Conditions: Depressive Disorder, Major
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 389
Healthy volunteers: no

Brief summary:
This study is open to adults with depression (major depressive disorder) for whom standard treatment with antidepressants alone does not work sufficiently. The purpose of the trial is to find out whether a medicine called BI 1358894 helps to improve symptoms of depression. Four different doses of BI 1358894 are tested in the study. Participants continue their standard antidepressant therapy throughout the study. Participants are put into 6 groups by chance. Participants in 4 of the 6 groups take different doses of BI 1358894, and placebo. Participants in the fifth group take quetiapine, a medicine already used to treat depression, and placebo. Participants in the sixth group take placebo only.

Participants take BI 1358894, quetiapine, or placebo as tablets. Placebo tablets look like BI 1358894 or quetiapine tablets but do not contain any medicine. Each participant takes tablets twice a day. Participants are in the study for about 3 months. During this time, they visit the study site about 8 times and get about 2 phone calls. At the visits, doctors ask participants about their symptoms.

The results between the BI 1358894 groups, the quetiapine group, and the placebo group are then compared. The doctors also regularly check the general health of the participants.

Detailed description:

Arms:
arm 1: Participants with an established diagnosis of MDD administered one 5 milligram (mg) dose of BI 1358894 in the morning as film-coated tablet, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks.

During the trial, participants also continued treatment with their OAD. arm 2: Participants with an established diagnosis of Major Depressive Disorder (MDD) administered one dose of placebo matching BI 1358894 in the morning as film-coated tablets, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks.

During the trial, participants also continued treatment with their Ongoing Antidepressants (OAD). arm 3: Participants with an established diagnosis of MDD administered one dose of placebo matching BI 1358894 in the morning as film-coated tablets, and one 150 or 300 mg dose of quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks.

The daily active dose at the start of therapy was 50 mg on Day 1, 100 mg at Day 2 and 150 mg on Day 3 and 4. Beginning with Day 5, the recommended daily dose of 300 mg was taken. If not tolerated by a participant, the dose was reduced to 150 mg in Week 1. Thereafter, this finally chosen dose had to be stable until end of treatment at Week 6.

During the trial, participants also continued treatment with their OAD. arm 4: Participants with an established diagnosis of MDD administered one 25 mg dose of BI 1358894 in the morning as film-coated tablet, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks.

During the trial, participants also continued treatment with their OAD. arm 5: Participants with an established diagnosis of MDD administered one 75 mg dose of BI 1358894 in the morning as film-coated tablets, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks.

During the trial, participants also continued treatment with their OAD. arm 6: Participants with an established diagnosis of MDD administered one 125 mg dose of BI 1358894 in the morning as film-coated tablets, and one dose of placebo matching quetiapine in the evening as tablets. Each administration was performed orally once daily, for 6 weeks.

During the trial, participants also continued treatment with their OAD.

Interventions: intervention 1: BI 1358894 intervention 2: Placebo intervention 3: Quetiapine
Intervention descriptions: intervention 1: BI 1358894 intervention 2: Placebo intervention 3: quetiapine

Protocol document:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
 
Document Number:
c29983007-12
EudraCT No.
EU Trial No.
2019-004264-21
BI Trial No.
1402-0011
BI Investigational
Medicinal Product(s)
BI 1358894
Title
A Phase II, 6-week, multicenter, randomized, double-blind, 
double-dummy, placebo-controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, tolerability and safety of 
oral BI 1358894 in patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Lay Title
A study to test the effect of different doses of BI 1358894 and 
quetiapine in people with depression.
Clinical Phase
II
Clinical Trial Leader
Phone: 
, Fax: 
Email: 
Coordinating 
Investigator
Phone:
Fax:
Email:
Version and Date
Version: 11.0
Date: 07 Jun 2023
Page 1 of 135
Proprietary confidential information.
2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
16 Dec 2019
Revision date
07 June 2023
BI trial number
1402-0011
Title of trial
A Phase II, 6-week, multicenter, randomized, double-blind, double-
dummy, placebo-controlled, parallel group trial with a quetiapine
arm to evaluate the efficacy, tolerability and safety of oral BI 
1358894 in patients with Major Depressive Disorder with inadequate 
response to antidepressants.
Coordinating 
Investigator
Phone:
Fax:
Email:
Trial site(s)
Multi-centre trial
Clinical phase
II
Trial rationale
Patients with Major Depressive Disorder (MDD), who inadequately 
respond to first line treatment, will receive augmentation treatment. 
However, there remains significant unmet medical need in those 
patients who either do not respond to or do not tolerate current 
augmentation approaches (e.g., atypical antipsychotics, lithium) and 
for whom last line therapies (ECT and ketamine) are either not 
available or unsuitable. A product that would show similar efficacy 
to the above mentioned augmentation treatments, but without the 
side effects and/or resource requirements would constitute a major 
medical advance.
Only quetiapine has been approved in both the US and the EU in 
patients with inadeaquate response on first line treatment (SSRI; 
SNRI; bupropion), and has therefore been included as an additional 
treatment arm in this Phase II trial.


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Trial objective(s)
The main objectives of this trial are to provide proof of concept 
(PoC) and dose-ranging data of BI 1358894 compared to placebo in 
patients with Major Depressive Disorder (MDD) to support dose
selection for pivotal studies.
Trial endpoints
Primary Endpoint:

Change from baseline in MADRS total score at Week 6.
Secondary Endpoints:

Response defined as ≥ 50% MADRS reduction from baseline at 
Week 6

Change from baseline in STAI State and Trait version scores at 
Week 6

Change from baseline in Clinical Global Impression Severity 
Scale (CGI-S) score at Week 6

Change from baseline in SMDDS total score at Week 6
Trial design
A 6-week parallel-group multicenter, randomized, double blind, 
double-dummy, placebo controlled trial with different doses of BI 
1358894 and with a quetipine arm in patients with Major Depressive 
Disorder (MDD) with inadequate response to ongoing treatment with 
an SSRI or an SNRI or bupropion.
Total number of 
participants 
randomized 
Approximately 431 male and female participants with MDD meeting 
the entry criteria are planned to be randomized into this trial.
Number of 
participants on each 
treatment

Placebo arm
Approx. 144 
participants

BI 1358894
5 mg: 
Approx. 41 
participants

BI 1358894 
25 mg:
Approx. 41 
participants

BI 1358894 
75 mg:
Approx. 41 
participants

BI 1358894 
125 mg:
Approx. 82 
participants

quetiapine
150/300 mg:
Approx. 82 
participants
Diagnosis
Patients with an established diagnosis of Major Depressive Disorder 
(MDD) confirmed at the time of screening by Structured Clinical 
Interview for DSM-5 Clinical Trials (SCID-5)


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Main in- and 
exclusion criteria
Main Inclusion Criteria:
Established diagnosis of Major Depressive Disorder (MDD), 
single episode or recurrent, as confirmed at the time of 
screening by the Structured Clinical Interview for DSM-5 
(SCID-5), with a duration of current depressive episode ≥ 8 
weeks and ≤ 24 months at the time of screening visit.
Montgomery-Åsberg Depression Rating Scale (MADRS) 
total score ≥ 24 at screening, as confirmed by a trained site 
based rater AND interactive, computer administered 
MADRS. The difference in the rater and computer 
administered MADRS must not exceed more than 7 points. 
In addition, trial participants must have a score of ≥ 3 on the 
Reported Sadness Item on both MADRS scales (computer-
administered and rater-administered MADRS).
A documented ongoing monotherapy treatment of ≥ 4 weeks 
at the screening visit, with bupropion or a protocol specified 
SSRI or SNRI at adequate dose (at least minimum effective 
dose as per prescribing information and as confirmed per 
detectable drug levels in the screening blood or urine 
sampling).
Male and female participants, 18 to 65 years of age, both 
inclusively at the time of consent. 
Women who are of childbearing potential (WOCBP) must be 
able and willing, to use two methods of contraception, 
confirmed by the investigator,
Main Exclusion Criteria:
Per DSM-5, has ever met diagnostic criteria for 
schizophrenia, schizoaffective disorder, schizophreniform 
disorder, bipolar disorder, delusional disorder or MDD with 
psychotic features as assessed by the SCID-5 at the time of 
screening.
Diagnosis of any other mental disorder (in addition to those 
as described in EX#1) that was primary focus of treatment 
within 6 months prior to screening or at baseline (as per 
clinical discretion of the investigator).
Diagnosis with antisocial, paranoid, schizoid or schizotypal 
personality disorder as per DSM-5 criteria, at the time of 
screening visit. Any other personality disorder at screening 
visit that significantly affects current psychiatric status and 
likely to impact trial participation, as per the judgement of 
investigator.
Diagnosis of a substance related disorder within 3 months 
prior to screening visit (with exception of caffeine and 
tobacco).


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History of seizure disorders, stroke, brain tumor or any other 
major neurological illness that can impact participation in the 
trial.
History of more than 2 unsuccessful monotherapy treatments 
(at adequate dosage and duration, per local prescribing 
information of the product) with an approved antidepressant 
medication for the current ongoing major depressive episode.
These include ongoing monotherapy treatment with 
bupropion or a protocol specified SSRI or SNRI as described 
in inclusion criteria #3.
Any suicidal behavior in the past 12 months prior to 
screening (per investigator judgement including an actual 
attempt, interrupted attempt, aborted attempt, or preparatory 
acts or behaviour).
Any suicidal ideation of type 4 or 5 in the Columbia Suicide 
Severity Rating Scale (C-SSRS) in the past 3 months prior to 
screening or at screening or baseline visit (i.e., active suicidal 
thought with method and intent but without specific plan, or 
active suicidal thought with method, intent and plan). 
Has initiated psychotherapy or other non-drug therapies (e.g., 
acupuncture or hypnosis) within 3 months prior to screening 
or planning to start any time during the trial. The participant 
should not have a change in type, intensity and/or frequency 
of psychotherapy within the last 8 weeks prior to screening 
and it is not anticipated to change during the entire course of 
trial.
Any use of restricted medications within 7 days prior to 
randomization and during the entire course of the trial 
Please note:
Investigators may use their clinical discretion to wash out (at 
least 3 half-lives of referenced medication) the restricted 
medications during the screening period. The participant
must adhere to the screening visit dose of the background 
SSRI/SNRI or bupropion until the end of the trial or end of 
treatment (eEOT/EOT), respectively
Participants, who, in addition to their monotherapy with an 
SSRI/SNRI or bupropion, are taking additional low dose 
antidepressant medications for purposes other than treating 
depressive symptoms, are not excluded. The dose must be 
less than the lowest dose indicated for MDD (see ISF for
details). 
Participants who are on stable treatment with ongoing 
benzodiazepines and/or non-benzodiazepine hypnotics for 
insomnia or anxiety for at least 28 days prior to screening 
should continue without change for the entire trial duration. 
For participants who are not on current treatment of insomnia 
and anxiety symptoms at the time of screening, the protocol 


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will allow short term treatment of these symptoms during the 
course of trial.
Participants who must or wish to continue the intake of 
restricted medications or any drug considered likely to 
interfere with the safe conduct of the trial. 
Use of alternative medicine (e.g. Chinese traditional 
medicine, herbal medication, St. John’s wort, etc.) during the 
entire course of the trial.
Have received electroconvulsive therapy and/or 
administration of Ketamine /S-Ketamine for the current 
ongoing depressive episode and/or transcranial magnetic 
stimulation (TMS) for the current ongoing depressive 
episode or within 12 months pior to screening.
Resting QTcF ≥450 msec (male) or ≥460 msec (female) at 
screening.
Test product(s)
BI 1358894
dose
5 mg, 25 mg, 75 mg, 125 mg; once daily
mode of 
administration
Per os
Comparator 
product / Active 
reference

Placebo

quetiapine extended release 
dose

NA for placebo, matching BI 1358894 and quetiapine

quetiapine, after uptitration, either 300 or 150 mg, once daily
mode of
administration
Per os
Duration of 
treatment
6 weeks
Statistical methods
To demonstrate proof of concept and to evaluate the dose response 
relationship for BI 1358894, a multiple comparison procedure with 
modelling techniques (MCPMod) approach is planned for the 
primary analysis of the BI 1358894 and placebo treatment arms. As 
a basis for the MCPMod analysis and to assess quantitative 
treatment benefit, a mixed model for repeated measure (MMRM) 
analysis will be used to generate covariate adjusted estimates of 
mean change from baseline to Week 6 in MADRS total score and 
associated covariance matrices. No formal hypothesis testing will be 
performed to compare the quetiapine and BI 1358894 arms or the 
quetiapine and placebo arms.




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Dispense trial drugs
x
x
x
Administration of trial drugs at trial site
x
x
x
x
Drug Accountability 3
x
x
x
x
x
Termination of trial medication
x
x
Sample for confirmation of urine or blood levels 
SSRI/SNRI/bupropion 12
Please note: Duloxetine in serum only
x
x
x
x
x
x
x
x
x
Optional sampling for 
x6
x5
x5
Trial specific examinations
(see Flow Chart 2)
x
x
x
x
x
x
x
x
x
x
All AEs/SAEs/AESIs 7
x
x
x
x
x
x
x
x
x
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
Substance use
x
x
x
x
x
x
x
x
x
Completion of participant’s participation 
x
x
At the screening visit, all clinical assessments (Flow Chart 1) should be performed first, followed by the scale administrations, top to down, in the order as shown in Flow Chart 2. For all further 
clinical visits, scale administrations should be done first, top to down, in the order as shown in Flow Chart 2, followed by the clinical assessments, e.g., Flow Chart 1 (also refer to section 
6.2 further details for the order of clinical assessments and scale performance).
* End of treatment (EOT) for participants who complete the treatment period at Visit 8.
** Participants who discontinue trial drug prematurely must perform an early EOT visit within 7 days and should ideally be observed until trial end as if they were still receiving blinded trial 
treatment, e.g., follow the regular visit schedule after the early EOT visit. In addition, all early D/C participants must also complete the FUP visit (early drug discontinuation date + 28+2 
days) for a full trial safety follow-up. There are 2 options for observing participants after premature drug discontinuation (refer to section 3.3.4 for additional information).












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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART 1.....................................................................................................................7
FLOW CHART 2...................................................................................................................11
TABLE OF CONTENTS ......................................................................................................14
ABBREVIATIONS................................................................................................................18
1.
INTRODUCTION...............................................................................................23
1.1
MEDICAL BACKGROUND.............................................................................23
1.2
DRUG PROFILE................................................................................................23
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................27
1.4
BENEFIT - RISK ASSESSMENT.....................................................................27
1.4.1
Benefits.................................................................................................................27
1.4.2
Risks .....................................................................................................................27
1.4.3
Discussion.............................................................................................................36
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................37
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........37
2.1.1
Main objectives....................................................................................................37
2.1.2
Primary endpoint(s)............................................................................................37
2.1.3
Secondary endpoint(s) ........................................................................................37
2.2.3
Safety....................................................................................................................38
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................39
3.1
OVERALL TRIAL DESIGN.............................................................................39
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................40
3.3
SELECTION OF TRIAL POPULATION .......................................................41
3.3.1
Main diagnosis for trial entry ............................................................................41
3.3.2
Inclusion criteria .................................................................................................42
3.3.3
Exclusion criteria ................................................................................................43
3.3.4
Withdrawal of participants from treatment or assessments...........................45
3.3.4.1
Discontinuation of trial treatment .........................................................................45
3.3.4.2
Withdrawal of consent to trial participation .........................................................46
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................46
4.
TREATMENTS...................................................................................................48
4.1
INVESTIGATIONAL TREATMENTS ...........................................................48
4.1.1
Identity of the Investigational Medicinal Products..........................................48
4.1.2
Selection of doses in the trial and dose modifications......................................49
4.1.2.1
Treatment with BI 1358894..................................................................................49








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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike Information Criteria
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AMP
Auxiliary Medicinal Products
AST
Aspartate Aminotransferase
ATRQ
Antidepressant Treatment Response Questionnaire
AUC
Area under the Curve
BCRP
Breast Cancer Resistance Protein
BI
Boehringer Ingelheim
BoPD
Borderline Personality Disorder
CA
Competent Authority
CCK-4
Cholecystokinin Tetrapeptide
CGI-S
Clinical Global Impression Severity Scale
CI
Confidence Interval
ClinRO
Clinical Reported Outcome
Cmax
Maximum Concentration
Cmin
Minimum Plasma Concentration
CNS
Central Nervous System 
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CRP
C-reactive protein
C-SSRS
Columbia Suicide Severity Rating Scale
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CYP
Cytochrome P450
DASM
Data Analysis Methodology
DBL
Database Lock


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DDI
Drug Drug Interaction
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DSM
Diagnostic and Statistical Manual of Mental Disorders
EC
Ethics Committee
EC50
Half maximal effective concentration
ECG
Electrocardiogram
eCOA
electronic Clinical Outcome Assessment
eCRF
Electronic Case Report Form
ECT
Electroconvulsive Therapy
ED
Effectiove Dose
eDC
Electronic Data Capture
EoStudy / EoS
End of Study
EoT
End of Treatment
ESR
Erythrocyte Sedimentation Rate
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
FDA
Food and Drug Administration
FST
Forced Swim Test
FU / FUP
Follow Up
GCP
Good Clinical Practice
GGT
Gamma-Glutamyltransferase
GMP
Good Manufacturing Practice
HA
Health Authority
HDL
High Densitiy Lipoprotein
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
IC
Informed Consent


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ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine System
LDL
Low Density Lipoprotein
LPLT
Last Patient Last Treatment
LS
Least Square
MADRS
Montgomery-Asberg Depression Rating Scale
MAR
Missing at random
MCPMod
Multiple comparisons procedure – modelling
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligramme
MGH
The Massachusetts General Hospital
MMRM
Mixed effects model for repeated measurements
MRTpo
gMean of mean residence time after oral dosing
MRD
Multiple Rising Dose
nM
Nanomole
NIMH
National Institute for Mental Health
NOAEL
No Observed Adverse Effect Level
OAD
Ongoing Antidepressants
OAT
Organic Anion Transporter
OPU
Operative Unit
PCR
Polymerase chain reaction
P-gp
P-Glykoprotein
PK
Pharmacokinetics
PoC
Proof of concept
PRO
Patient Reported Outcomes


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PSS
panic symptoms
PV
Pharmacovigilance
QD
quaque die (once a day)
QM
Qualification Methodology
QTcF
Corrected QT interval by Fredericia
RA
Regulatory Authority
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
SAE
Serious Adverse Event
SC
Steering Committee
SCID-5
Structured Clinical Interview for DSM-5 Clinical Trials
SCR
Screening
SD
Standard deviation
SE
Standard Errors
SIB
Suicidal Ideation and Behavior
SMDDS
Symptoms of Major Depressive Disorder Scale
SmPC
Summary of Product Characteristics
SNRI
Serotonin Norepinephrine Reuptake Inhibitor
SNDRI
Selective Norepinephrine Dopamine Reuptake Inhibitor
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SSRI
Selective Serotonin Reuptake Inhibitor
STAI
State-Trait Anxiety Inventory 
STAR*D
Sequenced-Treatment-Alternatives to Relieve Depression
SUSAR
Suspected Unexpected Serious Adverse Reactions
t.i.d.
ter in die (3 times a day)
t1/2
Half Life Time
tmax
Timepoint of Maximum Plasma Concentration
TS
Treated Set
TSAP
Trial statistical analysis plan


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UGT
UDP-Glucuronosyltransferase
ULN
Upper Level of Normal
VAS
Visual Analogue Scale
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


























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Other risks

Hypersensitivity and 
allergic reactions
As with all drugs, the 
potential for 
hypersensitivity and 
allergic reactions has to be 
taken into consideration 
when BI 1358894 and 
quetiapine is administered.
First dose of BI 1358894 
administered on site, with 
safety clinic visit at Week 
1. Monitoring and 
management of symptoms 
and treatment as needed, 
including discontinuation of 
trial treatment as per 
investigators clinical 
judgment.




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2.
TRIAL OBJECTIVES AND ENDPOINTS
The main objectives of this trial are to provide proof of concept (PoC), assess dose-ranging 
data of BI 1358894 compared to placebo in participants with Major Depressive Disorder who 
show inadequate response to ongoing antidepressant treatment and to support the dose 
selection for pivotal studies.
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary trial objectives are to demonstrate a non-flat dose response curve, to evaluate the 
dose response relationship, and to assess the treatment effect size.
The trial will be performed to characterize the dose-response curve for BI 1358894 in 
participants with MDD by assessing 4 doses and placebo. The response is the change from 
baseline in MADRS total score at Week 6 summarized per arm by the adjusted mean. The 
multiple comparison procedure with modelling (MCPMod) approach will be used to 
characterize the dose-response curve.
The primary characterization will be on treatment which will assume all participants took 
randomized treatment for the duration of the trial.
Assessments of secondary and further efficacy and safety parameters will further support the 
selection of a dose (range).
2.1.2
Primary endpoint(s)

Change from baseline in MADRS total score at Week 6
2.1.3
Secondary endpoint(s)
MADRS

Response defined as ≥ 50% MADRS reduction from baseline at Week 6
STAI

Change from baseline in STAI State and Trait version scores at Week 6
CGI-S

Change from baseline in Clinical Global Impression Severity Scale (CGI-S) score at 
Week 6
SMDDS

Change from baseline in SMDDS total score at Week 6


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2.2.3
Safety
There are no safety end points defined for this trial; however, safety will be assessed 
descriptively in participants who received at least one dose of trial drug (e.g., AEs, SAEs, 
AESI, extrapyramidal AEs, C-SSRS, physical examination, vital signs ECG and laboratory 
tests).




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After the completion of the 6-week double-blind treatment period, or following early 
discontinuation of trial at any point, participants will complete the 4-week follow-up period at 
the end of study (EoStudy) visit. All (S)AEs, including those persisting after individual 
participant’s end of study must be followed up until they have resolved, have been assessed 
as “chronic” or “stable”, or no further information can be obtained. Individual participant
participation is concluded when the participant has completed their last planned visit (End of 
study visit) (refer to sections 3.3.4.1 and 3.3.4.2).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is a randomized double-blind, placebo-controlled, parallel-design trial with an additional 
quetiapine arm as reference. This design is appropriate for providing proof-of- concept/dose
range finding and assessing the safety and efficacy of BI 1358894 compared to placebo in 
participants with MDD. It is important to have a placebo control to address potential 
confounding factors. This is acceptable as participants will remain on their standard anti-
depressive treatment (including ongoing stable psychotherapy, where applicable) and the 
duration of the placebo treatment will be limited to 6 weeks.
As BI 1358894 is a First-in-Class compound with a new therapeutic concept and mode of 
action, inclusion of an approved medication arm for the targeted population (i.e. quetiapine) 
is planned in this trial for reference. Descriptive comparisons between the quetiapine and 
placebo arms will be conducted to monitor the impact of placebo response in this trial. No 
formal hypothesis testing will be performed to compare BI 1358894 to quetiapine or to 
compare quetiapine to placebo.
The design of the trial will provide efficacy, safety and dosing information to support proof 
of concept. In order to achieve both aims in an efficient way the generalized MCPMod 
approach has been implemented as the statistical design. This approach is widely accepted 
[R15-1961], [R19-1647] and is able to incorporate potential relationships between the 
different doses into the evaluations via optimal test contrasts and uses the available data 
better than the commonly applied pairwise comparisons.
A total of four active BI-doses will be administered to provide reasonable coverage for most 
monotonic shapes. A sufficiently broad set of candidate shapes for the dose-response 
relationship has also been chosen. In addition, an unequal allocation ratio (3.5:1:1:1:2) has 
been selected for the treatment and placebo groups. In general, an allocation of a higher 
proportion of participants to the placebo and active dose of interest versus other treatment 
arms will lead to better precision which then leads to a higher power. In addition, increasing 
the proportion of participants in the placebo group compared to other treatment arms may 
lead to the observation of a greater separation between the placebo and active treatment 
arms [P09-01434]. Details of the statistical approach including the set of candidate models as 
well as a sample size justification are given in section 7.5.
Data at Week 6 will provide evidence of efficacy and dosing information of BI 1358894 
compared to placebo. In addition, we will also obtain safety data through the end of 
observation period (early drug discontinuation date / eEOT+28+2 days). 
 




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Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Established diagnosis of Major Depressive Disorder (MDD), single episode or recurrent, 
as confirmed at the time of screening by the Structured Clinical Interview for DSM-5 
(SCID-5), with a duration of current depressive episode ≥ 8 weeks and ≤ 24 months at the 
time of screening visit.
2. Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 24 at screening, as 
confirmed by a trained site based rater AND interactive, computer administered MADRS.
The difference in the rater and computer administered MADRS must not exceed more 
than 7 points (for details refer to section 6.2). In addition, trial participants must have a 
score of ≥ 3 on the Reported Sadness Item on both MADRS scales (computer-
administered and rater-administered MADRS).
3. A documented ongoing monotherapy treatment of ≥ 4 weeks at the screening visit, with 
bupropion or a protocol specified SSRI or SNRI (refer to the ISF) at adequate dose (at 
least minimum effective dose as per prescribing information and as confirmed per 
detectable drug levels in the screening blood or urine sampling).
4. Male and female participants, 18 to 65 years of age, both inclusively at the time of 
consent.
5. Women who are of child-bearing potential (WOCBP) 1 must be able and willing, as 
confirmed by the investigator, to use two methods of contraception which include one 
highly effective method of birth control per ICH M3 (R2) that result in a low failure rate
of less than 1%, plus one additional barrier (refer to section 4.2.2.3).
6. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
7. Able to communicate well, and to understand and comply with trial requirements.
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 occlusion/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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3.3.3
Exclusion criteria
1. Per DSM-5, had ever met diagnostic criteria for schizophrenia, schizoaffective disorder, 
schizophreniform disorder, bipolar disorder, delusional disorder or MDD with psychotic 
features as assessed by the SCID-5 at the time of screening.
2. Diagnosis of any other mental disorder (in addition to those as described in Exclusion 
Criterion #1) that was the primary focus of treatment within 6 months prior to screening 
or at baseline (as per clinical discretion of the investigator).
3. Diagnosis with antisocial, paranoid, schizoid or schizotypal personality disorder as per 
DSM-5 criteria, at the time of screening visit. Any other personality disorder at screening 
visit that significantly affects current psychiatric status and likely to impact trial 
participation, as per the judgement of investigator.
4. Diagnosis of a substance related disorder within 3 months prior to screening visit (with 
exception of caffeine and tobacco).
5. History of seizure disorders, stroke, brain tumor or any other major neurological illness 
that can impact participation in the trial.
6. History of more than 2 unsuccessful monotherapy treatments (at adequate dosage and 
duration, per local prescribing information of the product) with an approved 
antidepressant medication for the current ongoing major depressive episode. These 
include ongoing monotherapy treatment with bupropion or a protocol specified SSRI or 
SNRI as described in Inclusion Criterion #3.
7. Any suicidal behavior in the past 12 months prior to screening (per investigator 
judgement including an actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behaviour).
8. Any suicidal ideation of type 4 or 5 in the Columbia Suicide Severity Rating Scale (C-
SSRS) in the past 3 months prior to screening or at screening or baseline visit (i.e. active 
suicidal thought with method and intent but without specific plan, or active suicidal 
thought with method, intent and plan).
9. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix.
10. Known history of HIV infection and/or a positive result for ongoing Hepatitis B or C 
infection.
11. Have initiated psychotherapy or other non-drug therapies (e.g., acupuncture or hypnosis) 
within 3 months prior to screening or planning to start any time during the trial. The 
participant should not have a change in type, intensity and/or frequency of psychotherapy 
within the last 8 weeks prior to screening and it is not anticipated to change during the 
entire course of trial.
12. Any use of restricted medications within 7 days prior to randomization and during the 
entire course of the trial (refer to section 4.2.2).


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Please note:

Investigators may use their clinical discretion to wash out (at least 3 half-lives of 
referenced medication) the restricted medications during the screening period. The 
participant must adhere to the screening visit dose of the background 
SSRI/SNRI/bupropion until the end of the trial or end of treatment (eEOT/EOT), 
respectively.

Participants, who, in addition to their monotherapy with an SSRI/SNRI/bupropion, are 
taking additional low dose antidepressant medications for purposes other than treating 
depressive symptoms, are not excluded. The dose must be less than the lowest dose 
indicated for MDD (see ISF for details). 

Participants who are on stable treatment with ongoing benzodiazepines and/or non-
benzodiazepine hypnotics (refer to the ISF) for insomnia or anxiety for at least 28 days 
prior to screening should continue without change for the entire trial duration. For 
participants who are not on current treatment of insomnia and anxiety symptoms at the 
time of screening, the protocol will allow short term treatment of these symptoms during 
the course of trial (see section 4.2.2.1 and ISF for details on allowed medications and 
permitted dosages).
13. Participants who must or wish to continue the intake of restricted medications (refer to 
ISF) or any drug considered likely to interfere with the safe conduct of the trial.
14. Use of alternative medicine (e.g. Chinese traditional medicine, herbal medication, St. 
John’s wort, etc.) during the entire course of the trial.
15. Have initiated or discontinued hormone treatment (including hormone replacement 
therapy) within the 3 months prior to screening (however use of hormonal contraceptives 
is allowed).
16. Known hypersensitivity to any of the excipients of BI 1358894 or quetiapine or the 
matching placebos, respectively.
17. Use of any investigational procedure within 30 days prior to randomization. In case of 
exposure to an investigational medicinal product, investigator must ensure that it is 
adequately washed out prior to randomization (at least 5 half-lives of the investigational 
medicinal product).
18. Positive drug screen at the screening visit. (In case of positive drug screen for 
benzodiazepines or cannabis, investigator to confirm that there is no active substance 
related disorder).
19. Have received electroconvulsive therapy and/or administration of Ketamine /S-Ketamine 
for the current ongoing depressive episode and/or transcranial magnetic stimulation 
(TMS) for the current ongoing depressive episode or within 12 months prior to screening.
20. Have a lifetime history of vagal nerve stimulation or psychosurgery.
21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
22. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening.
23. Participants not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled.
24. Considered by the investigator, for any other reason, to be an unsuitable candidate for the 
trial.


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25. Participants who were confined to an institution by court or administrative order.
26. Participants who are dependent on the Sponsor, the investigator or the trial site.
3.3.4
Withdrawal of participants from treatment or assessments
Every effort should be made to keep the participants in the trial: if possible on treatment, or at 
least to collect important trial data. Measures to control the withdrawal rate include careful 
participant selection, appropriate explanation of the trial requirements and procedures prior to 
trial enrolment, as well as the explanation of the options for early discontinuation in case of 
withdrawals (see section 6.2.2).
Participants may discontinue trial treatment or withdraw consent to trial participation as a 
whole (“withdrawal of consent”) with very different implications; please see sections below.
If a participant discontinues trial treatment prior to the completion of protocol-specified end 
of treatment (EOT) visit, every effort should be made by the site staff to encourage 
participants to remain in the trial if medically safe. Participants who discontinue trial drug 
prematurely should ideally be observed until the end of the trial (week 10) as if they were still 
receiving blinded trial treatment. Participants should complete the early End of Treatment
(eEOT) procedures as described in the Flow Charts and Section 6.2.2. If a participant refuses 
to return for all further visits after early treatment discontinuation, the participant should be 
encouraged to complete at least the week 6 visit as scheduled and a FUP visit 28+2 days after 
date of trial drug discontinuation. If FUP visit (early drug discontinuation + 28+2 days) can 
be completed prior to the date of the planned Visit 8, no additional FUP is needed.  However, 
end of study participation must be completed.
Participants who refuse all of the above are considered to have fully withdrawn consent to 
participate in the trial. In this case, the participant does not need to justify the decision and 
should be withdrawn from the trial and all follow-up assessments.
Withdrawal from the trial of an individual participant may be considered also in case of 
administrative reasons, such as but not limited to multiple important protocol violations and
persistent non-compliance. No participant should be withdrawn from the trial before 
discussion with CTL.
3.3.4.1
Discontinuation of trial treatment
An individual participant will discontinue trial treatment if:

The participant wants to discontinue trial treatment, without the need to justify the 
decision.

The participant has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.

The participant needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment; refer to the ISF.

The participant undergoes an ECT or TMS.

Participant receives Ketamine /S-Ketamine treatment during the course of the trial.


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
The participant can no longer receive trial treatment for serious medical reasons (such as 
surgery, adverse events, other diseases, or pregnancy), per investigator’s clinical 
judgement. In case of a temporary reason, trial treatment should be restarted if medically 
justified.

Pregnancy occurs during the trial. (Once a participant has been enrolled in the clinical 
trial and has taken trial medication, the investigator must report any drug exposure during 
pregnancy which occurred in a female trial participant to the Sponsor immediately (within 
24 hours) by means of Part A of the Pregnancy Monitoring Form to the Sponsor’s unique 
entry point).

The participant must discontinue treatment with trial medication if: 
o
The participant develops suicidal ideation of type 4 or 5 in the C-SSRS (i.e., 
active suicidal thought with intent but without specific plan, active suicidal 
thought with plan and intent) or suicidal behaviour (i.e. actual attempt, interrupted 
attempt, aborted attempt or preparatory acts or behavior).
o
In the event of worsening of MDD which requires medical treatment which is on 
the list of restricted medications (refer to ISF), the trial drug has to be 
discontinued.
In addition to these criteria, the physician may discontinue treatment at any time based on his 
or her clinical judgment. For all participants 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.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
participants or take any other appropriate action to ensure the safety of the trial participants.
3.3.4.2
Withdrawal of consent to trial participation
Participants may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a participant wants to withdraw consent, the investigator should be 
involved in the discussion with the participant and explain the difference between trial 
treatment discontinuation and withdrawal of consent to trial participation, as well as explain 
the options for continued follow-up after trial treatment discontinuation, please see section
3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall, or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further follow up of participants affected will occur as described in section 3.3.4.1.


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The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).












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Participant assignment to the treatment groups will be determined by a computer-generated 
random sequence. Randomization sequence will be generated using validated randomisation 
software. Access to the randomization code will be controlled and documented.
Randomization into each treatment groups will be stratified by baseline MDD severity 
(baseline MADRS score ≤19 versus >19).
The kit(s) corresponding to the assigned medication number(s) should be given to the 
participant and entered in the eCRF. Using this procedure, relevant parties will be blinded to 
the treatment group assignment.
4.1.4
Drug assignment and administration of doses for each participant
The medication assignment will be provided through IRT. The assigned medication 
number(s) must be entered in the eCRF, and the corresponding medication kit(s) must be 
given to the participant. The duration of treatment is 6 weeks. The last dose of trial 
medication should be taken on the day before the EOT Visit.
At Visit 2, after randomization, participants will receive medication kits for the double-blind 
treatment period. The morning dose of trial medication will be taken at the trial site under 
supervision of the investigator or site staff. Participants will bring trial medication 
(used/unused blister and covering packages) to site visits for compliance check 
(V3/V4/V6/V8). At visits V2, V4 and V6, participants will return used/unused medication 
kits and receive new supplies for a total of 14 treatment days (14 treatment days plus 3 days 
reserve) for BI 1358894 and quetiapine.
Participants should be instructed not to take their trial medication in the morning of Visit 4 
and Visit 6, as participants will be dosed at the site 
. Participants 
should also be instructed not to take their trial medication in the morning of 
Visit 8/EOT/eEOT Visit, as a 
 at that visit. For participants 
who complete the treatment period, the last dose of trial medication should be taken on the 
day before the EOT Visit. Participants who fail to do so should have the visit rescheduled as 
soon as possible, ideally on the following day.
Participants should be instructed to take the BI 1358894 tablets or matching placebos orally 
with water and in a consistent way, i.e., either with or without food every morning at 
approximately the same time. If a morning dose is missed by more than 12 hours, that dose 
should be skipped and the next dose should be taken as scheduled. On days prior to a visit, 
the morning dose should be taken approximately 24 hours before the planned morning dose at 
the clinic visit. A dose reduction of BI 1358894 is not possible.


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Table 4.1.4: 1
Dosage and Treatment Schedule for BI 1358894 / Matching Placebo
5mg tablet
25mg tablet
50mg tablet
PBO 
matching 
5mg tablet
PBO 
matching 
25mg tablet
PBO 
matching 
50mg tablet
Dose group
Number of tablets to be taken daily – in the morning ☼
PBO
0
0
0
1
1
2
5 mg
1
0
0
0
1
2
25 mg
0
1
0
1
0
2
75 mg
0
1
1
1
0
1
125 mg
0
1
2
1
0
0
Quetiapine or matching placebo should be taken prior to bedtime. The daily active dose at the 
start of therapy is 50 mg on Day 1, 100 mg at Day 2 and 150 mg on Day 3 and 4. Beginning 
with Day 5, the recommended daily dose of 300 mg will be taken. If an evening dose is 
missed before midnight, that dose should be skipped and the next dose should be taken the 
next evening. On days prior to a visit, the evening dose should be taken at least 8 hours 
before the planned dose at the visit.
Table 4.1.4: 2
Dosage and Treatment Schedule for Quetiapine / Matching Placebo 
Titration and Maintenance Phase
50 mg tablets or matching placebo 
150 mg tablets or matching placebo 
Trial Day
Number of tablets to be taken daily – in the evening 
Day 1
1
0
Day 2
2
0
Day 3
0
1
Day 4
0
1
Day 5 - 43
0
2
The need to decrease the dose from 300 to 150 mg/day should be based on individual 
participant evaluation. In this case, the PI will instruct the participant to only take one tablet 
of the evening dose instead of two. This dose reduction is a one-time option at Visit 3 after 
the first week of treatment.
During the COVID-19 pandemic, there might be situations that would not allow a participant
to come to the site for the study visit. If the investigator judges it as acceptable and safe to 
continue trial medication, trial medication might be shipped from the site to the participant
(for more details see section 6.1 and 10.4).




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Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
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 Clinical Research 
Associate CRA (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Participants should be instructed to 
return used (empty blisters) partially-used and unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each participant, 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 medicinal product and trial
participants. The investigator or designee will maintain records that document adequately that 
the participants were provided the doses specified by the Clinical Trial Protocol (CTP) and 
reconcile all investigational medicinal products received from the sponsor. At the time of 
return to the sponsor or appointed CRO, the investigator or designee must verify that all 
unused or partially used drug supplies have been returned by the clinical trial participant and 
that no remaining supplies are in the investigator’s possession.




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duration of treatment is needed, further re-evaluation is required by investigator for every 
7 days per treatment cycle (and possibly more cycles if needed). Refer to ISF for dose 
equivalence information and comprehensive list of allowed concomitant medications.

In case of AEs, any treatment deemed necessary per the clinical judgment of investigator 
for the management of AEs considering participant safety is allowed.
For further guidance investigators are referred to the actual Investigator´s Brochure or may 
contact the sponsor.
4.2.2.2
Restrictions on diet and life style
In general, participants should keep their usual habits throughout the trial for diet and 
exercise, as well as nicotine, alcohol and caffeine intake. It should be within acceptable daily 
amounts in discretion of the investigator and not be drastically changed throughout the trial
conduct.
Note the following restrictions:

Use of traditional medicine (e.g. Chinese traditional medicine, herbal medication, St. 
John’s wort, etc.) during treatment period.

Participants should not abuse alcohol or use drugs of abuse during the trial. A urine drug 
screen will be performed at selected trial visits (see Flow Chart 1). For a list of drugs 
assessed by the urine drug screen please refer to table 5.3.3: 1.

Participants should not enter or modify a smoking-cessation program during the conduct 
of the trial.

It is recommended that participants should exercise caution when driving or operating 
machinery until they are reasonably certain that the study medication does not adversely 
affect their ability to engage in such activities.
Participants do not have to come fasted to any trial visit.
4.2.2.3
Contraception requirements
Women of childbearing potential (WOCBP - for the definition please refer to section 3.3.2)
must use two methods of contraception, which include one highly effective method of birth 
control per ICH M3 (R2) that result in a low failure rate of less than 1%, plus one additional 
barrier method. Contraception must be used during the treatment and follow-up period.
Women of childbearing potential must agree to periodic pregnancy testing during 
participation in the trial. If a urine pregnancy test is positive, a serum test needs to be 
performed for confirmation.
Counseling about the importance of having birth control measures in place will be performed 
at study entry visit (during consenting process), informing woman about the risk of 
medication-induced births defects when exposed to potentially teratogenic medication. 
Investigator must ensure that the patient understands the contraception requirements for the 
study and must confirm that the patient can reliably comply with contraception use during the 
study. Patients not expected to comply with contraception requirements should not be 
included in the study.


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The importance of continuing with their chosen forms of birth control during study conduct 
will be emphasized to mitigate this risk and it must be reiterated at all visits as per Flow Chart
(including phone visits).This must include confirmation from the patient that she is using 
required contraception consistently and appropriately. Counseling and contraception 
confirmation must be recorded in CRFs. If contraceptive protection can not be confirmed, as 
deemed by the investigator, the patient must be discontinued from study drug and can only 
resume once contraception is used again and sufficient protection is reached.
Acceptable forms of contraception are:
One of the highly effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1%:

Use of hormonal methods of contraception associated with inhibition of ovulation
o
a. combined (estrogen and progestogen containing) hormonal contraception:

oral

intravaginal

transdermal
o
b. progestogen-only hormonal contraception:

oral

injectable

Implantable

Placement of intrauterine device (IUD) or intrauterine hormone releasing system (IUS).

Bilateral tubal occlusion or ligation.

Vasectomy (with appropriate post-vasectomy documentation of the absence of sperm in 
the ejaculate and provided that male partner is the sole sexual partner of the WOCBP trial 
participant).

Complete sexual abstinence when this is in line with the preferred and usual lifestyle of 
the patient (note: periodic abstinence such as calendar, ovulation, symptothermal, post-
ovulation methods and withdrawal are not acceptable methods of contraception) - in this 
specific case the barrier methods as mentioned below are not applicable. Sexual 
abstinence as a contraceptive method will not be allowed for WOCBP who are 
heterosexually active.
plus one of the barrier methods:

Male or female condom with or without spermicide.

Cap, diaphragm or sponge with spermicide.
4.3
TREATMENT COMPLIANCE
Participants are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on non-missing tablet counts, treatment compliance for the morning and separately for 
the evening dose between following clinic visits will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the sponsor.












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5.3.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in table 5.3.3:1. For the sampling time 
points please see the Flow Chart 1.
Analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the lab manual, except in cases where the ESR will be done locally in which case 
the ESR results must be recorded in the CRF.
Confirmation of detectable levels of background SSRI/SNRI/bupropion, either shown in 
urine or serum (as applicable), will be accepted for eligibility. The test in serum is mandatory 
and must be performed at screening and EOT. If a negative result in serum is received prior 
to randomization, then the patient will be a screen failure. Please also note, that Duloxetine 
cannot be measured in urine but in serum, only.
Participants 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.
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 adverse events (please refer to section 5.3.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see section 5.3.6.1 and the DILI Checklist provided in the ISF and 
electronic data capturing (eDC) system). The amount of blood taken from the participant
concerned will be increased due to this additional sampling.
Capturing the results of various drug screens (e.g., Cannabis, Benzodiazepine, Barbiturates, 
Opiates, Cocaine, Amphetamines, Methadone, PCP) in the clinical database is planned to 
permit examination the use in this study population, impact of use on the recruitment failure 
rate, frequency of benzodiazepine use as sleeping aids and the impact of occasional use of 
Canabis in light of the planning of Phase III of this development.
The central laboratory will transfer the results of the analysis to the sponsor.


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Table 5.3.3:1 
Safety laboratory tests
Category
Test name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)
Red Blood Cell Count/ Erythrocytes
Erythrocyte sedimentation rate (ESR)
(either assessed centrally or locally)*
Reticulocyte Count
White Blood Cells / Leucocytes
Platelet Count/ Thrombocytes
MCV, MCH, RDW, MCHC
Diff. Automatic
Neutrophils (relative and absolute count)
Eosinophils (relative and absolute count)
Basophils (relative and absolute count)
Monocytes (relative and absolute count)
Lymphocytes (relative and absolute count)
Diff. Manual (if Diff Automatic is 
abnormal)
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
Chemistry
Albumin
AST(GOT)
ALT(GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Lipase
Chemistry Amylase
Calcium
Sodium
Urea (BUN)
Potassium
Glucose
Creatinine
Bilirubin Total, fractionated if increased


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Category
Test name
Chemistry (continued)
Protein, Total
C-Reactive Protein
Cholesterol, total
Triglycerides
TSH (Reflex testing for fT3 and fT4 if TSH > ULN)
Testosteron3
LH3
FSH3
Folate
eGFR using the CKD-EPI equation
SSRI/SNRI/bupropion detectable drug 
levels in serum1 or urine4 (as applicable)
Bupropion
Duloxetine1
Citalopram / Escitalopram
Paroxetine
Sertraline and Desmethylsertraline
Fluoxetine and Norfluoxetine
Venlafaxine and Desmethylvenlafaxine
Desvenlafaxine
Urine (dipstick) Pregnancy test (only for 
female participants of childbearing potential 
- test done at all clinic visits beginning with 
Visit 2)
Human Chorionic Gonadotropin in the urine
Serum Pregnancy test (only for female 
participants of childbearing potential) at 
screening or if urine pregnancy test is 
positive) 
Human Serum Chorionic Gonadotropin 
Urinalysis (dipstick), with microscopic 
examination if urine analysis is abnormal
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Blood
Leukocyte Esterase
Urine pH
Urinalysis
Albumin (quantitative)
Creatinine


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Category
Test name
Drug screening (urine)2
Cannabis
Benzodiazepine
Barbiturates
Opiates
Cocaine
Amphetamines
Methadone
PCP
Infections screening2
Hepatitis B Surface Antigen (qualitative) 
Hepatitis C Antibody (qualitative)
Hepatitis C Vaccine (HCV) RNA – only if 
Hepatitis C antibodies (qualitative) are 
positive
1 At screening and EOT only, duloxetine in serum only
2 At screening only
3 Males only
4 At screening only (as applicable)
* In this protocol, ESR testing is used solely for the collection of data for analysis purpose at the end of the trial, per FDA’s 
recommendation. The ESR Testing results are not intended to be used as Safety Parameter or for medical management 
decisions. For medical management decisions of Safety relevant inflammation parameter, the CRP test should be used.
For assessment of the kidney function, the formula of the estimated glomerular filtration rate 
(EGFR) CDK-EPI (Chronic Kidney Disease Epidemiology Collaboration) and EGFR CKD-
EPI –JAPAN, respectively, will be used. This requires that ethnicity need to be captured. See 
details in the ISF.
5.3.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart 1. Twelve-lead ECGs (I, 
II, III, aVR, aVL, aVF, V1 – V6) will be recorded using equipment provided by a central 
ECG vendor. The ECGs will be recorded for at least 10-second duration after the participants 
have rested for at least 5 minutes in a supine position and prior to lab sampling. Electrode 
placement will be performed according to the method of Einthoven/Goldberger (ankles and 
wrists). At all time points indicated in the Flow Chart, single ECGs will be recorded. ECG 
recordings at planned time points may be repeated for quality reasons like alternating current 
artefacts, muscle movements and electrode dislocation. In this case the repeated ECG 
recordings will be used if quality was better.
The investigator or a designee will evaluate whether the ECG is normal or abnormal and 
whether it is clinically significant, if abnormal. The electronic version of the ECG is regarded 
as source data. Dated and signed printouts will be stored in the participant’s medical file if 
there is no validated and certified e-medical record for ECG data.
Additional ECGs may be collected by the investigator for safety reasons. Clinically relevant 
findings noticed at baseline assessment (Visit 1) should be reported as baseline condition. 


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Clinically relevant abnormal findings noticed after baseline assessment will be reported as 
AEs and followed up and/or treated locally until normal or stable condition.
All ECGs will be transmitted electronically to the central ECG vendor in order to enable a 
centralized and independent re-evaluation of all 12-lead ECGs. A centralized and 
independent re-evaluation will be done. Abnormalities detected during this centralized ECG 
evaluation will not necessarily qualify as AE.
Central evaluation on individual ECG level will be performed by the vendor and a report will 
be provided to the site. Decisions on eligibility for the trial and treatment or further follow-up 
of any findings are in the responsibility of the investigator.
5.3.5
Other safety parameters
5.3.5.1
Assessment of Suicidality
Suicidal risk assessed by the C-SSRS (clinician interview version equivalent to the paper-
version, shall be administered electronically via a tablet/rater station):
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsellor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on participants. 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. Freetext 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 first at screening (Visit 1) (using the ‘Baseline / Screening’ version) with the 
aim to exclude participants with active moderate or severe symptomatology within a 
specified time prior to screening. The lifetime history of suicidal ideation and behavior will 
also be recorded.
After screening (Visit 1) the assessment ‘since last visit’ will be performed at each clinic visit 
(‘Since Last Visit version’). The investigator is to review/consider the C-SSRS results for 
plausibility and clinical relevance. Doubtful reports may be repeated or reports may be 
validated by a consulting psychiatrist. If there is a confirmed positive report of suicidal 
behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to immediately 
interview the participant during the clinic visit (if the investigator did not administer the C-
SSRS leading to the positive report), and/ or is to consult a psychiatrist if considered 
necessary. If the positive report is confirmed, appropriate actions for the participant’s safety 
have to be initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.


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For each report of 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. Please note, that adverse event 
reports, that get coded to terms like suicidal depression, suicidal ideation, suicidal threat or
similar, are on the “Always serious AE List” and therefore must be reported as SAEs (refer to 
section 5.3.6.1.3).
For ‘Self-injurious behaviour, no suicidal intent’ standard AE / SAE reporting rules are to be 
applied.
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of AEs 
5.3.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
Regarding AEs in the context of suicidal risk assessment by C-SSRS, section 5.3.5.1 should be 
adhered.
5.3.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfills at least one of the 
following criteria:

results in death,

is life-threatening, which refers to an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if more severe,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly / birth defect,


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
is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the participant 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.
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
5.3.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in section 5.3.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.3.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
Suicidal ideation terms are also part of the Always Serious AE list.
5.3.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.3.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold 
ULN measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN.


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
These lab findings constitute a hepatic injury alert and the participants 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 other AESIs have been defined for this trial.
5.3.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.3.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given trial treatment, 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 reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 


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drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.3.6.2
Adverse event collection and reporting
5.3.6.2.1
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 participant’s end of study
(the End of study (EoStudy) visit): 
all AEs (serious and non-serious) and all AESIs.

After the individual participant’s end of study: 
the investigator does not need to actively monitor the participant for new AEs but should 
only report any occurrence of cancer and trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form (see 
section 5.3.6.2.2), but not on the CRF.
5.3.6.2.2
AE reporting to the 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 immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process 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 send 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. All (S)AEs, including those persisting after individual participant’s end of study
must be followed up until they have resolved, have been assessed as “chronic” or “stable”, or 
no further information can be obtained.


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5.3.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a participant 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 written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for 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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (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 Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.










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5.8
APPROPRIATENESS OF MEASUREMENTS
The measurements performed during this trial are standard measurements in MDD treatment 
trials and will be performed in order to monitor safety aspects or assess treatment response in 
an appropriate way. Therefore, the appropriateness of all measurements applied in this trial is 
given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All participants have to adhere to the visit schedule as specified in the Flow Chart 1 and Flow 
Chart 2. Each visit date (with its window) is to be counted from Day 1. If any visit has to be 
rescheduled, subsequent visits should follow the original visit date schedule. Additional visits 
for the purpose of re-testing of laboratory parameters or AE monitoring may be included as 
deemed necessary by the investigator.
During the COVID-19 pandemic, there might be situations when participants might not be 
able to come to the site for the scheduled visit. This might be e.g. due to restrictions set by 
authorities or by the investigator site/institution, because the participant is quarantined, or 
because of any participant-specific situation that the investigator judges as being not safe for 
the participant to come to the site.
For details on potential modifications of the trial conduct related to the COVID-19 pandemic, 
please refer to section 10.4.
For detailed description of the trial procedures, please refer to the Flow Charts.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Trial procedures to be performed at each visit are listed in the Flow Charts. Additional details 
regarding visit procedures are provided below.
The following requirements for the conduct of the neuropsychological assessments need to be 
followed:

The site staff must be properly trained on all trial procedures and training documentation 
filed in the ISF.

Qualification, training, remediation (if needed) and central reading of the scales will be 
provided by a specialized vendor. The training standards and standards for the conduct of 
the assessments will be defined for each assessment individually and can be found in the 
ISF; it is the responsibility of the Principal Investigator at the site to ensure that all 
members of the site staff involved in the neuropsychological assessments undergo 
qualification and training by the vendor.

At the screening visit, all clinical assessments (Flowchart 1) should be performed first, 
followed by the clinical outcome measurements (scale assessments - Flow Chart 2). After 
the screening visit, the scales should be performed first (Flow Chart 2), followed by the 
other clinical examinations (Flow Chart 1). All scales should be completed in the order as 
noted in the Flow Chart 2, top to down.
Each assessment of the site-rater administered scales (MADRS, CGI-S) should preferentially 
be done by the same members of the site staff for a given participant throughout the trial
period. However, the rater who performs the C-SSRS and/or AEs should not also perform the 
MADRS and CGI-S for the same patient to prevent bias.

Results of the MADRS assessments at screening are part of the eligibility evaluation 
(see below).










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Phone visits
Visits V5 (week 3) and V7 (week 5) will be conducted via phone.


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Visit 8 / End of Treatment (EOT) Visit
Visit EOT (at treatment Week 6) represents the regular end of the treatment period. Last trial
drug administration should occur one day before the Visit EOT. The overall duration of the 
anticipated treatment period (1st drug administration to the last drug administration (1 day 
prior to EOT Visit) should be 42 days. Visit 8 will be performed only for participants that had 
early treatment discontinuation.
Participants prematurely discontinuing trial drug
Participants who discontinue trial drug prematurely should ideally be observed until trial end 
as if they were still receiving blinded trial treatment. If this is not possible, then participants 
should be encouraged to come back to the site and complete week 6 visit procedures, with the 
performance of the MADRS scale as a minimum requirement. See section Flow Charts and 
3.3.4. for further options.
Withdrawal of consent
If a participant is not willing to continue in the trial until to the end of the trial, Visit 8 should 
be scheduled and completed instead of the next scheduled visit as soon as possible. Also the 
EoStudy visit should be performed to assess and monitor safety. If the participant refuses to 
participate at an EOT Visit and withdraws consent for any reason (without the need to justify 
the decision), the trial completion page of the eCRF has to be filled in. All unused trial 
medication will be collected and trial drug diary will be checked by the site. If participant
discontinues prematurely for safety reasons or withdraws consent, trial medication
administration and 
 will not be performed at EOT Visit (please refer to section 
3.3.4.1).
It is important to distinguish between premature trial drug discontinuation, i.e. early 
discontinuation, and complete withdrawal of consent to participate in further trial procedures.
6.2.2
Follow-up period and trial completion
For all participants who had at least one dose of trial medication, the follow-up visits will be 
performed as described in section 3.3.4.
If the last day of trial drug intake is different from the day prior to the EOT visit, the date of 
the last day of trial drug intake will be used for calculation of the FUP visit dates.
Participants who finish the randomized treatment period according to the protocol, will return 
to the clinic for the end of study (EoStudy) Visit 9. Trial completion is defined as participants 
having reached the FUP visit within the specified window per the Flow Chart 1. The trial
completion page in the eCRF has to be entered.
For all randomized participants, termination of trial medication and trial completion must be 
recorded on the corresponding eCRFs.
Should it be not possible for the participant to attend a follow up visit at the trial site, a visit 
out of time window should be performed as soon as possible; if a visit at the site is not 
possible at all, at least a phone contact should occur at the scheduled follow-up visit time 
point.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The primary trial objective of this Phase II trial includes demonstration of proof of concept of 
the clinical activity of BI 1358894 with respect to a non-flat dose response curve, 
characterization of the dose-response relationship within the therapeutic range, and selection 
of the dose range for phase III development. For this purpose, the primary analysis uses 
methodology for dose finding employing both multiple comparison procedures and modelling 
techniques (MCPMod) to analyse 4 doses of BI 1358894 and placebo [R10-1424]. In 
addition, the benefit of BI 1358894 compared to placebo will be evaluated.
As a basis for the MCPMod analysis, a mixed model for repeated measure (MMRM) analysis 
will be used to generate covariate adjusted estimates of mean change from baseline to Week 
6 in MADRS total score and associated covariance matrices. These estimates will be used as 
the basis for the PoC analysis using MCPMod. If PoC is established, dose response models 
will be evaluated to select suitable doses for confirmatory testing in future studies.
7.1
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis is that there is a flat dose response curve comparing placebo and the BI 
1358894 dose groups. The alternative hypothesis is that there is a non-flat dose response 
curve indicating a benefit of BI 1358894 over placebo.
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, while protecting the overall false positive rate (probability of Type I error) 
using a one-sided, nominal α level of 10%. The pre-specified models and their parameters 
used for this test are outlined in section 7.2.2.


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7.2
PLANNED ANALYSES
7.2.1
General considerations
All data will be listed and summarized by treatment group using appropriate methods. For 
continuous data, the number of observations, mean, standard deviation (SD), minimum, 
median and maximum will be provided. The frequency and proportion of participants in each 
category will be presented for categorical data.
Analysis sets defined for this trial include the full analysis set (FAS) and the treated set (TS). 
The FAS comprises all randomized participants who received at least one dose of trial 
medication during the trial and had a baseline observation recorded. Unless otherwise 
specified, efficacy analyses will be performed on the FAS and will be based on assigned 
treatment. Full specifications for the FAS will be provided in the TSAP.
Safety analyses will be conducted on the TS, which includes all randomized participants who 
have received at least one dose of the trial medication. Safety analyses will be conducted 
using actual treatment received. Data from participants who were screened but not 
randomized will be listed but not included in any summaries or inferential statistics.
Important protocol deviations (iPDs) will be collected throughout the trial conduct and will 
be summarized in the CTR as defined in the iPD specification document.
7.2.2
Primary endpoint analyses
7.2.2.1
Primary analysis of the primary endpoint
As defined in section 2.1.2, the primary endpoint is the change from baseline to Week 6 in 
MADRS total score. Baseline MADRS total score is the last non-missing value recorded 
prior to first dose of trial medication and is typically recorded at Visit 2. If data from Visit 2 
are missing, the value recorded at Visit 1 will be considered the baseline value. The 
investigator-reported MADRS total scores will be used for the primary analysis.
The primary estimand of interest is the treatment effect assuming all participants remained 
adherent to the assigned trial medication and the trial protocol using a hypothetical approach, 
i.e. trial drug is taken as directed. The primary analysis of the primary endpoint will include 
all data collected while on treatment, which is defined as the time from the date of the first 
dose of trial medication until the date of the last dose of trial medication plus 7 days (3 times 
the estimated elimination half-life). Any data collected after a participant discontinues trial
drug, regardless of reason, will be censored and will not be included in the primary analysis. 
Data from participants assigned to the quetiapine arm will not be included in the primary 
analysis.
MCPMod is used to evaluate several possible dose response models (patterns) and to identify 
the best-fitting model or subset of models based on the BI 1358894 and placebo treatment 
groups. To account for the longitudinal nature of the data and covariates of interest, a 
restricted maximum likelihood (REML) based MMRM analysis will be carried out to obtain 
covariate adjusted estimates of the mean change from baseline to Week 6 in MADRS total 
score for each treatment group with an associated covariance matrix. The analysis model will 


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include discrete fixed effects for treatment at each visit, baseline MADRS severity level, 
concomitant psychotherapy use and the continuous effects of baseline MADRS total score at 
each visit. Additional covariates identified prior to database lock may be included in the 
MMRM model as applicable. Visit will be treated as a repeated measure with an unstructured 
covariance matrix used to model within-participant error.
The primary treatment comparisons will be the contrasts between each BI 1358894 treatment 
arm and placebo at Week 6. Procedures to be followed if the planned analysis fails to 
converge will be described in the TSAP. Resulting adjusted estimates from the MMRM will 
then be extracted for use in the MCPMod analysis.
For the PoC testing and for the sample size calculations, the basic shape of each of the 
models to be tested must be predefined. The following candidate models were selected based 
on healthy volunteer data to cover a plausible and diverse range of dose response patterns for 
the trial medication. Associated graphs of each model are shown in Figure 7.2.2.1: 1.

Emax1:
50% of the maximum effect is achieved at 25 mg; corresponding to the 
assumed true ED50 = 25 mg.

Emax2:
70% of the maximum effect is achieved at 5 mg; corresponding to a 
drug effect achieved mainly with low doses, ED50 = 2.14 mg.

Sigmax:
50% of the maximum effect is achieved at 25 mg, and

90% of the maximum effect is achieved at 75 mg; corresponding to a 
more flexible model of the assumed true ED50 = 25 mg.

Exponential:
5% of the maximum effect is achieved at 25 mg; corresponding to a
drug effect achieved mainly at higher doses.

Linear:
No parameter assumptions required. Corresponding dose response is
linear.






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7.2.3.4
SMDDS
Descriptive statistics will be presented for the responses to the SMDDS individual domains 
responses and total score. As described in section 7.2.2.1 for the primary efficacy analysis, an 
MMRM model will be used to compare change in SMDDS total score from baseline to Week 
6 between each of the BI 1358894 treatment arms and placebo.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 28 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.










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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014, the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997) and other relevant regulations.
Investigators and site staff must adhere to these principles. Deviation from the protocol, the 
principles of ICH GCP or applicable regulations as will be treated as protocol deviation.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the participant.
The investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial participants against any immediate hazard, as well as of any serious breaches 
of the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the Sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the participants, 
and is stored in the ISF.
The certificate of insurance cover is made available to the investigator and the participants, 
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 participant participation in the trial, written informed consent must be obtained from 
each participant 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 participant.
The investigator or delegate must give a full explanation to trial participants based on the
patient information form. A language understandable to the participant should be chosen, 
technical terms and expressions avoided, if possible.


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The participant must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the participant’s own free will with the 
informed consent form after confirming that the participant understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
If study conduct needs to be adjusted (see sections 4.1.4, 6.1 and 10.4) during the COVID-19 
pandemic, participants must be made aware of any modifications and their consent needs to 
be obtained prior to implementation.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial participant protection and reliability of the results as 
well as identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
In order to achieve a high level of standardized processes, data collection of efficacy 
endpoints is coordinated centrally: 
has been selected as service provider to 
support tasks related to the neuropsychological assessments. A detailed description of 
services can be found in the vendor contract. The services of 
include:

Necessary Rater prequalification

Site Rater training for neuropsychological assessments used as primary and secondary 
endpoints (online and at investigator meeting)

Provision of Rater materials

Central Quality Review of SCID-5 and the MADRS; for that purpose, the SCID-5 and the 
rater administered MADRS will be audio recorded


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Details of rater prequalifications, Rater Training, Rater Materials (including assessments) and 
of the Central review procedures will be available in separate documents Qualification 
Methodology document and Data Analysis Methodology filed in the ISF.
8.3
RECORDS
CRFs for individual participants 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 participant. Source data as well as 
reported data should follow the “ALCOA principles” and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Electronic records, i.e. clinician administered assessment data, related audio recordings (for 
central review) and patient reported outcome data entered into the tablet computer (Rater 
Station) will be regarded as source data. These may be further analysed by the delegated third 
party vendor.
The electronic version of the ECG is regarded as source data. Dated and signed printouts will 
be stored in the participant’s medical file.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the participant 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 should make up to three documented 
attempt to retrieve previous medical records. If this fails, a verbal history from the 
participant, documented in their medical records, would be acceptable.
If the participant is not compliant with the protocol, any corrective action e.g. re-training 
must be documented in the participant file.
For the CRF, data must be derived from source documents, for example:

Participant identification: gender, year of birth (in accordance with local laws and 
regulations)

Participant participation in the trial (substance, trial number, participant number, date 
participant was informed)

Dates of participant’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))


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
Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Patient reported outcome forms and investigator assessment forms, if done on paper

Completion of participant’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a participant to a treatment into a clinical trial, there must be
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the participant or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the participant eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the 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.
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.
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 PARTICIPANT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of participant data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual participant data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the participant’s personal physician or to other 
appropriate medical personnel responsible for the participant’s welfare. Data generated at the 
site as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.


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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, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first participant in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last participant in the whole 
trial (“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
participant in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request. The IEC / competent authority in each participating EU member state will be notified 
about the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all participants 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 participant
(EU or non-EU).


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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
Relevant documentation on the participating (Principal) Investigators and sub-investigators 
(e.g. their curricula vitae) will be filed in the ISF. The investigators will have access to the BI 
clinical trial portal 
 to facilitate document exchange and maintain electronic ISF.
BI has appointed a Clinical Trial Leader (CT 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 Managers), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or delegated to a Contract Research Organisation (CRO) with 
which the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the clinical trial.
If applicable, in addition to the Protocol, approved and effective local protocol amendment(s) 
should be followed by investigators.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A DMC will be established. Members of the DMC are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician.
The main focus of the DMC will be the evaluation of safety data. Efficacy data may be 
reviewed if requested by the DMC to support the risk/benefit assessment. The DMC will 
receive urgent significant safety concerns including severe infections, suicidality reports and 
DILI, for immediate evaluation. While DMC members may be unblinded, measures are in 
place to ensure the blinding for everyone else involved in the trial conduct. Regular DMC 
meetings will be held at specified intervals. The DMC will recommend continuation, 
modification or termination of the trial as detailed in the DMC charter. DMC 
recommendations as well as the final BI decision will be reported to the appropriate 
Regulatory Authorities (RAs)/Health Authorities (HAs), IRBs/ECs, and to investigators as 
requested by local law. The tasks and responsibilities of the DMC are specified in a charter.












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Safety lab, other laboratory tests
If taking blood samples for central lab is not possible, blood analysis for safety lab can be 
done in a local lab. The results of the lab tests are to be reported and transferred to the 
investigator, who has to ensure medical review and proper documentation. 
Safety lab parameters should at least include liver enzymes and Bilirubin, haematology 
including differential test, blood glucose, sodium, potassium, creatinine, urea (BUN) and 
eGFR. It is important that always the reference values of the local lab are also provided.
Dispensation of Trial medication (IMP)
If a participant is not able to come to visit 4 as planned and the investigator considers it 
acceptable and save for participant to continue with IMP, IMP can be shipped from site 
directly to the participant (if legally acceptable according to local regulations).
If home visits by trial staff members or e.g. “Home Healthcare Nurse” are possible, further 
assessments can be done like e.g. vital sings, blood draw for safety lab and biomarkers as 
well as collection of urine samples to be sent to central lab, or compliance check.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
05 Mar 2020
EudraCT number
EU number
2019-004264-21
BI Trial number
1402-0011
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 6-week, multicenter, randomized, 
double-blind, double-dummy, placebo-
controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, 
tolerability and safety of oral BI 1358894 in 
patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Global Amendment due to urgent safety 
reasons
No


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Global Amendment
1
Sections to be changed
Synopsis; 
Flow charts;
1.3;
1.4.2;
Table 1.4.2:1;
3.1; + 3.2;
3.3.2 - 3.3.4;
4.1.2.1;
4.1.4.;
4.1.5.1;
4.2.2.3;
4.3;
5.1;
5.2.2; + 5.2.3;
5.3.3;
Table 5.3.3:1;
5.4.2.;
5.7.1.2;
5.7.2;
6.2;
6.2.1; + 6.2.2;
7.5;
8.1; + 8.2;
8.3.1;
8.7;
9.2;
Description of change
See below
Rationale for change
Typos removed; Clarifications; Specifying 
details; Alignment with sister trials
Section to be changed
1.2. Drug Profile;
1.4.2 Risks;
Table 1.4.2:1;
4.2.2.1 Restrictions reg. concomitant 
treatment
4.2.2.2 Restrictions on diet and life style


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Description of change
Updated Data from IB included; 
Rationale for precautions for concomitant use 
of statins added.
Precaution measure for operating machinery 
and driving automobiles added.
Update on drug-drug interaction data
Rationale for change
Consistancy with IB update
Section to be changed
4.1.4 Drug assignment and administr. of 
doses
Description of change
Advice added to take IMP with or without 
food in a consistent way
Rationale for change
Following advice from PMDA
Section to be changed
Flowchart 2;
6.2 Details on Trial Procedures
Description of change
Participant Placebo Response Mitigation 
Video added
Rationale for change
To teach participants about the placebo effect 
in order to mitigate this effect during the trial 
performance


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11.2
GLOBAL AMENDMENT 2
Date of amendment
07 Jul 2020
EudraCT number/EU 
number
2019-004264-21
BI Trial number
1402-0011
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 6-week, multicenter, randomized, 
double-blind, double-dummy, placebo-
controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, 
tolerability and safety of oral BI 1358894 in 
patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Global Amendment due to urgent safety 
reasons
No
Global Amendment
2
Sections to be changed

Synopsis

Flow Chart 1

Flow Chart 2

3.1 Overall Trial Design

1.3 Rationale for performing the trial

3.3.2 Inclusion criteria

3.3.3 Exclusion criteria

5.2.1 MADRS

5.2.2 ATRQ

5.3.3 Safety laboratory parameters

6.2 Details of trial procedures
Description of change

Removal of typos, clarifications, re-
wording
Rationale for change

Clarifications
Sections to be changed

Flow Charts 1

Flow Charts 2

1.4.2 Risks

4.1.4 Drug assignment and administration 
of doses for each participant

6.1 Visit Schedule

8.1Trial Approval, Pateint Information, 
Inforemd Consent

Appendix 10.4






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11.3
GLOBAL AMENDMENT 3
Date of amendment
07 Sep 2020
EudraCT number/EU 
number
2019-004264-21
BI Trial number
1402-0011
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 6-week, multicenter, randomized, 
double-blind, double-dummy, placebo-
controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, 
tolerability and safety of oral BI 1358894 in 
patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Global Amendment due to urgent safety 
reasons
Global Amendment
3
Sections to be changed

Synopsis

Flow chart 1

Section 1.2 Drug Profile 

Section 2.1.3 Secondary endpoint(s)

Section 5.2.2. ATRQ - Antidepressant 
Treatment Response Questionnaire

Section 10.4 Potential Modification of 
trial conduct n case of restrictions due to 
COVID-19
Description of change

Removal of typos
Rationale for change

Clarification
Sections to be changed

Flowcharts - Footnotes

Section 6.2 Details of trial procedures
Description of change

Specification added how to split the 
screening visit on separate days, if needed
Rationale for change

Clarifications








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11.5
GLOBAL AMENDMENT 5
Date of amendment
28 Jun 2021
EudraCT number/EU 
number
2019-004264-21
BI Trial number
1402-0011
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 6-week, multicenter, randomized, 
double-blind, double-dummy, placebo-
controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, 
tolerability and safety of oral BI 1358894 in 
patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Global Amendment due to urgent safety 
reasons
No
Global Amendment
5
Sections to be changed
4.2.2.3 Contraception requirements
Description of change
WOCBP, who are sexually abstinent, fulfill 
the requirement of safe contraception
Rationale for change
Clarification. Sexual abstinence, as defined in 
the protocol, meets the criterion of an highly 
effective method of contraception
Sections to be changed
6.2
DETAILS OF TRIAL 
PROCEDURES AT SELECTED VISITS
Description of change
Optional extention of the screening            
period by additional 7 days added (i.e. 28 
days in total)
Rationale for change
For administrative reason like delayed 
reporting of SSRI/SNRI blood levels
Sections to be changed
Section 8.3.1 Source documents
Description of change
Audio recordings for central review are also 
regarded as source data 
Rationale for change
Clarification 
Sections to be changed
8.7
ADMINISTRATIVE STRUCTURE 
OF THE TRIAL




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11.6
GLOBAL AMENDMENT 6
Date of amendment
28 Sep 2021
EudraCT number/EU 
number
2019-004264-21
BI Trial number
1402-0011
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 6-week, multicenter, randomized, 
double-blind, double-dummy, placebo-
controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, 
tolerability and safety of oral BI 1358894 in 
patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Global Amendment due to urgent safety 
reasons
No
Global Amendment
6
Sections to be changed
Synopsis and Section 3.3.2 Inclusion criteria
Description of change
Duration of the current depressive episode 
extended from 12 months to 18 months
Rationale for change
COVID-19 pandemic impacts the timely 
access to medical treatment and consequently 
to the diagnosis. Therefore, it is considered 
justified to extend the duration of the current 
episode from 12 to 18 months.  
Sections to be changed
Synopsis and Section 3.3.2 Inclusion criteria; 
Section 6.2
Description of change
Change of MADRS entry score from total 
score “≥ 26” to “≥ 24”
Rationale for change
A MADRS score of 24 is still high enough 
for  signal detection in frame of potentially 
present placebo effect.


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Sections to be changed
Synopsis and Section 3.3.2 Inclusion criteria
Description of change
The minimal needed duration of ongoing 
monotherapy with an SSRI/SNRI at 
screening will be reduced from 8 to 6 weeks.
Rationale for change
To be aligned with the “APA Guideline for 
Treatment of Depression” [R21-3130] which 
recommends a change of pharmacotherapy 
for patients where no sufficient response 
could be demonstrated after 4 to 6 weeks of 
treatment. 
Sections to be changed
Synopsis; Flow Chart 1; Section 3.3.2; 
Section 5.3.3; Table 5.3.3:1: Section 6.2
Description of change
Confirmation of SSRI/SNRI levels in urine at 
screening added in addition to analysis in 
serum
Rationale for change
For operational reasons
Sections to be changed
Synopsis, Section 3.3.3 and 4.2.2.1
Description of change
Background SSRI/SNRI could alternatively 
already be stopped after (e)EOT instead at 
the end of the trial
Rationale for change
This allows investigators to change the 
treatment already at (e)EOT and not only 4 
weeks later at EOS. It supports adequate 
handling of patients who do not show any 
improvement of their depression during the 
treatment phase.
Sections to be changed
Synopsis, Section 3.3.3 and 4.2.2.1
Description of change
Allow for use of other antidepressants 
(excluding bupropion)  if  less than lowest 
dose indicated for MDD e.g., for treatment of 
anxiety or sleep disorder 
Rationale for change
This follows usual clinical practice as long as 
the given low doses are not listed in the table 
for treatment of depression. 
Sections to be changed
Flow Chart 1; Table 5.3.3:1 Safety Lab Tests
Description of change
ESR testing will be changed from central to 
on-site assessment
Rationale for change
For operational reasons 
Sections to be changed
Section 5.2.2


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Description of change
MH-ATRQ: Minimal required duration on 
adequate dose of an antidepressant 
medication was lowered from 8 weeks to 6 
weeks
Rationale for change
To be aligned with the referring adjustment 
of the inclusion criteria.
Sections to be changed
Section 5.3.5.1; 
Description of change
Note added that reporting of AE terms like 
suicidal depression, suicidal ideation or 
similar, are on the “Always serious AE List”
and therefore must be reported as SAEs
Rationale for change
Clarification
Sections to be changed
Section 5.3.5.1; Section 5.1.6.1.3; Section 
6.2; Section 6.2.1; Section 10.4
Description of change
Removal of typos; rewording
Rationale for change
Clarification


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11.7
GLOBAL AMENDMENT 7
Date of amendment
27 Apr 2022
EudraCT number/EU 
number
2019-004264-21
BI Trial number
1402-0011
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 6-week, multicenter, randomized, 
double-blind, double-dummy, placebo-
controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, 
tolerability and safety of oral BI 1358894 in 
patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Global Amendment due to urgent safety 
reasons
Yes
Global Amendment
7
Sections to be changed
Flowchart 1; Section 1.4.3; Section 4.2.2.3; 
Section 6.2
Description of change
Counseling about the need of contraception 
at V1 during IC. Additionally, reiteration of 
adherence to contraception at all visits.
Rationale for change
New safety information
Sections to be changed
Flowchart 1; section 5.3.3; Table 5.3.3:1
Description of change
Onsite ESR removed again (central ESR 
analysis will remain as is)
Rationale for change
Central laboratory cannot provide onsite ESR 
test kits. Therefore, the existing central ESR 
analysis will remain as the only 
measurement.   
Sections to be changed
Flowchart 1 (footnotes); Section 5.3.3; Table 
5.3.3:1; section 6.2
Description of change
Confirmation of SSRI/SNRI exposure can be 
done either in urine or serum under 
conditions as described in section 
Rationale for change
Clarification




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11.8
GLOBAL AMENDMENT 8
Date of amendment
26 Sep 2022
EudraCT number/EU 
number
2019-004264-21
BI Trial number
1402-0011
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 6-week, multicenter, randomized, 
double-blind, double-dummy, placebo-
controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, 
tolerability and safety of oral BI 1358894 in 
patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Global Amendment due to urgent safety 
reasons
No
Global Amendment
8
Sections to be changed
Synopsis; 3.3.2
Description of change
“Women who are of childbearing potential 
(WOCBP) must be able and willing to use 
two methods of contraception”.
Was changed to:
“Women who are of childbearing potential 
(WOCBP) must be able and willing to use 
two methods of contraception, confirmed by 
the investigator”
Rationale for change
To follow an FDA request and to ensure that 
the investigator confirms the contraception 
requirement with the patient.


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Sections to be changed
Flowchart 1; Table 1.4.2:1
Description of change
A footer on contraception counseling was 
added:
“This must include confirmation from the
patient that she is using required 
contraception consistently and appropriately. 
Counseling and contraception confirmation 
must be recorded in CRFs. If contraceptive 
protection can not be confirmed, as deemed 
by the investigator, the patient must be 
discontinued from study drug and can only 
resume once contraception is used again and 
sufficient protection is reached”.
Rationale for change
To follow an FDA request and to reinforce 
that contraception counselling is done at 
every visit and documented. Also to provide 
guidance for investigators who to handle non-
compliaces to contraception rules.
Sections to be changed
1.4.2. Risks
Description of change
“Additionally, investigators must counsel 
WOCBP with regard to the importance of 
contraception at all visits as per Flow Chart 
(including phone visits).”
Was changed to
“Additionally, investigators must counsel 
WOCBP with regard to the importance of 
contraception and confirmation of 
appropriate contraception use at all visits as 
per Flow Chart (including phone visits).”
Rationale for change
To follow an FDA request and to reinforce 
that contraception counselling is done at 
every visit and documented. 
Sections to be changed
Table 1.4.2:1: 4.2.2.3.


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Description of change
Investigator must ensure that the patient 
understands the contraception requirements 
for the study and must confirm that the 
patient can reliably comply with 
contraception use during the study. Patients 
not expected to comply with contraception 
requirements should not be included in the 
study.
Rationale for change
To follow an FDA request and to reinforce 
that contraception counselling is done at 
every visit and documented. Also to provide 
guidance for investigators not to include 
patients in the trial who are not expected to be 
able to comply with contraception 
requirements.






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Section to be changed
Synopsis; 3.3.3; 3.3.4.1; 4.2.2.1 
Description of change
Changing lifetime exclusion of transcranial 
magnetic stimulation to now only exclude 
TMS if used during the current depressive 
episode or within 12 months prior to 
screening.
Rationale for change
In order to account for the changes in clinical 
practice in some countries where TMS is now 
used more often and not only in proven 
treatment resistant depression.
Section of change
4.1.1: 4
Description of change
Manufacturer of placebo matching quetiapine 
was added
Rationale for change
To clarify that placebo matching quetiapine is
also packaged at BI 
Section to be changed
Section 5.2.2
Description of change
Customized ATRQ, defining the minimal 
required duration for stable antidepressant 
therapy at Screening, changed from 6 to 4 
weeks 
Rationale for change
To be aligned with the adjusted inclusion 
criterion #3 in section 3.3.2.
Section to be changed
Section 6.2
Description of change
Adding the recommendation for rater of C-
SSRS scale and rating of adverse events to be 
different
Rationale for change
To ensure that the rating of C-SSRS is not 
biased by the knowledge of adverse events 
from the patient.
Section to be changed
Section 8.3.1.
Description of change
Investigators should make three attempts to 
retrieve information on a patients’ medical 
history; was changed from only one attempt
Rationale for change
To be consistent with section 6.2.




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11.10
GLOBAL AMENDMENT 10 
Date of amendment
07 Jun 2023
EudraCT number
EU number
2019-004264-21
BI Trial number
1402-0011
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 6-week, multicenter, randomized, 
double-blind, double-dummy, placebo-
controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, 
tolerability and safety of oral BI 1358894 in 
patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Global Amendment due to urgent safety 
reasons
No
Global Amendment
10
Section to be changed
5.3.3 Safety laboratory parameters; 
Table 5.3.3:1 Safety laboratory tests
Description of change
Analysis of ESR can be either performed
centrally or locally
Rationale for change
Process updated to local ESR assessment.
Section to be changed
Table 5.3.3:1 Safety laboratory tests
Description of change
Cross reference (*) added for Erythrocyte
sedimentation rate (ESR) that the ESR 
Testing results are not intended to be used as 
Safety Parameter or for medical management 
decisions. For medical management decisions 
of Safety relevant inflammation parameter, 
the CRP test should be used.
Rationale for change
In this protocol, ESR testing is used solely for 
the collection of data for analysis purpose at 
the end of the trial, per FDA’s 
recommendation. The ESR Testing results are 
not intended to be used as Safety Parameter 
or for medical management decisions. For
medical management decisions of Safety 
relevant inflammation parameter, the CRP 
test should be used. 


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Section to be changed
Table 5.3.3:1 Safety laboratory tests
Description of change
Added Reflex testing (once technically 
implemented) for fT3 and fT4 if TSH > ULN
Rationale for change
Alignment with sister trials
Section to be changed
Section 11 - Global Amendment 7
Description of change
Correction of amendment date
Rationale for change
Typo


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12.
REFERENCES FOR CTP AUTHORS
Not applicable


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29983007
12.0
clinical-trial-protocol-version-11
A Phase II, 6-week, multicenter, randomized, double-blind, double-dummy,
placebo-controlled, parallel group trial with a quetiapine arm to evaluate the efficacy,
tolerability and safety of oral BI 1358894 in patients with Major Depressive Disorder
with inadequate response to antidepressants
Approval-Biostatistics
09 Jun 2023 16:12 CEST
Approval-Clinical Trial Leader
12 Jun 2023 08:09 CEST
Approval-Clinical Program Leaders
12 Jun 2023 08:47 CEST
Verification-Paper Signature
Completion
12 Jun 2023 09:13 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29983007
12.0

SAP_001.pdf: 
ABCD
BI-VQD-12681_50-415_AD-01 (4.0)
TRIAL STATISTICAL ANALYSIS PLAN
 
Document No.:
c42619468-01
BI Trial No.:
1402-0011
Title:
A Phase II, 6-week, multicenter, randomized, double-blind, 
double-dummy, placebo-controlled, parallel group trial with a 
quetiapine arm to evaluate the efficacy, tolerability and safety of 
oral BI 1358894 in patients with Major Depressive Disorder with 
inadequate response to antidepressants.
Investigational
Product(s):
BI 1358894
Responsible trial 
statistician(s):
Phone:
Date of statistical 
analysis plan:
18 DEC 2023
Version:
1.0
Page 1 of 46
Proprietary confidential information
© 2023 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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TRIAL STATISTICAL ANALYSIS PLAN
BI Trial No: 1402-0011
c42619468-01
Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies.
Date: 18 December 2023, Version 1.0
BI-VQD-12681_50-415_AD-01 (4.0)
2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike Information Criteria
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
CGI-S
Clinical Global Impression Severity Scale
CI
Confidence Interval
Cmax
Maximum Concentration
Cmin
Minimum Plasma Concentration
CNS
Central Nervous System 
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRP
C-reactive protein
C-SSRS
Columbia Suicide Severity Rating Scale
CT
Concomitant therapies
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DBLM
Database Lock Meeting
DDI
Drug Drug Interaction
DV 
Dataset Domain for Protocol Deviations
EC50
Half maximal effective concentration
ECG
Electrocardiogram
eCOA
electronic Clinical Outcome Assessment
eCRF
Electronic Case Report Form
ED
Effective Dose
EDMS
Electronic Document Management System


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TRIAL STATISTICAL ANALYSIS PLAN
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c42619468-01
Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies.
Date: 18 December 2023, Version 1.0
BI-VQD-12681_50-415_AD-01 (4.0)
Term
Definition / description
EoStudy / EoS End of Study
eEOT
Early End of Treatment
EOT
End of Treatment
FAS
Full Analysis Set
FDA
Food and Drug Administration
FU / FUP
Follow Up
ICE
Intercurrent event
ICF
Informed Consent Form
ICH
International Council on Harmonization
iPD
Important Protocol Deviation
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
LLT
Lower Level Term
LPLT
Last Patient Last Treatment
LS
Least Square
MADRS
Montgomery-Asberg Depression Rating Scale
MAR
Missing at random
MCPMod
Multiple comparisons procedure and modeling
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligram
MMRM
Mixed effects model for repeated measures
MQRM
Medical Quality Review Meeting
OAA
Overall 
 adherence
PD
Protocol deviation
PK
Pharmacokinetics


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TRIAL STATISTICAL ANALYSIS PLAN
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Term
Definition / description
PoC
Proof of concept
PPS
Per Protocol Set
PT
Preferred Term
QD
quaque die (once a day)
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
RPM
Report Planning Meeting
RUN
Data Ready to be Unblinded and/or Final Trial Closure Notification
SAE
Serious Adverse Event
SCID-5
Structured Clinical Interview for DSM-5 Clinical Trials
SD
Standard deviation
SMDDS
Symptoms of Major Depressive Disorder Scale
SNRI
Serotonin Norepinephrine Reuptake Inhibitor
SOC
System Organ Class
SS
Screened Set
SSRI
Selective Serotonin Reuptake Inhibitor
STAI
State-Trait Anxiety Inventory 
t.i.d.
ter in die (3 times a day)
t1/2
Half Life Time
tmax
Timepoint of Maximum Plasma Concentration
TMF
Trial Master File
TOM
Trial Oversight Meeting
TS
Treated Set
TSAP
Trial statistical analysis plan
UDAEC
User-defined AE categories
ULN
Upper Level of Normal
VAS
Visual Analogue Scale
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
R Version 3.3.2 with “DoseFinding” package (2) will be used for analyses based on Multiple 
Comparison Procedures and Modeling (MCPMod) and SAS® Version 9.4 will be used for all 
other analyses.
The main analyses of this TSAP will be conducted under the estimand concept. To quote ICH 
E9 R1, “An estimand is a precise description of the treatment effect reflecting the clinical 
question posed by a given clinical trial objective. It summarizes at a population level what the 
outcomes would be in the same patients under different treatment conditions being 
compared.” So, an estimand is a way for the clinical trial protocol to address how intercurrent 
events will be handled. According to ICH E9 R1, intercurrent events are events occurring 
after treatment initiation that affect either the interpretation or the existence of the 
measurements associated with the clinical question of interest. In other words, intercurrent 
events are occurrences after randomization that involve a change in treatment regimen. 




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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
Change from baseline in Montgomery–Asberg Depression Rating Scale (MADRS) total score 
at Week 6 is the primary efficacy endpoint. See CTP Section 5.2.1 for details.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
There is no key secondary endpoint in this trial.
5.2.2
Secondary endpoint(s)
The secondary efficacy endpoints are: 

Response defined as ≥ 50% MADRS reduction from baseline at Week 6.

Change from baseline in State-Trait Anxiety Inventory (STAI) State and Trait version 
scores at Week 6.

Change from baseline in Clinical Global Impression Severity Scale (CGI-S) score at 
Week 6.

Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) 
total score at Week 6.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For details on the treatment regimen, assignment of treatment groups, and the selection of 
doses, refer to CTP Section 4. Below in Table 1 are the description of the short and long 
names of the treatments in this trial. The definitions of the study phases for the analysis 
periods are in Table 2.
Table 1
Treatment descriptions
Long Name
Short Name
Placebo matching BI 1358894 and 
placebo matching quetiapine
Placebo
BI 1358894 5 mg qd
BI 5 mg
BI 1358894 25 mg qd
BI 25 mg
BI 1358894 75 mg qd
BI 75 mg
BI 1358894 125 mg qd
BI 125 mg
Quetiapine 300 / 150 mg
Quetiapine
Table 2
Study analysis phases
Study analysis 
phase
Description
Start Date (included)
End Date (excluded)
Screening phase
Screening 
(prior to 
treatment)
Date of informed 
consent
Date of first treatment 
administration minus 1 
day
Treatment phase 
and residual effects 
period (REP)
On-treatment 
period
Date of first 
treatment 
administration
Date of last treatment 
administration + REP
Follow-up phase
Off-treatment 
period
Date of last treatment 
administration + REP 
+ 1 day
Date of last visit planned 
in CTP
The defined treatment phases are the same for all treatment groups.






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Table 4
Patient sets analysed
Patient Set
Class of analyses
TS
SS
FAS
PPS
Primary and secondary endpoints, compliance, adherence
X
X*
Further endpoints 
X
Disposition
X
X
Safety variables and iPDs
X
Demographics, baseline variables, exposure
X
* If the percentage of patients in FAS with iPD that lead to the exclusion from the PPS is > 10%, then sensitivity analysis of 
the primary and secondary efficacy endpoints using PPS may be conducted.
Note that the number of patients with available data for an endpoint may differ. For details, 
refer to Section 6.6.




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selected for analysis. In the case for which there is no standard reference direction for the 
safety parameter, the average of all values for the same visit will be used for analysis.
Table 6
Planned study days and analysis time windows
Planned 
visit
Relative to treatment start
Planned test day
Analysis time windows
2
1
Up to Day 1 
3
8
Day 2 – Day 13
4
15
Day 14 – Day 20
5
22
Day 21 – Day 27
6
29
Day 28 – Day 34
7
36
Day 35 – Day 41
8 / EOT
43 for completed 
patients
Day 42 – treatment stop date (stopdt) + 7 days
eEOT
N/A (for early 
discontinued 
patients)
Date of the last administration of trial medication + 
7 days (for early discontinued patients). 
The number of days will be assigned to the visit. 
Thus, if days to eEOT is 35, it will be mapped to 
Visit 7. For those who discontinue treatment early
but continue with the collection of efficacy data, 
those data points will be mapped to the later visits 
as per the above visit window. Hence, if this same 
patient collects MADRS at Day 36, it will be 
mapped to Visit 7.
End of Trial
stopdt + 28 days
(stopdt + 8 days) to study end
-
Days are counted relative to the day of treatment start, which is defined as Day 1.
-
stopdt stands for treatment stop date.
There is no visit window mapping for C-SSRS given that it is collected every week 
throughout the study.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
Clinical Trials and Project Summaries" (9).
The individual values of all patients will be listed, sorted by dose group, patient number and 
visit. AE listings will be sorted by assigned treatment (see Section 7.8.1 for details). The 
listings will be contained in an Appendix of the CTR.
For End-Of-Text tables, the set of summary statistics is: N / Mean / Standard Deviation (SD)
/ Min / Median/ Max. For tables that are provided for endpoints with some extreme data, 
median, quartiles and percentiles are preferred to mean, standard deviation, minimum and 
maximum. In general, means, medians, and percentiles are presented to one more decimal 
place than the raw data and SDs are presented to two more decimal places than the raw data. 
Minima and Maxima are presented to the same number of decimal places as the raw data.
Disposition of the patient population participating in the trial will be analyzed by treatment 
and presented by the categories in the standard CRF groups and presented in the clinical trial 
report as a frequency-distribution.
For categorical data, tabulations of frequencies will include all defined categories even if 
there is no count in a category. Tabulations of frequencies will display the number of 
observations in a category as well as the percentage (%) relative to the number of patients in 
the respective treatment group. All patients in the respective patient set are used whether they 
have non-missing values or not, unless otherwise specified. Percentages will be rounded to 
one decimal place. The category missing will be displayed only if there are missing values.
If applicable, conversion from days to weeks, months and years will be as follows:
-
weeks = days ÷ 7
-
months = 12 × days ÷ 365.25
-
years = days ÷ 365.25.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only standard descriptive statistics and summary tables are planned for this section of the 
report. Data will be summarized by treatment group and a "total" column will be included in 
the summary table.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant diseases (i.e., baseline conditions) will be coded similarly as AEs using the most 
recent version of MedDRA. A summary of concomitant diseases will be provided by 


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treatment group, System Organ Class (SOC) and Preferred Term (PT). Concomitant diseases 
which are present at start of the study will be descriptively summarized by treatment. 
A medication/therapy will be considered concomitant to treatment if it (1) is ongoing at the 
start of randomized trial treatment or (2) starts within the on-treatment phase (see Section 6.1
for a definition of study analysis phases). A medication/therapy will be considered as prior 
medication/therapy, if the end date of the medication/therapy is at any time prior to the start 
of randomized trial treatment.
Concomitant therapies (CTs) are coded according to WHO Drug Dictionary. CTs will be 
classified according to the Anatomical Therapeutic Chemical (ATC) classification system. 
The third ATC level will be used to categorize CTs by therapy type. In situations where a 
medical product may be used for more than one equally important indication, there are often 
several classification alternatives. As appropriate, patients receiving CTs with more than one 
possible ATC level-three category will be counted more than once and footnote will clarify 
this possible multiple counting in tables. The most current WHO Drug Dictionary version
will be used.
7.3
TREATMENT COMPLIANCE
7.3.1
Compliance
Only descriptive statistics are planned for this section of the report. Treatment compliance is 
the percentage of tablets that were correctly taken by a patient, and is calculated at Weeks 1, 
2, 4, and 6 (EOT) as follows, based on the CTP’s flow chart:
Treatment compliance (%) = 
	 
 
  
	 
 
  
     	  
	 ∗100
The cumulative treatment compliance during the entire treatment period is derived using the
following examples:
For completers: if a patient’s observed treatment compliance rates are 80%, 81%, 82%, 83% 
at Weeks 1, 2, 4, and 6, then the cumulative treatment compliance percent = 
(.8*1 + .81*1 + .82*2 + .83*2)/6*100 = 81.83%.
For early discontinued patient: if a patient’s observed treatment compliance rates are 80% at
Week 1, 81% at Week 2, 82% at Week 4, 50% at eEOT, then the cumulative treatment 
compliance rate = (0.80*1 + 0.81*1 + 0.82*2 + 0.5*((eEOT date – drug start date + 1)/7 –
4))/((eEOT date – drug start date + 1)/7) * 100% = 74.3% if the quantity (eEOT date – drug 
start date + 1) is assumed to be 36 days.
If at a particular visit a participant did not return the trial drug kits, then the compliance at 
that visit is zero.
Treatment compliance will be summarised overall and by visit for the FAS using descriptive 
statistics (N, mean, SD, minimum, median, maximum). The number and percentage of 




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7.4
PRIMARY OBJECTIVE ANALYSIS
7.4.1
Main analysis 
The primary endpoint is the change from baseline to Week 6 in MADRS total score. Baseline 
MADRS total score is the last non-missing value recorded prior to first dose of trial 
medication and is typically recorded at Visit 2. If data from Visit 2 are missing, the value 
recorded at Visit 1 will be considered the baseline value. The investigator reported MADRS 
total scores will be used for the primary analysis.
Total scores as delivered by the vendor will be re-calculated and in case of discrepancies, the 
re-calculated scores will be used for analysis.
The primary analysis of the primary endpoint will use a hypothetical estimand. The 
hypothetical approach focuses on the treatment effect assuming all patients remained 
adherent to the assigned trial medication and the trial protocol, i.e., took study drug as 
directed. The primary analysis of the primary endpoint will include all data collected while 
on treatment, which is defined as the time from the date of the first dose of trial medication 
until the date of the last dose of trial medication plus 7 days (3 times the estimated 
elimination half-life). Any data collected after any intercurrent event listed in Table 3 will be 
censored and not included in the primary analysis. Data from participants assigned to the 
quetiapine arm will not be included in the primary analysis.
The Multiple Comparison Procedures and Modeling (MCPMod) approach (10, 11) is 
implemented in two main stages: (1) trial design stage; (2) trial analysis stage. The 
procedures for the trial design stage, including the selection of candidate models covering a 
suitable range of dose-response shapes and sample size and power calculations are provided 
in the CTP Sections 7.2.2 and 7.5. The procedures for the trial analysis stage are specified 
below. FAS is used for the primary analysis of the primary efficacy endpoint.
MMRM analysis
The change from baseline in MADRS total score at Week 6 for each dose group as well as 
the corresponding variance-covariance matrix will be estimated by an MMRM model 
including the fixed categorical effects of treatment at each visit, concomitant psychotherapy 
use (yes vs. no), and the fixed continuous effect of baseline MADRS total score at each visit.
Visit will be treated as a repeated measure with an unstructured covariance matrix used to 
estimate within patient error variability. The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom and adjust standard errors. Significance tests 
will be based on least-squares (LS) means using a two-sided α = 0.1 (two-sided 90% 
confidence intervals (CIs)). Analyses will be implemented using SAS 9.4 PROC MIXED. 
More specifically, the change in MADRS total score from baseline at Visits 3, 4, 6, and 8 
(Weeks 1, 2, 4, and 6) will be evaluated using an MMRM accounting for the following 
sources of variation: ‘concomitant psychotherapy use’, ‘treatment*visit’ interaction, and 
‘baseline MADRS total score*visit’ interaction as fixed effects, and visit as a repeated 
measure within each patient. The methods described in Section 10.1.1 will be utilized to 
resolve model non-convergence. 


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The following SAS code will be used to run the MMRM model, with some modifications if 
necessary:
PROC MIXED DATA=indata cl method=reml;
CLASS visit trt(REF='placebo') ptno conPTuse;
MODEL aval = conPTuse visit*trt base*visit / ddfm=kr s;
REPEATED visit / subject= ptno type=un r rcorr;
LSMEANS visit*trt / pdiff=all om cl alpha=0.10 slice=visit;
RUN;
Results of the MMRM (N, LS means, standard errors, and 90% CIs per dose group) will be
presented in tables and displayed graphically.
Descriptive summaries for observed values and change from baseline in MADRS total score 
at Weeks 1, 2, 4 and 6 will be presented by treatment arm, including the quetiapine arm. The 
frequency and proportion of participants reporting each response category for each MADRS 
item at baseline and up to Week 6 will also be displayed.
MCPMod Analysis
The adjusted mean estimates of the change from baseline at Week 6 for each dose and their 
estimated variance-covariance matrix from the MMRM model will be used in the trial 
analysis stage. Then, the multiple pair-wise comparison procedure will be implemented using 
the optimal contrast tests which control the family-wise type I error rate at one-sided α = 
0.10. 
The basic shape of each of the models to be tested must be predefined in the trial analysis 
stage. The following candidate models were selected based on healthy volunteer data to cover 
a plausible and diverse range of dose response patterns for the trial medication. 

Emax1:
50% of the maximum effect is achieved at 25 mg; corresponding to the 
assumed true ED50 = 25 mg.

Emax2:
70% of the maximum effect is achieved at 5 mg; corresponding to a 
drug effect achieved mainly with low doses, ED50 = 2.14 mg.

Sigmax:
50% of the maximum effect is achieved at 25 mg, and

90% of the maximum effect is achieved at 75 mg; corresponding to a 
more flexible model of the assumed true ED50 = 25 mg.

Exponential:
5% of the maximum effect is achieved at 25 mg; corresponding to a 
drug effect achieved mainly at higher doses.

Linear:
No parameter assumptions required. Corresponding dose response is 
linear.
For the MCPMod test, the optimal contrasts corresponding to the candidate models are 
calculated as in the trial design stage (using the R-function optContr using weights 
proportional to the sample size of each dose group) and are shown in Table 7 below. These 
contrasts will be updated using the expected model means from the candidate set and the 




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The MCPMod trial analysis will be implemented by calling an R function/package within 
SAS. Please see Section 10.1.2 for the R code to implement the MCPMod analysis.
7.4.3
Supplementary analysis
An additional analysis of the primary endpoint will repeat the primary analysis methodology 
(MMRM/MCPMod) specified in Section 7.4.1, but under a treatment policy estimand, i.e., 
effectiveness/intention to treat. This estimand approach will use all available MADRS data, 
including data collected after any intercurrent event listed in Table 3. As discussed in Section 
6.3, an intercurrent event of death will be handled using a hypothetical approach.


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7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
This section is not applicable as no key secondary endpoints were specified in the protocol.
7.5.2
Secondary objective analysis
Data from participants assigned to the quetiapine arm will not be included in the analysis
models for the secondary endpoints.
7.5.2.1
MADRS response
Response is defined as ≥ 50% reduction in MADRS total score from baseline to a specific 
post-baseline visit (Visit X), where percent reduction from baseline at Visit X is calculated 
as:
% *0.FGH,)+ = (8>IJK H)H56 /G)*0 5H L5/06,+0 −8>IJK H)H56 /G)*0 5H M,/,H N)
8>IJK H)H56 /G)*0 5H L5/06,+0
∗100
The proportions of participants achieving response for each analysis visit up to Week 6 (Visit 
8/EOT) will be summarized as the frequency and percentage of participants in each treatment 
arm.












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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. Adverse events (AEs) will be coded based 
on the most current version of MedDRA. Analyses will be performed as defined in CTP 
Section 7.2.5.
7.8.1
Adverse Events
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs. The reporting and analyses of 
AEs will follow the BI guideline (14).
For further details on summarisation of AE data, please refer to (7, 14).
The analysis of AEs will be based on the concept of treatment emergent adverse events. 
Thus, all AEs occurring between the date of the first administration of trial treatment through
the date of the last administration of trial treatment + residual effect period, a period of 28
days after the last dose of trial medication, will be assigned to the on-treatment period for 
evaluation. AEs that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’. Adverse event data will be summarized by treatment 
taken at the onset of the event. AEs that occur before first drug intake will be assigned to 
‘screening’, and adverse events that occur within 28 days after the residual effect period will 
be assigned to ‘follow-up’ (for listings only).
For details on the treatment definitions, see Section 6.1.
Adverse events of special interest (AESIs)
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
-
Marked peak aminotransferase (ALT and / or AST) elevations ≥ 10-fold ULN.
Refer to CTP Section 5.3.6.1.4 for details.
Other significant AE (according to ICH E3)
According to ICH E3 (15), AEs classified as "other significant" needs to be reported and will 
include those non-serious and non-significant AEs with
1. Action taken = ‘discontinuation' or action taken = ‘reduced'; or
2. Marked hematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor / Investigator during medical quality 
review at TOM.
AE summaries


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An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarized by treatment taken at the onset of the event, primary 
system organ class (SOC) and preferred term (PT) according to MedDRA. The SOCs will be 
sorted by default alphabetically and PTs will be sorted by frequency within an SOC. Separate 
tables will be provided for patients with:
-
drug-related AEs
-
serious AEs
-
serious related AEs
-
AESIs
-
other significant AEs (according to ICH E3)
-
AEs leading to death
-
AEs leading to discontinuation of trial medication
-
AEs occurred with incidence in the preferred term >2%
-
AEs occurred with incidence in the preferred term >5%
-
AEs occurred during the follow-up period
-
Extrapyramidal AEs (AEs in the ‘extrapyramidal syndrome’ SMQ and all of its sub-
SMQs (akathisia, dyskinesia, dystonia, and Parkinson-like events)).
AEs suggestive of abuse potential
In support of an evaluation of human abuse potential, user-defined AE categories (UDAEC) 
are defined in Section 10.2. In addition, frequency of patients with AEs suggestive of abuse 
potential will be summarized by treatment, UDAEC, and PT. A listing of the AEs and a 
listing of patients with >100% compliance or unreturned medication kits will also be 
provided.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (16). Only patients with at least one available on-treatment value will be included 
in the analysis of an individual laboratory parameter. All individual data will be presented in 
listings. Study visits will be presented by the Visit labels in Table 6.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report. In case of multiple 
measurements including unscheduled visits, the value for the vital sign measurement will be 
the average of all the measurements for the corresponding visit.
7.8.4
ECG
12-lead ECG measurements will be assessed as described in the CTP Flow Chart. 12-lead 
ECG-findings before first intake of trial drug will be considered as baseline condition, or as 




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2.
Bornkamp B, Pinheiro J, Bretz F. Package ‘DoseFinding’ (February 19, 2015). 
Comprehensive R Archive Network 2015; [R15-2001]
3.
Rubin D. Inference and missing data. Biometrika 1976; 63: 581–592 [R12-2371]
4.
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11
HISTORY TABLE
Table 8
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
18-DEC-23
None
This is the final TSAP