of about 90 % (EC90) is 
intended to be achieved during PSS evaluation in order to ensure adequate target inhibition 
during the short lasting CCK-4 related stimulus. 


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4.1.3
Method of assigning subjects to treatment groups
Prior to start of the study, subjects willing to participate will be recruited to cohorts according 
to their temporal availability. According to the planned sample size, at least 4 cohorts are 
planned. After assessment of all in- and exclusion criteria, each eligible patient will be 
randomised to treatment groups in the morning of Day 1 (Visit 2) prior to first administration 
of trial medication and the appropriate medication number will be assigned. The
randomisation will be provided by the sponsor to the trial site in advance.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
Subject Numbers are automatically pre-populated via the BRAVE system (during data entry, 
in an ascending order).
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a 2-way crossover study. All subjects will receive the 2 treatments in 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
Formulation
Unit strength
Dosage
Total dose
T (Test)
BI 1358894
Tablet
25 mg
4 tablets (25 mg) q.d for 1 day
100 mg
R (Reference)
Placebo
Tablet
n.a. mg
4 tablets (n.a. mg ) q.d for 1 day
n.a. mg
The investigator (or authorised designee) will administer the trial medication as a single oral 
dose together with about 240 mL of water to subjects who are in a sitting position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
CCK-4 will be provided in vials containing 50 μg lyophilized CCK-4. Immediately prior to 
use, 5 mL of sterile normal saline (0.9% NaCl) for injection will be added to the vial 
containing lyophilized CCK-4 powder and mixed to produce a solution for injection. Before 
CCK-4 administration, 5 mL (50 μg CCK-4) of the solution is withdrawn from the vial into a 
syringe. Then the CCK-4 will be administered to the subjects as a bolus injection over 5 
seconds (maximum of 8 seconds) via a venous cannula.
In each treatment period, a high-fat, high-calorie meal will be served 30 min before BI drug 
administration. The subjects must completely consume the meal prior to drug intake. The 
composition of the standard high-fat, high-calorie meal is detailed in Table 4.1.4: 2; this meal 
is in compliance with the FDA guidance ‘Food-Effect Bioavailability and Fed 
Bioequivalence Studies’ [R03-2269]. For restrictions with regard to diet, see Section 4.2.2.2.


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Table 4.1.4: 2
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 fried eggs (in 15 g butter/margarine) (approximately 
100 g)
220
40 g fried bacon2
151
2 toasted slices of whole-wheat bread
154
15 g margarine for buttering toast slices
112
115 g fried potatoes
130
240 mL whole milk (3.5% fat)
151
Sum1
918
1
The total caloric content was supplied approximately as following: 156 kcal as protein, 
235 kcal as carbohydrate, and 500 to 600 kcal as fat. 
2
Vegetarians may replace bacon with 40 g brie 60+ (148 Kcal)
Subjects will be kept under close medical surveillance for 8 days after drug administration as 
described in the Flow Chart.
During the first 2 h after drug administration, subjects will only be allowed to lie down if 
supine positioning is required for trial-related measurements (e.g. recording of 12-lead ECG).
The treatments will be separated by a wash-out phase of at least 17 days.
4.1.5
Blinding and procedures for unblinding
The trial is designed double-blind. Neither subject nor investigator will be aware of the trial 
treatments. The investigator will be supplied with a set of sealed envelopes containing the 
medication codes. The envelopes will be kept unopened at the study site until the end of data 
collection or, in an emergency requiring the investigator to know a subject’s treatment 
allocation, opened with appropriate documentation. At the trial close-out visit, all envelopes 
will be collected.
Access to the randomisation schedule is restricted to the randomisation operators, the Clinical 
Trial Support group and the Pharmaceutics Department. 
Persons directly involved in the conduct of the trial will be blinded to trial treatments. The 
trial medication will be packed blinded. The trial will only be unblinded after locking of the 
database, which takes place only after the trial is clinically completed and all queries have 
been clarified. Access to the randomisation codes will be controlled and documented by a 
signed confidentiality statement, which will be stored in the TMF.
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical monitor, data manager, 
statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug metabolism scientist as 
well as dedicated CRO personnel). The objective of the trial is not expected to be affected.
.


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4.1.6
Packaging, labelling, and re-supply
4.1.6.1
BI 1358894
Drug supplies will be provided by BI. They will be packaged and labelled in accordance with 
local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.
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 in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.


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All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 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, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each study period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before until 24 h after each administration of trial 
medication.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the 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.


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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 and serum 
concentrations will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported),
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG, laboratory tests, a physical examination, and a 
neurological examination. At the end of trial examination, it will include review of vital 
signs, 12-lead ECG, laboratory tests, and a physical examination including determination of 
weight, and a neurological examination.
5.2.2
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 (e.g.
Dinamap VC 150,) at the times indicated in the Flow Chart, after subjects have rested for at 
least 5 min in a supine position. All recordings should be made using the same type of blood 
pressure recording instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count 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
BI test name [comment/abbreviation]
Haematology
Haematocrit 
Haemoglobin 
Red Blood Cell count/Erythrocytes
Reticulocyte count 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
Automatic WBC differential (relative 
and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic
differential WBC is abnormal and 
clinically relevant in the opinion of the 
investigator), according to local 
procedures
Polymorphnuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes and any 
abnormalities will be reported
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
ESR
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [CK-MB, only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
Hormones
Thyroid Stimulating Hormone1
Free T3 - Triiodothyronine1
Free T4 - Thyroxine 1
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Protein electrophoresis1
   Albumin
   Albumin (Protein Electrophoresis) 
   Alpha-1-Globulin (Protein Electrophoresis) 
   Alpha-2-Globulin (Protein Electrophoresis)
   Beta-Globulin (Protein Electrophoresis) 
   Gamma-Globulin (Protein Electrophoresis) 
C-Reactive Protein (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
Electrolytes
Sodium
Potassium
Chloride
Calcium
Inorganic phosphate


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
BI test name [comment/abbreviation]
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes 
Urine leucocytes 
Urine pH
Urine sediment (microscopic 
examination if erythrocytes, leukocytes 
nitrite or protein are abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1
Protein electrophoresis only at screening. Hormones only at screening and end of trial; for time points of 
assessment of 
, refer to Flow Chart. 
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Infectious serology will be performed 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 and drug restrictions, a urine alcohol and drug test
(e.g. ADVIA Chemistry XPT system) will be performed prior to each treatment period, and 
may be repeated at any time during the study at the discretion of an investigator or designee. 
The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
Urinanalysis stix and drug screening tests will be performed using e.g. Clinitek Novus test 
and ADVIA Chemistry XPT system, respectively.


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Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
Twelve-lead ECGs
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (e.g. Mortara Eli 250 C) at the times provided in the 
Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven. 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 12-lead ECG 
recording at visit 2 for at least 15 min before CCK-4 challenge until 30 min after the 
challenge and at visit 3 and 4 for at least 2 h before the BI 1358894 administration (for 
baseline assessment), and 6 h following drug administration using patient monitors (e.g. 
Mortara Telemetry System). Abnormal findings will be recorded as AEs if judged clinically 
relevant by the Investigator but no other data will be transferred to the database.
5.2.5
Other safety parameters
5.2.5.1
Local tolerability
Local tolerability will be assessed by the investigator or designee on the basis of swelling, 
induration, heat, redness, pain, and other findings.
5.2.5.2
Suicidality assessment
Suicidality assessment to further evaluate the psychological status of the subject will be 
performed at screening using the Columbia Suicidal Severity Rating scale (C-SSRS). The C 


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SSRS is a brief measure which is designed to assess severity and change of suicidality by 
integrating both, behaviour and ideation. The C-SSRS was designed to address the need for a 
summary measure to track change in the severity of suicidality across both clinical settings 
and treatment trials.
The original English version is shown in Appendix 10.2.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
The provoked panic symptoms in response to CCK-4 injection (as documented by the PSS 
score), which are prerequisite for demonstrating a potential effect of the investigational 
compound, will be considered PD parameters. Since they are an expected and desired 
response in the context of this trial (even though they constitute an untoward medical 
occurrence), they will not be recorded as AEs. All other observations not included on the PSS 
questionnaire occurring during the standard AE reporting time period (see Section 5.2.6.2.1) 
are to be documented as AEs.
Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation


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
Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in Section 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor 
and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
5.2.6.1.4
Detailed assessment of the adverse advent headache
If the subject reports headaches during the treatment period, the following information and 
data should be collected daily until the headache is resolved:

Onset after medication intake (hhh:min)

Headache severity on a Numeric Ranking Scale (NRS) ranging from 0 - 10

Quality of headache (new type of headache vs. similar to previous experienced 
episodes of known headaches)

Headache characteristics (pressing or tightening vs. burning vs. pulsating vs. 
aggravated by routine physical activity (such as walking or climbing stairs))

Location (all of the following that apply: unilateral, bilateral, holocephal, frontal, 
temporal, occipital, facial)

Any accompanying symptoms like all of the following that apply: nausea and/or 
vomiting, photophobia, phonophobia, lacrimation, other

If headache is resolved: overall duration of headache episode (start time and end time)


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5.2.6.1.5
Suicidal risk assessed by the C-SSRS (paper version)
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and behavior 
will also be recorded.
After the baseline visit, the assessment ‘since last visit’ will be performed at each clinic or 
phone visit (‘since last visit’ version). The investigator is to review positive and negative 
reports for plausibility and clinical relevance. Doubtful reports may be repeated or reports 
may be validated by a consulting psychiatrist. If there is a confirmed positive report of 
suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the subject during the clinic visit, and/or is to consult a psychiatrist. If 
the positive report is confirmed, appropriate actions for the subject’s safety have to be 
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behaviour, no suicidal intent’ (Type 11) standard AE / SAE reporting 
rules are to be applied.
For each negative report (suicidal ideation type 1, 2 or 3) after start of the trial, the
investigator is to decide based on clinical judgment whether it represents an adverse event 
(AE) as defined in the protocol, and if it is considered an AE then it must be reported 
accordingly.


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5.2.6.1.6
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following is considered an AESI:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are 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.
5.2.6.1.7
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
5.2.6.1.8
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure


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
Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 


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o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.2.6.2.4
Once a male subject has been enrolled in the clinical trial and has taken trial medication, and 
if the partner of the male trial participant becomes pregnant, the investigator must report any 
drug exposure during pregnancy in a partner of the male trial participant immediately (within 
24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s unique 
entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 


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is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
5.3.2
Methods of sample collection


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5.3.3
Analytical determinations
5.3.3.1
Analytical determination of analyte plasma concentration
5.3.4
Pharmacokinetic - pharmacodynamic relationship
5.4
ASSESSMENT OF BIOMARKERS
5.4.1
Methods of sample collection
5.4.2
Assessment of pharmacodynamic parameters
5.5
BIOBANKING
Not applicable.


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5.6
OTHER ASSESSMENTSS
5.6.1
Pharmacogenomic evaluation
5.6.2
CCK-4 challenge test
CCK-4 challenge tests (CCK-4 bolus iv injection of 50 µg) will be performed at the time 
points indicated in the Flow Chart. The CCK-4 injection time, 5 h after drug administration, 
must be recorded. PSS 
 assessments will be determined -15±1, 5 ± 1, 10±1, 20±1 
and 30 ±1 minutes after the injection to ensure a detailed compilation of potential changes in 
psychological conditions of the subjects. The time for the post CCK-4-injection blood 
samples must be recorded.
5.6.3
Pharmacodynamic parameters
The following pharmacodynamic parameters will be evaluated within this study:
-
Panic Symptom Scale (PSS, see Appendix 10.4)


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PSS:
The PSS is a patient reported outcome measurement from which the following factors are 
derived: physical symptoms of fear and the perception of alertness, anxiety, fear, and pain. 
The PSS assessments conducted on Day 1 15 min before drug administration will be 
considered as period baseline. At each measuring time point indicated in the Flow Chart, the 
subjects will assess their subjective impression of themselves by means of the panic symptom 
scale. The subjects will be asked to mark an adequate position on a scale from 0 (absent) to 4 
(very strong) of the characteristic 18 questions to be measured. The sum of the scale over all 
items will constitute the PSS sum intensity score. In addition to this sum intensity score, the 
number of positively rated PSS symptoms (total number of symptoms) will be also recorded. 
The score will be documented in the electronic case report form. It is anticipated that the 
highest PSS sum intensity score will be reached approximately 5 minutes after CCK-4
injection and will decrease thereafter.
The original English version is shown in Appendix 10.4.
5.7
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 


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pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an orally administered drug, 
and are widely used in clinical trials. The pharmacokinetic parameters and measurements 
outlined in Section 5.4 are generally used assessments of drug exposure. The biomarkers and 
pharmacodynamic parameters and measurements outlined in Sections 5.5 and 5.6 are of 
exploratory nature only.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests 
will be ± 30 min.
Study measurements and assessments scheduled to occur at ambulatory visits as indicated in 
the Flow Chart are to be performed and completed within a 3 h-period latest at 11:30 a.m.
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 venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening periods
In Screening Visit 1, after having been informed about the trial, all subjects will provide
written informed consent in accordance with GCP and local legislation prior to enrolment in 
the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
In Screening Visit 2 (on one day between Days -6 and -2), subjects will undergo a CCK-4
challenge test. Only subjects with sufficient CCK-4 sensitivity (see Section 3.3) will enter the 
treatment periods.
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days 1 till 9 in each period). 
The treatment periods will be separated by at least 17 days between drug administrations.


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On Day -1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for 8 days after drug administration. On Day 9, the 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. 
For details on times of all other trial procedures, refer to the Flow Chart. AEs and 
concomitant therapy will be assessed continuously from screening until the end of trial
examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.6.
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 assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s end of trial visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
This is a double-blind, randomised, two-way cross-over, single-dose trial, including a 
washout period of at least 17 days between the treatments (Section 3.1).
The main objective of this trial is to investigate the pharmacodynamic effects of a single dose 
of BI 1358894 (Test, T) on CCK-4 induced anxiogenic/ panic-like symptoms using the PSS 
compared to placebo (Reference, R) on the basis of the primary pharmacodynamic endpoint
as listed in Section 2.1.2. The trial is designed to allow intra-subject comparisons and will be 
evaluated statistically by use of a linear mixed effects model.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses with regard to any of the variables listed in 
Section 2 in a confirmatory sense. Two sided 90% confidence intervals (CIs) will be 
computed and will have to be interpreted in the perspective of the exploratory character of the 
study.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:
Enrolled set (ES):
This subject set includes all enrolled subjects that underwent screening procedures.
Entered set (ENTS):
This subject set includes all enrolled subjects that underwent screening procedures 
and entered the trial, whether treated or not.
Treated set (TS):
This subject set includes all subjects from the ENTS who were documented to have 
received at least one dose of study drug.
Pharmacodynamic set (PDS)
This subject set includes all subjects in the TS who provide at least one primary PD 
parameter that was not excluded according to the description below.
Pharmacokinetic set (PKS)
This subject set includes all subjects in the TS who provide at least one PK parameter 


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that was not excluded according to the description below.
All individual data will be listed.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(IPD) categories will be suggested in the IQRM plan. IPDs will be identified no later than in
the Report Planning Meeting, and the IPD categories will be updated as needed.
Pharmacokinetics


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Pharmacodynamics
PSS data of a subject will be included in the statistical analysis if they are not flagged for 
exclusion. Reasons for exclusion of single PSS parameters may be:

The subject experiences emesis at or before two times median tmax or before the 
subject completes PSS assessments on study day 1 according to Flow Chart. Median 
tmax is to be determined excluding the subjects experiencing emesis 

Time deviations

Use of restricted medications 

If a predose concentration value is greater than 5% of Cmax of the subjects´ 
pharmacokinetic data, the respective PD assessments in the respective period may be 
excluded from statistical assessments
7.3.1
Primary endpoint analyses
The derivation of the primary endpoint PSS sum intensity score per time point is outlined in 
Section 5.6.3. The maximum CfB is defined as the maximum of the differences of the PSS 
sum intensity score measured at each time point after the CCK-4 challenge minus the PSS 
sum intensity score measured at baseline. Further details on the calculation will be given in 
the TSAP. The primary endpoint analysis will be performed on the PDS (refer to 
Section 7.3).
Primary analyses
The statistical model used for the investigation of the primary endpoint PSS sum intensity 
score will be a mixed effects model given by
 = 	 +  +  +  + 
 +  + ,
where 

Maximum CfB (absolute change from period baseline) in PSS sum 
intensity score for the ith subject and the mth period, receiving 
randomised treatment j,
	
overall intercept, 

mth period effect, m = 1,2,

jth treatment effect, j = 1,2,

baseline value for subject i in period m (period baseline), 

associated covariate effect of period baseline, 


the subject baseline value (mean of the 2 period baselines) for 
subject i,

associated covariate effect of subject baseline,


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
the random effect of subject i,

the random error associated with subject i who received treatment j 
in period m.
The last value before administration of the CCK-4 challenge in each period is considered as 
the corresponding period baseline measurement. The PSS sum intensity score mean value of 
the two period baseline values is considered as the subject baseline.
The treatment comparison will be the difference between active treatment and placebo. 
Adjusted means (Least Squares Means) as well as 2-sided 90% CIs will be calculated.
Additionally, the difference in adjusted means relative to placebo will be provided. To 
support this analysis, listings and graphical displays may be generated if appropriate. 
As a sensitivity analysis, the same statistical model as stated above will be repeated for the 
primary endpoint but with all sources of variation considered as fixed effects.
Further details will be presented in the TSAP.
7.3.2
Secondary endpoint analyses
Not applicable.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.3) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Blinded Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first trial medication intake and end of 
REP (see Section 1.2.3) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
In case of two or more treatments, the follow-up will be summarized according to the 
immediately preceding treatment. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP. Note that AEs occurring after the last per 
protocol contact but entered before final database lock will be reported to Pharmacovigilance
only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.


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7.3.5
Pharmacokinetic and pharmacodynamic analyses
For a description of PK and PD analyses, please see Section 7.3.1 and Section 7.3.3.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure [001-MCS-36-472].
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.5.3
Pharmacodynamics
For the PD endpoints PSS 
 if the period baseline value is missing in treatment 
period 1, it will be imputed by the corresponding value measured in treatment period 2. If the 
period baseline value is missing in treatment period 2, it will be imputed by the 
corresponding value measured in treatment period 1. If a value is missing after CCK-4
injection, this value will not be imputed. If all four assessments after CCK-4 injection are 
missing for a subject, this subject is not evaluable for this endpoint in this period.
7.6
RANDOMISATION
Subjects will be randomised to one of the 2 treatment sequences in a 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 that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable. Access to the codes will be controlled and 
documented.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).


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7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 20 subjects in the trial, because this sample size is considered
sufficient to achieve the aims of this exploratory trial. At least 15 subjects need to be 
evaluable for the primary objective of this trial.
Based on this sample size, the probability to observe a meaningful reduction in PSS sum 
intensity score after a single dose of BI 1358894 when compared to placebo is given in 
Table 7.7: 1 for N=20 subjects and in Table 7.7: 2 for N=15 subjects.
For these calculations, the following assumptions are made. A total of N subjects are 
evaluable in this cross-over study. The standard deviation of the maximum change from 
baseline of the treatment contrast of PSS relative to placebo is 20%. The maximum change 
from baseline for PSS sum intensity score relative to placebo is 0% after the placebo 
treatment. Six different scenarios are displayed. 
Table 7.7: 1
Probability to observe a difference in the primary endpoint ≤ 20%, 
20% - 40% and > 40% relative to placebo for different scenarios and 
a sample size of N=20 evaluable subjects.
True maximum change from baseline
relative to placebo
Probability to observe a relative mean difference
(BI 1358894 vs. Placebo)
BI 1358894
Placebo
≤ 20%
20% - 40%
> 40%.
10%
0%
70.9
23.6
5.5
18%
0%
54.4
33.9
11.7
28%
0%
33.0
41.5
25.5
33%
0%
23.8
41.2
35.0
46%
0%
8.2
28.9
62.9
52%
0%
4.5
21.0
74.5
Table 7.7: 2
Probability to observe a difference in the primary endpoint ≤ 20%, 
20% - 40% and > 40% relative to placebo for different scenarios and 
a sample size of N=15 evaluable subjects.
True maximum change from baseline
relative to placebo
Probability to observe a relative mean difference
(BI 1358894 vs. Placebo)
BI 1358894
Placebo
≤ 20%
20% - 40%
> 40%.
10%
0%
68.2
23.3
8.6
18%
0%
53.8
30.9
15.4
28%
0%
35.3
36.1
28.6
33%
0%
27.1
35.9
37.0
46%
0%
11.6
27.3
61.2
52%
0%
7.3
21.3
71.4


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The calculations were performed using R version 3.3.2. The R code for the sample size 
calculations will be documented in a separate file and stored in the Trial Master File (TMF).


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs) and other 
relevant regulations. Investigators and site staff must adhere to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract.
As a general rule, no trial results should be published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject according to ICH-GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional subject-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each subject.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history


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
AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
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 valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 


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Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

If applicable, a fit for purpose approach will be used for assay/equipment validation 
depending on the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.


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The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at
, under the supervision of the Principal Investigator. Relevant documentation 
on the participating Principal Investigator (e.g. curricula vitae) will be filed in the ISF.
BI has appointed a Trial Clinical Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local clinical trial manager (CTM), 
Clinical Research Associates, and the participating trial site
The trial medication BI 1358894 will be provided by the Clinical Trial Supplies Unit 
(CTSU), 
Safety laboratory tests will be performed by the local laboratory of the trial site (
, 
).
The analyses of BI 1358894 concentrations in plasma will be performed at the Department of 
Drug Metabolism and Pharmacokinetics, 
 
or a contract research organisation appointed by BI.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
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Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath 
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longer-term outcomes in depressed outpatients requiring one or several 
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Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
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Guidance for industry: food-effect bioavailability and fed bioequivalence 
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Trivedi MH, Rush AJ, Wisniewski SR, Warden D, McKinney W, Downing 
M, Berman SR, Farabaugh A, Luther JF, Nierenberg AA, Callan JA, 
Sackeim HA. Factors associated with health-related quality of life among 
outpatients with major depressive disorder: a STAR*D report. J Clin 
Psychiatry 2006;67(2):185-195.
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Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao 
GL, Tsvetkov E, Rodig SJ, Veer A van't, Meloni EG, Carlezon WA, 
Bolshakov VY, Clapham DE. Essential role for TRPC5 in amygdala 
function and fear-related behavior. Cell 2009;137(4):761-772.
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Riccio A, Li Y, Tsvetkov E, Gapon S, Yao GL, Smith KS, Engin E, 
Rudolph U, Bolshakov VY, Clapham DE. Decreased anxiety-like behavior 
and Galphaq/11-dependent responses in the amygdala of mice lacking 
TRPC4 channels. J Neurosci 2014;34(10):3653-3667.
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Fowler MA, Sidiropoulou K, Ozkan ED, Phillips CW, Cooper DC. 
Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent 
brain. Plos One 2007;2(6):e573
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Koenigsberg HW, Denny BT, Fan J, Liu X, Guerreri S, Mayson SJ, et al. 
The neural correlates of anomalous habituation to negative emotional 
pictures in borderline and avoidant personality disorder patients. Am J 
Psychiatry 2014; 171(1):82-90.
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Mandell D, Siegle G, Shutt L, Feldmiller J, Thase ME. Neural substrates of 
trait ruminations in depression. J Abnorm Psychol 2014;123(1):35-48.


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IsHak WW, Elbau I, Ismail A, Delaloye S, Ha K, Bolotaulo NI, et al. 
Quality of life in borderline personality disorder. Harvard Rev Psychiatry 
2013;21(3): 138-150.
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McClintock SM, Husain MM, Wisniewski SR, Nierenberg AA, Stewart 
JW, Trivedi MH, et al. Residual symptoms in depressed outpatients who 
respond by 50 % but do not remit to antidepressant medication. J Clin 
Psychopharmacol 2011;31(2): 180-186.
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borderline personality disorder: prognosis, prediction of outcome, and axis 
II comorbidity. Can J Psychiatry 1998;43(3):265-270.
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Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Pfohl B, Widiger TA. 
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Ellison WD, Rosenstein L, Chelminski I, Dalrymple K, Zimmerman M. 
The clinical significance of single features of borderline personality 
disorder: anger, affective instability, impulsivity, and chronic emptiness in 
psychiatric outpatients. J Personal Disord 2016;30(2):261-270.
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channel superfamily. J Neurogenet 2010;24(4):216-233.
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Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to 
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Zwanzger P, Baghai TC, Schuele C, Stroehle A, Padberg F, Kathmann N, et 
al. Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced 
panic in healthy volunteers. Neuropsychopharmacology 2001;25(5):699-
703.
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Zwanzger P, Eser D, Padberg F, Baghai TC, Schule C, Roetzer F, et al. 
Effects of tiagabine on cholecystokinin-tetrapeptide (CCK-4)-induced 
anxiety in healthy volunteers. Depress Anxiety 2003;18(3):140-143.
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Zwanzger P, Eser D, Aicher S, Schuele C, Baghai TC, Padberg F, et al. 
Effects of alprazolam on cholecystokinin-tetrapeptide-induced panic and 
hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study. 
Neuropsychopharmacology 2003;28(5):979-984.
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Shlik J, Aluoja A, Vasar V, Vasar E, Podar T, Bradwejn J. Effects of 
citalopram treatment on behavioural, cardiovascular and neuroendocrine 
response to cholecystokinin tetrapeptide challenge in patients with panic 
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Bradwejn J, Koszycki D, Shriqui C. Enhanced sensitivity to 
cholecystokinin tetrapeptide in panic disorder: clinical and behavioral 
findings. Arch Gen Psychiatry 1991;48(7):603-610.


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R19-0565
Bradwejn J, Koszycki D, Meterissian G. Cholecystokinin-tetrapeptide 
induces panic attacks in patients with panic disorder. Can J Psychiatry 
1990;35(1):83
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Bradwejn J, Koszycki D, Payeur R, Bourin M, Borthwick H. Replication of 
action of cholecystokinin tetrapeptide in panic disorder: clinical and 
behavioral findings. Am J Psychiatry 1992; 149: 962-964
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Bradwejn J, Koszycki D, Couetoux du TA, Paradis M, Bourin M. Effects of 
flumazenil on cholecystokinin-tetrapeptide-induced panic symptoms in 
healthy volunteers. Psychopharmacology (Berl) 1994; 114: 257-261
R19-0627
van Megen HJ, Westenberg HG, den Boer JA, Kahn RS. The panic-
inducing properties of the cholecystokinin tetrapeptide CCK4 in patients 
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van Megen HJ, Westenberg HG, den Boer JA, Slaap B, Es-Radhakishun F, 
Pande AC. The cholecystokinin-B receptor antagonist CI-988 failed to 
affect CCK-4 induced symptoms in panic disorder patients. 
Psychopharmacology (Berl) 1997; 129: 243-248
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c10354149
 Investigator's brochure BI 1358894 in Major Depressive 
Disorder and Borderline Personality Disorder. 09 Jul 2018.
c13880029
. Safety, tolerability and pharmacokinetics 
of single rising oral doses of BI 1358894 in healthy male subjects (single-
blind, partially randomised, placebo-controlled parallel group design) and 
effect of food on the relative bioavailability of BI 1358894 (open-label, 
randomised, two-way cross-over). 1402.1. 25 Aug 2018
n00248384
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TRPM8,TRPC6, TRPA1, hERG, Kv1.3, Cav1.2, Nav1.2, Nav1.7 and 
Nav1.5. BI1358894-Just-1602-B. 20 January 2016.
n00250347
 
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toxicity study in Sprague Dawley rats
n00252179
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06 September 2012.
n00252207
 Effects of HC-122608 on mouse marble burying. Report #: 
213. 18 June 2013.
n00252277
 Effect of HC-122608 in the mouse elevated plus maze. Report #: 
168. 16 January 2013.


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n00252628
 [14C]BI 1358894: Distribution Study in the Male Pigmented Rat.
n00252903
 Effect of BI 1358894 in the mouse forced swimming test. Draft 
Report. 2 December 2016
n00253490
 Cytochrome P450 Inducibility in SD rat hepatocytes – Effect on 
in vitro clearance. KLC-BO16-01. 18 Nov 2016.
n00253492
 BI 1358894: In vitro inhibition studies on 
cytochrome P450 dependent metabolic reactions. A417/16LU. 08 Nov 2016
n00253628
 Prediction of BI 1358894 Pharmacokinetics and Therapeutic Dose 
in Human. Draft Report.
n00253723
 Influence of BI 1358894 (10, 30 and 100 mg/kg PO) on 
cardiovascular function (systolic and diastolic arterial pressure, heart rate
and ECG) and body temperature in conscious rats. GP2014/0251/PH5. 29 
Novembre 2016.
n00253725
 Effects of BI 1358894 on behavior assessed by observation of 
nocturnal activity or in a modified IRWIN-test after oral administration of 
10, 30 and 100 mg/kg. GP2014/0271/0272/PH3. 29 November 2016.
n00253727
. Influence of BI 1358894 (10, 30 and 100 mg/kg PO) 
on hemodynamic and electrocardiographic parameters in conscious dogs. 
GP2014/0269/PH5. 29 November 2016.
n00253729
 Effects of BI 1358894 (10, 30 and 100 mg/kg 
p.o.) on gastrointestinal function in the conscious rat. GP2014/0277/PH4. 
12 December 2016.
n00253732
 Effects of BI 1358894 (10, 30 and 100 mg/kg 
p.o.) on urine- and serum-derived parameters in conscious rats. 
GP2014/0274/PH4. 29 November 2016.
n00253734
 Partial validation of an LC-MS/MS method for the quantification of 
BI 1072668 in rat plasma, calibration range 5.00 - 25000 nmol/L. 16B133.
n00253752
Selectivity test of HC-122608 on TRPV1, TRPV3, TRPM8, 
TRPC6, TRPA1, hERG, Kv1.3, Cav1.2, Nav1.2, Nav1.7 and Nav1.5. 155. 
11 Jan 2013.
n00256526
Evaluation of Induction Potential of Cytochrome P450 Isoforms 
by BI 1358894 in Cultured Human Hepatocytes. 1701261. 19 Jul 2017


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10.
APPENDICES
10.1
PREPARATION INSTRUCTIONS FOR CCK-4
The CCK-4 will be prepared as follows:
-
A vehicle will be prepared with citrate buffer pH4, 1% polysorbate 80 and 10% 
mannitol in WFI
-
10 mg CCK-4 will be dissolved into 100 mL of this vehicle
-
The solution will be diluted to 1000 mL using normal saline solution (final 
concentration 10 µg/mL, dose will be 50 µg in 5 mL)
CCK-4 solution for injection will be prepared as follows:
-
10 mL vials with 6 mL fills of a sterile CCK-4 solution will be manufactured by 
 
and stored at -20°C.
-
Shortly before use the vial will be thawed; 5 mL of the solution will be drawn into a 5 
mL syringe and closed with a stopper.


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10.2
COLUMBA-SUICIDE SEVERITY RATING SCALE


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10.4
PANIC SYMPTOM SCALE
The Panic Symptom Scale
English Version
item
Symptom
Absen
t
Intensity
Very
Stron
1
dyspnea /difficulty breathing
0
1
2
3
4
2
dizziness
0
1
2
3
4
3
unsteadiness
0
1
2
3
4
4
faintness
0
1
2
3
4
5
palpitations
0
1
2
3
4
6
trembling
0
1
2
3
4
7
sweating
0
1
2
3
4
8
choking
0
1
2
3
4
9
nausea
0
1
2
3
4
10
abdominal distress
0
1
2
3
4
11
feeling unreal or detached
0
1
2
3
4
12
paresthesia/ numb or
tingling feelings
0
1
2
3
4
13
hot flushes
0
1
2
3
4
14
chest pain or discomfort
0
1
2
3
4
15
anxiety, fear or apprehension
0
1
2
3
4
16
fear of dying
0
1
2
3
4
17
fear of losing control
0
1
2
3
4
18
fear of going crazy
0
1
2
3
4


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
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
11.2
GLOBAL AMENDMENT 2
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
To be implemented only after approval of the IRB / IEC / Competent 
Authorities


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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21630258
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clinical-trial-protocol
A double-blind, randomised, two-way cross-over, single-dose, placebo-controlled
trial to investigate the effects of BI 1358894 on cholecystokinin tetrapeptide (CCK-4)
induced panic symptoms in healthy male subjects
Author-Trial Clinical
Pharmacokineticist
14 Mar 2019 11:25 CET
Approval-Therapeutic Area 
14 Mar 2019 12:11 CET
Approval-Team Member Medicine
14 Mar 2019 14:44 CET
Author-Trial Statistician
14 Mar 2019 15:15 CET
Author-Clinical Trial Leader
14 Mar 2019 15:27 CET
Verification-Paper Signature
Completion
18 Mar 2019 10:17 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21630258
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c27997646-01
BI Trial No.:
1402-0005
Title:
A double-blind, randomised, two-way cross-over, single-dose, 
placebo-controlled trial to investigate the effects of BI 1358894 on 
cholecystokinin tetrapeptide (CCK-4) induced panic symptoms in 
healthy male subjects
Including Protocol Amendment 2 [c26426667-03]
Investigational
Product:
BI 1358894
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
29 AUG 2019 SIGNED 
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3.3
Safety and Tolerability endpoints......................................................................11
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................16
6.5
POOLING OF CENTRES .................................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................18
7.
PLANNED ANALYSIS......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........20
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINT .....................................................................................20
7.4.1
Primary analysis of the primary endpoint........................................................20
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoints...............................................................................................22
7.5
SECONDARY ENDPOINTS.............................................................................22
7.6.1
Safety parameters ...............................................................................................22


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7.7
EXTENT OF EXPOSURE.................................................................................25
7.8
SAFETY ANALYSIS..........................................................................................25
7.8.1
Adverse Events ....................................................................................................25
7.8.2
Laboratory data ..................................................................................................26
7.8.3
Vital signs.............................................................................................................27
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................27
7.8.5.1 
Physical examination ..........................................................................................27
7.8.5.2 
Neurological examination...................................................................................28
7.8.5.3 
Suicidality assessment.........................................................................................28
8.
REFERENCES....................................................................................................29
10.
HISTORY TABLE..............................................................................................32


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs ................................................14
Table 6.2: 1
Handling of iPDs..............................................................................................16
Table 6.3: 1
Subject sets analyzed........................................................................................17
Table 10: 1
History table .....................................................................................................32


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BI 
Boehringer Ingelheim
BMI
Body mass index
BP
Blood pressure
CCK-4
Cholecystokinin tetrapeptide
CDR
Clinical Data Repository
CRF
Case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DNA
Desoxyribonucleic acid
ECG
Electrocardiogram
Emax
Maximum effect
ENTS
Entered Set
ES
Enrolled Set
FDA
Food Drug Administration
eCRF
Electronic case report form


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Term
Definition / description
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
iPD
Important protocol deviation
IQRMP
Integrated quality and risk management plan
MedDRA
Medical Dictionary For Regulatory Activities
NIMP
Non-investigational medicinal product
PD
Pharmacodynamic(s)
PDS
Pharmacodynamic parameter set
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PSS
Panic symptom scale
R
Reference treatment
RAGe
Report appendix generator
RPM
Report Planning Meeting
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class
T
Test product or treatment
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated set
TSAP
Trial Statistical Analysis Plan
tz
Time of last measurable concentration of the analyte in plasma
ULN
Upper limit of normal range
VAS
Visual Analogue Scale


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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 (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated by means of noncompartmental analysis using Phoenix 
WinNonlinTM software (current version Phoenix 6.3 or higher, Certara USA Inc., Princeton, 
NJ, USA). Outputs for the CTR will be generated using SASTM (current Version 9.4, by SAS 
Institute Inc., Cary, NC, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.
The following changes compared to the protocol will be made:
No ‘Enrolled set (ES)’ will be defined in the TSAP as data of subjects discontinued before 
first administration of investigational trial medication will not be entered in the CDR. A 
correct display of the ES is therefore not possible. Due to the same reason, the ‘Entered set 
(ENTS)’ will be similar to the ‘Treated set (TS)’. Therefore, no ‘Entered set (ES)’ will be 
defined in the TSAP as well.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is a PD endpoint, as defined in Section 2.1.2 of the CTP:

Maximum change from baseline of Panic symptom scale (PSS) sum intensity score 
after CCK-4 injection.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Not applicable.


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5.3.3
Safety and Tolerability endpoints
Safety and tolerability of BI 1358894 will be assessed based on parameters defined in 
Section 2.2.2.2 and Section 2.2.2.3 of the CTP:

Adverse events (including clinically relevant findings from the physical and 
neurological examinations)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS)
Local tolerability of CCK-4 injections (absence or presence of "swelling", "induration", 
"heat", "redness", "pain", or "other findings") will be summarized with counts and 
percentages overall (i.e. subject-wise worst case over all injections and time points) as well as
listed by injection and time point.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment 
groups, and selection of doses, cf. Section 4 of the CTP.
Each subject is planned to be treated in two subsequent treatment periods, with one single 
dose of BI 1358894 or placebo in each treatment period:

Test treatment (Treatment T):
4 x 25 mg BI 1358894 film-coated tablet in the fed state

Reference treatment (Treatment R):
4 x placebo film-coated tablets in the fed state
Each subject is planned to be randomly allocated to one of the two treatment sequences (T-R 
or R-T) in a 1:1 ratio.
In addition to the two investigational treatments stated above, the following non-
investigational provoking agent will be used:

provoking agent (NIMP)
50 μg CCK-4 (cholecystokinin tetrapeptide) as i.v. bolus injection
For the selection of subjects included in the trial, subjects able and willing to participate will 
be exposed to the provoking agent CCK-4 at screening. After identification of CCK-4 
sensitive subjects (cf. Section 3.3 of the CTP), trial subjects will be exposed to CCK-4 again 
within each treatment period. 
For statistical analyses of AEs, the following separate analysis phases will be defined for 
each subject:


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Table 6.1: 1
Analysis phases for statistical analysis of AEs
Study analysis 
phase
Label
Start
End
Screening
Screening
Date of informed consent
Date/time of first administration of BI 
1358894 or placebo
On treatment
BI 1358894
or 
Placebo,
respectively
Date/time of administration of
BI 1358894 or placebo, 
respectively
Date/time of administration of 
BI 1358894 or placebo in the next 
treatment period, if applicable,
otherwise
12:00 a.m. on day after subject's end of 
study participation date.
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only.
In CTR Section 15, AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 
AE tables), the following totals will be provided in addition: 

"Total on treatment", defined as the total over all on-treatment phases
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening and on-treatment
phases.
Additionally to the total defined above, the following total will be provided in CTR 
Section 16.1.13.1.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment)
Statistical analyses of safety laboratory tests and vital signs will be conducted by treatment 
period (BI 1358894 or Placebo), with clear differentiation between baseline (cf. Section 6.7) 
and on-treatment measurements.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting. At this meeting, it will be 


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decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an iPD. For definition of iPDs, and for the process of identification of these, 
refer to the BI reference document "Identify and Manage Important Protocol Deviations 
(iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the minutes of the Report Planning Meeting via an accompanying Excel spreadsheet (3).
Categories which are considered to be iPDs in this trial are defined in the integrated quality 
and risk management plan (IQRMP). If the data show other iPDs, the definition in the 
IQRMP will be supplemented accordingly by the time of the Report Planning Meeting.
iPDs will be summarized and listed. Table 6.2: 1 below specifies which kind of iPDs could 
potentially lead to exclusion from which analysis set. The decision on exclusion of patients 
from analysis sets will be made at the latest at the Report Planning Meeting, after discussion 
of exceptional cases and implications for analyses.


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Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Excluded from which analysis set
iPD B1 
Informed consent not available/not 
done
All
iPD B2 
Informed consent too late
None
iPD A1
Inclusion Criteria not met
PDS, PKS
iPD A2
Exclusion Criteria violated
PDS, PKS
iPD C2
Randomisation not followed
PDS, PKS
iPD C3
Non-compliance
PDS, PKS
iPD C4
Medication code broken 
inappropriately
PDS, PKS
iPD C5
Incorrect intake of trial medication
PDS, PKS
iPD C6
Improper washout between treatments
PDS, PKS
iPD D1
Prohibited medication use
PDS, PKS
iPD E1
Certain violations of procedures used 
to measure primary or secondary data
PDS, PKS
iPD E2
Certain violations of procedures (e.g. 
C-SSRS)
PDS, PKS
iPD F1
Certain violations of time schedule 
used to measure primary or secondary 
data
PDS, PKS
iPD G1
Certain violations of procedures used 
to measure primary or secondary data
PDS, PKS
iPD G2
PDs affecting safety and rights of 
subjects
None
6.3
SUBJECT SETS ANALYSED
As stated in Section 4 of this TSAP, the ES and ENTS will not be used, as the data of these 
subjects are not in the CDR. The PDS and PKS will be used as defined in the CTP, Section 
7.3. In this Section, the treated set was defined as:
Treated set (TS):
This subject set includes all subjects from the ENTS who were documented to have received 
at least one dose of study drug.


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For clarification, the definition of the TS will be specified further as:
Treated set (TS):
This subject set includes all subjects that underwent screening procedures, entered the trial 
and were documented to have received at least one dose of investigational study drug.
The following Table 6.3: 1 contains the information which subject is used for which class of 
endpoint:
Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PDS
PKS
Primary PD endpoint 
X
Further PD endpoints
X
Further PK endpoints 
X
Safety parameters & treatment exposure
X
Demographic/baseline endpoints
X
Important protocol deviations
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study is performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to first administration of 
investigational study drug will not be reported in the CTR.
Data of subjects who drop out or withdraw from the trial will be reported in the CTR as far as 
their data are available. All withdrawals will be documented and the reason for withdrawal 
reported in the CTR.
Handling of missing PD data will be done as described in CTP Section 7.5.3:
For the PD endpoints PSS 
, if the period baseline value is missing in treatment
period 1, it will be imputed by the corresponding value measured in treatment period 2. If the
period baseline value is missing in treatment period 2, it will be imputed by the


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corresponding value measured in treatment period 1. If a value is missing after CCK-4
injection, this value will not be imputed. If all four assessments after CCK-4 injection are
missing for a subject, this subject is not evaluable for this endpoint in this period.
CTP Section 7.5.1: It is not planned to impute missing values for safety parameters.
One exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards.
CTP Section 7.5.2: PK parameters that cannot be reasonably calculated based on the 
available drug concentration-time data will not be imputed.
Missing data and outliers of PK data are handled according to BI standards (4).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
A separate baseline is defined for each study treatment. The baseline is the last available 
value before administration of the CCK-4 challenge in the respective treatment period. E.g. 
for PSS sum intensity score 
 baseline is the value measured 15 minutes before 
administration of the CCK-4 challenge within the respective treatment period.
In addition, for vital signs displays where PTM -2:00 are considered as baseline will be 
provided.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the Report Planning Meeting.
Unscheduled measurements of laboratory data or vital signs data will be assumed to be repeat 
measurements of the most recent scheduled measurement (e.g. for follow-up or confirmation 
of a particular value). Therefore, unscheduled measurements will be assigned to the planned 
time point of the previous scheduled measurement.
Descriptive statistics of laboratory data will be calculated by planned time point based on the 
worst value of the subject at that planned time point (or assigned to that planned time point).
For vital signs, descriptive statistics will be calculated by planned time point based on the last 
value of the subject at that planned time point (or assigned to that planned time point).


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the standards defined in the BI standards
with the exception of those generated for PK-calculations (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment 
sequence, subject number and visit (if visit is applicable in the respective listing). AE listings 
will be sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.
Only descriptive statistics are planned for this section of the CTR.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analyzed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINT
CTP Section 7.3.1: “The derivation of the primary endpoint PSS sum intensity score per time 
point is outlined in Section 5.6.3. The maximum CfB is defined as the maximum of the 
differences of the PSS sum intensity score measured at each time point after the CCK-4 
challenge minus the PSS sum intensity score measured at baseline.”
7.4.1
Primary analysis of the primary endpoint
The primary endpoint will be analyzed based on the PDS.
Descriptive statistics and boxplots of the primary endpoint by treatment will be provided.
As main analysis, the following model will be applied:
Statistical model
CTP Section 7.3.1: “The statistical model used for the investigation of the primary endpoint 
PSS sum intensity score will be a mixed effects model given by
 = 	 +  +  +  + 
 +  + ,


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where 

Maximum CfB (absolute change from period baseline) in PSS sum 
intensity score for the ith subject and the mth period, receiving 
randomised treatment j,
	
overall intercept, 

mth period effect, m = 1,2,

jth treatment effect, j = 1,2,

baseline value for subject i in period m (period baseline), 

associated covariate effect of period baseline, 


the subject baseline value (mean of the 2 period baselines) for 
subject i,

associated covariate effect of subject baseline,

the random effect of subject i,

the random error associated with subject i who received treatment j 
in period m.
The last value before administration of the CCK-4 challenge in each period is considered as 
the corresponding period baseline measurement. The PSS sum intensity score mean value of 
the two period baseline values is considered as the subject baseline.
The treatment comparison will be the difference between active treatment and placebo. 
Adjusted means (Least Squares Means) as well as 2-sided 90% CIs will be calculated. 
Additionally, the difference in adjusted means relative to placebo will be provided. To 
support this analysis, listings and graphical displays may be generated if appropriate. 
As a sensitivity analysis, the same statistical model as stated above will be repeated for the 
primary endpoint but with all sources of variation considered as fixed effects.”
For the random ‘subject’ effect in the above model a Variance Components (VC) covariance 
structure will be used; in case of convergence problems refer to Additional Section 9.2. The 
SAS procedure MIXED will be used involving the restricted maximum likelihood estimation 
and the Kenward-Roger approximation for denominator degrees of freedom. This approach is 
described in Kenward and Roger (8).
Programming details are provided in Section 9.1.1.


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7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoints
CTP Section 7.3.1: As a sensitivity analysis, the same statistical model as stated above will 
be repeated for the primary endpoint but with all sources of variation considered as fixed 
effects.
7.5
SECONDARY ENDPOINTS
Not applicable.
7.6.1
Safety parameters
Safety and tolerability will be analysed as described in Section 7.8 of this TSAP.


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7.7
EXTENT OF EXPOSURE
Treatment exposure will be listed by means of the date and time of drug administration.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to screening or on-treatment phases as defined in Section 6.1. 
AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (7) and for the class of 
AESIs.
CTP, Section 5.2.6.1.6: “The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
○
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN 
measured in the same blood sample, or 
○
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN”


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The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (7), AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs, subjects 
with AESIs and subjects with other significant AEs (according to ICH E3 (7)). The frequency 
of subjects with AEs and the frequency of subjects with AEs considered by the investigator to 
be drug related will also be summarised by maximum intensity, primary SOC and preferred 
term.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
If the subject reports headaches during the treatment period further information about the 
duration of headache, headache severity (NRS), location, characteristics, and signs and 
symptoms were recorded. The information will be summarized with descriptive statistics.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards.
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.


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Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the Report Planning Meeting at the latest. It is the 
Investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values in an 
automated manner will not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment)
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.4
ECG
Relevant ECG findings will be reported as relevant medical history/baseline condition (if a 
condition already exists before first administration of study treatment) or as AE (if condition 
emerges after first administration of study treatment) and will be summarized as such. No 
separate listing or analysis of ECG findings will be prepared.
7.8.5
Others
7.8.5.1 
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.


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7.8.5.2 
Neurological examination
Clinically relevant findings of the neurological examination will be reported as relevant 
medical history/baseline condition (if a condition already exists before first administration of 
study treatment) or as AE (if condition emerges after first administration of study treatment) 
and will be summarized as such. No separate listing or analysis of neurological examinations
will be prepared.
7.8.5.3
Suicidality assessment
Suicidality monitoring will be performed as described in Section 5.2.2 of the CTP, results 
will only be listed: No further analysis will be prepared.


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8.
REFERENCES


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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
29-AUG-2019
None
This is the final TSAP