A Phase II, 6-week, Multicenter, Randomized, Double Blind (Patient and Investigator) or Masked, Placebo Controlled, Dose-finding Trial to Evaluate the Efficacy, Tolerability, and Safety of Different Doses of Oral BI 1569912 as Adjunctive Therapy in MD
Phase: PHASE2
Conditions: Depressive Disorder, Major
Sponsor: Boehringer Ingelheim

BI-VQD-12177_40-106_AD-03 (23.0)
Clinical Trial Protocol
TITLE PAGE
Document Number:
c42937919-02
EU Clinical Trial No.
Universal Trial 
Number
2023-507942-10-00
U1111-1297-3126 
Boehringer 
Ingelheim Trial No.
1447-0005
Boehringer
Ingelheim
Investigational
Medicinal Product(s)
BI 1569912
Title
A Phase II, 6-week, multi-centre, randomised, double-blind 
(participant and investigator), placebo-controlled, dose-finding 
trial to evaluate the efficacy, tolerability, and safety of different 
doses of oral BI 1569912 as adjunctive therapy in patients with 
major depressive disorder
Lay Title
A study to test different doses of BI 1569912 in people with 
depression who take anti-depressive medicine
Clinical Phase
II
Clinical Trial Leader
Phone: 
, Fax: 
Email: 
Coordinating 
Investigator
Phone: 
 Fax: 
Email:
Current Version and 
Date
Final Version 2.0, 09 Oct 2024
Original Protocol 
Date
Version 1.0, 06 Nov 2023
Page 1 of 108
Proprietary confidential information.
© 2024 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.
/?.i'\ Boehringer 
~111111/ lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol 
date
Latest revision date
06 Nov 2023
Protocol Version 2.0 as of 09 Oct 2024
BI trial number
EU CT number
Universal Trial 
Number
1447-0005
2023-507942-10-00
U1111-1297-3126 
Title of trial
A Phase II, 6-week, multi-centre, randomised, double-blind 
(participant and investigator), placebo-controlled, dose-finding trial 
to evaluate the efficacy, tolerability, and safety of different doses of 
oral BI 1569912 as adjunctive therapy in patients with major 
depressive disorder
Coordinating 
Investigator
Phone: 
 Fax: 
Email:
Trial site(s)
Multi-centre trial conducted at approximately 65 trial centres in
7 countries
Clinical phase
II
Trial rationale
Major depressive disorder (MDD) is a common, severe, and 
frequently recurrent mental illness with an estimated global point 
prevalence of approximately 5%. Despite the array of available 
treatment options, there remains significant unmet medical need for
patients who either do not respond to or do not tolerate current 
augmentation approaches (e.g. atypical antipsychotics, lithium) or in 
cases where these are either not available or unsuitable. Adjunctive 
medications that act faster than standard treatments with improved 
efficacy but without the side effects and/or resource requirements of 
last-line treatment options (i.e. a monitored setting for esketamine) 
would constitute a major medical advance and fulfil a high unmet 
medical need for patients suffering from MDD.
Following Phase I studies in healthy volunteers and a proof of 
clinical principle trial in participants with MDD, the present trial is 
designed to assess dose-range finding data, provide proof of clinical 
concept, and confirm the safety and tolerability of BI 1569912 
compared with placebo when administered for 6 weeks as an adjunct 
to background antidepressant pharmaceutical therapy.

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Benefit-risk 
assessment and 
ethical 
considerations
BI 1569912 has the potential to address core symptoms of MDD 
faster than standard treatments as it targets the NR2B subunit of 
NMDA receptors. Non-selective NMDA antagonists such as 
ketamine and esketamine have been shown to improve response to 
standard-of-care antidepressants. Preclinical data have shown a 
larger therapeutic window for BI 1569912 compared with ketamine 
according to doses required for efficacy in behavioural tests and for 
the induction of psychotomimetic effects. Clinical data have shown 
preliminary efficacy signals after a single dose of BI 1569912 and a 
favourable safety profile after single and multiple doses. However, 
BI 1569912 is an experimental drug at an early stage of testing and 
therefore an individual benefit for participants cannot be guaranteed.
It is important to have a placebo control to address potential 
confounding factors. This is considered to be acceptable as 
participants will remain on their standard antidepressant treatment 
(including ongoing stable psychotherapy, where applicable).
Trial objective(s)
The overall objectives of this trial are to assess dose-range finding 
data of BI 1569912 compared with placebo as adjunctive therapy in 
patients with MDD who show inadequate response to ongoing 
antidepressant treatment, provide proof of clinical concept (PoCC), 
and to support dose selection for pivotal studies.
Trial endpoints
Primary endpoint:

Change from baseline in Montgomery-Åsberg Depression 
Rating Scale (MADRS) total score at Week 6
Secondary endpoints:

Change from baseline in MADRS total score at Day 8

Response defined as ≥50% MADRS reduction from baseline 
at Day 8

Response defined as ≥50% MADRS reduction from baseline 
at Week 6

Remission defined as MADRS total score ≤10 at Week 6

Change from baseline in Symptoms of Major Depressive 
Disorder Scale (SMDDS) total score at Day 8

Change from baseline in SMDDS total score at Week 4
Trial design
A 6-week, multi-centre, multi-national, randomised, double-blind, 
placebo-controlled, parallel-group trial in patients with MDD with 
inadequate response to ongoing antidepressant treatment.
Total number of 
trial participants 
randomised
Approximately 222 participants will be randomised, 
in order to have approximately 180 participants evaluable for the 
primary analysis.
Number of trial 
participants per
treatment group
Placebo: approx. 74 participants
BI 1569912 (5 mg): approx. 37 participants
BI 1569912 (10 mg): approx. 37 participants
BI 1569912 (20 mg): approx. 74 participants

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Diagnosis,
main inclusion and 
exclusion criteria
Main Inclusion Criteria/Diagnosis:
Established diagnosis of MDD, single episode or recurrent, as 
confirmed at the time of screening by the Mini International 
Neuropsychiatric Interview (MINI) with a duration of current 
depressive episode ≥8 weeks at the time of screening visit.
Hamilton Depression Rating Scale 17 (HDRS 17) – Severity 
scale score >17.
A documented ongoing monotherapy treatment of ≥6 weeks at 
the randomization visit, with an SSRI or SNRI at adequate dose 
(at least minimum effective dose as per prescribing information).
In the current episode, participants have shown insufficient 
treatment response (defined by less than 50% response to a 
maximum of 4 antidepressant drugs of adequate dose and 
treatment duration (according to Summary of Product 
Characteristics) as evaluated by ATRQ (Antidepressant 
Treatment Response Questionnaire).
Male and female participants, 18 to 65 years of age at the time of 
consent.
Women who are of childbearing potential (WOCBP) must be 
able and willing, to use two methods of contraception.
Main Exclusion Criteria:

Per MINI, had ever met diagnostic criteria for schizophrenia, 
schizoaffective disorder, schizophreniform disorder, bipolar 
disorder, or delusional disorder

Diagnosis with antisocial, paranoid, schizoid or schizotypal 
personality disorder, or MDD with psychotic features 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 any other mental disorder that was the primary 
focus of treatment within 6 months prior to screening (as per 
clinical discretion of the investigator). 

A current or recent history of clinically significant suicidal 
ideation with intent within the past 3 months, corresponding to a 
score of 4 or 5 for ideation on the C-SSRS, or a suicidal attempt 
within the past year, as indicated by the C-SSRS at screening 
visit.

Diagnosis of a moderate to severe substance related disorder 
within 6 months prior to screening visit (with exception of 
caffeine and tobacco).

Positive drug screen (amphetamines, opiates, cocaine, 
barbiturates, phencyclidine) at the screening or Visit 1A (if 
applicable). Participants with positive cannabis or
benzodiazepine can be included if the investigator confirms that 
there is no active substance related disorder.

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
Have started psychotherapy or other non-drug therapies (e.g. 
acupuncture, hypnosis) within 3 months prior to screening or 
plan to start at any time during the study. 

Use of alternative or traditional medicine (e.g. Chinese 
traditional medicine, herbal medication, St. John’s wort etc.) 
within 14 days prior to randomization and during the entire 
course of the study.

Use of NMDA inhibitors (including ketamine/esketamine) for 
the current ongoing depressive episode or any past treatment 
failure with ketamine.

Use of psychotropic medication, outside of ongoing SSRI/SNRI 
monotherapy and certain exceptions, which was not 
discontinued at least 5 half-lives prior to randomization.
Test product
BI 1569912
Dose and mode of 
administration
5 mg, 10 mg, 20 mg once per day, orally
Comparator
Placebo
Dose and mode of 
administration
Matching; once per day, orally
Duration of 
treatment
6 weeks
Statistical methods
To demonstrate proof of concept of clinical activity and to evaluate 
the dose response relationship for BI 1569912, a multiple 
comparison procedure with modelling techniques (MCPMod) 
approach is planned to be used for the primary analysis. 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 in MADRS total score at Week 6 and associated 
covariance matrices.

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SCHEDULE OF ASSESSMENTS (SOA)
Comments
Informed consent
X
Signing of main ICF is mandatory prior to 
any study-related procedure. Signing of 
ICFs for data tokenisation, biobanking,
and feedback questionnaires is optional.
Demographics
X
Medical history/baseline 
conditions
X
Participant duplicate 
check
X
If local regulatory approval has been 
obtained. See Section 5.6.3
Physical/Neurological
examination
X
X
X
X
X
X
X
Physical/Neurological exam to be 
performed after IMP administration. See 
Section 5.2.1
Height
X
See Section 5.2.1
Weight
X
X
X
See Section 5.2.1
Vital signs
X
X
X
X
X
X
X
See Section 5.2.2

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Comments
12-lead ECG1
X
X
X
X
X
X
If screening visit is conducted over 
multiple days, ECG should be done on the
first day. ECGs should be captured after
IMP administration during Visits 2 and 4.
See Sections 5.2.4 and 6.2
Review of in-/exclusion 
criteria
X
X
X
Inclusion criteria 6 & 7 do not need to be 
entered as failed during initial screening 
for participants taking part in the 
SSRI/SNRI lead-in. See Section 3.3
Concomitant therapy
X
X
X
X
X
X
X
MINI1
X
If the screening visit is conducted over 
multiple days, MINI should be done on 
the first day.
ATRQ1
X
X
If screening visits are conducted over 
multiple days, ATRQ should be done on 
first day. ATRQ to be completed one time 
during the screening period: at Visit 1 for 
those entering the study on stable 
SSRI/SNRI and at Visit 1A for 
participants completing the SSRI/SNRI 
lead-in.
HDRS-17
X
X
PCRS to be read before HDRS-17 during 
screening. If screening visits are 
conducted over multiple days, 
HDRS-17 should be done on first day.

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Comments
Interactive response 
technology use
X
X
X
X
X
X
IRT registration only at Visit 1
C-SSRS
X
X
All AEs/SAEs/AESIs
X
X
X
X
X
X
X
See Section 5.2.6
Placebo control reminder 
script (PCRS)
X
X
X
X
X
X
To be read by the rater to each subject 
immediately before administering the 
MADRS and HDRS-17 
MADRS
X
X
X
X
MADRS, 
, SMDDS, 
 
 should be assessed in this 
order prior to IMP intake at all visits, with 
the exception of Visit 4, where they 
should be assessed 1 to 2 h after IMP 
intake. See Section 6.2.2
SMDDS
X
X
X
See Section 5.2.5.3

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Comments
Safety laboratory tests1
X
X
X
X
X
X
X
If screening visits are conducted over 
multiple days, blood sampling should be 
done on first day. See Section 5.2.3
SSRI/SNRI drug levels 
(blood or urine)
X
X
X
Only required once during the screening 
period: at Visit 1 for those entering the 
study on stable SSRI/SNRI and at 
Visit 1A for participants completing the 
SSRI/SNRI lead-in
Urine drug screen
X
X
X
X
X
X
X
Pregnancy test
X
X
X
X
X
Women of childbearing potential only. If 
urine test is positive, serum pregnancy 
test is to be performed for confirmation. 
Optional sampling for 
biobanking (serum, 
plasma)
X
X
Two serum and two plasma samples will 
be taken, sample collection should adhere 
to the schedule, i.e. taken at Visit 2 
(baseline) and EoT; see Section 5.5
Optional DNA 
Biobanking
X
In total one sample will be taken, 
preferably at Visit 2. Collection at later 
visits is permitted as long as the ICF for 
biobanking remains valid. see Section 5.5
Placebo informational 
video
X
See Section 6.2.1

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Comments
Randomisation
X
Dispense IMP
X
X
X
Administer trial IMP
X
X
X
Participants should not take IMP in the 
morning of Visits 3 and 4 as they will be 
dosed at the site. The final dose of IMP 
should be taken the day before EoT. All 
procedures should occur prior to IMP 
intake with the exceptions of ECG 
collection during Visits 2 and 4, and 
MADRS/post-dose PK sampling during 
Visit 4. Participants should fast for 2 h 
prior to and 1 h after every IMP intake. 
See Section 6.2.2
IMP return/accountability
X
X
X
Participants must bring trial medication 
(used/unused blister and covering 
packages) to site visits for compliance 
checks. 
Completion of 
participant’s participation
X
See Section 3.3.4 for discontinuation 
details. See Section 5.6.6 and 
Appendix 10.1 for optional trial feedback 
questionnaires to be given at the start and 
end of the trial.
Footnotes provided on the next page

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1
Screening visits can be split if required due to logistical reasons. If the visits will be split, the blood sampling, ECG, MINI, ATRQ, and HDRS-17 should be done on the first day of 
screening (ATRQ only completed during Visit 1A for participants that are taking part in the lead-in phase). Documentation will be done only once. The first day of screening will be 
the starting point for the screening period calculation.
2
For participants who permanently discontinue (DC) the IMP prior to the scheduled Week 6 EoT Visit, an EoT Visit must be completed as soon as possible after IMP
discontinuation. If early DC participants do not agree to continue regularly scheduled visits after the EoT Visit, a EoS Visit should be scheduled (IMP discontinuation date + 8 days 
[+ 6 days]). See Section 3.3.4 for further details. An EoS Visit must be completed for all randomised participants. EoS = individual participant’s end of trial.
3
Day of randomisation/Day of first intake of randomised IMP – all activities must be done before IMP administration, except for ECG and the collection of AEs/SAEs. It is 
recommended to monitor participants for 2 h post IMP administration on Day 1 to record any potential AEs.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
SCHEDULE OF ASSESSMENTS (SOA) .............................................................................6
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS AND DEFINITIONS...........................................................................16
1.
INTRODUCTION...............................................................................................21
1.1
MEDICAL BACKGROUND.............................................................................21
1.2
DRUG PROFILE................................................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................25
1.4
BENEFIT - RISK ASSESSMENT.....................................................................26
1.4.1
Benefits.................................................................................................................26
1.4.2
Risks .....................................................................................................................26
1.4.3
Discussion.............................................................................................................31
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................32
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........32
2.1.1
Main objectives....................................................................................................32
2.1.2
Primary endpoint(s)............................................................................................32
2.1.3
Secondary endpoint(s) ........................................................................................32
2.2.3
Safety....................................................................................................................34
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................35
3.1
OVERALL TRIAL DESIGN.............................................................................35
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................35
3.3
SELECTION OF TRIAL POPULATION .......................................................36
3.3.1
Main diagnosis for trial entry ............................................................................37
3.3.2
Inclusion criteria .................................................................................................37
3.3.3
Exclusion criteria ................................................................................................38
3.3.4
Discontinuation of trial participants from treatment or assessments............40
3.3.4.1
Discontinuation of trial treatment .........................................................................41
3.3.4.2
Withdrawal of consent to trial participation .........................................................43
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................43
4.
TREATMENTS...................................................................................................44
4.1
INVESTIGATIONAL TREATMENTS ...........................................................44
4.1.1
Identity of the Investigational Medicinal Products..........................................44
4.1.2
Selection of doses in the trial and dose modifications......................................44
4.1.3
Method of assigning trial participants to treatment groups ...........................46
4.1.4
Drug assignment and administration of doses for each trial participant......46

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4.1.5
Blinding and procedures for unblinding...........................................................47
4.1.5.1
Blinding.................................................................................................................47
4.1.5.2
Emergency unblinding and breaking the code......................................................47
4.1.6
Packaging, labelling, and re-supply...................................................................48
4.1.7
Storage conditions...............................................................................................48
4.1.8
Drug accountability.............................................................................................48
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................49
4.2.1
Other treatments and emergency procedures..................................................49
4.2.1.1
Auxiliary medicinal products................................................................................49
4.2.1.2
Emergency procedures..........................................................................................49
4.2.2
Restrictions ..........................................................................................................49
4.2.2.2
Restrictions on diet and lifestyle...........................................................................51
4.2.2.3
Contraception requirements..................................................................................51
4.3
TREATMENT COMPLIANCE........................................................................52
5.
ASSESSMENTS..................................................................................................53
5.1
ASSESSMENT OF EFFICACY........................................................................53
5.1.1
Clinical outcome assessments (COAs)...............................................................53
5.1.1.1
MADRS – Montgomery-Åsberg Depression Rating Scale ..................................53
5.1.1.3
SMDDS – Symptoms of Major Depressive Disorder Scale .................................54
5.1.1.7
COA rater training and qualification ....................................................................55
5.1.1.8
COA/eCOA handling............................................................................................56
5.2
ASSESSMENT OF SAFETY.............................................................................57
5.2.1
Physical/Neurological examination ...................................................................57
5.2.2
Vital signs.............................................................................................................57
5.2.3
Safety laboratory parameters ............................................................................57
5.2.4
Electrocardiogram ..............................................................................................60
5.2.5
Other safety parameters.....................................................................................61
5.2.5.1
C-SSRS – Columbia-Suicide Severity Rating Scale.............................................61
5.2.6
Assessment of adverse events.............................................................................63
5.2.6.1
Definitions of AEs ................................................................................................63
5.2.6.1.1
Adverse event........................................................................................................63
5.2.6.1.2
Serious adverse event............................................................................................63
5.2.6.1.4
Adverse events of special interest.........................................................................64
5.2.6.1.5
Intensity (severity) of AEs....................................................................................65
5.2.6.1.6
Causal relationship of AEs....................................................................................66
5.2.6.2
Adverse event collection and reporting ................................................................66
5.2.6.2.1
AE Collection........................................................................................................66
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................67

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5.2.6.2.3
Pregnancy..............................................................................................................67
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................69
5.5
BIOBANKING ....................................................................................................69
5.5.1
Methods and timing of sample collection..........................................................69
5.6
OTHER ASSESSMENTS...................................................................................69
5.6.1
Confirmation of diagnosis ..................................................................................69
5.6.1.1
MINI – Mini International Neuropsychiatric Interview .......................................69
5.6.1.2
ATRQ – Antidepressant Treatment Response Questionnaire...............................70
5.6.1.3
HDRS-17 – Hamilton Depression Rating Scale-17..............................................70
5.6.2
PCRS – Placebo-Control Reminder Script.......................................................70
5.6.3
Verification of current and past research study status of the trial 
participant............................................................................................................71
5.6.5
Data tokenisation.................................................................................................71
5.6.6
Optional study feedback questionnaires...........................................................72
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................72
6.
INVESTIGATIONAL PLAN.............................................................................73
6.1
VISIT SCHEDULE.............................................................................................73
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................73
6.2.1
Screening and lead-in phase...............................................................................74
6.2.1.1
Rescreening of participants:..................................................................................75
6.2.1.2
Retesting................................................................................................................75
6.2.1.3
Demographics .......................................................................................................75
6.2.1.4
Baseline conditions ...............................................................................................76
6.2.1.5
Medical history .....................................................................................................76
6.2.1.6
Lead-in phase........................................................................................................77
6.2.1.7
Interactive Response Technology.........................................................................77
6.2.1.8
Participant Eligibility Review...............................................................................77
6.2.2
Treatment period(s)............................................................................................77
6.2.3
Follow-up period and trial completion..............................................................79
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE......................................................................................................................80
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................80
7.2
PLANNED ANALYSES.....................................................................................80
7.2.1
General considerations .......................................................................................80
7.2.2
Handling of Intercurrent Events .......................................................................81
7.2.3
Primary objective analyses.................................................................................82
7.2.3.1
Main analyses........................................................................................................82

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7.2.4
Secondary objective analyses.............................................................................85
7.2.4.1
Change from baseline in MADRS total score at Day 8 ........................................85
7.2.4.2
MADRS response/remission.................................................................................85
7.2.4.3
Change from baseline in SMDDS total score at Day 8 and Week 4 ....................85
7.2.6
Safety analyses.....................................................................................................86
7.2.8
Interim Analyses .................................................................................................87
7.3
HANDLING OF MISSING DATA ...................................................................88
7.4
RANDOMISATION ...........................................................................................88
7.5
DETERMINATION OF SAMPLE SIZE .........................................................88
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........91
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................91
8.2
DATA QUALITY ASSURANCE ......................................................................92
8.3
RECORDS...........................................................................................................93
8.3.1
Source documents ...............................................................................................93
8.3.2
Direct access to source data and documents.....................................................94
8.3.3
Storage period of records ...................................................................................94
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................94
8.5
STATEMENT OF CONFIDENTIALITY AND TRIAL PARTICIPANT 
PRIVACY ............................................................................................................95
8.5.1
Collection, storage, and future use of biological samples and 
corresponding data .............................................................................................96
8.6
TRIAL MILESTONES.......................................................................................96
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................97
9.
REFERENCES....................................................................................................98
9.1
PUBLISHED REFERENCES............................................................................98
10.
APPENDICES...................................................................................................103
10.1
TRIAL PARTICIPANT FEEDBACK............................................................103
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................105
11.1
GLOBAL AMENDMENT 1 ............................................................................105

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ABBREVIATIONS AND DEFINITIONS
AE
Adverse event
AESI
Adverse event of special interest
AIC
Akaike information criteria
ALCOA
Attributable, legible, contemporaneous, original, accurate
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
ATRQ
Antidepressant treatment response questionnaire
AUC0-24 h
Area under the plasma concentration-time curve from time 
zero to 24 h
BI
Boehringer Ingelheim
CK
Creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
CNS
Central nervous system
COA
Clinical outcome assessment
CRA
Clinical research associate
CRF
Case report form, paper or electronic (normally referred to as 
“eCRF”)
CRO
Contract research organisation
C-SSRS
Columbia-suicide severity rating scale
CTP
Clinical trial protocol
CTR
Clinical trial report
DBL
Database lock
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition

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ECG
Electrocardiogram
eCOA
Electronic clinical outcome assessment
ED50
Effective dose required to achieve 50% of the desired 
response
eDC
Electronic data capture
EEG
Electroencephalography
eGFR
Estimated glomerular filtration rate
Emax
Maximal efficacy
EoS
End of study (corresponds with end of trial)
EoT
End of treatment
ePRO
Electronic patient reported outcome
ESMS
Emergency Unblinding Service and Medical Support
FOT
Fully outsourced trial
FST
Forced swim test
GCP
Good clinical practice
GGT
Gamma glutamyl transpeptidase
gMean
Geometric mean
GMP
Good manufacturing practice
GOT
Glutamic oxaloacetic transaminase
GPT
Glutamate-pyruvate transaminase
HDRS-17
Hamilton depression rating scale-17
HIV
Human immunodeficiency virus
i.v.
Intravenous
IA
Interim analysis
IB
Investigator’s brochure
ICF
Informed consent form
IEC
Independent ethics committee
IMP
Investigational medicinal product
INR
International normalized ratio
iPD
Important protocol deviations
IRB
Institutional review board
IRT
Interactive response technology

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ISF
Investigator site file
ISPOR
International society for pharmacoeconomics and outcomes 
research
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LCMS/MS
Liquid chromatography-tandem mass spectrometry
LPLT
Last participant last treatment
LPLVPE
Last participant last visit primary endpoint
MADRS
Montgomery Åsberg depression rating scale
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
MDD
Major depressive disorder
MedDRA
Medical dictionary for regulatory activities
MHLW
Ministry of Health, Labour and Welfare (Japan)
MINI
Mini-international neuropsychiatric interview 
MMRM
Mixed-effect model for repeated measures 
MoA
Mode of action
MRD
Multiple rising dose
mRNA
Messenger ribonucleic acid
NAM
Negative allosteric modulator
NDA
New drug application (FDA)
NMDA
N-methyl-D-aspartate
NR2B
N-methyl-D-aspartate receptor subtype 2B 
p.o.
Per os (oral)
PAS
Primary analysis set
PCP
Phencyclidine
PFC
Prefrontal cortex
PK
Pharmacokinetics
PoCC
Proof of clinical concept
PoCP
Proof of clinical principle

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PRO
Patient-reported outcome
PSPV
Patient safety pharmacovigilance
PT
Prothrombin time
qd
Quaque die (once a day)
RBC
Red blood cell
RDW
Red blood cell distribution width
REML
Residual maximum likelihood method
REP
Residual effect period
RFI
Request for information
SAE
Serious adverse event
SDTM
Study data tabulation model
SMDDS
Symptoms of major depressive disorder scale
SNRI
Serotonin and norepinephrine reuptake inhibitor
SoA
Schedule of assessments
SoC
Standard of care
SOP
Standard operating procedure
SRD
Single rising dose
SSRI
Selective serotonin reuptake inhibitor
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal half-life
tmax
Timepoint of maximum plasma concentration
TMF
Trial master file
TMS
Transcranial magnetic stimulation
TRD
Treatment-resistant depression
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
Woman of childbearing potential

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Terms synonymous with those used in this CTP are listed below.
Term
Synonymous term
Trial participant or participant
Subject or patient
End of study
End of trial
Investigational medicinal product
Trial medication (or medication), or trial drug (or
drug), or trial treatment (or treatment), or trial 
intervention, or intervention, or investigational 
product
MADRS
Structured Interview Guide for the Montgomery-
Åsberg Depression Rating Scale (MADRS-SIGMA)
HDRS-17
Structured Interview Guide for the Hamilton 
Depression Rating Scale (HDRS-SIGH-D)

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Major depressive disorder (MDD) is a common, severe, and frequently recurrent mental 
illness with an estimated global point prevalence of approximately 5% [R14-3147]. MDD 
poses a serious social and economic threat to modern societies, as it is a major cause of 
disability according to the Global Burden of Disease Study [R19-0778]. First-line 
antidepressants targeting the monoamine system alleviate symptoms in only 50% of patients 
after 12 weeks [R06-0086], and the overall cumulative remission rate with multiple treatment 
trials including drug switch, combination, and/or augmentation is only 67% after up to 1 year
of treatment [P06-11895]. Current treatments with selective serotonin reuptake inhibitors 
(SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) have also a long onset of 
action, usually 3 to 4 weeks, and a fast onset of action would be significantly beneficial for 
patients and carers. Therefore, adjunctive medications that could improve first-line treatment 
efficacy with a fast onset of action are warranted.
The role of glutamate in depression became apparent after it was reported that tricyclic 
antidepressants blocked the cation (sodium and calcium) channel associated with the 
N-methyl-D-aspartate (NMDA) glutamate receptor [R19-0681] and that functional 
antagonists of the NMDA receptor had antidepressant-like behavioural effects in animals. 
These effects were confirmed by a trial in patients with depression in which a single 
intravenous (i.v.) infusion of ketamine, an unspecific NMDA receptor antagonist used for 
anaesthesia, alleviated depressive symptoms within hours, peaking some days later 
[R19-0772]. Since then, ketamine has demonstrated antidepressant efficacy in multiple 
exploratory clinical trials in treatment-resistant depression (TRD). The responder rate in these 
trials was approximately 50%, the onset was fast, and the average antidepressant effect lasted 
for approximately 1 week after a single infusion [R19-0553]. Meanwhile, the intranasal 
S-enantiomer esketamine received new drug application (NDA) approval by the FDA for 
treatment-resistant depression in conjunction with an oral antidepressant [R19-0829]. 
However, transient perceptual disturbances (dissociative reaction), sedation, blood pressure 
increases and abuse potential (being a scheduled drug) require controlled distribution as well 
as cardiovascular and behavioural monitoring after drug application. Those unwanted effects 
may, at least in part, derive from ketamine’s lack of selectivity, as ketamine blocks the cation 
channel across all NMDA subtypes [R19-0555].
Based on genetic mouse models, the NR2B subunit was identified as a key mediator of 
ketamine’s efficacy [R19-0549]. In a small Phase II study with traxoprodil, an NR2B-specific 
negative allosteric modulator (NAM), the lower dose produced a rapid and robust 
antidepressant response without eliciting a dissociative reaction [R17-3810]. These data 
indicate that NR2B-selective NAMs (e.g. traxoprodil) have a better therapeutic window 
compared with non-selective NMDA inhibitors (e.g. ketamine).

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1.2
DRUG PROFILE
BI 1569912 is a NR2B NAM to be developed for the treatment of MDD.
 
A summary of the BI 1569912 profile is briefly described below, for a more detailed 
description, please refer to the current IB [c29289852].
Mode of action
 
Key Pharmacokinetic characteristics
The analysis of pharmacokinetic (PK) parameters in humans have shown an overall good fit 
with predictions based on animal models. A dose-proportional increase was observed for the 
PK endpoints AUC and Cmax in the single rising dose (SRD) trial 1447-0001 (completed)
 
 
 After administration of a 
 
 in the fasted state, BI 1569912 reached rapid maximum plasma concentrations within 
a median tmax of about 0.5 h. After reaching the maximum concentration, there was a fast 
decline with a parallel terminal phase for all dose groups with a short terminal half-life of 
about 4 h. 
Urinary PK analysis revealed that the amount excreted in urine increased with increasing 
dose. The gMean fraction of dose excreted in urine was very low and ranged from 0.100% to 
0.205%. 
Preliminary PK parameters (gMean [%gCV]) after single and multiple oral administrations of 
BI 1569912 as a tablet in healthy volunteers in MRD trial 1447-0002 are summarized in the 

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current IB [c29289852] and Table 5. 
 
 
 
. Food intake instructions for this trial are described in 
Section 4.1.4.
Drug interactions
, according to the basic models from the FDA 
[R20-0261], EMA [P21-11010], and MHLW [P19-01288] DDI guidelines, 
 
using the software DDI risk calculator v2.0 from PharmaPendium. This tool contains the 
official equations provided by the above-mentioned FDA guidance [R20-0261].
Consequential restricted medications of all described drug interactions are described in
Section 4.2.2.1 and listed in the ISF.
Residual Effect Period

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present. Based on the observed terminal half-life of about 4 h in humans, a REP of ~20 to 
Data from non-clinical studies

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Safety data from clinical studies
In clinical trials to date, BI 1569912 has been well tolerated with a low frequency of adverse 
events (AEs) in all dose groups. Across observed AEs, no dose-dependent increase in 
frequency has been observed for any of these AEs. None of the observed AEs were of severe 
intensity; there were no AEs considered to be dose limiting and no serious AEs (SAEs).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Despite the array of available treatment options, there remains significant unmet medical 
need for patients with MDD who either do not respond to or do not tolerate current 
augmentation approaches (e.g. atypical antipsychotics, lithium) or in cases where these are 
either not available or unsuitable. Adjunctive medications that act rapidly with improved 
efficacy but without the side effects and/or resource requirements of last-line treatment 
options (i.e. a monitored setting for esketamine) would constitute a major medical advance 
and fulfil a high unmet medical need for patients suffering from MDD.
Disruption of complex mood-related circuitry has been implicated in depression. Among the 
findings of altered brain structure and function in depression, the most consistent finding is 
the hypoactivity in the medial prefrontal cortex (PFC). Ketamine [R19-0550, R19-0556] as 
well as NR2B NAMs [R19-0855] cause a burst of glutamate in the PFC that is understood to 
occur via a biased inhibition of GABA-ergic interneurons thus disinhibiting the glutamatergic 
neurons [R19-0556]. This transient increase in glutamate triggers neuronal activation and 
enhances synaptic plasticity [R19-0548, R19-0549, R19-0554, R19-0552].

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Following Phase I studies in healthy volunteers and a proof of clinical principle trial in 
participants with MDD, the present trial is designed to assess dose-range finding data, 
provide proof of clinical concept, and confirm the safety and tolerability of BI 1569912 
compared with placebo when administered for 6 weeks as an adjunct to background 
pharmaceutical therapy. These results will be used to characterise the dose-response 
relationship within the therapeutic range, and to select the target dose(s) for pivotal studies.
In order to be able to address future scientific questions, trial participants will be asked to 
voluntarily donate biospecimens for banking (please see Section 5.5). If the trial participant
agrees, banked samples may be used for future biomarker research and drug development 
projects, e.g. to identify patients that are more likely to benefit from a treatment or experience 
an AE, or to gain a mechanistic or genetic understanding of the product’s effects and thereby 
better match patients with therapies.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
BI 1569912 has been given to healthy volunteers in a single dose escalation study 
(1447-0001) and in a Japanese dose escalation study (1447-0004) at up to
 which 
were assessed as safe and well tolerated showing no dose limiting effects,
 
. Single doses of BI 1569912 in an ongoing blinded trial 
in participants with MDD (1447-0003) have not presented any safety signals
 
 
 Doses selected for the current study 
in MDD participants (refer to Section 4.1.2) had a favourable safety profile and were well 
tolerated in both the SRD and MRD healthy volunteer studies.
Participants with MDD receiving oral BI 1569912 adjunctive to their standard of care (SoC) 
antidepressant may experience relief of symptoms related to depression during the study. 
However, BI 1569912 is an experimental drug at an early stage of testing and therefore an 
individual benefit for participants cannot be guaranteed. Nevertheless, participation in this 
trial is of major importance for the development of a new orally available treatment with the 
potential to relieve depressive symptoms faster than standard treatments in MDD patients 
who show insufficient response to their current SoC treatment.
1.4.2
Risks
Table 1 provides an overview of the potential risks related to exposure to the trial 
investigational medicinal product (BI 1569912), known risks related to the compound class, 
known risks related to psychoactive drugs and trial procedure-related risks. For further details 
on treatment-related risks, refer also to Section 1.2 of the current clinical trial protocol (CTP) 
and the current version of the IB [c29289852].

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Table 1
Overview of trial related risks
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale for the risk Mitigation strategy
Investigational Medicinal Product – BI 1569912
Nonclinical data:
Healthy volunteer data:
Phase I SRD
Up to 
 no AE 
occurred more than once 
across all 7 dose groups.
Therefore, no specific AE 
risk associated with 
BI 1569912 has been 
identified.
There might be 
compound-related unknown 
risks at the same dose levels 
in participants with a 
psychiatric disorder.
All reported AEs were transient and a
majority were of mild intensity.
None of the participants experienced any 
serious adverse events (SAEs) or relevant 
alterations in laboratory parameters, vital 
signs, or ECG.
Whether participants with MDD show a 
different sensitivity to BI 1569912 
compared with healthy volunteers is not 
known, although a higher sensitivity is 
not expected. However, the doses 
required for efficacy might be higher than 
expected based on animal data using the 
forced swim test as a sign of potential 
antidepressant activity. In the first 
participants with MDD in the ongoing 
PoCP clinical trial (1447-0003), no SAEs, 
AESIs, or adverse events of severe 
intensity have been observed.
Extensive standard safety laboratory 
measurements, ECG measurements, 
monitoring of vital signs, and 
physical examinations will be 
performed before IMP
administration and at every site visit 
thereafter. Management of 
symptoms, evaluation, and 
follow-up will be conducted as 
needed to ensure participant safety, 
per the investigator’s clinical 
judgement.

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Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale for the risk Mitigation strategy
Drug-induced liver injury 
(DILI)
Rare but severe event, thus under constant 
surveillance by sponsors and regulators.
Timely detection, evaluation, and 
follow-up of laboratory alterations in 
selected liver laboratory parameters 
to ensure the safety of trial 
participants.
General risks of psychoactive drugs
Occurrence or increase of 
suicidality
Some patients with MDD have an 
increased risk of suicidality. Some studies 
have shown a correlation of increased 
suicide risk with the use of certain 
antidepressants. Although there is no 
precedent from clinical data implicating 
an association between NR2B negative 
allosteric modulation and suicidal ideation 
and behaviour, this risk cannot be ruled 
out completely.
Participants with a recent history of 
clinically significant suicidal 
ideation are to be excluded from the 
current trial (refer to Section 3.3.3). 
In the interest of ensuring participant 
safety, trial participants will be 
proactively screened and monitored 
throughout the trial for suicidal 
ideation and behaviour in 
accordance with regulatory 
guidance.

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Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale for the risk Mitigation strategy
Sedation, combined with 
impaired thinking, 
judgement, and/or motor 
skills
Psychoactive drugs are known to 
potentially cause unwanted side effects on 
brain function.
It is recommended to observe 
participants for >2 h after first dose.
During site visits, participants will 
be continuously monitored for AEs 
and neurological examinations will 
be performed throughout the trial.
While no AEs involving 
somnolence, vision impairment, or 
psychomimetic effects associated 
with BI 1569912 have been 
observed in clinical trials,
participants should be cautioned 
about operating machinery, 
including automobiles, until they are 
reasonably certain that the IMP does 
not adversely affect their ability to 
engage in such activities. It is 
recommended that participants 
should exercise caution when 
driving or operating machinery.
Potential compound class effects:
Dissociative symptoms
NMDA antagonists, in particular 
ketamine, and some NR2B-specific 
modulators such as traxoprodil, are 
associated with the occurrence of 
dissociative symptoms; expected to occur 
in a dose-dependent manner
Participants with a history of 
psychotic episodes or positive drug 
screening are to be excluded from 
the current clinical trial; IMP should 
be administered in quiet ambient 
conditions. Clinical assessment of 
psychiatric symptoms associated 
with dissociation will be assessed
during the course of the study via 
 
 
AE reporting to 
monitor and assess the severity of
specific symptoms.
Blood pressure increase
Same risk and rationale as dissociative 
symptoms
Monitoring of arterial blood pressure 
at site visits
Potential for drug abuse
Some drugs, including ketamine, are 
associated with a risk of abuse. While the 
potential for abuse liability with 
BI 1569912 appears low based on the 
currently available nonclinical data, 
specific clinical abuse liability studies 
have not yet been performed with 
BI 1569912.
Participants with a history of 
substance use disorders are to be 
excluded from the current clinical 
trial, clinical assessments of 
psychiatric symptoms will be 
conducted throughout the trial

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Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale for the risk Mitigation strategy
Matching placebo to BI 1569912
Worsening of depression
and/or the occurrence or 
increase in suicidality
Even though mitigation measures are 
applied, this risk cannot be ruled out 
completely.
Participants will remain on their 
stable antidepressant treatment with 
an SSRI/SNRI and psychotherapy, 
where applicable. Placebo is 
adjunctive to this treatment. 
Participants will be monitored 
during the treatment and follow-up 
periods to ensure that worsening of 
pre-existing conditions or any newly 
occurring events are detected and 
any necessary actions taken 
according to stopping criteria.
Trial procedures
General discomfort
Participants might experience some 
general discomfort due to the procedural
nature of clinical trial conduct
Management of discomfort, 
evaluation, and follow-up will be 
conducted as needed to ensure 
participant safety.
Blood draw
The potential risks of a blood draw 
include fainting and pain, bruising, 
swelling, or rarely infection where the 
needle is inserted.
In rare cases, a nerve may be damaged, 
inducing long-lasting abnormal sensations 
(paraesthesia), impaired sensation of 
touch and persistent pain.
The total volume of blood withdrawn 
during the entire study per participant will 
not exceed the volume of a normal blood 
donation (approximately 500 mL).
No health-related risk is expected 
from blood withdrawal.
Other risks
Hypersensitivity and 
allergic reactions
As with all drugs, the potential for 
hypersensitivity and allergic reactions has 
to be taken into consideration with 
BI 1569912 administration.
First dosing of BI 1569912 will be 
conducted on site with a 
recommendation of at least 2 h of 
post-administration surveillance;
monitoring and management of 
symptoms and treatment as needed 
throughout the course of the trial, 
including discontinuation of trial 
participation as per the investigator’s 
clinical judgement.

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1.4.3
Discussion
Major depressive disorder was ranked as the third highest cause of the burden of disease 
worldwide in 2008 by the WHO, which has projected that MDD will rank first by 2030. Both 
patients, caregivers, and healthcare providers are seeking more effective therapies that 
address the core symptoms of MDD, with a faster onset of action, a higher response rate, 
higher remission rate, and a more tolerable safety profile than what is currently available. 
NR2B-specific negative allosteric inhibitors have shown rapid efficacy in reducing 
depressive symptoms in multiple exploratory trials with no serious safety concerns
[R17-3810, R19-0986, R22-0355, c42998816]. In contrast to other compounds with a similar 
mode of action, which are delivered intravenously or intranasally under medical supervision, 
BI 1569912 is an oral medication that allows for non-monitored, home administration. This 
means that BI 1569912 could be given in 
 than NMDA receptor 
antagonists such as esketamine.
The nature of the target and the mechanism of action of BI 1569912 is well understood. The 
preclinical safety package has shown a favourable profile of BI 1569912 at doses in the range 
of the expected human exposure. 
 
 
Close monitoring was conducted in Phase I trials for 
signs indicative of these events, with no reported occurrences. 
In view of the patient population expected for the current trial and the need to adequately 
monitor suicidality; frequent clinic visits, 
 
, are planned to monitor participants. Additionally, all 
participants will be on stable treatment of MDD with an SSRI/SNRI at the time of trial entry 
and throughout the conduct of the trial. In addition to the standard situations, treatment 
should be discontinued if there are signals consistent with disease worsening as listed in 
Section 3.3.4.1. With regard to the mechanism of action of BI 1569912 and the AEs reported 
in clinical trials to date, there is no undue risk related to stopping the IMP during the 
treatment period or at the end of the treatment period, nor any major risk related to potential 
aggravation of the side effect profile/s of the background medication/s. Considering the 
medical need for the development of a better tolerated and more effective treatment for 
patients with MDD, the expected benefit outweighs the potential risks.
In the context of the unmet medical need, anticipated benefit of BI 1569912, and available 
non-clinical and clinical information, the benefit-risk evaluation of the compound is
favourable.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
The main aims of this trial are to assess dose-range finding data of BI 1569912 compared 
with placebo as adjunctive therapy in participants with MDD who show inadequate response 
to ongoing antidepressant treatment and to provide proof of clinical concept (PoCC) to 
support 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 quantitative treatment effect size.
The trial will be performed to characterise the dose-response curve for BI 1569912 in 
participants with moderate to severe MDD by assessing 3 active doses and placebo. Response 
is defined as the change from baseline in Montgomery-Åsberg Depression Rating Scale 
(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 characterisation will be on treatment which will assume all participants took 
randomised 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)

Change from baseline in MADRS total score at Day 8

Response defined as ≥50% MADRS reduction from baseline at Day 8

Response defined as ≥50% MADRS reduction from baseline at Week 6

Remission defined as MADRS total score ≤10 at Week 6

Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS)
total score at Day 8

Change from baseline in SMDDS total score at Week 4
No key secondary endpoints have been defined for this trial.

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2.2.3
Safety
There are no specific safety endpoints defined for this trial, however, safety will be assessed 
descriptively in participants who received at least one dose of IMP (e.g. AEs, SAEs, AESI, 
 physical examination, vital signs, ECG, and safety 
laboratory tests).

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
This is a multi-centre, randomised, double-blind (participant and investigator), 
placebo-controlled parallel group Phase II trial to examine the efficacy and safety of oral 
BI 1569912 once daily over a 6-week treatment period in adult patients with moderate to 
severe MDD on stable antidepressants. Participants will be enrolled into the trial once 
informed written consent has been obtained. For those participants who are not already taking 
an SSRI/SNRI, a 6-week lead-in phase is built into the study. 
Participants suitable after screening (Visit 1 for participants already on an SSRI/SNRI, 
Visit 1A for participants that are taking part in the lead-in phase) will be randomised to the 
6-week double-blind treatment period and will be assigned to placebo or one of 3 doses of 
active BI 1569912 drug (low to high dose) in a 2:1:1:2 ratio. Visit 1 will occur prior to the 
lead-in phase for participants not on an SSRI/SNRI. Participants who are receiving other 
background therapy (psychotherapy, pharmacotherapy, or both) and are on a stable regimen 
at randomisation will remain on their regimen throughout the trial. 
Once treatment is completed, participants will have an 8-day follow-up visit and complete 
study participation (EoS Visit). Individual participation is concluded when the participant has 
completed their last planned visit. The overall trial design is depicted in Figure 1.
Figure 1
Study Design
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is a randomised double-blind, placebo-controlled, parallel-design trial. This design is 
appropriate for providing proof-of-concept/dose-range finding and assessing the safety and 
efficacy of BI 1569912 compared with placebo in participants with MDD. It is important to 
have a placebo control to address potential confounding factors. This is acceptable as 
Optional 
6-week --0--------------
lead-in 7;;J" 
phase* 
Screening 
2:1 :1 :2 
SSRI/SNRI + Bl 1569912 once daily (5 mg) 
SSRI/SNRI + placebo once daily 
6 weeks (double blind treatment) 
Follow up 
I< --------------*---------------------------,i>i< 
··············
;>I 
i 
i 
Day -21 to -3 
Visit 1 /1A 
Day 1 
Visit 2 
Randomisation 
i 
Day 8 
Visit 3 
*6-week lead-in for participants not already on SSRI/SNRI antidepressant therapy 
i 
Day 29 
Visit 4 
S = Screening (Visit 1 for participants already on an SSRI/SNRI, 2"d screeningN isit 1A for lead-in participants) 
R = Randomisation 
EoT = End of Treatment 
EoS = End of Study 
i 
i 
Day43 
EoT Visit 
EoT +8 days 
EoS Visit 

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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.
The design of the trial will provide efficacy, safety, and dosing information to support PoCC. 
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.
The trial design and schedule of assessments was put through a trial simulation. The trial 
simulation objective was to engage with patients and trial sites early in the development of 
the trial. Trial simulations were conducted with MDD trial nurses, coordinators, and patients 
living with MDD. Key learnings around insights and potential challenges should lead to 
solutions to ensure a positive clinical trial experience by sites and patients.
A total of 3 active BI 1569912 doses will be administered to provide reasonable coverage for 
most monotonic shapes of the dose-response relationship. A sufficiently broad set of 
candidate shapes for this relationship has also been chosen. In addition, an unequal allocation 
ratio (2:1:1:2) 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 with 
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 a sustained effect. Data at Day 8 will provide further 
evidence of efficacy and dosing information of BI 1569912 compared with placebo in an 
acute setting where a rapid onset of efficacy is desirable. In addition, we will also obtain 
safety data through the end of observation period (early IMP discontinuation date/EoT
+8 days [+6 days]). Collectively, this information will help facilitate the design of pivotal
studies.
This trial will include an option for participants to complete questionnaires to provide 
feedback on their clinical trial experience. Providing this feedback is not required for trial 
participation, and information collected from these questionnaires will not be analysed as part 
of the clinical data for the trial (see Section 10.1).
3.3
SELECTION OF TRIAL POPULATION
Approximately 222 participants are planned to be randomised into the trial, in order to have
approximately 180 participants evaluable for the primary analysis. It is planned that about 
65 trial centres in 7 countries will be participating in this trial to ensure a sufficient number of 
participants are randomised.
It is expected that approximately 4-8 participants will be randomised at each trial centre. If 
enrolment is delayed, additional sites may be recruited. To avoid differential centre influence 

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on trial results, permission to randomise more than 15 participants per site must be obtained 
from the sponsor, designee. This will only be allowed after a careful review of the enrolment 
status and the site.
Screening of participants for this trial is competitive, i.e. screening for the trial will stop at all 
centres when such a number of participants has been screened that it is anticipated that a 
sufficient number of participants will be randomised to trial treatment. Investigators will be 
notified about screening completion and will then not be allowed to screen additional 
participants for this trial. Participants already in screening at this time will be allowed to 
continue to randomisation if eligible. A log of all participants screened for the trial (i.e. who 
have signed informed consent) will be maintained in the ISF, irrespective of whether or not
IMP was administered to the participant.
The following information, at minimum, will be collected, including for participants who are 
determined to be ineligible for enrolment: participant number, visit date, demographics, 
eligibility criteria, information on AEs (if applicable), concomitant treatment relevant for the 
AE.
If retrospectively it is found that a trial participant has been randomised in error (i.e. did not 
meet all the inclusion criteria or met one of more exclusion criteria), the sponsor or delegate 
should be contacted immediately. Based on an individual benefit-risk assessment, a decision 
will be made as to whether continued trial participation is possible.
3.3.1
Main diagnosis for trial entry
Participants meeting diagnostic criteria of MDD per Diagnostic and Statistical Manual of 
Mental Disorders (DSM-5) and diagnosis confirmed at time of screening by 
Mini-International Neuropsychiatric Interview (MINI) will be screened for suitability for the 
trial. In addition, participants must meet criteria for moderate to severe depression as assessed 
and confirmed by the Hamilton Depression Rating Scale-17 (HDRS-17) and show 
insufficient response to their current antidepressant therapy as assessed and by the 
Antidepressant Treatment Response Questionnaire (ATRQ).
Please refer to Section 5.6.1 for further details regarding the confirmation of diagnosis and 
Section 8.3.1 (Source Documents) for the documentation requirements pertaining to the 
inclusion and exclusion criteria.
3.3.2
Inclusion criteria
For inclusion in the randomised trial, all inclusion criteria must be satisfied prior to 
randomisation. For participants taking part in the SSRI/SNRI lead-in, inclusion criteria 6 & 7
must be met by the 2nd screening visit (Visit 1A) and can remain blank in the clinical 
database during the initial screening visit (Visit 1). All inclusion criteria must be 
reassessed/confirmed at the 2nd screening visit (Visit 1A) for participants taking part in the 
SSRI/SNRI lead-in.
1. Male and female participants, 18 to 65 years of age, both inclusively at the time of 
consent.

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2. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
3. Women of childbearing potential (WOCBP; see Section 4.2.2.3) must be ready and able 
to use a highly effective method of birth control per ICH M3 (R2) that results in a low 
failure rate of less than 1% per year when used consistently and correctly plus one 
additional barrier method. A list of contraception methods meeting these criteria and 
instructions on the duration of use is provided in the participant information and in 
Section 4.2.2.3.
4. Established diagnosis of MDD, single episode or recurrent, as confirmed at the time of 
screening by the MINI with a duration of current depressive episode ≥8 weeks at the time 
of screening visit.
5. Hamilton Depression Rating Scale-17 (HDRS-17) – Severity scale score >17.
6. A documented ongoing monotherapy treatment of ≥6 weeks at the randomisation visit, 
with an SSRI or SNRI specified in the ISF at adequate dose (at least minimum effective 
dose as per prescribing information).
The participant must adhere to the screening visit dose of the background SSRI/SNRI 
until the end of the trial (EoS Visit). Participants should be on a stable dose for at least 
4 weeks prior to randomisation.
Participants, who, in addition to their monotherapy with an SSRI/SNRI, are taking 
additional low dose antidepressant medications for purposes other than treating 
depressive symptoms, are not excluded (see Section 4.2.2.1). The dose must be less 
than the lowest dose indicated for MDD.
7. In the current episode, participants have shown insufficient treatment response defined by 
less than 50% response to a maximum of 4 antidepressant treatments of adequate dose 
and treatment duration (according to Summary of Product Characteristics) as evaluated 
by the ATRQ.
3.3.3
Exclusion criteria
All exclusion criteria must be assessed during the first screening visit (Visit 1) regardless of 
participation in the SSRI/SNRI lead-in. All exclusion criteria are to be reconfirmed at the 
2nd screening visit (Visit 1A) for participants that are taking part in the SSRI/SNRI lead-in.
1. Per MINI, have ever met diagnostic criteria for schizophrenia, schizoaffective disorder, 
schizophreniform disorder, bipolar disorder, or delusional disorder.
2. Diagnosis with antisocial, paranoid, schizoid or schizotypal personality disorder, or MDD 
with psychotic features 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.
3. Diagnosis of any other mental disorder that was the primary focus of treatment within 
6 months prior to screening (as per clinical discretion of the investigator).

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4. History or presence (upon clinical examination) of seizure disorders or an increased risk 
of seizures (first degree relative with epilepsy), stroke, brain tumour or any other major 
neurological illness that could impact participation in the trial.
5. A current or recent history of clinically significant suicidal ideation with intent within the 
past 3 months, corresponding to a score of 4 or 5 for ideation on the C-SSRS or a suicidal 
attempt within the past year, as indicated by the C-SSRS at screening visit.
6. Participants with a body mass index (weight [kg]/height [m]²) lower than 18 kg/m² or 
greater than 40 kg/m2 at screening.
7. Diagnosis of a moderate to severe substance related disorder within 6 months prior to 
screening visit (with exception of caffeine and tobacco).
8. Positive drug screen (amphetamines, opiates, cocaine, barbiturates, phencyclidine) at 
screening or Visit 1A (if applicable). Participants with positive cannabis and 
benzodiazepine drug tests can be included if the investigator confirms that there is no 
active substance related disorder.

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3.3.4
Discontinuation of trial participants from treatment or assessments
Trial participants may discontinue trial treatment or withdraw consent to trial participation as 
a whole (“withdrawal of consent”) with very different implications; please see 
Sections 3.3.4.1 and 3.3.4.2.
Measures to control the withdrawal rate include careful trial participant selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the

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explanation of the consequences of withdrawal. Every effort should be made to collect data 
on all randomised participants. This includes randomised participants who never took the 
IMP and participants who permanently discontinued the IMP.
The decision to discontinue trial IMP or withdraw consent to trial participation and the reason
(if provided) must be documented in the trial participant files and eCRF. If applicable, 
consider the requirements for AE collection and reporting (see Section 5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual trial participant will discontinue trial IMP if:

The trial participant wants to discontinue trial IMP. The trial participant will be asked 
to explain the reasons but has the right to refuse to answer.

The trial participant has repeatedly shown to be non-compliant with important trial 
procedures and, in the opinion of the investigator, the safety of the trial participant 
cannot be guaranteed as they are not willing or able to adhere to the trial requirements 
in the future.

The trial participant needs to take concomitant medication that interacts with the IMP, 
see Section 4.2.2.1.

If it is found that a trial participant took restricted medication, the sponsor or delegate 
should be contacted immediately. Based on an individual benefit-risk assessment, a 
decision will be made as to whether the trial participant can continue the IMP or 
should be discontinued.

The trial participant can no longer receive trial IMP for medical reasons such as 
surgery, AEs, other diseases, or pregnancy. In case of a temporary reason, trial IMP 
should be restarted if medically justified; please see Section 4.1.4.

Pregnancy occurs during the trial. (Once a participant has been enrolled in the clinical 
trial and has taken the IMP, the investigator must report any IMP exposure during 
pregnancy which occurred in a female trial participant to the Sponsor immediately 
(within 24 h) by means of Part A of the Pregnancy Monitoring Form to the Sponsor’s 
unique entry point).

The participant must discontinue treatment with the IMP if: 
o
The participant develops suicidal ideation
 
or suicidal behaviour
 
o
In the event of worsening of MDD which requires medical treatment which is 
on the list of restricted medications (refer to Restrictions Section 4.2.2.1 and
ISF), the IMP has to be discontinued.
If a participant permanently discontinues the IMP, an EoT Visit must be performed as soon as 
possible after the last dose of IMP, ideally 24 h after final IMP intake. It is extremely 
important that participants are encouraged to complete at least the MADRS, 
 
 assessments. 
 
. The reason for discontinuation of treatment must be recorded in the eCRF, if given.
Participants who discontinue IMP prematurely should ideally be observed as if they were still 
receiving blinded trial treatment. 

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If it is not possible to attend all regularly scheduled visits after the EoT Visit, at least phone 
contacts should occur at the scheduled visit time points. It is vital to explain to these 
participants the importance of continued trial participation. If the participant is not willing to 
continue to attend regularly scheduled visits after the EoT Visit, an EoS Visit should be 
scheduled for 8 days (+6 days) after discontinuation of the IMP. Additional information will 
be provided in the ISF.
When discussing options for continued trial participation, sites must present the first option 
outlined in Table 2 to the participant and discuss this option thoroughly before presenting the 
next option for follow-up.
Table 2
Follow-up of participants who prematurely discontinue the IMP
Early DC Option 1
EoT Visit performed as soon as possible, ideally 24 h after last IMP 
intake. Continue to conduct regularly scheduled trial visits as per 
protocol
 
If participant does not 
agree to Option 1, present:
Early DC Option 2
EoT Visit as soon as possible and attend the EoS Visit in person; 
other in person visits can be replaced with teleconference visits. 
Focus on key efficacy and safety endpoints MADRS,
 
 (at minimum MADRS should be completed) and safety 
assessments per Section 5.2.6.2.1
If participant does not 
agree to Option 2, present:
Early DC Option 3
EoT Visit and proceed to EoS Visit (8 days [+6 days] after last 
intake of IMP)
Participants should be encouraged to choose the most rigorous follow-up schedule they are 
willing and able to comply with. The investigators should inform these participants that they 
will be allowed to change this schedule later if needed. If the patient refuses any further 
follow-up after treatment discontinuation, this will be considered as “withdrawal of consent” 
by the patient and must be recorded as such in the eCRF.
Participants may choose to re-start the IMP at any time within the planned treatment period 
as long as there is no safety concern, in the opinion of the investigator, and the maximum 
interruption period is less than 2 weeks.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the IMP for all trial participants 
or take any other appropriate action to guarantee the safety of the trial participants. Even if 
the IMP is discontinued, the trial participants will remain in the trial and, given their 
agreement, undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the SoA and Section 6.2.3.

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3.3.4.2
Withdrawal of consent to trial participation
Trial participants may withdraw their consent to trial participation at any time without the 
need to justify the decision.
If a trial participant wants to withdraw consent, the investigator should be involved in the 
discussion with the trial participant and explain the difference between IMP discontinuation 
and withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after IMP discontinuation (see Section 3.3.4.1).
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. New efficacy or safety information invalidating the earlier positive benefit-risk
assessment; please see Section 3.3.4.1
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate 
conduct of the trial
Further treatment and follow up of trial participants affected will occur as described in 
Section 3.3.4.1.
The investigator/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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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 1569912 tablets and matching placebo are provided by Boehringer Ingelheim Pharma 
GmbH & Co. KG, Germany.
See Section 1.2 and the current IB [c29289852] for more details regarding BI 1569912.
4.1.1
Identity of the Investigational Medicinal Products
Table 3
BI 1569912
Substance:
BI 1569912
Pharmaceutical formulation:
Tablets
Unit strength:
2.5 mg and 10 mg
Posology:
qd
Mode of administration:
p.o.
Table 4
Placebo matching BI 1569912
Substance:
Placebo matching in size and weight to BI 1569912 tablets
Pharmaceutical formulation:
Tablet
Unit strength:
Not applicable
Posology:
qd
Mode of administration:
p.o.
4.1.2
Selection of doses in the trial and dose modifications
The following doses of BI 1569912 have been selected for this trial:

5 mg, qd

10 mg, qd

20 mg, qd
The criteria for dose selection are based on preclinical and clinical data of BI 1569912 
gathered during research and development (See Section 1.2). Doses from 5 to 20 mg 
BI 1569912 once daily were selected based on the following considerations:
Safety and tolerability of BI 1569912 have been evaluated in healthy volunteers for up to 
14 days for doses ranging from 2.5 to 20 mg and in single doses from 0.25 to 30 mg. Across 
all observed AEs, there has been no dose dependent-increase in frequency for any AEs. There 
were no AEs considered to be dose limiting and no SAEs. In the first 42 randomised 
participants of a double-blinded single dose trial in patients with a similar profile to those 
expected in the current trial, there were no reports of SAEs, AESIs, or AEs of severe 
intensity.

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4.1.3
Method of assigning trial participants to treatment groups
After the assessment of all inclusion and exclusion criteria during Visit 2, each eligible trial 
participant will be randomised to a treatment group according to a randomisation scheme
described in Section 7.4. Randomisation codes will be generated through a validated software 
and kept blinded to the trial team, sites, and trial participants. Access to the codes will be 
controlled and documented. An Interactive Response Technology (IRT) system will be used 
to screen participants, create a participant number, perform treatment assignment, manage 
initial/re-supply ordering of IMP supplies, and handle emergency unblinding. Instructions for 
the use of IRT are provided in the ISF.
4.1.4
Drug assignment and administration of doses for each trial participant
The IMP assignment will be provided through IRT. The assigned medication numbers must 
be entered in the eCRF, and the corresponding medication kits must be given to the 
participant. The duration of treatment is 6 weeks. The final dose of IMP should be taken on 
the day before the EoT Visit.
Participants should be instructed to swallow the IMP in its entirety (without chewing) with 
water, every day at approximately the same time (ideally in the morning). The ideal time 
between intake of IMP is 24 h. Participants should not eat (i.e. fast) for 2 h prior to and 1 h
post every IMP intake. There are no restrictions for water intake. On Visit 4, participants 
should be instructed not to eat 
 (2 h after IMP 
administration). The time of IMP and food intake should be recorded in the eCRF as 
described in Section 5.3.1. If a daily dose is missed by more than 12 h, that dose should be 
skipped and the next dose should be taken as scheduled. On days prior to a visit, the daily 
dose should be taken approximately 24 h before the planned dose at the visit. 
Participants should take their background medication as usual (with or without food) 
regardless of trial visits. On Visit 4, background therapy should be taken before or after, but 
not during the site visit.
After randomisation during Visit 2, patients will receive their first medication kit. A dose of 
IMP consists of 2 tablets to be taken once daily. The first dose of IMP will be taken at the 
study site under supervision of the investigator or site staff. At Visit 2, participants will 
receive a medication kit containing supplies for a total of 10 treatment days (7 treatment days
plus 3 days reserve). At Visits 3 and 4, kits will contain supplies for a total of 30 treatment 
days (21 treatment days plus 9 days reserve), and 20 treatment days (14 treatment days plus 
6 days reserve), respectively. Return of the used/unused medication kits will occur at Visits 3, 
4, and EoT. After a temporary interruption, trial treatment may be restarted (Section 3.3.4.1).
Site visits should be scheduled according to the usual IMP intake time, which is ideally in the 
morning. Participants should be instructed not to take the IMP on the day of Visits 3 and 4 
 
 For participants that are 

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unable to come to the site during their typical dosing time, they should take their IMP as 
usual at home and reschedule the site visit as soon as possible. For patients that complete the 
treatment period, the final dose of IMP should be taken on the day before the EoT visit. 
Participants who have taken a dose of IMP on the day of the EoT Visit should have the visit 
rescheduled as soon as possible, ideally on the following day.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Trial participants, investigators, central reviewers, and everyone involved in the trial conduct 
or analysis will remain blinded regarding the randomised treatment assignments until the 
database is declared ready for final analysis (after database lock after last patient last visit) 
according to the sponsor’s standard operating procedures (SOPs). Further details regarding 
the timepoint of unblinding the database for analyses are provided in the TSAP.
Access to the randomisation code will be kept restricted until its documented release per 
sponsor SOP.
Exploratory interim analyses may be performed by an independent team at the sponsor for 
internal planning purposes. Details are given in Section 7.2.8, including how access to 
unblinded data and results will be controlled and documented in the Logistics and Access 
Plans. 
The ECGs do not represent a risk of unblinding.
4.1.5.2
Emergency unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must be used only in
an emergency when the identity of the trial IMP must be known to the investigator in order to
provide appropriate medical treatment or otherwise assure safety of trial participants. In 
addition, trial investigators who are unable to access the IRT system or external healthcare 
professionals (in case of medical emergency outside of the trial site) can contact the 
Emergency Unblinding Service and Medical Support (ESMS). ESMS has immediate, 24/7 
access to the randomisation codes. It must be used only in an emergency when the identity of 
the trial drug must be known in order to provide appropriate medical treatment or otherwise 
assure safety of trial participants. The treatment allocation should not be disclosed to the 

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sponsor/designee unless this is explicitly requested. The reason for unblinding must be 
documented in the source documents and/or appropriate eCRF page.
Due to the requirements to report suspected unexpected serious adverse reactions (SUSARs), 
it may be necessary for a representative from Boehringer Ingelheim’s Pharmacovigilance
group to access the randomisation code for individual trial participants during trial conduct. 
The access to the code will only be given to authorised PSPV representatives for processing 
in the Pharmacovigilance database and not be shared further.
4.1.6
Packaging, labelling, and re-supply
The IMP will be provided by Boehringer Ingelheim or a designated CRO. The IMP will be
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP).
Re-supply to the sites will be managed via an IRT system, which will also monitor expiry 
dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
IMP 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, immediately contact the 
CRA (as provided in the list of contacts) and follow the procedures for assessing and 
reporting temperature excursions provided in the ISF.
4.1.8
Drug accountability
The investigator or designee will receive the IMP delivered by the sponsor or delegate 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 or 
delegate and the investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of a signed and dated clinical trial protocol

Availability of the curriculum vitae of the Principal Investigator

Availability of the proof of a medical license for the Principal Investigator

Availability of FDA Form 1572
The IMP is not allowed to be used outside the context of this protocol and must not be 
forwarded to other investigators or clinics. Trial participants should be instructed to return 
unused IMP (refer to Section 4.3 for more details regarding compliance).

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The investigator or designee must maintain records of the product’s delivery to the trial site, 
inventory at the site, use by each trial participant, and the return to the sponsor or
warehouse/drug distribution centre or alternative disposal of unused products in alignment 
with the sponsor, if applicable. 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 IMP and trial participants. The investigator or 
designee will maintain records that adequately document that trial participants were provided 
the medication kits specified by this clinical trial protocol and reconcile all IMPs 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 IMP supplies have been returned by the 
trial participant and that no remaining IMP supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
4.2.1.1
Auxiliary medicinal products
Participants will remain on their stable antidepressant treatment with an SSRI/SNRI
throughout the duration of the trial. Concomitant treatments which are allowed or restricted 
before and during trial participation are listed in the ISF. In case participants are participating 
in the SSRI/SNRI lead-in phase, BI/designee will reimburse the cost of SSRI/SNRI treatment 
for the duration of the trial as pass-through costs. Participants must adhere to the screening 
visit dose of the background antidepressant for the entire duration of the trial. Rescue therapy 
will be allowed, as per judgement of the investigator.
4.2.1.2
Emergency procedures
There are no special emergency procedures to be followed. If AEs require treatment, the 
investigator can authorise symptomatic therapy. In those cases, site staff will follow SOPs 
and participants will be treated as necessary and, if required, kept under supervision at the 
trial site or transferred to a hospital until all results of medical evaluations are acceptable and 
have returned to normal or values that are considered clinically non-relevant.
For handling participants with positive report of suicidal ideation and/or behaviour, please 
refer to Section 5.2.5.1.
4.2.2
Restrictions

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All uses of concomitant or rescue therapies are to be recorded (including time of intake) on 
the appropriate pages of the eCRF.
The list of these restricted medications can be found in the ISF. The list is not comprehensive. 
For example, drugs that are solely indicated for diseases that are excluded in this trial (i.e. 
cancer drugs) may not be listed.
4.2.2.2
Restrictions on diet and lifestyle
In general, participants should keep their usual habits throughout the trial for diet and 
exercise, as well as nicotine, alcohol, and caffeine intake. These habits should be within 
acceptable daily amounts in discretion of the investigator and not be drastically changed 
throughout the trial conduct.
Note the following restrictions:

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 SoA). For a list of drugs 
assessed by the urine drug screen please refer to Table 6.

Participants should not enter or modify a smoking-cessation program during the 
conduct of the trial.

Patients should not have a change in type, intensity and/or frequency of allowed 
psychotherapy or other non-drug therapies (e.g. acupuncture or hypnosis) 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 IMP does not adversely affect 
their ability to engage in such activities.
4.2.2.3
Contraception requirements
A woman is considered of childbearing potential, i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilisation methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Tubal ligation is 
not a method of permanent sterilisation. A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause.
Throughout the trial and for a period of at least 28 days after the final dose of IMP, trial 
participants who are WOCBP must use a highly effective method of birth control per 
ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently 
and correctly, plus one barrier method if their sexual partner is a man able to father a child.
Acceptable forms of contraception are:

Combined (oestrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal)

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
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomised sexual partner (with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate) and provided that the partner is the sole sexual partner 
of the WOCBP clinical trial participant

Complete sexual abstinence is allowed when this is in line with the preferred and usual 
lifestyle of the participant. 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 (i.e. periodic abstinence such as calendar, 
ovulation, symptothermal, post-ovulation methods, and withdrawal are not acceptable 
methods of contraception). 
Plus one of the following barrier methods:

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide
There are no contraceptive requirements for male participants. Please see the current IB
[c29289852] for details regarding nonclinical reproductive/developmental toxicity studies.
4.3
TREATMENT COMPLIANCE
Investigational medicinal product will be dispensed to the participant at the study site by 
responsible site personnel. Details regarding dispensing of the IMP to each participating 
patient, including patient identification, the amount of IMP dispensed, the date the IMP was 
dispensed, and the numbers of tablets returned to the site, will be recorded in the drug 
accountability log. All dispensed IMP should be recorded in the drug accountability log of 
the investigator site file. 
Trial participants are requested to bring all remaining trial IMP, including empty package 
material, with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below.
Treatment compliance (%) =
Number of doses actually taken 100
Number of doses which should have been taken as directed by the 
investigator
The potential for IMP abuse will be closely monitored. Events including overdose, misuse, 
lost, and unaccounted for IMP must be thoroughly documented in the participant’s source 
documentation and on the appropriate pages of the eCRFs. Furthermore, if the treatment 
compliance is less than 80% or greater than 100%, site staff should discuss with the trial 
participant the importance of compliance and document the reasons for non-compliance in 
the eCRF.

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Clinical outcome assessments (COAs)
5.1.1.1
MADRS – Montgomery-Åsberg Depression Rating Scale
The Structured Interview Guide for the Montgomery-Åsberg Depression Rating Scale 
(MADRS-SIGMA) will be used to collect MADRS scores. For the purpose of this document, 
MADRS is synonymous with MADRS-SIGMA. The MADRS is a clinician‐reported 
interview guide designed to assess the severity of symptoms in depressive illness and to be 
sensitive to treatment effects [R24-1238]. The MADRS consists of 10 items:
1. reported sadness
2. apparent sadness
3. inner tension
4. reduced sleep
5. reduced appetite
6. concentration difficulties
7. lassitude
8. inability to feel
9. pessimistic thought
10. suicidal thoughts
The MADRS evaluates core symptoms of depression [R96-0101]. MADRS items are rated 
on a 7 point Likert scale (0 = no abnormality, 6 = severe). Definitions of severity are 
provided at 2 point intervals. The possible total score could range from 0 to 60 (from normal 
with absence of symptoms to severe depression). The MADRS will be used with a recall 
period of 7 days at all visits.
A qualified clinician can administer the MADRS after completing a training session. The 
MADRS assessment is based on a clinical interview, which will be audio recorded for quality 
assurance. This assessment should take approximately 25 to 30 min. The MADRS score will 
be captured using a paper questionnaire provided by the vendor. The Placebo Control Script 
Reminder (PCRS) should be read to, and audio recorded, prior to each MADRS assessment at 
every visit. See Section 5.6.2 for details regarding the PCRS.

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5.1.1.3
SMDDS – Symptoms of Major Depressive Disorder Scale
The SMDDS is a 16-item, patient-reported outcome (PRO) measure developed to capture the 
core symptoms of MDD [R19-1931]. The scale will be collected using an eCOA device.
The different categories and associated 16 items are:
1. Negative Emotions/Mood: sadness, hopeless/helpless, irritability, anhedonia
2. Anxiety: feeling overwhelmed, worry
3. Low Energy: tiredness
4. Cognition: intrusive thoughts, poor concentration
5. Sleep Disturbances: general sleep adequacy
6. Self-Harm/Suicide: life not worth living
7. Low Motivation: lack of drive, no interest in activities
8. Sense of Self: self-blame
9. Eating Behaviour: poor appetite, overeating
The SMDDS uses a recall of “over the past 7 days” and participants respond to each question 
using a rating scale between 0 ("Not at all" or "Never") to 4 ("Extremely" or "Always"). The 
total score ranges from 0 to 60 with a higher score indicating more severe depressive 
symptomatology. It is calculated by creating first a single score for items 11 and 12 by 
selecting the highest severity on either item, and then creating the sum of the 15 responses.

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5.1.1.7
COA rater training and qualification
Rater training and qualification on COAs will be managed by the vendor as per vendor 
qualification methodology that has been agreed with the sponsor.
The vendor will manage rater training and qualification by evaluating the rater’s experience 
and scoring performance, tracking required training, and collecting documentation of training 
and qualification. New raters joining the trial will be trained and qualified with the same 
defined rater training and qualification program using the vendor learning platform.
The MADRS, HDRS-17,
must be administered by a psychiatrist, psychologist, or 
other clinician demonstrating adequate experience in patients with MDD and relevant 
comorbidities after completion of a training session. Exceptional situations will be reviewed 
on a case-by-case basis.

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The C-SSRS must be administered by a trained staff member with a valid C-SSRS training 
certificate (See Section 5.2.5.1).
Each rater will complete a COA-specific training as defined in the rater training and 
qualification program before being considered qualified for rating a participant on the 
respective scale in the context of the trial. All raters for the trial will be trained on the 
handling of all assessments that they will be administering.
For raters handling PROs throughout the trial (i.e. SMDDS,
 
, and ATRQ), the completion of a PRO administrator training is 
obligatory.
The vendor will provide a Certification Memorandum indicating the status for all raters who 
have completed the rater training and qualification program as well as follow-up 
requirements. No participant is allowed to be assessed/rated before the Certification 
Memorandum confirming the qualified status for the rater, is filed in the ISF. The C-SSRS 
certificate will be filed separately.
For each individual participant, the same qualified rater should rate the participant throughout 
the trial if possible. In case of unforeseen circumstances, a qualified back-up rater must be 
available throughout the trial.
5.1.1.8
COA/eCOA handling
Administration of COAs/eCOAs will be handled according to guidance documents from 
regulatory authorities and international societies (e.g. ISPOR). Participants are to complete 
PRO assessments on their own in a quiet area/room at the frequency specified in the SoA, 
without being influenced by the investigator or other members of the trial team. PRO/ePRO
assessments are to be completed by the participant in the same language the participant 
provided written consent for the trial and without any help from or interpretation/translation 
by other people. If this is not possible, the PRO assessments are not to be done. Adequately 
trained and qualified site staff are to be available at any time for general questions and to 
support the participant, as well as to ensure PRO completion compliance. Whether the 
participant was able to complete the PRO assessment themselves and the mode of 
administration will be documented.
For the compilation of paper questionnaires, the site personnel should check questionnaires 
for completeness prior to the participant leaving the site, but the response to each item will 
not be tampered with, and a participant should not be influenced in any manner on how to 
respond to the questions. Scores for paper-based questionnaires will be entered into the eCRF 
by site personnel.
For COAs and PROs compiled on electronic devices, completeness and consistency checks 
will be programmed into the application and no further check by site personnel is needed. 
Data from these assessments will be electronically transferred to a vendor. The data flow for 
eCOA is described in the vendor data management plan. A back up device will be provided 
to sites.

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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical/Neurological examination
A complete physical examination will be performed at the time points specified in the SoA.
This examination includes, at a minimum, general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, skin, and a basic neurological assessment.
The neurological assessment includes:

General level of arousal (vigilance)

Orientation

Eye movement

Pupil size and pupil reactivity

Deep tendon reflexes

Assessment of muscle strength

Tremor

Point-to-point movements

Romberg test

Gait

Sensitivity
Measurement of height and body weight will be performed at the time points specified in the 
SoA. Results will be documented in source data at the clinical trial site and assessed for 
clinical relevance by an investigator, deputy investigator, or sub-investigator. Clinically 
relevant findings of the physical, mental, and neurological examination will be reported either 
as baseline conditions (at screening) or as AEs (during the trial). If symptoms which are 
indicative of seizure activity or convulsions are observed or reported at any time during the 
trial (e.g. muscle spasm, uncontrolled shaking, altered consciousness; investigators should 
make participants aware of these symptoms and the need to immediately report them), the 
participant should be referred to a neurologist/emergency services immediately for 
consultation. A neurological assessment of the symptoms including EEG, if required, for 
further clarification will be performed.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the SoA, prior to blood sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 min) in a comfortable seated position after 5 min of rest. Preferably 
measurements should be taken with the same device at every visit. The results must be 
included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 6, and the sampling time 
points are shown in the SoA.

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Trial participants do not have to be fasted for the blood sampling for safety laboratory tests.
Participants should be asked about fasting/last meal. If the last meal was at least 10 h before 
the blood sampling, participants should be marked as fasted on the lab requisition form.
Instructions regarding sample collection, sample handling/processing, and sample shipping 
are provided in the laboratory manual in the ISF.
All analyses will be performed by a central laboratory, and the respective reference ranges 
will be provided 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 AEs or as baseline conditions at screening
(refer to Section 5.2.6.1.1).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (see Section 5.2.6.1 and the DILI Checklist provided in the ISF). The amount of 
blood taken from the trial participant concerned will be increased due to this additional 
sampling.
The results of various drug screens (e.g. cannabis, benzodiazepines, barbiturates, opiates, 
cocaine, amphetamines, methadone, PCP) will be captured in the clinical database to 
ascertain the use of drugs in this study population, impact of use on the recruitment failure 
rate, to assess the frequency of benzodiazepine use as sleeping aids, and to assess the 
relevance of occasional cannabis use to facilitate the design of pivotal trials.
The results of infectious serology tests will be used by the investigator to assess each 
participant’s eligibility for the trial. Infectious serology laboratory results will not be reported 
to the sponsor.
The central laboratory will transfer the results of the analysis to the sponsor or delegate.
Table 6
Safety laboratory tests
Functional laboratory group
Test name
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
Reticulocyte Count
White blood cells (WBC)
Platelet count
MCV, MCH, MCHC, RDW
Automatic WBC differential
(relative and absolute)
Neutrophils total
Lymphocytes total
Eosinophils
Basophiles
Monocytes
Manual differential WBC (if 
automatic differential WBC is 
abnormal)
Polymorphonuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes

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Functional laboratory group
Test name
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
INR
Enzymes
Aspartate aminotransferase (AST, GOT)
Alanine aminotransferase (ALT, GPT)
Alkaline phosphatase (AP)
Gammaglutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated
Substrates
Glucose
Lactic dehydrogenase
Triglycerides
TSH
Creatinine, enzymatic
eGFR1
Urea nitrogen
Total bilirubin (fractionated if increased)
Total protein
Albumin
Globulin
Albumin / globulin ratio
C-reactive protein (CRP)
Total cholesterol
Electrolytes
Calcium
Sodium
Potassium
Chloride
Phosphate
Relevant antidepressant drug 
levels in serum or urine (as 
applicable)
Bupropion (exclusionary, see Section 3.3.3)
Duloxetine (only detectable in serum)
Citalopram/Escitalopram
Paroxetine
Sertraline and Desmethylsertraline
Fluoxetine and Norfluoxetine
Venlafaxine and Desmethylvenlafaxine
Desvenlafaxine
Fluvoxamine
Vilazodone
Vortioxetine
Milnacipran/Levomilnacipran
Urinalysis (qualitative 
determination)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urine bilirubin
Urine haemoglobin (detects erythrocytes)
Urine leukocyte esterase (detects leucocytes)
Urine pH
Specific gravity

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Functional laboratory group
Test name
Urine sediment (microscopic 
examination if erythrocytes, 
leukocytes, nitrite, or protein are 
abnormal in urine)
Only positive findings will be reported (e.g. presence of sediment 
bacteria, casts in sediment, squamous epithelial cells, erythrocytes, 
leukocytes)
Urine pregnancy test (only for 
female participants of 
childbearing potential) 
Human chorionic gonadotropin in the urine
Serum pregnancy test (only if 
urine pregnancy test is positive)
Human serum chorionic gonadotropin
Drug screening (urine). Use of 
cannabis and benzodiazepines 
are not exclusionary in 
accordance with exclusion 
criteria (Section 3.3.3).
Amphetamine
Barbiturates
Buprenorphine
Benzodiazepine
Cocaine
Methadone metabolite
Methadone
Methamphetamine
Ecstasy
Morphine
Opiates 
Oxycodone
Phencyclidine
Cannabis
Infectious serology (blood)2
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
Hepatitis C virus RNA (only if Hepatitis C antibodies are positive)
1
Estimated glomerular filtration rate (eGFR) will be calculated using the reported based on the Chronic Kidney Disease 
Epidemiology (CKD-EPI) equation for adults.
2
Additional testing for infectious diseases (such as HIV-1 and HIV-2) can be added as required.
5.2.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the SoA. 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 a duration of at least 10-seconds after the participants 
have rested for at least 5 min 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 timepoints indicated in the SoA, single ECGs will be recorded. ECG 
recordings at planned time points may be repeated for quality reasons (i.e. 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 in 
the latter case, whether it is clinically significant. 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 conditions. 

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Clinically relevant abnormal findings noticed after baseline assessment will be reported as 
AEs and will be followed up and/or treated as medically appropriate.
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 AEs.
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 the responsibility of the investigator.
5.2.5
Other safety parameters
5.2.5.1
C-SSRS – Columbia-Suicide Severity Rating Scale
Suicidal risk will be assessed by the C-SSRS. The C-SSRS is a semi-structured, investigator-
rated interview, developed by clinical experts in cooperation with the FDA, assessing both 
suicidal behaviour and suicidal ideation. It does not give a global score but provides some 
categorical and some severity information specifically for behaviour and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsellor, nurse, or coordinator with C-SSRS training and a 
valid C-SSRS certificate. It has a typical duration of 5 min and causes only a low burden on 
subjects. At a minimum, the interview consists of 2 screening questions related to suicidal 
ideation and 4 related to suicidal behaviour and may be expanded to up to 17 items in case of 
positive responses. Free text entries are allowed for; the investigator has to directly evaluate 
the scale and write a report.
The C-SSRS will be administered at the screening visit (using the ‘baseline/screening’
version) with the aim to exclude subjects with active moderate or severe symptomatology 
within a specified time prior to the screening or baseline visit. The lifetime history of suicidal 
ideation and behaviour will also be recorded.

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5.2.6
Assessment of adverse events
Data and information necessary for the thorough assessment of AEs, SAEs, and AESIs will 
be reported to the sponsor via eCRF. This may include specific data and information not 
prospectively specified in this protocol.
5.2.6.1
Definitions of AEs
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a trial participant or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded on the appropriate eCRF(s) and the Boehringer 
Ingelheim SAE form:

Worsening of the underlying disease or of other pre-existing conditions 
o
AEs in the context of suicidal risk assessment 
should be adhered to

Changes in vital signs, ECG, physical/neurological examination findings, and/or
laboratory test results, if 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.
5.2.6.1.2
Serious adverse event
An SAE is defined as any AE that fulfils 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

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
Requires inpatient hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly/birth defect

Is deemed serious for any other reason if it is an important medical event when based 
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: An event that possibly leads to disability will be handled as “deemed serious 
for any other reason” and, therefore, reported as an SAE.
5.2.6.1.4
Adverse events of special interest
The term “adverse event 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; see
Section 5.2.6.2.2.
The following is considered an AESI:

Potential severe drug induced liver injury (DILI)
Potential severe DILI
A potential severe drug-induced liver injury (DILI) that requires follow-up is defined by any 
of the following alerts (alterations) of hepatic laboratory parameters that occur after the first 
dose of IMP:

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1. AST or ALT elevation ≥3 × ULN and total bilirubin ≥2 × ULN measured at the same 
visit, or in samples drawn within 30 days of each other, OR
2. AST or ALT elevation ≥3 × ULN and INR ≥1.5 × ULN measured at the same visit, or in 
samples drawn within 30 days of each other, OR
3. AST or ALT elevation ≥3 × ULN with new onset, or worsening of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%), 
OR
4. AST or ALT elevation ≥5 × ULN
These laboratory findings constitute a hepatic injury alert, and participants showing any of
these laboratory abnormalities need to be followed up according to the “DILI Checklist” 
provided in the ISF.
In case of clinical signs or symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory
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.
Additionally, with participants having a normal AST and ALT at baseline, the emergence of 
an isolated AST or ALT elevation between ≥3-fold and <5 × ULN requires repeat testing 
within 72 h. DILI Checklist is not required unless repeat testing triggers alerts 1, 2, 3, or 4.
The following events should lead to immediate discontinuation of trial IMP:

Hepatic injury alert numbers 1, 2, or 3

Hepatic injury alert number 4, if persists >2 weeks

AST or ALT elevation >8 × ULN
Following completion of the DILI Checklist, if the IMP cannot be excluded as a possible 
cause of the DILI event, discontinuation should be made permanent without rechallenge. If 
an alternate causality, e.g. acute viral hepatitis, is confirmed by the DILI Checklist 
evaluation, IMP may be re-started, if warranted.
5.2.6.1.5
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

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5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the AE and the 
IMP, 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 a reasonable possibility of a causal relationship could be:

The event is consistent with the known pharmacology of the IMP

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 IMP exposure

Evidence that the event is reproducible when the IMP is reintroduced

No medically sound alternative aetiologies that could explain the event (e.g. 
pre-existing or concomitant diseases, or comedications)

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 no reasonable possibility of a causal relationship could be:

No plausible time to onset of the event relative to the time of IMP exposure is evident 
(e.g. pretreatment cases, diagnosis of cancer or chronic disease within days/weeks of 
IMP administration; an allergic reaction weeks after discontinuation of the IMP
concerned)

Continuation of the event despite the withdrawal of the IMP, considering 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

There is an alternative explanation, e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
IMP concerned

Disappearance of the event even though trial IMP treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the participant files.
Per default, SAEs/AESIs should be reported via the eCRF in the EDC system. If the EDC 
system is not or no longer available (e.g. after database lock), the Boehringer Ingelheim paper 
SAE form should be used; see Section 5.2.6.2.2.

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The following must be collected and documented:

From signing the informed consent onwards until the individual participant’s end of trial
(usually the EoS Visit; please see Sections 3.3.4 and 6.2.3):
•
all AEs (serious and non-serious) and all AESIs

After the individual participant’s end of trial: 
•
the investigator does not need to actively monitor the participant for new AEs but 
should only report any occurrence of cancer of new histology, IMP-related SAEs,
and IMP-related AESIs of which the investigator may become aware by any 
means of communication, e.g. phone call
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI on the AE eCRF immediately (within 24 h of becoming aware of the 
event) triggering a data transfer to the sponsor’s unique entry point. The country-specific 
process will be described in the ISF. On specific occasions, the investigator could inform the 
sponsor upfront via telephone in addition. 
With receipt of any further information on these events, follow-up reports must be provided. 
For follow-up information, the same rules and timelines apply as for initial information. All
AEs/SAEs, including those persisting after an individual participant’s end of trial must be 
followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
Should the EDC system not be available for more than 24 h, reporting must occur via the 
Boehringer Ingelheim paper SAE form.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a trial participant has been 
enrolled in the clinical trial and has taken trial IMP, the investigator must report any IMP
exposure during pregnancy in a trial participant immediately (within 24 h) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential IMP 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 IMP exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for Studies 
(Parts 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 Studies is to be 
completed. However, an SAE and/or AESI associated with the pregnancy must be reported as 
described in Section 5.2.6.2.2.

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5.4
ASSESSMENT OF BIOMARKER(S)
Biomarkers will not be assessed in this trial.
5.5
BIOBANKING
Biobanking will be performed only in countries where allowed by local laws and regulations. 
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will occur only after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements.
5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment, and storage of 
biobanking samples are provided in the laboratory manual. For sampling timepoints, see the
SoA.
In total, approximately 45.5 mL of blood will be drawn for DNA, plasma, and serum for 
banking purposes.
5.6
OTHER ASSESSMENTS
5.6.1
Confirmation of diagnosis
Eligibility of potential participants will be based on a combination of a neuropsychiatric 
diagnosis via the MINI, the degree of treatment response to the current antidepressant therapy 
through the ATRQ, and the severity of the current depressive episode as assessed through the 
HDRS-17 scale. The MINI and HDRS-17 assessments will be administered on paper while 
audio recorded at the Screening Visit 1 and Visit 1A. The MINI and HDRS-17 recordings 
will be reviewed by an independent external clinical reviewer provided by a specialised 
vendor. The eligibility of potential participants will be confirmed by an external clinical 
reviewer, in which screening data will be obtained to evaluate psychiatric status.
5.6.1.1
MINI – Mini International Neuropsychiatric Interview
The MINI will be used during screening for confirmation of the diagnosis of MDD and to 
exclude trial participants with other psychiatric disorders as described in the exclusion 
criteria. The MINI is a structured interview for making the major DSM-5 diagnoses 
[R97-1075, R07-1303]. It is administered by a clinician or trained mental health professional 

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who is familiar with the DSM-5 classification and diagnostic criteria. Administration of the 
MINI should take approximately 15 min. Raters will complete the questionnaire with the 
participants as a paper version. Any diagnoses identified though the MINI must be recorded 
as baseline conditions.
5.6.1.2
ATRQ – Antidepressant Treatment Response Questionnaire
The Massachusetts General Hospital ATRQ will be used to determine treatment resistance in 
MDD. The ATRQ customised for this study defines the minimal required duration of at least 
6 weeks before randomisation on an adequate dose of antidepressant medication. It also 
provides specific operational criteria for adequate dosage for each of the most commonly 
used antidepressants. In this trial, the ATRQ will be used to assess satisfaction with baseline 
medication (i.e. current SSRI/SNRI). The ATRQ responses will be captured on paper.
5.6.1.3
HDRS-17 – Hamilton Depression Rating Scale-17
The Structured Interview Guide for the Hamilton Depression Rating Scale (HDRS-SIGH-D) 
will be used to collect HDRS-17 scores. For the purpose of this document, HDRS-17 is 
synonymous with HDRS-SIGH-D. The HDRS-17 consists of 17 items that evaluate the 
multidimensional symptoms of depression. The HDRS is administered as a structured 
interview where clinicians are to consider the intensity and frequency of the given symptoms 
based on patient responses and observations [R99-1131]. The HDRS-17 items are rated on a 
3 or 5 point Likert scale from 0 (absent/no disturbances) to 2 or 4 (constant/severe). The total
score is yielded from the sum of the 17 item ratings with possible scores ranging from 0 to 52 
(from normal with absence of symptoms to severe depression).
A qualified clinician can administer the HDRS-17 after completing a training session. The 
HDRS-17 will be administered as an interview in this study with a duration of approximately 
15 to 20 min. The PCRS (Section 5.6.2) should be read to participants just prior to 
administering the HDRS-17 during screening. The HDRS-17 score must meet inclusion 
thresholds (severity scale score >17), as described in the inclusion criteria (Section 3.3.2). 
Raters will complete the questionnaire with the participant as a paper version. 
5.6.2
PCRS – Placebo-Control Reminder Script
Although not an outcome measure, but rather a tool designed to mitigate the placebo and 
nocebo response, the PCRS© (Version 5.0, R20-4054) educates clinical trial participants of 
key causes of the placebo and nocebo effects. It does this namely through the tempering of 
participant study expectations, reminding subjects what a placebo is and how that relates to 
their reporting of symptoms and potential side effects, and explaining how interactions with 
research site staff differ from their experience with previous providers. As such, the PCRS 
informs subjects that they are to be honest about their symptoms, site staff have no 
expectations of symptom improvement or worsening and will not be disappointed if they feel 
better, worse or the same, and asks participants to explain in their own words its content to 
ensure comprehension. Per the instructions on the PCRS, the HDRS-17 or MADRS rater will 
read the script verbatim immediately before administering this scale. The PCRS is read to 
each subject at each Visit (time point) listed on the SoA, typically taking about 3 min to read. 
The PCRS has been empirically found to manage (reduce) the placebo and nocebo effects in 

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a relevant manner [R20-4054]. Reading of the PCRS to participants will be audio recorded 
for quality assurance.
5.6.3
Verification of current and past research study status of the trial participant
Duplicate enrolment and protocol violations are risk factors for poor quality data and safety 
concerns. These issues may result in increased placebo rates and failed clinical trials. Each 
participant, in this study, must have their current study status checked by utilizing the system 
of the vendor “Verified Clinical Trials”. This is a mandatory process where local regulatory 
approval has been obtained.
Following proper informed consent and after issuing a study subject number, the subject’s 
information will be checked against the Verified Clinical Trials database, as indicated in the 
SoA. Partial identifiers will be utilized. This will include checking a valid form of picture
identification when available.
The first 3 letters of the participant’s first and last name will be entered along with the middle 
initial, date of birth, sex, and last 5 digits of that identification. If the status of the research 
subject is a “Verification Success” they may proceed in the study. If, however, the status is a 
“Verification Failure” they will not be permitted to screen without sponsor/designee
approval. The duplicate participant check will be performed only after approval is received in 
accordance with local regulations.
5.6.5
Data tokenisation
Data tokenisation is a cutting-edge technology and the most advanced form of 
pseudonymisation. Data pseudonymisation is the process of replacing personally identifiable 
information, like birth year or first name, with a pseudonym. In the context of clinical trials, 
tokens can be used to establish a link between a patient’s participation in a BI study and the 
data collected from the same patient in other health care data bases. This type of data is also 
called real world data. Data tokenisation will be used in this study to allow potential future 
use of patient data for further research.

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The software used for data tokenisation generates a secure token (patient key) which maps to 
data available in commercial databases which include aggregate medical, claims, and 
laboratory data. The commercial databases include information on office visits, 
hospitalisations, laboratory tests, prescriptions, and other health care utilisation data. Once 
the patient data is tokenised, it is not possible to re-map the tokens to the individual patients. 
It is requested, but not required, that all sites in the countries where the data tokenisation can 
be conducted participate in this initiative. Data tokenisation will be allowed only in countries 
where approved by local authorities. All patients at participating sites will be invited to 
provide separate written IC to participate in data tokenisation.
If a patient provides consent to participate (participation is voluntary and does not impact 
their ability to participate in the main trial), patient identifiers will be collected and held by a 
CRO until data tokenisation is complete. The identifiers to be collected include: first name, 
last name, gender, birth date, postal/zip code. An independent review (data certification) will 
be done on the tokenised data to ensure that re-identification of individual patients is not 
possible.
Any activity using tokenised data will be out of scope of this study (1447-0005) and will be 
considered a separate observational and non-interventional study to evaluate utilisation of 
health care resources and associated costs, to provide empirical evidence to inform market 
access strategy and decisions.
5.6.6
Optional study feedback questionnaires
This trial will include an option for participants to complete an anonymised questionnaire, 
‘Study Participant Feedback Questionnaire’ to provide feedback on their clinical trial 
experience as detailed in Appendix 10.1. The start survey should be filled out during Visit 2 
or 3, and the end survey during EoT or EoS.
5.7
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
In the event of force majeure or other disruptive circumstance (e.g. pandemic, war), the 
execution of the investigational plan as per this clinical trial protocol may not be feasible. 
With the consent of the participant, the sponsor and investigator may agree on alternative, 
back-up, or rescue methodology which may include, but will not be limited to, virtual trial 
participant visits and assessments, home healthcare nurse visits, direct-to-participant
shipments of IMP, direct-from-participant shipments of IMP, or biological sample pick up 
from the participant’s home. The implementation of these measures will depend on the 
participant’s consent, operational feasibility, and local laws and regulations. Such alternative 
measures will be described in the participant information. If alternative methodology is 
implemented, the deviations from the original plan will be precisely documented.
6.1
VISIT SCHEDULE
The trial visit schedule is presented in the SoA. Each visit date (with its window) is to be 
counted from Day 1 (day of randomisation/first intake of IMP, Visit 2). If a participant 
misses an appointment, it should be rescheduled, if possible, subsequent visits should follow 
the original visit date schedule. The trial medication packs contain sufficient IMP to allow for 
the time windows described in the SoA. Additional visits for the purpose of re-testing of 
laboratory parameters or AE monitoring may be included as deemed necessary by the 
investigator.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Trial procedures and the order in which they are to be performed at each visit are listed in the 
SoA. Additional details regarding visit procedures are provided below.
Clinical outcome assessments
The following requirements for the conduct of the clinician administered COAs (C-SSRS, 
MINI, HDRS-17, MADRS, 
) need to be followed:

The site staff must be properly trained on all trial procedures and training 
documentation filed in the ISF. Qualification, training, and remediation (if needed) 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 primary 
investigator at each site to ensure that all members of the site staff involved in the 
neuropsychological assessments undergo qualification and training by the vendor.

Each assessment of the site-rater administered scales (C-SSRS, HDRS-17, MADRS,
 should preferentially be done by the same members of the site staff for a 
given participant throughout the trial period. 

All MINI, HDRS-17, MADRS, and PCRS rater performed administrations will be 
audio recorded for central review by the vendor for quality assurance.

During the neuropsychological testing, participants are allowed to take short breaks as 
needed, in the judgement of the rater/investigator. 

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The baseline/screening scale of the C-SSRS will be administered for eligibility confirmation 
 
for the assessment of suicidality. If there is an 
unscheduled visit due to suicidal ideation or behaviour, it is up to the investigator’s 
judgement as to what appropriate testing should be completed as part of that evaluation.
Safety laboratory and other laboratory tests 
If blood sampling for central laboratory is unable to be performed (in rare cases), safety 
laboratory analyses may be performed at a local laboratory. The results, and local lab 
standards, of the laboratory tests must be transferred to the investigator who ensures medical 
review and documents any clinically relevant safety issue as an AE.
The minimum required safety laboratory parameters are:

Haematology

Enzymes

Substrates

Electrolytes

SSRI/SNRI drug levels (only at screening and EoT)

Urinalysis

Pregnancy test

Drug screening

Infectious serology (only if clinical sign or symptoms)
6.2.1
Screening and lead-in phase
No trial procedures should be done unless the participant has consented to taking part in the 
trial. After the participant has given informed consent in accordance with GCP and local 
legislation, the screening period will start with the first trial related procedure. The 
participants should be recorded on the enrolment log. The participant should be registered in 
IRT as a screened participant. 
At participating sites, participants will be invited to participate in data tokenisation (see 
Section 5.6.5). A separate informed consent will be required for participation in data 
tokenisation.
Within the screening period, screening procedures may be extended to more than one 
physical visit (in addition to Visit 1A), if needed. If the visit will be split, blood sampling, 
ECG, MINI, ATRQ, and HDRS-17 should be done on the first day of screening. 
Documentation will be done only once. The first day of screening will be the starting point 
for the screening period calculation. The screening period (i.e. period between Visit 1 and 
Visit 2) should be kept as short as possible, but may be extended by an additional 7 days (i.e. 
28 or 70 days in total) for reasons including, but not limited to, the following: delayed receipt 
of safety laboratory tests and titration of background SSRI/SNRI dose. If screening period 
needs to be extended any further, the Clinical Trial Leader or designee should be contacted to 
discuss further steps.

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In addition, a short informational video intended to educate the participant about placebos, 
and why they are used in clinical trials may be available for participants. The video advises 
the participant not to attempt to guess if they are on active drug or placebo, reminds them that 
there is always a chance they have been randomly assigned to placebo, and stresses the 
importance of reporting all symptoms, be they positive or negative or neutral.
6.2.1.1
Rescreening of participants:
Rescreening of a participant can be done twice, if there is a reasonable explanation and 
expectation that the participant may have become eligible at the discretion of the investigator, 
post discussion with the Clinical Trial Leader or designee. The participant must re-consent to 
participation in the trial, all screening examinations must be repeated, and a new participant 
number assigned, in case of rescreening.
Potential reasons for rescreening could be:

Positive urine drug screen

Restricted medications like CYPs/alternative or traditional medicine

Clinically significant findings per the investigator’s judgement
6.2.1.2
Retesting
Participants with unexpected lab values at Visit 1 and/or Visit 1A may be retested once 
within the respective 18-day screening period if there is a reasonable explanation and 
expectation that the participant will meet the in- and exclusion criteria at retest at the 
discretion of the investigator. This doesn’t apply to the urine drug screen, which must not be 
retested.
6.2.1.3
Demographics
During the screening visit, demographics information will be collected. This includes:

Age (in years) on the day of informed consent

Sex (male or female, in order to describe the trial participant’s sex at birth)

Gender identity (male, female, non-binary, not answered, or other in order to describe 
how the trial participant self-identifies, regardless of their genotypic or phenotypic 
sex) if 1) locally accepted (i.e. based on HA/EC/IRB acceptance, independent of 
acceptance by investigators or participants), 2) investigators are willing to ask, and
3) participants are willing to reply

For women of childbearing potential, yes/no in order to characterize the participant
population and as a basis for contraception requirements

Ethnicity and race in order to sufficiently characterize the participant population, to 
support possible subgroup analyses if needed, and to support the calculation of the 
kidney function via the CKD EPI formula unless not acceptable according to local 
regulations

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6.2.1.4
Baseline conditions
Any diagnoses identified though the MINI must be recorded as baseline conditions.
Vital signs should always be measured before any blood samples are taken. For procedural 
details see Section 5.2.2. Any abnormal condition of clinical significance identified during 
physical examination, vital signs, ECG, and/or laboratory assessment should be recorded as a 
baseline condition.
For participants that are participating in the SSRI/SNRI lead-in, baseline conditions should be 
collected during the 1st screening visit (Visit 1) and reconfirmed during the 2nd screening visit 
(Visit 1A). Baseline ECG recordings and height measurement are only required during 
Visit 1, weight should be re-measured and recorded after completion of the lead-in phase.
6.2.1.5
Medical history
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least 3 documented attempts to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Information related to the history of depression, e.g. age at time of diagnosis, number of 
antidepressants used for the current episode, duration of current episode, and number of 
previous episodes, will also be recorded in the eCRF at screening.
Additional details regarding concomitant psychotherapy (e.g. duration of ongoing 
SSRI/SNRI therapy, other non-drug therapies) at screening and randomisation need to be 
recorded in the eCRF. Please refer to the current eCRF for information that needs to be 
collected. During the treatment period, the question whether there were any significant 
changes in psychotherapy will be recorded in eCRF during clinic visits.
Participants should be thoroughly questioned concerning their history with regard to seizure 
disorders in line with Exclusion Criterion #4 (Section 3.3.3). Increased risks of seizures 
include: a first degree relative with epilepsy, recurrent febrile seizures in childhood, 
eclampsia, traumatic brain injury, stroke, brain tumour, or any other major neurological 
illness that could reduce the participant’s seizure threshold in the opinion of the investigator.
Substance use, (e.g. nicotine, alcohol, caffeine, cannabis, etc.) will be collected throughout 
the trial from screening to the EoS Visit. Please refer to the current eCRF for details about 
substance use to be collected.
Concomitant treatments which are allowed or restricted before and during trial participation, 
including required washout durations, are listed in the ISF. Participants will be instructed to 
continue allowed/required background medication without changes and to adhere to their 
administration algorithm.

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6.2.1.6
Lead-in phase
All inclusion criteria must be satisfied prior to randomisation. For participants completing the 
SSRI/SNRI lead-in, inclusion criteria involving ongoing antidepressant therapy (criteria 6
and 7) must be met by the 2nd screening visit (Visit 1A) and can remain blank in the clinical 
database during the initial screening visit (Visit 1). All inclusion criteria must be 
reassessed/confirmed at the 2nd screening visit (Visit 1A).
All exclusion criteria must be satisfied at the first screening visit (Visit 1) regardless of 
participation in the SSRI/SNRI lead-in. All exclusion criteria are to be reconfirmed at the 
2nd screening visit (Visit 1A) for participants completing the SSRI/SNRI lead-in.
6.2.1.7
Interactive Response Technology
All potential participants who are screened must be registered with IRT. If the screening 
results in a screen failure, the participant must be recorded as screen failure in IRT as soon as 
possible and within the 18-day screening period. Details of IRT procedures can be found in 
the IRT Manual filed in the ISF.
6.2.1.8
Participant Eligibility Review
Eligibility of potential participants will be confirmed by an external vendor. At screening 
visits (Visits 1 and 1A, as applicable), participant eligibility will be based on an external 
clinical review of the HDRS-17 and MINI data as well as their audio recordings. Any 
uncertainty raised by the external clinical reviewer of these scales related to 
inclusion/exclusion criteria will be discussed with the investigator/rater in order to establish 
confidence in the diagnosis and level of symptom severity. The external clinical reviewer will 
determine whether the participant is eligible to be randomised pending other screening 
procedures and issue a notification to the site regarding the participant’s eligibility status. 
Participants for whom diagnostic/severity agreement between the investigator/study centre
clinician and the vendor clinician(s) cannot be reached, may not be appropriate for study 
participation and should not be enrolled. Sites will be issued a notification from the vendor 
regarding eligibility for a potential participant before randomisation can occur.
6.2.2
Treatment period(s)
General remarks
After all the screening procedures have been completed and the eligibility of screened 
patients is confirmed, Visit 2 can be conducted including randomisation via IRT. IRT should 
not be called in advance of Visit 2 until eligibility is fully confirmed, as randomisation of a 
patient cannot be reserved. Randomisation should not be performed in case of a positive urine 
pregnancy test (to be completed locally on-site using kits provided by central lab). In the 
event of the positive urine pregnancy test, a serum pregnancy test can be performed by the 
central lab for confirmation at the discretion of the investigator.
Unscheduled visits will be possible at the discretion of the investigator at any time in order to 
check the safety of the participant or to perform safety laboratory assessments.

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Upon randomisation via the IRT at Visit 2, medication kits will be dispensed. The first dose 
of IMP should be taken at the clinic after all assessments are completed, with the exception of 
the ECG assessment and the collection of any AEs. It is recommended to monitor participants
for 2 h post IMP administration. ECG readings should also be collected after IMP 
administration during Visits 2 and 4. Investigators should inform participants to continue 
daily dosing until their next visit.
Participants should be instructed to bring all IMP supplies (used and unused kits/packaging 
including blisters) with them to clinic visits.
Optional study feedback questionnaires
These questionnaires will be implemented after local regulatory approval, if required, and 
after consent of the trial participant. The start survey should be filled out during Visit 2 or 3, 
and the end survey during the EoT or EoS Visit. See Section 5.6.6 and Appendix 10.1 for 
more details. 
Optional biobanking samples
Participation in the collection of plasma and serum for biochemical markers and DNA for 
pharmacogenomic markers is voluntary and only allowed after the participant has given 
separate consent prior to the collection of the respective blood samples. Samples will be 
stored at a biobanking facility for future research.

Serum and plasma biobanking: in total two serum and two plasma samples will be 
taken, the sample collection should adhere to the schedule (i.e. taken at Visit 2 prior to 
administration of the IMP and the EoT Visit).

DNA biobanking: in total one sample will be taken, preferably at Visit 2. However, 
collection at later visits is permitted as long as the informed consent for biobanking 
remains valid.
Background medications (SSRI/SNRIs)
Ongoing antidepressant medications should be taken as usual (also on days of clinical visits) 
by the participant, according to the requirements as described in this protocol and in the 
investigator’s recommendations and national guidelines. Participants should take their 
background medication as usual (with or without food) regardless of trial visits. On Visit 4, 
background therapy should be taken before or after, but not during the site visit.
Order of rating scales assessments
 
During all clinic 
visits, the placebo control reminder script should be performed just prior to the MADRS 
assessment
. The SMDDS should then be assessed 
 
 The remaining scales (
can be 
performed in any order. 
During Visit 4, MADRS and ECG should be completed between 1 and 2 h post IMP 
administration followed by other COAs, as feasible. See Table 10 for the schedule of 
 

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, MADRS, and ECG capture during Visit 4. During 
all other visits during the treatment period, COAs should be completed prior to IMP intake.
EoT Visit
The EoT Visit (at treatment Week 6) represents the regular end of the treatment period. The 
final IMP intake should occur one day before the EoT Visit. If it is found that a participant 
has taken the final dose of IMP in the morning of the EoT Visit, the visit should be 
rescheduled as soon as possible, ideally on the following day. The overall anticipated 
treatment duration (first IMP intake to the final IMP intake) should be 42 days; therefore, the 
EoT Visit is scheduled at Day 43 with a visit window of up to +2 days. See Section 3.3.4.1
for procedures with regard to premature discontinuation of the IMP.
6.2.3
Follow-up period and trial completion
For all participants who had at least one dose of IMP, the EoS Visit will be performed as 
described in the SoA. The sequence of visit procedures will be the same as in the treatment 
period. In case of early discontinuation, the procedures detailed in Section 3.3.4.1 should be 
followed.
EoS Visit is the final scheduled visit and the End of Study eCRF must be entered including 
termination of IMP and trial completion. If it is not possible for the patient to attend the 
EoS Visit at the study site as scheduled, a visit outside of the visit 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 EoS Visit time point.
A trial participant is considered to have completed the trial if one of the following applies:

Completion of planned follow-up period (i.e. EoS Visit completed)

Lost to follow-up

Refusal to be followed-up

Death
If needed, in the opinion of the investigator, additional visits may be scheduled after the 
EoS Visit for continued safety monitoring.
Abnormal assessments or laboratory values judged clinically relevant by the investigator will 
be monitored until they return to a medically acceptable level.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The purpose of this trial is to demonstrate proof of concept of clinical activity of BI 1569912 
on the primary endpoint change from baseline in MADRS total score at Week 6. An
MCPMod approach is applied to detect a statistically significant non-flat dose-response. 
7.1
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis of the MCPMod test is that there is a flat dose response curve comparing 
placebo and the BI 1569912 dose groups on the primary endpoint of change from baseline in 
MADRS total score at Week 6. The alternative hypothesis is that there is a non-flat dose 
response curve indicating a benefit of BI 1569912 over placebo.
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, while protecting the overall probability of Type I error (one-sided, α level 
of 10%). The pre-specified models and their parameters used for this test are outlined in 
Section 7.2.3.
7.2
PLANNED ANALYSES
7.2.1
General considerations
Statistical analyses will be based on the following main analysis sets:

Treated set (TS):
The TS includes all participants who were randomised and treated with the IMP. The 
TS will be used for safety and most of the efficacy analyses. Safety analyses will be 
conducted using actual treatment received. For efficacy analyses, treatment 
assignment will be as randomised, unless specified otherwise.

Primary analysis set (PAS):
The PAS comprises all randomised participants who received at least one dose of IMP
during the trial and had a baseline MADRS total score ≥24. The primary analysis will 
be performed on the PAS and will be based on assigned treatment. 
Further analysis sets may be specified in the TSAP.
In general, baseline will be defined as the last available value prior to the first administration 
of the IMP. Further details will be provided in the TSAP.

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Adherence to the protocol will be assessed by the trial team. Important protocol deviations 
(iPDs) categories and how to handle iPDs in the analysis will be specified in the SDTM DV 
domain specifications, which are stored in the TMF. The iPD categories will be updated as 
needed. Also, the extent and impact of the receipt of incorrect trial medication will be 
assessed. Details will be specified in the TSAP.
7.2.2
Handling of Intercurrent Events
The expected intercurrent events of interest in this trial are:

Death

Treatment discontinuation 
o
due to reasons related to IMP
o
due to reasons unrelated to IMP

Change in background antidepressant treatment 
o
SSRI/SNRI
o
psychotherapy
The primary treatment effect of interest is the effect obtained at the primary time point if the 
participant had stayed on randomised IMP, i.e. cases of treatment discontinuation, regardless 
of reason, will be handled using a hypothetical approach (Table 7). Data collected after 
treatment discontinuation + REP will be censored and will not be included in the analysis. 
Changes in antidepressant treatment will be disregarded in the primary analysis of treatment 
effect, i.e. they will be handled using the treatment policy approach as defined in 
ICH E9(R1).

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Table 7
Strategies for handling intercurrent events
Intercurrent event
Primary 
Death
Hypothetical 
Treatment 
discontinuation related to 
IMP
Hypothetical
Treatment 
discontinuation unrelated 
to IMP
Hypothetical
Change in antidepressant 
treatment (SSRI, SNRI, 
psychotherapy)
Treatment policy
Each analysis will reference the strategy for handling intercurrent events that it will be 
estimating. The estimand for each main analysis in this protocol is the combination of the 
relevant detailed clinical objective from Section 2.1 and this strategy. The handling of 
intercurrent events that are not listed will be decided during blinded review and will be 
documented in the TSAP.
7.2.3
Primary objective analyses
7.2.3.1
Main analyses
As defined in Section 2.1.2, the primary endpoint is the change from baseline to Week 6 in 
MADRS total score.
MCPMod (multiple comparison and modelling techniques) [R10-1424] is used to evaluate 
several possible dose response models (patterns). As a basis for the MCPMod analysis, a 
restricted maximum likelihood estimation (REML) based on a mixed-effect model for 
repeated measures (MMRM) analysis will be used to generate covariate adjusted estimates of 
mean change from baseline in MADRS total score at Week 6 and associated covariance 
matrices. The model will include fixed categorical effects of treatment at each visit, cohort 
(with/without lead-in phase), and fixed continuous effects of baseline MADRS total score at 
each visit. Participants from the PAS with a baseline and at least one post-baseline value with 
their MADRS values of all post-baseline visits (including those after Week 6) will be 
included in the model, according to the considered strategy for handling intercurrent events.
The primary treatment comparisons will be the contrasts between each BI 1569912 treatment 
arm and placebo at Week 6. Procedures to be followed if the planned analysis fails to 
converge will be described in the TSAP. 
The dose-response relationship of these estimates from the MMRM will then be analysed 
using MCPMod. Thereby, several possible dose response models (patterns) will be evaluated 

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(while keeping full control of the type I error at 10%, one-sided) to identify the best-fitting 
model or subset of models.
A monotone dose-response relationship is assumed. For the PoCC testing and for the sample 
size calculations the following model assumptions (Table 8) and resulting graphs (Figure 2)
have been selected to cover both the plausible and a diverse range of potential dose response 
patterns.
Table 8
Dose response pattern assumptions and rationale
Model
Description
Linear
Linear dose response
Emax1
50% of the maximum effect (ED50) is achieved at the 5 mg dose
Emax2
95% of the maximum effect (ED95) is achieved at the 10 mg dose
Exponential
5% of the maximum effect is achieved at the 5 mg dose, 
i.e. high effect only at a high dose
Sigmoid Emax
20% of the maximum effect (ED20) is achieved at the 5 mg dose, 
80% of the maximum effect (ED80) is achieved at the 10 mg dose, 
i.e. effect of 5 mg and 10 mg are further apart
(fixed hill parameter h=4)

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Figure 2
Shape and considered dose response patterns for the MCPMod 
analysis
The optimal contrasts corresponding to the candidate models will be shown in the TSAP. For 
the final evaluation, these contrasts will be updated using the expected model means from the 
candidate set and the estimated variance-covariance matrix extracted from the MMRM 
model.
A non-flat dose response is established if at least one dose response pattern is statistically 
significant, rejecting the null hypothesis of a flat dose response relationship on change from 
baseline in MADRS total score at Week 6 jointly for each of the candidate dose response 
models, with a contrast test controlled for the family–wise type I error rate at a one-sided 
α = 10%. 
If a non-flat dose response is established, the statistically significant (i.e. best fitting) 
model(s) from the above candidate set are refitted to the data to generate new estimates for all 
model parameters. The dose-response curve is then obtained via model averaging across the 
significant models based on Akaike Information Criteria (AIC). The target dose(s) for further 
clinical development can be estimated from each significant model by incorporating 
information on the minimum clinically relevant effect. The totality of evidence, including 
secondary and further efficacy and safety parameters, will be taken into account in the 
selection of dose(s) for pivotal studies.
0 
10 
15 
20 
linear 
emax1 
emax2 
0.0 
-0.2 
-0.4 
-0.6 
-0.8 
(/) 
C m -1.0 
<ID 
E 
<ID 
""O 
0 
0.0 
2 
-0.2 
-0.4 
-0.6 
-0.8 
-1.0 
0 
5 
10 
15 
20 
Dose 

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7.2.4
Secondary objective analyses
7.2.4.1
Change from baseline in MADRS total score at Day 8
The secondary endpoint change from baseline in MADRS total score at Day 8 will be 
evaluated in a similar manner as described for the primary endpoint.
7.2.4.2
MADRS response/remission
Response at Day 8 or at Week 6 will be assessed using the MADRS total score at the 
respective time point. Participants with ≥50% reduction in MADRS total score from baseline 
to Day 8 and Week 6, respectively, are considered responders for this time point. Participants 
experiencing <50% reduction in MADRS total score are considered non-responders. Percent 
reduction from baseline at a specific post-baseline visit (Visit X) is calculated as:
% 	
 = ( 

 	 
  − 

 	 
 
 )
 

 	 
 
∗100
Remission at Week 6 is defined as a MADRS total score ≤10 at this time point.
For these binary endpoints, comparisons between treatment groups will be performed using a 
logistic regression model, adjusting for baseline MADRS total score as continuous covariate 
and for cohort (with/without lead-in phase). Estimates and the two-sided 95% confidence 
intervals will be provided for the adjusted odds ratios (between each of the BI 1569912 
treatment arms and placebo). Analyses will be based on the PAS.
7.2.4.3
Change from baseline in SMDDS total score at Day 8 and Week 4
Changes from baseline in SMDDS score at Day 8 and Week 4 will be analysed using a mixed 
model with repeated measurements (MMRM), including fixed categorical effects of 

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treatment at each visit, cohort (with/without lead-in phase) and baseline MADRS total score 
(< or ≥24), and fixed continuous effects of baseline SMDDS total score at each visit. All 
participants from the TS with a baseline and at least one post-baseline value of the considered 
score will be included in the model, with all their values of all post-baseline visits of this 
score.
7.2.6
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Standard Boehringer Ingelheim summary tables and listings will be produced. All AEs with 
an onset between start of treatment and end of the REP, a period of 8 days after the last dose 
of trial IMP, will be assigned to the on-treatment period for evaluation.
All treated trial participants will be included in the safety analysis and summarised by the 
actual trial medication received at randomisation. In general, safety analyses will be 
descriptive in nature and will be based on Boehringer Ingelheim standards. No hypothesis 
testing is planned.

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Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs, i.e. all 
AEs occurring between the start of treatment and the end of the REP. AEs that start before 
first IMP intake and deteriorate under treatment will also be considered ‘treatment-emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA) at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of trial participants with abnormal values or clinically 
relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial, and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared with findings before the start of treatment.
7.2.8
Interim Analyses
Exploratory interim analyses (IA) for internal project planning may be performed. The 
decision to conduct such an IA will be documented in the decision log. In order to support the 
double-blinded conduct of the trial, the trial team will be kept blinded to the individual 
participant’s treatment group assignment at interim. An independent team will be formed to 
perform the interim analysis.
Personnel involved with trial conduct at study sites will not have access to unblinded data 
from the IA. Secure folders with restricted access will be used for the storage of unblinded 
interim data and results. Further operational details of who will perform the IA, and the steps 
to be taken to protect the integrity of the ongoing trial, will be specified in a Logistics Plan. 
Details of the Boehringer Ingelheim personnel who will have access to unblinded interim 
data or results, and how interim results will be communicated within BI, will be specified in 
an Access Plan. These documents will be finalised prior to unblinding treatments at interim 
database lock.

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Such an IA will not have an impact on the trial conduct; it will not be used for sample size 
recalculations or adjustments of enrolment targets.
7.3
HANDLING OF MISSING DATA
For the primary efficacy endpoint, which is continuous in nature, the use of a restricted 
maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach in 
the primary analysis will ensure that missing data are handled implicitly, via a missing at 
random assumption, by the statistical model. The same holds true for secondary and further 
continuous endpoints which will be analysed via MMRM.
In case there is a relevant number of missing values (e.g. ≥5% for a visit), a multiple 
imputation approach will be used to handle missing data in the analysis of secondary and 
further endpoints response and remission in MADRS.
More details for missing data handling will be included in the TSAP.
7.4
RANDOMISATION
Participants will be randomly assigned in a 2:1:1:2 ratio to one of these treatment groups:
1. Placebo
2. 5 mg BI 1569912 qd
3. 10 mg BI 1569912 qd
4. 20 mg BI 1569912 qd
Randomisation will be stratified by cohort (with/without lead-in phase) and baseline MDD 
severity, defined as baseline MADRS total score <24 versus ≥24.
Boehringer Ingelheim will arrange for the randomisation and the packaging and labelling of 
trial IMP. The randomisation list will be generated using a validated system, which involves a 
pseudo-random number generator so that the resulting treatment will be both reproducible 
and non-predictable. Specific parameters used for the creation of the randomisation schedule 
(e.g. block size) will be documented in the CTR. Access to the codes will be controlled and 
documented.
7.5
DETERMINATION OF SAMPLE SIZE
The study is intended to show a benefit of BI 1569912 over placebo in terms of the difference 
in change from baseline in MADRS total score at Week 6.
The aim of this study is to show a significant non-flat dose-response curve across the 
different doses and placebo. The probability of success of this trial is therefore defined as the 
probability to obtain a significant test for non-flat dose-response curve.
The sample size calculation is based on an assumed maximum difference in change from 
baseline in MADRS total score of BI 1569912 vs. placebo of ≤-4, as well as on the 
pre-specified models listed in Section 7.2.3.1. The standard deviation of change from baseline 
in MADRS total score is assumed to be 10 (i.e. the assumed maximum difference of ≤-4

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corresponds to a standardized effect size of ≤-0.4). For placebo, a fixed rate of -9 change 
from baseline in MADRS total score at Week 6 will be considered. 
The following calculations and presented operating characteristics use a sample size of 
180 evaluable patients with a baseline MADRS total score ≥24 (assigned to placebo and low 
to high dose regimes, respectively, in a 2:1:1:2 ratio). Adjusting for a drop-out rate of 
approximately 18% (randomised patients not included in the PAS, or without primary 
endpoint assessment), the total sample size required is then approximately 222 (with 
74/37/37/74 per dose group).
Using a total sample size of 180 evaluable patients, the probability for a successful trial (as 
defined above) was estimated using simulations. For each dose group, samples of the 
required size were drawn from a normal distribution. 
Based on these assumptions, if the maximum difference between active doses and placebo is 
-4, the success probability is approximately 82% on average across the different considered 
dose response models. The probability to observe an effect of at least -3.5 in the trial is 65%.
If the maximum difference between active doses and placebo is -5, the success probability is 
approximately 93% on average across the different considered dose response models. In this 
case, the probability to observe an effect of at least -3.5 in the trial is 83%.
If the difference between active doses and placebo is low, i.e. -1 (which is assumed to be 
clinically not relevant), the success probability is approximately 23% on average. The 
probability to observe an effect of at least -3.5 in the trial is 10%. In the case that there is no 
treatment benefit, the false positive probability is limited by the α-level for the significance 
testing of the non-flat dose-response curve of 10% (one-sided).
The following table provides success probabilities under different scenarios (i.e. different 
treatment effects and dose-response curves).

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Table 9
Success probability given expected change from baseline in MADRS 
total score at Week 6 and a total sample size of 180 patients (with 
60/30/30/60 per dose group) based on MCPMod nominal alpha-level 
of 10% (one-sided).
Scenario
(Assumed) true model
Expected max. 
resp. diff.
(BI-Plac)
Linear
Emax1
Emax2
Exponential Sigmoid Emax
Average
(1)
(2)
(1)
(2)
(1)
(2)
(1)
(2)
(1)
(2)
(1)
(2)
-5
92.2
81.5
92.4
81.3
93.8
84.2
93.7
83.7
94.1
84.4
93.3
83.0
-4
81.1
63.9
81.4
63.6
83.5
65.7
82.7
65.8
83.3
66.1
82.4
65.0
-3
62.3
41.6
64.1
42.4
66.2
44.6
63.9
43.8
65.2
44.1
64.3
43.3
-2
42.3
23.1
42.3
23.4
42.4
23.4
42.9
23.7
44.1
23.9
42.8
23.5
-1
22.3
9.2
22.9
10.2
23.6
10.2
22.8
10.1
23.2
9.7
22.9
9.9
0
9.5
3.1
10.2
3.7
9.9
3.4
9.9
3.4
9.8
3.2
9.9
3.3
(1) success probability (%): significant non-flat dose-response achieved based on at least one of the candidate set models 
(one-sided α-level of 10%), 
(2) probability (%) to observe a response difference of at least -3.5 compared with placebo for at least one modelled dose 
within the considered dose range. 
Probabilities have been calculated using R Version 4.0.1 based on simulations (10000 simulations per scenario). Thereby the 
calculations for the MCPMod step have been performed using DoseFinding R-package 1.0-2.

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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 GCP,
relevant Boehringer Ingelheim SOPs, 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 will be treated as 
‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the treating physician of the trial participant.
The investigator will inform the sponsor or delegate 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 trial 
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 participation in the trial, written informed consent must be obtained from each 
participant according to ICH GCP and the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent form and any additional participant-information form retained by the 
investigator as part of the trial records. A signed copy of the informed consent and any 
additional participant information must be given to each participant.
A separate informed consent form will be required for participation for tokenisation of 
participant-level medical data (see Section 5.6.5). Consent for tokenisation may be provided 
at any time during study participation, but preferable will be done during screening.The 
investigator or delegate must give a full explanation to trial participants based on the
participant information form. A language understandable to the trial participant should be 
chosen, technical terms and expressions avoided, if possible. 

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The trial participant must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the trial participant’s own free will with 
the informed consent form after confirming that the trial 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 be necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A 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 or alternative plan, in line with the guidance provided by ICH Q9 and ICH
GCP E6, 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 
designee, IRB/IEC, or 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 standardised processes, data collection of efficacy 
endpoints is coordinated centrally: a service provider has been selected to support tasks 
related to the neuropsychological assessments. These services include:

Necessary rater pre-qualification

Site rater training for COAs used as primary and secondary endpoints 

Provision of rater materials

Central quality review of MINI, HDRS-17, MADRS, and PCRS. For this purpose, the 
MINI, HDRS-17, MADRS, and PCRS interviews will be audio recorded
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 TMF.

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8.3
RECORDS
Case Report Forms for individual trial 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. A description of the transmission of electronic data 
is provided in the data management plan. Changes to the data in EDC should be traceable 
(audit trail).
Data reported on the eCRF must be consistent with the source data, or the discrepancies must 
be explained. Electronic records, i.e. clinician administered assessment data, related audio 
recordings (for central review) and patient reported outcome data, entered into the tablet 
(eCOA device) will be regarded as source data. These may be further analysed by the third-
party vendor.
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 must make at least 3 documented attempts
to retrieve previous medical records. If this fails, a verbal history from the participant, 
documented in their medical records, would be acceptable.
The electronic version of the ECG is regarded as source documentation. Dated and signed 
printouts should be stored in the patient’s medical file.
Copies of source documents necessary for central clinical review of COAs and ECGs, as 
applicable, will be provided to the corresponding vendor. Before sending or uploading those 
copies, the investigator must ensure that all participant identifiers (e.g. participant’s name, 
initials, address, phone number, social security number) have been properly removed or 
redacted from all copies of the participant’s source documents.
If the trial participant is not compliant with the protocol, any corrective action (e.g. 
re-training) must be documented in the participant file.
For the eCRF, data must be derived from source documents, for example:

Participant identification: sex, 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 IMP

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

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
AEs and outcome events (onset date [mandatory] and end date [if available])

SAEs (onset date [mandatory] and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

Completion of participant’s participation in the trial (end date; in case of premature 
discontinuation, document the reason)

Prior to allocation of a trial participant to a treatment in 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 eCRF and all source 
documents/data, including progress notes and copies of laboratory and medical test results, 
which must always be available for review by the CRA, auditor, and regulatory inspector 
(e.g. FDA). They may review all eCRFs and informed consent forms. The accuracy of the 
data will be verified by direct comparison with the source documents described in 
Section 8.3.1. The sponsor or delegate will also monitor compliance with the protocol and 
GCP.
In the event of force majeure or other disrupting circumstance (e.g. pandemic or war; see 
Section 6), site access may be restricted, thus limiting the ability to perform standard site 
monitoring activities on site, such as source data review and source data verification. 
Therefore, some of these activities may be performed remotely or replaced by centralized 
monitoring to the extent possible, based on a documented risk assessment and in alignment 
with local regulations.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
the contract or local requirements valid at the time of the end of the trial (whichever is 
longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
Boehringer Ingelheim is responsible for fulfilling their legal and regulatory reporting 
obligation in accordance with regulatory requirements.

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8.5
STATEMENT OF CONFIDENTIALITY AND TRIAL 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. 

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred

The participant must be informed that their personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent

The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, appropriate IRB/IEC members, and inspectors from regulatory 
authorities

The sponsor has implemented privacy and security controls designed to help 
protect participants’ personal data, including information security controls, 
firewalls, incident detection, and secure transfer measures

In the event of an accidental or unlawful destruction, loss, alteration, unauthorized 
disclosure, or access to personal data (“breach”), the sponsor has implemented 
procedures and measures to promptly address and mitigate any risk to the 
participant. In the event of a breach, the sponsor will notify the appropriate 
regulatory authorities and/or the participant(s) in accordance with applicable data 
protection law

The contract between sponsor and trial sites specifies the responsibilities of the 
parties related to data protection, including the handling of data security breaches 
and respective communication and cooperation of the parties

Information technology systems used to collect, process, and store trial-related 
data are secured by technical and organizational security measures designed to 
protect such data against accidental or unlawful loss, alteration, or unauthorized 
disclosure or access
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 must be in accordance with the separate biobanking informed 
consent

The Boehringer Ingelheim 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, including 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 first act of recruitment represents the start of the trial and is defined as the date when 
the first trial 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 trial participant in the 
whole trial (“last participant completed”).
The “last participant last treatment” (LPLT) date is defined as the date on which the last 
trial participant in the whole trial is administered the last dose of trial IMP (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial IMP until 30 days after LPLT at their site.
The “last participant last visit primary endpoint” (LPLVPE) date is defined as the date on 
which the last randomised participant reaches the Week 6 Visit (EoT).
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 sponsor will notify the IEC/competent authority in each participating EU member state 
about all required trial milestones according to the respective laws.

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A final report of the clinical trial data will be written only after all trial participants have 
completed the trial in all countries (EU or non-EU) to incorporate and consider all data in the 
report. The sponsor will prepare a clinical trial report within 1 year from the end of trial.
The sponsor will submit to the EU database a summary of the final trial results within 1 year 
from the end of a clinical trial as a whole, regardless of the country of the last trial participant
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim. In EU/EEA countries, the trial is sponsored 
by Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216 Ingelheim am 
Rhein, Germany.
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 (e.g. their curricula 
vitae) will be filed in the ISF.
The trial will be managed by a fully outsourced trial (FOT) vendor based on a contract which
specifies the delegated responsibilities and duties. Boehringer Ingelheim has appointed a 
Clinical Trial Leader responsible for coordinating all required activities, in order to:

Oversee and manage the trial in accordance with applicable regulations and SOPs

Direct the clinical trial team and oversee the FOT vendor in the preparation, conduct, 
and reporting of the trial

Ensure appropriate training
In the participating countries, the trial will be performed by a Contract Research Organisation 
(CRO) based on a contract. The CRO will perform project management, clinical field 
monitoring, medical monitoring, and reporting.
Data management, statistical evaluation, and reporting of clinical trial results will be done by 
Boehringer Ingelheim according to Boehringer Ingelheim SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to Boehringer Ingelheim SOPs. A list of responsible persons and relevant local 
information can be found in the ISF.
A central laboratory service, a speciality laboratory for ECG, a service provider for data 
collection related to COAs, and an IRT vendor will be used in this trial. Details will be 
provided in the central laboratory manual and IRT manual, available in the ISF.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Homayoun H, Moghaddam B. NMDA receptor hypofunction produces 
opposite effects on prefrontal cortex interneurons and pyramidal neurons. 
J Neurosci 2007;27(43):11496-11500.  
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Reynolds IJ, Miller RJ. Tricyclic antidepressants block N-methyl-D-
aspartate receptors: similarities to the action of zinc. Br J Pharmacol 
1988;95:95-102.  
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Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of 
ketamine in depressed patients. Biol Psychiatry 2000;47(4):351-354.  
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Global, regional, and national incidence, prevalence, and years lived with 
disability for 328 diseases and injuries for 195 countries, 1990 - 2016: a 
systematic analysis for the Global Burden of Disease study 2016. Lancet 
2017;390(10100):1211-1259.  
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FDA approves new nasal spray medication for treatment-resistant 
depression; available only at a certified doctor's office or clinic (FDA news 
release, for immediate release, March 5, 2019). 2019.  Website: 
fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm 
(access date: 13 March 2019).
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Nagy D, Stoiljkovic M, Menniti FS, et al. Differential effects of an NR2B 
NAM and ketamine on synaptic potentiation and gamma synchrony: 
relevance to rapid-onset antidepressant efficacy. 
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controlled, sequential parallel study of CERC-301 in the adjunctive 
treatment of subjects with severe depression and recent active suicidal 
ideation despite antidepressant treatment. NNDC 2015, Ann Conf of the 
National Network of Depression Centers (NNDC), Ann Arbor, 
2015-11-05; 2015.  
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Request for qualification of MCP-Mod as an efficient statistical 
methodology for model-based design and analysis of Phase II dose finding 
studies under model uncertainty (applicant: Janssen Pharmaceuticals and 
Novartis Pharmaceuticals, application date: 22 April, 2015). 2015.  
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Bushnell DM, McCarrier KP, Bush EN, et al. Symptoms of Major 
Depressive Disorder scale (SMDDS): performance of a novel patient-
reported symptom measure. Value Health 2019. doi: 
10.1016/j.jval.2019.02.010 
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Guidance for industry: in vitro drug interaction studies - cytochrome P450 
enzyme- and transporter-mediated drug interactions (January 2020, clinical 
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Cohen EA, Hassman HH, Ereshefsky L, et al. Placebo response mitigation 
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10.
APPENDICES
10.1
TRIAL PARTICIPANT FEEDBACK
Optional Trial Participant Feedback Questionnaire:
This trial will include an option for participants to complete a ‘Trial Participant Feedback 
Questionnaire’, to provide feedback on their clinical trial experience. Individual participant 
level responses will not be reviewed by investigators. Responses will be used by the sponsor 
to understand where improvements can be made in the clinical trial process. These 
questionnaires will not collect data about the participant’s disease, symptoms, treatment 
effect, or AEs and therefore will not be part of the trial data or clinical trial report. The 
questionnaires will be implemented after local regulatory approval, if required, and after 
consent of the trial participant. Providing feedback is optional and not required for 
participation in the trial.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
This amendment is considered to be substantial based on the criteria set forth in Regulation 
(EU) No 536/2014 of the European Parliament and the Council of the European Union.
Overall rationale for the amendment:
To modify the primary endpoint from “Change from baseline in MADRS total score at
Day 8” to “Change from baseline in MADRS total score at Week 6”, while moving 
“Change from baseline in MADRS total score at Day 8” to a secondary endpoint.
To update the determination of sample size in accordance with the updated primary 
endpoint (based on drop-out rate over 6 weeks instead of 7 days).
To add exclusion criteria with specific eGFR parameters.
To incorporate changes requested in the frame of the EU Clinical Trial Application 
Request for Information (RFI) process.
To incorporate minor corrections and clarifications identified during study start-up.
Amendment and 
date of amendment
Amendment 1, [09 Oct 2024]
Global Amendment
X
Global Amendment due to urgent safety reasons
Section changed
Description of change
Rationale for change
Throughout
Primary endpoint modified from 
“change from baseline in 
MADRS total score at Day 8” to
“change from baseline in 
MADRS total score at Week 6”.
Moved “change from baseline in 
MADRS total score at Day 8” to 
a secondary endpoint.
Modified in alignment with
available development guidelines 
from FDA and CHMP requiring 
short-term efficacy at Week 6 to 
be demonstrated.
Throughout
Updated sample size calculation 
and number of participants
Updated to account for change in 
primary endpoint and the 
corresponding assumed higher 
drop-out rate of individuals 
evaluable for the primary endpoint 
after 6 weeks vs after 7 days of 
treatment.
Schedule of 
Assessments
Specified the timing of the 
physical/neurological assessment 
to after IMP intake.
Added in compliance with EU RFI
to clarify monitoring of CNS 
parameters. As described in the 
current IB, no increased risk for 
seizures has been observed since 
Version 1.0 of the CTP.

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Section changed
Description of change
Rationale for change
Schedule of 
Assessments
Removed instances (X) from all 
visits except for Visit 1 for the 
participant duplicate check.
Correction, the participant 
duplicate check is only conducted 
at the first screening visit.
3.3.3
Added specifications for Grades 2 
and 3 hypertension.
For clarity.
3.3.3
Added Exclusion Criterion #28: 
Indication of renal impairment, 
defined as an estimated 
glomerular filtration rate (eGFR) 
≤30 mL/min at screening.
Added in order to have more 
standardised and objective 
assessments across clinical trial 
sites to exclude participants with 
severe renal impairment
(commitment in the frame of FDA 
request to define renal 
impairment) in addition to
clinically relevant concomitant 
renal impairment which is 
excluded per Exclusion Criteria
#20 and #27.
4.1.4
Amended text detailing the 
procedures for participants that 
are unable to come to the site 
during their typical dosing time.
Clarification, participants should 
take their daily dose at the site 
during Visits 3 and 4 or have the 
visit rescheduled if they have 
taken IMP prior to arrival at the 
trial site.
4.1.5.2
Added ESMS description.
Incorporation of recently available 
service for emergency unblinding.
4.2.2.1
Added text regarding the 
exception of low dose 
antidepressants to treatment 
restrictions in accordance with 
Exclusion Criterion #4
Clarification.
5.1.1.1
Modified text to specify that the 
MADRS-SIGMA is being used to 
collect MADRS scores. Added 
additional text and references 
regarding scoring.
For clarity. No change to trial 
conduct or statistical analysis.

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Section changed
Description of change
Rationale for change
5.2.1
Added text that explicitly states 
that participants should be 
referred to a neurologist or 
emergency services for further 
testing if signs indicative of 
seizure activity are observed.
Added in compliance with EU RFI 
to clarify monitoring of CNS 
parameters.
5.2.3
Added eGFR to the list of safety 
laboratory tests.
To clarify that calculated eGFR 
will be reported.
5.2.3
Replaced “Hepatitis C vaccine
RNA” with “Hepatitis C virus 
RNA”.
Correction, typo. No change to 
trial conduct.
5.6.1.2 and 6.2
Removed text describing the 
ATRQ as clinician administered
and amended response method.
Correction, the participant 
reported, paper version of the 
ATRQ is being used.
5.6.1.3
Modified text to specify that the 
HDRS-SIGH-D is being used to 
collect HDRS-17 scores. Added 
additional text and references 
regarding scoring.
For clarity. No change to trial 
conduct or statistical analysis.
6.2.1
Update to screening window and 
examples of circumstances for 
which the screening period can be 
extended.
Correction and clarification, 
screening window was incorrectly 
calculated.
6.2.1.3
Included collection of gender 
identity under demographics.
Gender identity has been collected 
to further characterise the 
participant population in 
adherence with the FDA’s 2022 
guidance regarding diversity in 
clinical trials.
6.2.1.5
Incorporated further examples of 
characteristics associated with an 
increased risk of seizures to be 
examined during the medical 
history evaluation.
Added in compliance with EU RFI
to clarify monitoring of CNS 
parameters.
7.2.4.2
Added that the analysis will be 
based on the PAS
For clarity.
9.1
References added
In accordance with text updates.

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Section changed
Description of change
Rationale for change
Throughout
“Rater station” changed to 
“eCOA device”.
Changed in accordance with 
vendor terminology.
Throughout
Updated the protocol version 
number and date.
To align with the amendment.
Throughout
Minor editorial and document 
formatting revisions.
For clarity.

 
 
 
 
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clinical-trial-protocol-version-02
A Phase II, 6-week, multi-centre, randomised, double-blind (participant and
investigator), placebo-controlled, dose-finding trial to evaluate the efficacy,
tolerability, and safety of different doses of oral BI 1569912 as adjunctive therapy in
patients with major depressive disorder
Author-Trial Statistician
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Author-Clinical Trial Leader
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Completion
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