Conditions: Depressive Disorder, Major
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 45
Healthy volunteers: no

Brief summary:
This is a home-based study in adults with depression. People who have been diagnosed with Major Depressive Disorder can participate in the study. Participants can take part if they are being treated for their depression but still have symptoms. The purpose of this study is to find out whether a medicine called BI 1358894 helps people with depression.

Participants are in the study for about 2 months and do not need to visit a study site during this time. All study visits are conducted at participant's home by a mobile study nurse, by videoconference, and by phone calls. Participants are put into 2 groups by chance. One group takes BI 1358894 tablets. The other group takes placebo tablets. Placebo tablets look like BI 1358894 tablets but do not contain any medicine.

The participants answer questions about the symptoms of their depression. We then compare the results between the BI 1358894 and placebo groups. The doctors and nurses also regularly check the general health of the participants.

Detailed description:

Arms:
arm 1: 125 milligram (mg) BI 1358894 taken orally as three film-coated tablets (1x 25mg and 2x 50mg) once a day in the morning for six weeks. arm 2: Placebo matching BI 1358894 taken orally as three film-coated tablets once a day in the morning for six weeks.

Interventions: intervention 1: BI 1358894 intervention 2: Placebo
Intervention descriptions: intervention 1: 125 milligram (mg) BI 1358894 taken orally as three film-coated tablets (1x 25mg and 2x 50mg) once a day in the morning for six weeks. intervention 2: Placebo matching BI 1358894 taken orally as three film-coated tablets once a day in the morning for six weeks.

Protocol document:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
TITLE PAGE
Document Number:
c30650673-03
EudraCT No.
EU Trial No.
NA
BI Trial No.
1402-0014
BI Investigational
Medicinal Product(s)
BI 1358894
Title
A phase II 6-week, randomized, double-blinded, placebo-
controlled, parallel group decentralised clinical trial to evaluate 
efficacy and safety of oral BI 1358894 in patients with Major 
Depressive Disorder with inadequate response to antidepressants
Lay Title
A home-based study using mobile technology to test whether BI 
1358894 is effective in people with depression
Clinical Phase
II
Clinical Trial Leader
Telephone: +
Fax: +
Email: 
Principal 
Investigator
Phone: +
Fax: +
    
E-mail:  
Version and Date
Version: 3.0
Date: 20-Jul-2021
Page 1 of 108
Proprietary confidential information.
2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
24-Mar-2020
Revision date
20-Jul-2021
BI trial number
1402-0014
Title of trial
A phase II 6-week, randomized, double-blinded, placebo-controlled, parallel group 
decentralised clinical trial to evaluate efficacy and safety of oral BI 1358894 in 
patients with Major Depressive Disorder with inadequate response to 
antidepressants
Principal Investigator
Phone: +
Fax: +
    
E-mail:  
Trial site(s)
Clinical phase
II
Trial rationale
Based on the pre-clinical data and the data from the proof of clinical principle 
(PoCP), there is reason to believe that BI 1358894 may be efficacious in major 
depressive disorder (MDD) and that there are no safety signals precluding this 
assessment.
The decentralized clinical trial (DCT) model will be used to conduct this study, 
bringing the clinical trial to study participants in their homes through deployment of 
mobile research nurses. This model integrates telemedicine technology into the 
clinical research process and supports the management of research activities 
remotely, including data collection.  
With more advanced technology now available and the understandable desire to 
reduce participant burden, DCTs allow for a more patient-centric alternative for 
conduct of clinical trials. The DCT model will be piloted in this trial, offering the 
opportunity to assess the safety and efficacy of BI 1358894 in participants with 
MDD with a decentralized approach.  
Trial objective(s)
The trial will be performed to compare BI 1358894 with placebo in participants 
with MDD with inadequate response to antidepressants (selective serotonin 
reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI). 
The primary comparison of interest is the change from baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) total score at Week 6 summarized per 
arm by the adjusted mean. The primary trial objective is to assess superiority of BI 
1358894 verses placebo in a DCT model. 
Trial endpoints
Primary endpoint:

Change from baseline in MADRS total score at Week 6
Secondary endpoints:

Response defined as ≥50% MADRS reduction from baseline at Weeks 6

Change from baseline in State-Trait Anxiety Inventory (STAI) scores at 
Week 6

Change from baseline in Clinical Global Impression Severity Scale (CGI-
S) score at Week 6


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
Change from baseline in Symptoms of Major Depressive Disorder Scale 
(SMDDS) total score at Week 6

Change from baseline in Patient Global Impression Severity Scale (PGI-S) 
score at Week 6

Patient Global Impression Severity Scale (PGI-C) score at Week 6
Trial design
This study will be conducted as decentralized clinical trial (DCT).  It is a 6-week 
parallel-group, randomized, double-blinded, placebo-controlled Phase II trial in 
participants with MDD with inadequate response to ongoing treatment of an SSRI 
or SNRI. This trial will be conducted in the US, with 
 as the single 
decentralized site enrolling in the study.
Total number of 
participants randomised 
164
Number of participants 
on each treatment
BI 1358894 125 mg = 82
Placebo = 82
Diagnosis
Participants with an established diagnosis of Major Depressive Disorder confirmed 
at the time of screening by Structured Clinical Interview for DSM-5 (Diagnostic 
and Statistical Manual of Mental Disorders, Fifth Edition) (SCID-5) Clinical Trials 
version. 
Main in- and exclusion 
criteria
Inclusion criteria:
1.
Established diagnosis of Major Depressive Disorder, single episode or 
recurrent, as confirmed at the time of screening by the Structured Clinical 
Interview for DSM-5 (SCID-5), with a duration of current depressive episode ≥ 
8 weeks and ≤ 18 months at the time of screening visit.
2.
Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 22 at 
screening, as confirmed by a trained rater. In addition, trial participants must 
have a score of ≥ 3 on the Reported Sadness item  on MADRS. 
3.
A documented ongoing monotherapy treatment of ≥ 8 weeks at the screening 
visit, with a protocol specified SSRI or SNRI at adequate dose (at least 
minimum effective dose as per prescribing information and as confirmed per 
detectable drug levels in the screening blood or urine sampling).
4.
Male and female participants, 18 to 65 years of age, both inclusively at the time 
of consent. 
5.
Women of child-bearing potential (WOCBP)1 able and willing to use two 
methods of contraception, which include one highly effective method of birth 
control per ICH M3 (R2) that results in a low failure rate of less than 1%, plus 
one barrier method.
Exclusion criteria:
1.
Per DSM-5, had ever met diagnostic criteria for schizophrenia, schizoaffective 
disorder, schizophreniform disorder, bipolar disorder, delusional disorder or 
MDD with psychotic features as assessed by the SCID-5 at the time of 
screening.
2.
Diagnosis of any other mental disorder (in addition to those as described in 
Exclusion Criterion #1) that was the primary focus of treatment within 6 
months prior to screening or at baseline (as per clinical discretion of the 
investigator).
3.
Diagnosis with antisocial, paranoid, schizoid or schizotypal personality 
disorder as per DSM-5 criteria, at the time of screening visit. Any other 
personality disorder at screening visit that significantly affects current 
psychiatric status and likely to impact trial participation, as per the judgement 
of investigator.
4.
Diagnosis of a substance related disorder within 3 months prior to screening 
visit (with exception of caffeine and tobacco).
5.
History of seizure disorders, stroke, brain tumor or any other major 
neurological illness that can impact participation in the trial. 
6.
History of 4 or more unsuccessful monotherapy treatments (at adequate dosage 


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and duration, per local prescribing information of the product) with an 
approved antidepressant medication for the current ongoing major depressive 
episode. These include ongoing monotherapy treatment with a protocol 
specified SSRI or SNRI as described in Inclusion Criterion #3.
7.
Any suicidal behavior in the past 12 months prior to screening (per investigator 
judgement including an actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behaviour). 
8.
Any suicidal ideation of type 4 or 5 in the Columbia Suicide Severity Rating 
Scale (C-SSRS) in the past 3 months prior to screening or at screening or 
baseline visit (i.e. active suicidal thought with method and intent but without 
specific plan, or active suicidal thought with method, intent and plan). 
Test product(s)
BI 1358894
dose
125 mg daily
mode of 
administration
per os / oral (p.o.)
Comparator product(s)
Placebo
dose
Matching
mode of
administration
per os / oral (p.o.)
Duration of treatment
6 weeks
Statistical methods
A two-sided test using the mixed model with repeated measurements (MMRM)
model will be carried out to assess the primary endpoint, with an α level of 10%.
The primary analysis will be the restricted maximum likelihood (REML) based 
approach using a MMRM comparing the change from baseline of MADRS score at 
week 6.
Response rate over the 6-week treatment period will be assessed using the MADRS 
total score. Participants with ≥ 50% reduction in MADRS total score from baseline 
to Week 6 are considered responders. The proportions of participants achieving 
response at Week 6 will be summarized as the frequency and percentage of 
participants in each treatment arm. In addition, if a sufficient number of responders 
is observed, a logistic regression model adjusted for treatment (BI 1358894 or 
placebo) will be used to calculate the odds ratio for response between the BI
1358894 arm and placebo and corresponding confidence interval.
Change from baseline to Week 6 in STAI, CGI-S and SMDDS scores will be 
analyzed using an MMRM model similar to the model described for the primary 
endpoint analysis.
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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FLOW CHART
Trial Periods
Scree
ninga
Randomi
zationb
Treatment
Early 
D/C
Follow-
up/End 
of Study
Visit1
1
1A

2c
3

4
5
3
6
7
3
8 /
EOT5
eEOT5
9
EoStudy6
Week 
0
1
2
3
4
5
6
10
Day
-28 to 
-3
-7 to 
-1
14
8 ±1
15±1
22 
±1
29 
±1
36 
±1
43 ±2
EOT
(early 
drug d/c 
date) +28 
+4 days 
Informed  
consents 2 (include
consents for 
participant’s 
duplicate check)
X
Demographics
X
Medical history
X
SCID-5
X
ATRQ
X
Physical 
examination7
X
X
X
X
Vital signs, incl. 
body weight
X7
X
X
X
X
X
X
Laboratory tests 
(incl. pregnancy test) 
8
X
X
X
X
X
X
X
12 lead-ECG
X
X
X
X
X
X
X
Review of in-
/exclusion criteria
X
X
Randomization
X
Assignment (IRT) 
and dispense of trial 
drug9
X
X
X
Administration of 
trial drugs 
X
X
X
Drug Accountability 
10
X
X
X
X
Sample for 
confirmation of 
blood/urine levels 
SSRI/SNRI11
X
X
X
PK Sampling BI 
135889412
X
X
X
X
X
X
Optional sampling 
for biobanking of 
serum, plasma and 
DNA13
X14
X14
X14
MADRS 
X
X
X
X
X
X
X
SMDDS d
X
X
X
X
X
X
PGI-S d
X
X
X
X
X
X


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FLOW CHART (cont.)
Trial Periods
Scree
ninga
Randomi
zationb
Treatment
Early 
D/C
Follow-
up/End 
of Study
Visit1
1
1A

2c
3

4
5
3
6
7
3
8 /
EOT5 eEOT5
9
EoStudy6
Week 
0
1
2
3
4
5
6
10
PGI-C d
X
X
STAI d
X
X
X
X
X
X
C-SSRS 
X15
X16
X16
X16
X16
X16
X16
X16
X16
X16
X16
CGI-S 
X
X
X
X
X
X
 
 
 
 
Medication 
adherence
↔
↔
↔
↔
↔
↔
←
Smartphone App 
training/
set-up 20
X
All AEs/SAEs/ 
AESIs
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Substance Use
X
X
X
X
X
X
X
X
X
X
Termination of trial 
medication
X21
X
Completion of 
participant’s
participation 
X
Participant Feedback 
Questionnaire22
X
a Screening visit may be completed in multiple days, for example: with first day SCID-5, C-SSRS, 
demographics (completed via videoconferencing) and second day MADRS, repeat C-SSRS, medical history, 
patient report questionnaires, physical exams, vitals and laboratory. Note, for safety, C-SSRS needs to be 
completed on each day that other assessments/procedures are completed, if multiple days are needed for 
screening. Screening MADRS must be completed within 21 days of randomization (repeat of MADRS is 
allowed once to maintain within this 21-day window). Physical exams and medical history will be conducted by 
physician interview and guided assessments through videoconference calls (a method known as telemedicine). 
b Randomization and assignment of trial drugs via IRT system may occur up to 7 days before Visit 2 to allow for 
the drug kit assignment in the IRT system, as well as shipment and delivery of trial drugs to the participant’s 
home. Training and set-up of Smartphone App may start at Visit 1 and repeated/continued to this visit, however 
all must be completed within this time between randomization and Visit 2.  All eligibility criteria must be 
confirmed, including C-SSRS, confirmation of positive blood levels of SSRI/SNRI in the screening lab, before
randomization can be registered in IRT.
c On day of Visit 2, all assessments, including ClinROs (Clinician Reported Outcomes: MADRS, CGI-S and C-
SSRS) and PROs (Patient reported outcomes) assessments need to be completed before dosing, not including 
 


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d PROs = self-reported assessments.  All scales, including PROs, are recommended to be completed in the order 
top down as indicated here on the Flow Chart, most importantly the SMDDS must be completed before the PGI-
S and PGI-C.  If participant discontinues early, only one PGI-C will be collected at eEOT Visit
 
 
1 As part of the Decentralized Clinical Trial (DCT) model, study visits will be conducted in several ways: i) at 
participant’s home by mobile study nurse; ii) by videoconference only (indicated by symbol); and iii) by 
telephone contact only (indicated by symbol).  Unless indicated, visits are conducted by mobile study nurse 
at participant’s home.
2 Informed consent must be completed prior to any trial related procedure, may also be done at an extra visit up 
to 2 weeks before V1.
3 indicates telephonic contact visits.  Participant’s visits to be conducted by telephone contact, but a
videoconference may also be conducted, depending on clinical needs.
4 Day 1 = Day of first intake of randomised medication.
5 EOT (end of treatment) for participants who complete the treatment period, Week 6 (Visit 8) will be 
completed. 
Participants who discontinue (D/C) trial drug prematurely should ideally be observed until trial end as if they 
were still receiving blinded trial treatment.  All early D/C participants will complete the FUP visit (early drug 
discontinuation date + 28 days) for a full trial safety follow-up.  There are 2 options for observing participants 
after premature drug discontinuation. Option 1 is most preferred, and Option 2 is only when Option 1 can’t be 
completed.
Early D/C Participants:
Option 1: An eEOT Visit must be conducted within 7 days of the last dose of trial medication for participants 
who agree to conduct regularly scheduled visits after premature drug discontinuation. Thereafter, participants 
will be followed up according to the regular visit schedule for both home and phone visits, including FUP visit.  
All visit procedures will be completed, with the exception of trial drug procedures and PK samples, Meal intake, 
and PGI-C collections. 
If FUP visit (early drug discontinuation date + 28 days) coincides with and can be completed at a visit prior to 
the planned Visit 8, no additional FUP visit is needed.  Assessments under both FUP and that visit need to be 
completed without duplicates. If planned FUP is within 7 days prior to planned Visit 8, then no FUP is needed, 
Visit 8 should be completed.
Option 2: An eEOT Visit must be conducted within 7 days of the last dose of trial medication for participants, 
FUP visit, and then Visit 8.  All FUP and Visit 8 procedures will be completed, with the exception of trial drug 
procedures and PK samples, Meal intake, and PGI-C collections. If FUP visit (early drug discontinuation date + 
28 days) is within 7 days prior to planned Visit 8, then no FUP is needed; V8 should be completed, however, the 
completion of participation must be completed.  
6 After the EoStudy visit (=individual participant’s end of the study) the investigator will report only any cancers 
of new histology and exacerbations of existing cancer, trial treatment related SAEs and trial treatment related 
AESIs of which the investigator may become aware of and only via the BI Serious Adverse Event (SAE) form. 
See section 5.3.6.2.1.
7 Physical examinations will be conducted via telemedicine with the mobile nurse conducting the physician-
guided examination through videoconference with study investigator or physician. Vital signs at Visit 1 will 
include the collection of height.  Measurements of vital signs should precede blood sampling. 
8 Urine drug screens will be completed at screening visit only.  For WOCBP, a serum pregnancy test will be 
performed at screening and urine pregnancy tests at all home visits beginning with V2. If a urine pregnancy test 
is positive, a serum test needs to be performed for confirmation.
9 Assignment of trial drugs via IRT system and dispensing may occur up to 7 days before actual visit to allow 
for the drug kit assignment in the IRT system, as well as shipment and delivery of trial drugs to the participant’s 
home. Once trial drug is received at participant’s home, site staff will confirm drug fit for use and dosing of 
(received) trial drugs will be done on day of planned visit with mobile nurse at participants’ home.


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10 Drug accountability will be completed for drug compliance by pill counts of the trial medication (used/unused 
blister and covering packages) returned/shipped back to site. Last regular intake of the trial drug is the day 
before EOT visit.
11 Blood sample for confirmation that participants are on SSRIs or SNRIs at Visit 1 and EOT; urine sample only 
collected at Visit 1 (except for Duloxetine which is serum only).  
12 PK-blood trough samples to be collected pre-dosing, within 30 minutes before drug administration, and will 
be taken together with safety lab.  Meal intake will also be collected at each PK sample collection. No dosing is 
done at Visit 8/EOT and FUP visit, therefore PK may be completed at any time. If participant discontinues 
early, only one PK sample will be collected at eEOT Visit.
13 Collection of biobanking samples is optional. Samples will be collected at Visit 2 (serum, plasma and DNA 
samples) and Visit 8 (serum, plasma only). If participant discontinues early, the Visit 8 serum and plasma
sample will be collected at eEOT Visit. Participants are required to sign a separate informed consent for 
biobanking. Samples will be stored at a biobanking facility for future research.
14 One sample for DNA biobanking will be taken, preferably at Visit 2. However, collection at later visits is 
permitted as long as the informed consent for biobanking remains valid.
15 C-SSRS: Columbia Suicide Severity Rating Scale baseline/screening scale.
16 C-SSRS: Columbia Suicide Severity Rating Scale since-last-visit scale; version to be completed after the first 
C-SSRS baseline/screening version was completed.  At Visit 1A, C-SSRS will be completed before 
randomization.
 
 
 
 
 
 
 
 
 
  
 
21 For participants who early discontinue treatment and following Option 1, this does not apply at Visit 8 as this 
would have been completed at eEOT.
22 At the End of Study, participants will be asked to complete a feedback questionnaire, provided through a 
separate website (BI’s MyStudyWindow website).  See section 5.6.5 for details.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................21
1.4
BENEFIT - RISK ASSESSMENT.....................................................................22
1.4.1
Benefits.................................................................................................................22
1.4.2
Risks .....................................................................................................................23
1.4.3
Discussion.............................................................................................................29
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................30
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........30
2.1.1
Main objectives....................................................................................................30
2.1.2
Primary endpoint(s)............................................................................................30
2.1.3
Secondary endpoint(s) ........................................................................................30
2.2.3
Safety....................................................................................................................32
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................33
3.1
OVERALL TRIAL DESIGN.............................................................................33
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................34
3.3
SELECTION OF TRIAL POPULATION .......................................................34
3.3.1
Main diagnosis for trial entry ............................................................................35
3.3.2
Inclusion criteria .................................................................................................35
3.3.3
Exclusion criteria ................................................................................................36
3.3.4
Withdrawal from treatment...............................................................................38
3.3.4.1
Discontinuation of trial treatment .........................................................................38
3.3.4.2
Withdrawal of consent to trial participation .........................................................39
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................40
4.
TREATMENTS...................................................................................................41
4.1
INVESTIGATIONAL TREATMENTS ...........................................................41
4.1.1
Identity of the Investigational Medicinal Products..........................................41
4.1.2
Selection of doses in the trial and dose modifications......................................42
4.1.3
Method of assigning participants to treatment groups....................................43


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4.1.4
Drug assignment and administration of doses for each participant ..............44
4.1.5
Blinding and procedures for unblinding...........................................................45
4.1.5.1
Blinding.................................................................................................................45
4.1.5.2
Unblinding and breaking the code ........................................................................46
4.1.6
Packaging, labelling, and re-supply...................................................................46
4.1.7
Storage conditions...............................................................................................46
4.1.8
Drug accountability.............................................................................................46
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................47
4.2.1
Other treatments and emergency procedures..................................................47
4.2.2
Restrictions ..........................................................................................................47
4.2.2.1
Restrictions regarding concomitant treatment ......................................................47
4.2.2.2
Restrictions on diet and life style..........................................................................48
4.2.2.3
Contraception requirements..................................................................................48
4.3
TREATMENT COMPLIANCE........................................................................49
5.
ASSESSMENTS..................................................................................................51
5.1
CONFIRMATION OF DIAGNOSIS................................................................51
5.2
ASSESSMENT OF EFFICACY........................................................................51
5.2.1
MADRS - Montgomery–Åsberg Depression Rating Scale..............................51
5.2.2
SMDDS - Symptoms of Major Depressive Disorder Scale..............................52
5.2.3
STAI - The State-Trait Anxiety Inventory .......................................................52
5.2.4
CGI-S - The Clinical Global Impression Severity Scale..................................53
5.2.5
PGI-S - Patient Global Impression Severity Scale...........................................53
5.2.6
PGI-C - Patient Global Impression of Change Scale.......................................54
5.3
ASSESSMENT OF SAFETY.............................................................................55
5.3.1
Physical examination ..........................................................................................55
5.3.2
Vital signs.............................................................................................................55
5.3.3
Safety laboratory parameters ............................................................................55
5.3.4
Electrocardiogram ..............................................................................................59
5.3.5
Other safety parameters.....................................................................................59
5.3.5.1
Assessment of Suicidality.....................................................................................59
5.3.6
Assessment of adverse events.............................................................................60
5.3.6.1
Definitions of AEs ................................................................................................60
5.3.6.2
Adverse event collection and reporting ................................................................63
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................64
5.4.1
Methods of sample collection .............................................................................64
5.4.3
Assessment of biomarker(s) ...............................................................................65
5.5
BIOBANKING ....................................................................................................65
5.5.1
Methods and timing of sample collection..........................................................65
5.6
OTHER ASSESSMENTS...................................................................................65


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5.6.4
Medication Adherence and Reminder System.................................................69
5.6.5
End of Study Participant Feedback Questionnaire .........................................70
5.6.6
Verification of Current and Past Research Study Status of Trial Participant
...............................................................................................................................70
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................71
6.
INVESTIGATIONAL PLAN.............................................................................72
6.1
VISIT SCHEDULE.............................................................................................72
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................72
6.2.1
Screening period(s) .............................................................................................74
6.2.2
Treatment period(s)............................................................................................77
6.2.3
Withdrawal of consent........................................................................................78
6.2.4
Follow-up period and trial completion..............................................................78
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
Primary endpoint analyses.................................................................................81
7.2.2.1
Primary analysis of the primary endpoint.............................................................81
7.2.2.2
Supplemental analysis of the primary endpoint....................................................82
7.2.3
Secondary endpoint analyses .............................................................................82
7.2.3.1
MADRS response .................................................................................................82
7.2.3.2
STAI......................................................................................................................83
7.2.3.3
CGI-S ....................................................................................................................83
7.2.3.4
PGI-S.....................................................................................................................83
7.2.3.5
PGI-C ....................................................................................................................83
7.2.3.6
SMDDS.................................................................................................................83
7.2.5
Safety analyses.....................................................................................................84
7.2.6
Other analyses .....................................................................................................85
7.2.7
Interim analyses ..................................................................................................85
7.3
HANDLING OF MISSING DATA ...................................................................85
7.4
RANDOMISATION ...........................................................................................86
7.5
DETERMINATION OF SAMPLE SIZE .........................................................86
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........88
8.1
TRIAL APPROVAL, PARTICIPANT INFORMATION, INFORMED 
CONSENT ...........................................................................................................88


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8.2
DATA QUALITY ASSURANCE ......................................................................89
8.3
RECORDS...........................................................................................................90
8.3.1
Source documents ...............................................................................................90
8.3.2
Direct access to source data and documents.....................................................91
8.3.3
Storage period of records ...................................................................................91
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................91
8.5
STATEMENT OF CONFIDENTIALITY AND PARTICIPANT PRIVACY92
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................92
8.6
TRIAL MILESTONES.......................................................................................92
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................93
9.
REFERENCES....................................................................................................95
9.1
PUBLISHED REFERENCES............................................................................95
9.2
UNPUBLISHED REFERENCES......................................................................97
10.
APPENDICES.....................................................................................................98
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................99
11.1
GLOBAL AMENDMENT 1 ..............................................................................99
11.2
GLOBAL AMENDMENT 2 ............................................................................104


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ABBREVIATIONS
ACTH
Adrenocorticotropic Hormone
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Variance
App
(Smartphone) Application
AST
Aspartate Aminotransferase
ATRQ
Antidepressant Treatment Response Questionnaire
AUC
Area under the Curve
BA
Bioavailability
BCRP
Breast Cancer Resistance Protein
BI
Boehringer Ingelheim
CA
Competent Authority
CCK-4
Cholecystokinin Tetrapeptide
CDK-EPI
Chronic Kidney Disease Epidemiology Collaboration
CGI-S
Clinical Global Impression Severity Scale
ClinRO
Clinician Reported Outcome
Cmax
Maximum Concentration
Cmin
Minimum Plasma Concentration
CNS
Central Nervous System 
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
C-SSRS
Columbia Suicide Severity Rating Scale
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CYP
Cytochrome P450
DBL
Database Lock


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DCT
Decentralized Clinical Trial
D/C
Discontinue
DDI
Drug-Drug Interaction
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic Acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, v5
EC
Ethics Committee
EC50
Half maximal effective concentration
eCDF
Empirical Cumulative Distribution Function
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ECT
Electroconvulsive Therapy
eDC
Electronic Data Capture
EGFR
Estimated Glomerular Filtration Rate
EoStudy
End of Study
EOT
End of Treatment
ESR
Erythrocyte Sedimentation Rate
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
FDA
Food and Drug Administration
FUP
Follow Up
GCP
Good Clinical Practice
GGT
Gamma-Glutamyltransferase
GMP
Good Manufacturing Practice
HA
Health Authority
HDL
High Density Lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICH
International Council on Harmonisation


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IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine System
LC-MS/MS 
Liquid Chromatography Tandem Mass Spectrometry)
LPLT
Last Patient Last Treatment
LS
Least Square
MADRS
Montgomery-Asberg Depression Rating Scale
MAR
Missing at random
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligram
MGH
The Massachusetts General Hospital
MMRM
Mixed effects model for repeated measurements
MRD
Multiple Rising Dose
nM
Nanomole
NIMH
National Institute for Mental Health
NOAEL
No Observed Adverse Effect Level
OATP
Organic Anion Transporter Protein
OPU
Operative Unit
PANAS
Positive And Negative Affect Scales
P-gp
P-Glycoprotein
PGI-C
Patient Global Impression of Change Scale
PCG-S
Patient Global Impression Severity Scale
PK
Pharmacokinetics
p.o
Per Os
PoCP
Proof of Clinical Principle
PRO
Patient Reported Outcomes
PV
Pharmacovigilance


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QD
quaque die (once a day)
QIDS-SR (D)
Quick Inventory of Depressive Symptomatology – Self Report Daily
QTcF
Corrected QT interval by Fredericia
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
SAE
Serious Adverse Event
SCID-5
Structured Clinical Interview for DSM-5 
SD
Standard deviation
SIB
Suicidal Ideation and Behavior
SMDDS
Symptoms of Major Depressive Disorder Scale
SNRI
Serotonin Norepinephrine Reuptake Inhibitor
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SSRI
Selective Serotonin Reuptake Inhibitor
STAI
State-Trait Anxiety Inventory 
STAR*D
Sequenced-Treatment-Alternatives to Relieve Depression
SUSAR
Suspected Unexpected Serious Adverse Reactions
TMS
Transcranial Magnetic Stimulation
TRPC
Transient Receptor Potential Channel
TS
Treated Set
TSAP
Trial statistical analysis plan
UGT
UDP-Glucuronosyltransferase
ULN
Upper Level of Normal
VAS
Visual Analogue Scale
VCT
Verified Clinical Trial
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Major Depressive Disorder (MDD) is a debilitating disease that is difficult to treat, even 
when using systematic antidepressant strategies. In the National Institute for Mental Health 
(NIMH) funded Sequenced-Treatment-Alternatives to Relieve-Depression (STAR*D) trial in 
more than 4000 patients with nonpsychotic depression, about 30% of the patients did not 
reach remission after 4 different medications [P06-11895] and continued to experience 
residual symptoms [R16-5475] which significantly impacted the patients’ quality of life.
Studies have also reported that up to 50% of patients diagnosed with MDD do not respond to 
an initial antidepressant treatment of adequate dose and duration [R16-5475]. When 
monotherapy with a Selective Serotonin Reuptake Inhibitor (SSRI) / Serotonin 
Norepinephrine Reuptake Inhibitor (SNRI) is insufficient, clinicians employ different 
augmentation strategies including add-on treatment with lithium, thyroid hormones, 
antiepileptic agents or atypical antipsychotics [R17-0163]. When augmentation strategies fail, 
somatic therapies such as electroconvulsive therapy (ECT), vagal nerve stimulation or 
transcranial magnetic stimulation (TMS) can be used.
In clinical practice, telepsychiatry has become an accepted method of managing many 
psychiatric conditions, and its adoption has improved access to mental health care
[R20-0034]. The literature in this field points to substantial growth in evidence to support 
equivalence of telepsychiatry care when compared to treatment rendered in-person 
[R20-0034, R19-4127, R19-4092).  In clinical trials, preliminary efforts employed various 
telemedicine technologies (ranging from webcams and telephones to smartphone apps and 
videoconferencing) that demonstrated how decentralized trials can augment traditional 
research and development methods  and provide data from a broader, more diverse group of 
patients in real-world practice settings [R20-0033].
Given that many assessments in psychiatric research are interview-based, bringing 
telepsychiatry to mental health research is an inevitable and logical extension of mental 
health care. Benefits of telemedicine for clinical research in MDD include diminished patient 
burden, broadened access to clinical research for the target population by enabling home 
participation, increased likelihood that the MDD study population represents the 
demographics of the U.S. population with this condition, and potentially accelerated study 
conduct, which in turn, can speed patient access to potentially important treatments 
[R19-4127, R19-4092, P10-04017].
1.2
DRUG PROFILE
Transient Receptor Potential Cation (TRPC) channels 4 and 5 are involved in the regulation 
of neuronal excitability. They are highly expressed in the amygdala, frontal cortex, 
hippocampus, and hypothalamus [R15-3888] which are the brain regions involved in 
modulation and processing of emotion and affect.


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BI 1358894 is a TRPC4/5 inhibitor that is being developed for symptomatic treatment of 
Major Depressive Disorder 
Therefore, it is expected that treatment with BI 1358894 has the potential to improve 
affective symptoms and emotion control, especially in patients with MDD who inadequately 
respond to the current standard of care (SSRI; SNRI) 
 
Mode of action
BI 1358894 is a highly potent and selective TRPC4/5 inhibitor (transient receptor potential 
cation channel, subfamily C, members 4 and 5). It has the potential to address core symptoms 
of MDD and BoPD as it targets TRPC4/5 ion channels. TRPC4 and TRPC5 are highly 
expressed in pyramidal neurons of the amygdala in the frontal cortex, hippocampus, and 
hypothalamus, brain areas that are involved in circuits contributing to emotional control. It is 
hypothesized that in patients with mood disorders, an overactive amygdala is a major 
contributor to attentional bias to negative stimuli, pessimistic thoughts and anxiety 
[R16-5473].
BI 1358894 is thought to decrease neuronal excitability leading to normalization of the 
activation state of limbic circuits which are known to be important for emotional control. 
Therefore, it is expected that augmentation treatment with BI 1358894 has the potential to
improve symptoms of patients with MDD who do not adequately respond to monotherapy 
treatment with SSRIs/SNRIs.
Data from non-clinical studies
 
 
 
 
 
 
 
 
 
 


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Data from clinical studies
Overall, 217 healthy volunteers and 73 participants with MDD had been exposed to BI 
 
 
 
Key pharmacokinetic characteristics
 


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Drug interactions


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Residual Effect Period
The Residual Effect Period (REP) of BI 1358894 is 28 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
For a more detailed description of the BI 1358894 profile, please refer to section 1.4 and the 
current IB [c10354149]. For the most frequently reported adverse events refer to 
Table 1.4.2: 1.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Despite the array of available treatment options for patients with MDD, there remains 
significant unmet medical need in 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. A product that would show similar efficacy to the 
above-mentioned augmentation treatments, but without the side effects (e.g., weight gain, 
akathisia, somnolence, abuse potential), would constitute a major medical advance.
Based on the pre-clinical data and the data from the proof of clinical principle (PoCP), there 
is reason to believe that BI 1358894 may be efficacious in MDD and that there are no safety 
signals precluding this assessment.
The underlying hypothesis of the therapeutic concept is that stress and emotion dysregulation 
are core features of MDD and that a reduction of these abnormalities will lead to a decrease 
of the symptom burden related to the depressive symptomatology, including negative valence, 
anxiety and rumination. If that is achieved, such a treatment approach will lead to a 
significant improvement in disease burden and an improvement in overall functioning.
To address future scientific questions, participants will be asked in this trial to voluntarily 
donate biospecimens for banking (please see section 5.5). If the 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 less likely to experience 
an adverse event, or to gain a mechanistic or genetic understanding of drug effects and 
thereby better match patients with therapies.
The decentralized clinical trial (DCT) model will be used to conduct this study. This model 
integrates telemedicine technology into the clinical research process and supports the 
management of research activities remotely, including data collection.  
 will be the 
site responsible for the conduct of this DCT.


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Clinician Reported Outcomes (ClinROs) assessments that are commonly and traditionally 
used to assess the efficacy of investigational products for MDD will be employed in this DCT 
but will be administered via telemedicine. Similar to interviews administered in-person, 
telemedicine-administered ClinROs are administered by an investigator or sub-investigator, 
occur "live" with the subject (i.e. in real-time, so each party can observe the other), are 
documented in real-time by the investigator, and can be recorded. The difference in the 
methodology is that the investigator or sub-investigator administers the ClinRO during a 
videoconference rather than physically being together with the subject.
In 2011, the REMOTE trial was the first randomized controlled clinical trial to be conducted 
under a U.S. IND (Investigational New Drug application) that enrolled and managed study 
participants entirely remotely using the Internet and smartphone technology, with no 
participant visits to investigator sites [R20-0033, R20-0032].  Though the resulting efficacy 
observations were consistent with conventional trials, the trial was terminated early due to 
recruitment challenges [R20-0032]. Following the REMOTE trial, other studies have been 
conducted using a decentralized model across different therapeutic areas [R20-0033].  
For this study, 
 will apply a DCT model that will bring the clinical trial to study 
participants in their homes through telemedicine using a study-issued smartphone and 
through deployment of mobile research nurses. 
will use its technology platform to 
support the conduct this study.  The 
 platform is also utilized as a mobile 
application downloaded to the participant’s study-issued smartphone, enabling remote 
management of all research activities in this study. Given that participants can participate 
from their homes, regardless of where they live, the enrolled MDD population is expected to 
represent the real-world U.S. MDD population more closely.
With more advanced technology now available and the understandable desire to reduce 
participant burden, DCTs allow for a more patient-centric alternative for conduct of clinical 
trials. The DCT model will be piloted in this trial, offering the opportunity to assess the safety 
and efficacy of BI 1358894 in participants with MDD with a decentralized approach.  
1.4
BENEFIT - RISK ASSESSMENT
The overall safety profile of BI 1358894 is outlined in the current IB c10354149.
1.4.1
Benefits
This is an experimental drug at an early stage of testing and therefore an individual benefit 
cannot be guaranteed. Potential efficacy has been demonstrated in pre-clinical and PoCP data.
BI 1358894 is a highly potent and selective TRPC 4/5 inhibitor (transient receptor potential 
cation channel, subfamily C, members 4 and 5). It has the potential to address core symptoms 
of MDD as it targets TRPC 4/5 ion channels. TRPC4 and TRPC5 are highly expressed in 
pyramidal neurons of the amygdala in the frontal cortex, hippocampus, and hypothalamus, 
brain areas that are involved in circuits contributing to emotional control. 


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It is hypothesized that in participants with mood disorders, an overactive amygdala is a major 
contributor to attentional bias to negative stimuli, pessimistic thoughts and anxiety 
[R16-5473]. Therefore, it is expected that treatment with BI 1358894 has the potential to 
improve affective symptoms and emotion control in participants with MDD.
1.4.2
Risks
In a comprehensive package of safety pharmacology, genetic toxicology, general toxicology, 
and nonclinical studies, BI 1358894 was demonstrated to be safe in humans for up to 13
weeks. Based on the mode of action, the pharmacological target, non-clinical toxicology data 
and clinical data, BI 1358894 is not considered a high risk compound for clinical studies. As 
in other clinical trials, trial participants are exposed to the risks related to the exposure to the 
trial medication and to the risks of the trial procedures.
While there are no precedent clinical data implicating association between TRPC4/5
antagonism and Suicidal Ideation and Behavior (SIB), in the interest of ensuring participant
safety, trial participants will be proactively screened and monitored throughout the trial for 
SIB in accordance with available regulatory guidance.
Because psychoactive drugs may impair thinking, judgment, and/or motor skills, participants 
should be cautioned about operating machinery, including automobiles, until they are 
reasonably certain that the study medication does not adversely affect their ability to engage 
in such activities. It is recommended that participants should exercise caution when driving or 
operating machinery.
Participants will be closely monitored during the trial participation (including AE monitoring 
beyond planned visits and assessment of suicidal ideation during visits) to ensure that 
worsening of pre-existing conditions or any newly occurring events are detected and any 
necessary actions taken according to stopping criteria.
BI 1358894 is a highly specific inhibitor of TRPC 4/5 channels, which are predominantly 
located in the CNS. All investigation into distribution and function of TRPC 4/5 (preclinical 
and clinical) so far have not identified any interference with the immune system, the 
respiratory system or the cardio-vascular system.
For the Phase II trial, the benefit-risk for the trial participants treated with BI 1358894 remain 
unchanged in relation to the COVID-19 pandemic since

The mode of action does not appear to have a substantial effect on clinically relevant 
organs (e.g. respiratory or cardiovascular system) critically affected by COVID-19

There is currently no evidence that intake of BI 1358894 leads to immunosuppression

There is currently no evidence that their underlying disease (MDD) makes the patients 
at higher risk to SARS-CoV-2 infection or to develop severe COVID-19

The MDD patients are relatively young patients (30 – 50 years) and in general without 
common co-morbidities associated with severe course of COVID-19


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Therefore, the risk for subjects or patients participating in these studies will not differ from 
the current general risk for humans of SARS-CoV 2 infection with all its potential 
consequences. A specific SARS-CoV 2 PCR serving as a tool for inclusion or exclusion of 
trial participants during the screening phase is not foreseen, since it is not believed that study 
substance implies an elevated risk for the patient to develop COVID-19. It is also not 
believed that a SARS-CoV2 infection or clinical apparent COVID-19 impacts the activity of 
the investigational compound.
As part of the screening safety procedures, every participant will be assessed thoroughly, and 
individual benefit-risk assessments are made prior to study entrance and during the study by 
the investigator in respect of SARS-CoV2 infection. The investigators will take the totality of 
information related to each single participant, including but not limited to physical exam, 
vitals, ECG, safety labs, etc., and the local COVID-19 situation into consideration when 
performing the individual benefit-risk assessment. Considering all aspects, the investigator 
will decide upon each participant’s inclusion and continued participation in the trial. BI as the 
sponsor, where required, will support the investigator in their decision finding. It is 
acknowledged that the investigator may decide to implement protocol deviations where this 
protects the safety, wellbeing and/or is in the best interest of the participant and the mobile 
nurse.
For details on treatment related risks, refer to CTP section 1.2 and the IB, version 6
[c10354149].


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Table 1.4.2:1 
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 1358894
Most commonly reported 
AEs in Phase I were:

Headache

Dizziness

Orthostatic intolerance

Fatigue

Disturbance in attention

Dyspepsia

Nasopharyngitis
All reported AEs were of 
mild or moderate intensity. 
None of the participants 
experienced any serious 
SAE or relevant alterations 
in laboratory parameters, 
vital signs, and 
Electrocardiogram (ECG). 
Refer to IB for more details
Management of symptoms, 
evaluation, and follow-up as 
needed to ensure participant
safety, per investigators 
clinical judgment.
Concomitant use of:

sensitive substrate of 
CYP2B6

Strong inducers of 
CYP3A4
Based on current non-
clinical and BI 1358894 
drug-drug interactions data, 
use of certain concomitant 
medications may increase or 
decrease such medications 
or BI 1358894.  Refer to the 
Investigator Site File (ISF)
for more information on 
restricted medications.
Participants on these 
medications will be 
excluded from trial and use 
of these drugs will be 
restricted during the 
treatment period. If such 
medication is used during 
the trial for some reason, 
Investigator should stop 
either this medication or 
Investigational Medicinal 
Product (IMP) per the 
clinical judgment.


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Table 1.4.2:1 
Overview of trial related risks (cont.)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Investigational Medicinal Product - BI 1358894
Concomitant use of:

Statins
Drug-drug interactions 
suggest a minor to moderate 
increase in rosuvastatin
levels when concomitantly 
taken with BI 1358894. This 
interaction takes place on an 
OATP transporter level and 
is expected to affect all 
statins.
Participants on statins 
should be monitored for 
statin related toxicity 
including signs of myopathy
weakness, muscle pain, etc. 
along with clinical lab 
results. If statins are 
concomitantly used during 
the trial, the highest dose 
should not be taken together 
with the investigational 
compound. If participant in 
this trial is on the highest 
recommended statin dose, 
investigator should consider 
changing the statin dose to 
the next lower dose 
recommended for the 
respective statin if 
appropriate. 
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 
participant safety.


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Table 1.4.2:1 
Overview of trial related risks (cont.)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
BI 1358894 - Placebo

Worsening of the 
depression 

Occurrence or increase of 
suicidality
Even though mitigation 
measures are applied, this 
cannot be completely ruled 
out
Participants will remain on
their stable anti-depressive 
treatment with an 
SSRI/SNRI and 
psychotherapy, where 
applicable. Placebo is 
adjunctive to this treatment.
Frequencies of visits with 
suicidality assessments are
optimized.
Suicidal participants will be 
excluded from trial 
participation (refer to 
section 3.3.4.1)
General risk of psychoactive drugs

Impair thinking, 
judgment, and/or motor 
skills
Psychoactive drugs are 
known to potentially cause 
unwanted side effect on 
brain function.   
Participants should be 
cautioned about operating 
machinery, including 
automobiles, until they are 
reasonably certain that the 
study medication does not 
adversely affect their ability 
to engage in such activities.


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Table 1.4.2:1 
Overview of trial related risks (cont.)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Trial procedures
General discomfort

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 
withdrawal per participant
during the trial will be 
approximately up to 83 mL 
over 14 weeks. This amount 
may be exceeded if 
additional unscheduled (in 
case of necessary safety 
follow-up) monitoring of 
laboratory results is needed.
Management of discomfort, 
evaluation, and follow-up as 
needed to ensure participant
safety.
No health-related risk is 
expected from this 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 when BI 
1358894 is administered.
First dose of BI 1358894 
administered with mobile 
nurse oversight and safety 
videoconference visit at 
Week 1. Monitoring and 
management of symptoms 
and treatment as needed, 
including discontinuation of 
trial treatment as per 
investigators clinical 
judgment.


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1.4.3
Discussion
Considering this population, and the need to adequately monitor suicidality, frequent visits,
which include Columbia Suicide Severity Rating Scale (C-SSRS) assessments, are planned in 
this trial to monitor participants.  Participants are able to access the investigator and site staff 
directly for any concerns or questions through the 
application available on the 
provisioned smartphone.
Additionally, all participants will be on stable treatment of MDD with an SSRI/SNRI at the 
time of trial entry and throughout their entire trial participation or until the end of treatment if 
a change is clinically needed per investigator discretion. Considering the mechanism of 
action of BI 1358894 and the adverse events reported in clinical trials to date, there is no 
undue risk related to stopping the trial drug 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.
Given the acceptable and manageable safety profile of BI 1358894 as demonstrated in 
pharmacology and toxicology studies and the good tolerability in clinical studies performed 
to date, and the close monitoring planned during the trial visits, the potential risks to the 
participating participants will be minimized and outweighed by a potential therapeutic benefit 
of the trial drug.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
The main objectives of this trial are to evaluate the efficacy and safety of oral BI 1358894
compared to placebo over a 6-week treatment period in participants with Major Depressive 
Disorder (MDD) and with inadequate response to antidepressants (SSRI or SNRI) utilizing a 
decentralized clinical trial (DCT) model. 
2.1.1
Main objectives
The trial will be performed to compare BI 1358894 with placebo in participants with MDD 
with inadequate response to antidepressants (SSRI or SNRI). The primary comparison of 
interest is the change from baseline in MADRS total score at Week 6 summarized per arm by 
the adjusted mean. The primary trial objective is to assess superiority of BI 1358894 versus 
placebo in a DCT model. A mixed model with repeated measurements (MMRM) method will 
be used to assess the efficacy. 
The primary characterization will be on treatment which will assume all participants took
randomized treatment for the duration of the trial.
The secondary and further efficacy and safety parameters will be assessed to support the 
understanding of the efficacy and safety of BI 1358894.
2.1.2
Primary endpoint(s)

Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total 
score at Week 6
2.1.3
Secondary endpoint(s)
Montgomery-Asberg Depression Rating Scale (MADRS)

Response defined as ≥ 50% MADRS reduction from baseline at Week 6
State-Trait Anxiety Inventory (STAI)

Change from baseline in STAI State and Trait version scores at Week 6
Clinical Global Impression Severity Scale (CGI-S)

Change from baseline in CGI-S score at Week 6
Symptoms of Major Depressive Disorder Scale (SMDDS)

Change from baseline in SMDDS total score at Week 6
Patient Global Impression Severity Scale (PGI-S)

Change from baseline in PGI-S score at Week 6


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Patient Global Impression of Change Scale (PGI-C)

PGI-C score at Week 6


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


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This study will be conducted as decentralized clinical trial (DCT). It is a 6-week parallel-
group, randomized, double-blinded, placebo-controlled Phase II trial in participants with
MDD with inadequate response to ongoing treatment of an SSRI or SNRI. This trial will be 
conducted in the US, with 
 as the single decentralized site enrolling in the study.
This DCT will employ telemedicine technology for interactions between the investigator/ 
trial staff and trial participants. The method of telemedicine allows for practice of medicine 
using technology to deliver care remotely at a distance. Through Health Insurance Portability 
and Accountability Act (HIPAA) compliant videoconferencing tools, study physicians and 
staff will conduct relevant study procedures and assessments. In this trial, clinical and guided 
assessments will be conducted through videoconference calls, i.e. telemedicine. Additionally, 
mobile trial personnel will visit each participant’s home to complete the designated trial 
procedures, such as collecting vitals and lab samples, assisting with the study devices, and 
administering the investigational product. Trial supplies and investigational products will be 
shipped direct-to-participant in the appropriate shippers, and the 
 trial team will 
perform a fit for use assessment upon the participant’s receipt of the investigational drug (see
Investigational Product section 4.1.4 for more information).
In total, approximately 164 male and female participants with MDD meeting the entry criteria 
are planned to be randomized into this trial.
  
           Day -28      Day -7
Day 1      Week 1      Week 2    Week 3     Week 4     Week 5       Week 6                   EOT+28 days
           V1            V1A     V2         V3           V4           V5       V6            V7         V8/EOT
   V9/ EoStudy
  
  Screening        Randomization
       End of
     End of Study
     Treatment
       
        
Screening Period
Treatment Period
Follow-up Period
= Videoconferencing visit
= Telephonic contact visit
Figure 3.1: 1 Trial design
S
R
BI 1358894 125 mg once daily         
N = 82
Placebo once daily            
N = 82


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Trial participants are enrolled into the trial once consent has been signed. Participants suitable 
after screening will be randomized to the 6-week double-blind treatment period and will be 
assigned to placebo or treatment with BI 1358894, refer to Figure 3.1: 1.
After the completion of the 6-week double-blind treatment period, or following early 
discontinuation of trial medication at any point, participants will complete the 4-week follow-
up period at the end of study (EoStudy) visit. All (S)AEs, including those persisting after an 
individual participant’s end of study must be followed up until they have resolved, have been 
assessed as “chronic” or “stable”, or no further information can be obtained. Individual 
participation is concluded when the participant has completed their last planned visit (End of 
Study visit) (refer to sections 3.3.4.1 and 3.3.4.2).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is a decentralized clinical trial (DCT) of a Phase II, 6-week parallel-group, randomized, 
double-blinded, placebo-controlled trial in MDD participants with inadequate response to 
ongoing monotherapy treatment of an SSRI or SNRI. It is important to have a placebo control 
to address potential confounding factors. This is acceptable as participants will remain on 
background treatment of standard of care and the duration of the placebo treatment will be 
limited to 6 weeks. Since participants will remain on their standard antidepressants with 
either an SSRI or SNRI, no intolerable disease progression is to be expected during this 
period.
The design of the trial will provide efficacy and safety data for BI 1358894, as well as the 
proof of concept of the DCT model.
Specifically, data at Week 6 will provide evidence of efficacy and dosing information of BI 
1358894 compared to placebo. In addition, we will also obtain safety data through the end of 
observation period (eEOT + 28 days).
 
3.3
SELECTION OF TRIAL POPULATION
Approximately 164 participants will be randomized into the trial. Participants will be 
recruited through a highly targeted, multi-channel, adaptive recruitment strategy that covers 
both digital and conventional forums.  Participants who express interest will be contacted via 
phone where the study staff will complete a pre-screening questionnaire to determine a 
participant's eligibility to move forward.  In addition, trial staff will collect medical records 
from the participant's primary care physician and/or specialist to further determine eligibility 
to move forward in the trial.  Screening for the trial will stop when the number of participants 
screened is expected to result in a sufficient number of participants randomized to trial 


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treatment.
A log of all participants enrolled in the trial (i.e., who have signed informed consent) will be 
maintained in the 
 platform irrespective of whether they have been randomized 
and treated with investigational drug or not.  A final copy of the enrolled patients log will be 
filed in the ISF after the last trial participant visit.
If a participant is randomized in error (does not meet all inclusion criteria or meets one or 
more exclusion criteria on the day of enrolment), the sponsor should be contacted 
immediately.
3.3.1
Main diagnosis for trial entry
Participants with an established diagnosis of Major Depressive Disorder confirmed at the 
time of screening by Structured Clinical Interview for DSM-5 (SCID-5), Clinical Trial 
version.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Established diagnosis of Major Depressive Disorder, single episode or recurrent, as 
confirmed at the time of screening by the Structured Clinical Interview for DSM-5 
(SCID-5), with a duration of current depressive episode ≥ 8 weeks and ≤ 18 months at the 
time of screening visit.
2. Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 22 at screening, as 
confirmed by a trained rater. In addition, trial participants must have a score of ≥ 3 on the 
Reported Sadness item on MADRS. 
3. A documented ongoing monotherapy treatment of ≥ 8 weeks at the screening visit, with a 
protocol specified SSRI or SNRI (refer to the ISF) at adequate dose (at least minimum 
effective dose as per prescribing information and as confirmed per detectable drug levels 
in the screening blood or urine sampling).
4. Male and female participants, 18 to 65 years of age, both inclusively at the time of 
consent.


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5. Women of child-bearing potential (WOCBP)1 able and willing to use two methods of 
contraception, which include one highly effective method of birth control per ICH M3 
(R2) that results in a low failure rate of less than 1%, plus one barrier method.
6. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
7. Able to communicate well, and to understand and comply with trial requirements.
______________
1A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
3.3.3
Exclusion criteria
1. Per DSM-5, had ever met diagnostic criteria for schizophrenia, schizoaffective disorder, 
schizophreniform disorder, bipolar disorder, delusional disorder or MDD with psychotic 
features as assessed by the SCID-5 at the time of screening.
2. Diagnosis of any other mental disorder (in addition to those as described in Exclusion 
Criterion #1) that was the primary focus of treatment within 6 months prior to screening 
or at baseline (as per clinical discretion of the investigator).
3. Diagnosis with antisocial, paranoid, schizoid or schizotypal personality disorder as per 
DSM-5 criteria, at the time of screening visit. Any other personality disorder at screening 
visit that significantly affects current psychiatric status and likely to impact trial 
participation, as per the judgement of investigator.
4. Diagnosis of a substance related disorder within 3 months prior to screening visit (with 
exception of caffeine and tobacco).
5. History of seizure disorders, stroke, brain tumor or any other major neurological illness 
that can impact participation in the trial. 
6. History of 4 or more unsuccessful monotherapy treatments (at adequate dosage and 
duration, per local prescribing information of the product) with an approved 
antidepressant medication for the current ongoing major depressive episode. These 
include ongoing monotherapy treatment with a protocol specified SSRI or SNRI as 
described in Inclusion Criterion #3.
7. Any suicidal behavior in the past 12 months prior to screening (per investigator 
judgement including an actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behaviour). 
8. Any suicidal ideation of type 4 or 5 in the Columbia Suicide Severity Rating Scale (C-
SSRS) in the past 3 months prior to screening or at screening or baseline visit (i.e. active 
suicidal thought with method and intent but without specific plan, or active suicidal 
thought with method, intent and plan).


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9. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix.
10. Known history of HIV infection and/or a positive result for ongoing Hepatitis B or C 
infection.
11. Have initiated psychotherapy or other non-drug therapies (e.g., acupuncture or hypnosis) 
within 3 months prior to screening or planning to start any time during the trial. The 
participant should not have a change in type, intensity and/or frequency of psychotherapy 
within the last 8 weeks prior to screening and it is not anticipated to change during the 
entire course of trial.
12. Any use of restricted medications within 7 days prior to randomization and during the 
entire course of the trial (refer to section 4.2.2).
Please note:

Investigators may use their clinical discretion to wash out (at least 3 half-lives of 
referenced medication) the restricted medications during the screening period. The 
participant must adhere to the screening visit dose of the background SSRI/SNRI for the 
entire duration of the trial or until end of treatment. 

Other uses of antidepressants or quetiapine, at a dose less than indicated for MDD, or at 
dose less than recommended dose for MDD may be included (see ISF for details on 
allowed medication and doses restrictions). Use of bupropion is not allowed.

Participants who are on stable treatment with ongoing benzodiazepines and/or non-
benzodiazepine hypnotics (refer to the ISF) for insomnia or anxiety for at least 28 days 
prior to screening should continue without change for the entire trial duration. For 
participants who are not on current treatment of insomnia and anxiety symptoms at the 
time of screening, the protocol will allow short term treatment of these symptoms during 
the course of trial (see section 4.2.2.1 and ISF for details on allowed medications and 
permitted dosages).
13. Participants who must or wish to continue the intake of restricted medications (refer to 
ISF) or any drug considered likely to interfere with the safe conduct of the trial. 
14. Use of alternative medicine (e.g. Chinese traditional medicine, herbal medication, St. 
John’s wort, etc.) during the entire course of the trial.
15. Have initiated or discontinued hormone treatment (including hormone replacement 
therapy) within the 3 months prior to screening (however use of hormonal contraceptives 
is allowed).
16. Known hypersensitivity to any of the excipients of BI 1358894 or matching placebos. 
17. Use of any investigational procedure within 30 days prior to randomization. In case of 
exposure to an investigational medicinal product, investigator must ensure that it is 
adequately washed out prior to randomization (at least 5 half-lives of the investigational 
medicinal product).
18. Positive drug screen at the screening visit. (In case of positive drug screen for 
benzodiazepines or cannabis, investigator to confirm that there is no active substance 
related disorder; this also applies to prescribed medications).


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19. Have received electroconvulsive therapy and/or administration of Ketamine /S-Ketamine 
for the current ongoing depressive episode.
20. Have a lifetime history of vagal nerve stimulation, transcranial magnetic stimulation, or 
psychosurgery
21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
22. Participants not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled.
23. Considered by the investigator, for any other reason, to be an unsuitable candidate for the 
trial.
3.3.4
Withdrawal from treatment
Every effort will be made to keep the participants in the trial, if possible on treatment, or at 
least to collect important trial data. Measures to control the withdrawal rate include careful 
selection, appropriate explanation of the trial requirements and procedures prior to trial 
enrolment, as well as the explanation of the options for early discontinuation in case of
withdrawals (see section 6.2.2).
Participants may discontinue trial treatment or withdraw consent to trial participation as a 
whole (“withdrawal of consent”) with very different implications; please see sections below.
If a participant discontinues trial treatment prior to the completion of protocol-specified end 
of treatment (EOT) visit/Visit 8, every effort will be made by the site staff to encourage 
participants to remain in the trial if medically safe. Participants who discontinue trial drug 
prematurely will ideally be observed until the end of the study as if they were still receiving 
blinded trial treatment. Participants will complete the early End of Treatment (eEOT) 
procedures as described in the Flow Chart and section 6.2.2. If a participant refuses to 
participate in completing all further visits after early treatment discontinuation, the participant
will be encouraged to complete at least the Week 6/Visit 8 as scheduled and a FUP visit 28 
days after early drug discontinuation. If FUP visit (early drug discontinuation date + 28 days) 
is within 7 days prior to planned Visit 8, then no additional FUP visit is needed.
Participants who refuse all of the above are considered to have fully withdrawn consent to 
participate in the trial. In this case, the participant does not need to justify the decision and 
should be withdrawn from the trial and all follow-up assessments (see section 6.2.3). 
Withdrawal from the trial of an individual participant may be considered also in case of 
administrative reasons, such as but not limited to multiple important protocol violations and 
persistent non-compliance. No participant will be withdrawn from the trial before discussion 
with the CT Leader.
3.3.4.1
Discontinuation of trial treatment
An individual participant will discontinue trial treatment if:


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
The participant wants to discontinue trial treatment, without the need to justify the 
decision. 

The participant has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future. 

The participant needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment; refer to the ISF

The participant undergoes an ECT

Participant receives Ketamine /S-Ketamine treatment during the course of the trial

The participant can no longer receive trial treatment for serious medical reasons (such as 
surgery, adverse events, other diseases, or pregnancy), per investigator’s clinical 
judgement. In case of a temporary reason, trial treatment will be restarted if medically 
justified.

Pregnancy occurs during the trial. Once a participant has been enrolled in the clinical trial 
and has taken trial medication, the investigator must report any drug exposure during 
pregnancy which occurred in a female trial participant to the Sponsor immediately (within 
24 hours) by means of Part A of the Pregnancy Monitoring Form to the Sponsor’s unique 
entry point (refer to ISF).

The participant must discontinue treatment with trial medication if: 
-
The participant develops suicidal ideation of type 4 or 5 in the C-SSRS (i.e., active 
suicidal thought with intent but without specific plan, active suicidal thought with 
plan and intent) or suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted 
attempt or preparatory acts or behavior).
-
In the event of worsening of MDD which requires medical treatment which is on the 
list of restricted medications (refer to ISF), the trial drug has to be discontinued.
In addition to these criteria, the physician may discontinue treatment at any time based on his 
or her clinical judgment.
For all participants the reason for withdrawal from trial treatment (e.g. AEs) must be recorded 
in the eCRF. These data will be included in the trial database and reported.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
participants or take any other appropriate action to ensure the safety of the trial participants.
A single episode of an interruption of the trial treatments due to an AE or a concomitant 
illness, up to a maximum of 3 subsequent days, is permissible in the discretion of the 
investigator.  
3.3.4.2
Withdrawal of consent to trial participation
Participants may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a participant wants to withdraw consent, the investigator will be involved in the discussion 


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with the participant and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for the following 
reasons:
1. Failure to meet expected enrolment goals overall.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further follow up of participants affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 1358894 film-coated tablets have been manufactured by BI Pharma GmbH & Co. KG, 
Germany. Placebos, matching BI 1358894 film-coated tablets, have been manufactured by BI 
Pharma GmbH & Co. KG, Germany and 
.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
BI 1358894
Substance:
BI 1358894
Pharmaceutical formulation:
Film-coated Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, 
Germany
Unit strength:
25 mg, 50 mg
Posology:
QD
Method and route of administration:
Per os
Table 4.1.1: 2
Placebo matching BI 1358894
Substance:
Placebo matching BI 1358894
Pharmaceutical formulation:
Film-coated Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, 
Germany
Unit strength:
N.A.
Posology:
QD
Method and route of administration:
Per os
As part of this DCT, 
’s designated vendor will receive/store/ship and provide trial
treatment and all required trial supplies via direct-to-participant shipments. 
’s
designated vendor will receive supply of trial treatment from the Sponsor and store it as 
required per protocol until ready to send to participant. Storage conditions are temperature-
controlled, with continuous temperature monitoring and alarm system. Once randomization 


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procedures are completed and a unique medication number for the kit to be distributed to the 
participant is obtained, shipments are prepared and sent out for delivery to participant’s 
home/preferred address; shipments will be confirmed as delivered, with appropriate 
documentation in the participant’s trial records. The trial treatment will be confirmed as 
received in good condition and within the acceptable temperature range (i.e. fit for use). The 
appropriate supplies and instructions will be provided to trial subjects for shipment of unused 
study treatment back to the site’s designated vendor. All records of shipments, returns, and 
drug accountability will be maintained by the site and/or site’s designated vendor as required.
Drug compliance will be monitored through drug accountability.
4.1.2
Selection of doses in the trial and dose modifications
The dose of 125 mg BI 1358894, once daily, is selected for this trial
 
 
 
 
 
 
 
 
 
 
 
 


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4.1.3
Method of assigning participants to treatment groups
After the assessment of all in- and exclusion criteria, each eligible participant will be 
randomized to treatment groups according to a randomisation sequence at Visit 1A via 
Interactive Response Technology (IRT). Note that the medication number is different from 
the participant number (the latter is generated during screening via the IRT System). To 
facilitate the use of the IRT, the Investigator will receive all necessary instructions.
Participants will be randomly assigned by IRT with an allocation ratio of 1:1 to the following 
treatment groups:
1. Placebo matching BI 1358894
2. 125 mg BI 1358894


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Participant assignment to each of the treatment groups will be determined by a computer 
generated random sequence. Randomization sequence will be generated using validated 
randomisation software. Access to the randomization code will be controlled and 
documented.
The kit(s) corresponding to the assigned medication number(s) should be given to the 
participant and the number of kit(s) that was/were dispensed will be entered in the eCRF. 
Using this procedure, relevant parties will be blinded to the treatment group assignment.
4.1.4
Drug assignment and administration of doses for each participant
The medication assignment will be provided through IRT. The assigned medication 
number(s) must be entered in the eCRF, and the corresponding medication kit(s) must be 
given to the participant. Dosing per treatment assignment is noted in Table 4.1.4: 1. The 
duration of treatment is 6 weeks. The last dose of trial medication should be taken on the day 
before the EOT Visit.
Once participant’s eligibility has been confirmed, randomization and assignment of trial 
drugs via IRT system may occur up to 7 days (Visit 1A) before Visit 2 to allow for the drug 
kit assignment in the IRT system, as well as shipment and delivery of trial drugs to the 
participant’s home. Each trial medication kit contains supplies for 14 days of treatment. For 
the first trial medication kit supplies, participants will receive two kits (one kit for the 14 
treatment days plus a reserve kit), and all following re-supplies will be one kit of BI 1358894 
or matching placebo.
Training and set-up of Smartphone apps will also be completed at this time (Randomization 
Visit 1A).  All eligibility criteria must be confirmed, including C-SSRS, before 
randomization can be registered in IRT.
At Visit 2 with the home visit, the first (preferably in the morning) dose of trial medication 
will be taken under supervision of the mobile nurse. Thereafter, assignment of trial drugs via 
IRT system may occur up to 7 days before actual visit (Visit 4, 6) to allow for the drug kit 
assignment in the IRT system, as well as shipment and delivery of trial drugs to the 
participant’s home. Participants will be instructed to take their medication once a day, in the 
morning time.  Compliance check of medication taken will be completed by mobile nurse at 
the home visits at Visits 4, 6, and 8 (or eEOT) and returns /shipping back all used and
partially used medication kits.  The unused kit may be kept as a reserve until V8/eEOT.
Participants will be instructed not to take their trial medication in the morning of Visit 4 and 
Visit 6, as participants will be dosed under supervision of the mobile nurse after pre-dose PK 
sampling. 
Participants will also be instructed not to take their trial medication at Visit 8/EOT/eEOT 
Visit.  Trough PK sample will be taken at that visit. For participants who complete the 
treatment period, the last dose of trial medication will be taken on the day before the EOT 


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Visit. Participants who fail to do so will have the visit rescheduled as soon as possible, ideally 
on the following day.
Participants will be instructed to take the BI 1358894 tablets or matching placebos orally with 
water and in a consistent way, i.e. either with or without food every morning at 
approximately the same time. If a morning dose is missed by more than 12 hours, that dose 
will be skipped, and the next dose should be taken as scheduled. On days prior to a home 
visit, the morning dose should be taken approximately 24 hours before the planned morning 
dose at the home visit. Home visits should be scheduled in the morning, to the extent 
possible; should this not be possible due to participant’s conflict, afternoon or evening visits 
may occur where the visit dosing is no more than 36 hours from last IMP dose. A dose 
reduction of BI 1358894 is not possible.
If the participant must temporarily stop trial treatment for medical reasons (such as adverse 
events), per investigator’s clinical judgement, trial treatment may be restarted as soon as 
possible if medically justified.  
Table 4.1.4: 1
Dosage and Treatment Schedule for BI 1358894 / Matching Placebo
25mg film-
coated tablet
50mg film-
coated tablet
PBO matching 
25mg film-coated
tablet
PBO matching 
50mg film-coated 
tablet
Dose group
Number of tablets to be taken daily – in the morning ☼
PBO
0
0
1
2
125 mg
1
2
0
0
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
At each treatment day, all participants will take three tablets of trial medication (either of BI 
1358894 or matching placebo).  Packaging design is the same for both treatment groups to 
ensure blinding. Participants, investigators, mobile nurses, and everyone involved in trial 
conduct or analysis or with any other interest in this double-blind trial will remain blinded 
with regard to the randomized treatment assignments until the time specified in the database 
lock process, with the exceptions described in this section below.
The access to the randomization code will be kept restricted until its release for analysis.
The randomization codes will be provided to bioanalytics prior to last participant completed
to allow for the exclusion from the analyses of pharmacokinetic (PK) samples taken from 
placebo participants. Bioanalytics will not disclose the randomization code or the results of 
their measurements until the trial is officially unblinded.


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4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in 
an emergency situation when the identity of the trial drug must be known to the investigator 
in order to provide appropriate medical treatment or otherwise assure safety of trial 
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual participants during trial conduct. The access to 
the code will only be given to authorised Pharmacovigilance representatives for processing in 
the PV database system and not be shared further.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated Contract 
Research Organisation (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice (GMP).  Re-supply to the site will be managed via 
an IRT system, which will also monitor expiry dates of supplies available at the site.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate CRA (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor 
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator, 

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. 
Participants will be instructed to return used, partially-used and unused investigational drug.


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The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each participant, and the return to the sponsor or 
warehouse / drug distribution centre or alternative disposal of unused products. If applicable, 
the sponsor or warehouse / drug distribution centre will maintain records of the disposal.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial 
participants. The investigator or designee will maintain records that document adequately that 
the participants were provided the doses specified by the Clinical Trial Protocol (CTP) and 
reconcile all investigational medicinal products received from the sponsor. At the time of 
return to the sponsor or appointed CRO, the investigator or designee must verify that all 
unused or partially used drug supplies have been returned by the clinical trial participant and 
that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Please refer to section 5.3.5.1 for handling participants with positive report of suicidal 
ideation and/or behavior.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The following restrictions for comedications are defined for this trial, until clinical DDI 
studies are conducted to determine the potential drug interaction: 

Sensitive substrates of CYP2B6

Strong inducers of CYP3A4
A list of restricted concomitant medications and drugs with potential pharmacokinetic 
interactions with the trial compound BI 1358894 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 - like cancer drugs - may not be listed.
Use of ECT and Ketamine/S-Ketamine are restricted during the study, that would lead to 
study discontinuation (refer to section 3.3.4.1).
Participants on statins should be monitored for statin related toxicity including signs of 
myopathy, weakness, muscle pain, etc. along with clinical lab results. If statins are 
concomitantly used during the trial, the highest dose should not be taken together with the
investigational compound. If participant in this trial is on the highest recommended statin 
dose, investigator should consider changing the statin dose to the next lower dose 
recommended for the respective statin if appropriate.
Please note:


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
Concomitant use of benzodiazepines or non-benzodiazepine hypnotics are allowed during 
study for up to 7 days at dose equivalent to ≤ 1.0 mg lorazepam per day, for management 
of AEs (e.g. anxiety and/or insomnia). Such drugs should be stopped after the AE is 
resolved, at the discretion of Investigator. If longer duration of treatment is needed, 
further re-evaluation is required by investigator for every 7 days per treatment cycle (and 
possibly more cycles if needed).  Refer to ISF for dose equivalence information and 
comprehensive list of allowed concomitant medications.

In case of AEs, any treatment deemed necessary per the clinical judgment of investigator 
for the management of AEs considering participant safety is allowed.
For further guidance investigators are referred to the Investigator´s Brochure [c10354149] or 
may contact the sponsor.
4.2.2.2
Restrictions on diet and life style
In general, participants should keep their usual habits throughout the trial for diet and 
exercise, as well as nicotine, alcohol and caffeine intake. It should be within acceptable daily 
amounts in discretion of the investigator and not be drastically changed throughout the trial
conduct. 
Note the following restrictions:

Use of traditional medicine (e.g. Chinese traditional medicine, herbal medication, St. 
John’s wort, etc.) during treatment period.

Participants should not abuse alcohol or use drugs of abuse during the trial. Substance 
use, e.g., nicotine, alcohol, cannabis, caffeine, will be collected throughout the trial from 
screening to FUP visit. Please refer to the current CRFs for details about substance use to 
be collected. A urine drug screen will be performed at screening visits (see Flow Chart).
For a list of drugs assessed by the urine drug screen please refer to Table 5.3.3: 1.

Participants should not enter or modify a smoking-cessation program during the conduct 
of the trial.
It is recommended that patients should exercise caution when driving or operating machinery 
until they are reasonably certain that the study medication does not adversely affect their 
ability to engage in such activities.
Participants do not have to be fasted to any trial visit.
4.2.2.3
Contraception requirements
Women of childbearing potential (WOCBP - for the definition please refer to section 3.3.2) 
must use two methods of contraception, which include one highly effective method of birth
control per ICH M3 (R2) that result in a low failure rate of less than 1%, plus one barrier
method. Contraception must be used during the treatment and follow-up period.
Women of child-bearing potential must agree to periodic pregnancy testing during 
participation in the trial.  If a urine pregnancy test is positive, a serum test needs to be 
performed for confirmation.


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Acceptable forms of contraception for females are:
One of the highly effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1%:

Use of hormonal methods of contraception associated with inhibition of ovulation
a.
combined (estrogen and progestogen containing) hormonal contraception:

oral

intravaginal

transdermal
b. progestogen-only hormonal contraception:

oral

injectable

Implantable

Placement of intrauterine device (IUD) or intrauterine hormone releasing system (IUS)

Bilateral tubal occlusion or ligation

Vasectomy (with appropriate post-vasectomy documentation of the absence of sperm in 
the ejaculate and provided that male partner is the sole sexual partner of the WOCBP trial 
participant)

Complete sexual abstinence when this is in line with the preferred and usual lifestyle of 
the patient (note: periodic abstinence such as calendar, ovulation, symptothermal, post-
ovulation methods and withdrawal are not acceptable methods of contraception) - (in this 
specific case the barrier methods, as mentioned below, are not applicable).
Plus with one barrier method:

Male or female condom with or without spermicide

Cap, diaphragm or sponge with spermicide
4.3
TREATMENT COMPLIANCE
Upon delivery of study medication shipment, participants are requested to confirm receipt 
and store at secure place until instructed to use by site staff.  Secure place includes out of 
reach of children, in a place that is not freely accessible to other members of the household. 
All unused remaining trial medication will be accounted and then collected by mobile nurse 
at appropriate home visits (as noted in Flow Chart).
Based on non-missing tablet counts, treatment compliance for a visit will be calculated as 
shown in the formula below. Compliance will be verified by the CRA authorised by the 
sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
Number of tablets which should have been taken as 
directed by the investigator
The potential for trial drug abuse will be closely monitored. Events including overdose, 
misuse, lost and unaccounted for medication must be thoroughly documented in the 


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participant’s source and on the appropriate eCRFs.  Furthermore, if the treatment compliance 
is less than 80% or greater than 100%, site staff will discuss and document the reasons on the 
eCRFs.
Additionally, as an exploratory approach, the intake of the trial drug will be monitored by the 
participant with a smartphone 
 app (see section 5.6.4). The identification of the tablet 
shapes and sizes, time and day, the participant face-ID, and the drug intake process will be 
captured in selfie mode of the smartphone camera, by the participant. The face of the 
participant will be anonymized by the managing software of the vendor before the data are 
submitted to the vendor for potential further analysis.


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5.
ASSESSMENTS
All clinical assessments in this DCT will be conducted via telemedicine (e.g. physician-
guided physical exam, adverse events evaluations) and/or videoconference with direct 
participant-clinician facing calls. Mobile nurse will also be performing safety assessments at 
home visits.  All self-reported (or PROs, patient reported outcome) questionnaires and scales 
are completed by the participant under the oversight of a trained site staff,
 
 
5.1
CONFIRMATION OF DIAGNOSIS
The (SCID-5) Structured Clinical Interview for DSM-5 (Clinical Trial version) will be used 
during screening for confirmation of the diagnosis of Major Depressive Disorder (MDD) and 
to exclude trial participants with other psychiatric disorders as described in the exclusion 
criteria. The SCID-5 is a semi-structured interview guide for making the major DSM-5 
diagnoses. It is administered by a clinician or trained mental health professional who is 
familiar with the DSM-5 classification and diagnostic criteria.  The SCID-5 interview, 
conducted via videoconferencing, takes approximately 90 minutes to administer.
The Massachusetts General Hospital (MGH) Antidepressant Treatment Response 
Questionnaire (ATRQ) will be used to determine treatment history of MDD. The MGH 
ATRQ defines 6 weeks on an adequate dose of antidepressant medication as an adequate 
duration of treatment. 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. The ATRQ will be administered by a clinician
rater; it takes about 10 minutes, one-time during screening.  
5.2
ASSESSMENT OF EFFICACY
The current status of MDD will be assessed during the course of the trial by using the 
MADRS and SMDDS scores and, in a wider perspective, with the outcomes of the STAI, 
PGI-S, PGI-C, CGI-S,
 
 
(detailed instructions how to administer the assessments can be found in the 
respective user manuals which will be filed in the ISF).
5.2.1
MADRS - Montgomery–Åsberg Depression Rating Scale
The MADRS consists of 10 items:
1. apparent sadness
2. reported sadness
3. inner tension
4. reduced sleep
5. reduced appetite
6. concentration difficulties


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7. lassitude
8. inability to feel
9. pessimistic thought
10. suicidal thoughts
The MADRS evaluates core symptoms of depression. Nine of the items are based upon 
participant reports, and one is on the rater’s observation (apparent sadness) during the rating 
interview. MADRS items are rated on a 0–6 continuum (0=no abnormality, 6=severe). The 
possible total score could range from 0 to 60 (from normal with absence of symptoms to 
severe depression).
The administration of MADRS takes about 30 minutes, and is performed by a trained rater to 
the participant through videoconferencing.
5.2.2
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. 
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 Behavior: 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 64 with a higher score indicating more severe depressive 
symptomatology.
The self-reporting of the SMDDS takes about 10 minutes.  Participants will be instructed 
when and how to complete the scale, at visits as specified in the Flow Chart.
5.2.3
STAI - The State-Trait Anxiety Inventory
The State-Trait Anxiety Inventory (STAI) for adults has been used extensively in research 
and clinical practice. It comprises separate self-report scales for measuring state and trait 
anxiety. The S-Anxiety scale (STAI Form Y-1) consists of twenty statements that evaluate 
how respondents feel “right now, at this moment.” The T-Anxiety scale (STAI Form Y-2) 
consists of twenty statements that assess how people generally feel.


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Each STAI item is given a weighted score of 1 to 4. A rating of 4 indicates the presence of a 
high level of anxiety for ten S-Anxiety items and eleven T-Anxiety items (e.g., “I feel 
frightened,” “I feel upset”). A high rating indicates the absence of anxiety for the remaining 
ten S-Anxiety items and nine T-Anxiety items (e.g., “I feel calm,” “I feel relaxed”). The 
scoring weights for the anxiety-present items are the same as the chosen numbers on the print 
inventory form. The scoring weights for the anxiety-absent items are reversed, i.e., responses 
marked 1, 2, 3, or 4 are scored 4, 3, 2, or 1, respectively. The anxiety-absent items for which 
the scoring weights are reversed on the S-Anxiety and T-Anxiety scales are:
S-Anxiety: 1, 2, 5, 8, 10, 11, 15, 16, 19, 20
T-Anxiety: 21, 23, 26, 27, 30, 33, 34, 36, 39
To obtain scores for the S-Anxiety and T-Anxiety scales, simply add the weighted scores for 
the twenty items that make up each scale, taking into account the fact that the scores are 
reversed for the above items. Scores for both the S-Anxiety and the T-Anxiety scales can 
vary from a minimum of 20 to a maximum of 80. Higher scores indicate greater anxiety.
The self-reporting of the STAI takes about 10 minutes.  Participants will be instructed when 
and how to complete the scale, at visits as specified in the Flow Chart.
5.2.4
CGI-S - The Clinical Global Impression Severity Scale
The Clinical Global Impression Severity (CGI-S) rating scale measures the clinician's 
impression of the severity of illness exhibited by a participant that takes into account all 
available information, including knowledge of the participant's history, psychosocial 
circumstances, symptoms, behavior, and the impact of the symptoms on the participant's 
ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. 
Considering total clinical experience with the depression population, a participant is assessed 
on severity of illness at the time of rating according to: 1=normal (not at all ill); 2=borderline 
ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most 
extremely ill participants. Higher scores indicate worsening.
The clinician-reporting of the CGI-S takes about 5-10 minutes, at specific visits as noted in 
the Flow Chart.  
5.2.5
PGI-S - Patient Global Impression Severity Scale
The PGI-S, similar to the CGI-S, will be used to measure the patient’s impression of the
severity of their illness (R03-0520, R19-1931). It is a single item 4-point scale that asks
patients to rate the severity of their illness.
The PGI-S question states “Please choose the response below that best describes the overall
severity of your depressioin symptoms over the past week.”
1. None
2. Mild
3. Moderate
4. Severe


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The PGI-S is completed by the patient and should take a few minutes to complete, to be 
completed after the SMDDS.
5.2.6
PGI-C - Patient Global Impression of Change Scale
The PGI-C is a one-time assessment at the end of treatment (EoT) to measure the patient’s 
impression of the how their illness has changed over time. It is a single item 7-item scale that 
asks patients to rate the overall change since the start of treatment.
The PGI-C question states “Please choose the response below that best describes the overall
change in your depression symptoms since you started taking the study medication.”

Very much improved 

Much improved

Minimally improved

No change

Minimally worse

Much worse

Very much worse


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5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart. It includes at a minimum clinical assessments of general appearance, neck, lungs, 
cardiovascular system, abdomen, extremities, and skin.
The results must be included in the source documents available at the site. Clinically relevant 
abnormal findings noticed after baseline assessment will be reported as (S)AEs.
5.3.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling. This includes systolic and diastolic blood pressure and pulse rate (electronically or 
by palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must 
be included in the source documents available at the site.
Measurement of height (Visit 1 only) and body weight will be performed at the time points 
specified in the Flow Chart.
5.3.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.3.3:1. For the sampling time 
points please see the Flow Chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the Laboratory Manual.
Participants do not have to be fasted for the blood sampling for the safety laboratory.
Should there be a need for a re-test or repeat lab, participants may be advised to have the lab 
drawn at a nearby local lab, or if feasible, by mobile nurse or lab technician at home.  The 
coordination and lab kits and lab requisition form for the blood draw will be completed by the 
study staff, and guidance will be provided to the participant as to when, which local lab to go, 
and which lab kits to bring.  If the participant does not have the available lab kit at home, an 
appropriate kit will be shipped. Samples collected at the local lab will be sent to central 
laboratory for analyses.
If taking blood samples for central lab using the provided lab kit is not possible, blood 
analysis for safety lab can be done in a local lab. The results of the lab tests are to be reported 
and transferred to the investigator, who has to ensure medical review and proper 
documentation. Safety lab parameters should at least include liver enzymes and bilirubin, 
haematology including differential test, blood glucose, sodium, potassium, creatinine, urea 
(BUN) and eGFR. It is important that the reference values of the local lab are also provided. 


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Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF.
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as baseline condition (if at screening) or adverse 
events during study (please refer to section 5.3.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see section 5.3.6.1.4 and the DILI Checklist provided in the ISF and 
electronic data capturing (eDC) system). The amount of blood taken from the participant
concerned will be increased due to this additional sampling.
Capturing the results of various drug screens (e.g., Cannabis, Benzodiazepine, Barbiturates, 
Opiates, Cocaine, Amphetamines, Methadone, PCP) in the clinical database is planned to 
permit examination of the use in this study population, impact of use on the recruitment 
failure rate, frequency of benzodiazepine use as sleeping aids and the impact of occasional 
use of Canabis in light of the planning of Phase III of this development program.
The central laboratory will transfer the results of the analysis to the sponsor.
Table 5.3.3:1 
Safety laboratory tests
Category
Test name
Haematology
Haematocrit (Hct)
Haemoglobin (Hb)
Red Blood Cell Count/ Erythrocytes
Erythrocyte sedimentation rate (ESR)
Reticulocyte Count
White Blood Cells / Leucocytes
Platelet Count/ Thrombocytes
MCV, MCH, RDW, MCHC
Diff. Automatic
Neutrophils (relative and absolute count)
Eosinophils (relative and absolute count)
Basophils (relative and absolute count)
Monocytes (relative and absolute count)
Lymphocytes (relative and absolute count)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes


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Table 5.3.3:1 
Safety laboratory tests (cont.)
Category
Test name
Chemistry
AST(GOT)
ALT(GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Lipase
Chemistry Amylase
Calcium
Sodium
Urea (BUN)
Potassium
Glucose
Creatinine
Bilirubin Total, fractionated if increased
Protein, Total
C-Reactive Protein
Cholesterol, total
Triglycerides
TSH
Testosterone3
LH3
FSH3
Folate
eGFR using the CKD-EPI equation
SSRI/SNRI detectable drug levels1
Duloxetine
Citalopram/Escitalopram
Paroxetine
Sertraline and Desmethylsertraline
Fluoxetine and Norfluoxetine
Venlafaxine and Desmethylvenlafaxine
Desvenlafaxine
Urine (dipstick) Pregnancy test (only for female 
participants of childbearing potential - test done at all 
home visits beginning with Visit 2)
Human Chorionic Gonadotropin in the urine
Serum Pregnancy test (only for female participants 
of childbearing potential) at screening or if urine 
pregnancy test is positive) 
Human Serum Chorionic Gonadotropin 


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Table 5.3.3:1 
Safety laboratory tests (cont.)
Category
Test name
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Blood (Hemoglobin) and Myoblobin
Leukocytes Esterase
Urine pH
Urine-Sediment (microscopic examination, only if 
urine analysis abnormal)*
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells 
Urine Sed. Crys., Unspecified 
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
Urine
Albumin (quantitative)
Creatinine
Drug screening (urine)2
Cannabis
Benzodiazepine
Barbiturates
Opiates
Cocaine
Amphetamines
Methadone
PCP
Infections screening2
Hepatitis B Surface Antigen (qualitative) 
Hepatitis C Antibody (qualitative)
Hepatitis C Virus (HCV) RNA – only if Hepatitis C 
antibodies (qualitative) are positive
1 At screening and EOT only (at screening, urine samples will also be collected, except for Duloxetine); 
2 At screening only; 3 Males only
* Urine Sediment microscopic analysis, performed only if any of the urinalysis is positive, and reported (any of 
the following) only what is identified (positive). 
RBC 
WBC 
Sq EPI
Bacteria
Hyaline Casts
Epithelial Casts
WBC Casts
RBC Casts
Granular Casts 
Fatty Casts
Cellular Casts
Broad Casts
Waxy Casts
Tri Phos Crystals
Ca Oxalate Crystals
Ca Phosphate Crystals
Ca Carbonate Crystals 
Am Biurate Crystals
Bilirubin Crystals
Uric Acid Crystals
Amorphous Crystals
Leucine Crystals
Tyrosine Crystals
Cystine Crystals
For assessment of the kidney function, the formula of the estimated glomerular filtration rate


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(EGFR) CDK-EPI (Chronic Kidney Disease Epidemiology Collaboration) will be used. This 
requires that ethnicity need to be captured. 
5.3.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart. Twelve-lead ECGs (I, 
II, III, aVR, aVL, aVF, V1 – V6) will be recorded using equipment provided by a central 
ECG vendor. The ECGs will be recorded for at least 10-second duration after the participants 
have rested for at least 5 minutes in a supine position and prior to lab sampling. Electrode 
placement will be performed according to the method of Einthoven/Goldberger (ankles and 
wrists). At all time points indicated in the Flow Chart, single ECGs will be recorded. ECG 
recordings at planned time points may be repeated for quality reasons like alternating current 
artefacts, muscle movements and electrode dislocation. In this case the repeated ECG 
recordings will be used if quality was better.
The investigator or a designee will evaluate whether the ECG is normal or abnormal and 
whether it is clinically significant, if abnormal. The electronic version of the ECG is regarded 
as source data. Dated and signed printouts will be stored in the participant’s medical file if 
there is no validated and certified e-medical record for ECG data.
Additional ECGs may be collected by the investigator for safety reasons. Clinically relevant 
findings noticed at screening assessment (Visit 1) will be reported as baseline condition. 
Clinically relevant abnormal findings noticed after baseline assessment will be reported as 
AEs and followed up and/or treated locally until normal or stable condition.
All ECGs will be transmitted electronically to the central ECG vendor in order to enable a 
centralized and independent re-evaluation of all 12-lead ECGs. Abnormalities detected 
during this centralized ECG evaluation will not necessarily qualify as AE.
Central evaluation on individual ECG level will be performed by the vendor and a report will 
be provided to the site. Decisions on eligibility for the trial and treatment or further follow-up 
of any findings are the responsibility of the investigator.
5.3.5
Other safety parameters
5.3.5.1
Assessment of Suicidality
Suicidal risk assessed by the Columbia Suicide Severity Rating Scale (C-SSRS, clinician 
interview version equivalent to the paper-version) shall be administered via videoconference
or telephone by trained study staff.
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS interview may be administered by any physician, psychologist, clinical social 
worker, mental health counsellor, nurse, or coordinator with C-SSRS training. It has a typical 


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duration of five minutes, and causes only a low burden on participants. At a minimum, the 
interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered first at screening (Visit 1) (using the ‘Baseline / Screening’ version) with the 
aim to exclude participants with active moderate or severe symptomatology within a 
specified time prior to screening. The life time history of suicidal ideation and behavior will 
also be recorded.
After screening (Visit 1) the assessment ‘since last visit’ will be performed at each visit 
(‘Since Last Visit version’). The investigator is to review/consider the C-SSRS results for 
plausibility and clinical relevance. Doubtful reports may be repeated or reports may be 
validated by a consulting psychiatrist. If there is a confirmed positive report of suicidal 
behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to immediately 
interview the participant during the visit (if the investigator did not administer the C-SSRS 
leading to the positive report), and/ or is to consult a psychiatrist if considered necessary. If 
the positive report is confirmed, appropriate actions for the participant’s safety have to be 
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behaviour, no suicidal intent’ (Type 11) standard AE / SAE reporting 
rules are to be applied.
For each report of suicidal ideation type 1, 2 or 3, after start of the trial, the investigator is to 
decide based on clinical judgment whether it represents an AE as defined in the protocol, and 
if it is considered an AE then it must be reported accordingly.
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of AEs 
5.3.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a participant or clinical 
investigation participant administered a medicinal product and which does not necessarily 
have to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following will also be recorded as an AE in the eCRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 


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
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and will be collected in the eCRF only.
Regarding AEs in the context of suicidal risk assessment by C-SSRS, section 5.3.5.1 should be 
adhered.
5.3.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which 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,

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.
5.3.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events will always be 
reported as SAEs as described in section 5.3.6.1.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in section 5.3.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.3.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 


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other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.3.6.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

An elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 
fold ULN measured in the same blood draw sample, or

Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the participants showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
5.3.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.3.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given trial treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing 
or concomitant diseases, or co-medications).


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
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.3.6.2
Adverse event collection and reporting
5.3.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the participant files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until the individual participant’s end of study
(the End of Study (EoStudy) visit): all AEs (serious and non-serious) and all AESIs. 

After the individual participant’s end of study: the investigator does not need to actively 
monitor the participant for new AEs but should only report any occurrence of cancer and 
trial treatment related SAEs and trial treatment related AESIs of which the investigator 
may become aware of by any means of communication, e.g. phone call. Those AEs 
should be reported on the BI SAE form (see section 5.3.6.2.2), but not on the CRF.
5.3.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available.
In specific occasions, the investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and send the BI SAE form.”


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With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual participant’s end of study 
must be followed up until they have resolved, have been assessed as “chronic” or “stable”, or 
no further information can be obtained.
5.3.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a participant has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.4.1
Methods of sample collection
For the quantification of BI 1358894 plasma concentrations, blood samples will be collected 
as indicated in the Flow Chart. The actual sampling times and time of dosings will need to be 
recorded. Detailed instructions on sampling, preparation, processing, shipment and storage 
are provided in the laboratory manual. Plasma samples will be stored frozen at about -20°C or 
below at central laboratory and bioanalytical laboratory. The samples will be shipped on dry 
ice.
If collection of PK samples is scheduled at the visit when local lab is used, PK samples will 
not be taken.


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5.4.3
Assessment of biomarker(s)
Not applicable
5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur 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 are provided 
in the laboratory manual. For sampling time points, see Flow Chart.
Approximately 45.5 mL blood will be drawn for DNA (1 x 8.5 ml), Plasma (2 x 10 ml) and 
Serum (2 x 8.5 ml) banking purposes.


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5.6.4
Medication Adherence and Reminder System
In addition to the regular calculation of treatment compliance as described in section 4.3, this 
trial will employ an additional medication adherence monitoring platform (“Platform”) for all 
participants in the trial.  The Platform uses artificial intelligence through a smartphone


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 app to confirm medication ingestion. In addition, built-in reminders and a 
communication system allow real-time intervention in case of drug interruptions. 
These measures will not supersede or replace the physician and/or prescribed medication 
protocol of the participants.  The platform encourages adherence to the predefined protocol 
but does not change the medication protocol of the participants; thus, use of this platform 
presents minimal risk to the participants. Use of the platform will be required for all 
participants in the trial. 
The monitoring Platform requires that all participants take each dose of the medication while 
using the smartphone
 app. The 
app will be provided to participants preloaded 
on the provisional smartphone.
When at home, participants will receive medication reminders for their daily morning dosing. 
This notification reminds participants to take their medication dose while using their 
provisional smartphones through the
 app.  Participants will follow a series of 
prescribed steps in front of the front-facing webcam to visually confirm their ingestion of the 
medication. The application on the smartphone will make an automated determination of 
whether the participant has properly taken their medication at the prescribed time. There is no 
need for a healthcare provider to review the administration, nor would a healthcare provider 
need to be available at the time the participant takes their medication. 
5.6.5
End of Study Participant Feedback Questionnaire
This trial will include an option for participants to complete an anonymized questionnaire, 
‘Study 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. This questionnaire does not collect data about the participant’s disease, 
symptoms, treatment effect or adverse events and therefore would not be part of the trial data
or clinical trial report.
5.6.6
Verification of Current and Past Research Study Status of 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” (VCT). 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 
Flow Chart. Partial identifiers will be utilized. This will include checking a valid form of 
picture ID when available.
The first 3 letters of the first and last name will be entered along with the middle initial, 
DOB, Sex, and last 5 digits of that ID. If the status of the research subject is a “Verification 


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Success” he/she may proceed in the study. If, however, the status is a “Verification Failure” 
he/she will not be permitted to screen without sponsor approval. The duplicate patient check 
will be performed only after approval is received in accordance with local regulations.
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
6.1
VISIT SCHEDULE
All participants have to adhere to the visit schedule as specified in the Flow Chart. Each visit 
date (with its window) is to be counted from Day 1. If any visit has to be rescheduled, 
subsequent visits should follow the original visit date schedule. Additional visits for the 
purpose of re-testing of laboratory parameters or AE monitoring may be included as deemed 
necessary by the investigator.
During the COVID-19 pandemic, there might be situations when participants might not be 
able to complete the scheduled study visit. This might be e.g. due to participant not feeling 
well enough for the telemedicine or telespychiatric procedures, or  because the participant is 
quarantined or showing symptoms that may deem unsafe for mobile nurse’s home visit, or 
because of any particular situation that the investigator judges as being not safe for the 
participant or mobile nurse. 
For such cases, the visit procedures or home visit may be adjusted or rescheduled to 
maximize opportunities, after evaluation of operational feasibility and minimal required data 
(i.e. primary /secondary /exploratory endpoints. etc.). Such cases will be documented in 
eCRFs and/or patient source.
For detailed description of the trial procedures, please refer to the Flow Chart.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
As part of the DCT model, study visits will be conducted in three ways, as indicated in the 
Flow Chart: 
1. Home visits by mobile study nurse at participant’s home
2. Videoconference (indicated by symbol)
3. Telephone contact (indicated by symbol).  
Unless indicated, visits are home visits, conducted by mobile study nurse at participant’s 
home.
Trial procedures to be performed at each visit are listed in the Flow Chart. In this DCT, all 
trial visits (e.g. Visits 1, 2, 4, 6, 8, 9) requiring physical exams and/or laboratory testing, will 
be conducted with home visits by mobile study nurse, and other visits (Visits 1A, 3, 5, 7) 
will be conducted remotely by a trained trial staff.  Additional details regarding visit
procedures are provided below.
Procedures and assessments at study visits will be conducted through several methods and are 
broken down as below:
-
Screening procedures including demographics, medical history, ATRQ, 
inclusion/exclusion criteria interview, will be completed via telephone or 
videoconference.


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-
Neuropsychological assessments by qualified rater (SCID-5, MADRS) will be
completed via videoconferencing
-
Physical examinations will be conducted via telemedicine with the mobile nurse 
conducting the physician-guided examination through videoconference with study 
investigator or physician.
-
C-SSRS, AEs, and concomitant medications review may also be conducted by 
telephone or videoconference by trained study staff or by mobile nurse during home 
visits.
-
Vital signs, ECG, blood draws (for PK, laboratory tests, and biobanking), 
administration of trial medications (at Visits 2, 4, 6), and drug accountability will be 
conducted by mobile nurse at participant’s home. 
-
PRO questionnaires (SMDDS, PGI-S, PGI-C, STAI, 
) will be 
completed by participants with guidance from mobile nurse during home visit or by 
study staff via videoconference (Visit 3) as indicated per Flow Chart.
For study procedures and communications with trial staff during the study, participants will 
be provided with a smartphone with the 
 platform application installed.  Most of 
the patient-reported outcome and procedures will be through this smartphone’s
 
and 
 apps, with the exception of the Beiwe app for the optional Digital Phenotyping
which is installed on the participant’s personal smartphone.  Participants will be instructed on 
the use and access of the 
 app and how to use the installed apps for the study 
procedures during and between visits. 
The following requirements for the conduct of the clinical and neuropsychological 
assessments need to be followed:

The site staff must be properly trained on all trial procedures and training 
documentation filed in the ISF.

Qualification, training, remediation (if needed) and central reading of the scales will 
be provided by a specialized vendor. The training standards and standards for the 
conduct of the assessments will be defined for each assessment individually and can 
be found in the ISF; it is the responsibility of the Principal Investigator at the site to 
ensure that all members of the site staff involved in the neuropsychological 
assessments undergo qualification and training by the vendor.

All scales are recommended to be completed in the order as indicated at each visit in 
the Flow Chart (ClinROs [MADRS, CGI-S, C-SSRS], then PROs [SMDDS, PGI-S, 
PGI-C, STAI, ED-5D-5L, SDS]).

All neuropsychological assessments are recommended to be completed in the 
morning. In rare cases where participants are unable to arrange for morning home 
visits, MADRS must still be completed in the morning via videoconference.


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
Each assessment of the site-rater performed scales (MADRS, CGI-S) should 
preferentially be done by the same member of the site staff for a given participant
throughout the trial period.

Results of the MADRS and SCID-5 assessments at screening are part of the eligibility 
evaluation (see below). 

During the neuropsychological testing, participants are allowed to take short breaks as 
needed, in the judgement of the rater/investigator.

All C-SSRS (baseline/screening and since-last-visit) scales completed during 
screening will be evaluated for eligibility confirmation, and the since-last-visit C-
SSRS scale to be used for all following visits for assessment of suicidality.
In general, the following should be noted for the conduct of trial procedures:

PRO (self-reported assessments) should be completed before physical exams.

Vitals and ECG should be completed before blood draws.

Unscheduled visits/calls will be possible at the discretion of the investigator at any 
time in order to check the safety of the participant including additional safety 
laboratory assessments.

The background antidepressant medications (SSRI/SNRIs) will be taken as usual 
throughout the study (including on the day of a clinical visit) by the participant, 
according to the requirements as described in this protocol and in the investigator’s 
recommendations and prescribing guidelines.

Quality control of MADRS and SCID-5 assessments will be monitored by central 
reviewer from qualified vendor. 
6.2.1
Screening period(s)
Screening Period
No trial procedures should be done unless the participant has consented to taking part in the 
trial. The participant information and informed consent may be done up to 2 weeks before 
Visit 1. After the participant has signed the informed consent and completed the first study 
activity or assessment, the screening period will start. The participant will be registered in 
IRT as a screened participant and recorded on the enrolment log.
Consenting process in this DCT will be completed electronically (via eConsent) involving 
several steps within the 
 platform eConsent. Before study eConsent is initiated, 
potential participants will be assessed as preliminarily eligible after review of medical records 
by the investigator/study team.  Once this is confirmed, an informed consent discussion will 
be scheduled.
During the informed consent discussion, eConsent will present the informed consent 
materials. The participant will review the documents and discuss them with the investigator 
by phone call, during which all their questions about the study will be answered and all 
elements of the informed consent process will be covered. Once the discussion is completed, 
the participant will be provided with the independent opportunity to consider participation in 
the study. If agreed, he or she will provide a handwritten signature executed to an electronic 
record in the designated signature block using a computer mouse, touchscreen, or stylus 
depending on the capability of their device. The investigator administering the consent will 


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countersign in the same manner as soon as possible within 3 business days of the 
participant’s signature.
For participants who elect not to sign the informed consent materials, the reason(s) for not 
signing will be documented in the 
 platform and all study related procedures will 
be stopped. The consent process must be completed prior to initiation of any study 
procedures.
Visit 1 – Home visit
The screening visit will take place no more than 28 days before Visit 2. Within the 28 days 
screening period, the screening visit may be completed in multiple days; for example, with 
first day SCID-5, ATRQ, C-SSRS, demographics (completed via videoconferencing) and 
second day MADRS, repeat C-SSRS, Medical history, patient-report questionnaires, physical 
exams, vitals and laboratory (home visit by mobile nurse). Note, for safety, C-SSRS needs to 
be completed at each day, if multiple days are needed for screening. Screening MADRS
however must be completed within 21 days of randomization.  Baseline/screening C-SSRS 
and the most recent C-SSRS results will be used for eligibility.
Visit 1A – Videoconference  
This will be scheduled after confirmation of eligibility, including positive blood levels of 
SSRI/SNRI in the screening lab which may be up to 7 days but not less than 1 day prior to the 
planned home Visit 2 date. During this visit, the IRT randomization transaction will be 
registered by the investigator or designee.  This allows for the drug kit assignment in the IRT 
system, shipment and delivery of trial drugs to participant’s home. At this visit, participants 
will be guided through the set-up of all relevant smartphone apps and provided training on 
usage and navigations. Trainings on smartphone apps may start at Visit 1 and be 
repeated/continued to this visit, however all trainings must be completed by Visit 2. An 
assessment of a C-SSRS will also be performed prior to randomization.
All eligibility criteria must be confirmed, including C-SSRS, before randomization can be 
registered in IRT. The IRT transaction should not take place (or be registered) until eligibility 
is fully confirmed, as randomization of a participant cannot be reversed.
 
 
 
he medication adherence assessments will start with the 
first administration of the trial drug at Visit 2. 
Optional
Participation in the sampling of biobanking of plasma and serum for biochemical markers 
and DNA is voluntary and only allowed after the participant has given separate consent prior 
to the collection of the respective blood samples.
Participation in the Beiwe Digital Phenotyping is optional and implemented only after the 
participant has given a separate consent, and to start collection 2 days prior to Visit 2 (first 
drug administration).


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Demographics, Baseline Conditions and Physical Examinations
Information on race will be collected because this demographic information is required for 
the calculation of eGFR (CKD-EPI formula). Physical examinations will be conducted via 
telemedicine with the mobile nurse conducting the physician-guided examination through 
videoconference with study investigator or physician. Blood pressure will always be 
measured before any blood samples are taken. Any abnormal condition of clinical 
significance identified during physical examination, vital signs, 12 lead ECG and/or 
laboratory assessment will be recorded as a baseline condition.
Medical History
It is important to collect previous medical records to document exact dates/diagnoses of 
relevant medical conditions and prior medications. Three attempts to obtain records on 
different days should be documented. In the case that medical records cannot be obtained 
after the minimum of three attempts, a verbal medical history obtained by the investigator 
will be sufficient. However, at a minimum, medical record confirming use of SSRI/SNRI for 
diagnosis of MDD should be available.
Additional details regarding headaches need to be recorded in CRFs for all headaches that
occurred up to 3 months prior to the screening visit. Please refer to the current CRFs for
information that needs to be collected.
Additional details regarding concomitant psychotherapy at screening need to be recorded in
CRFs. Please refer to the current CRFs for information that needs to be collected. During the
treatment, the question whether there were any significant changes in psychotherapy will be
recorded in CRFs only at study visits.
Concomitant treatments which are allowed or restricted before and during trial participation, 
including required washout durations, are listed in the ISF.
Substance use, e.g., nicotine, alcohol, cannabis, caffeine, will be collected throughout the trial 
from screening to FUP visit. Please refer to the current CRFs for details about substance use 
to be collected.
Clinical outcome assessments will also be performed as summarized in the trial Flow Chart. 
Participants will be instructed to continue allowed/ required background medication without 
changes and to adhere to their administration algorithm.
Re-testing
Participants with unexpected lab values at Visit 1 may be re-tested once within the 4 week
screening period if there is a reasonable explanation and expectation that the participant will 
meet the in- and exclusion criteria at re-test at the discretion of the investigator. This doesn’t
apply to the urine drug screen, which must not be repeated.
In case of a need for a lab re-test, participants may be advised to have the lab drawn at a 
nearby local lab, or if feasible, by mobile nurse or lab technician at home (see section 5.3.3).  
The coordination and lab kits and requisition form for the blood draw will be completed by 


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the study staff, and guidance will be provided to the participant as to when, which local lab to 
go, and which lab kits to bring.  
Re-screening of participants
Rescreening of a participant can be done once, 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 CTL. All screening examination must be repeated, and new 
participant number assigned, in case of re-screening.
Potential reasons for re-screening could be:

Positive urine drug screen

Restricted medications like CYPs/ alternative or traditional medicine

Clinically significant findings per Investigator’s judgement
In addition, participants will watch a short informational video intended to educate the 
participant about placebo, and why they are used in clinical trials. 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 may have been randomly assigned to placebo, and stresses the 
importance of reporting all symptoms, whether the symptoms are positive, negative or neutral.
6.2.2
Treatment period(s)
Visit 2 (Baseline/Day 1) – Home visit
Before the planned Visit 2 home visit by mobile nurse, all participant trial supplies (e.g. lab 
kits, etc.) and investigational products (trial medication) must be confirmed delivered at 
participant’s home.  
At Visit 2, all ClinRO and PRO assessments need to be completed before dosing.  In the 
event of a positive urine pregnancy test, a serum pregnancy test must be performed by the 
central lab for confirmation, and a negative serum pregnancy test result must be received 
before the participant can be dosed.  In this case, all (baseline) study procedures will be 
completed as planned for Visit 2, however first dose of study medication will be withheld.  
Once the result of serum pregnancy test is confirmed negative, first dosing will be conducted 
via videoconference under the direction of the study staff.  If the serum pregnancy test is re-
confirmed positive, the participant will be discontinued from study.
The participant will have received sufficient trial drug for 14 days (treatment kit plus a
reserve kit). The first dose will be taken under the supervision of the mobile nurse, with 
further practice using the medication adherence app, after all Visit 2 assessments are 
completed. In addition to pre-dose PK and safety laboratory samples, a sample for optional 
plasma/serum and DNA biobanking will be collected if Informed Consent is provided. A 
sample for optional DNA biobanking is preferentially collected at Visit 2 but can be collected 
at another time point thereafter.
Participants will be instructed to continue taking trial medication with the medication 


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adherence platform, daily in the morning.  
Visit 3 – Videoconference visit
All visit procedures as specified in Flow Chart will be assessed through videoconference call.
Visit 4, Visit 6 – Home visits
Up to 7 days before the planned home Visits 4 and 6, IRT registrations must be completed for 
new assignments of trial medications to allow time for shipment and delivery of trial drugs to 
the participant’s home.  On the day of the home visit, the participant will take the morning 
dose of the trial drug after pre-dose PK samples are collected.
Visit 5, Visit 7 – Phone visits 
Visits V5 (Week 3) and V7 (Week 5) are planned be conducted via phone, but may be 
conducted as a videoconferencing visit if there is a clinical need at the discretion of the 
investigator.
Visit 8 / End of Treatment (EOT) / early end of treatment (eEOT) – Home Visit
Visit 8 represents the regular end of the treatment period. Last trial drug administration 
should occur one day before the Visit 8. The overall duration of the anticipated treatment 
period (first dose to EOT) should be 42 days +4 days.  The End of Treatment visit must be 
registered in the IRT system.
Premature discontinuation of trial drug
Participants who discontinue trial drug prematurely should ideally be observed until trial end 
as if they were still receiving blinded trial treatment (Option 1, see Flow Chart and section
3.3.4). If this is not possible, then participants should be encouraged to complete Week 6/
Visit 8 procedures, with the performance of the MADRS scale as a minimum requirement
(Option 2). See Flow Chart and section 3.3.4 for prematurely discontinue options details. The 
early End of Treatment visit must be registered in the IRT system.
6.2.3
Withdrawal of consent
If a participant is not willing to continue in the trial, or early discontinued and not chose 
Option 1 or Option 2, then this is considered withdrawal from study.  If the participant
withdraws consent for any reason (without the need to justify the decision), the EoStudy/FUP
visit (+28 days after drug discontinuation) is highly recommended to be performed to assess 
and monitor safety, and End of Treatment and Trial Completion pages of the eCRF have to 
be filled in. All unused trial medication will be collected and returned to site. It is important 
to distinguish between premature trial drug discontinuation, i.e. early discontinuation, and 
complete withdrawal of consent to participate in further trial procedures.
6.2.4
Follow-up period and trial completion
For all participants who had at least one dose of trial medication, the follow-up visits will be 
performed as described in section 3.3.4. 


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If the last day of trial drug intake is different from the day prior to the EOT visit, the date of 
the last day of trial drug intake will be used for calculation of the FUP visit dates.
Participants who finish the randomized treatment period according to the protocol will 
complete the end of study (EoStudy/FUP) visit. Trial completion is defined as participants 
having reached the FUP visit within the specified window per the Flow Chart.
For all randomized participants, termination of trial medication and trial completion must be 
recorded on the corresponding eCRFs.
Should it be not possible for the participant to complete the planned FUP visit, a visit out of 
time window should be performed as soon as possible; if this visit is not possible at all, at 
least a phone contact should occur at the scheduled follow-up visit time point. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This study will be conducted as a decentralized clinical trial (DCT). It will be a Phase II, 6-
week parallel-group, randomized, double blinded, placebo-controlled, parallel-group trial in 
MDD participants with inadequate response to ongoing treatment with antidepressants (SSRI 
or SNRI). The main objectives of this trial are to evaluate the efficacy and safety of BI 
1358894 compared to placebo utilizing a DCT model. 
The primary endpoint is change from baseline in MADRS score at Week 6. The restricted 
maximum likelihood estimation based on a mixed-effect model for repeated measures 
analysis (MMRM) will be used to obtain adjusted means for the treatment effects. This model 
will include categorical fixed effects of treatment, visit, treatment by visit interaction, and 
continuous fixed effects of baseline, and baseline by visit interaction. The primary treatment 
comparisons will be the contrast between treatments at Week 6 in MADRS total score.
A detailed description of the model utilized is provided in section 7.2.
7.1
NULL AND ALTERNATIVE HYPOTHESES
The trial is designed to assess the effect of BI 1358894 and placebo in participants with MDD 
with inadequate response to ongoing treatment of an SSRI or an SNRI. 
The null hypothesis is that the mean change from baseline in MADRS total score at Week 6 
for BI 1358894 is equal to the mean change from baseline in MADRS total score at Week 6 
for the placebo group. The alternative hypothesis is mean change from baseline in MADRS 
total score at Week 6 for BI 1358894 is not equal to the mean change from baseline in 
MADRS total score at Week 6 for the placebo group.
A two-sided test using the MMRM model will be carried out to assess the primary endpoint, 
with an α level of 10%.
7.2
PLANNED ANALYSES
7.2.1
General considerations
All data will be listed and summarized by treatment group using appropriate methods. For 
continuous data, the number of observations, mean, standard deviation (SD), minimum, 
median and maximum will be provided. The frequency and proportion of participants in each 
category will be presented for categorical data.
Analysis sets defined for this trial include the full analysis set (FAS) and the treated set (TS).
The FAS comprises all randomized participants who received at least one dose of trial 
medication during the trial and had a baseline and a post-baseline observation recorded. 
Unless otherwise specified, efficacy analyses will be performed on FAS and will be based on 


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assigned treatment. Full specifications for the FAS will be provided in the Trial statistical 
analysis plan (TSAP).
Safety analyses will be conducted on the TS, which include all randomized participants who 
have received at least one dose of the trial medication. Safety analyses will be conducted 
using actual treatment received. Data from participants who were screened but not 
randomized will be listed but not included in any summaries or inferential statistics.
Any deviations from the TSAP will be carefully monitored and reported in the CTR.
Important protocol deviation are those protocol deviations that have significant impact on
patient safety or trial results. Important protocol deviations will be collected throughout the
trial conduct and will be summarized in the CTR as defined in the TSAP.
7.2.2
Primary endpoint analyses
7.2.2.1
Primary analysis of the primary endpoint
As defined in section 2.1.2, the primary endpoint is the change from baseline to Week 6 in
MADRS total score. Baseline MADRS total score is the last non-missing value recorded 
prior to first dose of trial medication and is typically recorded at Visit 2. If data from Visit 2 
are missing, the last value recorded prior to Visit 2 will be considered the baseline value. The 
investigator-reported MADRS total scores will be used for the primary analysis.
The primary estimand of interest is the treatment effect assuming all subjects remained 
adherent to the assigned trial medication and the trial protocol using a hypothetical approach, 
i.e. trial drug is taken as directed. The primary analysis of the primary endpoint will include 
all data collected while on treatment, which is defined as the time from the date of the first 
dose of trial medication until the last date of last dose of trial medication plus 7 days (3 times 
the estimated elimination half-life). Any data collected after a participant discontinues trial 
drug, regardless of reason, will not be included in the primary analysis.
The primary analysis will be the restricted maximum likelihood (REML) based approach 
using a mixed model with repeated measurements (MMRM) comparing the change from 
baseline of MADRS score at week 6.
The analysis will include the fixed, categorical effects of treatment, visit, treatment by visit 
interaction, as well as the continuous fixed covariates of baseline MADRS score and baseline 
by visit interaction. 
Participant will be considered as random effect. Visit will be treated as the repeated measure 
with an unstructured covariance structure used to model the within patient measurements 
error. Additional covariates identified prior to database lock may be included in the MMRM 
model as applicable.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom


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and adjust standard errors. Significance tests will be based on least-squares (LS) means using 
a two-sided α = 0.1. Analyses will be implemented using SAS (version 9.4) PROC MIXED.
The primary treatment comparisons will be between BI 1358894 and placebo with respect to 
the mean change from baseline in the MADRS total score at week 6. Adjusted mean change 
from baseline as well as treatment contrasts will be presented together with the 90% 
confidence intervals. The primary treatment comparisons will be the contrast between BI 
1358894 treatment arm and placebo at week 6.
If the analysis fails to converge, alternative covariance structures will be tested, details will 
be provided in the TSAP.
Sensitivity analyses for the primary analysis of the primary endpoint.
Sensitivity analyses to be conducted to assess the robustness of the primary analysis 
outcomes to the assumption of missing at random (MAR) will be described in the TSAP. 
7.2.2.2
Supplemental analysis of the primary endpoint
 
 
 
 
 
 
7.2.3
Secondary endpoint analyses
7.2.3.1
MADRS response
Response over the 6-week treatment period will be assessed using the MADRS total score.
Participants with ≥ 50% reduction in MADRS total score from baseline to Week 6 are 
considered responders. Participants experiencing < 50% reduction in MADRS total score 
values are considered non-responders. Percent reduction from baseline at a specific post-
baseline visit (Visit X) is calculated as:
% 	
 = ( 

 	 
  − 

 	 
 
 )
 

 	 
 
∗100
The proportions of participants achieving response at Week 6 will be summarized as the 
frequency and percentage of participants in each treatment arm. In addition, if a sufficient 
number of responders are observed, a logistic regression model adjusted for treatment (BI 
1358894 or placebo) will be used to calculate the odds ratio for response between the 
BI1358894 arm and placebo and corresponding confidence interval. Additional covariates 


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identified prior to database lock may be included in the MMRM model as applicable. The 
likelihood ratio test will be used to test for differences between the active treatment arm and 
placebo.
7.2.3.2
STAI
Change from baseline to Week 6 in STAI state and trait scores will be analyzed using an 
MMRM model similar to the model described for the primary endpoint analysis.
Comparisons will be performed for the BI 1358894 arm versus placebo.
7.2.3.3
CGI-S
Change from baseline in CGI-S will be summarized by treatment arm as both a continuous 
and an ordinal variable. Mean change from baseline to Week 6 and standard deviation will be 
presented. In addition, the frequency and proportion of participants reporting each response 
category at baseline and at Week 6 will be displayed. To compare change in depression 
severity as assessed by the CGI-S between the BI 1358894 treatment arm and placebo, an 
MMRM model similar to the model described for the primary efficacy analysis will be used.
7.2.3.4
PGI-S
The secondary endpoint of change from baseline in PGI-S at Week 6 will be analyzed in a
similar fashion as CGI-S (described above in 7.2.3.3).
7.2.3.5
PGI-C
The analysis of the secondary endpoint for PGI-C at Week 6 will be described in the TSAP.
7.2.3.6
SMDDS
Descriptive statistics will be presented for the responses to the SMDDS individual domains 
responses and total score. As described in section 7.2.2.1 for the primary efficacy analysis, an 
MMRM model will be used to compare change in SMDDS total score from baseline to Week 
6 between the BI 1358894 treatment arm and placebo.


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7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 28 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
All treated participants, i.e. all participants in the TS, will be included in the safety analysis. 
In general, safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’. Adverse event data will be summarized by 
treatment taken at the onset of the event.
Frequency, severity, and causal relationship of adverse events 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 the time specified in the database 
lock process.
Laboratory data will be analyzed 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 summarized. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as with regard to frequency and percentage of participants with abnormal values or 
clinically relevant abnormal values. Laboratory values of particular interest include:


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
Low values of HDL, haemoglobin, and neutrophil count

High values of triglyceride levels, total cholesterol, blood glucose, eosinophil count, 
ALT and GGT
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.2.6
Other analyses
Additional analyses will be specified in the TSAP if deemed necessary. 
7.2.7
Interim analyses
No interim analyses are planned for this trial.
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits.
The primary estimand of interest is the treatment effect assuming all participants remain 
adherent to the assigned trial medication and trial protocol using a hypothetical approach. For 


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the primary analysis of the primary endpoint, missing data will not be imputed. Data 
collected after discontinuation of trial medication will be considered missing for the primary 
analysis.
The mixed effects model will handle missing data based on a likelihood method under the 
assumption of missing at random.
 
Sensitivity analyses will be conducted and will be described in the TSAP, for the primary and 
supplemental analyses of the primary endpoint.
Similar methods for handling missing data will be used for secondary efficacy endpoints, as 
applicable.
With respect to safety evaluations, it is not planned to impute missing values.
More details for missing data handling will be included in the TSAP, if needed.
7.4
RANDOMISATION
Participants will be randomly assigned to treatment or placebo in a 1:1 ratio as described in 
section 4.1.3. 
BI will arrange for the randomization and the packaging and labelling of trial medication. 
The randomization list will be generated using a validated system, which involves a 
pseudorandom number generator so that the resulting treatment will be both reproducible and 
non-predictable.
The block size will be documented in the Clinical Trial Report. Access to the codes will be 
controlled and documented as described in section 4.1.5.
7.5
DETERMINATION OF SAMPLE SIZE
In this DCT home-based study, a nurse will be visiting the participant to execute the survey 
with a physician via computer and other study related activities.  It is expected that the 
variability for a DCT will be less compared to a regular trial.  Thus, the sample size is 
estimated assuming a standardized effect size of 0.375, which is based on a mean difference 
between placebo and BI 1358894 of 3.0 and standard deviation of 8.0. [P11-04859] A two-
sided alpha of 0.10 will be used for the sample size calculation using a treatment allocation 
ratio of 1:1 for the placebo and BI 1358894 arms. Under these assumptions, a few different 
scenarios are summarized in Table 7.5:1.


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Table 7.5:1   
Sample size calculations based on two-sided alpha of 0.1
Treatment mean 
difference
3
3
3
3
3
Standard Deviation
8.5
8.0
8.0
7.5
7.0
Power
80
80
77
75
75
N for each treatment 
arm
100
89
82
68
60
Total
200
178
164
136
120
The sample size calculations in Table 7.5:1 include a fixed delta of 3 and a range of standard 
deviation values. Based on the sample size assumptions, 82 evaluable participants per arm are 
required to achieve a power of 77%. Evaluable participants are defined as those who have 
been randomized, received at least one dose of study medication, have a MADRS baseline 
measurement and at least one post-baseline MADRS measurement. The participants who 
dropout from the trial prematurely, but are evaluable will be included in the analysis set. For 
such participants, missing values will be handled by the MMRM model.
The missing data patterns and the proportion of non-evaluable subjects out of randomized 
subjects will be monitored during the conduct of the trial in a blinded fashion. The sample 
size may be re-evaluated if unexpected data patterns are observed. The details will be 
provided in the TSAP. 
Calculations were performed using nQuery + nTerim 4.0 statistical package by 
 


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014, and other relevant regulations. 
Investigators and site staff must adhere to these principles. Deviation from the protocol, the 
principles of ICH GCP or applicable regulations as will be treated as protocol deviation.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the participant.
The investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial participants against any immediate hazard, as well as of any serious breaches 
of the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the Sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the participants, 
and is stored in the ISF.
The certificate of insurance cover is made available to the investigator and the participants, 
and is stored in the ISF.
8.1
TRIAL APPROVAL, PARTICIPANT 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 to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional 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 or the participant’s legally accepted 
representative.


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The investigator or delegate must give a full explanation to trial participants based on the 
participant information form. 
The participant must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the participant’s own free will with the 
informed consent form after confirming that the participant understands the contents. The 
investigator or
 delegate must sign and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial participant protection and reliability of the results as 
well as identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
In order to achieve a high level of standardized processes, training and quality check of 
efficacy endpoints and C-SSRS is monitored centrally: 
 has been selected as 
service provider to support tasks related to the neuropsychological assessments. A detailed 
description of services can be found in the vendor contract. The services of 
include:

Necessary Rater prequalification

Site Rater training for neuropsychological assessments used as primary and secondary 
endpoints (online and at investigator/rater’s meeting)

Provision of Rater materials

Central Quality Review of Assessments; for that purpose, assessment procedures will be 
audio recorded (paper source may be used if audio is not available).


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Details of rater prequalification, Rater Training, Rater Materials (including assessments) and 
of the Central review procedures will be available in separate documents Qualification 
Methodology document and Data Analysis Methodology filed in the ISF.
8.3
RECORDS
eCRFs for individual participants will be provided by the sponsor. See section 4.1.5.2 for
rules about emergency code breaks. For drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial participant. Source data as well as 
reported data should follow the “ALCOA principles” and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Neuropsychological rating scales data entered into the 
 platform will be regarded 
as source data. For electronic participant reported outcomes the electronic record is the 
source document. These may be centrally reviewed and may be further analysed by the 
delegated third party vendor.
The electronic version of the ECG is regarded as source data. Electronic ECG will be 
uploaded to the participant's 
 profile and electronically signed and dated by the 
investigator.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the participant may not be sufficient to confirm eligibility for 
the trial and the investigator may need to request previous medical histories and evidence of 
any diagnostic tests. In this case, the investigator must make at least three documented 
attempt to retrieve previous medical records. If this fails, a verbal history from the participant, 
documented in their medical records, would be acceptable. However, at a minimum, medical 
record confirming use of SSRI/SNRI for diagnosis of MDD should be available.
Copies of source documents necessary for SAE processing may be requested and provided to 
BI. 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 properly been removed or redacted from any copy of the participants’ source documents.
If the participant is not compliant with the protocol, any corrective action e.g. re-training 
must be documented in the participant file.
For the eCRF, data must be derived from source documents, for example:

Participant identification: gender, year of birth (in accordance with local laws and 
regulations)


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
Participant participation in the trial (substance, trial number, participant number, date 
participant was informed)

Dates of participant’s visits, including dispensing of trial medication

Medical history (including trial indication, current depressive episode, and 
concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if 
available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

Completion of participant’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a participant to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the participant or 
testing conducted specific for a protocol) to support inclusion/exclusion criteria does 
not make the participant eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 


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8.5
STATEMENT OF CONFIDENTIALITY AND PARTICIPANT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of participant data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual participant data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the participant’s personal physician or to other 
appropriate medical personnel responsible for the participant’s welfare. Data generated at the 
site as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first participant in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last participant in the whole 
trial (“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined 
as the date on which the last participant in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.


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Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all participants have 
completed the trial in all countries (EU or non-EU) to incorporate and consider all data in the 
report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last participant
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
Relevant documentation on the participating Principal Investigator and sub-investigators (e.g. 
their curricula vitae) will be filed in the ISF. The investigators will have access to the BI 
clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic ISF.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of Clinical Trial Managers (CT Managers), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
Vendors will be used in this trial for central laboratory services, IRT, central ECG services, 
ClinRO/PRO scales assessments including, medication intake monitoring, 
 


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. Details will be provided in the respective manuals 
available in the ISF.
Bioanalysis of BI 1358894 is done by 
,
.


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9.
REFERENCES
9.1
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and psychosomatics, 49(3-4), 179-186 (1988).
R20-0669
Cummins N, Scherer S, Krajewski J, Schnieder S, Epps J, Quatieri TF. A 
review of depression and suicide risk assessment using speech analysis. 
Speech Communication , 71, 10-49 (2015).
R20-0670
Trifu RN, Nemes B, Bodea-Hategan C, Cozman D. Linguistic Indicators of 
Language in Major Depressive Disorder (MDD). An Evidence Based 
Research. Journal of Evidence-Based Psychotherapies, 17(1) (2017).
R20-0679
Alghowinem S, Goecke R, Wagner M, Parker G, Breakspear M. Eye 
movement analysis for depression detection. In 2013 IEEE International 
Conference on Image Processing (pp. 4220-4224). IEEE (2013, 
September).
R20-0680
Williamson J R, Quatieri TF, Helfer BS, Horwitz R, Yu B, Mehta DD. 
Vocal biomarkers of depression based on motor incoordination. In 
Proceedings of the 3rd ACM international workshop on Audio/visual 
emotion challenge (pp. 41-48). ACM (2013).
9.2
UNPUBLISHED REFERENCES
c10354149 
Investigator’s Brochure BI13558894; 1402.P1-P2;
 
.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
17-Dec-2020
EudraCT number
EU number
NA
BI Trial number
1402-0014
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A phase II 6-week, randomized, double-blinded, 
placebo-controlled, parallel group decentralised 
clinical trial to evaluate efficacy and safety of oral 
BI 1358894 in patients with Major Depressive 
Disorder with inadequate response to 
antidepressants
Global Amendment due to urgent 
safety reasons
Global Amendment
1
Sections to be changed
Protocol synopsis and Abbreviations
Description of change
Updated to align with new text in within this 
revised CPT.
Rationale for change
See below for specific sections and study 
procedures
Sections to be changed
Flow Chart
Description of change
Add new procedures and data collection to the 
study, including PGI-S, PGI-C, Substance Use, 
Meal intake and Participant Feedback 
Questionnaire.
Update text to footnotes:

dPROs – to include PGI-S and PGI-C

Early discontinuation, Option 2 – to 
include text re. meal intake and PGI-C

#12 – to include collection of Meal intake 
at PK sampling timepoints

#19 – update to align within protocol re. 
collection of data from day -2 to until end 


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of study (EoStudy)

#20 – to further clarify different apps used 
and addition of participant placebo video

#22 – new footnote to explain the End of 
Study Participant Feedback Questionnaire.
Rationale for change
See further below for specific sections and study 
procedures
Sections to be changed
Various sections where NORA was mention
Description of change
NORA was changed to 
 Platform
Rationale for change
 rebranded the NORA flatform to 
 Platform
Sections to be changed
ABBREVIATIONS
Description of change
Added new relevant abbreviations and removed 
ones no longer applicable.
Rationale for change
Updates and edits of CTP contents.
Section to be changed
1.2. Drug Profile;
Table 1.4.2:1;
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Updated Data from IB included:

Additional text re. data from clinical studies

Rationale added for restriction of CYP2B6 and 
CYP3A4

Update on drug-drug interaction data Removed 
restriction for “combined CYP3A4 and UGT 
inhibitors” as co-meds

Precaution measure for operating machinery 
and driving automobiles added.

Revised text referring to drug administered on 
‘site’ to mobile nurse oversight
Rationale for change
Consistency with updated IB
Sections to be changed
1.3 Rationale
Description of change
General wording changes regarding MDD
Rationale for change
Align with text in parent trial (1402-0011)
Sections to be changed
1.4.2 Risks
Description of change
Assessment of BI 1358894 safety in the scope of 
COVID-19
Rationale for change
Providing safety and consideration for patient 


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participating in study
Sections to be changed
2.1.3 Secondary endpoints
2.2.2 Further endpoints
7.2.3 Secondary endpoint analysis
Description of change
Added endpoints to include PGI-S and PGI-C. 
Also add PK endpoints.
Rationale for change
Per FDA request to add PGI-S and PGI-C as 
anchors for the SMDDS.  PK was not previously 
included.
Sections to be changed
3.3.2 Inclusion criteria
Description of change
Replaced MADRS item #2 with actual description 
of ‘Reported Sadness’.
Rationale for change
For better clarity of item #2 on the MADRS
Sections to be changed
4.1 Investigational treatments;
Table 4.1.1: 2 Placebo matching BI 1358894
Description of change
Added
 as the manufacturer of 
placebo tablets.
Rationale for change
Correct the missed manufacturer of placebo
tablets.
Section to be changed
5.2 Assessment of efficacy
Description of change
Added two sub-sections:

5.2.5 PGI-S

5.2.6 PGI-C
Renumbered sequential sections as:
 
Rationale for change
Per FDA request to add PGI-S and PGI-C as 
anchors for the SMDDS.
Section to be changed
Description of change
 
 
Rationale for change
Texts added to further clarify scale and align with 
sister trial (1402-0012)
Section to be changed
5.5.3 Safety laboratory parameters
Description of change
Information and rational added that drug screen 


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results will be included in the clinical database
Updates to Table 5.3.3: 1 include:

ESR test added to Haematology

Revision of Urinalysis test to align with 
 lab testing

Added details regarding urine sediment 
microscopic analysis

Added Norfluoxetine to Fluoxetine
Rationale for change
Added ESR per FDA request (in sister trial 1402-
0012). 
Adding inclusion of drug screen results to better 
understand reasons of screening failures and 
potential impact of drug use on the efficacy
Norfluoxetine is active component of Fluoxetine
also being tested by central laboratory.
Section to be changed
Description of change
 
 
 
Rationale for change
 
.
Section to be changed
New section
5.6.5 End of study participant feedback 
questionnaire
Description of change
New section added
Rationale for change
To allow of collection of patient experience 
feedback at the end of study.
Section to be changed
6.1 Visit schedule
Description of change
Updates to this section include:

Revised and aligned collection of Beiwe 
data to End of Study.

Added language for consideration of 
potential study visit impact due to COVID
Rationale for change
Align Beiwe collection period within CTP, and to 
acknowledge for COVID circumstances
Sections to be changed
6.2 Details on Trial Procedures 


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Description of change
Addition of texts related to:

PGI-S and PGI-C

Clarification of only MADRS and SCID-5 
are to be reviewed by central reviewer, not 
PROs 

Participant Placebo Response Mitigation 
Video added 
Rationale for change
Provide details of when PGI-S and PGI-C are to be 
completed.
Administrative edit for clarification re. central 
reviewer.
To teach participants about the placebo effect in 
order to mitigate this effect during the trial 
performance
Sections to be changed
7.2.3 Secondary endpoint analysis
Description of change
Updates to this section include:

Added endpoints to include PGI-S and 
PGI-C

Clarify Beiwe data analysis will provided 
in a separate plan
Rationale for change
Per FDA request to add PGI-S and PGI-C as 
anchors for the SMDDS.  
Beiwe data is not to be part of the CTR.
Sections to be changed
Description of change
Rationale for change
Sections to be changed
7.2.6 Other analyses
Description of change
Add within patient change analyses for SMDDS 
score using PGI-S and PGI-C
Rationale for change
Per FDA request to add PGI-S, PGI-C and CGI-S 
as anchors for the SMDDS.  
Sections to be changed
9.1 Published references
Description of change
Added two new references
Rationale for change
New references related to PGI-S.
Sections to be changed
9.2 Unpublished references
Description of change
Remove IB version number and date
Rationale for change
Reference to the IB should the latest and current, 


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not the version noted in the CTP.
11.2
GLOBAL AMENDMENT 2
Date of amendment
20-Jul-2021
EudraCT number
EU number
NA
BI Trial number
1402-0014
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A phase II 6-week, randomized, double-blinded, 
placebo-controlled, parallel group decentralised 
clinical trial to evaluate efficacy and safety of oral 
BI 1358894 in patients with Major Depressive 
Disorder with inadequate response to 
antidepressants
Global Amendment due to urgent 
safety reasons
Global Amendment
2
Sections to be changed
Title Page and Protocol Synopsis
Description of change
Site and investigator address
Rationale for change
Change of addresss
Sections to be changed
Protocol Synopsis and Abbreviations
Description of change
Updated to align with new updates within this 
revised CPT.
Rationale for change
As noted per respective sections.
Sections to be changed
Flowchart
Description of change

Informed consents, added texts ‘(include 
consents for participant’s duplicate check)’.

Sample for confirmation of blood/urine levels 
SSRI/SNRI, added ‘urine’.
Rationale for change

Specify new VCT consent needed for 
participant’s duplicate check.


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
Added urine sample collection for testing of 
SSRI/SNRI
Sections to be changed
Flowchart, Footnote
Description of change
Changes made to the following Footnotes:

Footnote ‘a’ – added texts ‘(repeat of MADRS 
is allowed once to maintain within this 21-day 
window)’

#6, correct typo ‘Adverse’ Event

#8, delete extra wording ‘at screening’

#11, added text for Visits 1 and 8 for collection 
of SSRI/SNRI samples; urine sample only 
collected at Visit 1 (except for Duloxetine 
which is serum only).  

#18, changed Visit 8 to EOT
Rationale for change

Footnote a, allow for flexibility of repeating 
MADRS, reducing patient burden of 
rescreening procedures.

#6, correct typo

#8, remove duplicated texts

#11, added clarification to specify visits when 
SSRI/SNRI serum and urine samples are to be 
collected.

#18, correct Visit 8, should be EOT
Sections to be changed
Section 1.4.3 Discussion
Description of change
Added ‘or till end of treatment if a change is 
clinically needed per investigator discretion’ for 
duration of continued use of background 
SSRI/SNRI
Rationale for change
Allow flexibility for when and if clinically needed 
or participants want to change their dosing of 
background SSRI/SNRI after ending study 
treatment
Sections to be changed
Section 3.3.2 Inclusion criteria
Description of change
Changes made to the following Inclusion criteria:

#1, changed duration of current major 
depressive episode to ≤ 18 months

#3, added urine to screening SSRI/SNRI
samplings
Rationale for change

Increase of MDD episode duration to more 
reflect real-world patient population


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
Inclusion of urine sampling to allow flexible 
testing and turnaround time for results
Sections to be changed
Section 3.3.3 Exclusion criteria
Description of change
Changes made to the following Exclusion criteria:

#6, changed to history 4 or more unsuccessful 
monotherapy treatments 

#12 a) changed duration of background 
SSRI/SNRI use to end of treatment period 
(EOT), and b) allow for use of other anti-
depressants not indicated for MDD to be used.

#18, added texts ‘this also applies to prescribed 
medications’
Rationale for change

#6, with increase of major depressive episode 
duration to 18 months, this allow for possible 
unsuccessful treatments

#12, allow flexibility for a) if clinical need and 
participants want to change their dosing of 
background SSRI/SNRI and b) flexible for 
other common use of medications.

#18, allow for patients who are currently taking 
prescribed medications (e.g. opioids) testing 
positive that are not drugs of abuse 
Sections to be changed
Section 4.1.1 Identity of the IMP
Description of change
Update to change from 
 to 
’s 
‘designated vendor’ as the responsible party for 
IMP management.
Rationale for change
 outsourced IMP management to 
Vendor.
Sections to be changed
Section 4.1.4 Drug assignment and administration 
of doses for each participant
Description of change
Added text regarding home visits to occur in 
afternoon or evening visits
Rationale for change
Allow for some flexibility of afternoon or evening 
visits due to participant’s scheduling conflicts.
Sections to be changed
Section 4.2.2.3 Contraception requirements
Description of change
WOCBP, who are sexually abstinent, fulfil the 
requirement of safe contraception
Rationale for change
Clarification. Sexual abstinence, as defined in the 
protocol, meets the criterion of a highly effective 
method of contraception


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Sections to be changed
Section 5.3.3 Safety laboratory parameters
Description of change
Added text to allow use of local labs without study 
provided lab kits. 
Rationale for change
Ensuring flexibility to allow for changes due to 
disruption, such as central lab stock out (shortage)
Sections to be changed
Table 5.3.3:1
Description of change
Added texts below to footnote 1:
(at screening, urine samples will also be collected, 
except for Duloxetine)
Rationale for change
Provided clarification for collection of urine and 
serum SSRI/SNRI samples
Sections to be changed
Section 5.4.1
Description of change
Added text:
If collection of PK samples is scheduled at the visit 
when local lab is used, PK samples will not be 
taken.
Rationale for change
Provided clarification that PK samples are not 
taken when using local lab.
Sections to be changed
Description of change
 
Rationale for change
Sections to be changed
Description of change
Rationale for change
 
 
Sections to be changed
 
Description of change
 
 
 
 


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Rationale for change
 
Sections to be changed
Added.
Section 5.6.6 Verification of current and past 
research study status of trial participant
Description of change
Verification of duplicate participants (VCT) added
Rationale for change
Prevention of simultaneous trial participation by 
study participants
Sections to be changed
Section 6.2.1 Screening period(s)
Description of change

Added text ‘completed the first study activity 
or assessment after’ 

Changed 72 hours to ‘3 business days’ for 
countersigning of consent 
Rationale for change

Additional text to clarify the start of screening 
window

Aligning with 
 SOP.
Sections to be changed
Section 7.2.1
Description of change
Added texts: Any deviations from the TSAP will 
be carefully monitored and reported in the CTR.
Rationale for change
Provided further clarification re. monitoring of 
deviations.
Sections to be changed
Section 8.2 Data Quality Assurance
Description of change
Add text in parentheses:
Central Quality Review of Assessments; for that 
purpose, assessment procedures will be audio 
recorded (paper source may be used if audio is not 
available).
Rationale for change
Allow vendor to quality review paper source if 
there are (technical/computer/programmatic) issues 
that make audio not available. 
Sections to be changed
Section 8.7
Description of change
Changed 
 lab name to
 
Rationale for change
Vendor name change

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c36743592-01
BI Trial No.:
1402-0014
Title:
A phase II 6-week, randomized, double-blinded, placebo-
controlled, parallel group decentralised clinical trial to evaluate 
efficacy and safety of oral BI 1358894 in patients with Major 
Depressive Disorder with inadequate response to antidepressants
Investigational
Product(s):
BI 1358894
Responsible trial 
statistician(s):
Phone: +
Date of statistical 
analysis plan:
01 JUL 2022 SIGNED
Version:
1
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2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONETNTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONETNTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION...............................................................................................10
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY....................11
5.
ENDPOINT(S).....................................................................................................12
5.1
PRIMARY ENDPOINT(S) ................................................................................12
5.2
SECONDARY ENDPOINT(S) ..........................................................................12
5.2.1
Key secondary endpoint(s).................................................................................12
5.2.2
Secondary endpoint(s) ........................................................................................12
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENT(S)................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................19
7.3
TREATMENT COMPLIANCE........................................................................20
7.3.1
Treatment compliance........................................................................................20
7.3.2
Treatment adherence..........................................................................................20
7.4
PRIMARY ENDPOINT(S) ................................................................................21
7.4.1
Primary analysis of the primary endpoint(s) ...................................................21
 
7.5
SECONDARY ENDPOINT(S) ..........................................................................23
7.5.1
Key secondary endpoint(s).................................................................................23
7.5.2
(Other) Secondary endpoint(s) ..........................................................................23
7.7
EXTENT OF EXPOSURE.................................................................................27
7.8
SAFETY ANALYSIS..........................................................................................28
7.8.1
Adverse events.....................................................................................................28
7.8.2
Laboratory data ..................................................................................................29


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7.8.3
Vital signs.............................................................................................................29
7.8.4
ECG......................................................................................................................29
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............31
9.
REFERENCE......................................................................................................31
11.
HISTORY TABLE..............................................................................................33


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LIST OF TABLES
Table 6.1: 1 Analyzing Treatment Periods*.............................................................................14
Table 6.3: 1 Subject Sets Analyzed..........................................................................................16
Table 6.7: 1 Planned and actual visit days ...............................................................................18
Table 11: 1 History table..........................................................................................................33


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ACTH
Adrenocorticotropic Hormone
AE 
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Variance
App
(Smartphone) Application
AST
Aspartate Aminotransferase
ATRQ
Antidepressant Treatment Response Questionnaire
AUC
Area Under the Curve
BA
Bioavailability
BI
Boehringer Ingelheim
BPD 
Borderline Personality Disorder
CA
Competent Authority
CCK-4
Cholecystokinin Tetrapeptide
CDK-EPI
Chronic Kidney Disease Epidemiology Collaboration
CGI-S
Clinical Global Impression Severity Scale
ClinRO
Clinician Reported Outcome
Cmax
Maximum Concentration
Cmin
Minimum Plasma Concentration
CNS
Central Nervous System
CRA
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
C-SSRS
Columbia Suicide Severity Rating Scale
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CYP
Cytochrome P450


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Term
Definition / description
DBL
Database Lock
DCT
Decentralized Clinical Trial
D/C
Discontinue
DDI
Drug-Drug Interaction
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic Acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, v5
EC 
Ethics Committee
EC50
Half Maximal Effective Concentration
eCDF
Empirical Cumulative Distribution Function
ECG
Electrocardiogram
 
eCRF
Electronic Case Report Form
ECT
EDMS
Electroconvulsive Therapy
Electronic Document Management System
eDC
Electronic Data Capture
EGFR
Estimated Glomerular Filtration Rate
EoStudy
End of Study
eEOT
Early End of Treatment
EOT
End of Treatment
ESR
Erythrocyte Sedimentation Rate
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
FDA
Food and Drug Administration
FUP
Follow Up
GCP
Good Clinical Practice
GGT
Gamma-Glutamyltransferase
GMP
Good Manufacturing Practice
HA
Health Authority
HDL
High Density Lipoprotein


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Term
Definition / description
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
IB 
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD 
Intrauterine Device
LC-MS/MS
Liquid Chromatography Tandem Mass Spectrometry
LPLT
Last Patient Last Treatment
LS
Least Square
MADRS
Montgomery-Asberg Depression Rating Scale
MAR
Missing at Random
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligram
MGH
The Massachusetts General Hospital
MMRM
MQRM
Mixed Effects Model for Repeated Measurements
Medical Quality Review Meeting
MRD
Multiple Rising Dose
nM
Nanomole
NIMH
National Institute for Mental Health
NOAEL
No Observed Adverse Effect Level
OATP
Organic Anion Transporter Protein
OPU
Operative Unit
 
P-gp
P-Glycoprotein
PGI-C
Patient Global Impression of Change Scale
PGI-S
Patient Global Impression Severity Scale


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Term
Definition / description
PK
Pharmacokinetics
p.o
Per Os
PoCP 
Proof of Clinical Principle
PRO
Patient Reported Outcomes
PV
Pharmacovigilance
QD
Quaque Die (once a day)
QTcF
Corrected QT interval by Fredericia
REML
Restricted Maximum Likelihood
REP
RSI
Residual Effect Period
Random Slope and Intercept Model
SAE
Serious Adverse Event
SCID-5
Structured Clinical Interview for DSM-5
SD
Standard Deviation
SIB
Suicidal Ideation and Behavior
SMDDS
Symptoms of Major Depressive Disorder Scale
SNRI 
Serotonin Norepinephrine Reuptake Inhibitor
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SSRI
Selective Serotonin Reuptake Inhibitor
STAI
State-Trait Anxiety Inventory
STAR*D
Sequenced-Treatment-Alternatives to Relieve Depression
SUSAR
TMF
Suspected Unexpected Serious Adverse Reactions
Trial Master File
TMS
TOM
Transcranial Magnetic Stimulation
Trial Oversight Meeting
TRPC
Transient Receptor Potential Channel
TS
Treated Set 
TSAP
Trial Statistical Analysis Plan
UGT
UDP-Glucuronosyltransferase
ULN
Upper Level of Normal
VAS
Visual Analogue Scale


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Term
Definition / description
VCT
Verified Clinical Trial
WHO
World Health Organization
WOCBP 
Woman of Child Bearing Potential


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3.
INTRODUCTION
As per ICH E9 (11), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.
The main analyses of this TSAP will be conducted under the estimand concept. To quote ICH 
E9 R1 (11), “An estimand is a precise description of the treatment effect reflecting the clinical 
question posed by a given clinical trial objective. It summarizes at a population level what the 
outcomes would be in the same patients under different treatment conditions being 
compared.” So, an estimand is a way for the clinical trial protocol to address how intercurrent 
events will be handled. And according to ICH E9 R1 (11), intercurrent events are events 
occurring after treatment initiation that affect either the interpretation or the existence of the 
measurements associated with the clinical question of interest. Or in other words, intercurrent 
events are occurrences after randomization that involve a change in treatment regimen. 


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The analyses will be performed as planned. However, results will be interpreted in descriptive 
manner since the trial was terminated early and the specified number of patients required for 
the analyses was not obtained. 
Due to early termination and the small sample size, the analysis for within-patient SMDDS
will be challenging. Therefore, it will not be performed.


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5.
ENDPOINT(S)
The primary objective of this trial is to evaluate the efficacy and safety of oral BI 1358894 
compared to placebo over a 6-week treatment period in MDD participants with inadequate 
response to antidepressants (selective serotonin reuptake inhibitor (SSRI) or serotonin 
norepinephrine reuptake inhibitor (SNRI)).
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is the change from baseline at Week 6 in Montgomery-Asberg 
Depression Rating Scale (MADRS) total score. 
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
There is no key secondary endpoint in the trial.
5.2.2
Secondary endpoint(s)
Montgomery-Asberg Depression Rating Scale (MADRS)

Response defined as ≥ 50% reduction in MADRS total score from baseline at Week 6
State-Trait Anxiety Inventory (STAI)

Change from baseline in STAI state and trait version scores at Week 6
Clinical Global Impression Severity Scale (CGI-S)

Change from baseline in CGI-S at Week 6
Symptoms of Major Depressive Disorder Scale (SMDDS)

Change from baseline in SMDDS total score at Week 6
Patient Global Impression Severity Scale (PGI-S)

Change from baseline in PGI-S score at Week 6
Patient Global Impression of Change Scale (PGI-C)

PGI-C score at Week 6


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
Participants who meet all in- and exclusion criteria will be enrolled into the trial. These 
participants will be randomized to the following treatment groups for the 6-week double blind 
treatment period with allocation ratio of 1:1:

125 mg BI 1358894 once daily


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
Placebo matching BI 1358894 once daily
The randomization will be handled by IRT. Details about the participants randomization, drug 
assignment, dose selection and administration can be found in the Section 4 of study protocol.  
Participants will be analyzed according to the treatment to which they were treated. The study 
periods based on actual start and stop dates of study treatment administration are defined as 
follow:
Table 6.1: 1 Analyzing Treatment Periods*
Study analysis phase
Description
Start Date (included)
End Date (included)
Screening 
Screening (prior to 
enrollment)
Date of informed 
consent
Date of first treatment 
administration minus 
1 day
Treatment and 
residual effects
On-treatment period
Date of first 
treatment 
administration
Date of last treatment 
administration + REP
Follow-up
Off-treatment period
Date of last 
treatment 
administration + 
REP + 1 day
Date of last protocol 
visit
*The defined treatment periods are the same for all treatment groups.
REP stands for Residual Effect Period, which is defined as 28 days for safety analysis and 7 days for efficacy analysis.
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase will 
not extend beyond the start date of the following phase. 
Participants who discontinue trial medication prior to the completion of protocol-specified 
end of treatment visit are still encouraged to remain in the trial if medically safe. They will 
ideally be observed until the end of study as if they were still receiving blinded trail treatment. 
Their study periods will be defined the same as the participants who complete all the study 
procedures. For participants who refuse to complete all further visits after early treatment 
discontinuation, refer the Section 6.2.3 of study protocol for visit schedule and study period 
definition. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
database (i.e., enrolled subjects). Consistency check listings (for identification of violations of 
time windows) and a list of protocol deviations will be provided and will be discussed at the 
Report Planning Meeting (RPM) / Database Lock Meeting (DBLM) / Medical Quality 
Review Meeting (MQRM). Decisions regarding whether a discrepant data value can be used 
in analyses and / or whether it must be quired in the clinical database will be made during 
these meetings. Each protocol deviation must be assessed to determine if it is an important 
Protocol Deviation (iPD). Refer to the BI reference document “Identify and Manage 
Important Protocol Deviations (iPD)” (7) for definition of iPDs and their identification 


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process. Generally, a Protocol Deviation (PD) is important if it affects the rights or safety of 
study subjects, or if it can potentially influence the primary outcome measurement(s) in a non-
negligible way. 
If any iPDs are identified, they will be summarized into categories and will be captured in the 
RPM / DBLM / MQRM minutes via an accompanying DV domain specifications Excel 
spreadsheet (14). It contains all the iPD categories in this trial. If the data present any 
additional iPDs, the DV domain specifications will be supplemented accordingly at Trial 
Oversight Meetings (TOMs) or RPMs or through team review of the manual PD log. 
The decision whether a subject will be excluded from the analyses will be made at the final 
RPM prior to Database Lock (DBL). The documentation of the iPD categories and how to 
handle iPDs in the analyses are listed in the DV domain specifications and are stored within 
the Trial Master File (TMF) in Electronic Document Management System (EDMS). IPDs 
leading to exclusion from analysis sets are indicated by the DV domain specifications. IPDs 
will be summarized and listed for the treated set. IPDs from patients in the screened set will 
be listed but not be summarized. 
6.3
SUBJECT SETS ANALYSED
The following analysis sets have been defined for this trial:  

Screened Set (SS): This subject set includes all subjects who signed informed consent 
and were screened for the trial with at least one screening procedure done at Visit 1.

Treated Set (TS): This set includes all subjects in SS which are randomized and have 
received at least one administration of study drug. The TS will be the main analysis set 
for the evaluation of safety. Subjects are analysed according to the actual received 
treatment.

Full Analysis Set (FAS): This set includes all subjects in TS that have a baseline and 
at least one evaluable post-baseline on-treatment measurement for the primary 
endpoint. This is the main analysis set for the evaluation of efficacy data. 

Per Protocol Set (PPS):  This is a subset of FAS, for subjects with adequate protocol 
compliance. It consists of all subjects in FAS without any important protocol 
deviations that impact efficacy assessments. 

Adherence Set (AS): This set includes all subjects in FAS that are at least 60% overall 
 adherent to study medication. See Section 7.3.2 for further information. 
The safety analyses will be conducted on the TS. Data collected from patients in SS will be 
included in the disposition table and listings. The SS will not be included in any other 
summaries or inferential statistics. 


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Table 6.3: 1 Subject Sets Analyzed 
Subject Set
Class of Endpoints
SS
TS
FAS
AS
Primary endpoints
X
Secondary endpoints
X
Further endpoints
X
Disposition
X
iPD
X
Demographics, baseline 
characteristics
X
Exposure, adherence
X
X
Safety
X
Primary endpoint adjusted for 
overall study 
adherence
X
If the percentage of subjects in FAS with iPD that lead to the exclusion from the PPS is > 10%, then sensitivity analysis of 
the primary and secondary efficacy endpoints using PPS may be conducted.
6.5
POOLING OF CENTRES
This section is not applicable, because the study is a decentralized clinical trial.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing data are not explicitly imputed and remain missing for all main analyses. Most 
efficacy endpoints are continuous and will be analysed by a restricted maximum likelihood 
(REML)-based mixed model known as Mixed Effect Model with Repeated Measurements 


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(MMRM). This model assumes data are missing at random (MAR) and can handle the 
missingness implicitly. For the calculation of summary statistics and the binary endpoint 
MADRS response and remission, missing data will not be imputed.
Missing or incomplete AE dates will be imputed according to “Handling of missing and 
incomplete AE dates” (12). 
 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline refers to the last non-missing value recorded prior to first dose of trial medication 
and is typically recorded at Visit 2. If data from Visit 2 are missing, the last value recorded 
prior to Visit 2 will be considered as the baseline value. If a subject is randomized at Visit 2 
but does not get trial medication until further visit (e.g., Visit 4), then his / her baseline is the 
latest assessment performed at Visit 2. 
However, for laboratory safety measurements, the last value prior to the first drug 
administration will be considered as the baseline value. 
The visit schedule with accompanying details can be found in Flow Chart in the study 
protocol. The midpoint between two on-treatment visits defines the end of a time window, 
with the midpoint being included in the time window of the preceding visit. 
Planned and actual visit days are included in the analysis data sets and are calculated relative 
to the beginning of study as indicated in Table 6.7: 1.
Repeated and unscheduled efficacy measurements will be assigned to the nominal visits 
according to the time windows described in Table 6.7: 1.  
For efficacy measurements, only one observation per time window will be selected for 
statistical analysis – the first one in the corresponding time window. If there are two 
observations having the same difference in days to the planned visit day, or if there are two 
observations on the same day, the first value will be selected. If an observation is available on 
the last day of treatment, this observation will be preferably selected over any later 
observation that is still within the time window. Non-imputed (observed) data will be utilized 
to assign efficacy observations to nominal visits which are defined based on time window. 
For safety measurements, collected visit numbers will be used. For repeated and unscheduled 
safety measurements for the same visit on treatment, the worst of these will be selected for 
analysis. In the case where there is no standard reference direction for the safety parameter, 
the average of all values for the same visit will be used for analysis.
Repeated and unscheduled efficacy, safety, and biomarker measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date of measurement.  


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Table 6.7: 1 Planned and actual visit days
Visit
Relative to study start
Planned visit day
Actual visit day
2
1
Day 1 – Day 5
3
8
Day 6 – Day 12
4
15
Day 13 – Day 19
5
22
Day 20 – Day 26
6
29
Day 27 – Day 33
7
36
Day 34 – Day 40
8/EoT
43
Day 41 – Day 47
eEoT
N/A
Date of last administration of trial 
medication + 7 days (for early 
discontinued subjects)
EoStudy
EoT / eEoT + 28 days + 4 days
(EoT + 30 days) to (EoT + 32 days)
Days are counted relative to the day of first trial medication administration, which is defined as Day 1. 
7.
PLANNED ANALYSIS
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Standards for Reporting of Clinical Trials and Project Summaries” (13).
The individual values of all subjects will be listed, sorted by dose group, subject number and 
visit. AE listings will be sorted by assigned treatment. The listings will be contained in 
Appendix of the CTR. 
For continuous data summarized in End-Of-Text (EoT) tables, the set of summary statistics is: 
N / Mean / Standard Deviation (SD) / Min / Median / Max. For tables that are provided for 
endpoints with some extreme data, median, quartiles and percentiles should be preferred to 
mean, standard deviation, minimum and maximum. In general, means, medians, and 
percentiles are presented to one more decimal place than the raw data and SDs are presented 
to two more decimal places as the raw data. 
For categorical data, tabulations of frequencies will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all subjects in the respective subject 


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set whether they have non-missing values or not). The percentages should be rounded to one 
decimal place, unless the denominator is smaller than 100 (in all treatment columns), in which 
case percentages are given in integer numbers. The category missing will be displayed only if 
there are actually missing values. 
Disposition of patient population participating in the trial will be analyzed by treatment and 
presented by the categories defined in the standard CRF groups. The results will be reported 
in form of frequency tables in CTR to show the distribution of trial population. 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics and summary tables are planned for this section of the report based 
on the treated set and other subject sets as appropriate. Data will be summarized by treatment 
group, and a “total” column will be included in the summary table. The results will be 
presented by the categories defined in the standard CRF groups. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant diagnoses (concomitant diseases) will be coded using the latest version of 
MedDRA. A summary of concomitant diagnoses will be provided by treatment group, System 
Organ Class (SOC), and Preferred Term (PT). Frequency tables will be utilized to summarize 
the concomitant diagnoses recorded at baseline and throughout the study. 
A medication / therapy is considered as concomitant to treatment if it (1) is ongoing at the 
start of randomized trial treatment or (2) starts within the on-treatment period. A medication / 
therapy is considered as a prior medication / therapy if its end date is at any time prior to the 
start of randomized trial treatment. 
Concomitant therapies (CTs) are coded according to WHO Drug Dictionary. CT will be 
classified according to the Anatomical, Therapeutic, Chemical (ATC) classification system. 
The third ATC level will be used to categorize CTs by therapy type. In situations where a 
medical product may be used for more than one equally important indication, there are often 
several classification alternatives. As appropriate, subjects receiving CTs with more than one 
possible ATC level-three category will be counted more than once, and footnote will clarify 
this possible multiple counting in tables. 
Non-drug concomitant therapies are handled similar to concomitant therapies and are 
classified into general non-drug therapies and psychotherapies. 
Summary of certain concomitant medications will be presented in addition to the 
forementioned analyses, which include SSRI, SNRI, Benzodiazepines, and Non-
Benzodiazepines hypnotics. 


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7.3
TREATMENT COMPLIANCE
7.3.1
Treatment compliance
Only descriptive statistics are planned for this section of the report. Treatment compliance 
will be summarized on the TS and will be reported basing on the calculation defined in CTP 
section 4.3 and shown below. 
 	
	 (%) =

   	 

   ℎ	ℎℎ ℎ 
  	  ℎ 
∗100%
According to the study protocol, mobile nurses will collect all unused remaining trial 
medications at home visits (Week 0, Week 2, Week 4, and Week 6 / EOT / eEOT) and report 
treatment compliance. The overall compliance will be calculated basing on the compliance 
rates from all the visits. For patients who discontinued the study treatment prematurely, only 
the visits on or before premature discontinuation will be used for the calculation of overall 
compliance. 
If at a particular visit a participant did not return the trial medication kits, and if there is no 
other reasonable evidence to suggest that the participant did take trial medication as specified 
in the protocol, then the compliance at that visit is zero.
Summary statistics of overall compliance rates as well as rates at each home visit (Week 0, 
Week 2, Week 4, and Week 6 / EOT / eEOT) will be presented for patients in the treated set. 
In addition, the percentages with compliance in the following categories will be reported for 
overall compliance and home visits:
-
< 80% of planned
-
80 - 100% of planned
-
> 100% of planned
-
Missing
7.3.2
Treatment adherence
The Overall 
 Adherence, abbreviated as OAA, is defined as the adjusted percentage of 
pills taken by an individual, i.e., 
#$$ = %
    ℎ	 −
  , ,   
3 ∗42
∗100%

42 = Number of days on treatment 

3 = Number of tablets per dose
Tablet adherence is the successful administration of a pill as captured by 
 video. Red 
alerts are tablet administrations for which the 
 video captures the dosing process but 
includes strong visual proof of deceptive behaviors, non-adherence, and / or overdose of study 
drug. Examples include removing study drug from the mouth, ‘cheeking’, spitting out the 
drug, or using non-IP to dose. Also, in cases for which more than one pill was ingested 
simultaneously, a red alert is flagged. For orange alerts, the video captures the dosing 


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process, but contains suggested visual proof of potentially deceptive behaviors, potential non-
adherence, or shows potential overdose of study drug. And lastly, for yellow alerts the video 
is missing visual information necessary to confirm adherence. 
Note that tablet adherence is the administration of a tablet by visually confirmed via 
 
app.
The adjustment in OAA definition is made to exclude pills that are flagged as red, orange, and 
yellow alerts by the app. For subjects that discontinue treatment early, 42, which is the 
number of days from randomization to the planned treatment end, will be replaced by the total 
number of days from randomization to the respective date of early treatment discontinuation. 
Like the treatment compliance, summary statistics of OAA will be displayed in tables by 
different treatment groups. Additionally, the percentages with OAA in different levels (<80%, 
80-100%, >100%, missing) will be reported in the table.
As defined in Section 6.3, the Adherent Set (AS) consists of all subjects in FAS that achieved 
an OOA of at least 60%. Within these subjects, flags (or classifications) will be built to denote 
increasing thresholds of adherence. Hence, it may be of interest to evaluate the effect of 
varying levels (≥60%, ≥70%, ≥80%, ≥90%, 100%) of overall adherence on efficacy.
An evaluation of the primary endpoint to varying levels of adherence to treatment may be of 
interest. If so, the AS will be used to re-evaluate the primary endpoint, and of course, using 
the same MMRM methods.  
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
The primary endpoint in this study is change from baseline in MADRS score at Week 6. Due 
to the premature termination of the trial, the specified number of patients required for the 
analyses was not obtained. Therefore, the results will be interpreted in a descriptive manner in 
the CTR.  
Baseline MADRS total score is the last non-missing value recorded prior to first dose of trial 
medication and is typically recorded at Visit 2. If data from Visit 2 are missing, the last value 
recorded prior to Visit 2 will be considered as the baseline value. The investigator reported 
MADRS total scores will be used for the primary analysis.
The primary estimand of interest is the treatment effect assuming all subjects remained 
adherent to the assigned trial medication and the trial protocol using a hypothetical approach, 
i.e., trial drug is taken as directed. The primary analysis of the primary endpoint will include 
all data collected while on treatment, which is defined as the time from the date of the first 
dose of trial medication until the last date of last dose of trial medication plus 7 days (3 times 
the estimated elimination half-life). Any data collected after a participant discontinues trial 
drug, regardless of reason, will be censored and not included in the primary analysis. 


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The primary analyses will be the restricted maximum likelihood (REML) based approach 
using a mixed model with repeated measurements (MMRM) will be applied to compare the 
change from baseline of MADRS score at Week 6.
The analysis will include the fixed, categorical effects of treatment, visit, treatment by visit 
interaction, as well as the continuous fixed covariates of baseline MADRS score and baseline 
by visit interactions. 
Participants will be considered as random effects. Visit will be treated as the repeated measure 
with an unstructured covariance structure used to model the within patient measurements 
error. Additional covariates identified prior to database lock may be included in the MMRM 
model as applicable. 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom
and adjust standard errors. Significance tests will be performed based on least-square (LS) 
means using a two-sided α = 0.1. 
Analyses will be implemented using SAS (version 9.4) PROC MIXED. The following SAS 
code may be used with some modifications to calculate the MMRM
PROC MIXED DATA=indata cl method=reml;
CLASS visit trt subject;
MODEL madrs_change = trt visit visit*trt base base*visit / ddfm = kr s CL;
REPEATED visit/subject = subject type = un r rcorr;
LSMEANS visit*trt / pdiff=all om cl alpha = 0.10 slice = visit;
RUN;
Results of the MMRM will presented in tables and displayed graphically. 
The primary treatment comparisons will be between BI1358894 and placebo with respect to 
the mean change from baseline in the MADRS total score at week 6. Adjust mean change 
from baseline as well as treatment contrasts will be presented together with the 90% 
confidence intervals. The treatment contrast at Week 6 is the primary treatment comparison 
between our study drug and placebo. 
In addition to the MADRS total score, the scores of the individual MADRS items at baseline, 
Week 1, Week 2, Week 4, and Week 6 will be summarized by treatment groups. The changes 
from baseline in these individual items at the forementioned time points will also be 
summarized similarly. The results will be presented in tables.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
Analyses for different secondary endpoints are listed below and will be performed on the 
FAS. Like the primary analysis, there will be limited interpretation for the analysis results 
included in the CTR because of the premature termination of the trial.


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The definition of baseline measurements for the secondary endpoints is the same as that for 
the primary endpoint. Baseline score is the last non-missing value recorded prior to first dose 
of trial medication and is typically observed at Visit 2. If data from Visit 2 are missing, the 
last value recorded prior to Visit 2 will be considered as the baseline value.
For endpoints that will be analyzed with MMRM model, the SAS implementation and display 
plan are similar to the primary analysis (refer to Section 7.4.1) and would not be included in 
the following description. Implementation for other statistical analyses will still be included. 
MADRS Response
Response over the 6-week treatment period will be assessed using the MADRS total score. 
Participants with ≥ 50 % reduction in MADRS total scores from baseline to Week 6 are 
considered as responders. Participants experiencing < 50% reduction in MADRS total score 
are considered as non-responders. Percent reduction from baseline at a specific post-baseline 
visit (Visit X) is calculated as:
% 	 =
(+,-./ 01023 45167 20 824739:7;+,-./ 01023 45167 20 <9490 =)
+,-./ 01023 45167 20 824739:7
* 100 
The proportions of participants achieving response at Week 6 will be summarized as the
frequency and percentage of participants in each treatment arm. In addition, if sufficient
number of responders is observed, a logistic regression model adjusted for treatment (BI
1358894 or placebo) and baseline MADRS severity will be used to calculate the odds ratio for 
response between each of the BI treatment arms and placebo and corresponding 90 %
confidence intervals. The likelihood ratio test will be used to test for differences between each 
active treatment arm and placebo.
A logistic regression model adjusted for treatment will be used to calculate the odds ratio for 
response between the treatment and placebo arms if enough responders are observed. The 
logistic regression model would include all the covariates in the MMRM model from primary 
analysis as well as additional variables identified prior to database lock. 
The SAS code for the logistic regression model is as follow:
PROC LOGISITC DATA=indata;
CLASS trt   / param=GLM; /* include (ref=”placebo”) for trt */
MODEL resp = trt base / link=LOGIT covb;
  
LSMEAN trt / cl;
RUN;
The above SAS code may be used with some modifications, if necessary. Estimate including 
point estimates for the model parameters, adjusted odds ratios, and 90% confidence intervals 
will be summarized and presented in tables. 
STAI
Change from baseline to Week 6 in STAI state and trait scores will be analyzed using an
MMRM model similar to the model described for the primary endpoint analysis. A 
comparison between study medication and placebo will also be performed. 


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CGI-S
CGI-S will be summarized by treatment arm as both a continuous variable and an ordinal 
variable. Mean CGI-S change from baseline to Week 6 and its standard deviation will be 
presented. In addition, the frequency and proportion of participants reporting each response 
category at baseline and at Week 6 will be displayed. The results will be included in a single 
table which includes both numerical summary statistics and frequencies. 
To compare change in depression severity as assessed by the CGI-S between the BI 1358894 
treatment arm and placebo, an MMRM model similar to the model described for the primary 
efficacy analysis will be used. CGI-S change from baseline at Week 6 will be the model 
response variable, and covariates will be those used in the primary analysis. Same model 
assumptions will be used here.  
PGI-S
The secondary endpoint of change from baseline in PGI-S at Week 6 will be analyzed in the 
same way as CGI-S.
PGI-C
PGI-C at Week 6 will be analyzed as both a continuous variable and an ordinal variable. A 
single summary table will be presented and includes: (1) mean PGI-C score and SD at the end 
of treatment; and (2) frequency and proportion of patients reporting each category of response 
defined in the CRF. 
SMDDS
The analysis for SMDDS includes both a descriptive part and a MMRM-based inferential 
part. The descriptive analysis includes: (1) summary of SMDDS total score change from 
baseline at Week 6 (as a continuous variable); and (2) frequency and proportion of patients 
reporting each category of response in every individual domain. Responses to all 16 domains 
at baseline and Week 6 will be summarized in the tables and aggregated by visit.  
A MMRM model will also be used to compare change in SMDDS total score from baseline to 
Week 6 between treatment and placebo arms. The model response variable will be SMDDS 
change from baseline at Week 6, and covariates are those used in the primary analysis. Same 
model assumptions will be used in this analysis. 


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7.7
EXTENT OF EXPOSURE
Extent of exposure will be calculated as the difference between last intake of study drug and 
the first administration of the study drug plus one day. Descriptive statistics will be provided 
for number of days of exposure for each treatment arm. Also, cumulative exposure of number 
and percentage (N, %) of subjects will also be displayed as 
-
< 1 week
-
1 to < 2 week
-
2 to <3 weeks
-
3 to <4 weeks
-
4 to <6 weeks
-
6 to <8 weeks
-
8 to <10 weeks
-
10 to <12 weeks
-
12 weeks
-
Missing


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. Analysis will be performed as defined 
in Section 7.2.5 of the CTP.
7.8.1
Adverse events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and NOT on the number of AEs. AEs 
will be coded based on the latest version of Medical Dictionary for Drug Regulatory 
Activities (MedDRA) at the specified in the database lock process.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs occurring between first drug intake and the day of last drug intake + residual effect 
period will be assigned to the “on-treatment”. All AEs occurring before first drug intake will 
be assigned to “screening”, and all AEs occurring after last drug intake + residual effect 
period will be assigned to “follow-up” (for listings only). For details on the treatment period 
definition, see Section 6.1.
For analysis of AE attributes such as duration, severity, etc. multiple AE occurrence data on 
the CRF will be collapsed into one AE event if all the following apply:

All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, and outcome)

The occurrences were time-overlapped or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)
For further details on summarization of AE data, please refer to (12) and (16).
According to ICH E3 (10), in addition to Deaths and serious adverse events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g., discontinuation or dose 
reduced or interrupted).
AE summaries
An overall summary of adverse events will be presented. The frequency of subjects with AEs 
will be summarized by treatment, primary system organ class and PT (mention MedDRA 
levels to be displayed in the tables). Separate tables will be provided for subjects with:
-
Serious AEs
-
AEs leading to treatment discontinuation
-
AEs of at least moderate severity
-
Drug related AEs. 
-
AE of special interest (AESI)
-
AE leading to death
-
Other significant AEs (according to ICH E3)


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The system organ classes (SOC) will be sorted by default alphabetically, PTs will be sorted 
by frequency (within SOC). Customized sorting orders may also be used based on trial needs, 
e.g., SOC sorted by frequency.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards
(15). Baseline for safety laboratory parameters will be the last available measurement before 
the start of randomized study drug. Laboratory measurements taken up to the residual effect 
period of 28 days after the last administration of randomized study drug will be considered as 
on-treatment. Only patients with at least one available on-treatment value will be included in 
the analysis of an individual laboratory parameter. All individual data will be presented in 
listings. Laboratory values of particular interest include:
-
Assessments of CRP and erythrocyte sedimentation rate
-
Lipid panel (triglyceride, cholesterol, HDL-C, LDL-C)
-
Central hematology laboratory values including RBC, Hct, Hb levels, Reticulocytes, 
WBC and differential
-
Hormone panel (TSH, LH, FSH, Testosterone)
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report. In case of multiple 
measurements including unscheduled visits, the value for the vital sign measurement will be 
average of all measurements for the corresponding visit. Vital signs of particular interest 
include mean Systolic Blood Pressure (SBP), Diastolic BP, pulse rate over time, and weight 
change over time. 
7.8.4
ECG
12-lead ECG measurements will be assessed as described in the CTP Flow Chart. 12-lead 
ECG-findings before first intake of trial drug will be considered as baseline condition or as 
AEs (during the trial) if judged clinically relevant by the investigator and will be analyzed as 
such. No separate listing or analysis of ECG data will be prepared.
 
 
 


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be released to unblind the trial database after the last patient 
has completed their End-of-Study / Follow-up visit and all data has been entered and cleaned 
as defined in the “Data Ready to be Unblinded and / or Final Trial Closure Notification” 
(RUN) form.
9.
REFERENCE
1.
001-MCS-50-415_RD-02: “Project Analysis Dataset (PADS) Template (template) “, 
current version, Group “Biostatistics & Data Sciences”, IDEA for CON.
2.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.


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3.
001-MCS-50-415_RD-03: “Clinical Trial Analysis Decision Log (template) Decision 
Log”, current version, Group “Biostatistics & Data Sciences”, IDEA for CON.
4.
001-MCS-36-472: “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics”, current version, Group “Biostatistics & Data 
Sciences”, IDEA for CON.
5.
001-MCS-40-106_RD-03: “Clinical Trial Protocol general template for Phase I-IV”, 
current version, Group “Clinical Operations”, IDEA for CON.
6.
001-MCS-80-606: “Management of Non-Compliances”, current version, Group 
“Quality Medicine”, IDEA for CON.
7.
001-MCS-40-413: Identify and Manage Important Protocol Deviations (iPD)”, current 
version, Group “Clinical Operations”, IDEA for CON.
8.
001-MCS-40-135_RD-01: “Integrated Quality and Risk Management Plan”, current 
version, Group “Clinical Operations”, IDEA for CON.
9.
REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF 
THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human 
use, and repealing Directive 2001/20/EC, European Commission webpage.
10. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports,
current version, EMA webpage.
11. CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9,Note For Guidance on Statistical Principles for Clinical Trials, current version.
12. BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE dates”, current 
version, Group “Med Biostatistics & Data Sciences”, Vault Quality
13. BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project 
Summaries” current version, Group “Med Biostatistics & Data Sciences”, Vault Quality
14. BI-KMED-COPS-TMP-0001: "Important Protocol Deviation (iPD) log", current
version; IDEA for CON
15. BI-KMED-BDS-HTG-0042: "How to Guide: Handling, Display and Analysis of 
Laboratory Data", current version; IDEA for CON.
16. BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event Data from 
Clinical Trials", current version; IDEA for CON.


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11.
HISTORY TABLE
Table 11: 1 History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1 
01-JUL-22
None
Creation of the TSAP 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c36743592
1.0
8-01-tsap-core
A phase II 6-week, randomized, double-blinded, placebo-controlled, parallel group
decentralised clinical trial to evaluate efficacy and safety of oral BI 1358894 in
patients with Major Depressive Disorder with inadequate response to antidepressants
Approval
01 Jul 2022 16:30 CEST
Approval-Project Statistician
01 Jul 2022 16:38 CEST
Approval-Clinical Program Leaders
01 Jul 2022 16:58 CEST
Approval-Medical Writer
04 Jul 2022 03:38 CEST
Approval-Clinical Trial Leader
04 Jul 2022 08:28 CEST
Author-Trial Clinical
Pharmacokineticist
04 Jul 2022 08:35 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c36743592
1.0