Clinical trial NCT03854578
Conditions: Depressive Disorder, Major
Sponsor: Boehringer Ingelheim
Start date: 2019-03-12; Completion date: 2019-09-23
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess the effect of a single dose of BI 1358894 compared to placebo on BOLD responses in modulating brain processing of emotional and cognitive stimuli on the amygdala and related brain structure using fMRI in in unmedicated patients with depression.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: BI 1358894 intervention 2: Placebo matching BI 1358894 intervention 3: Citalopram
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet intervention 3: Film-coated tablet

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c17663416-03
EudraCT No.:
EU Trial No:
2017-004763-12
BI Trial No.:
1402-0003
BI Investigational 
Product(s):
BI 1358894
Title:
A single dose, randomized, placebo controlled Phase I study on 
the effects of BI 1358894 on functional MRI measurements in an 
emotional processing paradigm in patients with Major 
Depressive Disorder
Lay Title:
A study in people with depression to test the effects of 
BI 1358894 on parts of the brain that are involved in emotions.
Clinical Phase:
I
Clinical Trial  
Leader:
Phone 
, Fax 
Principal 
Investigator:
Phone 
, Fax
Status:
Final Protocol
(Revised Protocol (based on global amendment No.2))
Version and Date:
Version: 3.0
Date: 21 Feb 2019
Page 1 of 77
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 
Finished product name:
NA
Active ingredient name:
BI 1358894
Protocol date :
29 Nov 2018
Revision date :
21 Feb 2019
Trial number:
1402-0003
Title of trial:
A single dose, randomized, placebo controlled Phase I study on the effects of 
BI 1358894 on functional MRI measurements in an emotional processing paradigm 
in patients with Major Depressive Disorder
Principal Investigator:
Phone 
, Fax 
Trial site(s):
Mono-centre trial
Clinical phase:
I
Objective(s):
To assess the effects of a single dose of BI 1358894 (100 mg) compared to placebo 
on functional MRI measurements on the amygdala and related brain structures
activated by emotional stimuli using functional Magnetic Resonance Imaging 
(fMRI) in unmedicated patients with Major Depressive Disorder
Methodology:
placebo-controlled, randomized, single dose, parallel-group design with three 
treatment arms
Number of patients
entered: 
Minimum 72
Number of patients on 
each treatment:
24
Diagnosis:
Depression
Main in- and exclusion 
criteria:
Inclusion: Male and female patients with major depressive disorder aged 18 to 
45 years and a Montgomery–Åsberg Depression Rating Scale (MADRS) total score
≥7 and < 26 at screening. Exclusion: Meeting any diagnostic criteria for any major 
psychiatric disorder (other than a unipolar mood disorder), as determined by 
DSM-V at screening. Has received prescribed medication (including 
antidepressants) within 28 days prior to Visit 1 (apart from the contraceptive pill).
Test product(s):
BI 1358894
dose:
100 mg
mode of 
administration:
p.o.


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Comparator products:
1.
Placebo
2. Citalopram
dose:
1.
NA
20 mg
mode of 
administration:
p.o.
Duration of treatment:
Single Dose
Criteria for 
pharmacodynamics:
Primary endpoint: mean Blood Oxygen Level Dependent (BOLD) signal percent
change in an emotional paradigm (emotional face task) in the corticolimbic system, 
consisting of the following eight brain regions:

Amygdala left

Amygdala right

Dorsolateral prefrontal cortex left

Dorsolateral prefrontal cortex right

Insula left

Insula right

Anterior cingulate cortex left

Anterior cingulate cortex right
Secondary endpoint: mean BOLD signal percent change in the corticolimbic 
system, based on an affective picture task (OASIS task) and the eight brain regions 
from the primary endpoint
Criteria for safety:
Primary safety endpoint:
Number and percentage of subjects with adverse events
Further criteria of interest:

Adverse events including clinically relevant findings from the physical 
examination, 

Safety laboratory tests

12-lead electrocardiogram

Vital signs (blood pressure, pulse rate)
Statistical methods:
Descriptive statistics will be calculated for all endpoints. The statistical model to 
compare the brain regions of the primary and secondary endpoint between 
BI 1358894 and placebo and between Citalopram and placebo will be an analysis of 
variance (ANOVA) including effects for treatment and for severity of depression 
(MADRS ≥20 versus < 20). The adjusted mean difference and the corresponding 
two sided 90% confidence intervals (CIs) will be provided.


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FLOW CHART
Visit
Day
Planned time (relative  to 
trial activities 2) [h:min] 
Approximate clock time 
of actual day [h:min]
Event and comment
Standard safety laboratory 
Physical Examination
fMRI
Vital signs (BP, PR)
Questioning for AEs and 
Conmeds4)
ECG5)
Randomisation
C-SSRS
1 
Screen
ing
-35 
-
-5
NA
NA
Informed consent1)
X
X
X
X
X
Screening Procedures as per 
section 6
2
-1
Admission to trial site, 
review of In/Exclusion 
Criteria 
allocation to patient number, 
MADRS
X
X
X
X
X8)
X
1
-0:30
07:30
Breakfast
X
X
X
X
X8)
X
0:00
08:00
Drug Intake BI 1358894 or 
Placebo7)
X
X
2:00
10:00
3:00
11:00
Drug Intake Citalopram or 
Placebo7)
4:00
12:00
Light Lunch (optional)
X
X
X
5:30
13:30
Headache Severity NRS
6:00
14:00
fMRI
X
7:10
15:10
Headache Severity NRS
X
8:00
16:00
Light Snack
10:00
18:00
Dinner
X
X
X
X
14:00
22:00
X
X
2
24:00
08:00
X
X
X
X
X
3
48:00
08:00
X
X
X
4
72:00
08:00
Discharge6)
X
X
X
X
X
X
5
96:00
08:00
X
6
120:00
08:00
X
7
144:00
08:00
X
X
3
28 
± 
10
NA
NA
End of Trial Visit
X
X
X
X
X
1)
Subject must be informed and written informed consent obtained prior to starting any screening procedures. The 
informed consent may be obtained before the screening period and is not necessarily the start of the screening time 
window. Screening procedures include physical examination, check of vital signs, electrocardiogram (ECG), safety 
laboratory (including drug screening), demographics (including determination of body height and weight, smoking 
status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. 
The clinical scales/assessments DSM-V, PANAS, BAI, BDI and MADRS will be performed.
2)
The time is approximate; a deviation from the scheduled time of the day of ± 60 minutes is acceptable. The relative 
time deviations from time of administration should be kept as minimal as possible and should be below ± 15 minutes
. The exact time of sample collection should be collected in electronic Case Report Form (eCRF).
Allocation to subject number may be performed at any time following enrolment.
3)
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.


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4)
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.
5)
The ECG recording may be repeated by investigator judgment for medical or quality reasons.
6)
Discharge is not mandatory and always at discretion of the investigator. Patient in-house stay may be extended at any 
time if deemed clinically necessary.
7)
For a complete dosing schedule see Table 4.1.4: 2.
8)
To be performed once, either on day -1 or day 1.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................6
ABBREVIATIONS................................................................................................................10
1.
INTRODUCTION...............................................................................................12
1.1
MEDICAL BACKGROUND.............................................................................12
1.2
DRUG PROFILE................................................................................................13
1.2.1
Nonclinical pharmacology..................................................................................13
1.2.2
Safety pharmacology...........................................................................................13
1.2.3
Toxicology............................................................................................................14
1.2.3.1
Single dose toxicity...............................................................................................14
1.2.3.2
Repeat-dose toxicity studies..................................................................................15
1.2.3.3
Genotoxicity..........................................................................................................17
1.2.3.4
Reproductive and developmental toxicity.............................................................17
1.2.3.5
Phototoxicity.........................................................................................................17
1.2.4
Nonclinical pharmacokinetics............................................................................17
1.2.5
Clinical experience in humans ...........................................................................19
1.2.5.1
Drug product .........................................................................................................27
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................27
1.4
BENEFIT - RISK ASSESSMENT.....................................................................28
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................29
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........29
2.1.1
Main objectives....................................................................................................29
2.1.2
Primary endpoint................................................................................................29
2.1.3
Secondary endpoint(s) ........................................................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................31
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................31
3.3
SELECTION OF TRIAL POPULATION .......................................................32
3.3.1
Main diagnosis for trial entry ............................................................................32
3.3.2
Inclusion criteria .................................................................................................32
3.3.3
Exclusion criteria ................................................................................................33
3.3.4
Withdrawal of patients from therapy or assessments .....................................35
3.3.4.1
Withdrawal from trial treatment ...........................................................................35
3.3.4.2
Withdrawal of consent for trial participation........................................................36


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3.3.4.3
Discontinuation of the trial by the sponsor...........................................................36
4.
TREATMENTS...................................................................................................37
4.1
INVESTIGATIONAL TREATMENTS ...........................................................37
4.1.1
Identity of the Investigational Medicinal Products..........................................37
4.1.2
Selection of doses in the trial..............................................................................38
4.1.3
Method of assigning patients to treatment groups...........................................38
4.1.4
Drug assignment and administration of doses for each patient......................39
4.1.5
Blinding and procedures for unblinding...........................................................40
4.1.5.1
Blinding.................................................................................................................40
4.1.5.2
Unblinding and breaking the code ........................................................................41
4.1.6
Packaging, labelling, and re-supply...................................................................41
4.1.7
Storage conditions...............................................................................................41
4.1.8
Drug accountability.............................................................................................41
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................42
4.2.1
Other treatments and emergency procedures..................................................42
4.2.2
Restrictions ..........................................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment ......................................................42
4.2.2.2
Restrictions on diet and life style..........................................................................43
4.2.2.3
Restrictions regarding women of childbearing potential......................................43
4.3
TREATMENT COMPLIANCE........................................................................43
5.
ASSESSMENTS..................................................................................................44
5.1
ASSESSMENT OF PHARMACODYNAMICS...............................................44
5.1.1
Primary endpoint................................................................................................44
5.1.2
Secondary endpoints...........................................................................................45
5.1.4
MRI scanning ......................................................................................................45
5.2
ASSESSMENT OF SAFETY.............................................................................46
5.2.1
Physical examination ..........................................................................................46
5.2.2
Suicidal risk assessment and reporting.............................................................46
5.2.3
Vital signs.............................................................................................................47
5.2.4
Safety laboratory parameters ............................................................................47
5.2.5
Electrocardiogram ..............................................................................................49
5.2.6
Assessment of adverse events.............................................................................49
5.2.6.1
Definitions of AEs ................................................................................................49
5.2.6.2
Adverse event collection and reporting ................................................................52
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................53
5.3.2
Methods of sample collection .............................................................................54
5.3.3
Analytical determinations ..................................................................................54
5.3.4
Pharmacogenomic evaluation............................................................................55
5.3.4.1
Methods and timing of sample collection.............................................................55


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5.3.4.2
Analytical determinations .....................................................................................55
5.4
APPROPRIATENESS OF MEASUREMENTS..............................................55
6.
INVESTIGATIONAL PLAN.............................................................................57
6.1
VISIT SCHEDULE.............................................................................................57
6.1.1
Telephone and letter pre-screening...................................................................57
6.1.2
Screening visit (visit 1)........................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................57
6.2.1
Screening..............................................................................................................57
6.2.2
Visit 2....................................................................................................................58
6.2.3
End of trial visit...................................................................................................59
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................60
7.1
STATISTICAL DESIGN - MODEL.................................................................60
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................60
7.3
PLANNED ANALYSES.....................................................................................60
7.3.1
Primary endpoint analyses.................................................................................61
7.3.2
Secondary endpoint analyses .............................................................................61
7.3.4
Safety analyses.....................................................................................................62
7.4
INTERIM ANALYSES ......................................................................................63
7.5
HANDLING OF MISSING DATA ...................................................................63
7.6
RANDOMISATION ...........................................................................................64
7.7
DETERMINATION OF SAMPLE SIZE .........................................................64
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........66
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................66
8.2
DATA QUALITY ASSURANCE ......................................................................67
8.3
RECORDS...........................................................................................................67
8.3.1
Source documents ...............................................................................................67
8.3.2
Direct access to source data and documents.....................................................68
8.3.3
Storage period of records ...................................................................................68
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................69
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........69
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................69
8.6
TRIAL MILESTONES.......................................................................................69
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................70
9.
REFERENCES....................................................................................................71
9.1
PUBLISHED REFERENCES............................................................................71
9.2
UNPUBLISHED REFERENCES......................................................................72
10.
APPENDICES.....................................................................................................74


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10.1
DERIVATION OF BOLD SIGNAL .................................................................74
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................75
11.1
GLOBAL AMENDMENT 1 ..............................................................................75
11.2
GLOBAL AMENDMENT 2 ..............................................................................77


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ABBREVIATIONS
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANOVA
Analysis of Variance
ASL
Arterial Spin Labeling
AUC
Area Under the Curve
BAI
BDI
Beck Anxiety Inventory
Beck Depressions Inventar 
BI
Boehringer Ingelheim
BOLD
Blood Oxygenation Level Dependent
BPD
Borderline Personality Disorder
CI
Confidence Interval
CNS
Central Nervous System
CRA
Clinical Research Associate
CRO
Contract Research Organisation
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
CYP
Cytochrome P450
DILI
Drug Induced Liver Injury
DSM-V
Diagnostic and Statistical Manual of Mental Disorders-V
ECG
Electrocardiogram
ECT
Electro-Convulsive Therapy
EDC
Electronic Data Capture
ES
Evaluable Set
EudraCT
European Clinical Trials Database
FE
Food Effect
FDA
Food and Drug Administration
FST
Forced Swim Test
fMRI
Functional Magnetic Resonance Imaging
GCP
Good Clinical Practice
GLP
Good Laboratory Practice 
GMP
Good Manufacturing Practice
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IPD
Important Protocol Deviations
IQRM
Integrated Quality and Risk Management
IRB
Institutional Review Board
ISF
Investigator Site File
LPDD
Last Patient Drug Discontinuation
MADRS
Montgomery–Åsberg Depression Rating Scale


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MANOVA
multivariate analysis of variance
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Drug Regulatory Activities
MNI
Montreal Neurological Institute
MRI
Magnetic Resonance Imaging
NOAEL
No-observed-adverse-effect level
NIMH
National Institute of Mental Health
NRS
Numeric Ranking Scale
OASIS
Open Affective Standardized Image Set
OPU
Operating Unit
PANAS
PD
Positive and Negative Affect Schedule
Pharmacodynamics
PK
Pharmacokinetics
p.o.
per os (oral)
PT
Preferred Term
REP
Residual Effect Period
RS
Randomised Set
SAE
Serious Adverse Event
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SoC
Standart of Care
SOP
Standard Operating Procedure
SS
Safety Set
SSRI
Selective Serotonin Re-uptake Inhibitor
SUSAR
Suspected Unexpected Serious Adverse Reactions
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
WBC
White Blood Cells
WHO
World Health Organization
WOCBP
WSEFEP
Women Of Childbearing Potential
Warsaw Set of Emotional Facial Epression Pictures


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Boehringer Ingelheim (BI) is developing BI 1358894, an oral, small-molecule inhibitor 
 
 for 
major depressive disorder (MDD) as an adjunct to antidepressant therapy and for the 
treatment of borderline personality disorder (BPD).
MDD is a debilitating disease characterised by low mood and often by low self-esteem, low 
energy, and a loss of interest. It can strongly impact a person’s life and health, including 
significantly increased risk of suicidality, and is difficult to treat, even with systematic 
antidepressant strategies. In the National Institute of Mental Health (NIMH) funded STAR*D 
trial of > 4000 patients with nonpsychotic depression, about 30% of the patients did not 
reach remission after 4 different medications [P06-11895] and continued to experience 
residual symptoms [R16-5475] that significantly impacted the patients’ quality of life 
[R06-2872]. When monotherapy is insufficient, clinicians employ different augmentation 
strategies including add-on treatment with lithium or atypical antipsychotics. When 
augmentation strategies also fail, convulsive therapies such as electro-convulsive therapy 
(ECT) may be used.
It is hypothesized that in patients with affective disorders, an overactive amygdala is a major 
contributor to attentional bias to negative stimuli, pessimistic thoughts, and anxiety 
[R16- 5473] and there is growing evidence supporting the role of amygdala in the emotion 
processing disturbances observed in patients with BPD [R16-5472]. Therefore, treatment 
with BI 1358894 has the potential to improve affective symptoms and emotion control in 
patients with MDD and BPD.
In patients with MDD, it has been demonstrated that hyperactivity in the corticolimbic 
system, in particular of the amygdala, in response to emotional stimuli (e.g. by showing 
emotional faces) can be visualized by magnetic resonance imaging (MRI). Drug treatment 
(e.g. by treatment with a single dose of an anti-depressive drug such as Citalopram) can 
reduce this hyperactivation resulting in decreased signals in the MRI [R17-4219], 
[R18-3446]. The aim of this study is to show similar effects by treatment with BI 1358894, 
whereby Citalopram serves as positive control. 


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1.2
DRUG PROFILE
1.2.1
Nonclinical pharmacology
BI 1358894 was investigated in several standard behavioural tests in rodents, such as Forced 
Swim Test (FST) [n00252903], Marble Burying Test [n00252207] and Elevated Plus Maze 
Test [n00252277]. The in vivo pharmacology studies demonstrated consistent 
pharmacological effects in line with anxiolytic and/or antidepressant efficacy. In the FST, 
half maximal efficacy was demonstrated at a plasma exposure of 77 nM, indicating that at 
this plasma exposure, free brain levels are in the range of the in vitro IC50 [n00253628].
 BI 1358894 was 
shown to be highly selective.
1.2.2
Safety pharmacology
General and safety pharmacology studies have been conducted with BI 1358894 to address 
the core battery of CNS [n00253725], cardiovascular [n00253723, n00253727, n00253734], 
renal and hepatic [n00253732], respiratory [n00253732], and GI function [n00253729]. The 
results demonstrated an acceptable profile for clinical trials in healthy volunteers.
BI 1358894-related effects on the central nervous system (CNS) of rats were limited to 
 


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 These preclinical data do not suggest a proarrhythmic risk.
1.2.3
Toxicology
The nonclinical safety program investigating the in vivo toxicological profile of BI 1358894
comprised repeat-dose studies up to 4 weeks of once daily oral (gavage) treatment and a 
complete battery of in vitro and in vivo studies assessing the genotoxic potential of the 
compound. Additionally, a 4-week oral repeat-dose (non-GLP) study in mice was performed.
Rats and dogs were employed as the animal species for general toxicology investigations on 
BI 1358894, because in vitro and in vivo profiling supported the suitability of both species 
for nonclinical safety profiling of BI 1358894. 
1.2.3.1
Single dose toxicity
No single dose toxicity assessments have been conducted with BI 1358894. Relevant 
information was obtained from the repeat-dose toxicity studies in mice, rats, and dogs. The 
maximum tolerated dose was considered to be
 
 
of the Investigator's Brochure (IB) [c10354149].


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1.2.3.2
Repeat-dose toxicity studies 
Repeat dose non-GLP toxicity study in mice, rats and dogs revealed toxicologically relevant 
effects on the skin, Harderian glands, and hepatic function in mice, the vascular system in rats, 
the CNS function in dogs, and the digestive tract in all three species. In addition, 
haematology evaluation revealed
.
A 4-week toxicity testing in mice identified 
 
Repeat-dose toxicity testing in rats revealed no serious clinical signs of toxicity, no 
toxicologically relevant effects on body weight and food and water consumption, and no 
ophthalmology findings were noted. The main findings in clinical pathology were indicative 
 All changes were fully reversible or 
greatly ameliorated over a 4-week off-treatment recovery period. 
In repeat-dose toxicity testing in dogs, no spontaneous deaths occurred up to 1000 mg/kg, the 
highest tested dose, administered for 11 days. 
 


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1.2.3.3
Genotoxicity
The genotoxic potential of BI 1358894 was investigated in an ICH-compliant test battery of 
in vitro and in vivo studies (for details see Section 5.3.9 of the IB, [c10354149]. There was 
no evidence that BI 1358894 is associated with genotoxic activity.
1.2.3.4
Reproductive and developmental toxicity
BI 1358894 has been tested in dose range finding studies for embryofetal development in rats 
and rabbits (non-GLP, according to standard procedures and with validated bioanalytical 
methods).
In these preliminary studies on embryofetal development, BI 1358894 was well tolerated in 
pregnant rats and had no effect on embryofetal viability, 
 
1.2.3.5
Phototoxicity
BI 1358894 is unlikely to cause phototoxicity. For a more detailed description of the 
BI 1358894 profile please refer to the current IB [c10354149].
1.2.4
Nonclinical pharmacokinetics
Drug Absorption and Disposition
The disposition of BI 1358894 is characterized in rats by
 


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1.2.5
Clinical experience in humans
In trial 1402-0001, 55 healthy male subjects assigned to the SRD part and 20 healthy male 
subjects assigned to the food effect (FE) part have completed the study at the time of 
finalisation of this protocol. The tested dose levels in the SRD part were 3 mg, 6 mg, 10 mg, 
25 mg,
50 mg, 100 mg or 200 mg of BI 1358894 or placebo. Tested dose levels in the FE part were 
50 mg or 100 mg of BI 1358894 administered under fasted and fed conditions (two 
consecutive single doses at least one week apart). Safety evaluations of trial 1402-0001 
included physical examination, vital signs, ECG, laboratory tests, and adverse events (AEs). 
Data analysis from this study is currently on-going. In the tested dose range, BI 1358894 was 
well tolerated with a low frequency of AEs in all dose groups. There were no AEs considered 
to be dose limiting and no serious adverse events (SAEs); all subjects completed the study 
per protocol. 
Adverse Events
There were no AEs considered to be dose limiting and no SAEs. All subjects completed the 
study per protocol. All AEs were of mild to moderate intensity; no AE of severe intensity was
reported. 
The following results were observed (see also Table 1.2.5: 1 and Table 1.2.5: 2 for a more 
detailed overview of AEs):

In the SRD part, 22 of 42 subjects on BI 1358894 and 3 of 13 subjects on placebo 
reported at least one AE.

In the FE part, 16 of 20 subjects (all on BI 1358894) reported at least one AE. The 
higher prevalence of AEs in the FE part compared to the SRD part might be related to 
the two treatment periods and the longer period of safety monitoring.

SRD: The frequency of subjects with at least one AE in the highest dose group 
(200 mg fasted) was comparable to the 50 mg and 100 mg fasted dose groups.

Food Effect: The frequency of subjects with at least one AE in the 50 mg dose group 
(fasted and fed period) was higher compared to the SRD part. In contrast, the 
frequency of subjects with at least one AE in the dose group 100 mg (fasted and fed 
period) was similar to the SRD part. The subjects with the highest exposure
(100 mg fed period) had a slightly lower frequency of AEs compared to the fasted 
period.

At the System Organ Class (SOC) level, the most frequently reported AEs were 
nervous system disorders, reported in 21 subjects in the SRD part (19 of 42 subjects 
on BI 1358894 and 2 of 13 subjects on placebo) and 16 of 20 subjects in the FE part 
(all on active). 

At the Preferred Term (PT) level, the following AEs were observed in more than one 
subject:

Headache in 18 subjects in the SRD part (17 of 42 subjects on active and 1 of 
13 subjects on placebo) and in 15 of 20 subjects in the FE part (all on active),

Dizziness in 3 subjects in the SRD part (2 of 42 subjects on active and 1 of 
13 subjects on placebo) and 7 of 20 subjects in the FE part (all active),


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
Fatigue in 3 subjects in the FE part (all on active), and

Disturbance in attention in 2 subjects in the FE part (all on active).

No dose dependent increase in frequency was observed for any of these AEs.

AEs of moderate intensity were mainly observed in subjects on BI 1358894:

Injury due to a cycling accident in one subject 6 days after dosing 
(6 mg SRD);

Syncope because of a vasovagal reaction during blood drawing in one subject 
on placebo (25 mg dose group, SRD);

Back pain in one subject 2 days after dosing, resolved in 11 hours 
(50 mg SRD);

Nasopharyngitis in one subject 4 days after dosing (100 mg, FE, fasted).

Headache in 10 subjects (2 SRD, 8 FE, all on active) with an onset mostly 
4 - 7 hours after dosing and resolved mainly within a few hours.
There were no protocol-specified AEs of special interest (AESI) and no other significant AEs 
according to ICH E3. Per protocol AESI was hepatic injury, as defined by AST and/or ALT 
≥3-fold ULN combined with total bilirubin ≥2-fold ULN, and/or aminotransferase 
elevations ≥10 fold ULN.
There were isolated events of apathy, auditory disorder and abnormal dreams in 3 subjects 
treated with either 3 mg or 6 mg of BI 1358894. A short episode of syncope in the 25 mg 
dose group in one subject treated with placebo was related to blood withdrawal. Since no 
comparable events were reported for the remaining dose groups up to a single dose of 200 mg 
of BI 1358894 and due to the lack of a temporal relationship between dosing and event, these 
events are considered as chance findings and not drug related.
Additional Safety Assessments
There were no clinically relevant changes of lab values. In particular there were no changes 
of ESR or CRP suggesting an inflammatory event.
Explorative analysis of the Bowdle-VAS scores showed a comparable pattern between 
subjects across all dose groups. There were in particular no abnormalities for the score 
‘feeling high’ and ‘changes of perception’, which may indicate psychedelic effects. The 
occasional occurrence of ‘drowsy’ was evenly distributed between active and placebo.
The suicidality assessment based on C-SSRS did not reveal an individual subject who 
developed suicidal ideation by end of the study.
ECGs recorded from Day 1 pre-dose until Day 2 /34 h post-dose were analyzed centrally. 
After each dose group absolute values and changes in ECG parameters were reported by the 
ECG core lab to the sponsor and CRO.  No dose dependent trend of a possible QTcF 
prolongation was observed (the maximum individual QTcF interval across all dose groups of 
the SRD part was 432 ms, and for the FE part 450 ms). 
Based on the prespecified criteria of the trial protocol orthostatic testing did not reveal a 
subject with a positive test after dosing, i.e. no reduction in systolic BP of ≥20 mm Hg or in 
diastolic BP of ≥10 mm Hg within 3 minutes of standing , no orthostatic symptoms and no 
increase of heart rate > 100/min during orthostatic testing.  Monitoring of vital signs and AEs 
conducted in the further course of the study did also not reveal findings suggesting orthostatic 
effects of BI 1358894.


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Table 1.2.5: 1
Frequency [N (%)] of subjects with adverse events treated with 
BI 1358894 or placebo - SRD part 1402-0001
Placebo 
(DG1-7)
(N=13)
BI 3 mg
(DG1)
(N=6)
BI 6 mg
(DG2)
(N=6)
BI 10 mg
(DG3)
(N=6)
BI 25 mg
(DG4)
(N=6)
BI 50 mg
(DG5)
(N=6)
BI 100
mg
(DG6)
(N=6)
BI 200 mg
(DG7)
(N=6)
System organ 
class/
Preferred term
N (%)
N (%)
N (%)
N (%)
N (%)
N(%)
N (%)
N (%)
Number of 
subjects
13 (100.0)
6 (100.0)
6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0)
Total with 
adverse events
3 (23.1)
3 (50.0)
6 (100.0) 0 (0.0)
2 (33.3)
4 (66.7)
4 (66.7)
3 (50.0)
Nervous system 
disorders
2 (15.4)
2 (33.3)
5 (83.3)
0 (0.0)
2 (33.3)
3 (50.0)
4 (66.7)
3 (50.0)
Headache
1
(7.7)
2 (33.3)
4 (66.7)
0 (0.0)
2 (33.3)
3 (50.0)
3 (50.0)
3 (50.0)
Dizziness
1
(7.7)
0
(0.0)
1 (16.7)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Head 
discomfort
0
(0.0)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Syncope
1
(7.7)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Musculoskeletal 
and connective 
tissue disorders
0
(0.0)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
2 (33.3)
0 (0.0)
0 (0.0)
Back pain
0
(0.0)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Pain in 
extremity
0
(0.0)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Ear and 
labyrinth 
disorders
0
(0.0)
0
(0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Auditory 
disorder
0
(0.0)
0
(0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Gastrointestinal 
disorders
2 (15.4)
1 (16.7)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Oral discomfort
0
(0.0)
1 (16.7)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Abdominal pain
1
(7.7)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Abdominal pain 
upper
1
(7.7)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Nausea
1
(7.7)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)


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Table 1.2.5: 1 (con’t)
Frequency [N (%)] of subjects with adverse events treated with 
BI 1358894 or placebo - SRD part 1402-0001
Placebo 
(DG1-7)
(N=13)
BI 3 mg
(DG1)
(N=6)
BI 6 mg
(DG2)
(N=6)
BI 10 mg
(DG3)
(N=6)
BI 25 mg
(DG4)
(N=6)
BI 50 mg
(DG5)
(N=6)
BI 100
mg
(DG6)
(N=6)
BI 200 mg
(DG7)
(N=6)
System organ 
class/
Preferred 
term
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
Number of 
subjects
13 (100.0)
6 (100.0)
6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0)
Total with 
adverse events
3 (23.1)
3 (50.0)
6 (100.0) 0 (0.0)
2 (33.3)
4 (66.7)
4 (66.7)
3 (50.0)
General 
disorders and 
administration 
site conditions
0
(0.0)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Fatigue
0
(0.0)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Injury, 
poisoning and 
procedural 
complications
1
(7.7)
0
(0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Limb injury
0
(0.0)
0
(0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Road traffic 
accident
0
(0.0)
0
(0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Vascular 
procedure 
complication
1
(7.7)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Psychiatric 
disorders
0
(0.0)
1 (16.7)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Abnormal 
dreams
0
(0.0)
1 (16.7)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Apathy
0
(0.0)
0
(0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Metabolism 
and nutrition 
disorders
1
(7.7)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Decreased 
appetite
1
(7.7)
0
(0.0)
0
(0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Note: AEs may be ongoing and AE information may change up to data base lock of the trial


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Table 1.2.5: 2
Frequency [N (%)] of subjects with adverse events treated with 
BI 1358894– FE part
System Organ Class,
   Preferred Term
BI 50 mg 
(fast)
(N=8)
N (%)
BI 50 mg 
(fed)
(N=8)
N (%)
BI 100 mg 
(fast)
(N=12)
N (%)
BI 100 mg 
(fed)
(N=12)
N (%)
Total with adverse events
7 (87.5)
7 (87.5)
8 (66.7)
6 (50.0)
Nervous system disorders
7 (87.5)
7 (87.5)
8 (66.7)
5 (41.7)
Headache
7 (87.5)
6 (75.0)
7 (58.3)
4 (33.3)
Dizziness
3 (37.5)
2 (25.0)
3 (25.0)
2 (16.7)
Disturbance in attention
2 (25.0)
0 (0.0)
0 (0.0)
0 (0.0)
Head discomfort
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Paraesthesia
1 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
Skin and subcutaneous tissue 
disorders 
0 (0.0)
2 (25.0)
0 (0.0)
1 (8.3)
Pruritus generalised
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Rash macular
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Skin reaction
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Acne
0 (0.0)
0 (0.0)
0 (0.0)
1 (8.3)
General disorders and 
administration site conditions
1 (12.5)
0 (0.0)
0 (0.0)
2 (16.7)
Fatigue
1 (12.5)
0 (0.0)
0 (0.0)
2 (16.7)
Musculoskeletal and connective 
tissue disorders
0 (0.0)
1 (12.5)
2 (16.7)
0 (0.0)
Musculoskeletal chest pain
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Arthralgia
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Back pain
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Gastrointestinal disorders
1 (12.5)
1 (12.5)
0 (0.0)
0 (0.0)
Flatulence
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Nausea
1 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
Infections and infestations
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Nasopharyngitis
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Pharmacokinetics:
Following oral administration of film coated tablets in fasted state (SRD part, doses 3 mg to 
200 mg), BI 1358894 reached maximum plasma concentrations between 1 and 5 hours 
(median tmax). Cmax, AUC0-24, AUC0-72 and AUC0-∞increased dependent on dose 
(Table 1.2.5: 3). However, preliminary statistical analysis of dose proportionality (see 
summary in Table 1.2.5: 4) indicates a less than dose-proportional increase in exposure of 


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BI 1358894 formulated as tablet and administered in fasted state over the tested dose range 
from 3 mg to 200 mg.
After reaching Cmax, BI 1358894 plasma concentrations declined in a multiphasic fashion 
implying multicompartmental distribution and exhibited a long terminal phase, which seems 
to be dose-independent. The apparent terminal half-life (t1/2) after oral dosing was calculated
based on available data until 192 h after administration. Considering the last 3 time points for 
extrapolation (96 h to 192 h planned sampling times, all doses apart from 3 mg DG), the 
percentage of extrapolation beyond the last measured time point (%AUCtz-∞) was in a range 
of 2.75% to 26.0%. However, in 4 subjects %AUCtz-∞ extrapolated was above 20%; in the
majority of subjects % AUCtz-∞extrapolated was less than 20%. Some inaccuracy in 
determination of AUC0-∞may be apparent if extrapolation exceeded 20%. However, since 
this occurred only in 4 subjects, the results are considered adequate estimates overall. The 
resulting t1/2 (gMean) was between 50.2 and 74.4 hours. The gMean of mean residence time 
after oral dosing (MRTpo) was between 54.8 and 82.5 hours. t1/2 and MRTpo appear to be 
independent of dose based on PK data of BI 1358894 after a single dose oral administration. 
The observed limitation on rate of absorption is likely due to low gastrointestinal solubility of 
BI 1358894.
Within the Food Effect part of the study, BI 1358894 was administered under fasted 
conditions and after a high calorie, high fat breakfast in a 2-way-crossover design. 
A positive food effect (based on AUC0-∞and Cmax, see Table 1.2.5: 5 and Table 1.2.5: 6) was 
observed when BI 1358894 was administered after a high calorie, high fat breakfast in 
comparison to fasted state. An increase of about a factor of 1.6 was observed at the 50 mg 
dose whereas an increase of a factor of about 2.5 was observed after 100 mg between fasted 
and fed state (Table 1.2.5: 6). In general in the SRD part and also within the FE part of the 
study, plasma concentrations under fasted conditions increased less than dose-proportional 
(as evident based on SRD data and data in the FE part under fasted conditions). However, 
under fed conditions comparing PK data from 50 mg and 100 mg cohort, the exposure was 
about doubled by doubling the dose.
Further information is provided in current IB [c10354149].


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Table 1.2.5: 3
Summary of gMean (gCV %) PK parameters of 3, 6, 10, 25, 50, 100 
and 200 mg BI 1358894 administered under fasted conditions 
[SRD part; clinical trial 1402-0001]
Dose Group:
DG1
DG2
DG3
DG4
DG5
DG6
DG7
Dose [mg], 
formulation
3 mg, 
tablet
6 mg, 
tablet
10 mg, 
tablet
25 mg, 
tablet
50 mg, 
tablet
100 mg, 
tablet
100 mg, 
tablet
200 mg, 
tablet
fasted
fasted
fasted
fasted
fasted
fasted
fasted
fasted
N=6
N=6
N=6
N=6
N=6
N=6
Without 
#
N=5
N=6
AUC0-24
[nmol*h/L]
166 
(15.7)
269 
(28.9)
400 
(13.9)
937 
(43.4)
1670 
(32.8)
919 
(1130)
2210 
(58.4)
4130 
(30.4)
AUC0-24/D 
[nmol*h/L/mg]
55.5 
(15.7)
44.8 
(28.9)
40.0 
(13.9)
37.5 
(43.4)
33.4 
(32.8)
9.19 
(1130)
22.1 
(58.4)
20.7 
(30.4)
AUC0-72 
[nmol*h/L]
261 
(17.9)
445 
(31.6)
651 
(14.5)
1780 
(31.1)
3040 
(27.7)
2000 
(1320)
5010 
(40.4)
8720 
(32.1)
AUC0-72/D 
[nmol*h/L/mg]
87.1 
(17.9)
74.1 
(31.6)
65.1 
(14.5)
71.2 
(31.1)
60.9 
(27.7)
20.0 
(1320)
50.1 
(40.4)
43.6 
(32.1)
AUC0-∞
[nmol*h/L]
353*
(25.1)
603 
(33.6)
930 
(20.4)
2580 
(30.2)
4530 
(24.5)
3000 
(1570)
7730 
(39.8)
13900 
(44.8)
AUC0-∞/D 
[nmol*h/L/mg]
118*
(25.1)
100 
(33.6)
93.0 
(20.4)
103 
(30.2)
90.6 
(24.5)
30.0 
(1570)
77.3 
(39.8)
69.7 
(44.8)
Cmax
[nmol/L]
27.6 
(30.0)
35.9 
(33.8)
59.7 
(13.4)
84.2 
(44.2)
183 
(56.3)
94.3 
(735)
206 
(72.8)
385 
(26.8)
Cmax/D 
[nmol/L/mg]
9.20 
(30.0)
5.99 
(33.8)
5.97 
(13.4)
3.37 
(44.2)
3.66 
(56.3)
0.943 
(735)
2.06 
(72.8)
1.92 
(26.8)
tmax [h]1
2.0 (1-4)
2.5 (1-5)
1 (1-3)
5 (1-6)
1 (0.5-
2.5)
2.25 (1-
6)
3 (1-6)
5 (1-8)
t1/2
46.6* 
(31.9)
53.1 
(14.4)
58.5 
(11.5)
60.6 
(18.7)
58.4 
(13.3)
50.2 
(28.0)
54.0 
(23.7)
60.2 
(39.6)
MRTpo
51.5*
(33.1)
54.8 
(21.2)
61.2 
(24.0)
66.9 
(16.0)
67.3 
(15.1)
66.3 
(26.7)
71.3 
(21.7)
76.4 
(23.8)
1 tmax median (range), D Dose-normalized, DG dose group, 
2 sensitivity analysis without subject 
 who had substantially lower BI 1358894 plasma concentrations
* values are based on planned sampling time points up to 96 h only 


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Table 1.2.5: 4
Summary of preliminary statistical evaluation of dose-proportionality 
[SRD part]
PK Parameter
N
ß
95 % Confidence Interval
Cmax
42
0.55
0.37
0.74
AUC0-24
42
0.68
0.49
0.88
AUC0-72
42
0.76
0.56
0.96
AUC0-∞
42
0.80
0.59
1.00
Table 1.2.5: 5
Summary of gMean (gCV %) PK parameters of 50 mg and 100 mg 
BI 1358894 administered under fasted conditions and after a high 
calorie, high fat meal [relative BA food effect (FE) part; 
clinical trial 1402-0001]
Dose [mg]/
condition
50 mg
Fasted
(N=8)
50 mg
Fed
(N=8)
100 mg
Fasted
(N=12)
100 mg
Fed
(N=12)
AUC0-24
[nmol*h/L]
1570 (36.7)
2980 (25.1)
2350 (40.6)
6780 (12.2)
AUC0-24/D 
[nmol*h/L/mg]
31.4 (36.7)
59.6 (25.1)
23.5 (40.6)
67.8 (12.2)
AUC0-72 
[nmol*h/L]
3120 (20.9)
5110 (28.9)
4600 (49.2)
11600 (14.8)
AUC0-72/D 
[nmol*h/L/mg]
62.4 (20.9)
102 (28.9)
46.0 (49.2)
116 (14.8)
AUC0-∞
[nmol*h/L]
5060 (29.3)
7900 (42.9)
6930 (54.6)*
17200 (21.8)
AUC0-∞/D 
[nmol*h/L/mg]
101 (29.3)
158 (42.9)
69.3 (54.6)*
172 (21.8)
Cmax
[nmol/L]
149 (59.4)
237 (24.9)
210 (38.8)
517 (8.61)
Cmax/D 
[nmol/L/mg]
2.99 (59.4)
4.74 (24.9)
2.10 (38.8)
5.17 (8.61)
tmax [h]1
5 (1-5)
5 (2.98-6)
2.5 (1-6)
6 (0.5-7)
t1/2
71.2 (24.7)
74.4 (27.7)
68.9 (34.6)*
66.7 (25.8)
MRTpo
82.5 (24.1)
76.7 (35.9)
78.8 (30.8)*
70.1 (29.4)
*N=11 due to drop out of subject #
 PK samples of this subject up to 96 hours available only


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Table 1.2.5: 6
Summary of preliminary statistical evaluation of food effect (FE) part 
– adjusted by-treatment geometric means and relative bioavailability
Dose
PK 
Parameter
Fasted 
adjusted 
gMean
Fed 
adjusted 
gMean
Ratio 
fed/fasted
90 % Confidence Interval
50 mg 
(n = 8)
Cmax
149 nmol/L
237 nmol/L
1.59 
1.14
2.21
AUC0-24
1570 
nmol*h/L
2982 
nmol*h/L
1.90
1.46
2.47
AUC0-72
3121 
nmol*h/L
5112 
nmol*h/L
1.64
1.38
1.94
AUC0-∞
5059 
nmol*h/L
7904 
nmol*h/L
1.56
1.32
1.85
100 mg 
(n = 12)
Cmax
210 nmol/L
517 nmol/L
2.46
2.03
2.98
AUC0-24
2353 
nmol*h/L
6777 
nmol*h/L
2.88
2.36
3.51
AUC0-72
4601 
nmol*h/L
11598 
nmol*h/L
2.52
2.04
3.12
AUC0-∞
6966 
nmol*h/L
17232 
nmol*h/L
2.47
2.00
3.06
1.2.5.1
Drug product
For a more detailed description of the BI 1358894 profile please refer to the current IB 
[c10354149] and for Citalopram to the Summary of Product Characteristics (SmPC).
Citalopram (Cipramil®, Europe), a Selective Serotonin Re-uptake Inhibitor (SSRI), is a
racemic bicyclic phthalane derivative and it has a high affinity for the primary binding site on 
the serotonin transporter.  
Citalopram is rapidly absorbed reaching peak concentrations 1 – 4 hours after dosing and has 
a half-life of approximately 35 hours.  The effective dose range is 20 - 40 mg and for this 
study 20 mg will be dosed 3 hrs before a functional magnetic resonance imaging (fMRI)
scanning session. 
1.3
RATIONALE FOR PERFORMING THE TRIAL
 
 They are highly expressed in the amygdala and other CNS regions [R15-3888; 
R16-5350] involved in modulation and processing of emotion and affect. It is hypothesized 
that in patients with affective disorders, an overactive amygdala is a major contributor to 
attentional bias to negative stimuli, pessimistic thoughts, and anxiety [R16-5473].
 
 BI 1358894 may have the potential to improve affective 
symptoms and emotion control in patients with affective disorders. This trial will use fMRI to 


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study Blood Oxygen Level Dependent (BOLD) response in patients with depression as a 
potential pharmacodynamics (PD) effect of BI 1358894 in the brain regions of interest. These 
PD data will help to support future development of BI 1358894 in major depression and other 
affective disorders.
The therapeutic benefit or specific AEs in patients cannot always be anticipated during the 
trial setup. Later on there may be new scientific knowledge about biomarkers and other 
factors contributing to diseases or the action of a drug. In order to be able to address future 
scientific questions, patients will be asked to voluntarily donate biospecimens for banking. If 
the patient agrees, banked samples may be used for future drug development projects, e.g. to 
identify patients that are more likely to benefit from a treatment or experience an AE, and 
thereby better match patients with therapies.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this study is without any immediate (therapeutic) benefit for the participating 
patients. Their participation in the study, however, is of major importance to the development
of BI 1358894. The patients are exposed to the risks of the study procedures and the risks 
related to the exposure to the trial medication.
This study will include patients with depression that are currently receiving no pharmacologic 
therapy for their depressive discoder. During the whole trial all patients are under close 
surveillance of the study site and will benefit from the close contact to the clinical site. 
Patients where it is foreseen that a delay of initiation of standard of care therapy for the 
depressive disorder is medically not justifiable will not enter the trial (see exclusion criteria 
for details). From day 14 after trial treatment pharmacological standard of care can be 
initiated by the study site as appropriate. The initiation of psychotherapy is allowed from 
day 2. If SoC has for any reason to be provided earlier, it should preferentially be initiated 
based on a list of compounds that will be discussed between the sponsor and the 
investigational site (see Section 4.2.2 for details). This list will be made available to the 
investigator in the Investigator Site File (ISF).
Patients will be hospitalised throughout the study from Day -1 to Day 4 relative to drug 
intake 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 unexpected AEs.
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 patients´ 
safety, see also Section 5.2.6, adverse events of special interest (AESI).


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
To assess the effect of a single dose of BI 1358894 (100 mg) compared to placebo on BOLD 
responses in modulating brain processing of emotional and cognitive stimuli on the amygdala 
and related brain structure using fMRI in in unmedicated patients with depression.
2.1.2
Primary endpoint
The primary PD endpoint is the mean BOLD signal % change in an emotional paradigm 
(emotional faces task from the Warsaw Set of Emotional Facial Epression Pictures 
(WSEFEP) [R18-3440]) in the corticolimbic system, consisting of the following eight brain 
regions:

Amygdala left

Amygdala right

Dorsolateral prefrontal cortex left

Dorsolateral prefrontal cortex right

Insula left

Insula right

anterior cingulate cortex left

anterior cingulate cortex right
The time frame for the primary PD endpoint is from the start of treatment to the end of the 
fMRI measurement. 
The primary endpoint of safety is the 

Number and percentage of subjects with AEs
The time frame for the primary endpoint of safety is from the start of treatment to the end of
the residual effect period (REP).
2.1.3
Secondary endpoint(s)
The secondary PD endpoint is the mean BOLD signal % change in the corticolimbic system, 
based on the Open Affective Standardized Image Set (OASIS) [R-18-3459] task and the eight 
brain regions from the primary endpoint.
The time frame for the secondary PD endpoint is from the start of treatment to the end of the 
fMRI measurement. 


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Further safety criteria of interest are

AEs including clinically relevant findings from the physical examination, 

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a single dose Phase I single center, placebo-controlled, randomised, parallel groups 
design study with three treatment conditions (BI 1358894, Citalopram, and placebo). A total 
of 72 unmedicated male and female patients with MDD will undergo the fMRI procedures. 
Subjects with severe headaches will not be included in the primary fMRI analysis and will 
therefore be needed to be replaced after randomisation (see Section 6.2.2 for details). 
Headaches are a known of AE of single dose treatment with BI 1358894. The headaches were 
usually mild or moderate in nature. Based on the data from the Phase I trial 1402-0001 we 
expect that less than 1/3rd of patients randomised to treatment with BI 1358894 will 
experience headaches. Patients with servere headaches will need to be replaced, for details 
see Section 5.1.4. and 6.2.2. The treatment allocation is 1:1:1. The randomisation will be 
stratified by the severity of depression (Montgomery–Åsberg Depression Rating Scale
(MADRS) ≥20 and < 20).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial will use three treatment conditions (BI 1358894, Citalopram, and placebo). Brain 
responses to emotional stimuli, particularly the amygdala response, are implicated in the 
therapeutic benefit of known antidepressant drugs. It was demonstrated for Citalopram that 
this compound modulates brain responses to emotional stimuli [R17-4219]. BI 1358894 will 
be compared with placebo to determine whether it can modulate brain responses to emotional 
stimuli. Citalopram will be compared to placebo to ensure that the study design is sufficiently 
sensitive to detect the effects of a known antidepressant and serves as a positive control. It is 
not intended to compare the effects of BI1358894 and Citalopram. Therefore, no matching 
placebo for Citalopram will be provided.
Several measures have been taken to minimise bias.
This is a blinded study. BI 1358894 and placebo for BI 1358894 will be of identical 
appearance regardless of the treatment arm in order to protect the blinding vis-à-vis the 
participants and the investigators. No matching placebo for Citalopram will be used. 
Citalopram treatment will be blinded to the patient and the MR-technicians.
The three treatments will be allocated at Visit 2 by 1:1:1 randomisation.
The Citalopram treatment arm acts as a positive control group. It is not planned to compare 
PD or safety endpoints between Citalopram and BI 1358894. The primary and secondary PD
endpoints will be compared between the Citalopram and the placebo group to investigate if 
the relevant signal changes as described by Murphy et al. 2009 [R17-4219] can be detected.  
To minimize the effect of the severity of depression on the trial results, patient randomization 
will be stratified by MADRS ≥20 and < 20.


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3.3
SELECTION OF TRIAL POPULATION
This study will be performed in 72 unmedicated patients with MDD.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
This trial will include patients with the diagnosis of a MDD.
3.3.2
Inclusion criteria
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
1. Patients having a diagnosis of a MDD according to Diagnostic and Statistical Manual of 
Mental Disorders-V (DSM-V) (single episode or recurrent) with a MADRS total score 
between ≥7 and < 26 at screening.
2. Male or female aged 18 to 45 years, inclusive at screening.
3. Patients must be normotensive with resting (5 minutes) blood pressure between the range 
of 90 to 150 mm Hg systolic, inclusive, and 60 to 90 mm Hg diastolic, inclusive, at 
Visit 1. 
4. Patients must have resting (5 minutes) heart rate ≥ 50 beats per minute at screening.
5. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to 
father a child must be ready and able to use highly effective methods of birth control from 
screening until 90 days after receiving study drug per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and correctly. A list of 
contraception methods meeting these criteria and restrictions for male patients are 
provided in Section 4.2.2.3 and in the patient information.
6. Patients must have not clinically significant ECG abnormalities, including 
QTcF < 450 msec (for men) or <470 ms (for women) (based on the Fridericia correction 
where QTcF = QT/RR0.33) at Visit 1.
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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7. Patients must be, in the opinion of the Investigator, capable of and eligible for completing 
the fMRI and tasks. 
8. Patients must be right-handed.
9. Patients must have acceptable weight as defined by BMI (weight [kg]/height [m]²) range 
of 18 to 30 kg/m², inclusive at Visit 1.
10. Patients must be a non-smoker or light smoker (≤ 5 cigarettes per day). 
11. Patients must have signed the informed consent form prior to the first study-related 
procedure indicating they understand the purpose of and procedures required for the study 
and are willing to participate in the study.
3.3.3
Exclusion criteria
1. Meeting any diagnostic criteria for a major psychiatric disorder (other than MDD), as 
determined by DSM-V at screening.
2. Has received a prescribed medication (including antidepressants) within 28 days prior to 
Visit 1 (apart from the contraceptive pill) or having received over the counter medication 
(including pain killers) within 10 days prior to screening. Participants who have taken 
prescription medication may still be entered into the study, if, in the opinion of the 
Investigator, the medication received will not interfere with the study procedures or 
compromise safety. 
3. Patients where it is foreseen (per investigator judgement) that a delay of initiation of 
standard of care therapy for the depressive disorder to 14 days after day 1 of Visit 2 is 
medically not justifiable.
4. A history of alcohol or substance dependence or abuse within the last 12 months from 
Visit 1.  
5. A positive urine drug screen (amphetamines, benzodiazepines, opiates, cannabis and 
cocaine) at Visit 1 or Visit 2. One re-test within 1 to 3 days is permitted if positive result 
is for example believed to be due to ingestion of poppy seeds. In this event, re-test result 
will be used for assessing entry criterion and must be completed prior to randomisation.  
6. Has a current or recent history of clinically significant suidal ideation within the past 
6 months, corresponding to a score of 4 or 5 for ideation on the C-SSRS, or a history of 
suicidal behavior within the past year, as validated by the C-SSRS at screening or 
treatment visit.
7. A positive alcohol breath test at Visit 1 or Visit 2.  


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8. A female patient with a positive serum pregnancy test at Visit 1 or Visit 2.  
9. Females currently pregnant or trying to get pregnant or currently breast feeding.  
10. Consumption of large amounts of caffeinated drinks (defined as more than 8 cups of 
standard caffeinated drinks (tea, instant coffee) or 6 cups of stronger coffee or other 
drinks containing methylxanthines such as coca cola or Red Bull per day). 
11. With a relevant history, or presence upon clinical examination, of cardiac, 
ophthalmologic, pulmonary, endocrine (diabetes), blood disease, gastro-intestinal, hepatic 
or renal disease or other condition which in the opinion of the Investigator could interfere 
with the test procedures.  
12. A history of cancer, except for basal cell or Stage 1 squamous cell carcinoma of the skin 
which has been in remission for at least 5 years prior to Visit 2.
13. Has a history of, or presents (in the opinion of the Investigator) with, significant 
neurological or psychiatric conditions (such as stroke, traumatic brain injury, seizures, 
space occupying lesions, multiple sclerosis, Parkinson’s disease, vascular dementia, 
transient ischemic attack, schizophrenia, blackouts requiring hospitalisation).
14. History of known HIV infection.
15. Patients who have undergone operations to the head.  
16. With a significant hearing impairment which, in the opinion of the Investigator, may 
interfere with the performance of the fMRI tasks. 
17. With a significant visual impairment, or history of ocular treatment including corrective 
laser eye surgery, or ongoing condition, which in the opinion of the Investigator may 
interfere with the performance of the behavioural tasks or fMRI tasks.  
18. Has received non-prescription medication, including supplements such as vitamins and 
herbal supplements within 48 hours prior to Visit 2. Participants who have taken non-
prescription medication may still be entered into the study, if, in the opinion of the 
Investigator, the medication received will not interfere with the study procedures or 
compromise safety.
19. Has received an experimental drug and / or used an experimental medical device within 
30 days of randomisation or within a period less than 5 times the drug’s half-life, 
whichever is longer.  


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20. With a known hypersensitivity to BI1358894 or Citalopram or any of their excipients.
21. With a history of severe drug allergy or hypersensitivity. 
22. Patient is unable or unwilling to comply with study procedures, including study 
prohibitions and restrictions.
23. With a history of claustrophobia or inability to tolerate scanner environment.
24. Any contraindication to undergo an MRI radiography (e.g. history of surgery involving 
metal implants).
25. A planned medical treatment within the study period that might interfere with the study 
procedures.
26. Patients who are institutionalized due to regulatory or juridical order; dependent on 
sponsor, site or investigator; or not able to consent.
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from the trial as a whole (“withdrawal of consent”)
with very different implications, please see Sections 3.3.4.1 and 3.3.4.2 below.
Every effort should be made to keep the randomised patients in the trial: at least to collect all 
safety data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to randomization, as well as the
explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and Case Report Form (CRF).
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from the trial if:
The patient wants to withdraw from trial, without the need to justify the decision.
The patient needs to take concomitant drugs that interfere with fMRI assessments.
The patient cannot be treated with trial medication for other medical reasons (such as surgery, 
AEs, other diseases, or pregnancy).
The patient has repeatedly shown to be non-compliant with important trial procedures and, in 
the opinion of both, the investigator and sponsor representative, is not willing or able to stick 
to the trial requirements in the future.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart and Section 6.2.3.


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For all patients the reason for withdrawal from trial treatment (e.g. AEs) must be recorded in 
the CRF. These data will be included in the trial database and reported.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see Section 3.3.4.1
above.
3.3.4.3
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Violation of Good Clinical Practice (GCP), the trial protocol, or the contract impairing
the appropriate conduct of the trial
Emergence of any efficacy / safety information invalidating the earlier positive benefit risk-
assessment that could significantly affect the continuation of the trial will result in a risk-
benefit assessment by the sponsor /investigator. If this risk-benefit assessment is regarded 
unfavourable further trial treatments will be stopped. Participants that already received 
treatment will be followed further to collect safety data.
In case one related (=causal relationship with trial drug cannot be excluded) SAE or repeated 
(≥2) severe related AEs are reported, the trial will be interrupted and no further treatments 
will be administered. The trial will only be restarted after a substantial amendment of the trial 
application has been submitted by the sponsor and a favourable opinion of the health 
authority and the ethics committee has been received. Participants that already received 
treatment will be followed further to collect safety data.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product BI 1358894 has been manufactured by BI Pharma GmbH & Co. 
KG.
4.1.1
Identity of the Investigational Medicinal Products
Substance:
BI 1358894
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
4-0-0
Route of administration:
p.o.
Duration of use:
1 single dose
Substance:
Placebo matching BI 1358894
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
4-0-0
Route of administration:
p.o.
Duration of use:
1 single dose
Substance:
Citalopram
Pharmaceutical formulation: Film-coated tablet
Source:
ratiopharm GmbH 
Unit strength:
20 mg
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
1 single dose


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4.1.2
Selection of doses in the trial
The Citalopram dose selected for this trial reflects standard clinical doses and has been 
previously used in trials with a comparable design [R17-4219].
4.1.3
Method of assigning patients to treatment groups
After assessment of all in- and exclusion criteria, each eligible patient will be randomised to 
treatment groups at Visit 2 and the appropriate medication number will be assigned. The 
randomisation will be stratified by severity of depression (MADRS ≥20 and < 20). Note that 
the medication number is different from the patient number (the latter is assigned directly 
after informed consent was obtained). Site personnel will enter the medication number in the 
source data and CRF.
During visit 2, eligible patients will be randomised to receive in a 1:1:1 ratio according to a 
randomization plan.
If a patient is not eligible to undergo or complete the fMRI procedures (see Section 3.3.4.2) 
the patient will be replaced with the next patient eligible for the same MADRS stratum. At 
the end of the study, screening will continue until all patients have been replaced. 
Excemptions from the replacement strata are only possible after a discussion between the 
Clinical Trial Leader (CT Leader) as a representative of the sponsor and the investigational 
site.


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4.1.4
Drug assignment and administration of doses for each patient
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)
AC (Active 
Control)
BI 1358894
Citalopram
Tablet
Tablet
25 mg
20 mg
4 tablets (25 mg) q.d for 1 day
1 tablet (20 mg) q.d for 1 day
100 mg
20 mg
P (Placebo)
Placebo
Tablet
n.a. mg
n.a. mg (mg) q.d  for 1 day
n.a.  mg
Depending on the treatment, the following dosing schedule will be used at Visit 2 Day 1.
Table 4.1.4: 2
Dosing schedule for the different treatments
Planned time
Treatment
T (Test)
AC (Active 
Control)
Placebo
00:00
4 tablets (25 mg) BI
4 Placebo tablets
4 Placebo tablets
03:00
1 Placebo tablet
1 tablet (20 mg) 
Citalopram
1 Placebo tablet
The medication (BI 1358894 or placebo) will be administered at the time points described in 
the Flow Chart with about 240 mL of water to a subject in the sitting position under 
supervision of the investigating physician or an authorised designee after consumption of a 
high calorie, high fat breakfast. The so-called four-eye principle (two-person rule) should be 
applied for administration of trial medication and – if applicable – its preparation (e.g. 
reconstitution), if correct dosage cannot be ensured otherwise.
In each treatment a high calorie, high-fat breakfast will be served 30 minutes before
administration of BI 1358894 or placebo. The breakfast must be completely consumed prior 
to drug administration. The composition of the standard high calorie, high-fat breakfast will 
be in compliance with the FDA guidance ‘Food-Effect Bioavailability and Fed 
Bioequivalence Studies’ [R03-2269] as detailed in Table 4.1.4: 3.


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Table 4.1.4: 3
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (in 15 g butter/Halvarine) (approximately 
100 g)
220
15 g Halvarine
112
40 g fried bacon2
151
2 toasted slices of whole-wheat bread
154
15 g butter 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 brie 60+ (148 kcal)
During the first 2 h after drug administration, they will not be allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture). For restrictions 
with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The database of this trial will be handled open-label from the sponsor site, because no bias 
with regard to data cleaning of safety measures is expected. This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
The trial team may look at unblinded patient data in order to ensure patient safety, proper 
data flow, adequate patient recruitment, influence of relevant external data, consideration of 
project needs, compliance with the clinical trial protocol (CTP) and data quality.
For the conduct of this study BI 1358894 as well as matching placebo will administered in a 
double-blind fashion at the site. Doses will be prepared by an unblinded member of the study 
team. This unblinded member will not be involved in any study assessments. No matching 
placebos for Citalopram will be used and therefore the administration of Citalopram is 
regarded to be single-blind. Anyone who is involved in patient related asessments will be 
blinded with regards to the treatment assigned.
Patients and investigators will remain blinded with regard to the randomised treatment 
assignments of BI 1358894 and placebo until after database lock. 
The derivation of the fMRI endpoints will be done in a blinded fashion meaning that all 
members of the study team involved in the generation of the MRI data and the derivation of 
the fMRI endpoints will be blinded throughout the trial.


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4.1.5.2
Unblinding and breaking the code
An emergency code break (envelope) will be available to the investigator / pharmacist / 
investigational drug storage manager. This code break may only be opened in an emergency 
situation when the identity of the trial drug must be known to the Investigator in order to 
provide appropriate medical treatment or otherwise assure safety of trial participants. If the 
code break for a patient is opened, the sponsor must be informed immediately. The reason for 
opening the code break must be documented on the envelope and/or appropriate CRF page 
along with the date and the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives and not be shared 
further. 
4.1.6
Packaging, labelling, and re-supply
BI 1358894 and matching placebo will be provided by BI or a designated Contract Research 
Organisation (CRO). They will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP). Citalopram will be sourced locally by the study site. 
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. 
A temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:
Approval of the CTP by the Institutional Review Board (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 CTP,
Availability of the proof of a medical license for the Principal Investigator,
Availability of FDA Form 1572 (if applicable).


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Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator and/or pharmacist and/or investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the sponsor or warehouse / drug distribution centre or 
alternative disposal of unused products. If applicable, the sponsor or warehouse / drug 
distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator / pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
No concomitant therapy is allowed from screening until the end of day 1 of Visit 2. Intake of 
any concomitant therapy (including pain killers for headache) between screening and end of 
the fMRI scan immediately excludes the individual patient to take part in the fMRI scanning 
procedures. All concomitant or rescue therapies will be recorded (including time of intake on 
study days) on the appropriate pages of the CRF.
Pharmacological standard of care (SoC) treatement e.g. SSRI/SNRI for the MDD may by 
initated from day 14 as per clinical discretion of the investigator and per standard of the 
clinical site and patient’s preference. If pharmacological SoC has to be provided earlier than 
day 14, it should preferentially be initiated based on a list of compounds that will be 
discussed between the sponsor and the investigational site. This list will be made available to 
the investigator in the ISF.


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4.2.2.2
Restrictions on diet and life style
After intake of study medication on Day 1 of Visit 2, all smokers are allowed to smoke one 
cigarette between drug intake and start of the MRI scan; no smoking is allowed within 1 hour 
prior to the start of the MRI scan.
No caffeine intake is allowed from 4 hours before start of the fMRI scan until its completion.  
For females: fMRI scanning should not be done in the pre-menstrual week
4.2.2.3
Restrictions regarding women of childbearing potential 
Male and female participants of child bearing potential must maintain adequate contraception 
!"#$"%&' 
($)* #" +,#!" -. /#0! 1,() $, "2, (%$!" #/*%&%!"$#"%)& 
and up to 90 days (due to the long 
half live) after the last study drug administration. The contraception methods will also be 
described in the patient information.
Highly effective methods of birth control for female participants and female partner(s) of 
male participants who are able to become pregnant include the methods below (according to 
the CTFG Recommendations related to contraception and pregnancy testing in clinical trials, 
methods with a failure rate of less than 1% per year)3

Use of adequate contraception, e.g. any of the following methods plus condom: 
implants, injectables, combined oral or vaginal contraceptives (inhibition of 
ovulation)

Hormonal intrauterine device

Sexually abstinent (defined as refraining from heterosexual intercourse during the 
entire period of risk).

A vasectomised sexual partner (provided that vasectomy was performed at least 1 
year prior to enrolment and the vasectomised partner has received medical assessment 
of the surgical success)

Surgically sterilised (including bilateral tubal occlusion, hysterectomy)

Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in 
questionable cases a blood sample with simultaneous levels of FSH above 40 U/L and 
estradiol below 30 ng/L is confirmatory)
Men must avoid sperm donation for up to 90 days after treatment.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study center under
supervision of the investigating physician or a designee. The measured plasma concentrations
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 PHARMACODYNAMICS
The following emotional paradigms and MRI scans will be performed to derive the primary 
and secondary endpoints and to evaluate the further objectives:
First, a high-resolution anatomical MRI scan from the brain will be performed, lasting 
approximately 8 minutes. During this scan, the participants are asked to relax and can watch a 
relaxation movie. To investigate processing of facial expressions, participants are then shown 
facial stimuli from the WSEFEP in a block design with negative emotional faces and 
scrambled faces (control condition). This first emotional paradigm will last about 15 minutes. 
During the task, BOLD-fMRI measurements will be performed. Then emotion processing 
will be investigated by a picture viewing task with pictures from the OASIS picture set. 
Pictures with negative affective valence and high arousal (aversive condition) in a block-
design are presented. Scrambled pictures are used in a non-affective control condition 
(neutral condition).  As in the first task, BOLD-fMRI measurements will be performed. The 
paradigm will also last about 15 minutes. To study blood diffusion in the brain, an MRI 
technique called arterial spin labeling (ASL) will be used. During the ASL measurements, 
participants will not be engaged in a task, but are asked to close their eyes and relax. ASL 
provides quantitative parametric images of tissue perfusion. The ASL sequence will last 
about 10 minutes.
More information on the processing and analysis of the MRI data can be found in the
Appendix 10.1 and will be described in further detail in an imaging analysis plan and in the 
TSAP.
5.1.1
Primary endpoint
The primary endpoint is mean BOLD signal % change in an emotional paradigm (emotional 
faces from WSEFEP) in the corticolimbic system, consisting of the following eight brain 
regions:

Amygdala left

Amygdala right

Dorsolateral prefrontal cortex left

Dorsolateral prefrontal cortex right

Insula left

Insula right

Anterior cingulate cortex left

Anterior cingulate cortex right
The effect of treatment on emotional processing will be assessed at Visit 2. 


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5.1.2
Secondary endpoints
The secondary endpoint is the mean BOLD signal % change in an emotional paradigm
(affective picture set (OASIS task) in the corticolimbic system, consisting of the following 
eight brain regions:

Amygdala left

Amygdala right

Dorsolateral prefrontal cortex left

Dorsolateral prefrontal cortex right

Insula left

Insula right

Anterior cingulate cortex left

Anterior cingulate cortex right
This endpoint will be derived in the same way as the primary endpoint. Please refer to 
Section 5.1.1.
5.1.4
MRI scanning
The MRI scans will be in the following order:
Structural MRI (~ 8 min)
Tasks (~ 30 min) 

Primary endpoint: Emotional face task: (~ 15 min)

Secondary endpoint: OASIS task (~ 15 min)
Break (~ 2 min)
ASL (~ 10 min)
The total duration of the scan will be approximately 50 minutes.
Severe headaches do potentially interfere with the planned fMRI assessments. On the one 
hand, acompanying symptoms like nausea and/or vomiting, photophobia, phonophobia, 
lacrimation impair patients’ ability to comply with the scanner environment. On the other 
hand, pain and headache might potentially introduce a bias in the BOLD signal percent
change in the emotional paradigms in the regions of interest. Therefore, patients reporting 
severe headaches prior to the fMRI scan may still undergo the fMRI assessment but will not 
be included in the fMRI statistical analysis in order not to introduce any bias. The same will 


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apply for patients that are not able to complete the fMRI assessment as planned for any 
unforeseen reason, for example an unexpected panic attack during the scan. Please see 
Section 6.2.2 for details. Patients replaced will be randomised as described in Section 7.6. 
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A medical history and a complete physical examination will be performed at screening. 
In the medical history, information will be collected on the occurrence of previous primary 
headache episodes (Yes vs. No). If yes, the type of headache will be specified further 
(migraine vs. tension-type headache vs. trigeminal-autonomic headache).
The physical examination includes at a minimum general appearance, neck, lungs, 
cardiovascular system, abdomen, extremities, and skin.
The neurological examination is part of the complete physical examination. It will also be 
performed at the timepoints specified in the Flow Chart and will include the following 
assessments:

General level of arousal

Orientation

Eye movement

Pupil size and pupil reactivity

Reflexes

Assessment of muscle strength

Gait

Romberg test

Tremor

Point-to-point movements

Sensitivity
Clinically relevant findings of the neurological examination will be reported either as 
baseline condition (if identified at the screening visit) or otherwise as AEs.
Measurement of height and body weight will be performed at screening as part of the 
complete physical examination. 
The results of the physical examinations must be included in the source documents available 
at the site. 
5.2.2
Suicidal risk assessment and reporting
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the Food and Drug Administration (FDA), assessing both suicidal 


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behaviour and suicidal ideation. It does not give a global score, but provides some categorical 
and some severity information specifically for behaviour and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsellor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of 5 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 behaviour, 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 a life time history of suicidal ideation and behaviour. 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 behaviour 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 behaviour 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 AE as defined in the protocol, and if it is considered an AE 
then it must be reported accordingly.
5.2.3
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. 
5.2.4
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.4: 1. For the sampling time 
points please see the Flow Chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 


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The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as AEs or baseline conditions (at screening) 
(please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the ISF Electronic 
Data Captured (EDC) system. The amount of blood taken from the patient concerned will be 
increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
Table 5.2.4: 1
Safety laboratory parameters – whole blood, serum or plasma
Hematology
Haematocrit
Haemoglobin
MCV, MCH, RDW, MCHC
Red Blood Cells (RBC) / Erythrocytes
WBC / Leukocytes
Platelet Count / Thrombocytes
Differential Automatic (relative and absolute 
count): 
Neutrophils, Eosinophils, Basophils, 
Monocytes, Lymphocytes
Erythrocyte sedimentation rate
Clinical chemistry
Albumin 
Alkaline phosphatase
- -GT (gamma-glutamyl transferase) 
reflex test triggered by elevated alkaline 
phosphatase on two sequential measures
ALT (alanine aminotransaminase, SGPT)
AST (aspartate aminotransaminase, 
SGOT) 
Bilirubin total, fractionated if increased 
Calcium 
Chloride 
Creatinine
Human serum chorionic gonadotropin 
(HCG)*
Creatine kinase (CK)
CK-MB, troponin (reflex tests if CK is 
elevated)
Lactate dehydrogenase (LDH)
Lipase
Phosphate 
Potassium
Protein total 
Sodium
Urea (BUN)
TSH
CRP
*Will be done at each visit, result at V2 needs to be available before treatment is administered


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Table 5.2.4: 2
Safety laboratory parameters – urine
Urinalysis 
Semi quantitative

Nitrite

Protein

Glucose

Hemoglobin

Ketone

Urine pH

Leukocyte esterase (for WBC)
Urine drug screen**

Cannabis

Cocaine

Benzodiazepine

Amphetamines

Barbiturates

Methadone

Opiates
** To be done at V1 and day -1 of V2, see exclusion criterion #5
5.2.5
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the Flow Chart. The investigator or a 
designee will evaluate whether the ECG is normal or abnormal and whether it is clinically 
relevant, if abnormal. ECGs may be repeated for quality reasons and the repeated recording 
used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.


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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death,

is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect, or

is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement 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”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI 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.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and AE reporting to sponsor and 
timelines”.
The latest list of “Always Serious AEs” can be found in the EDC system.  These events 
should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 


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
an elevation of AST and/or ALT > 3 fold ULN combined with an elevation of total 
bilirubin > 2 fold ULN measured in the same blood draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
No further AESIs have been defined for this trial.
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
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event 
(e.g. pre-existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).


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
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
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
- all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only 
report 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.
The REP for BI 1358894, when measurable drug levels or PD effects are still likely to be
present after the last administration, is not known at this early stage of development.
Therefore, all AEs reported until the trial termination date will be considered on treatment;
please see Section 7.3.4.
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication.


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The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions.
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable”, or no further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS


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The results of such modelling, if to be conducted, will be described
outside the CTR for this trial.
5.3.2
Methods of sample collection
BI 1358894
 will be taken from
an antecubital or forearm vein into a K-EDTA (potassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will be
withdrawn by means of either an indwelling venous catheter or by venipuncture with a metal
needle.
Sample handling will be described in detail in a separate lab manual.
All samples will be stored at about -20 °C or below until transfer to the analytical laboratory.
At a minimum, the sample tube labels should list the following information: BI trial number,
patient number, visit, and planned sampling time. Further information such as matrix and
analyte may also be provided. After completion of the trial, the plasma samples may be used 
for further methodological investigations, e.g. for stability testing, assessment of metabolites. 
However, only data related to the analyte and/or its metabolite(s) including anti-drug 
antibodies (if applicable) will be generated by these additional investigations. The study 
samples will be discarded after completion of the additional investigations but not later than 
5 years after the final study report has been signed
Citalopram
5.3.3
Analytical determinations


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5.3.4
Pharmacogenomic evaluation
Pharmacogenomics investigates genetic variations to explain and to predict an individual’s 
response to drugs. Therefore, a blood sample for pharmacogenomic testing will be taken 
predose on day 1 from each subject. In case of unexplainable variability in PK parameters, 
DNA might be extracted from these samples and used for exploratory analysis of variance
(ANOVA) of genes involved in Absorption, Distribution, Metabolism and Excretion 
(ADME) of drugs. It is not intended to include these data in the final report. However, the 
data may be part of the report if necessary. All remaining samples will be destroyed no later 
than three years after the end of the trial.
5.3.4.1
Methods and timing of sample collection
One blood sample of at most 10 mL will be taken from an arm vein in a PAXgene blood 
DNA drawing tube prior to the first study drug administration (Visit 2, Day 1). The blood 
sample has to be stored at a temperature of approximately -20°C or below. Once frozen, 
thawing of the samples should be avoided.
Frozen blood samples should be shipped on dry ice to:
5.3.4.2
Analytical determinations
Genomic DNA will be extracted from blood samples according to standard molecular 
genetics methods and analysed by DMET analysis or other standard genotyping technologies.
5.4
APPROPRIATENESS OF MEASUREMENTS
Antidepressants have an effect on emotional processing that is important for their therapeutic 
response and that can be detected by fMRI [R17-4219]. More recently,
it has been shown that this early effect of antidepressants on emotional processing is
predictive of clinical outcome (Godlewska et al. 2016)[R18-3516]. The fMRI procedures 
which are used in the clinical trial will therefore deliver pharmaodynamic data for 
BI 1358894 that are relevant for further clinical development.


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All other measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to 
 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. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
6.1.1
Telephone and letter pre-screening 
A brief telephone interview may be used to determine suitability based on the study entry 
criteria. 
6.1.2
Screening visit (visit 1)
All trial visits should take place as pointed out in the Flow Chart and all patients are to adhere 
to the visit schedule as specified in the Flow Chart. 
If any visit has to be rescheduled, subsequent visits should follow the original visit date 
schedule.
The end of the trial is defined as “Last Patient Out”, i.e. the last visit completed by the last 
patient.
Patients must sign Informed Consent before any study related procedures are performed. 
Signing of the Informed Consent is not necessarily the start of the screening visit.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening 
Laboratory samples will be collected as described in Flow Chart.
Once Visit 1 procedures are complete and laboratory results are received, inclusion/exclusion 
criteria must be reviewed. If patient meets inclusion/exclusion criteria, patient should be 
contacted to schedule next visit.
If patient does not meet inclusion/exclusion criteria the patient must be recorded in CRF as a 
screen failure. Re-screening is only possible after discussion with clinical trial lead.
Baseline Conditions:
Medical findings/events identified prior to first drug administration should be recorded as
baseline conditions.
Medical History:
History of previous primary headache episodes will be collected. If the subject has a history 
of headaches, please the type of headaches needs to be specified (migraine vs., tension-type 
headache vs. trigeminal-autonomic headache).


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Clinical Scales/Assessments:
The following clinical scales/assessments will be performed during the screening visit in 
order to characterize the baseline characteristics of study subjects (details on the versions 
used and respective published references can be found in the ISF):
DSM-V
PANAS
BAI
BDI
MADRS
Handedness: To be assessed by clinical observation and self reporting of the patient.
6.2.2
Visit 2
Visit 2 is the randomisation visit and marks the beginning of the treatment period.This visit 
consists of several consecutive days.

Laboratory samples will be collected as described in Flow Chart.

Pharmacogenomic sample should be collected for randomised patients only.

The unblinded member of the study team randomises the patient using the treatment
allocation code provided by BI.
The MADRS will be repeated to re-confirm MDD severity assessed at the screening visit. 
If the subject reports headaches during the treatment period the following information and 
data should be collected immediately and daily (planned time 08:00 am) until the headache is 
resolved:

Onset after medication intake (hh: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 acompanying 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)
Directly prior to and after the fMRI assessment:
Headache severity will be assessed on a NRS ranging from 0 - 10. Despite that all patients
will undergo the fMRI procedures in order to avoid any bias in the reporting of headaches, 
only patients with a reported headache severity of 0 - 6 on the NRS will be used for the 
primary analysis of the fMRI, while subjects with a reported headache severity of 7 - 10 will 
not be included in the statistical fMRI analysis (see Section 5.1.4. for details).


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6.2.3
End of trial visit
The end of trial visit will need to be performed for any patients who have been treated with 
study medication at Visit 2. 
For patients who wish to withdraw from the trial the end of treatment visit should be 
scheduled immediately.
Assessments should be performed as mentioned in Flow Chart and the respective protocol 
sections.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomised, mono-centre, placebo-controlled, parallel group design trial with three 
treatment arms. The main objective is to assess the effect of a single dose of BI 1358894
(100 mg) compared to placebo on BOLD responses in modulating brain processing of 
emotional stimuli on the amygdala (left/right), dorsolateral prefrontal cortex (left/right), 
insula (left/right), and anterior cingulate cortex(left/right) using BOLD-fMRI. 
The primary and secondary PD endpoints will be compared between BI 1358894 and 
placebo. The Citalopram treatment arm acts as a positive control group. It is not planned to 
compare PD effects between Citalopram and BI 1358894. 
 
7.2
NULL AND ALTERNATIVE HYPOTHESES
All analyses are exploratory. It is not planned to test any hypothesis in a confirmatory sense.
Confidence intervals (CIs) will be computed and will have to be interpreted in the perspective 
of the exploratory character of the study, i.e. CIs are considered as interval estimates for 
effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement,
compliance with intake of trial medication, treatment dispensing errors, prohibited
concomitant medication, completeness and consistency of data) will be checked. Important
protocol deviations (IPDs) will be identified no later than in the Blinded Report Planning 
Meeting and provided in the Integrated Quality and Risk Management (IQRM) plan.
All PD analyses will be based on the evaluable set (ES) which is defined as all randomised 
patients who performed the fMRI measurements and did not experience severe headaches 
before or during the fMRI measurements. In particular, patients that have to be replaced due 
to severe headaches will be excluded from the ES. More details on the definition of the ES 
and any potential updates will be provided in the TSAP.
As part of a sensitivity analyses, selected analyses may be repeated on the randomised set 
(RS) i.e. all patients who were randomised to receive BI 1358894, Citalopram or placebo.
Patients without any post-randomization data will be included from the primary and 
secondary PD analyses.


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All safety analyses will be based on the safety set (SS) i.e. all randomised patients who 
received the study drugs (BI 1358894, Citalopram or placebo). In particular, patients that 
received treatment but have to be replaced will be included in the SS. All analyses will be 
performed by randomized treatment.
7.3.1
Primary endpoint analyses
The derivation of the primary endpoint is outlined in Section 5.1.1 and Appendix 10.1.
The primary endpoint analysis will be performed on the ES.
Primary Analysis:
Each brain region of the primary endpoint will be analysed separately. Each brain region will 
be summarised descriptively.
An ANOVA model with treatment (BI 1358894 versus placebo) and severity of depression
(MADRS ≥20 versus < 20) as fixed effects will be used. The model is described by the 
following equation:
Yikl = + k + λl + eikl,
where
Ykli = mean BOLD signal % change measured on patient i,
= the overall mean,
k = the kth treatment effect, = 1 (placebo), 2 (BI 1358894),
λl = the lth effect of depression=1 (MADRS ≥20) , 2 (MADRS < 20)
eikl = the random error associated with patient i.
The absolute difference between BI 1358894 and placebo will be estimated by the difference 
of the arithmetic means. 90% CIs will be calculated based on the residual error from ANOVA. 
7.3.2
Secondary endpoint analyses
The secondary endpoint will be derived and analysed in the same way as the primary 
endpoint.


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7.3.4
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Standard BI summary tables and listings will be produced. All AEs with an onset between 
start of treatment and end of the REP, a period of 14 days after the last dose of trial
medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs, i.e. all 
AEs occurring between start of treatment and end of the REP. AEs that start before first drug 
intake and deteriorate under treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and PT after coding according to the current version of the MedDRA at the database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
 Exclusion of a subject's data will be documented in the CTR.


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7.4
INTERIM ANALYSES
No interim analysis is planned for this study.
7.5
HANDLING OF MISSING DATA
In general, it is not planned to impute missing values. Within each task and each brain region, 
all available data will be used in the analysis.  
More details regarding missing values in the generation of the fMRI data and the derivation 
of the fMRI endpoints may be provided in the imaging manual.


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7.6
RANDOMISATION
Randomisation will be stratified by severity of depression (MADRS ≥20 versus < 20). The 
treatment allocation ratio will be 1:1:1. BI will arrange for the randomisation and the 
packaging and labelling of trial medication. The randomisation lists will be generated using a 
validated system, which involves a pseudo-random number generator so that the resulting 
treatment will be both reproducible and non-predictable. The block size will be documented 
in the CTR. Access to the codes will be controlled and documented.
Patients with severe headache when undergoing the fMRI assessment or patients or patients 
not undergoing the fMRI procedures for any reason will need to be replaced. For that purpose 
the next patient eligible for the same MADRS stratum will be randomised to the same 
treatment group according to mirrored randomisation lists (see Section 3.3.4.2 and 4.3 or 
details).
7.7
DETERMINATION OF SAMPLE SIZE
This is an exploratory trial and the sample size is not based on any formal sample size 
estimation. Based on available literature, a sample size of 24 within each treatment arm is 
considered sufficient to detect relevant effects. The same sample size is chosen for each 
treatment arm to allow the comparison of effects (BI 1358894 versus placebo and Citalopram 
versus placebo).
The subsequent considerations are based on the following assumptions:


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Based on these results, the sample size of 72 (24 in each treatment arm) was considered 
sufficient.
Calculations were performed using R statistical package 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 its version of Somerset West (1996)), in accordance with 
the ICH Harmonized Tripartite Guideline for GCP, relevant BI SOPs, the EU regulation 
536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH / GCP.
The BI transparency and publication policy can be found on the following web page:
trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor with regard 
to publication of the results of this trial are described in the investigator contract. As a rule, 
no trial results should be published prior to finalization of the CTR.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT 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 patient participation in the trial, written informed consent must be obtained from each 
patient according to ICH / GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional patient-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional patient
information must be given to each patient.
The investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign 
(or place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent.


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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.
8.2
DATA QUALITY ASSURANCE
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 patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s Clincal Research Associate (CRA) or auditor must be 
granted access to the original patient file (please see Section 8.3.2). The investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted from any copy of the patients’
source documents before sending them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents. 


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8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). 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.
An adaptive approach to clinical trial monitoring will be utilised. The sponsor will perform a 
risk assessment of the trial to determine the extent and nature of monitoring required in order 
to ensure the reliability and robustness of the results. Regular review of risk reports will 
provide sponsor oversight during trial conduct and direct monitoring activities to the areas of 
greatest risk which have the most potential impact to patient safety and data quality.
The investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results. 
The CRA and auditor may review all CRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in Section 8.3.1.
The sponsor will also monitor compliance with the protocol and ICH / GCP.
An adaptive approach to clinical trial monitoring will be utilised. This is initiated by an 
assessment of the risk associated with the trial combined with identification of critical data 
and processes. An IQRM Plan documents the strategies involved with the implementation of 
onsite, offsite and central monitoring activities in order to direct focus to the areas of greatest 
risk which have the most potential impact to patient safety and data quality. Trial oversight is 
achieved by regular review of a report of risk which then influences any monitoring 
adaptations. 
The investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results
The CRA and auditor may review all CRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in 
Section 8.3.1. The sponsor will also monitor compliance with the protocol and ICH / GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the 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.


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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 PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the World Health 
Organization (WHO) GCP handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of GCP as outlined in 'Note For Guidance On Good Clinical Practice' 
(CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by BI are regularly audited. The analytical groups and the banking facility
are therefore assessed to be qualified for the storage and use of biological samples and 
data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed insent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out”). The “Last Patient Drug Discontinuation” (LPDD) date is defined as 
the date on which the last patient at an individual trial site ends trial medication (as scheduled 
per protocol or prematurely). Individual investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LPDD at their site. Early termination of the 
trial is defined as the premature termination of the trial due to any reason before the end of 
the trial as specified in this protocol.


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Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
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).
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Clinical Trial Leader, responsible for coordinating all required activities, 
in order to 

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of Clinical Trial Managers (CT Manager), 
CRAs, and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial.
Data Management and Statistical Evaluation will be done by BI or by a suitable CRO under 
the responsibility of BI and 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.
A central laboratory service  will be used in this trial. Details will be provided in the Central 
Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P06-11895 
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, 
Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath 
PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and 
longer-term outcomes in depressed outpatients requiring one or several 
treatment steps: a STAR*D report. Am J Psychiatry 2006. 
163(11):1905-1917.
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S.Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 
2002:1-9.
R06-2872
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.
R16-5472
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.
R16-5473
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.
R16-5475
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.
R17-4218
Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM. Increased positive 
versus negative affective perception and memory in healthy volunteers 
following selective serotonin and norepinephrine reuptake inhibition. 
Am J Psychiatry 2004. 161(7):1256-1263.
R17-4219
Murphy SE, Norbury R, O'Sullivan U, Cowen PJ, Harmer CJ. Effect of a 
single dose of citalopram on amygdala response to emotional faces. 
Br J Psychiatry 2009. 194(6):535-540.


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R18-3440
Olszanowski M, Pochwatko G, Kuklinski K, Scibor-Rylski M, Lewinski P, 
Ohme RK. Warsaw set of emotional facial expression pictures: a validation 
study of facial display photographs. Front Psychol 2015. 5:1516.
R18-3441
The Wellcome Trust Centre for Neuroimaging is now the Wellcome Centre 
for Human Neuroimaging. https://www.fil.ion.ucl.ac.uk/ (access date: 5 
November 2018) ; London: Wellcome Trust Centre for Neuroimaging 
2018.
R18-3442
MarsBaR region of interest toolbox for SPM (MarsBaR 0.44 
documentation). http://marsbar.sourceforge.net/ (access date: 5 November 
2018) 2018.
R18-3446
Klomp A, Wingen GA van, Ruiter MB de, Caan MWA, Denys D, Reneman 
L. Test-retest reliability of task-related pharmacological MRI with a single-
dose oral citalopram challenge. Neuroimage 2013. 75:108-116.
R18-3459
Kurdi B, Lozano S, Banaji MR. Introducing the Open Affective 
Standardized Image Set (OASIS). Behav Res Methods 49:2, 457-470 
(2017).
R18-3516
Godlewska BR, Browning M, Norbury R, Cowen PJ, Harmer CJ.Early 
changes in emotional processing as a marker of clinical response to SSRI 
treatment in depression. Transl Psychiatry 2018. 6(11):e957.
9.2
UNPUBLISHED REFERENCES
c10354149
 Investigator's Brochure BI 1358894 in Major Depressive 
Disorder and Borderline Personality Disorder.
n00248384
 
 
n00252179
 Selectivity/Safety Pharmacology of HC-122608 (HC-122608 = 
BI 1358894). Version1. 06 Sep 2012.
n00252207
 Effects of HC-122608 on mouse marble burying (HC-
122608 = BI 1358894). Version 1. 18 Jun 2013.
n00252277
 Effect of HC-122608 in the Mouse Elevated Plus Maze (HC-
122608 = BI 1358894). Version 1. 16 Jan 2013.
n00252628
 [14C]BI 1358894: Distribution Study in the Male Pigmented Rat. 
Version 1. 27 Sep 2016.
n00252903
Effect of BI 1358894 in the mouse forced swimming test. 
Version 1. 05 Oct 2016.
n00253490
 Cytochrome P450 Inducibility in SD rat hepatocytes – Effect on 
in vitro clearance. Version 1. 18 Nov 2016.
n00253492
 BI 1358894: In vitro inhibition studies on 
cytochrome P450 dependent metabolic reactions. Version 1. 08 Nov 2016.
n00253628
 Prediction of BI 1358894 Pharmacokinetics and 
Therapeutic Dose in Human. Version 1. 16 Feb 2017.
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. Version 1. 29 Nov 2016.


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n00253725
 Effects of BI 1358894 on behavior assessed by observation of 
nocturnal motility or in a modified IRWIN-test after oral administration of 
10, 30 and 100 mg/kg. Version 1. 29 Nov 2016.
n00253727
 Influence of BI 1358894 (10, 30 and 100 mg/kg PO) 
on hemodynamic and electrocardiographic parameters in conscious dogs. 
Version 1. 29 Nov 2016.
n00253729
 Effects of BI 1358894 (10, 30 and 100 mg/kg 
p.o.) on gastrointestinal function in the conscious rat. Version 1. 
12 Dec 2016.
n00253732
 Effects of BI 1358894 (10, 30 and 100 mg/kg 
p.o.) on urine- and serum-derived parameters in conscious rats. Version 1. 
29 Nov 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. 
Version 1. 09 Feb 2017.
n00253752
 
 
n00256526
 Evaluation of Induction Potential of Cytochrome P450 Isoforms 
by BI 1358894 in Cultured Human Hepatocytes. Version 1. 19 Jul 2017.
001-MCS-36-472
Corporate SOP: Standards and processes for analyses performed within
Clinical Pharmacokinetics/Pharmacodynamics. Version 3.0


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10.
APPENDICES
10.1
DERIVATION OF BOLD SIGNAL
The pre-processing of the functional images and the derivation of the primary and secondary 
PD endpoints will be performed by 
Functional images will be pre-processed using MATLAB 2015a (The Mathworks, Natick, 
MA) and SPM12 (Statistical parametric mapping software, SPM; Wellcome Department of 
Imaging Neuroscience, London, UK [R18-3441]. Data will be corrected for differences in 
slice acquisition time, realigned to the first volume, corrected for motion artifacts, mean-
adjusted by proportional scaling, normalized into standard stereotactic space [template 
provided by the Montreal Neurological Institute (MNI)], and spatially smoothed using a 
8 mm FWHM Gaussian kernel. The time series will be high-pass filtered to eliminate low-
frequency components.
To derive the BOLD signal % change, statistical analysis will be performed by modeling the 
different conditions convolved with a hemodynamic response function as explanatory 
variables within the context of the general linear model on a voxel-by-voxel basis. 
Realignment parameters will be included as additional regressors in the statistical model. 
Region of interest [ROI: x, y, z, in MNI space] analyses will be performed to investigate
BOLD signal % changes in the above mentioned brain regions. Accordingly, spherical 
(radius = 6 – 10 mm) ROIs will be built and BOLD signal % changes will be extracted for the 
different conditions for each patient separately using MarsBaR [R18-3442].


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
04 Feb 2019
EudraCT number
EU number
2017-004763-12
BI Trial number
1402-0003
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A single dose, randomized, placebo controlled 
Phase I study on the effects of BI 1358894 on 
functional MRI measurements in an emotional 
processing paradigm in patients with Major 
Depressive Disorder
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


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Section to be changed
Study title, synopsis, section 7
Description of change
The study title was changed from active-controlled 
to placebo-controlled.
Rationale for change
HA request in order to reflect that placebo is the 
only comparison group regarding the IMP.
Section to be changed
Section 1.2.3.2
Description of change
An additional Table 1.2.3.2: 2 displaying the safety 
margins for BI 1358894 after intake of 100mg fed 
dose was added.
Rationale for change
HA request
Section to be changed
Section 3.3.2 inclusion criteria 9
Description of change
The upper range of the BMI value changed to 30.0 
kg/m².
Rationale for change
HA request
Section to be changed
Section 3.3.4.3
Description of change
The number of related SAEs that need to occur in 
the same organ class until the trial is discontinued 
was changed to one and repeated severe AEs were 
added.
Rationale for change
HA request
Section to be changed
Section 3.3.4.3
Description of change
The wording related to discontinuation of the trial 
was changed.
Rationale for change
HA request
Section to be changed
Section 8
Description of change
Reference to the medical device directive 93/42/EC 
and the harmomized standard ISO 14155 was 
deleted. The applied version of the Declaration of 
Helsinki was added. The reference to the 
information and consent of the patients legally 
accepted representative was deleted as the trial will 
not include subjects unable to provide informed 
consent.
Rationale for change
HA request


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11.2
GLOBAL AMENDMENT 2
Date of amendment
21 Feb 2019
EudraCT number
EU number
2017-004763-12
BI Trial number
1402-0003
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A single dose, randomized, placebo controlled 
Phase I study on the effects of BI 1358894 on 
functional MRI measurements in an emotional 
processing paradigm in patients with Major 
Depressive Disorder
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Section 3.3.4.3
Description of change
The wording related to discontinuation of the trial 
in case of AEs/SAEs was changed.
Rationale for change
HA and IRB request


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17663416
3.0
clinical-trial-protocol-version-03
A single dose, randomized, placebo controlled Phase I study on the effects of BI
1358894 on functional MRI measurements in an emotional processing paradigm in
patients with Major Depressive Disorder
Author-Trial Clinical
Pharmacokineticist
25 Feb 2019 14:55 CET
Author-Clinical Trial Leader
25 Feb 2019 14:59 CET
Author-Trial Statistician
25 Feb 2019 15:16 CET
Approval-Therapeutic Area 
25 Feb 2019 15:18 CET
Approval-Translational Medicine
Expert
25 Feb 2019 16:04 CET
Approval-Team Member Medicine
25 Feb 2019 17:28 CET
Verification-Paper Signature
Completion
26 Feb 2019 11:35 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17663416
3.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c28590228-01
BI Trial No.:
1402-0003
Title:
A single dose, randomized, placebo controlled Phase I study on the 
effects of BI 1358894 on functional MRI measurements in an
emotional processing paradigm in patients with Major Depressive
Disorder
Including Protocol Amendment 2 [c17663416-03]
Investigational
Products:
BI 1358894
Responsible trial 
statistician:
 
Phone:
Fax:
Date of statistical 
analysis plan:
22 OCT 2019 REVISED
Version:
Revised
Page 1 of 32
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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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TSAP for BI Trial No: 1402-0003
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINTS...................................................................................20
7.5
SECONDARY ENDPOINTS.............................................................................24
7.7
EXTENT OF EXPOSURE.................................................................................24
7.8
SAFETY ANALYSIS..........................................................................................24
7.8.1
Adverse events.....................................................................................................24
7.8.2
Laboratory data ..................................................................................................27
7.8.3
Vital signs.............................................................................................................27
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................28
7.8.5.1
Physical examination ............................................................................................28
7.8.5.2 
Neurological examination.....................................................................................28
7.8.5.3 
Suicidality assessment...........................................................................................28
8.
REFERENCES....................................................................................................29


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10.
HISTORY TABLE..............................................................................................32


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................12
Table 6.2: 1
iPDs and handling of iPDs ...............................................................................14
Table 6.3: 1
Subject sets analysed........................................................................................16
Table 10: 1
History table .....................................................................................................32


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
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
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
BI
Boehringer Ingelheim
BMI
Body mass index
BP
Blood pressure
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRA
Clinical research associate
CRF
Case report form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug induced liver injury
ECG
Electrocardiogram 
EDC
Electronic data capture
ES
Evaluable set
EudraCT
European Union Drug Regulating Authorities Clinical Trials
gCV
Geometric coefficient of variation
gMean
Geometric mean
HV
Healthy Volunteer
ICH
International Conference on Harmonisation


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Term
Definition / description
iPD
Important Protocol Deviation
ISF
Investigator site file
λz
Terminal rate constant in plasma
LLT
Lower level term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PK
Pharmacokinetics
PKS
PK parameter analysis set
PR
Pulse rate
PT
Preferred term
Q1
1st quartile
Q3
3rd quartile
RAGe
Report Appendix Generator system
REP
Residual effect period
RPM
Report planning meeting
RS
Randomised set
SASTM
Statistical Analysis System
SD
Standard deviation
SOC
System organ class
SOP
Standard operating procedure
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
The pre-processing of the functional images and the derivation of the primary and secondary 
PD endpoints will be performed by 
. Functional
images will be pre-processed using MATLAB 2015a (The Mathworks, Natick, MA) and 
SPM12 (Statistical parametric mapping software, SPM; Wellcome Department of Imaging 
Neuroscience, London, UK).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including 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).


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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. No changes compared to the protocol were made.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 5.1.1 of the CTP: The primary endpoint is mean BOLD signal % change in an 
emotional paradigm (emotional faces from WSEFEP) in the corticolimbic system, consisting 
of the following eight brain regions:

Amygdala left

Amygdala right

Dorsolateral prefrontal cortex left

Dorsolateral prefrontal cortex right

Insula left

Insula right

Anterior cingulate cortex left

Anterior cingulate cortex right
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 5.1.2 of the CTP:  The secondary endpoint is the mean BOLD signal % change in an 
emotional paradigm (affective picture set (OASIS task) in the corticolimbic system, consisting 
of the following eight brain regions:

Amygdala left

Amygdala right

Dorsolateral prefrontal cortex left

Dorsolateral prefrontal cortex right

Insula left

Insula right

Anterior cingulate cortex left

Anterior cingulate cortex right
This endpoint will be derived in the same way as the primary endpoint. Please refer to


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Section 5.1.
Safety:
Section 2.2.2 of the CTP: Further safety criteria of interest are:

Adverse events (including clinically relevant findings from the physical and 
neurological examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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Age [years] will be determined as the difference between year of informed consent and year 
of birth.
BMI will be calculated as weight [kg] / (0.01 * height [cm])2.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment sequences, 
and selection of doses, please see CTP, Sections 3 and 4.
The study will be performed as placebo-controlled, randomized, single dose, parallel group 
design with three treatment arms (BI 1358894, Citalopram, and placebo).
In total, it was planned to assign 24 patients with major depressive disorder aged 18 to 45 
years and a Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥ 7 and < 26 
at screening to each of the three treatment sequences in a 1:1:1 ratio.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
Short label for footnote
D
4 x 25 mg tablets of BI 1358894
BI 1358894
BI 1358894 100mg 
E
1 x 20 mg tablets of Citalopram
Citalopram
Citalopram 20mg
P
Placebo, tablet
Placebo
Placebo
The following separate study phases will be defined for the analyses of AEs, safety 
laboratory data and vital signs:
Screening (ranging from 0:00 h on day of informed consent until administration time 
of study drug)
On treatment (ranging from the time of administration of BI 1358894 or BI-matching 
placebo (in the placebo and Citalopram arm) until time of administration of BI 1358894 
or BI-matching placebo + REP (14*24 h) or 0:00 AM on day after subject’s trial 
termination date, whatever occurs earlier),
Follow up (ranging from time of administration of BI 1358894 or BI-matching placebo
(in the placebo and Citalopram arm) + REP(14*24 h) until 0:00 AM on day after 
subject’s trial termination date).
Displays of AEs will be presented separately for the treatments described in Table 6.1: 1
above. In the Citalopram arm, AE´s occurring between administration of placebo at 0:00 and 
administration of Citalopram at 3:00 (planned time) cannot be treatment related. If applicable, 
these AE´s will be checked individually in the listings and described in the CTR. 
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting. At this meeting, all manual 
deviations identified at the sites by the CRAs and deviations too complex to program will be 
reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM minutes via an accompanying Excel spreadsheet (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 RPM. Table 6.2: 1 specifies which kind of iPDs 
should be excluded from which analysis set. The decision on exclusion of subjects from 
analysis sets will be made at the latest at the RPM, after discussion of exceptional cases and
implications for analyses.


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Table 6.2: 1
iPDs and handling of iPDs
Category / 
iPD Code
Description
Excluded from which 
analysis set
A
Entrance criteria not met
A1
Inclusion criteria violated
None
A2
Exclusion criteria violated
None
B
Informed consent
B1
Informed consent not available/not done
All
B2
Informed consent date after start of study activities
None
C
Trial medication and randomisation
C1
Randomisation not followed (patients do not receive the treatment 
they were initially randomised to)
PKS, ES
C2
Non-compliance
PKS, ES
C3
Trial medication not taken according to protocol
PKS, ES
D
Concomitant medication
D1
Concomitant medication with the potential to affect the assessment 
of the trial medication
PKS
E
Missing data
E1
Certain violations of procedures used to measure primary or 
secondary data
None
F
Incorrect timing
F1
Certain violations of time schedule used to measure primary or 
secondary data
PKS
G
Other trial specific important deviation
G1
Incorrect intake of meal before administration of treatment
PKS
G2
Protocol deviations affecting safety and rights
None 
6.3
SUBJECT SETS ANALYSED

Evaluable Set (ES) 
This subject set includes all randomised patients who performed the fMRI 
measurements and did not experience severe headaches directly before or during the 
fMRI measurements. In particular, patients that have to be replaced due to severe 
headaches will be excluded from the ES. 
Severe headaches are those with a severity of 7-10 assessed on the Numerical 
Ranking scale (NRS) scale. 


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
Randomised Set (RS)
This subject set includes all patients who were randomised to receive BI 1358894, 
Citalopram or placebo. Patients without any post-randomization data will be excluded 
from the primary and secondary PD analyses.
All analyses based on the randomised set will be done using the planned 
(i.e.randomised) treatment.

Safety Set (SS)
This subject set includes all randomised patients who received the study drugs 
(BI 1358894, Citalopram or placebo). In particular, patients that received treatment 
but have to be replaced will be included in the SS. It is used for safety analyses.
All analyses based on the safety set will be done using the treatment actually received.

PK parameter analysis set (PKS)
The PK parameter analysis set (PKS) includes all subjects in the SS who provide at 
least one PK parameter that was not excluded according to the description below. 
Thus, a subject will be included in the PKS, even if he/she contributes only one PK 
parameter value for one period to the statistical assessment. 
Section 7.3.5 of the CTP: Plasma concentration data and parameters of a subject will be 
included in the statistical PK analyses, if they are not flagged for exclusion due to a protocol
deviation relevant to the evaluation of PK (to be decided no later than in the Blinded Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject's data will be documented in the CTR.
Relevant protocol deviations may be but are not restricted to:

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to.

Incorrect dose of trial medication taken.

Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example:

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis) or at least until completion of the fMRI procedures on day 1.

The subject experiences emesis at any time during the labelled dosing interval.

A pre-dose concentration is > 5% of the Cmax value of that subject.

Missing samples/concentration data at important phases of PK disposition curve.
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.


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The following Table 6.3: 1 contains the information which subject is used for which class of 
endpoint:
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
ES
RS
SS
PKS
Primary and secondary PD analyses
Primary 
analysis
Sensitivity 
analysis*
Safety endpoints 
X
Demographic/ baseline endpoints
X
X*
Important protocol deviations
X
PK endpoints
X
* In case the ES and the RS differ by three or more patients (see section 7.1 and 7.4), analyses will be repeated 
for the RS.
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For vital signs baseline is defined as the last measurement prior to administration of BI 
1358894 or BI-matching placebo (in the placebo and Citalopram arm).


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For laboratory parameters baseline is defined as the last measurement prior to administration 
of BI 1358894 or BI-matching placebo (in the placebo and Citalopram arm).
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows are provided in the Flow Chart of the CTP. Adherence to time 
windows will be checked via the consistency check listings at the RPM. 


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by Datamap GmbH and will be 
presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of primary and secondary endpoints (refer to Section 7.4 and 
Section 7.5) will also be performed by Datamap GmbH and will be presented in Section 15.7
of the CTR and in Appendix 16.1.13.4.
Descriptive data analysis of PK parameters and concentrations will be performed by the 
department Translational Medicine and Clinical Pharmacology at BI and will be presented in 
Section 16.1.13.3 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations (7).
The individual values of all subjects will be listed, sorted by treatment, subject number, visit 
and actual treatment (if appropriate). 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.


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Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment sequence/group. Percentages will be rounded to one decimal place and will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not. The category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The ADS ADPP (PK parameters) contains column variables indicating inclusion/exclusion 
(APEXC) of a PK parameter and an analysis flag comment (APEXCO). All analyses based 
on the PKS will include parameters if they are not flagged for exclusion, that is APEXCO is 
equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (12).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the ES.
Treatment allocation and demographics will be summarised also for the RS. 
The data will be summarised by treatment and in total.
In case the ES and the RS differ by three or more patients (e.g. at least three patients have 
been excluded from the RS due to severe headaches before or during the fMRI 
measurements), the descriptive statistics will also be provided for the RS. 


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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the ES.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
In case the ES and the RS differ by three or more patients, the frequency tables will also be 
provided for the RS. 
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations of trial medication will provide additional confirmation of 
compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
The primary endpoint analysis will be performed on the ES.
Section 7.3.1. of the CTP:
Primary Analysis:
Each brain region of the primary endpoint will be analysed separately. Each brain region 
will be summarised descriptively.
An ANOVA model with treatment (BI 1358894 versus placebo) and severity of depression 
(MADRS ≥ 20 versus < 20) as fixed effects will be used. The model is described by the 
following equation:
Yikl = + k + λl + eikl,
where
Ykli = mean BOLD signal % change measured on patient i,
= the overall mean,


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k = the kth treatment effect, = 1 (placebo), 2 (BI 1358894),
λl = the lth effect of depression=1 (MADRS ≥ 20) , 2 (MADRS < 20)
eikl = the random error associated with patient i.
The absolute difference between BI 1358894 and placebo will be estimated by the difference 
of the arithmetic means. 90% CIs will be calculated based on the residual error from ANOVA. 


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7.5
SECONDARY ENDPOINTS
The secondary endpoint will be derived and analysed in the same way as the primary 
endpoint. 
Safety:
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the ES. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the SS.
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.


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The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (9).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
For analysis, multiple AE occurrence data on the case report form (CRF) will be collapsed 
into one AE provided that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence).
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (9) and "Handling of missing and incomplete AE 
dates" (4).
Section 7.3.4 of the CTP:  Statistical analysis and reporting of AEs will concentrate on 
treatment-emergent AEs, i.e. all AEs occurring between start of treatment and end of the 
REP. AEs that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’.
All AEs will be assigned to screening, on-treatment or follow-up 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 (including AESIs) will be presented.
Section 5.2.6.1 of the CTP: 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 and/or ALT  > 3 fold ULN combined with an elevation of total 
bilirubin > 2 fold ULN measured in the same blood draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN […]


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According to ICH E3 (10), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken with trial drug = discontinuation’ or ‘action taken with trial drug = reduced’, 
or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant
therapy as identified by the Clinical Monitor/Investigator at a MQRM. 
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (10), for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs.
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
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 adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening and follow-up periods will not be included in this analysis. 
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of the 
CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))


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
FU Phase
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all study phases ("Total")
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
Descriptive statistics will be calculated by treatment including change from baseline. 
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible 
clinically significant will be flagged in the data listings.
It is the investigator's responsibility to decide whether a lab value is clinically significantly
abnormal or not (at the RPM at the latest).
The analyses of laboratory data will be based on BI standards "Display and Analysis of 
Laboratory Data" (11).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
Descriptive statistics including change from baseline will be performed for vital signs (blood 
pressure and pulse rate) by treatment.
Clinically relevant findings in vital signs will be reported as baseline conditions (at screening) 
or as AEs (during the trial) if judged clinically relevant by the investigator, and will be 
analysed as such.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment).


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7.8.5
Others
7.8.5.1
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition
(i.e., a condition already existent before intake of study drug) or as AE and will be
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.
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
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON.
3
BI-KMED-COPS-TMP-0001: "iPD log", current version; IDEA for GEN.
4
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; KMED
5
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies”, current version; IDEA for CON.
6
KM Asset BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
7
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
8
Neuenschwander B, Wandel S, Roychoudhury S, Bailey S. Robust exchangeability
designs for early phase clinical trials with multiple strata. Pharm Stat 2015; 15:123-134 
[R17-3435]
9
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event 
Data from Clinical Trials", current version; KMED
10
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version.
11
KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED
12
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Revision
22-OCT-19
None
This is the final TSAP