Clinical trial NCT04566601
Conditions: Borderline Personality Disorder
Sponsor: Boehringer Ingelheim
Start date: 2020-11-13; Completion date: 2023-01-25
Enrollment: 390 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with borderline personality disorder. The purpose of this study is to find out whether a medicine called BI 1358894 helps to reduce symptoms in people with borderline personality disorder. Four different doses of BI 1358894 are tested in the study.

Participants are put into 5 groups by chance. Participants in 4 of the 5 groups take different doses of BI 1358894. Participants in the fifth group take placebo. Participants take BI 1358894 and placebo as tablets once a day. Placebo tablets look like BI 1358894 tablets but do not contain any medicine.

Participants are in the study for about 5 months. During this time, they visit the study site about 12 times and get about 6 phone calls. At the visits, doctors ask participants about their symptoms. The results between the BI 1358894 groups and the placebo group are then compared. The doctors also regularly check the general health of the participants.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: BI 1358894 intervention 2: Placebo
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106 RD-03 (18 0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
 
Document Number:
c29157684-05
EudraCT No.
EU Trial No.
2020-000078-12
BI Trial No.
1402-0012
BI Investigational
Medicinal Product(s)
BI 1358894
Title
A phase II randomized, double-blinded, placebo-controlled 
parallel group trial to examine the efficacy and safety of 4 oral 
doses of BI 1358894 once daily over 12 week treatment period in 
patients with borderline personality disorder
Lay Title
A study to test different doses of BI 1358894 and find out 
whether they reduce symptoms in people with borderline 
personality disorder
Clinical Phase
II
Clinical Trial Leader
Telephone: 
Coordinating 
Investigator
Telephone: 
Version and Date
Version: 5.0
Date: 23 Sep 2022
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Proprietary confidential information.
! 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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
26-Mar-2020
Revision date
23 Sep 2022
BI trial number
1402-0012
Title of trial
A phase II randomized, double-blinded, placebo-controlled parallel group trial to 
examine the efficacy and safety of 4 oral doses of BI 1358894 once daily over 12 
week treatment period in patients with Borderline Personality Disorder
Coordinating 
Investigator
Trial site(s)
Multi-center
Clinical phase
II
Trial rationale
This study is designed to provide the proof of concept (PoC) for 
 
 BI 1358894 in patients with borderline personality disorder (BoPD)
and provide data for further development of BI 1358894.
Trial objective(s)
The main objectives of this trial are to provide PoC and dose-ranging data of BI 
1358894 compared to placebo in patients with BoPD to support dose selection for 
pivotal studies.
Trial endpoints
Primary endpoint: 
∀
Change from baseline in Zanarini rating scale for Borderline personality 
disorder (ZAN-BPD) total score at Week 10. 
Secondary endpoints:
∀
Response defined as ≥30% ZAN-BPD reduction from baseline at Week 10
∀
Change from baseline in Difficulties in Emotion Regulation Scale (DERS-16) 
total score at Week 10
∀
Change from baseline in State-Trait Anxiety Inventory (STAI-State) total 
score at Week 10
∀
Change from baseline in Patient Health Questionnaire (PHQ-9) total score at 
Week 10
∀
Change from baseline in Clinical Global Impression Severity Scale (CGI-S) at 
Week 10 
∀
Change from baseline in Patient Global Impression Severity Scale (PGI-S) at 
Week 10
Trial design
A 12-week multi-center, multi-national, randomized, double-blind, placebo-
controlled parallel-group trial in patients with BoPD.  
Total number of 
patients randomized
Approximately 355 
Number of patients on 
each treatment
Placebo
119
BI 1358894 5 mg qd
47
BI 1358894 25 mg qd
47
BI 1358894 75 mg qd
47
BI 1358894 125 mg qd
95
Diagnosis
Patients meeting diagnostic criteria of BoPD per Diagnostic and Statistical Manual 
of Mental Disorders (DSM-5) and diagnosis confirmed at time of screening by 
Structured Interview for DSM-5 Personality Disorder (SCID-5-PD)
Main in- and exclusion 
criteria
Inclusion criteria:
∀
Patients meeting diagnostic criteria of BoPD per DSM-5 at screening visit, 
confirmed by SCID-5-PD.
∀
ZAN-BPD of ≥ 9 at screening (Visit 1) and randomization (Visit 2), with 
question #2 Affective Instability score of ≥2.


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∀
Male or female patients, 18-65 years of age at the time of consent
∀
Women of childbearing potential (WOCBP) able and willing to use two 
methods of contraception, confirmed by the investigator
Exclusion criteria:
∀
Current diagnosis of paranoid, schizoid, schizotypal and antisocial personality 
disorders, as confirmed by SCID-5-PD at screening visit
∀
Lifetime diagnosis for schizophrenia, schizoaffective disorder, 
schizophreniform disorder, bipolar I disorder, or delusional disorder as 
confirmed by the SCID-5 at the screening visit.
∀
Any other mental disorder that is the primary focus of treatment in the last 6 
months prior to randomization, as per the clinical judgement of the 
investigator. 
∀
Inpatient stay or hospitalization due to worsening of BoPD within 3 months 
prior to randomization. 
∀
Initiation or change in any type or frequency of psychotherapy for BoPD 
within the last 3 months prior to screening.
∀
Any ongoing use of psychotropic medications within 7 days prior to 
randomization or during the course of study 
∀
Any suicidal behavior in the past 1 year 
∀
Any suicidal ideation of type 4 or 5 in the Columbia Suicidal Severity Rating 
Scale (C-SSRS) in the past 3 months
Test product(s)
BI 1358894
dose
5 mg qd, 25 mg qd, 75 mg qd, 125 mg qd
mode of 
administration
Per os
Comparator product(s)
Placebo
dose
Matching
mode of
administration
Per os
Duration of treatment
12 weeks
Statistical methods
The primary analysis is performed using MCPMod, a methodology for dose 
finding employing both multiple comparison procedures and modelling 
techniques. The MCPMod procedure allows for simultaneous evaluation of 
different potential dose response patterns, while protecting the overall false 
positive rate (probability of Type I error) using a one-sided, nominal α level of 
10%. As a basis for the MCPMod analysis, a mixed model for repeated measure 
(MMRM) analysis will be used to generate covariate adjusted estimates of mean 
change from baseline to Week 10 in ZAN-BPD total score and associated 
covariance matrices. 




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Trial Periods
Screening 
Treatment 
Early 
D/C
Follow-up 
End of 
Trial
Visit
1 1
1A
2
3
4
4A
☎
5
5A
☎
6
6A
☎
7
7A
☎
8
8A
☎
9 
EoT 19
eEOT 2
FUP1
FUP2
☎
EoTrial
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
16
Day
-28 to 
-7
-5
1 3
8
15
22
29
36
43
50
57
64
71
78
85
EoT +7 EoT +14
EoT +28
Time window for 
visits (in days)
-28 to 
-7
-7 to
-5
V1 + 
7 to 28
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
Vital signs
X
X
X
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
Infection screening
X
Urine drug screening
X
X
Pregnancy test 6
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception 
counseling for 
WOCB 22
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 lead-ECG
X
X
X
X
X
X
X
Review of inclusion/
exclusion criteria
X
X
Randomization
X
Dispense trial drugs 7
X
X
X
Administer trial drugs 
on site 8, 7
X
X
X
X
X
X
X
Optional sampling for 
biobanking 9, 7
X 10
X




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Trial Periods
Screening 
Treatment 
Early 
D/C
Follow-up 
End of 
Trial
Visit
1 1
1A
2
3
4
4A
☎
5
5A
☎
6
6A
☎
7
7A
☎
8
8A
☎
9 
EoT 19
eEOT 2
FUP1
FUP2
☎
EoTrial
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
16
Day
-28 to 
-7
-5
1 3
8
15
22
29
36
43
50
57
64
71
78
85
EoT +7 EoT +14
EoT +28
Time window for 
visits (in days)
-28 to 
-7
-7 to
-5
V1 + 
7 to 28
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
Termination of trial 
medication
X 7
X
Completion of patient 
participation 
X
☎ Phone visit
1
Visit 1 procedures are not required to be completed on the same day. 
2
For patients who permanently discontinue trial drug prior to the scheduled Week 12 EoT visit, the Early EoT (eEoT) visit must be completed as soon as possible after trial 
drug discontinuation. See section 6.2.3 for further details regarding patient follow-up after premature treatment discontinuation.
3
Day of Randomization / Day of first intake of randomized medication
4
Serum/ plasma and DNA biobanking is optional. To allow the collection of additional blood samples for serum/plasma and DNA biobanking, a separate informed consent 
must be obtained.
6
Women of childbearing potential must perform urine (dipstick) pregnancy test. Urine pregnancy test can be performed more frequently if required by local regulations. 
Additionally, serum pregnancy test must be completed at Visit 1 and Visit 1A to rule out pregnancy before dosing.  If urine (dipstick) pregnancy test is positive at any 
other visits, a serum test is required.
7
Not performed for visits conducted after early treatment discontinuation/eEOT visit. See section 6.2.3 for further details.  
8
On the days of on-site visits, patients should not take their study drug at home, but bring their study drugs to site visit and take it there, especially at the visits when 
.
9
Collection of biobanking samples is optional. Samples will be collected at Visit 2 (serum, plasma and DNA samples) and Visit 8 (serum and plasma samples only). 
Patients are required to sign a separate informed consent for biobanking. 
10 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.
11 Clinician-administered assessments, approximate total time: ZAN-BPD = 30 minutes, C-SSRS = 15 minutes, CGI-S = 5 minutes.
12 ZAN-BPD and C-SSRS must be completed before randomization (and IRT registration) take place.




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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................22
1.4
BENEFIT - RISK ASSESSMENT.....................................................................22
1.4.1
Benefits.................................................................................................................22
1.4.2
Risks .....................................................................................................................23
1.4.3
Discussion.............................................................................................................28
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................29
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........29
2.1.1
Main objectives....................................................................................................29
2.1.2
Primary endpoint(s)............................................................................................29
2.1.3
Secondary endpoint(s) ........................................................................................29
2.2.3
Safety....................................................................................................................31
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................32
3.1
OVERALL TRIAL DESIGN.............................................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................33
3.3
SELECTION OF TRIAL POPULATION .......................................................34
3.3.1
Main diagnosis for trial entry ............................................................................34
3.3.2
Inclusion criteria .................................................................................................34
3.3.3
Exclusion criteria ................................................................................................35
3.3.4
Withdrawal of patients from treatment or assessments..................................37
3.3.4.1
Discontinuation of trial treatment .........................................................................37
3.3.4.2
Withdrawal of consent to trial participation .........................................................38
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................38
4.
TREATMENTS...................................................................................................39
4.1
INVESTIGATIONAL TREATMENTS ...........................................................39
4.1.1
Identity of the investigational medicinal products...........................................39
4.1.2
Selection of doses in the trial and dose modifications......................................39
4.1.3
Method of assigning patients to treatment groups...........................................42








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ABBREVIATIONS
AE
Adverse event
AESI
Adverse event of special interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
BA
Bioavailability
BI
Boehringer Ingelheim
BoPD
Borderline personality disorder
BP
Blood pressure
BRCP
Breast cancer resistance protein
CA
Competent Authority
CBT
Cognitive behavior therapy
CCK-4
Cholecystokinin tetrapeptide
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum concentration
Cmin
Minimum concentration
CNS
Central nervous system
CRA
Clinical research associate
COVID-19
Disease caused by SARS-CoV-2 virus
CRF
Case report form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract research organization
CRP
C-reactive protein
C-SSRS
Columbia Suicidal Severity Rating Scale
CT Leader
Clinical trial leader
CT Manager
Clinical trial manager


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CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P450
DERS-16
Difficulties in Emotion Regulation Scale
DBL
Database lock
DBT
Dialectical behavior therapy
DDI
Drug-drug interaction
DILI
Drug Induced Liver Injury
DIPD-4
Diagnostic Interview for DSM-4 Personality Disorder
DMC
Data monitoring committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders
ECG
Electrocardiogram
EcMA
Ecological Momentary Assessment
EDC
Electronic data capturing system
eGFR
Estimated glomerular filtration rate
(e)COA
(electronic) Clinical outcome assessment
eEoT
Early End of Treatment
EoT
End of Treatment
EoTrial
End of Trial
ESR
Erythrocyte sedimentation rate
EudraCT
European Clinical Trials Database
EVAS
Emotional visual analog scale
FAS
Full analysis set
FUP
Follow-up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HA
Health Authority
IB
Investigator’s Brochure
ICH
International Council on Harmonization
IEC
Independent Ethics Committee


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IRB
Institutional Review Board
IRT
Interactive response technology
ISF
Investigator Site File
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LPLT
Last Patient Last Treatment
MAR
Missing at random
MCPMod
Multiple comparison procedure with modelling
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed model repeated measures model
MRD
Multiple rising dose
MRTpo
gMean of mean residence time after oral dosing
NOAEL
No Observed Adverse Effect Level
OATP
Organic-anion-transporting polypeptide
OPU
Operative Unit
P-gp
P-glycoprotein
PCR
Polymerase chain reaction
 
PGI-S
Patient Global Impression Severity scale
PHQ-9
Patient Health Questionnaire
PK
Pharmacokinetic
po
per os (oral)
PoC
Proof of concept
PR
Pulse rate
PRO
Patient reported outcome
qd
quaque die (once a day)
QTcF
Heart rate corrected QT interval using Fridericia's formula
RA
Regulatory Authority




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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Borderline personality disorder (BoPD) is a chronic mental disorder with an estimated 
prevalence of around 2% in the general community and severe impairment on quality of life 
(R16-5474). Patients with BoPD often have psychiatric comorbidities; concomitant mood, 
anxiety, substance use, and eating disorders have been reported at high rates (R19-1118). The 
main symptom clusters of BoPD include impulsive-behavioral dyscontrol, cognitive-
perceptual symptoms, disturbed interpersonal relations, and affective instability. Affective 
symptoms and impulsivity have been considered core symptoms of BoPD. Patients typically 
experience intense fears of real or imagined abandonment, which may result in inappropriate 
anger even when faced with a realistic short-term separation or when there are unavoidable 
changes in plans (R19-1313). Even the presence of a single diagnostic feature of BoPD is 
predictive for poor functioning and psychiatric illness burden (R16-5483). Patients with 
BoPD have high rates of deliberate self-harm and a rate of completed suicide that is 50 times 
that in the general population (R16-5477). 
Treatment guidelines recommend psychotherapy as the mainstay of treatment for BoPD 
(R17-0164). Particularly dialectical behavior therapy (DBT) has proven to be effective in 
BoPD. A disadvantage of DBT in clinical practice is that it is costly, time intensive, and 
requiring specialized clinical providers, making access for all patients in need of therapy 
difficult (R19-1550). While generalist models of care have shown potential, not all patients 
respond to them and patients with greater personality dysfunction still require intensive 
specialist treatment (R19-1092).
Pharmacotherapy is commonly used as an off-label adjunctive, symptom-targeted component 
of treatment. This includes treatment of affective dysregulation symptoms such as depressive 
symptoms (with selective serotonin reuptake inhibitors (SSRIs), mood stabilizers or related 
drugs), impulsive-behavioral dyscontrol symptoms such as impulsivity, aggression, self-
destructive behavior (initially also with SSRI), and cognitive-perceptual symptoms such as 
paranoid thinking (with low-dose neuroleptics, (R17-0164). However, no drug is approved 
for the treatment of BoPD, and no standard-of-care pharmacological treatment of the disease 
exists.
The last large clinical studies exploring pharmacologic treatment for BoPD were conducted
about a decade ago.  The lamotrigine study assessing clinical effectiveness and cost 
effectiveness of lamotrigine vs. placebo in patients with BoPD (R19-1645) included 276 
participants, of whom 195 were followed up 52 weeks later. Efficacy assessments using the 
Zanarini rating scale for Borderline personality disorder (ZAN-BPD) were performed at 
Weeks 12, 24 and 52. The primary efficacy outcome was the ZAN-BPD total score at Week 
52. While the study failed to meet its primary efficacy outcome, the ZAN-BPD total score 
decreased from baseline to Week 12 and remained rather stable thereafter (R19-1645). 
Similarly, the olanzapine vs. placebo study was a 12-week randomized, double-blind, 
placebo-controlled study in 451 patients with BoPD. In this study, statistically significant 
separation of olanzapine from placebo on ZAN-BPD was observed at Weeks 2, 4, 6, 8 and 


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10, while the result at Week 12 was not statistically significant and thus the study failed to 
meet its primary efficacy outcome at 12 weeks (R19-1108).
Despite the efforts in the therapy of BoPD, a sizeable portion of patients (about 40%) never 
achieve recovery from the disorder. In addition to their severely impacted quality of life, 
those patients have a poor prognosis for other important outcomes, such as vocational 
impairment, disability, physical morbidity, and mortality (R19-1119). As current 
pharmacological treatments are symptomatic and not supported by robust clinical evidence, a 
great unmet medical need remains for agents improving core characteristics of the disorder 
such as affective symptoms and emotion control.
In absence of any approved drug therapy and limitations related to availability and 
accessibility of psychotherapy for most BoPD patients, there is great unmet medical need to 
address and BI 1358894 would represent major therapeutic advance.


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worsening of pre-existing conditions or any newly occurring events are detected and any 
necessary actions taken according to stopping criteria (see section 3.3.4).
The study will be monitored by an external Data Monitoring Committee (DMC), independent 
from the sponsor; refer to section 8.7 for further DMC details.  
For the Phase II trial, the benefit-risk for trial patients treated with BI 1358894 remains
unchanged in relation to the COVID-19 pandemic given that:
∀
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 BoPD increases the risk for SARS-CoV-2 infection or
for developing severe COVID-19
∀
The BoPD patients are relatively young patients (30-50 years) and, in general, without 
common co-morbidities associated with severe course of COVID-19
Therefore, the risk for patients participating in the study will not differ from the current 
general risk for SARS-CoV-2 infection with all its potential consequences. The use of a 
specific SARS-CoV-2 polymerase chain reaction (PCR) as a tool for inclusion or exclusion 
of trial participants during the screening phase is not foreseen, since it is not believed that 
study drug raises the risk for the patient to develop COVID-19. It is also not believed that a 
SARS-CoV-2 infection or clinically apparent COVID-19 impacts the activity of the 
investigational or comparator compound.
Every patient will be assessed thoroughly, and individual benefit-risk assessments will be
made prior to study entrance and during the study by the investigator in respect of SARS-
CoV-2 infection. The investigators will take the totality of information related to each patient 
and the local COVID-19 situation into consideration when performing the individual benefit-
risk assessment. Considering all aspects, the investigator will decide upon each patient’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 patient and the site environment.
For details on treatment related risks, refer to protocol section 1.2 and the IB.






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Table 1.4.2: 1
Overview over trial related risks (continued)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
visits as per Flow Chart 
(including phone visits). 
Refer to section 4.2.2.3 for 
more details regarding 
contraception counseling.
BI 1358894 Placebo
∀
Worsening of BoPD
∀
Occurrence or increase 
of suicidality
Even though mitigation 
measures are applied, this 
cannot be completely ruled 
out.
Frequency of visits with 
suicidality assessments are
optimized.
Suicidal patients will be 
excluded from trial 
participation (refer to section 
3.3.4.1)
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 
(paresthesia), impaired 
sensation of touch and 
persistent pain.
The total volume of blood
withdrawal per subject 
during the trial will be 
approximately 180 mL over 
20 weeks. This amount may 
be exceeded if additional 
unscheduled monitoring of
laboratory results is needed
(in case of necessary safety
follow-up).
Management of discomfort, 
evaluation, and follow-up as 
needed to ensure patient 
safety.




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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
The main objectives of this study are to provide PoC and dose-ranging data of BI 1358894 
compared to placebo in patients with BoPD to support dose selection for pivotal studies.
2.1.1
Main objectives
The primary study objectives are to demonstrate a non-flat curve, evaluate the dose-response
relationship and assess the treatment effect size.
The study will be performed to characterize the dose-response curve for BI 1358894 in 
patients with BoPD by assessing four BI 1358894 doses and placebo. The response is the 
change from baseline in ZAN-BPD at Week 10 summarized per arm by the adjusted mean.  
The multiple comparison procedure with modelling (MCPMod) approach will be used for the 
characterization of the dose-response curve.
The primary characterization will be on treatment which will assume all patients took 
randomized treatment for the duration of the study. See section 3.2 for justification of
assessing endpoints at Week 10. 
Assessments of secondary and further endpoints will also be performed to help support 
selection of a dose (range) and assess the treatment effect size.
2.1.2
Primary endpoint(s)
Change from baseline in ZAN-BPD total score at Week 10. 
2.1.3
Secondary endpoint(s)
ZAN-BPD
∀
Response defined as ≥30% ZAN-BPD reduction from baseline at Week 10.
Difficulties in Emotion Regulation Scale (DERS-16)
∀
Change from baseline in (DERS-16) total score at Week 10. 
State-Trait Anxiety Inventory (STAI-S)
∀
Change from baseline in STAI-S total score at Week 10.
Patient Health Questionnaire (PHQ-9)
∀
Change from baseline in PHQ-9 total score at Week 10.
Clinical Global Impression Severity scale (CGI-S)
∀
Change from baseline in CGI-S at Week 10. 
Patient Global Impression Severity scale (PGI-S)
∀
Change from baseline in PGI-S at Week 10.


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2.2.3
Safety
Safety will be assessed in patients who received at least one dose of study drug, including:
∀
Percentage of patients with (S)AEs (including clinically relevant abnormalities of 
physical examination, vital signs, ECG test and laboratory tests)
∀
Suicidality as assessed by C-SSRS
∀
Occurrence of protocol-specified adverse events of special interest (AESI)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a Phase II, 12-week multi-center, multi-national, randomized, double-blind, placebo-
controlled parallel-group trial in patients with BoPD. A targeted total of 355 patients with 
BoPD meeting the entry criteria are planned to be randomized into this trial. 
V = Visit, W = Week, FUP = Follow-up, EoT = End of treatment, EoTrial = End of trial
 = Telephone visit
Figure 3.1: 1
Study design
Patients will be enrolled into the trial once consent has been signed. Patients suitable after 
screening will be randomized to the 12-week double-blind treatment period at Visit 2 and will 
be assigned to placebo or one of the four treatment groups in 2.5:1:1:1:2 ratio (Figure 3.1: 1).
After the completion of the 12-week double-blind treatment period or following early 
discontinuation of trial medication at any point, patients will complete the 4-week follow-up 
period.  Individual patient participation is concluded when the patient has completed their last 
planned visit (End of Trial visit). Safety will be formally evaluated at each visit until the end 
of the observational period which is 28 days after the end of treatment or for a longer time in 
case of unresolved AEs.  


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is a randomized double-blind, placebo-controlled, parallel-design study. This design is 
appropriate for providing proof-of-concept and dose-ranging and assessing the safety and 
efficacy of BI 1358894 compared to placebo in patients with BoPD. It is important to have a 
placebo control to address potential confounding factors.
The design of the study will provide efficacy, safety and dosing information to support PoC. 
In order to achieve both aims in an efficient way the generalized MCPMod approach has 
been implemented as the statistical design. This approach is widely accepted (R15-1961, 
R19-1647) and is able to incorporate potential relationships between the different doses into 
the evaluations via optimal test contrasts and uses the available data better than the 
commonly applied pairwise comparisons. 
A total of four BI 1358894 doses were chosen to provide reasonable coverage for most
monotonic shapes. A sufficiently broad set of candidate shapes for the dose-response 
relationship has also been chosen. In addition, an unequal allocation ratio (2.5:1:1:1:2, 
PBO:5mg:25mg:75mg:125mg) has been selected for the treatment and placebo groups. An 
unequal allocation ratio will lead to better precision of the dose response modelling. In 
addition, increasing the proportion of patients in the placebo group compared to other 
treatment arms may lead to the observation of a greater separation between the placebo and 
active treatment arms (P09-01434). Details of the statistical approach including the set of 
candidate models as well as a sample size justification are given in section 7.
Efforts to avoid real or imagined abandonment is one of the core and most prominent 
symptoms of BoPD. Patients with BoPD experience intense fears of abandonment, which 
may result in inappropriate anger even when faced with a realistic short-term separation or 
when there are unavoidable changes in plans (R19-1313). This phenomenon has not been 
understood adequately in context of a large controlled clinical trial setting; however, the 
observation of loss of effect towards the end of a large global clinical study can be 
hypothetically explained on the basis of fear of abandonment (R19-1108). Anecdotally, 
clinicians are sensitive to issue of perceived abandonment towards the end or change of a 
therapeutic relationship with a patient with BoPD. 
Although this study is a 12-week treatment duration, we plan to evaluate the primary 
endpoint change in ZAN-BPD total score at Week 10, to avoid any potential issues related to 
perceived abandonment at the end of treatment period as explained above. 
All efficacy will be collected and assessed until Week 12, i.e. until the end of treatment. In 
addition, safety measures will be collected until end of trial. Collectively, this information 
will help facilitate the design of the Phase III program.


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3.3
SELECTION OF TRIAL POPULATION
The total of 355 patients are planned to be randomized into the study. It is planned that 
approximately 70 trial centers will be participating in this trial to ensure sufficient number of 
patients are randomized. 
It is expected that approximately 5-10 patients will be randomized at each trial center.  If 
enrollment is delayed, additional sites may be recruited. To avoid differential center influence 
on study results, permission to randomize more than 15 patients per site must be obtained 
from the sponsor. This will only be allowed after a careful review of the enrollment status 
and of the site.
Screening of patients for this trial is competitive, i.e., screening for the trial will stop at all 
centers when such a number of patients has been screened that it is anticipated that a 
sufficient number of patients will be randomized to trial treatment. Investigators will be 
notified when the screening is complete and will not be allowed to recruit additional patients 
for this trial. Patients who have completed Visit 1 procedures prior to notification of the 
termination of recruitment will be allowed to continue in the trial, if they meet all entry 
criteria and they are able to follow the visit schedule specified in the protocol.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not. If a patient is enrolled 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
Patients meeting diagnostic criteria of BoPD per Diagnostic and Statistical Manual of Mental 
Disorders (DSM-5) and diagnosis confirmed at time of screening by Structured Interview for 
DSM-5 Personality Disorder (SCID-5-PD) will be screened for suitability for the study.
Please refer to section 8.3.1 for the documentation requirements pertaining to the in- and 
exclusion criteria.
3.3.2
Inclusion criteria
1. Patients meeting diagnostic criteria of BoPD per DSM-5 at screening visit, confirmed by 
SCID-5-PD.
2. ZAN-BPD of ≥ 9 at screening (Visit 1) and randomization (Visit 2), with question #2 
Affective Instability score of ≥2.
3. Male or female patients, 18-65 years of age at the time of consent


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4. Women of childbearing potential (WOCBP) 1 able and willing to use two methods of 
contraception, as confirmed by the investigator, 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 (refer to section 4.2.2.3).
5. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
 
3.3.3
Exclusion criteria
1. Current diagnosis of paranoid, schizoid, schizotypal and antisocial personality disorders, 
as confirmed by SCID-5-PD at screening visit
2. Lifetime diagnosis for schizophrenia, schizoaffective disorder, schizophreniform disorder, 
bipolar I disorder, or delusional disorder as confirmed by the SCID-5 at the screening 
visit.
3. Any other mental disorder (in addition to those described in Exclusion 1 and 2) that is the 
primary focus of treatment in the last 6 months prior to randomization, as per the clinical 
judgement of the investigator. 
4. Inpatient stay or hospitalization due to worsening of BoPD within 3 months prior to 
randomization. 
5. Initiation or change in any type or frequency of psychotherapy (e.g. DBT, cognitive 
behavior therapy (CBT), Interpersonal therapy) for BoPD within 3 months prior to 
screening. Patients with ongoing, stable psychotherapy >3 months prior to screening (and
intend to maintain the same frequency during the study) may qualify as per clinical 
judgement of the investigator.
6. Any ongoing use of psychotropic medications within 7 days prior to randomization or 
during the course of study (unless allowed per protocol, see section 4.2.2.1). Investigators 
may use their clinical discretion to wash out (at least 3 half-lives of referenced 
medication) psychotropic medications during screening period. Such wash-out of ongoing 
psychotropic medication must complete at least 7 days prior to randomization.
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile.
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal occlusion/ ligation is NOT a method of permanent sterilization.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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7. Any suicidal behavior in the past 1 year (i.e. actual attempt, interrupted attempt, aborted 
attempt, or preparatory acts or behavior) prior to screening and during the screening 
period. 
8. Any suicidal ideation of type 4 or 5 in the C-SSRS in the past 3 months (i.e. active 
suicidal thought with intent but without specific plan, or active suicidal thought with plan 
and intent) prior to screening and during the screening period.
9. Any non-suicidal self-injury that leads to hospitalization within 3 months prior to
randomization.
10. Diagnosis of moderate or severe substance use disorder within the last 3 months of 
screening visit (as defined in DSM-5-substance use disorder) or at randomization visit. In 
case of a positive drug screen, patient may be considered for inclusion in the study, at the 
discretion of the investigator, if patient does not have moderate or severe substance use 
disorder as per DSM-5.
11. Use of alternative or traditional medicine (e.g. Chinese traditional medicine, herbal 
medication, St. John’s Wort, etc.) at the time of randomization and/or planned use during 
the course of the study.
12. Patients who must or wish to continue the intake of restricted medications (see section
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
13. Known history of HIV infection or positive result for active, ongoing Hepatitis B or C 
infection.
14. History of seizure disorders, stroke, brain tumor or any other major neurological or 
developmental illness 
15. Major surgery (major according to the investigator’s assessment) performed within 4
weeks prior to randomization or planned elective surgery requiring general anesthesia or 
hospitalization for more than 1 day during the study period, e.g. hip replacement.
16. 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.
17. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (that, in the investigator’s opinion, makes the patient an 
unreliable trial participant).
18. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
19. Clinically significant finding of the physical examination, vital signs [including blood 
pressure (BP) and pulse rate (PR)], ECG or laboratory value that would jeopardize the 
patient´s safety while participating in the trial or their capability to participate in the trial.
20. Symptomatic/unstable/uncontrolled or clinically relevant concomitant disease (e.g. renal 
failure, hepatic dysfunction, cardiovascular disease, etc.) or any other clinical condition 


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that would jeopardize the patient´s safety while participating in the trial or capability to 
participate in the trial.
21. 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 30 days or 5 half-lives of the 
investigational medicinal product, whatever is longer). 
22. Patients with an allergy to BI 1358894 and/or any of the excipients. A list of BI 1358894 
and placebo ingredients will be provided in the ISF.
 
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see sections 3.3.4.1 and 
3.3.4.2 below.
After premature study drug discontinuation, patients will be asked to further attend scheduled
trial visits unless they withdraw consent to participate in the study. If it is not possible to
attend all visits, at least phone contacts will occur at the scheduled visit time points (section
6.2.3). It is vital to explain to patients the importance of continuing trial participation and the
value of collecting data for all randomized patients. Measures to control the withdrawal rate 
include careful patient selection, appropriate explanation of the trial requirements and 
procedures prior to trial enrolment, as well as the explanation of the consequences of 
withdrawal. See section 6.2.3 for procedures handling early discontinuation and patient 
follow-up.
The decision to discontinue trial treatment or withdraw consent to trial participation, together 
with the reason, must be documented in the patient files and case report form (CRF). If 
applicable, consider the requirements for Adverse Event collection reporting (please see 
sections 5.2.6.2.1 and 5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:
∀
The patient wants to discontinue trial treatment, without the need to justify the decision.
∀
The patient has repeatedly shown to be non-compliant with 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 patient can no longer receive trial treatment for medical reasons (such as surgery, 
AE, or other diseases), per investigator’s clinical judgement.


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∀
The patient shows disease progression/worsening that precludes further participation in 
the trial per investigator’s clinical judgement.
∀
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 behavior (i.e. actual attempt, interrupted attempt, aborted attempt
or preparatory acts or behavior).
∀
Any Non-suicidal self-injury that impacts safety of the study participant and jeopardize 
continued participation in the trial as per the clinical judgement of investigator.
∀
Pregnancy occurs during the trial.
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 patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients should remain in the trial and, given 
their agreement, will undergo the procedures for early treatment discontinuation and follow-
up as outlined in the Flow Chart and section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see section 3.3.4.1.
Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
An unexpected and unusually high dropout rate.
Further follow up of patients affected will occur as described in section 3.3.4.1 and 6.2.2.
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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4.1.3
Method of assigning patients to treatment groups
After the assessment of all inclusion and exclusion criteria, each eligible patient will be 
randomized to treatment groups according to a randomization plan at Visit 2 via Interactive 
Response Technology (IRT). Note that the medication number is different from the patient 
number. Instructions for the use of IRT are provided in the ISF.
Patients will be randomly assigned by IRT, in a 2.5:1:1:1:2 ratio to one of these treatment 
groups: 
1. Placebo 
2. BI 1358894 5 mg qd
3. BI 1358894 25 mg qd
4. BI 1358894 75 mg qd
5. BI 1358894 125 mg qd
Patient assignment to the treatment groups will be determined by a computer-generated 
random sequence. Randomization sequence will be generated using validated randomization
software. Access to the randomization code will be controlled and documented.
Randomization will be stratified by baseline ZAN-BPD total score (≤18 vs. ≥19).
4.1.4
Drug assignment and administration of doses for each patient
The medication assignment will be provided through IRT. The assigned medication numbers 
must be entered in the eCRF, and the corresponding medication kits must be given to the 
patient. 
At Visit 2, after randomization, patients will receive their first medication kit. The first dose 
of trial medication will be taken at the study site under supervision of the investigator or site 
staff. At each dispensing visit (Visits 2, 5, and 7), patients will receive one medication kit 
containing supplies for a total of 35 treatment days (28 treatment days plus 7 days reserve).
Return of the used/unused medication kits will occur at Visit 5, 7 and EoT/eEoT.
Patients should be instructed not to take their trial medication in the morning of Visits 3, 4, 5, 
6, 7 and 8, as patients will be dosed at the site after pre-dose PK sampling. Patients should 
also be instructed not to take their trial medication in the morning of EoT visit, as a trough 
PK sample will be taken at that visit (approximately 24 hours after the last dose). For patients 
that complete the treatment period, the last dose of trial medication should be taken on the 


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day before the EoT visit. Patients who fail to do so should have the visit rescheduled as soon 
as possible, ideally on the following day.
Each dose will consist of 4 tablets (Table 4.1.5.1: 1). Patients should be instructed to take the
study medication orally with water and with or without food, every morning at approximately 
the same time. It is recommended that patients continue to take study medication in a 
consistent way, i.e. either with or without food. If a morning dose is missed by more than 12 
hours, that dose should be skipped and the next dose should be taken as scheduled. On days 
prior to a visit, the morning dose should be taken approximately 24 hours before the planned 
dose at the visit.
During the COVID-19 pandemic, there may be instances that will prevent a patient from 
going to the site for a study visit. If the investigator concludes that it is acceptable and safe 
for the patient to continue trial medication, it is permissible for the trial medication to be 
shipped from the site to the patient (for more details see section 6.2 and 10.3).
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Study medications will be administered double-blinded. In order to maintain blinding in 
regard to each treatment, each dose will contain 4 tablets in a double-dummy design, as 
shown in Table 4.1.5.1: 1. Double-dummy design is required since BI 1358894 tablets (5 mg, 
25 mg, 50 mg) are different sizes. Placebo tablets are identical in size and appearance to the 
corresponding active tablet and are combined with active tablets as needed in each dose 
group to maintain the blinding.
Table 4.1.5.1: 1
BI 1358894 and placebo tablets administration per dose group
Dose group
5mg 
tablet
25mg 
tablet
50mg 
tablet
Placebo
matching 
5mg tablet
Placebo
matching 
25mg tablet
Placebo
matching 
50mg tablet
Placebo
0
0
0
1
1
2
5 mg
1
0
0
0
1
2
25 mg
0
1
0
1
0
2
75 mg
0
1
1
1
0
1
125 mg
0
1
2
1
0
0
Patients, investigators, central reviewers, 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 after database lock, 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 patient completed to 
allow for the exclusion from the analyses of PK samples taken from placebo patients. 


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Bioanalytics will not disclose the randomization code or the results of their measurements 
until the trial is officially unblinded.
Dedicated database snapshots (no partial database lock (DBL)) will be generated prior to 
DBL to allow for development and refinement of population PK and exposure-response 
models (“Fast-track” PK/PD analysis). The exact time points for the data cut-offs will be 
aligned with general project planning. Details of this analysis will be defined in the PK/PD 
analysis plan. Only personnel involved in the population PK and exposure-response analyses 
will be granted access to the unblinded data before DBL, whereas the trial team and all other
functions not involved in the population PK and exposure-response analyses will remain 
blinded. The analysis plan for the population PK and exposure-response analyses will be 
finalized and signed prior to this database snapshot for ‘fast-track’ PK/PD analyses.
No formal interim report will be generated. Final PK and PK/PD analyses will be reported 
separately from the clinical trial report (CTR) after availability of data from DBL.
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 randomization code for individual patients during trial conduct. The access to the 
code will only be given to authorized 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. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP).
Initial study drug supplies will be sent to the site after the first patient is screened at the site.  
Re-supply to the sites will be managed via an IRT system, which will also monitor expiry 
dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies must 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.


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If the storage conditions are found to be outside the specified range, the process outlined in 
the ISF should be followed.
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 Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC),
∀
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 (for USA).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records in the ISF that adequately document the 
investigational medicinal product’s (IMP) delivery to the trial site, inventory at the site, and 
distribution to and return from each patient. On-site destruction or return of IMP to the 
sponsor/vendor must also be documented in the ISF. If applicable, the sponsor/vendor will 
maintain records of destruction for any returned IMP. 
These records must include the dates, quantities, batch/serial numbers, expiry (‘use- by’) 
dates, IMP kit numbers and patient numbers, as applicable. The investigator or designee must 
maintain records that adequately document the dose and amount of IMP distributed to each 
patients as specified in the protocol and must reconcile all investigational medicinal products 
received from the sponsor. Drug accountability at the site level will also be documented in 
the IRT. At the time of the final IMP return to the sponsor/ vendor, or the final destruction at 
the site, the investigator or designee must verify that all unused or partially used drug 
supplies distributed to patients have been returned by all patients and that no IMP supplies 
remain in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.




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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. 
Counseling about the importance of having birth control measures in place will be performed 
at study entry visit (during consenting process), informing women about the risk of 
medication-induced births defects when exposed to potentially teratogenic medication. 
Investigator must ensure that the patient understands the contraception requirements for the 
study and must confirm that the patient can reliably comply with contraception use during the 
study. Patients not expected to comply with contraception requirements should not be 
included in the study.
The importance of continuing with their chosen forms of birth control during study conduct 
will be emphasized to mitigate this risk and it must be reiterated at all visits as per Flow Chart
(including phone visits). This must include confirmation from the patient that she is using 
required contraception consistently and appropriately. If contraceptive protection cannot be 
confirmed, as judged by the investigator, the patient must be discontinued from the study 
drug. Study drug can be restarted only when contraception is used again, and sufficient 
protection is reached. Counseling and contraception confirmation must be recorded in CRFs.
Acceptable forms of contraception are:
One of the following 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).
Sexual abstinence as a contraceptive method will not be allowed for WOCBP who are 
heterosexually active.




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5.
ASSESSMENTS
The current status of BoPD will be assessed during the course of the trial by using the ZAN-
BPD (Zanarini rating scale for Borderline personality disorder) as the primary scores and, for
a wider perspective, with the outcomes of the DERS-16, STAI-S, PHQ-9, S-UPPS-P, CGI-S, 
PGI-S, EQ-5D-5L, and SDS scores. EcMA outcomes will be utilized as an additional source 
of information in an exploratory manner to examine its potential use in future trials.
5.1
ASSESSMENT OF EFFICACY
Zanarini rating scale for Borderline personality disorder (ZAN-BPD)
The ZAN-BPD scale has been widely used in borderline personality research in both 
academic and clinical research settings. The psychometric properties of the ZAN-BPD have 
been evaluated, and the results indicate that it is a sensitive scale for assessing changes in 
BoPD over time (R15-1332). The ZAN-BPD scale is based on the borderline module of the 
Diagnostic Interview for DSM-4 Personality Disorder (DIPD-4). Considering that there has 
been no change in the core diagnostic criteria for BoPD from DSM-4 to DSM-5, the ZAN-
BPD scale remains relevant as a clinical outcome measure for BoPD. 
The ZAN-BPD scale reflects the nine DSM-5 disease criteria and intrinsically aims to cover 
the entire symptomology of BoPD. The ZAN-BPD scale includes a 5-point rating scale (i.e., 
0 = No Symptoms to 4 = Severe Symptoms) for each criterion and measures frequency and 
severity of BoPD over time with a 1-week recall period. In addition, the scale has 4 sector 
scores that reveal reflect core areas of BoPD (i.e., affective, cognitive, impulsive and 
interpersonal symptoms). The total ZAN-BPD score is the sum of these 4 sector scores and 
ranges from 0 to 36. 
The ZAN-BPD scale will be administered as an interview in this study. This assessment 
should take approximately 25-30 minutes. The ZAN-BPD will be captured using the rater 
station/tablet provided by the vendor.
Difficulties in Emotion Regulation Scale – 16 item (DERS-16) 
The DERS is a widely-used, theoretically driven, and psychometrically sound self-report 
measure of emotion regulation difficulties (R19-1172, R19-1186). While the DERS was 
originally developed as a 36-item self-report measure, the brief, 16-item version (DERS-16), 
was developed to reduce patient burden (e.g. in larger studies and clinical trials that required
repeated assessments) (R19-1171). 
The DERS-16 is to be completed by the patient using the rater station/tablet provided by the 
vendor and should take about 5-8 minutes to complete. It consists of 16 items that assess the 
following dimensions of emotion regulation difficulties: non-acceptance of negative emotions 
(three items), inability to engage in goal-directed behaviors when distressed (three items), 
difficulties controlling impulsive behaviors when distressed (three items), limited access to 
emotion regulation strategies perceived as effective (five items), and lack of emotional clarity 
(two items). Respondents rate the extent to which each item applies to them on a 5-point 
Likert-type scale, where 1 is “almost never (0-10%),” 2 is “sometimes (11-35%),” 3 is “about 
half the time (36-65%),” 4 is “most of the time (66-90%),” and 5 is “almost always (91-


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100%).” Total scores on the DERS-16 can range from 16 to 80, with higher scores reflecting 
greater levels of emotion dysregulation.
The DERS-16 is completed by the patient, and should take approximately 5-8 minutes to 
complete. The DERS-16 will be captured using the rater station/tablet provided by the 
vendor.
State-Trait Anxiety Inventory (STAI)
The STAI has been used extensively in research and clinical practice (R98-0762). It is
comprised of separate self-report scales for measuring state and trait anxiety. For this study, 
only the state anxiety questions (STAI-S) will be used.
The STAI-S (STAI Form Y-1) consists of 20 item statements that evaluate how respondents 
feel “right now, at this moment.” All items are rated on a weighted score of 1 to 4 scale (e.g. 
from ‘Almost Never to ‘Almost Always’); with higher scores indicating greater anxiety.  
The STAI-S is to be completed by the patient and should take approximately 10-12 minutes 
to complete. The STAI-S will be captured using the rater station/tablet provided by the 
vendor.
Patient Health Questionnaire-9 (PHQ-9) 
The PHQ-9 is a 9-item brief self-reported tool used for screening, diagnosing, monitoring and 
measuring the severity of depression (R12-3115). The PHQ-9 asks patient ‘Over the last 
two weeks, how often have you been bothered by any of the following problems?’ in 
nine questions, with a maximum total score of 27. Depression Severity is assessed as: 
none (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), or severe (20-
27).
The PHQ-9 is to be completed by the patient and should take approximately 5 minutes to 
complete. The PHQ-9 will be captured using the rater station/tablet provided by the vendor.




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electronic data capturing (EDC) system). The amount of blood taken from the patient
concerned will be increased due to this additional sampling.
The results of various drug screens (e.g., cannabis, benzodiazepine, barbiturates, opiates, 
cocaine, amphetamines, methadone, PCP) will be captured in the clinical database to 
ascertain the use of drugs in this study population, impact of use on the recruitment failure 
rate and to assess the frequency of benzodiazepine use as sleeping aids.
The central laboratory will transfer the results of the analysis to the sponsor.
Table 5.2.3: 1 
Safety laboratory tests
Category
Test name
Hematology
Hematocrit
Hemoglobin
Red blood cell count/ erythrocytes
Reticulocyte count
White blood cells / leucocytes
Platelet count/ thrombocytes
MCV, MCH, RDW, MCHC
Erythrocyte sedimentation rate
Diff. Automatic
Neutrophils (relative and absolute count)
Eosinophils (relative and absolute count)
Basophils (relative and absolute count)
Monocytes (relative and absolute count)
Lymphocytes (relative and absolute count)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
Chemistry
AST
ALT
Alkaline phosphatase (AP)
Creatine kinase (CK)
CK-MB, only if CK is elevated
Gamma-glutamyl transferase (GGT/γ-GT)
Lactic dehydrogenase (LDH)
Lipase
Amylase
Calcium
Chemistry (continued)
Sodium
Urea (BUN)
Potassium
Glucose
Creatinine
eGFR
Bilirubin total, fractionated if increased
Protein, total
C-reactive protein
Cholesterol, total
Triglycerides
Free fatty acids
Insulin
TSH 1 (Reflex testing for T3 and T4 if TSH is positive)


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Table 5.2.3: 1 
Safety laboratory tests (continued)
Category
Test name
Hormones (male patients only)
LH
FSH
Testosterone
Urine (dipstick) pregnancy test (WOCB only) 2
Human chorionic gonadotropin
Serum pregnancy test (WOCB only) at screening 
or if urine pregnancy test is positive
Human chorionic gonadotropin 
Urinalysis (dipstick), with microscopic 
examination if urine analysis is abnormal
Color and clarity
Specific gravity
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Blood
Leukocyte esterase
Urine pH
Urinalysis
Albumin (quantitative)
Creatinine
Drug screening (urine)
Cannabis
Benzodiazepine
Barbiturates
Opiates
Cocaine
Amphetamines
Methadone
PCP
Infections screening 1
Hepatitis B surface antigen (qualitative) 
Hepatitis C antibody (qualitative)
Hepatitis C RNA – only if Hepatitis C antibody
(qualitative) is positive
1 Screening only
2 Completed locally on-site using kits provided by central lab.
Estimated glomerular filtration rate (eGFR) will be calculated using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation (2009).
5.2.4
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 subjects 
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 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.


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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 patient’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 Visit 1 should be reported as baseline conditions. Clinically relevant,
abnormal findings noticed after Visit 1 should be reported as AEs and followed up and/or 
treated locally until the condition returns to normal or becomes stable condition.
All ECGs will be transmitted electronically to the central ECG vendor in order to enable a 
centralized and independent re-evaluation of all 12-lead ECGs. A centralized and 
independent re-evaluation will be done.
Central evaluation on an individual ECG level will be performed by the vendor and a report 
will be provided to the site. Decisions on eligibility for the trial and treatment or further 
follow-up of any findings are in the responsibility of the investigator.
5.2.5
Other safety parameters
5.2.5.1
Assessment of suicidality
Suicidal risk will be assessed by the C-SSRS. The C-SSRS is a semi-structured, investigator-
rated interview, developed by clinical experts in cooperation with the FDA, assessing both 
suicidal 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 is completed by the interviewer and is captured using the rater station/tablet 
provided by the vendor.
The C-SSRS has been widely used in large multi-national clinical trials. The C-SSRS will be 
administered first at screening (Visit 1) (using the ‘Baseline / Screening’ version) with the 
aim to exclude subjects with active moderate or severe symptomatology within a specified 
time prior to screening. 
After screening (Visit 1) the assessment ‘since last visit’ will be performed at each clinic visit 
(‘Since Last Visit version’). The investigator is to review/consider the C-SSRS results for 
plausibility and clinical relevance. If the positive report is confirmed, appropriate actions for 
the subject’s safety have to be initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behavior, no suicidal intent’ standard AE / SAE reporting rules are to be 
applied.
For each C-SSRS report of suicidal ideation type 1, 2 or 3 after start of the trial, the 
investigator is to decide based on clinical judgment whether it represents an AE as defined in 
the protocol, and if it is considered an AE then it must be reported accordingly. Please note, 


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that AEs, that get coded to terms like suicidal depression, suicidal ideation, suicidal threat or 
similar, are on the “Always serious AE List” and therefore must be reported as SAEs (refer to 
section 5.2.6.1.3).
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀Worsening of the underlying disease or of other pre-existing conditions 
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
Regarding AEs in the context of suicidal risk assessment by C-SSRS, section 5.2.5.1 should be 
adhered.
5.2.6.1.2
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 patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalization or prolongation of existing hospitalization
-
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 jeopardize the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 


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For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the EDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
∀
An elevation of AST (Aspartate aminotransferase) and/or ALT (Alanine 
aminotransferase) ≥3 fold upper level of normal (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 patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the EDC 
system.  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 
analyzed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
No other AESIs have been defined for this trial.


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5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.6
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 study 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 etiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.


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5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
For patients who complete the treatment period, the following must be collected and 
documented on the appropriate CRF(s) by the investigator:
∀
From signing the informed consent onwards until the individual patient’s end of trial (the 
EoTrial visit): 
all AEs (serious and non-serious) and all AESIs. 
∀
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for 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 5.2.6.2.2), but not on the CRF.
For patients who discontnue treatment  prematurely and continue follow-up in the study (see 
section 6.2.3), the following must be collected and documented on the appropriate CRF(s) by 
the investigator:
∀
From signing the informed consent onwards until the 28 days after the last study drug 
administration:
all AEs (non-serious and serious) and all AESIs.
∀
After 28 days follow-up until the individual patient’s end of trial:
cancers of new histology and exacerbations of existing cancer, all trial treatment 
related SAEs and all trial treatment related AESIs.
∀
After the individual patient’s end of the trial: 
the investigator does not need to actively monitor the patient for new AEs but should 
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 5.2.6.2.2), but not on the CRF.
Patients who discontinue trial medication prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed up as described in section 3.3.4.1, 
withdrawal from trial treatment. From then on until the individual patient’s end of the trial the 
investigator must report all deaths/fatal AEs regardless of relationship, and trial treatment 
related SAEs and trial treatment related AESIs the investigator becomes aware of.
5.2.6.2.2
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 patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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5.4
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.
5.6
OTHER ASSESSMENTS
5.6.1
Confirmation of diagnosis
The Structured Clinical Interview for DSM-5 (SCID-5) will be used during screening for 
confirmation of the diagnosis of BoPD (SCID-5-PD) and to exclude patients with other 
psychiatric disorders (SCID-5-CT) as described in the exclusion criteria. The SCID-5 is a 
semi-structured interview guide for making the major DSM-5 diagnoses. 


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SCID-5 is administered as an interview and is captured on the paper form provided by the 
vendor.


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5.6.4
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


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of the vendor Verified Clinical Trials. This is a mandatory process where approval is received 
in accordance with local regulations.
Following proper informed consent and after issuing a study subject number, the participant’s
information will be checked against the Verified Clinical Trials database. Partial identifiers 
will be utilized. This will include checking a valid form of picture ID when available.
The first 3 letters of the participant’s first and last name will be entered along with the middle 
initial, date of birth, sex, and last 5 digits of that ID. If the status of the research subject is a 
‘Verification 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
All measurements performed during this trial are standard measurements 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.
Information about race should be obtained from all study participants as allowed by local
regulations. It is necessary to collect these data to assess consistency of treatment effects 
across different patient populations.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients 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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart. Additional details 
regarding visit procedures are provided below.
The following requirements for the conduct of the rating scales assessments need to be 
followed:
∀
The ZAN-BPD and CGI-S assessments should preferentially be done by the same 
rater for a given patient throughout the study period.
∀
During the assessments, patients are allowed to take short breaks as needed, in the 
judgement of the rater/investigator 
∀
The site staff must be properly trained and certified by the trial vendor and training 
documentation has to be filed in the ISF; 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 proper training of all members of the site staff involved in the 
neuropsychological assessments 
It must be reiterated at all visits per Flow Chart, that WOCBP must use the appropriate 
method of safe contraception according to section 4.2.2.3. 
During the COVID-19 pandemic, there may be instances that will prevent a patient from 
going to the site for a study visit. This may be, for example, due to restrictions set by 
authorities or by the investigator site/institution, because the patient is quarantined, or 
because of any patient-specific situation that the investigator judges as being not safe for the 
patient to come to the site. 
For details on potential modifications of the trial conduct related to the COVID-19 pandemic, 
please refer to section 10.3.
6.2.1
Screening and run-in period(s)
Informed Consent for trial participation
All patients must sign an Informed Consent consistent with ICH-GCP guidelines prior to any 
study specific procedures. Please refer to section 8.1 for details.




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Substance use, e.g., nicotine, alcohol, caffeine, cannabis, etc., will be collected at screening 
and at subsequent clinic visits. Please refer to the current CRFs for details about substance 
use to be collected.
IRT
All patients who are screened must be registered with IRT. If the screening results in a screen 
failure, patient must be recorded as screen failure in IRT as soon as possible and within the 
28-day screening period. Details of IRT procedures can be found in the IRT Manual filed in 
the ISF.
Eligibility Review
Eligibility assessment will be performed by an external vendor based on clinical review of the 
SCID-5-CT, SCID-5-PD and ZAN-BPD data and audio recordings from the screening visit, 
in regard to certain inclusion and exclusion criteria. Uncertainties identified by the external 
clinical reviewer related to inclusion/exclusion criteria will be discussed with the rater. In 
cases where an agreement on a patient’s assessments cannot be reached between the site and 
the external reviewer, the patient should not be randomized. At the conclusion of the 
eligibility review, the vendor will send a Subject Eligibility Notification to the site. The 
Subject Eligibility Notification will indicate whether the patient is “eligible” or “ineligible” to 
proceed to the next steps toward randomization (pending results of other screening
procedures). 
Retesting
Screening evaluations may be repeated once during the screening period. 
Rescreening
Rescreening of patients may be done only once based on investigator judgement and prior 
permission from CTL. Patient who are re-screened need to be re-consented and will be given 
a new patient number. All the study procedures for screening (Visit 1) must be repeated.
Potential reasons for rescreening could be: 
∀
Suicidality (once the required EX period is over) (EX 7, 8)
∀
Substance abuse (EX 10)
∀
Restricted meds like CYPs/ alternative or traditional medicine (EX 11, 12)
∀
Clinically significant findings per Investigators judgement (EX 19, 20)
6.2.2
Treatment period
General remarks
After all the screening procedures have been completed and eligibility of screened patients is 
confirmed, Visit 2 can be conducted including randomization via IRT. IRT should not be 
called in advance of Visit 2 until eligibility is fully confirmed, as randomization of a patient 
cannot be reserved.
Unscheduled visits will be possible at the discretion of the investigator at any time in order to 
check the safety of the patient or to perform safety laboratory assessments.






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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The primary trial objective of this Phase II trial includes demonstration of PoC of the clinical 
activity of BI 1358894 with respect to a non-flat dose response curve, characterization of the 
dose-response relationship by assessing 4 doses and placebo, and selection of the dose range 
for phase III development. For this purpose, the primary analysis uses methodology for dose
finding employing both multiple comparison procedures and modelling techniques 
(MCPMod) to analyze 4 doses of BI 1358894 and placebo (R10-1424). In addition, the 
benefit of BI 1358894 compared to placebo will be evaluated. 
As a basis for the MCPMod analysis, a mixed model for repeated measure (MMRM) analysis 
will be used to generate covariate adjusted estimates of mean change from baseline to Week 
10 in ZAN-BPD total score and associated covariance matrices. These estimates will be used 
as the basis for the PoC analysis using MCPMod. If PoC is established, dose response models 
will be evaluated to select suitable doses for confirmatory testing in future studies.
7.1
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis is that there is a flat dose response curve comparing the placebo and the 
BI 1358894 dose groups. The alternative hypothesis is that there is a non-flat dose response 
curve indicating a benefit of BI 1358894 over placebo.
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, while protecting the overall probability of Type I error, using a one-sided, 
nominal α level of 10%. The pre-specified models and their parameters used for this test are 
outlined in section 7.2.2.
7.2
PLANNED ANALYSES
7.2.1
General considerations
Tabulations of frequencies for categorical data will include all possible categories and will
display the number of observations in a category as well as the percentage (%) relative to the
respective treatment group. The category “missing” will be displayed where applicable (i.e.,
if and only if there are actually missing values in the data). 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.
For in-text tables, the set of summary statistics is: N (number of patients with non-missing
values), mean, standard deviation (SD) or median, Q1, Q3, depending on the data. For end-
of-text tables, the set of summary statistics is: N/Mean/SD/Q1 (lower quartile)/Median/Q3 
(upper quartile). For appendix tables, the set of summary statistics is:
N/Mean/SD/Min/Q1/Median/Q3/Max.
Analysis sets defined for this trial include the full analysis set (FAS) and the treated set (TS). 
The FAS comprises all randomized patients who received at least one dose of trial medication 


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during the trial and had a baseline observation recorded. Unless otherwise specified, efficacy 
analyses will be performed on the FAS and will be based on assigned treatment. Full 
specifications for the FAS will be provided in the Trial statistical analysis plan (TSAP).
Safety analyses will be conducted on the TS, which includes all randomized patients who 
have received at least one dose of the trial medication. Safety analyses will be conducted 
using actual treatment received. Data from patients 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 analyses
As defined in section 2.1.2, the primary endpoint is the change from baseline to Week 10 in 
ZAN-BPD total score. Baseline refers to the measurement recorded at randomization (Visit 
2), if data at Visit 2 is missing, then data from Visit 1 will be considered baseline. 
The primary estimand of interest is the treatment effect assuming all subjects remained 
adherent to the assigned trial medication and the study protocol using a hypothetical 
approach, i.e. study drug is taken as directed. The primary analysis of the primary endpoint 
will include all data collected while on treatment which is defined as the time from the date 
of the first dose of trial medication until the date of the last dose of trial medication plus 7 
days (3 times the estimated elimination half-life). Any data collected after a patient 
discontinues trial drug, regardless of reason, will be censored and will not be included in the 
primary analysis. 
The analyses for PoC and dose-finding will be performed using multiple comparison and 
modelling techniques (MCPMod). MCPMod is used to evaluate several possible dose 
response models (patterns) and to identify the best-fitting model or subset of models based on 
the BI 1358894 and placebo treatment groups while keeping full control of the type I error at 
10%, one-sided. The primary endpoint will be analyzed using a mixed model repeated 
measures model (MMRM) which is valid under the missing at random (MAR) assumption.
Under the MMRM model, there’s no explicit imputation of missing data, rather, the future 
statistical behavior of those participants who drop out given their past measurements is 
assumed to be the same as those who remain with the same history.
In particular, between-treatment differences in the change in ZAN-BPD total score at Week 
10 (from baseline) will be evaluated using a MMRM adjusted for treatment arm, clinical visit 
and baseline ZAN-BPD total score. In addition, participants will be included in the model as 
a random effect. Additional covariates (such as stable concomitant psychotherapy use 
(yes/no) and sex) or factors identified prior to database lock may be included in the MMRM 
model as applicable. 


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The primary treatment comparisons will be the contrasts between each BI 1358894 treatment 
arm and placebo at Week 10. Procedures to be followed if the planned analysis fails to 
converge will be described in the TSAP. Resulting adjusted estimates from the MMRM will 
then be extracted for use in the MCPMod analysis. Parameter estimation of the MMRM will
be based on the residual maximum likelihood method (REML). 
For the PoC testing and for the sample size calculations, the basic shape of each of the 
models to be tested must be predefined. The candidate models in Table 7.2.2.1: 1 were
selected to cover a plausible and diverse range of dose response patterns for the trial 
medication. Associated graphs of each model are shown in Figure 7.2.2.1: 1.
Table 7.2.2.1: 1
Models for the MCPMod analysis
Model
Estimate
Rationale
Emax1
50% of the maximum effect is 
achieved at 25 mg
Emax curve corresponds the assumed true estimate of 
ED50=25 mg.
Emax2
70% of the maximum effect is 
achieved at 5 mg
To cover the possibility for which 70% of the 
maximum effect is achieved at 5 mg. This is a 
scenario in which much of the effect is achieved early 
on with relatively low doses. The rationale behind the 
two Emax models is to construct one (emax1) where 
the dose response is achieved as expected, while the 
other (emax2) accounts for the setting of which the 
assumed dose response is not as expected.
Sigmax
50% of the maximum effect is 
achieved at 25 mg, and
90% of the maximum effect is 
achieved at 75 mg
Another more flexible model to cover the new 
estimate ED50=25 mg
Exponential
5% of the maximum effect is 
achieved at 25 mg
To cover the case where the effect of drug is mainly 
achieved at the higher doses.
Linear
No parameter assumptions required
In the event, dose response is linear.
The models were based on the following assumptions:
∀
BI 1358894 dose groups 5mg, 25mg, 75mg, 125mg and 
∀
ED50 = 25 mg *
* ED50 assumes dose corresponding to EC50, FST = 77nM plasma concentration in trough at 16h.
EC50: Half maximal effective concentration
EC50 of a graded dose response curve represents the concentration of a compound where 50% of its maximal effect is 
observed.
FST: forced swim test (in mice)
A non-flat dose response is established if at least one dose response pattern is statistically 
significant, rejecting the null hypothesis of a flat dose response relationship over change from 
baseline to Week 10 in ZAN-BD total score jointly for each of the candidate models with a 
contrast test controlled for the family-wise type I error rate at one-sided α = 10%.


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If a non-flat response is established, the statistically significant (i.e., best fitting) model(s) are 
refitted to the data to generate new estimates for all model parameters. The final model will 
be obtained via model averaging across the significant models based on Akaike Information 
Criteria. The target dose(s) can be estimated from each significant model by incorporating 
information on the minimum clinically relevant effect. Safety will be taken into account in 
the selection of a target dose(s).
Figure 7.2.2.1: 1
Shape of the considered dose response patterns for the MCPMod 
analysis
If considered necessary and for the purpose of further model refinement, MCPMod might be 
repeated on the primary endpoint but with an extended set of shapes including the original 
candidates.
Sensitivity analyses to assess the robustness of the primary analysis outcomes to the 
assumption of MAR will be described in the TSAP. 


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7.2.3
Secondary endpoint analyses
ZAN-BPD response
The secondary endpoint of ZAN-BPD response (defined as ≥30% ZAN-BPD reduction from 
baseline at Week 10) is a binary endpoint. This endpoint will be analyzed through a logistic 
regression model to obtain an estimate of the population odds ratio and associated CIs


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between BI 1358894 and placebo. This statistical model may be adjusted for factors that may 
influence response to treatment for BoPD, such as baseline ZAN-BPD total score (≤18 vs 
≥19), stable concomitant psychotherapy (yes/no), and sex (male/female).
DERS-16
The secondary endpoint of change from baseline in DERS-16 total score at Week 10, will be 
analyzed by a MMRM model similar to that of the primary efficacy endpoint.
STAI-S
The secondary endpoint of change from baseline in STAI-S total score at Week 10, will be 
analyzed by a MMRM model similar to that of the primary efficacy endpoint.
PHQ-9
The secondary endpoint of change from baseline in PHQ-9 total score at Week 10, will be 
analyzed by a MMRM model similar to that of the primary efficacy endpoint.
PGI-S
The secondary endpoint of change from baseline in PGI-S will be summarized by treatment 
arm as follows. Mean change from baseline to Week 10 and standard deviation will be 
presented. In addition, the frequency and proportion of patients reporting each response 
category at baseline and at Week 10 will be displayed. To compare change in severity as 
assessed by the PGI-S between the BI 1358894 treatment arms and placebo, an MMRM 
model similar to the model described for the primary efficacy analysis will be used. 
CGI-S
The secondary endpoint of change from baseline in CGI-S at Week 10 will be analyzed in a 
similar fashion as PGI-S (described above).


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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 period of 28 days after the last dose of 
trial medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of 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’.
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 MedDRA
at database lock.
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 patients with abnormal values or clinically 
relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.


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7.2.7
Interim Analyses
No interim analysis is planned. A Data Monitoring Committee (DMC) will review safety data 
during the trial as described in section 8.7.
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 the primary analysis of the 
primary endpoint, missing data will not be imputed. Data collected after discontinuation of 
trial medication will be censored for the primary analysis. The mixed effects model will 
handle missing data based on a likelihood method under the assumption of missing at 
random. 
For the supplemental analysis of the primary endpoint based on a treatment policy estimand, 
i.e. intention to treat, all available data including data collected after treatment 
discontinuation or other intercurrent event will be analyzed. 
Sensitivity analyses may be conducted utilizing multiple imputation techniques 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 


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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 in a 2.5:1:1:1:2 ratio as described in 
section 4.1.3. Randomization will be stratified by baseline ZAN-BPD total score (≤18 vs.
≥19).
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 pseudo-
random 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 (CTR). Access to
the codes will be controlled and documented as described in section 4.1.5.1.
7.5
DETERMINATION OF SAMPLE SIZE
Sample size is estimated assuming a maximum standardized effect size of 0.32, which is 
based on a mean difference between placebo and BI 1358894 of 3.0 and standard deviation of 
9.5 for the primary endpoint, a one-sided alpha of 0.10, a treatment allocation ratio of 
2.5:1:1:1:2 (placebo, BI 5mg, BI 25mg, BI 75mg, BI 125mg, respectively) and the pre-
specified models listed in section 7.2.2.1. Information on the change from baseline and its 
standard deviation is limited since there is no BoPD approved drug. BoPD is a symptomatic 
and clinically heterogeneous condition and in clinical studies a high discontinuation rate has 
been observed. Consequently, sample size assumptions are based on expert opinion, previous 
BoPD research and a quetiapine pivotal trial (R19-1108, R19-1645, P11-04859).
For the PoC analysis of the BI 1358894 dose groups and placebo using MCPMod approach 
with the parameters as listed in section 7.2.2, a sample size of 285 (95:38:38:38:76) evaluable 
patients are needed to establish PoC with about 81% average power (one-sided 10% alpha 
level). The powers for each model shape under different assumptions are summarized in the 
table below.
Assuming a 20% dropout rate is considered reasonable based on unique characteristics of this 
population. Therefore, a total sample size of approximately 355 randomized patients are 
needed for this phase II trial:
∀
119 patients in placebo arm
∀
47 patients in each of the three lowest BI 1358894 arms
∀
95 patients in the highest BI 1358894 arm 
The calculations for the PoC step have been performed using DoseFinding R-package (R15-
2001).The R codes for the sample size calculations as well as the analyses using the 
MCPMod approach will be provided in the TSAP. The family–wise type I error rate at one 
sided α = 10% is controlled in the sample size calculations and the analyses.


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Table 7.5: 1
Power of MCPMod for each candidate set model and average power 
for change from baseline in ZAN-BPD at Week 10
Model
Assumption A
Assumption B
Assumption C
Maximum 
effect size
0.32
(Mean=3, 
SD=9.5)
0.35
(Mean=3.3, 
SD=9.5)
0.38
(Mean=3.6, 
SD=9.5)
Linear
81.9%
86.7%
91.6%
Emax 1
81.7%
87.7%
91.6%
Emax 2
75.2%
82.7%
86.6%
Sigmax
85.4%
89.1%
93.7%
Exponential
81.0%
85.8%
90.5%
Average
81.1%
86.4%
90.8%


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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, the EU directive 2001/20/EC / EU regulation 536/2014, the Japanese GCP 
regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997) and other 
relevant regulations. Investigators and site staff must adhere to these principles. Deviation 
from the protocol, the principles of ICH GCP or applicable regulations as will be treated as 
“protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The 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, if required locally, is made available to the investigator
and the patients, and is stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 


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informed consent form after confirming that the patient understands the contents. The 
investigator or his delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
If study conduct needs to be adjusted (see sections 4.1.4, 6.2 and 10.3) during the COVID-19 
pandemic, patients must be made aware of any modifications and their consent needs to be 
obtained prior to implementation.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
In order to achieve a high level of process standardization, data collection of 
neuropsychological assessments will be coordinated centrally by a third party vendor. 
Services to be provided include:
∀
Rater pre-qualification
∀
Rater training (face-to-face and online)
∀
Provision of rater materials
∀
Central quality review of the SCID-5-CT, SCID-5-PD and ZAN-BPD assessments. For 
this purpose, SCID-5-CT, SCID-5-PD and ZAN-BPD interviews will be recorded (audio 
only).
Details of raters’ pre-qualifications, raters’ training, raters’ materials (including assessments) 
and the central review procedures will be described in the vendor documentation available in 
TMF. 
All data corrections to rating assessments requested by the sites will be processed and tracked 
by the vendor. Data corrections made to rating assessments will be reviewed by a vendor


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clinician. Access to the system is restricted to authorized users, each with a unique username 
and password. All data collected in, and access to, the system is captured in an audit trail, 
which includes an unalterable time and date stamp and the authorized user’s identification for 
each data point and action.
In addition, patients will be offered to watch a short informational video intended to educate 
the patient about placebos, and why they are used in clinical trials. The video advises the 
patient 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 placebo, and stresses the 
importance of reporting all symptoms, be they positive or negative or neutral.
8.3
RECORDS
eCRFs for individual patients will be provided by the sponsor. See section 4.1.5.2  for rules 
about emergency code breaks. For drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail). Data reported on 
the eCRFs must be consistent with the source data or the discrepancies must be explained.
Electronic records, i.e. clinician administered assessment data, related audio recordings (for 
central review) and patient reported outcome data, entered into the tablet (Rater Station) will 
be regarded as source data. These may be further analyzed by the third-party vendor. 
The electronic version of the ECG is regarded as source documentation. Dated and signed 
printouts should be stored in the patient’s medical file.
In case local laboratory is used for ESR or due to COVID-19 related variations, local 
laboratory results report will be considered as source document. The investigator must 
maintain in the ISF both local laboratory results and corresponding reference ranges. 
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least three documented attempts to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)


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∀
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (indication, start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with proper 
documentation of medical evaluation (in validated electronic format, if available)
∀
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to allocation of a patient 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 patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria, does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
the 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 PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the World Health 
Organization (WHO) GCP handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalized treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated 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-purpose documentation (biomarker proposal, analysis plan and report) to 
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 patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient 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 patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A DMC will be established. Members of the DMC are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician. 
The main focus of the DMC will be the evaluation of safety data. Efficacy data may be 
reviewed if requested by the DMC to support risk/benefit assessment. The DMC will receive 
urgent, significant, safety concerns and DILI, for immediate evaluation. While DMC 
members may be unblinded, measures are in place to ensure the blinding for everyone else
involved in the trial. Regular DMC meetings will be held at specified intervals. The DMC 
will recommend continuation, modification or termination of the trial as detailed in the DMC 
charter. DMC recommendations as well as the final BI decision will be reported to the 
appropriate Regulatory Authorities (RAs)/Health Authorities (HAs), IRBs/ECs, and to 
investigators as requested by local law. The tasks and responsibilities of the DMC are 
specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal, Clinergize, to access documents 
provided by the sponsor. If applicable, in addition to the protocol, approved and effective 
local protocol amendment(s) should be followed by investigators.
BI has appointed a Clinical Trial Leader (CTL), 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,


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∀
ensure appropriate training and information of Clinical Trial Managers (CT Managers), 
CRAs, and investigators of participating countries.
The organization of the trial in the participating countries will be performed by the respective 
local or regional BI-organization (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organization (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 organize, 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, 
scales administration management, 
. Details will be 
provided in the respective manuals available in the ISF. Bioanalysis of BI 1358894 will be 
done by a vendor.








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R19-1186
Gratz KL and Tull MT. Emotion regulation as a mechanism of change in 
acceptance and mindfulness-based treatments. In: Baer RA. Assessing 
mindfulness and acceptance: Illuminating the processes of change. 
Oakland, CA: New Harbinger Publications; 2010.
R19-1313
Palihawadana V, Broadbear JH, Rao S. Reviewing the clinical significance 
of 'fear of abandonment' in borderline personality disorder. Australas 
Psychiatry 2019;27(1):60-63.
R19-1550
Paris J. Making psychotherapy for borderline personality disorder 
accessible. Ann Clin Psychiatry 2015;27(4):297-301.
R19-1645
Crawford MJ, Sanatinia R, Barrett B, Cunningham G, Dale O, Ganguli P, et 
al, LABILE Study Team. The clinical effectiveness and cost-effectiveness 
of lamotrigine in borderline personality disorder: a randomized placebo-
controlled trial. Am J Psychiatry 2018;175(8):756-764.
R19-1647
Request for qualification of MCP-Mod as an efficient statistical
methodology for model-based design and analysis of phase II dose finding 
studies under model uncertainty (applicant: Janssen Pharmaceuticals and 
Novartis Pharmaceuticals, application date: 22 April, 2015). 
https://www.fda.gov/media/99313/download (access date: 13 May 2019); 
U.S. Food and Drug Administration (FDA), Office of Clinical 
Pharmacology (OCP), Division of Pharmacometrics; 2015.
R19-1931
Bushnell DM, McCarrier KP, Bush EN, Abraham L, Jamieson C, 
McDougall F, et al, PRO Consortium's Depression Working Group. 
Symptoms of Major Depressive Disorder scale (SMDDS): performance of a 
novel patient-reported symptom measure. Value Health, Published online: 
May 17, 2019, doi: 10.1016/j.jval.2019.02.010; 2019.
R19-1932
Busner J, Targum SD. The Clinical Global Impressions scale: applying a 
research tool in clinical practice. Psychiatry (Edgemont) 2007;4(7):28-37.


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R19-4069
Hanke N, Frechen S, Moj D, Britz H, Eissing T, Wendl T, et al. PBPK 
models for CYP3A4 and P-gp DDI prediction: a modeling network of 
rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and 
digoxin. CPT Pharmacometrics Syst Pharmacol 2018;7:647-659.
9.2
UNPUBLISHED REFERENCES
c10354149-06
BI 1358894 Investigator's Brochure, Version No. 6, 31 January2020


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10.
APPENDICES


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10.3
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19
As mentioned in section 6.2, in case of any restrictions during the COVID-19 pandemic, 
study conduct may need to be adjusted. The following contingency measures have been 
introduced to ensure participant safety and appropriate trial continuation based on a thorough 
benefit-risk assessment (see section 1.4.2). In addition, collection of efficacy COAs remotely 
would support evaluation of study endpoints, with the focus on the primary and secondary 
endpoints, by reducing missing data. 
Accordingly, when it is impossible to conduct the visits at the trial site, visits may be 
performed via telemedicine (video-enabled internet-based means of communication or audio 
only) or at the patient’s home (e.g., by a study nurse). Visits may also be performed as a 
combination of home visit and telemedicine. For such cases, the visit procedures may be 
adjusted, after evaluation of operational feasibility and minimal required data (i.e. primary 
/secondary /exploratory endpoints. etc.), whereby critical safety measures will remain in 
place. All telemedicine/home visits must be discussed with and approved by the sponsor`s 
trial team.
Local regulatory and legal requirements of the participating country must be respected for all 
modifications. Under these circumstances, the below modifications can be considered. 
Patients must be informed about the modifications and give their consent before 
implementation.
Telemedicine visit
For telemedicine visits, video is the preferred mode. Every effort should be made to conduct 
the telemedicine visit via video. If for a visit, video communication is not possible, then 
assessments can be performed via audio. The mode of administration (i.e., in person, video, 
or audio only) will be recorded in the eCRFs.
Prior to implementing telemedicine visits, sites/raters will receive additional training on the 
administration of assessments remotely. The objectives of the training will be to standardize 
the administration of the assessments and ensure consistent monitoring of patient safety in a 
remote setting. Instructions on the logistics, recommended interview environment, and the 
identity verification plan will also be addressed in the training. The training will also include 
patient safety measures for telemedicine visit. At the beginning of each telemedicine visit, 
Telemedicine Checklist (available in the ISF) must be completed.
Prior to the first telemedicine visit, sites should conduct a brief session with the patient to 
evaluate the technology and connectivity requirements for the remote visit. 
The following should be ensured for remote visits:
∀
Raters must conduct telemedicine visit from a suitable location to protect patient privacy 
and confidentiality
∀
Identification of the reviewer and the patient must be confirmed
∀
Confirm patient’s location in case of emergency identified during the remote visit






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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
08-Dec-2020
EudraCT number
EU number
2020-000078-12
BI Trial number
1402-0012
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A phase II randomized, double-blinded, placebo-
controlled parallel group trial to examine the 
efficacy and safety of 4 oral doses of BI 1358894 
once daily over 12 week treatment period in 
patients with borderline personality disorder
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Flow chart
3.1
OVERALL TRIAL 
6.2.2
Treatment period
Description of change
Flow chart:
Rename EoT visit to Visit 9/EoT
Added footnote #19
Figure 3.1:1 was modified to rename EoT visit to 
Visit 9/EoT
End of Treatment (EoT) Visit
Was changed to:
Visit 9 / End of Treatment (EoT) Visit
For patients completing the 12-week treatment, 
this visit will be EoT visit. For patients who 
discontinue study treatment prematurely and 
continue with study visits, this visit will be Visit 
9 when they reach Week 12.
… Week 12 (EoT visit) …
Was changed to:
… Week 12 (Visit 9) …
Rationale for change
For patient who continue with study visits after 
discontinuing study drug, this visit will be Visit 9 
when the reach week 12.
This was included in the Administrative letter #1
07-May-2020.








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Urine RBC/ erythrocytes
Urine WBC/ leukocytes 
Was changed to:
Blood
Leukocyte esterase
“Urine-Sediment” section was deleted.
Rationale for change
Urinalysis section was revised to align with
central laboratory reporting.
Section to be changed
6.2
DETAILS OF TRIAL PROCEDURES 
AT SELECTED VISITS 
Description of change
• Each assessment of the rating scales should 
preferentially be done by the same rater …
Was changed to:
• The ZAN-BPD and CGI-S assessment should 
preferentially be done by the same rater …
Rationale for change
Clarification
Section to be changed
6.2
DETAILS OF TRIAL PROCEDURES 
AT SELECTED VISITS 
Description of change
Last two paragraphs were added.
Rationale for change
Description of alternate study procedures in case 
of COVID-19 restrictions.
Section to be changed
6.2.1
Screening and run-in period(s)
Description of change
Subject Eligibility Review section was added.
Rationale for change
Addition of eligibility verification by the vendor.
Section to be changed
6.2.2
Treatment period
Pharmacokinetic blood sampling
Description of change
The PK blood sampling times are given in 
Appendix 10.1. The actual time of drug 
administration and blood samplings must be 
recorded in the eCRF. Time of the last drug 
administration on the day before PK sampling 
must be recorded in the eCRF.
Was changed to:
The PK blood sampling times are given in 
Appendix 10.1. The actual date/times of drug 
administration and blood samplings must be 
recorded in the eCRF.  
Rationale for change
Clarification
Section to be changed
6.2.2
Treatment period




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conduct and will be summarized in the CTR as 
defined in the TSAP.
Rationale for change
Clarification request from Health Authority.
Section to be changed
7.2.2.1 Primary analyses
Description of change
The following sentence was deleted:
The Kenward-Roger approximation will be used 
to estimate the denominator degrees of freedom 
and adjusted standard errors. Significance tests 
will be based on least-square (LS) means using a 
two-sided α = 0.10 (two-sided 90% confidence 
intervals).
Rationale for change
Clarification request from Health Authority.
Section to be changed
ABBREVIATIONS
7.2.6
Other Analyses
Description of change
The following abbreviation was deleted:
MCID
MCID
Was changed to:
Within-patient change
Rationale for change
Correction
Section to be changed
8.1
TRIAL APPROVAL, PATIENT 
INFORMATION, INFORMED CONSENT
Description of change
The following sentence was added:
If study conduct needs to be adjusted (see 
sections 4.1.4, 6.1 and 10.3) during the COVID-
19 pandemic, participants must be made aware of 
any modifications and their consent needs to be 
obtained prior to implementation.
Rationale for change
Description of alternate study procedures in case 
of COVID-19 restrictions.
Section to be changed
8.2
DATA QUALITY ASSURANCE
Description of change
Last three paragraphs were added.
Rationale for change
To provide additional information regarding 
raters’ qualification and raters’ system access.
Information regarding placebo video.
Section to be changed
8.7
ADMINISTRATIVE STRUCTURE OF 
THE TRIAL 
Description of change
The DMC will evaluate safety and efficacy data. 
Was changed to:


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The main focus of the DMC will be the 
evaluation of safety data. Efficacy data may be 
reviewed if requested by the DMC to support 
risk/benefit assessment. 
Rationale for change
Clarification regarding DMC review of study 
data.
Section to be changed
8.7
ADMINISTRATIVE STRUCTURE OF 
THE TRIAL 
Description of change
The following sentence was added:
If applicable, in addition to the protocol, 
approved and effective local protocol 
amendment(s) should be followed by 
investigators.
Rationale for change
Request from Health Authority.
Section to be changed
10.2.5 Endpoints
Description of change
List of sub-study endpoint was revised.
Rationale for change
Correction
Section to be changed
ABBREVIATIONS
10.3
POTENTIAL MODIFICATION OF 
TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19
Description of change
The following abbreviation was added:
PCR
Section 10.3 was added.
Rationale for change
Description of alternate study procedures in case 
of COVID-19 restrictions.
11.2
GLOBAL AMENDMENT 2
Date of amendment
28-Jun-2021
EudraCT number
EU number
2020-000078-12
BI Trial number
1402-0012
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A phase II randomized, double-blinded, placebo-
controlled parallel group trial to examine the 
efficacy and safety of 4 oral doses of BI 1358894 
once daily over 12 week treatment period in 
patients with borderline personality disorder
Global Amendment due to urgent safety reasons


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Global Amendment
X
Section to be changed
10.3
POTENTIAL MODIFICATION OF 
TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19
Description of change
Multiple changes and additions throughout the 
section
Table 10.3: 1 was added
Rationale for change
Addition of telemedicine visits
To allow the use of local laboratory in case of 
COVID-19 related kit shortage
Section to be changed
7.2.2.2 Sensitivity analyses for the primary 
analysis of the primary endpoint  
Description of change
The section header was deleted.
The following text was added:
Implementation of telemedicine due to COVID-
19 – primary analysis
In this study, telemedicine refers to the 
administration of assessments via video or audio, 
please see Section 10.3 for further details. 
If telemedicine assessments need to be 
implemented due to COVID-19 related factors, it 
will be assumed that there is no discernible 
difference between the in-person and 
telemedicine (video) administration of the ZAN-
BPD. All data while patients are on treatment, 
whether in-person or telemedicine (video) will be 
included in the evaluation of the primary 
endpoint. However, any ZAN-BPD assessment 
conducted by audio administration will be 
excluded from the primary analysis. Any data 
collected after a patient discontinues trial drug, 
regardless of reason, will be censored and will not 
be included in the primary analysis.
Sensitivity analyses for the primary analysis of 
the primary endpoint - telemedicine
If telemedicine assessments need to be 
implemented, sensitivity analyses of the primary 
endpoint will be performed to assess the 
robustness of the primary analysis results.  The 
sensitivity analyses will assess the integration of 
the different modes (i.e., in-person, video, and 
audio) for administrating the ZAN-BPD. The 
details related to these sensitivity analyses will be 
provided within the TSAP. 


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The planned analyses will be reviewed and, if 
necessary, will be updated within the TSAP in 
order to adopt appropriate strategies. Additional 
analyses may be performed if deemed necessary 
(e.g., sub-group analyses, analyses to assess the 
impact of missing data and safety analyses).
Rationale for change
Addition of telemedicine visits
Section to be changed
7.2.2.3 Supplemental analyses of the primary 
endpoint
Description of change
Section number was changed from 7.2.2.3 to
7.2.2.2
Every attempt will be made to follow patients 
who discontinue treatment till the end of planned 
study participation.
Was changed to:
Attempts will be made to follow patients who 
discontinue treatment until the end of planned 
study participation.
The following paragraph was added:
If telemedicine assessments need to be 
implemented due to COVID-19 related factors, 
the treatment policy estimand will use all 
available data regardless of administration 
method (i.e. in-person, video and audio).
Rationale for change
Addition of telemedicine visits
Section to be changed
7.2.3
Secondary endpoint analyses
Description of change
The following paragraph was added:
If telemedicine assessments need to be 
implemented due to COVID-19 related factors, 
the details related to the PGI-S and CGI-S 
analyses will be provided in the TSAP.
Rationale for change
Addition of telemedicine visits
Section to be changed
7.2.6
Other Analyses
Description of change
The primary anchors for ZAN-BPD scale will be 
the Patient Global Impression of Severity (PGI-S) 
and Clinical Global Impression Severity Scale 
(CGI-S). In addition, the distribution-based 
methods will be utilized to assess the variability 
of the ZAN-BPD scale.
Was changed to:
The primary anchors for ZAN-BPD scale will be 
the Patient Global Impression of Severity (PGI-S) 






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5=markedly ill; 6=severely ill; 7=among the most 
extremely ill patients.
Was changed to:
The CGI-S question states “Considering your 
total clinical experience with this particular 
population, please choose the response below that 
best describes how mentally ill the patient was 
over the past week?”, and is rated on the 
following seven-point scale: 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 patients.
Rationale for change
Seven-day observation period is standard for 
CGI-S and this has been addressed during raters 
training. Changes in the protocol are just to 
reinforce the 7-day observation period. 
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Main in- and exclusion criteria
• Initiation or change in any type or frequency of 
psychotherapy for BoPD within the last 3 months 
prior to randomization
Was changed to:
• Initiation or change in any type or frequency of 
psychotherapy for BoPD within the last 3 months 
prior to screening.
Rationale for change
Correction
Section to be changed
FLOW CHART
Description of change
The following row was added to the Flow chart: 
IRT registration 
Rationale for change
Correction for consistency with section 6.2.1
Section to be changed
4.2.2.3 Contraception requirements
Description of change
WOCBP, who are sexually abstinent, fulfill the 
requirement of safe contraception 
Rationale for change
Clarification. Sexual abstinence, as defined in the 
protocol, meets the criterion of a highly effective 
method of contraception  
Section to be changed
FLOW CHART
5.6
OTHER ASSESSMENTS
Description of change
The following row was added to the Flow chart: 
Informed consent for participant’s duplicate 
check
The following section was added:


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5.6.5
Verification of current and past research 
study status of trial participant
Rationale for change
Addition of the procedure to check for patients 
enrolled in multiple trials
Section to be changed
Table 4.1.1: 2 Placebo matching BI 1358894
Description of change
The following was added as a source:
Boehringer Ingelheim Pharma GmbH & Co KG, 
Germany
Rationale for change
Correction
Section to be changed
6.2.3
Follow-up period and trial completion
Description of change
EoTrial visit is the final scheduled visit and the 
End of Study eCRF has to be entered. Should it 
be not possible for the patient to attend a follow 
up visit at the study site, a visit out of time 
window should be performed as soon as possible; 
if a visit at the site is not possible at all, at least a 
phone contact should occur at the scheduled 
follow-up visit time point.
Was changed to: 
EoTrial visit is the final scheduled visit and the 
End of Study eCRF must be entered. If it is not 
possible for the patient to attend a follow up visit 
at the study site as scheduled, a visit outside of 
the visit window should be performed as soon as 
possible. If a visit at the site is not possible at all, 
at least a phone contact should occur at the 
scheduled follow-up visit time point.
Rationale for change
Clarification
Section to be changed
6.2.3
Follow-up period and trial completion
Description of change
In case of early discontinuation, the patient 
should be asked to continue with study visits 
without study treatment. If the patient agrees, the 
patient will continue with the regular study visit 
schedule. Clinic visits, with the exception of Visit 
8 and Visit 9, can be performed via phone if the 
patient cannot attend the clinic.
Was changed to:
In case of early treatment discontinuation, the 
patient should be asked to continue with study 
visits without study treatment. If the patient 
agrees, the patient will continue with the regular 
study visit schedule. Alternatively, if patient does 
not agree to continue with regular study visits, 
patient should be asked to return to clinic for 


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Visit 8 (preferably) or Visit 9, and the remaining 
visits can be performed by phone.
Rationale for change
Requirement for follow-up was changed to one of 
the two visits, instead of both, to make it easier 
for patients.
Section to be changed
Table 7.2.2.1:1 Models for the MCPMod analysis
Table 7.5:1 Power of MCPMod for each 
candidate set model and average power for 
change from baseline in ZAN-BPD at Week 10
Description of change
Linearlog
Was changed to:
Linear
Rationale for change
Correction
Section to be changed
3.3.3
Exclusion criteria
Description of change
The following text was deleted from Exclusion 
criteria 19:
(as measured by the central laboratory)  
Rationale for change
To allow the use of local laboratory in case of 
COVID-19 related kit shortage
Section to be changed
5.2.3
Safety laboratory parameters
Description of change
The following text was added:
In case of COVID-19 related kit shortage, 
analyses can be performed at the local lab. Please 
refer to section 10.3 for further details.
Rationale for change
To allow the use of local laboratory in case of 
COVID-19 related kit shortage
Section to be changed
8.3.1
Source documents
Description of change
Neuropsychological rating scales data entered 
into the rater station will be regarded as source 
documentation. These may be centrally reviewed 
and further analyzed by the third-party vendor.
For electronic patient reported outcomes, the 
electronic record is the source document.
Was changed to:
Electronic records, i.e. clinician administered 
assessment data, related audio recordings (for 
central review) and patient reported outcome
data, entered into the tablet computer (Rater 
Station) will be regarded as source data. These 
may be further analyzed by the third-party 
vendor.
Rationale for change
Clarification








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Section to be changed
6.2
DETAILS OF TRIAL PROCEDURES 
AT SELECTED VISITS
Description of change
The following text was added:
It must be reiterated at all visits per Flow Chart, 
that WOCBP must use the appropriate method of 
contraception according to section 4.2.2.3.
Rationale for change
New safety information
Section to be changed
5.2.5.1 Assessment of suicidality
Description of change
For ‘Self-injurious behavior, no suicidal intent’ 
(Type 11) standard AE / SAE reporting rules are 
to be applied.
Was changed to:
For ‘Self-injurious behavior, no suicidal intent’ 
standard AE / SAE reporting rules are to be 
applied.
The following text was added to the last 
paragraph:
Please note, that adverse event reports, that get 
coded to terms like suicidal depression, suicidal 
ideation, suicidal threat or similar, are on the 
“Always serious AE List” and therefore must be 
reported as SAEs (refer to section 5.2.6.1.3).
Rationale for change
Clarification
Section to be changed
5.6.4 Verification of current and past research 
study status of trial participant
Description of change
This is a mandatory process where local 
regulatory approval has been obtained. 
Was changed to:
This is a mandatory process where approval is 
received in accordance with local regulations.
Rationale for change
Change per Protocol Administrative/Clarification 
Letter #2
11.4
GLOBAL AMENDMENT 4
Date of amendment
23 Sep 2022
EudraCT number
EU number
2020-000078-12
BI Trial number
1402-0012
BI Investigational Medicinal 
Product(s)
BI 1358894


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Title of protocol
A phase II randomized, double-blinded, placebo-
controlled parallel group trial to examine the 
efficacy and safety of 4 oral doses of BI 1358894 
once daily over 12 week treatment period in 
patients with borderline personality disorder
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
∀
Women of childbearing potential 
(WOCBP) able and willing to use two 
methods of contraception, …
Was changed to:
∀
Women of childbearing potential 
(WOCBP) able and willing to use two 
methods of contraception, confirmed by 
the investigator, …
Rationale for change
Request from the FDA
Section to be changed
FLOW CHART
Description of change
Contraception counseling for WOCB
Was changed to:
Contraception counseling for WOCB 22
22 This must include confirmation from the patient that she 
is using the contraception consistently and 
appropriately. Counseling and contraception 
confirmation must be recorded in CRFs. Refer to 
section 4.2.2.3 for more details regarding contraception 
counseling.
Rationale for change
Request from the FDA
Section to be changed
1.4.2
Risks
Description of change
Additionally, investigators must counsel WOCBP 
with regard to the importance of contraception at 
all visits as per Flow Chart (including phone 
visits).
Was changed to:
Additionally, investigators must counsel WOCBP 
with regard to the importance of contraception 
and confirmation of appropriate contraception use 
at all visits as per Flow Chart (including phone 
visits).
Rationale for change
Request from the FDA
Section to be changed
Table 1.4.2: 1 Overview of trial related risks
Description of change
Embryo-fetal development toxicity


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The following text was added:
Investigator must ensure that the patient 
understands the contraception requirements for 
the study and must confirm that the patient can 
reliably comply with contraception use during the 
study. Patients not expected to comply with 
contraception requirements should not be 
included in the study.
Investigators must counsel WOCBP with regard 
to the need for contraception, at all visits as per 
Flow Chart (including phone visits).
Was changed to:
Investigators must counsel WOCBP with regard 
to the need for contraception, including 
confirmation of the use of contraception, at all 
visits as per Flow Chart (including phone visits).
Refer to section 4.2.2.3 for more details regarding 
contraception counseling.
Rationale for change
Request from the FDA
Section to be changed
3.3.2
Inclusion criteria
Description of change
4. Women of childbearing potential (WOCBP) 1
able and willing to use two methods of 
contraception, which include …
Was changed to:
4. Women of childbearing potential (WOCBP) 1 
able and willing to use two methods of 
contraception, as confirmed by the 
investigator, which include …
Rationale for change
Request from the FDA
Section to be changed
4.2.2.3 Contraception requirements
Description of change
The following text was added:
Investigator must ensure that the patient 
understands the contraception requirements for 
the study and must confirm that the patient can 
reliably comply with contraception use during the 
study. Patients not expected to comply with 
contraception requirements should not be 
included in the study.
This must include confirmation from the patient 
that she is using the contraception consistently 
and appropriately. If contraceptive protection 
cannot be confirmed, as judged by the 




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done locally, results and normal ranges must be 
recorded in the CRFs.
Rationale for change
Incorporated by the Protocol Notification Letter 
#3
Section to be changed
8.3.1 Source documents
Description of change
In case local laboratory is used due to COVID-19 
related variations, local laboratory results report 
will be considered as source document.
Was changed to:
In case local laboratory is used for ESR or due to 
COVID-19 related variations, local laboratory 
results report will be considered as a source 
document.
Rationale for change
Incorporated by the Protocol Notification Letter 
#3


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Technical Version Number:
(Continued) Signatures (obtained electronically) 
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SAP_001.pdf: 




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7.8
SAFETY ANALYSIS..........................................................................................28
7.8.1
Adverse Events ....................................................................................................28
7.8.2
Laboratory data...................................................................................................30
7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG ......................................................................................................................30
7.8.5
Others ...................................................................................................................30
7.8.5.1
EcMA ....................................................................................................................30
7.8.5.2
Analysis of COVID Impact...................................................................................31
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............33
9. 
REFERENCES ....................................................................................................34
11.
HISTORY TABLE..............................................................................................55


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LIST OF TABLES
Table 6.1: 1
Treatment descriptions .....................................................................................11
Table 6.1: 2    Study analysis phases*......................................................................................11
Table 6.3: 1
Subjects’ sets analyzed .....................................................................................13
Table 6.7: 1
Planned and actual study days..........................................................................15
Table 7.4.1:1 Optimal contrast coefficients............................................................................20
Table 7.4.2.2: 1 Overview of the main analysis of the primary endpoint and its 
sensitivity/supplementary analyses...................................................................22
Table 11: 1
History table .....................................................................................................55


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike Information Criterion
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AS
Adherent set
ATC
Anatomical, Therapeutic, Chemical
BI
Boehringer Ingelheim
CGI-S
Clinical Global Impression – Severity
COVID-19
Coronavirus disease 2019
CRF
Case Report Form
C-SSRS
Columbia Suicide Severity Rating Scale
CT
Concomitant Therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DBLM
Database Lock Meeting
DV
Protocol Deviations
ECMA
Ecological Momentary Assessment
ECG
Electrocardiogram
EDMS
Electronic Document Management System
EOT
End of Treatment
EQ-5D-5L
Euro Quality of Life-5 Dimensions-5 Levels
FAS
Full Analysis Set
fMRI
Functional magnetic resonance imaging
FU
Follow-up
ICH
International Conference on Harmonisation
IDEA
International Document Management & Electronic Archiving
IPD
Important Protocol Deviation
IVRS
Integrated Voice Response System


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Term
Definition / description
LLT
Lowest Level Term
MAR
Missing at Random
MCPMod
Multiple Comparison Procedures and Modelling
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed effects Model Repeated Measures
MQRM
Medical Quality Review Meeting
MRI
Magnetic Resonance Imaging
OAA
Overall AiCure Adherence
PGI-I
Patient Global Impression – Improvement
PK
Pharmacokinetics
PKS
PK parameter analysis set
PPS
Per Protocol Set
PT
Preferred Term
PD
Pharmacodynamics
QD
Quaque Die (once a day)
RDC
Remote Data Capture
REP
Residual Effect Period
RPM
Report Planning Meeting
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SOC
System Organ Class
SS
Screened Set
STD
Standard Deviation
TMF
Trial Master File
TOM
Trial Oversight Meeting
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UDAEC
User-defined AE categories
ULN
Upper Limit of Normal
VAS
Visual Analog Scale


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Term
Definition / description
WHO
World Health Organisation
3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (1), the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the CTP, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomization.
R Version 3.3.2 with “DoseFinding” package (2) will be used for analyses based on Multiple 
Comparison Procedures and Modelling (MCPMod) and SAS® Version 9.4 will be used for 
all other analyses.
The main analyses of this TSAP will be conducted under the estimand concept. To quote ICH 
E9 R1, “An estimand is a precise description of the treatment effect reflecting the clinical 
question posed by a given clinical trial objective. It summarizes at a population level what the 
outcomes would be in the same patients under different treatment conditions being
compared.” So, an estimand is a way for the clinical trial protocol to address how intercurrent 
events will be handled. And according to ICH E9 R1, intercurrent events are events occurring 
after treatment initiation that affect either the interpretation or the existence of the 
measurements associated with the clinical question of interest. 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
In this TSAP the following are the changes to the statistical methods described in the CTP
(including amendments).
-
MCPMod analyses will be used to examine the relationship between change from 
baseline in ZAN-BPD score at Week 10 and BI 1358894 plasma concentration and 
will be reported in a separate analysis plan. 
Also, EcMA endpoints were revised due to further consultation with EcMA expert
The wording was changed from:
-
“Namely, the results of these assessments will be evaluated in an exploratory 
approach: a) Affective instability, b) Negative valence, c) Anxiety.”,
to the below:
-
There are a total of eight possible models, of which four are on psychological 
momentary states, namely, the effect of treatment on: (1) momentary negative affect, 
(2) momentary positive affect, (3) momentary anxiety and (4) momentary valence.
The other half of the models are on psychological instabilities, they are, the effect of 
treatment on: (5) instability of negative affect, (6) instability of positive affect, (7) 
instability of anxiety and (8) instability of valence.
The above changes in analyses are not of a primary or secondary endpoint, therefore
modifications do not warrant a CTP-amendment and can be done in this TSAP.
In addition, sensitivity analyses on PGI-S, CGI-S and PGI-Impact will not be performed due 
to the low rate of telemedicine assessments for the PGI-S, CGI-S and PGI-Impact.


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT
Change from baseline in ZAN-BPD total score at Week 10 is the primary efficacy endpoint. 
See CTP Section 5.1 for details.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
There is no key secondary endpoint in this trial.
5.2.2
Secondary endpoint(s)
The secondary efficacy endpoints are: 
-
Response defined as ≥30% ZAN-BPD reduction from baseline at Week 10.
-
Change from baseline in DERS-16 total score at Week 10.
-
Change from baseline in STAI-S total score at Week 10.
-
Change from baseline in PHQ-9 total score at Week 10.
-
Change from baseline in CGI-S at Week 10.
-
Change from baseline in PGI-S at Week 10.
5.3
FURTHER ENDPOINT(S)


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-
Percentage of patients with (S)AEs (including clinically relevant abnormalities of
physical examination, vital signs, ECG test and laboratory tests)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For details on the treatment regimen, assignment of treatment groups, and the selection of 
doses, refer to Section 4 of the CTP. Below in Table 6.1:1 are the descriptions of the short and 
long names of the treatments. Next, are the definitions of the study phases for the analysis 
periods (Table 6.1:2).
Table 6.1: 1
Treatment descriptions
Long Name
Short Name
Placebo
Placebo
BI 1358894 5 mg qd
BI 5 mg
BI 1358894 25 mg qd
BI 25 mg
BI 1358894 75 mg qd
BI 75 mg
BI 1358894 125 mg qd
BI 125 mg
Table 6.1: 2    Study analysis phases*
Study analysis phase
Description
Start Date (included)
End Date (included)
Screening phase
Screening (prior to 
treatment)
Date of informed consent
Date of first treatment 
administration minus 1
day
Treatment phase and residual 
effects period
On-treatment 
period
Date of first treatment 
administration 
Date of last treatment 
administration + REP
Follow-up phase
Off-treatment 
period
Date of last treatment 
administration + REP +1 
day 
Date of last CTP visit
* The defined treatment periods are the same for all treatment groups.
REP is the residual effect period which is defined as 28 days after the last dose of trial treatment for safety, and 7 days after 
last dose for efficacy
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. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the
database (i.e., randomized patients). Consistency check listings (i.e., identification of 
violations of time windows) and a list of CTP deviations will be provided to be discussed at 
the Report planning meeting (RPM)/Database lock meeting (DBLM)/Medical Quality Review 
Meeting (MQRM). At these meetings, it will be decided whether a discrepant data value can




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Table 6.3: 1
Subjects’ sets analyzed
Subject set
Class of endpoint
TS
SS
FAS
PPS
AS
Primary and secondary endpoints, 
compliance
X
X*
Further endpoints (except PK)
X
Disposition
X
Safety variables and iPDs
X
Demographics, baseline 
variables, exposure
X
(X)
Primary endpoint adjusted for 
overall study AiCure 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.
(X) An additional PPS presentation of the demographic/baseline endpoints may be provided in the End of Text (EoT) section, 
if there are a non-negligible number of subjects that were treated, but without any post randomization data for the primary 
endpoint.


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6.5
POOLING OF CENTERS
All subjects from all centers will be pooled for the statistical analysis of efficacy. The effect 
of region on the primary and selected secondary efficacy endpoints will also be investigated 
as described in Section 6.4. Therefore, this section is not applicable because center/country is 
not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing data are not explicitly imputed and remain missing for all main analyses. All but one 
of the CTP-defined primary and secondary efficacy endpoints are continuous. Therefore, for 
these efficacy endpoints which are continuous in nature, the use of a restricted maximum 
likelihood (REML)-based mixed model repeated measures (MMRM) approach will ensure 
that missing data are handled implicitly via a missing at random assumption (MAR) by the 
statistical model. For the binary efficacy endpoint of ZAN-BPD response, missing data will 
not be imputed.
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (5).  Missing data and outliers of PK data are handled 
according to (6).
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS
Baseline is defined as the last observation at, or prior to Visit 2. Hence, if a subject is
randomized at Visit 2, but does not start trial medication until a future 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.
Planned and actual test days are included in the analysis data sets and are calculated relative 
to the beginning of treatment as indicated in Table 6.7: 1 below. 
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 which have the same difference in days to the planned 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. Assignment of efficacy observations to visits 
based on time windows will be based on the non-imputed (observed) data. Repeated and 
unscheduled efficacy measurements will be assigned to the nominal visits according to the 
time windows described in Table 6.7: 1. 


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For safety measurements, data collected at all visits 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 for which there is no standard reference direction for the 
safety parameter, the average of all values for the same visit will be used for analysis.
Table 6.7: 1
Planned and actual study days
Visit
Relative to treatment start
Planned test day
Actual test day
2
1
Day 1 
3
8
Day 2 – Day 12
4
15
Day 13 – Day 19
4A
22
Day 20 – Day 26
5
29
Day 27 – Day 33
5A
36
Day 34 – Day 40
6
43
Day 41 – Day 47
6A
50
Day 48 – Day 54
7
57
Day 55 – Day 61
7A
64
Day 62 – Day 68
8
71
Day 69 – Day 75
8A
78
Day 76 – Day 82
9 / EOT
85 (for completed 
subjects)
Day 83 – treatment stop date (stopdt) + 7 days
eEOT
N/A (for early 
discontinued 
subjects)
Date of the last administration of trial medication + 7
days (for early discontinued subjects). 
The number of days will be assigned to the visit. Thus,
if days to eEOT is 56, it will be mapped to Visit 7. For 
those that early discontinue treatment but continue 
with the collection of efficacy data, those data points 
will be mapped to the later Visits as per the above 
Visit window. Hence, if this same subject collects 
ZAN-BPD at Day 74, it will be mapped to Visit 8.
FUP1
stopdt + 8 days
(stopdt + 8 days) to (stopdt + 11 days)
FUP2
stopdt + 14 days
(stopdt + 12 days) to (stopdt + 25 days)
End of Trial
stopdt + 28 days
(stopdt + 26 days) to stopdt + 30 days
-
Days are counted relative to the day of randomization, which is defined as Day 1.
-
stopdt stands for treatment stop date.
There is no visit window mapping for C-SSRS given that it is collected nearly every week throughout the study.


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


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treatment group, System Organ Class (SOC) and Preferred Term (PT). Concomitant diseases 
which are present at start of the study will be descriptively summarized by treatment.
A medication/therapy will be considered concomitant to treatment if it (1) is ongoing at the 
start of randomized trial treatment or (2) starts within the on-treatment period (see Section 6.1
for a definition of study analysis phases).  A medication/therapy will be considered as prior 
medication/therapy, if the end date of the medication/therapy is at any time prior to the start of 
randomized trial treatment.
Concomitant therapies (CTs) are coded according to WHO Drug Dictionary. CTs will be 
classified according to the Anatomical, Therapeutic, Chemical (ATC) classification system. 
The third ATC level will be used to categorize CTs by therapy type. In situations where a 
medical product may be used for more than one equally important indication, there are often 
several classification alternatives. As appropriate, 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. The most current MedDRA and WHO DD versions 
will be used. 
7.3
TREATMENT COMPLIANCE
7.3.1
CRF Compliance
Only descriptive statistics are planned for this section of the report. Treatment compliance is 
calculated at Week 1, 2, 4, 6, 8, 10 and 12(EOT) based on the CTP’s flow chart. 
Treatment Compliance = (number of tablets taken during a period) / (number of tablets that 
should have been taken during a period) * 100.
The cumulative treatment compliance during the entire treatment period is derived using the
following examples:
For completers: if a subject’s observed treatment compliance rates are 80%, 81%, 82%, 83%, 
84%, 85%, 86% at Weeks 1, 2, 4, 6, 8, 10 and 12, then the cumulative treatment compliance
percent = (.80*1 + .81*1 + .82*2 + .83*2 + .84*2 + .85*2 + .86*2)/12*100 = 83.42%.
For early discontinued subject: if a subject’s observed treatment compliance rates are 80% at
Week 1, 81% at Week 2, 82% at Week 4, 50% at eEOT, then the cumulative treatment 
compliance rate = (0.80*1 + 0.81*1 + 0.82*2 + 0.5*((eEOT date – drug start date + 1)/7 –
4))/((eEOT date – drug start date + 1)/7) * 100% = 74.3% if the quantity (eEOT date – drug 
start date + 1) is assumed to be 36 days.
If at a particular visit a participant did not return the trial drug kits, then the compliance at that 
visit is zero.
Treatment compliance will be summarised overall and by visit for the treated set (FAS) using 
descriptive statistics (N, mean, SD, minimum, median, maximum). The number and 
percentage of patients with the following overall compliance categories will be presented


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using descriptive statistics (N, mean, SD, minimum, median, maximum). The number and 
percentage of patients with the following overall compliance categories will be presented:  
-
"<80%", 
-
"80% to <100%",
-
">=100%",
-
missing.
7.3.2
AiCure Adherence
First, we define overall AiCure Adherence (abbreviated as OAA), as the sum of all tablet 
adherence minus the total number of tablets flagged as red, orange, or yellow alerts, divided 
by a denominator of 4 times 84. Or, in other words:
-
OAA = [[(Sum of all tablet adherence) – (total number of red, orange, and yellow
alerts)]/ 4*84] *100,
o
84 = Number of days on treatment, and 4 is the number of tablets per dose.
Tablet adherence is the successful administration of a pill as captured by AiCure video. Red 
alerts are tablet administrations for which the AiCure 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 
process, but contains suggested visual proof of potentially deceptive behavior, 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 the following method: visually 
confirmed by the AiCure app.
For subjects that discontinue treatment early, 84, 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. 
As defined in Section 6.3, the Adherent set (AS) consists of all subjects in FAS that achieved 
an OAA of at least 60%. Within these subjects, flags (or classifications) will be built to denote 
increasing thresholds of adherence (≥60%, ≥75%, ≥90%). Hence, it may be of interest to 
evaluate the effect of varying levels of overall adherence on efficacy. 
An evaluation of the primary endpoint to varying levels of adherence to treatment may be of 
interest, please see Section 7.4.2.3 for further details.


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7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
The primary endpoint is the change from baseline to Week 10 in ZAN-BPD total score. 
Baseline refers to the measurement recorded at randomization (Visit 2), if data at Visit 2 is 
missing, then data from Visit 1 will be considered baseline.
Despite the COVID-19 pandemic, the collection of complete data at all visits is our goal. 
Therefore, to avoid missing data due to a subject’s potential inability to attend their in-person 
clinical visit, a virtual assessment via videoconferencing will be available to ascertain the 
ZAN-BPD. For the primary analysis of the primary endpoint, we assume no discernible 
difference between the in-person and virtual collection of the ZAN-BPD. Hence, all data 
while subjects are on treatment, whether in-person or virtual, will be used in the evaluation of 
the primary analysis of the primary endpoint. 
The primary analysis of the primary endpoint will use a hypothetical estimand. The 
hypothetical approach focuses on the treatment effect assuming all subjects complied with the 
CTP and remained on the assigned trial medication, i.e., study drug is taken as directed. 
Hence, the hypothetical estimand evaluates the treatment effect if intercurrent events do not 
occur. Therefore, this analysis will include all data collected while on treatment which is 
defined as the time from the date of the first dose of trial medication until the date of the last 
dose of trial medication plus 7 days.  Any data collected after a patient discontinues trial drug, 
regardless of reason, will be censored and will not be included in the primary analysis. 
Therefore, the primary analysis of the primary endpoint will be evaluated under the 
hypothetical estimand regardless of the potential influence of COVID-19.
The Multiple Comparison Procedures and Modelling (MCPMod) approach (8, 9) is 
implemented in two main stages: (1) trial design stage; (2) trial analysis stage. The 
procedures for the trial design stage, including the selection of candidate models covering a 
suitable range of dose-response shapes and sample size and power calculations are provided 
in the CTP Section 7.2.2 and 7.5. The procedures for the trial analysis stage are specified 
below. FAS is used for the primary analysis of the primary efficacy endpoint.
MMRM analysis
The change from baseline in ZAN-BPD at Week 10 for each dose group as well as the 
corresponding variance-covariance matrix are estimated by a mixed effects model repeated 
measure (MMRM) including the fixed categorical covariates of treatment, visit and the 
baseline ZAN-BPD total score strata indicator (≤18 vs. ≥19), the continuous fixed covariate of 
baseline ZAN-BPD total score, and treatment-by-visit interaction, as well as baseline-by-visit 
interaction. Patient is considered as random. The unstructured covariance matrix is used to 
estimate the within subject variability. The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom. Analyses will be implemented using SAS 9.4 
PROC MIXED. 
More specifically, the change in ZAN-BPD from baseline (Visit 2), at Visits 3, 4, 5, 6, 7 and 8 
(Weeks 1, 2, 4, 6, 8 and 10) will be evaluated using an MMRM accounting for the following 
sources of variation: ‘treatment’, ‘visit’, ‘baseline ZAN-BPD strata indicator’ (≤18 vs. ≥19), 


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‘baseline ZAN-BPD’ as a continuous covariate, and the ‘treatment*visit’ and ‘baseline*visit’ 
interaction as fixed effects, as well as the random ‘subject’ effect. The methods described in 
Section 10.1 will be utilized to resolve model non-convergence.
SAS code for MMRM:
The following SAS code will be used to calculate the MMRM.
PROC MIXED DATA=indata cl method=reml;
CLASS visit trt stratum subject;’
MODEL ept = stratum visit*trt 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 (N, mean, SE and 95% CI per dose group and timepoint) will be
presented in tables and displayed graphically.
MCPMod Analysis
The adjusted mean estimates of the change from baseline at Week 10 for each dose and their 
estimated variance-covariance matrix from the MMRM model are used in the trial analysis 
stage. Then, the multiple pair-wise comparison procedure will be implemented using the 
optimal contrast tests which control the family-wise type I error rate at one-sided α = 0.10. 
For the MCPMod test, the optimal contrasts corresponding to the candidate models are 
calculated as in the trial design stage (using the R-function optContr using weights 
proportional to the sample size of each dose group) and are shown in Table 7.4.1: 1 below.
These contrasts will be updated using the expected model means from the candidate set and 
the estimated variance-covariance matrix from the data. The final contrasts will be presented 
in the CTR.
Table 7.4.1:1 Optimal contrast coefficients
Optimal Contrast Coefficients for Dose
Model
0
5mg
25mg
75mg
125mg
Linear
-0.583
-0.209
-0.110
0.136
0.765
Emax1
-0.736
-0.175
0.064
0.243
0.604
Emax2
-0.862
0.052
0.177
0.206
0.425
Sigmax
-0.684
-0.250
0.032
0.276
0.627
Exponential
-0.479
-0.187
-0.161
-0.016
0.842
Proof of concept is established if at least one dose-response model is statistically significant, 
i.e., the null hypothesis of a flat dose-response curve is rejected indicating a benefit of one BI 
1358894 dose over placebo.
Once the significance of a dose-response signal is established, the dose-response profile and 
the target dose can be estimated using the model averaging method. 


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The selected dose-response model(s) is re-fitted to the data without any parameter 
assumptions to generate a set of new estimates of the model parameters from the data. The 
final dose-response model is obtained via the weighted model averaging of the significant 
models (p-value<0.10) based on Akaike Information Criterion (AIC) (the smaller the AIC 
value the better the model fit). The weights for each significant model (Mk) are given by,
() =

(−0.5 ∗())
∑

(−0.5 ∗())


where AIC(Mk) is the AIC for model Mk.
The estimate of the target dose is the smallest dose producing an effect greater than or equal 
to the target effect size of 0.32 based on the final dose-response model (accounting for safety 
and other relevant information). Specifically, the target effect size considers the observed 
standard deviation (SD) and the adjusted mean treatment effect. Thus, if the observed SD is 
9.5, then to achieve the target effect size of 0.32, the observed placebo-adjusted difference 
would need to be at least 3. Test statistics and p-values will also be displayed for different 
dose-response models. Figures and tables will be displayed for the MCPMod modelling. 
The following displays are planned:
-
Table of the contrast coefficients per dose group and candidate model, together with 
the MCPMod test statistics and p-values for each model and the critical value
-
For the average model, figure of the dose-response curve
-
For all significant model shapes, figures of the dose-response curve plus 95% 
confidence band (of the predicted shape)
The MCPMod trial analysis will be implemented by calling an R function/package within 
SAS. Please see Section 10.3 for R code to implement the MCPMod analysis.
7.4.2
Sensitivity analysis, supplementary analysis, subgroup analysis, exploratory 
analysis of the primary endpoint(s)
7.4.2.1 Sensitivity analyses 
To explore the robustness of inferences (results) from the main estimator to deviations from 
its underlying assumptions, several sensitivity analyses will be conducted targeting the same 
estimand, the hypothetical estimand. In the sensitivity analyses that follow, a certain aspect of 
the main analysis of the primary endpoint is altered to allow the possibility of identifying 
which assumptions, if any, are responsible for potential differences observed.
Exclude virtual collections of ZAN-BPD
The first sensitivity analyses to the primary analysis of the primary endpoint will assess the 
assumption of no discernible difference between the in-person and virtual collection of the 
ZAN-BPD.  Unlike the primary analysis, this sensitivity analysis will assume a difference 
between the in-person and virtual data assessments and shall exclude all virtual collections of 


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the ZAN-BPD. This analysis of the primary endpoint will use the hypothetical estimand (the 
same estimand as that of the primary analysis). However, here we recognize the virtual 
collection as a deviation. This sensitivity analysis will follow the same analysis methodology 
(MCPMod/MMRM) as specified in the primary analysis, but with the exclusion of all virtual 
collections of the ZAN-BPD. 
Dose response patterns
If considered necessary and for the purpose of further model refinement, the MCPMod 
analysis may be repeated on the primary endpoint but with an extended set of dose response 
patterns, including the original candidates. 
Additional risk factors
Further sensitivity analyses to the primary analysis of the primary endpoint will be conducted 
with additional covariates of interest. The additional fixed categorical covariates of stable 
concomitant psychotherapy use (Yes, No) and Sex (Male, Female) will be included into the 
MMRM model.
PPS
Sensitivity analysis of the primary and secondary efficacy endpoints using the PPS may be 
conducted if more than 10% of patients in FAS have an iPD which lead to exclusion from the 
PPS.
7.4.2.2 Supplementary analyses to the primary endpoint
Supplementary analysis is a general description for analyses that are conducted in addition to 
the main and sensitivity analysis to provide additional insights into the understanding of the 
treatment effect. Supplementary analyses should generally be given lower priority than 
sensitivity analyses.  Please see below Table 7.4.2.2:1 for an overview of the supportive 
sensitivity and supplementary analyses to the main analysis of the primary endpoint.
Table 7.4.2.2: 1 Overview of the main analysis of the primary endpoint and its 
sensitivity/supplementary analyses.
Primary 
Analysis
Sensitivity 
Analysis
Supplementary 
Analysis 1
Supplementary 
Analysis 2
Hypothetical estimand
(main analysis)
Hypothetical estimand
Treatment policy
(repeats primary 
analysis)
Treatment policy
(repeats sensitivity 
analysis)


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Does not recognize alternate 
collection of the ZAN-BPD.
Assumes no discernible 
difference between in-
person and virtual ZAN-
BPD.
Recognizes alternate collection
of the ZAN-BPD.
Assumes a difference between 
the in-person and virtual 
assessment.
  Excludes virtual collections of   
  ZAN-BPD.
Does not recognize 
alternate collection of the 
ZAN-BPD.
Assumes no discernible 
difference between in-
person and virtual data
ZAN-BPD.
Recognizes alternate collection
of the ZAN-BPD.
Assumes a difference between 
the in-person and virtual 
assessment.
Excludes virtual collections of 
ZAN-BPD.
Treatment policy estimand
1. Supplementary analysis 1 repeats the primary analysis of the primary endpoint but 
under the treatment policy estimand i.e., effectiveness/intention to treat. Under 
treatment policy, we assess the treatment effect irrespective of intercurrent events, 
hence all measurements are relevant. We maintain the assumption of no discernible 
difference between the in-person and virtual collection of the ZAN-BPD. The 
treatment policy estimand will use all available ZAN-BPD data including data 
collected after treatment discontinuation or other intercurrent events. If telemedicine 
assessments need to be implemented due to COVID-19 related factors, the treatment 
policy estimand will use all available data regardless of administration method (i.e., 
in-person, video, and audio). This supplementary analysis to the primary endpoint will 
follow the same analysis methodology (MCPMod/MMRM) as specified in the primary 
analysis.
2. Supplementary analysis 2 repeats the sensitivity analysis of the primary endpoint
(exclude virtual collections of ZAN-BPD) but under the treatment policy estimand i.e., 
effectiveness/intention to treat. Here, and like the sensitivity analysis, we maintain the 
assumption of a discernible difference between the in-person and virtual collection of 
the ZAN-BPD and shall exclude all virtual collections of the ZAN-BPD. The 
treatment policy estimand will use all other available ZAN-BPD data including data 
collected after treatment discontinuation or other intercurrent events. This analysis to 
the primary endpoint will follow the same analysis methodology (MCPMod/MMRM) 
as specified in the primary analysis.
7.4.2.3 Subgroup analyses to the primary endpoint
The primary efficacy endpoint will be further analyzed for the AiCure adherent subgroup as
defined in Section 6.3 and 6.4. This study is not adequately powered to confirm treatment 
differences in any subgroup analysis.  Any subgroup analyses performed will be considered 
exploratory. This subgroup analysis will explore if the treatment effect differs in the AiCure 
adherent subgroup. The 3 subgroups are: (1) overall adherence >=60%, (2) overall adherence 
>=75%, and (3) overall adherence >=90%. The conduct of these analyses is subject to the 
available sample size of the subgroup and more categories could be defined. The same 
statistical approach and methods used for the primary analysis of the primary efficacy
endpoint will be used.  


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Subgroup analysis by Region and Race
The least square mean estimates from the MMRM model (as done for the primary endpoint) 
on the change from baseline in ZAN-BPD at Week 10 for each dose group will be compared 
against several subgroups of interest, particularly regions and race. For the subgroups on 
regions please see Table 10.2:1. For the subgroups on race, they are: white and non-white. 
The analyses of the subgroups will follow the same methods as detailed for the primary 
analysis of the primary endpoint. 
Subgroup analysis for Asian participants
The sample size of participants of Asian ethnicity at 4% is very limited and prohibitive to 
conducting meaningful statistical inference. However, there’s regulatory interest in 
quantifying the effect of treatment on the subgroup of Asian participants. Thus, the analysis 
on change from baseline at Week 10 in ZAN-BPD total score will be evaluated descriptively 
(by (i) treatment, and by (ii) combined active treatment vs placebo) using standard aggregate 
measures such as unadjusted mean, median, and quartile ranges.
Furthermore, there is interests in evaluating the subgroup of East Asians which is defined as 
Japanese participants from sites in Japan. Given the low numbers of participants, descriptive 
statistics and patient listings will be created for the clinical trial report.
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 CTP.
7.5.2
(Other) Secondary endpoint(s)
Logistic regression analysis
The binary secondary endpoint of ZAN-BPD response (defined as ≥30% ZAN-BPD reduction 
from baseline at Week 10) will be analyzed through a logistic regression model to obtain an 
estimate of the population odds ratio (OR) and associated confidence intervals between active 
arms and placebo. This logistic regression will be adjusted for fixed factors of treatment, 
baseline ZAN-BPD strata indicator (≤18 vs. ≥19), and the continuous covariate of baseline 
ZAN-BPD total score. The analysis will be performed on the FAS. Adjusted odds ratios 


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together with 95% confidence intervals will be used to quantify the effect of treatment, 
comparing all treatments to placebo. 
The SAS code for the logistic regression model is as follows:
proc logistic data=indata;
  class trt stratum/ param=GLM; /* include (ref=”placebo”) for trt*/
  model resp = trt base stratum / link=LOGIT covb;
  lsmeans trt / cl;
run;
Adjusted odds ratio together with 95% confidence intervals, comparing all treatments to 
placebo, will be presented.  
For the rest of the secondary endpoints: (i) change from baseline in DERS-16 total score at 
Week 10, (ii) change from baseline in STAI-S total score at Week 10, (iii) change from 
baseline in PHQ-9 total score at Week 10, (iv) change from baseline in CGI-S at Week 10, 
and (v) change from baseline in PGI-S at Week 10, an MMRM model like that described for 
the primary endpoint analysis will be used to obtain the adjusted change from baseline at 
Week 10 for each of the BI active arms versus placebo.
The analysis of standard PK parameters is performed according to (6).
7.5.3
Sensitivity analysis of ZAN-BPD response
Additional risk factors to ZAN-BPD response
The binary secondary endpoint of ZAN-BPD response (defined as ≥30% ZAN-BPD reduction 
from baseline at Week 10) will be analyzed through a logistic regression model as detailed in 
Section 7.5.2, but with the addition of further potential risk factors to the estimate of the 
population odds ratio (OR) and associated confidence intervals between active arms and 
placebo. The logistic regression model for ZAN-BPD response will be repeated (as given in 
Section 7.5.2) but with the addition of the covariates of stable concomitant psychotherapy 
(yes/no) and sex (male/female). The analysis will be performed on the FAS. Adjusted odds 
ratios together with 95% confidence intervals will be used to quantify the effect of treatment, 
comparing all treatments to placebo. In case zero event is observed in any of the combination 
of treatment arm and strata, a penalized regression based on the Firth’s bias reduction method 
(10, 11) will be used.


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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 weeks”, “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”, “>12 weeks”,  or “missing”.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. AEs will be coded based on the most 
current version of MedDRA. Analysis will be performed as defined in Section 7.2.5 of the 
CTP.
7.8.1
Adverse Events
The analyses of adverse events will be descriptive in nature. All analyses of AEs will be based 
on the number of patients with AEs and not on the number of AEs. The reporting and 
analyses of AEs will follow the BI guideline (12). AEs will be coded with the most current 
version of MedDRA.
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:


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∀
All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, and outcome).
∀
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
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 summarisation of AE data, please refer to (5, 12).
The analysis of AEs will be based on the concept of treatment emergent adverse events, thus, 
all adverse events occurring between the date of the first administration of trial treatment 
through the date of the last administration of trial treatment + residual effect period will be 
assigned to the on-treatment period. Adverse events that occur before first drug intake will be 
assigned to ‘screening’, and adverse events that occur within 28 days after the residual effect 
period will be assigned to ‘follow-up’. For details on the treatment definitions, see Section 
6.1.
Adverse events of special interest (AESIs)
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
-
an elevation of AST and / or ALT ≥ 3-fold ULN combined with an elevation of total
o
bilirubin ≥ 2-fold ULN measured in the same blood draw sample; and / or
-
marked peak aminotransferase (ALT and / or AST) elevations ≥ 10-fold ULN.
Refer to CTP Section 5.2.6.1.4 for details.
Other significant AE (according to ICH E3)
According to ICH E3 (13), AEs classified as "other significant" needs to be reported and will 
include those non-serious and non-significant AEs with
1. action taken = ‘discontinuation' or 'action taken = reduced'; or
2. marked hematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor / Investigator during medical quality 
review at TOM.
AE summaries
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarized by treatment, primary system organ class (SOC) and 
preferred term (PT) according to MedDRA. The SOCs will be sorted by default alphabetically 
and PTs will be sorted by frequency within an SOC. Separate tables will be provided for 
patients with:
-
drug-related AEs
-
serious AEs
-
serious related AEs
-
AESIs
-
other significant AEs (according to ICH E3)


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-
AEs leading to death
-
AEs leading to discontinuation of trial medication
-
AEs occurred with incidence in the preferred term >2%
-
AEs occurred with incidence in the preferred term >5%
-
AEs occurred during the follow-up period.
AEs suggestive of abuse potential 
In support of an evaluation of human abuse potential, user-defined AE categories (UDAEC) 
are defined in Section 10.5. In addition, frequency of subjects with AEs suggestive of abuse 
potential will be summarized by treatment, UDAEC, and preferred term. A listing of the AEs 
and a listing of subjects with >100% compliance or unreturned medication kits will also be 
provided.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(14).  Only patients with at least one available on-treatment value will be included in the 
analysis of an individual laboratory parameter. All individual data will be presented in 
listings.  Study visits will be presented by the Visit labels in Table 6.7.1.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report. In case of multiple 
measurements including unscheduled visits, the value for the vital sign measurement will be 
the average of all the measurements for the corresponding visit. 
7.8.4
ECG
12-lead ECG measurements will be assessed as described in the CTP Flow Chart. 12-lead 
ECG-findings before first intake of trial drug will be considered as baseline condition or as 
AEs (during the trial) if judged clinically relevant by the investigator and will be analysed as 
such. No separate listing or analysis of these ECG data will be prepared.
7.8.5
Others
7.8.5.1
EcMA
Ecological Momentary Assessment (EcMA)
Exploratory analyses of treatment effect onset will be conducted using Ecological
Momentary Assessment data (refer to section 5.6.2 of CTP), comparing change from baseline 
to Week 10 regarding momentary affect and instability on: negative affect, positive affect, 
anxiety, and valence.


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Negative affect is the arithmetic mean of the six PANAS negative scale items (upset, guilty, 
afraid, ashamed, scared, distressed). Positive affect is the arithmetic mean of the four PANAS 
positive scale items (active, enthusiastic, inspired, attentive). Anxiety is the arithmetic mean 
of the three PANAS-X FEAR negative scale items (afraid, frightened, and scared). And 
finally, valence = average [-1*Negative affect, Positive affect]. 
There are a total of eight possible models, of which four are on psychological momentary 
states, namely, the effect of treatment on:
-
(1) momentary negative affect, (2) momentary positive affect, (3) momentary anxiety 
and (4) momentary valence.
The other half of the models are on psychological instabilities, they are, the effect of treatment 
on:
-
(5) instability of negative affect, (6) instability of positive affect, (7) instability of 
anxiety and (8) instability of valence.
This EcMA is an intensive longitudinal assessment where extensive diary sampling is 
conducted. In this EcMA design, nesting comes from repeated measures over time, nested 
within subjects. Thus, the statistical method should account for statistical dependency that 
may result from nested (or clustered) data. Please see Section 10.4 for further details.
7.8.5.2
Analysis of COVID Impact
This section aims to characterize the impact of the SARS-CoV-2 infection/COVID-19 disease 
on subjects’: (i) adherence to the protocol, (ii) adverse events and (iii) efficacy. Regarding the 
first point, a descriptive analysis of premature discontinuations of trial medication/study due 
to COVID-19 disruption will be presented. In addition, the frequency of subjects with 
protocol deviations associated with COVID-19 disruption will be tallied. And lastly, we will 
look at the proportion of subjects that completed/missed the ZAN-BPD assessment at each 
clinic visit.
Now, for the second point (from the paragraph above), we propose four tables and a listing to 
study the distribution of adverse events in subjects infected with SARS-CoV-2, namely: 
∀
Adverse events overall summary on subjects with SARS-CoV-2 infection while on 
treatment with study drug
∀
Adverse events by treatment, primary system organ class and preferred term on 
subjects with SARS-CoV-2 infection while on treatment with study drug
∀
Adverse events leading to discontinuation by treatment, primary system organ class 
and preferred term on subjects with SARS-CoV-2 infection while on treatment with 
study drug
∀
Serious adverse events by treatment, primary system organ class and preferred term on 
subjects with SARS-CoV-2 infection while on treatment with study drug, and 
∀
Subjects with COVID-19 related study disruption.
Lastly, is the impact of COVID-19 on efficacy. The collection of complete data at all visits is 
our goal, despite the COVID-19 pandemic. To avoid missing data due to a subject’s potential 


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inability to attend their in-person clinical visit, we made provisions for a virtual assessment 
via videoconferencing to ascertain the ZAN-BPD. Please refer to Sections 7.4.2.1 and 7.4.2.2
where the Sensitivity Analysis, and the Supplementary Analysis 1 and Supplementary 
Analysis 2 are discussed in detail.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
Standard approach: This approach is the default option for double-blind pivotal trials, or 
trials that potentially could be pivotal and do not require expedited reporting, or non-pivotal 
double-blind trials that choose not to use a fast-track approach.
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.
The following plan for an End of Treatment database lock will be implemented if deemed 
necessary for decision making.
End of Treatment Lock (Interim Database Lock):
This section details the planned time point at which the database will be declared ready for the 
End of Treatment (interim database) lock. This interim database lock will consist of all data 
up through the End of Treatment (EoT), Week 12.
The treatment information will be released for this End of Treatment analyses, thus, given that 
the database will be unblinded with this lock, there is no need for specification in the logistics 
plan.
Once the last patient has completed their End-of-Treatment (EOT) visit and all corresponding 
data has been entered and cleaned to the level documented in the “Data Delivery Request” 
(DDR) form, the data will be declared ready to be unblinded via the “Data Ready to be 
Unblinded and/or Final Trial Closure Notification” (RUN) form. Then the treatment 
information will be released for analysis.
The data collection for the off-treatment residual effect period until the End-of-Study (EoS)/ 
Follow-Up visit will continue into the unblinded trial database. Once trial data collection has 
been completed and all data has been entered and cleaned as documented on the RUN form, a 
final data lock will be performed.
After the release of treatment information, it is expected that only trial data related to the off-
treatment residual effect period will be entered and changed. Therefore, after the timepoint of 
release of treatment information, all changes affecting trial data up to the End-of-Treatment 
(EoT) visit will be documented and summarized in the CTR.


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9.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
Bornkamp B, Pinheiro J, Bretz F. Package ‘DoseFinding’ (February 19, 2015). 
Comprehensive R Archive Network 2015; [R15-2001]
3
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”,
current version; IDEA for CON
4
BI-KMED-COPS-TMP-0001: "Important Protocol Deviation (iPD) log", current
version; IDEA for CON
5
BI-KMED-BDS-HTG-0035: "How to Guide: Handling of missing and incomplete 
AE dates", current version; IDEA for CON.
6
001 MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
7
BI-KMED-BDS-HTG-0045: "How to Guide: Standards for Reporting of Clinical
Trials and Project Summaries", current version; IDEA for CON.
8
Pinheiro J, Bomkamp B, Bretz F. Design and analysis of dose-finding studies 
combining multiple comparisons and modelling procedures. J Biopharm Stat 2006; 
16 (5): 639-656 [R10-1424]
9
Pinheiro J, Bomkamp B, Glimm E, et al. Model-based dose finding under model 
uncertainty using general parametric models. Stat Med 2014; 33 (10): 1646-1661 
[R15-4293]
10
Heinze G, Schemper M. A solution to the problem of separation in logistic
regression. Statistics in Medicine 21: 2409-2419 (2002).
11
Firth D. Bias reduction of maximum likelihood estimates. Biometrika 80, 27–38 
(1993)
12
BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event Data from 
Clinical Trials", current version; IDEA for CON.
13
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.
14
BI-KMED-BDS-HTG-0042: "How to Guide: Handling, Display and Analysis of 
Laboratory Data", current version; IDEA for CON.
15
Santangelo, P., Reinhard, I., Mussgay, L., Steil, R., Sawitzki, G., Klein, C., . . . 
Ebner-Priemer, U. W. (2014). Specificity of affective instability in patients with 
borderline personality disorder compared to posttraumatic stress disorder, bulimia 
nervosa, and healthy controls. Journal of Abnormal Psychology, 123, 258–272. 
http://dx.doi.org/10.1037/a0035619
16
Jahng, S., Wood, P. K., & Trull, T. J. (2008). Analysis of affective instability in 
ecological momentary assessment: Indices using successive difference and group 
comparison via multilevel modeling. Psychological methods, 13(4), 354.


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Boehringer Ingelheim
TSAP for BI Trial No: 1402.0012
c36236762-02
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TSAP for BI Trial No: 1402.0012
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TSAP for BI Trial No: 1402.0012
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TSAP for BI Trial No: 1402.0012
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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
Author
Sections 
changed
Brief description of change
1
19-JAN-23
None
This is the final TSAP
2
26-JAN-23
Throughout 
document
To address Checklist 
comments from the 
Archiving group


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F

WVDS
WVDS
$SSURYDO0HGLFDO:ULWHU
-DQ&(7
$SSURYDO%LRVWDWLVWLFV
-DQ&(7
$SSURYDO3URMHFW6WDWLVWLFLDQ
-DQ&(7
$SSURYDO&OLQLFDO7ULDO/HDGHU
-DQ&(7
$XWKRU7ULDO&OLQLFDO
3KDUPDFRNLQHWLFLVW
-DQ&(7


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F
