Conditions: Post-Traumatic Stress Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 318
Healthy volunteers: no

Brief summary:
This study is open to people aged 18 to 65 who have post-traumatic stress disorder. The purpose of this study is to find out whether a medicine called BI 1358894 improves symptoms in people with post-traumatic stress disorder.

Participants are put into 2 groups randomly, which means by chance. Participants take BI 1358894 or placebo as tablets every day for 2 months. Placebo tablets look like BI 1358894 tablets but do not contain any medicine.

Participants are in the study for about 3 months. During this time, they visit the study site about 8 times and get about 4 phone calls from the trial staff. During the study, participants answer questions in interviews and complete questionnaires so the doctors can check whether their symptoms change.

The doctors also regularly check participants' health and take note of any unwanted effects.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 1358894 intervention 2: Placebo
Intervention descriptions: intervention 1: BI 1358894 intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (19.0) / Saved on: 05 Nov 2020
Clinical Trial Protocol
TITLE PAGE
Document Number:
c34993667-05
EudraCT No.
EU Trial No.
2021-003154-23 
BI Trial No.
1402-0030
BI Investigational
Medicinal Product(s)
BI 1358894
Title
A Phase II, 8-week-treatment, multicenter, randomized, double-
blind, placebo-controlled, parallel group trial to evaluate the 
efficacy, tolerability and safety of orally administered BI 1358894 
in patients with Post-Traumatic Stress Disorder (PTSD)
Lay Title
A study to test whether taking BI 1358894 for 8 weeks helps 
adults with post-traumatic stress disorder
Clinical Phase
II
Clinical Trial Leader
Phone:
, Fax: 
Email: 
Coordinating 
Investigator
Phone:
, Fax: 
Current Version and 
Date
Version 5.0, 09 JUN 2023
Page 1 of 148
Proprietary confidential information.
2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Original Protocol date
22 Jul 2021
Revision date
09 JUN 2023
BI trial number
1402-0030
Title of trial
A Phase II, 8-week-treatment, multicenter, randomized, double-
blind, placebo-controlled, parallel group trial to evaluate the 
efficacy, tolerability and safety of orally administered BI 1358894 in 
patients with Post-Traumatic Stress Disorder (PTSD)
Coordinating 
Investigator
Phone: 
, Fax: 
Trial site(s)
Multi-centre trial conducted in approximately 10 countries
Clinical phase
II
Trial rationale
Currently the only generally approved medication for treatment of 
PTSD are the selective serotonin reuptake inhibitors (SSRIs) 
sertraline and paroxetine. These medications produce reduction in 
symptom severity rather than symptom remission, do not treat all 
symptoms, and have a relatively low usage in patients with PTSD. 
Currently most national guidelines recommend psychotherapy as 
first line treatment for PTSD in adults and medications to be used as 
second line treatment. Thus there is a significant unmet medical 
need for more efficacious medications for first-line treatment of 
PTSD.
Trial objective(s)
The main objective of this trial is to provide proof of concept (PoC) 
of orally administered BI 1358894 125mg after eight weeks 
treatment in patients with PTSD compared to placebo.
Trial endpoints
Primary Endpoint: 
Change from baseline in Clinician-Administered PTSD Scale for 
DSM-5 (CAPS-5) total severity score at Week 8
Secondary Endpoints:
Response defined as ≥30% CAPS-5 reduction from baseline at 
Week 8
Response defined as ≥50% CAPS-5 reduction from baseline at 
Week 8
Change from baseline on the PTSD Checklist for DSM-5 total 
score at Week 8
Trial design
A Phase II, 8-week-treatment, multicenter, randomized, double-
blind, placebo-controlled, parallel group trial in patients with Post-
Traumatic Stress Disorder (PTSD)


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Total number of 
patients randomised 
The planned maximum number of patients to be randomized is 286, 
which includes an expected drop-out rate of 30%
Number of patients per 
treatment group
Patients will be randomized in a 1:1 ratio
Diagnosis
Patients with an established diagnosis of Post-Traumatic Stress 
Disorder confirmed at the time of screening by the Clinician-
Administered PTSD Scale for DSM-5 (CAPS-5)
Main inclusion and 
exclusion criteria
Main Inclusion Criteria:
Established diagnosis of Post-Traumatic Stress Disorder (PTSD) 
corresponding to Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria.
Time since index event according to Life Events Checklist/
CAPS-5 Criterion A at least 3 months before screening visit.
PTSD must be the clinically pre-dominant disorder, as per 
investigator´s judgement. Other comorbid psychiatric disorders 
are allowed, unless specifically excluded in the exclusion criteria. 
A total severity score of ≥33 on the PCL-5 at the screening visit.
Moderate to severe PTSD confirmed by CAPS-5 range ≥ 30 
confirmed at screening visit. 
Male or female patients, 18 to 65 years of age, both inclusively at 
the time of informed consent.
Women who are of child-bearing potential (WOCBP) must be 
able and willing to use two methods of contraception, as 
confirmed by the investigator.
Main Exclusion Criteria:
Corresponding to DSM-5, had ever met diagnostic criteria for 
schizophrenia, schizoaffective disorder, schizophreniform 
disorder, bipolar disorder, delusional disorder, brief psychotic 
disorder or any other psychotic disorder as well as MDD with 
psychotic features as assessed by the MINI at the time of 
screening.
Any psychiatric or non-psychiatric medical condition likely to 
negatively impact trial participation as per the judgement of the 
investigator. 
Acute stress disorder or significant traumatic event within 3 
months prior to the screening visit.
Use of stimulant medications within 3 months prior to the 
screening visit (Attention deficit hyperactivity disorder (ADHD)
diagnosis alone is not exclusionary)
Severe traumatic brain injury (life-time) or moderate traumatic 
brain injury within the last 2 years prior to screening visit or 3 
months for mild traumatic brain injury, based on the Ohio State 
University TBI Identification Method Short Form. Or history of 
traumatic brain injury that would impact ability to complete trial 
assessments or procedures according to investigator.


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Current treatment with trauma focused therapy (i.e. Cognitive 
Processing Therapy (CPT), Prolonged Exposure Therapy (PE), 
Eye Movement Desensitization and Reprocessing (EMDR)). A 
psychotherapy in type, intensity and/or frequency other than 
trauma focused therapy is allowed if stable within the last 8 
weeks prior to screening and not anticipated to change during the 
entire course of the trial. Long-term psychotherapy is permitted 
as long as patients are not in an exposure phase during the trial.
Diagnosis of a current moderate or severe alcohol use disorder 
(AUD) according to MINI within 3 months prior to screening 
visit (mild AUD and patients in early remission = criterion not 
met for between 3 & 12 months are allowed).
Diagnosis of a substance use disorder (non-alcohol) according to 
MINI within 12 months prior to screening visit. Caffeine and 
nicotine are allowed. 
Positive urine drug screen at the screening visit. Exception: stable 
opioid-treatment with medically prescribed opioids. Please refer 
to section 3.3 Retesting for retesting options within the screening 
period.
Any suicidal behavior in the past 12 months prior to screening 
(per investigator judgement including an actual attempt, 
interrupted attempt, aborted attempt, or preparatory acts or 
behavior) and during the screening period. 
Any suicidal ideation of type 4 or 5 in the Columbia Suicide 
Severity Rating Scale (C-SSRS) in the past 3 months prior to 
screening or at screening or baseline visit (i.e. active suicidal 
thought with method and intent but without specific plan, or 
active suicidal thought with method, intent and plan). 
Treatment with benzodiazepines is allowed if stable in dose and 
frequency of use for at least 2 months prior to randomization 
visit. Note: PRN- use is not permitted.
Antipsychotics, antidepressants and other psychiatric medication 
are allowed if stable in dose and frequency of use for at least 2 
months prior to randomization visit
Any use of restricted medications within 7 days prior to 
randomization visit
Patients who must or wish to continue the intake of restricted 
medications or any drug considered likely to interfere with the 
safe conduct of the trial. 
Use of alternative medicine (e.g. Chinese traditional medicine, 
herbal medication, St. John’s wort, etc.) during the entire course 
of the trial.
History of seizure disorders, stroke, brain tumor or any other 
major neurological illness that can impact participation in the 
trial. 


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Resting QTcF ≥450 msec (male) or ≥460 msec (female) at 
screening.
Patients who are currently involved in any ongoing legal 
processes related to the index traumatic event (e.g. lawsuit or 
criminal prosecution).
In-patients are generally excluded, however in-patients who are 
admittedon a voluntary basis in an open-ward (i.e. "residential 
ward") and are non-suicidal are allowed.
Test product(s)
BI 1358894
dose
125 mg; once daily
mode of 
administration
Per os
Comparator product(s)
Placebo
dose
NA for placebo
mode of 
administration
Per os
Duration of treatment
8 weeks
Statistical methods
Restricted maximum likelihood (REML) based approach using a 
mixed effects model with repeated measures (MMRM) will be 
utilized as the main estimator of the primary estimand on the 
primary endpoint. Intercurrent events will be handled as specified in 
Section 7. The MMRM model will include the fixed categorical 
effects of treatment at each visit, fixed categorical effect of the 
stratification factor of presence of significant childhood trauma (yes 
vs. no) according to investigator´s judgement, assessed by CTQ at 
screening visit, and the fixed continuous covariates of time since 
index event (in years) and baseline CAPS-5 total score at each visit. 
Patient is treated as random effect. Visit will be treated as the 
repeated measure with an unstructured covariance structure used to 
model the within-subject measurements.
Sensitivity analyses for the primary estimand and analyses based on 
supplementary estimand(s) are planned to assess the robustness of 
the results from the primary estimand analysis, for details please see 
Section 7.2.3.
An interim analysis is planned for internal planning of the PTSD 
indication with BI 1358894. PoC could be established and the trial 
may be stopped early if at the interim analysis an impressive 
standardized effect size is observed. For more details, please refer to 
Section 7.2.8.


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FLOW CHART 1
Trial Periods
Screening
Randomized Treatment
Early D/C
Follow-up / End of Study
Visit
1
1A1
2
3
2
4
5
2
6
7
2
8
9
2
10/ 
EOT*
Early EOT
(eEOT)**
11
Follow-up Visit (FUP) / 
End of Study (EOS)
Week
0
1
2
3
4
5
6
7
8
12
Day
-28 days
V1A 
anytime up 
to 8 days 
before V2
13
8±2
15±2
22±2
29±2
36±2
43±2
50±2
57+2
EOT / (Early drug discontinuation 
date) plus 28+2 days
Informed consent 4
(including informed 
consents for patient’s 
duplicate check5, 
optional biobanking 
and speech recording; 
counseling about the 
need of contraception)
x
Demographics6
x
Medical history 
(including headaches)
x
Pandemic restrictions7
x
x
x
x
Physical examination
x
x
x
x
x
x
Vital signs, including 
body weight (height 
only at SCR)
x
x
x
x
x
x
x
x


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Trial Periods
Screening
Randomized Treatment
Early D/C
Follow-up / End of Study
Visit
1
1A1
2
3
2
4
5
2
6
7
2
8
9
2
10/ 
EOT*
Early EOT
(eEOT)**
11
Follow-up Visit (FUP) / 
End of Study (EOS)
Week
0
1
2
3
4
5
6
7
8
12
Day
-28 days
V 1A
anytime up 
to 8 days 
before V2
13
8±2
15±2
22±2
29±2
36±2
43±2
50±2
57+2
EOT / (Early drug discontinuation 
date) plus 28+2 days 
12 lead-ECG
x
x
x
x
x
Laboratory test 
(safety labs)
x
x
x
x
x
x
x
Pregnancy tests8
x
x
x
x
x
x
x
x
x
Contraception 
counseling for WOCB16
x
x
x
x
x
x
x
x
x
x
x
Infection testing9
x
Urine drug screening
x
x
x
x
x
x
Review of in-
/exclusion criteria
x
x
Randomisation
x
Interactive Response 
Technology Use
x
x
x
x
x
x
x
Patient Duplicate 
Check5
x
x
x
x
x


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Trial Periods
Screening
Randomized Treatment
Early D/C
Follow-up / End of Study
Visit
1
1A1
2
3
2
4
5
2
6
7
2
8
9
2
10/ 
EOT*
Early EOT
(eEOT)**
11
Follow-up Visit (FUP) / 
End of Study (EOS)
Week
0
1
2
3
4
5
6
7
8
12
Day
-28 days
V 1A 
anytime up 
to 8 days 
before V2
1 3
8±2
15±2
22±2
29±2
36±2
43±2
50±2
57+2
EOT / (Early drug discontinuation 
date) plus 28+2 days 
Administration of trial 
drugs at trial site10
x
x
x
x
Dispense trial drugs10
x
x
x
x
Drug Accountability10
x
x
x
x
x
Termination of trial 
medication
x
x
PTSD specific 
assessments / 
procedures
(see Flow Chart 2)
x
x
x
x
x
x
x
x
x
x
x
x
x


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Trial Periods
Screening
Randomized Treatment
Early D/C
Follow-up / End of Study
Visit
1
1A1
2
3
2
4
5
2
6
7
2
8
9
2
10/ 
EOT*
Early EOT
(eEOT)**
11
Follow-up Visit (FUP) / 
End of Study (EOS)
Week
0
1
2
3
4
5
6
7
8
12
Day
-28 days
V 1A 
anytime up 
to 8  days 
before V2
1 3
8±2
15±2
22±2
29±2
36±2
43±2
50±2
57+2
EOT / (Early drug discontinuation 
date) plus 28+2 days 
All AEs/SAEs/AESIs 
14
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
Substance use 15
x
x
x
x
x
x
x
x
x
Documentation of
meal intake11
x
x
x
x
x
x
Completion of patient’s 
participation 
x
At the screening visit, all clinical examinations and procedures as per Flow Chart 1 should be performed first, followed by PCL-5 (version comprising LEC, Extended Criterion A and 
PCL5),CAPS-5 and MINI, followed by the other clinical outcome assessments, listed in Flow Chart 2. Blood draws are preferably done after clinical outcome assessments . The order of 
assessments and procedures is described in detail in section 6.2.
For all further clinical visits, please refer to section 6.2.2 for details on order of assessments and procedures.
* End of treatment (EOT) for patients who complete the treatment period at Visit 10.


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** Patients who discontinue trial drug prematurely:
Ideally, the patients should attend all remaining visits and perform all study related procedures according to Flow Charts and section 6.2.2. An early EoT (eEOT) Visit shall be conducted 
within 7 days of the last dose of trial medication for patients who agree to conduct regularly scheduled visits after premature drug discontinuation (if consistent with the planned visit 
schedule, the eEOT can replace the next regularly scheduled clinic visit). After this early EOT visit, patients should be followed up according to the regularly scheduled visit for both 
clinic and phone visits including Visit 10 and should be encouraged to complete the FUP Visit 28+2 days after the drug discontinuation date. All procedures should be completed, with the 
exception of trial drug procedures and 
. If a regular planned visit is completed prior to the initially planned Visit10 (early drug discontinuation date + 28+2 days), no 
additional FUP Visit may be needed. However, end of study participation (EOS) must be completed.
If the patient does not agree to return for all remaining scheduled visits, the patient should be encouraged to return at least for an early EoT (eEOT) Visit within 7 days of the last dose of 
trial medication, for the regularly scheduled Visit 10 and FUP. If FUP visit (early drug discontinuation date + 28 +2 days) can be completed prior to the date of the planned Visit 10, no 
additional FUP Visit may be needed. However, end of study participation (EOS) must be completed.
1 Eligibility of patients is to be confirmed before Visit 1A is scheduled. Visit 1A must be scheduled at minimum 8 days  prior to V2 to allow for 7 days of EcMA assessments before 
randomization. The randomization visit V2 should be planned shortly (preferably within the same week) after completion of the 7 day EcMA baseline assessment period.
2 Visits 3, 5, 7 and 9 will be conducted via telephone or by video call, if in line with local regulation.
3 Day of Randomisation / Day of first intake of randomized medication – all activities, except 
, should be done before drug administration. For exceptions please refer to 
section 6.2.2.
4 Informed consent may also be done at an extra visit up to 2 weeks before V1., prior to any trial related procedure.The optional informed consent for speech recordings has to be signed prior to 
speech recording related study procedures at V1A at the latest.
5 Patients duplicate check is a mandatory process, local amendments will be prepared as applicable. Registration of patient in the 
system by site staff is only required 
during the Screening Visit; no further action for the site staff during the course of the study.
6 Demographics in the eCRF will include questions on potential disability payments related to PTSD
7 The patient will be asked to evaluate the impact of COVID-19 pandemic restrictions. Please refer to section 6.2.2. for detailed information. 
8 For WOCBP, a serum pregnancy test will be performed at screening and urine pregnancy tests at all clinic visits beginning with V1A. If a urine pregnancy test is positive, a serum test needs to 
be performed for confirmation. 
9 Infection testing during V1 for hepatitis B and hepatitis C.
10 Patients will bring trial medication (used/unused blister and covering packages) to site visits for compliance check (V4,V6,V8, EOT/eEOT) and for resupply (V4,V6,V8). Patients have to 
take the IMP at the trial site at all treatment visits (except V10/EOT) to allow adequate sampling of pharmacokinetic samples. Last regular intake of the trial drug is the day before EOT 


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13 One sample for 
 will be taken, preferably at Visit 2. However, collection at later visits is permitted as long as the informed consent 
 
remains valid
14 After the EoStudy visit (= individual patient’s end of the trial) the investigator should report only any cancers of new histology and exacerbations of existing cancer, trial treatment related 
SAEs and trial treatment related AESIs of which the investigator may become aware of and only via the BI SAE form, please see section 5.4.6.2.2.
15 Substance in the eCRF is defined as: caffeine, nicotine and alcohol.
16 This must include confirmation from the patient that she is using required contraception consistently and appropriately. Counseling and contraception confirmation must be recorded in CRFs
Refer to section 4.2.2.3 for more details regarding contraception counseling.
For potential modifications of trial conduct in case of restrictions due to COVID-19, please refer to sections 4.1.4, 6.1, 8.1 and 10.3


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FLOW CHART 2
Trial Periods
Screening
Randomized Treatment
Early 
D/C
Follow-up /
End of 
Study
Approx. 
performance 
duration per 
assessment
Visit
1
1A1
2
3
2
4
5
2
6
7
2
8
9
2
10/ 
EOT*
Early 
EOT
(eEOT)
**
11
Follow-up 
Visit (FUP)/ 
End of 
Study (EOS)
Week
0
1
2
3
4
5
6
7
8
12
Day
-28 days
V 1A 
anytime up 
to 8 days 
before V2
1 3
8±2
15±2
22±2
29±2
36±2
43±2
50±2
57+2
EOT / (Early 
drug discon-
tinuation 
date) plus 
28+2 days 
Clinician administered assessments
MINI
x
20 min
CAPS-54
x
x
x
x
x
45-60 min
CGI-S
(total and domain)
x
x
x
x
5-10 min
each
CGI-C
x
x
5-10 min
OSU TBI-ID-SF
x
5 min
C-SSRS5
x
x
x
X
x
x
x
x
x
x
x
x
x
5-10 min


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Trial Periods
Screening
Randomized Treatment
Early 
D/C
Follow-up /
End of 
Study
Approx. 
performance 
duration per 
assessment
Visit
1
1A1
2
3
2
4
5
2
6
7
2
8
9
2
10/ 
EOT*
Early 
EOT
(eEOT)
**
11
Follow-up 
Visit (FUP)/ 
End of 
Study (EOS)
Week
0
1
2
3
4
5
6
7
8
12
Day
-28 days
V 1A 
anytime up 
to 8 days 
before V2
1 3
8±2
15±2
22±2
29±2
36±2
43±2
50±2
57+2
EOT / (Early 
drug discon-
tinuation 
date) plus 
28+2 days 
Speech recordings 
(optional)
x
x
x
x
x
10 min
Patient Reported Outcomes
CTQ
x
10 min
PCL-56
x
x
x
x
x
5-10 min
PGI-S
x
x
x
x
5 min
PGI-C
x
x
5 min
STAI
x
x
x
x
10 min
PHQ-9
x
x
x
x
5 min


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Trial Periods
Screening
Randomized Treatment
Early 
D/C
Follow-up /
End of 
Study
Approx. 
performance 
duration per 
assessment
Visit
1
1A1
2
3
2
4
5
2
6
7
2
8
9
2
10/ 
EOT*
Early 
EOT
(eEOT)
**
11
Follow-up 
Visit (FUP)/ 
End of 
Study (EOS)
Week
0
1
2
3
4
5
6
7
8
12
Day
-28 days
V 1A 
anytime up 
to 8 days 
before V2
1 3
8±2
15±2
22±2
29±2
36±2
43±2
50±2
57+2
EOT / (Early 
drug discon-
tinuation 
date) plus 
28+2 days 
DERS-16
x
x
x
x
5-8 min
PSQI
x
x
x
x
5-10 min
SDS
x
x
x
3-5 min
EQ-5D-5L
x
x
x
5 min


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Trial Periods
Screening
Randomized Treatment
Early 
D/C
Follow-up /
End of 
Study
Approx. 
performance 
duration per 
assessment
Visit
1
1A1
2
3
2
4
5
2
6
7
2
8
9
2
10/ 
EOT*
Early 
EOT 
(eEOT)*
*
11
End of 
Study 
(EOS)
Week
0
1
2
3
4
5
6
7
8
12
Day
-28 days
V 1A 
anytime up 
to 8 days 
before V2
1 3
8±2
15±2
22±2
29±2
36±2
43±2
50±2
57+2
EOT / 
(Early drug 
discon-
tinuation 
date) plus 
28+2 days 
Additional Patient Assessments/Procedures
Patient informational 
video placebo response 
mitigation7
x
5 min
Patient training video
speech recording7
x
5 min
Training on 
Smartphone App8
x
10-15 min
Drug intake adherence
monitoring9
  all IMP intake at clinical site and at home 
5 min
EcMA assessments10
performed once daily/weekly for 7 days prior V2 and
until the day before V10 
5-10 min


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At the screening visit, all clinical examinations and procedures  as per Flow Chart 1 should be performed first, followed by PCL-5 (version comprising LEC, Extended Criterion A and 
PCL5),CAPS-5 and MINI, followed by the other clinical outcome assessments, listed in Flow Chart 2. Blood draws are preferably done after clinical outcome assessments . The order of 
assessments and procedures is described in detail in section 6.2.
For all further clinical visits, please refer to section 6.2.2 for details on order of assessments and procedures.
1 Eligibility of patients is to be confirmed before Visit 1A is scheduled. Visit 1A must be scheduled at minimum 8 days  prior to V2 to allow for 7 days of EcMA assessments before 
randomization. The randomization visit V2 should be planned shortly (preferably within the same week) after completion of the 7 day EcMA baseline assessment period.
2 Visits 3, 5, 7 and 9 will be conducted via telephone or by video call, if in line with local regulation.
3 Day of Randomisation / Day of first intake of randomized medication – all activities, except postdose PK sampling, should be done before drug administration. For exceptions please refer to 
section 6.2.2.
4 The CAPS-5 past month version will be used at the screening visit for PTSD diagnosis and eligibility assessment. At the randomization visit V2 and at all subsequent study visits, the CAPS-5  
past week version will be used.
5 C-SSRS: Columbia Suicide Severity Rating Scale baseline/screening version used at Screening, Columbia Suicide Severity Rating Scale since-last-visit version used for all subsequent study 
visits
6 At the screening visit, the PCL-5 version including Life Events Checklist, DSM-5 version (LEC-5) and Criterion A assessment; on all subsequent assessments in the trial., the PCL-5 only, will 
be used. Please refer to section 6.2.
7 Short educational videos will be presented to patient to provide guidance on how to perform the optional speech recording sampling and about placebos (mandatory at V1A) - see further 
details in section 6.2.1
8 During visit 1A, the patient will receive the Smartphone App and will be trained on the EcMA and drug adherence monitoring procedures. Site staff will configure the App for the planned 
randomization visit date. Visit 1A must be scheduled at minimum 8 days prior to V2 to allow for 7 days of EcMA assessments before randomization and start of drug treatment. 
9 Self-monitoring of IMP intake each treatment day by the patient via the Smartphone App. The drug-adherence assessments will start with the first administration of the trial drug at 
randomization. For site monitoring of patient adherence using the 
, please refer to section 5.8.3. 
10 EcMA assessments will be performed by the patient using the Smartphone App. The baseline EcMA assessments will start the day after V1A and last for 7 days prior to the planned V2 
(randomization visit date). Site staff will configure the App so that EcMAs will automatically start the day after V1A. EcMA assessments will then be performed daily/weekly in the 
evenings at each trial day until the end of treatment, the day before visit V10/EOT or eEOT. The exact timing of assessment can be defined by the patient and should be kept as consistent 
as possible throughout the study. For details, please refer to section 5.8.1. 


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART 1.....................................................................................................................6
FLOW CHART 2...................................................................................................................12
TABLE OF CONTENTS ......................................................................................................17
ABBREVIATIONS AND DEFINITIONS...........................................................................22
1.
INTRODUCTION...............................................................................................27
1.1
MEDICAL BACKGROUND.............................................................................27
1.2
DRUG PROFILE................................................................................................27
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................31
1.4
BENEFIT - RISK ASSESSMENT.....................................................................32
1.4.1
Benefits.................................................................................................................32
1.4.2
Risks .....................................................................................................................32
1.4.3
Discussion.............................................................................................................40
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................41
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........41
2.1.1
Main objectives....................................................................................................41
2.1.2
Primary endpoint(s)............................................................................................41
2.1.3
Secondary endpoint(s) ........................................................................................41
2.2.3
Safety....................................................................................................................42
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................43
3.1
OVERALL TRIAL DESIGN.............................................................................43
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................44
3.3
SELECTION OF TRIAL POPULATION .......................................................44
3.3.1
Main diagnosis for trial entry ............................................................................46
3.3.2
Inclusion criteria .................................................................................................46


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3.3.3
Exclusion criteria ................................................................................................46
3.3.4
Discontinuation of patients from treatment or assessments ...........................48
3.3.4.1
Discontinuation of trial treatment.....................................................................49
3.3.4.2
Withdrawal of consent to trial participation....................................................50
3.3.4.3
Discontinuation of the trial by the sponsor.......................................................50
4.
TREATMENTS...................................................................................................52
4.1
INVESTIGATIONAL TREATMENTS ...........................................................52
4.1.1
Identity of the Investigational Medicinal Products..........................................52
4.1.2
Selection of doses in the trial and dose modifications......................................52
4.1.3
Method of assigning patients to treatment groups...........................................54
4.1.4
Drug assignment and administration of doses for each patient......................54
4.1.5
Blinding and procedures for unblinding...........................................................55
4.1.5.1
Blinding................................................................................................................55
4.1.5.2
Unblinding and breaking the code ....................................................................56
4.1.6
Packaging, labelling, and re-supply...................................................................56
4.1.7
Storage conditions...............................................................................................56
4.1.8
Drug accountability.............................................................................................57
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................57
4.2.1
Other treatments and emergency procedures..................................................57
4.2.2
Restrictions ..........................................................................................................57
4.2.2.1
Restrictions regarding concomitant treatment ................................................57
4.2.2.2
Restrictions on diet and life style.......................................................................59
4.2.2.3
Contraception requirements..............................................................................59
4.3
TREATMENT COMPLIANCE........................................................................60
5.
ASSESSMENTS..................................................................................................62
5.1
CONFIRMATION OF DIAGNOSIS................................................................62
5.2
ASSESSMENT OF EFFICACY........................................................................63
5.2.1
Clinician administered assessments ..................................................................63
5.2.2
Patient Reported Outcomes ...............................................................................65
5.3
RATER QUALIFICATION...............................................................................69
5.4
ASSESSMENT OF SAFETY.............................................................................70


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5.4.1
Physical examination ..........................................................................................70
5.4.2
Vital signs.............................................................................................................70
5.4.3
Safety laboratory parameters ............................................................................70
5.4.4
Electrocardiogram ..............................................................................................74
5.4.5
Other safety parameters.....................................................................................74
5.4.5.1
Assessment of Suicidality....................................................................................74
5.4.6
Assessment of adverse events.............................................................................75
5.4.6.1
Definitions of AEs................................................................................................75
5.4.6.1.1
Adverse event.......................................................................................................75
5.4.6.1.2
Serious adverse event..........................................................................................76
5.4.6.1.3
AEs considered “Always Serious”.....................................................................76
5.4.6.1.4
Adverse events of special interest ......................................................................77
5.4.6.1.5
Intensity (severity) of AEs..................................................................................77
5.4.6.1.6
Causal relationship of AEs.................................................................................77
5.4.6.2
Adverse event collection and reporting.............................................................78
5.4.6.2.1
AE Collection.......................................................................................................78
5.4.6.2.2
AE reporting to the sponsor and timelines.......................................................79
5.4.6.2.3
Pregnancy ............................................................................................................79
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................79
5.6
ASSESSMENT OF BIOMARKER(S) ..............................................................80
5.7
BIOBANKING ....................................................................................................80
5.7.1
Methods and timing of sample collection..........................................................80
5.8
OTHER ASSESSMENTS...................................................................................80
5.8.1.2
Items .....................................................................................................................81
5.8.2
Speech recording.................................................................................................83
5.8.3
Medication Adherence and Reminder System.................................................84
5.8.4
Verification of current and past research study status of trial patient..........85


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5.9
APPROPRIATENESS OF MEASUREMENTS..............................................85
6.
INVESTIGATIONAL PLAN.............................................................................86
6.1
VISIT SCHEDULE.............................................................................................86
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................86
6.2.1
Screening Visit and Screening Period...............................................................87
6.2.2
Treatment period ................................................................................................91
6.2.3
Follow-up period and trial completion..............................................................93
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE .....................................................................................................................94
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................94
7.2
PLANNED ANALYSES.....................................................................................94
7.2.1
General considerations .......................................................................................94
7.2.2
Handling of Intercurrent Events .......................................................................94
7.2.3
Primary objective analyses.................................................................................96
7.2.4
Secondary objective analyses.............................................................................96
7.2.6
Safety analyses.....................................................................................................97
7.2.7
Other Analyses ....................................................................................................98
7.2.8
Interim Analyses .................................................................................................98
7.3
HANDLING OF MISSING DATA ...................................................................99
7.4
RANDOMISATION ...........................................................................................99
7.5
DETERMINATION OF SAMPLE SIZE .........................................................99
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY AND ADMINISTRATIVE STRUCTURE .......102
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .........................................................................................................102
8.2
DATA QUALITY ASSURANCE ....................................................................103
8.3
RECORDS.........................................................................................................103
8.3.1
Source documents .............................................................................................103
8.3.2
Direct access to source data and documents...................................................104


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8.3.3
Storage period of records .................................................................................104
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................105
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......105
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................105
8.6
TRIAL MILESTONES.....................................................................................105
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................106
9.
REFERENCES..................................................................................................108
9.1
PUBLISHED REFERENCES..........................................................................108
9.2
UNPUBLISHED REFERENCES....................................................................112
10.
APPENDICES...................................................................................................113
10.1
INSTRUCTIONS FOR USE............................................................................113
10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.......................................................................................................113
10.3
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19 ..........................................................114
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................115
11.1
GLOBAL AMENDMENT 1 ............................................................................115
11.2
GLOBAL AMENDMENT 2 ............................................................................132
11.3
GLOBAL AMENDMENT 3 ............................................................................143
11.4
GLOBAL AMENDMENT 4 ............................................................................147


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ABBREVIATIONS AND DEFINITIONS
ACTH
Adrenocorticotropic hormone
ADHD
Attention Deficit Hyperactivity Disorder
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate Aminotransferase
AUC
Area under the Curve
AUD
Alcohol use disorder
BA
Bioavailability
BCRP
Breast Cancer Resistance Protein
BI
Boehringer Ingelheim
BOLD
Blood-oxygenation-level-dependent
BoPD
Borderline Personality Disorder
BUN
Blood Urea Nitrogen
CA
Competent Authority
CAPS-5
Clinician-Administered PTSD Scale for DSM-5
CBT
Cognitive Behavioral Therapy
CCK
Cholecystokinin
CGI-C
Clinical Global Impression Change Scale
CGI-S
Clinical Global Impression Severity Scale
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum Plasma Concentration
ClinRo
Clinician-rated Outcome
CNS
Central Nervous System
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CPT
Cognitive Processing Therapy
CRO
Contract Research Organisation
C-SSRS
Columbia Suicide Severity Rating Scale


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CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTgov
ClinicalTrials.gov
CTP
Clinical Trial Protocol
CTQ
Childhood Trauma Questionnaire
CYP
Cytochrome
DBL
Database Lock
D/C
Discontinuation
DDI
Drug-Drug Interaction
DERS-16
Difficulties in Emotion Regulation Scale – 16 item
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid 
DOB
Date of Birth
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
EC
Ethics Committee
ECG
Electrocardiogram
ECT
Electroconvulsive therapy
EcMAs
Ecological Momentary Assessments
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EMDR
Eye Movement Desensitization and Reprocessing
EoS
End of Study (corresponds with End of Trial)
EoT
End of Treatment
eEOT
Early End of Treatment
EQ-5D-5L
The Euro Qol -5 Dimensions -5 Levels
ES
Effect Size
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration


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FUP
Follow-up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HA
Health Authority
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LC-MS/MS
Liquid Chromatography tandem Mass Spectrometry
LEC-5
Life Events Checklist (DSM-5 version)
LPLT
Last patient last treatment
MAR
Missing at Random
MedDRA
Medical Dictionary for Drug Regulatory Activities
MDD
Major Depressive Disorder
MINI
MINI Neuropsychiatric Interview
MMRM
Mixed model repeated measures
MRD
Multiple Rising Dose
NOAEL
No Observed Adverse Effect Level
OATP
Organic Anion Transporting Polypeptide
OSU TBI-ID-SF Ohio State University TBI Identification Method Short Form
PANAS
Positive And Negative Affect Scales
PCL-5
PTSD Checklist for DSM-5
PCP
Phenylcyclohexyl piperidine
PCR
Polymerase Chain Reaction
PD
Pharmacodynamics
PE
Prolonged Exposure Therapy
PGI-C
Patient Global Impression Change Scale


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PGI-S
Patient Global Impression Severity Scale
PHQ-9
Patient Health Questionnaire - 9 items
PK
Pharmacokinetics
PoC
Proof of Concept
PoCP
Proof of Clinical Principle
PRN
Pro re nata
PRO
Patient Reported Outcome
PSQI
Pittsburgh Sleep Quality Index
PTSD
Post-Traumatic Stress Disorder
PXR
Pregnane X Receptor
q.d.
quaque die (once a day)
QTcF
Corrected QT Interval by Fridericia
RA
Regulatory Authority
REML
Restricted maximum likelihood
REP
Residual effect period
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SARS-COV-2
Severe acute respiratory syndrome coronavirus 2
SDS
The Sheehan Disability Scale
SES
Standardized Effect Size
SIB
Suicidal Ideation and Behavior 
SNRI
Selective serotonin-noradrenalin-reuptake-inhibitor
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SSRI
Selective serotonin reuptake inhibitors
STAI
The State-Trait Anxiety Inventory for Adults
SUSAR
Suspected Unexpected Serious Adverse Reactions
TRPC
Transient receptor potential cation channel
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UGT
UDP-Glucuronosyltransferase
ULN
Upper limit of normal
WHO
World Health Organisation


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WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Post-Traumatic Stress Disorder (PTSD) is a serious debilitating disorder that may occur in 
people who have experienced or witnessed a traumatic event such as a natural disaster, a 
serious accident, a terrorist act, war/combat, rape or who have been threatened with death, 
sexual violence or serious injury. The lifetime prevalence is estimated at nearly 4% globally 
and over 8% in the USA[R21-1545, R21-0924]. Symptoms of PTSD include unwanted and 
intrusive thought and memories, avoidance of trauma-related thoughts, feelings, and 
reminders, negative thoughts or feelings following the trauma, and increased arousal and 
reactivity. 
Most treatment guidelines generally recommend cognitive behavioral therapy (CBT) as 1st 
line treatment for PTSD in adults and pharmacotherapy as 2nd line treatment [R21-1276].
Despite the high prevalence, there are limited licensed pharmacological treatment options; 
only two medications are currently approved for the treatment of PTSD by the US FDA, 
EMA and PMDA, sertraline and paroxetine. However, pharmacotherapy is widely 
acknowledged to be ineffective for many people with PTSD [R21-1829]. There is currently 
an urgent need to find novel effective pharmacologic treatments for PTSD [R21-1828]
1.2
DRUG PROFILE
Transient Receptor Potential Cation (TRPC) channels 4 and 5 are involved in the regulation 
of neuronal excitability. They are highly expressed in the amygdala, frontal cortex, 
hippocampus, and hypothalamus [R15-3888] which are the brain regions involved in 
modulation and processing of emotion and affect.
BI 1358894 is a TRPC4/5 inhibitor that is being developed for symptomatic treatment of 
Major Depressive Disorder and for the treatment of Borderline Personality Disorder (BoPD) 
and Post-Traumatic Stress Disorder (PTSD).
Therefore, it is expected that treatment with BI 1358894 has the potential to improve 
affective symptoms and impaired emotion regulation especially in patients with PTSD in 
order to develop a novel treatment option and in patients with MDD who inadequately 
respond to the current standard of care (SSRI; SNRI) and in patients with BoPD, where no 
approved treatment is currently available.
Mode of action
BI 1358894 is a highly potent and selective TRPC4/5 Inhibitor (transient receptor potential 
cation channel, subfamily C, members 4 and 5). It has the potential to address core symptoms 
of PTSD, MDD and BoPD as it targets TRPC4/5 ion channels. TRPC4 and TRPC5 are highly 
expressed in pyramidal neurons of the amygdala in the frontal cortex, hippocampus, and 
hypothalamus, brain areas that are involved in circuits contributing to emotional control. It is 
hypothesized that in patients with mood disorders, an overactive amygdala is a major 
contributor to attentional bias to negative stimuli, pessimistic thoughts and anxiety 


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[R16-5473].BI 1358894 is thought to decrease neuronal excitability leading to normalization 
of the activation state of limbic circuits which are known to be important for emotional 
control. Therefore, it is expected that augmentation treatment with BI 1358894 has the 
potential to improve symptoms of patients with PTSD addressing and improving core 
debilitating symptoms of the disease and helping patients to be less affected by triggers in 
daily life and develop healthier coping strategies.
Data from non-clinical studies
Pre-clinically, it has been demonstrated that lack of TRPC4 and TRPC5 or its 
pharmacological inhibition with BI 1358894 attenuated fear and anxiety without impairing 
other behaviours in mice.
BI 1358894 is a potent inhibitor of TRPC4 and TRPC5 containing channels. In vitro studies 
confirmed the high selectivity of the compound. In vivo the compound demonstrated efficacy 
in various rodent tests used to investigate circuits associated with depression and anxiety 
[c10354149].
BI 1358894-related effects on the central nervous system of rats were limited to an early and 
transient increase of motility at dose levels of 10, 30, and 100 mg/kg (nocturnal motility test). 
This is considered to reflect an increased arousal or decreased anxiety in a novel environment 
associated with the intended efficacy.
The toxicology profile of BI 1358894 has been evaluated so far in a comprehensive set of in
vitro and in vivo studies. Doses and concentrations were adequately high to explore the full 
range of potential adverse effects following exposure to BI 1358894. The studies support 
clinical trials of up to 13 weeks duration in adults, including women of childbearing potential.
The single dose toxicity of BI 1358894 was low in mice and rats and moderate in dogs. 
Repeat dose toxicity studies up to 13 weeks in mice, rats and dogs revealed toxicologically 
relevant effects on the skin (mice), Harderian glands (mice), hepatic function (mice), the 
vascular system (rats) male genital track (rats), the Central Nervous System (CNS) function 
(dogs), and the digestive tract, renal function, and white blood cell parameters in all three 
species. Further details on specific toxicity are available in the Investigator’s Brochure 
[IB, c10354149]. In addition, clinical pathology evaluation showed mild inflammatory 
response at high dose levels in rodents (for details including safety margins refer to section 
4.1.2)
BI 1358894 did not show any genotoxic potential when tested in a battery of in vitro and in 
vivo studies. No relevant immunotoxicity was demonstrated in mice, rats, and dogs.
BI 1358894 was negative in the in vitro 3T3 Neutral Red Uptake phototoxicity test.
Dedicated studies on fertility and early embryonic development were not yet conducted. So 
far repeat-dose toxicity studies revealed no adverse effects on the male or female 
reproductive tract. However, the weight of male sex organs was slightly reduced in rats after 
dosing for 13 weeks.


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Testing for embryo-fetal development in rats revealed no findings related to BI 1358894. The 
highest dose tested, 1000 mg/kg/day, represented the NOAEL (No Observed Adverse Effect 
Level) for maternal and embryo-fetal toxicity. Safety margins derived thereof were 5.6 and 
5.9 based on comparison of Cmax and AUC0-24h.
The well-known high sensitivity of rabbits to disturbances of intestinal physiology limited 
embryo-fetal toxicity testing in this species. Already sub-therapeutic doses of BI 1358894 
induced a non-obstructive ileus. A NOAEL for maternal toxicity could not be established in 
the pivotal study. However, there were no effect on the offspring at any dose that was 
considered to be directly related to dosing with BI 1358894. The highest tested dose
(10 mg/kg/day) was defined as the NOAEL for embryo-fetal toxicity in rabbits.
Oral administration of BI 1358894 to the pregnant Goettingen minipigs throughout 
organogenesis was associated with developmental effects including lower embryo-fetal 
survival (due to a reduced number of intrauterine implantations and an increased number of 
early resorptions) and decreased fetal weights, compared to control. In addition, there were 
higher incidences of skeletal malformations and/or variations. The NOAEL for embryo-fetal 
development (100 mg/kg/day) corresponded to a mean Cmax of 1,980 nmol/L and a mean 
AUC0-24h of 31,300 nmol∙h/L of BI 1358894, therefore providing safety margins of 1.4 and 
1.6, respectively (compared with the predicted exposure at the human dose of 125 mg).
Data from clinical studies
Overall, 211 healthy volunteers and 23 patients with MDD had been exposed to BI 1358894 
in 8 Phase I clinical trials. There were no deaths or SAEs in any of these trials. Headache was 
the most frequently reported adverse event (AE) with a higher frequency in the BI 1358894 
treated groups than in placebo. There was no evidence of a dose dependency based on the 
available data. Overall, BI 1358894 was well tolerated in healthy male patients, in male and 
female patients with MDD.
A comprehensive package of safety pharmacology and toxicology studies has been conducted 
and demonstrated that BI 1358894 can be safely administered to humans for up to 13 weeks.
Key pharmacokinetic characteristics
After administration of BI 1358894 tablets, maximum plasma concentration of BI 1358894 
occurred around 1 to 5 hours after dosing.
A long BI 1358894 terminal half-life of 188 hours with low plasma concentrations was found 
when blood samples were taken up to 672 hours. The terminal half-life was 41 to 52 hours for 
blood sampling up to 200 hours. Steady state was reached after 11 to 14 days of BI 1358894 
dosing, which is more in line with the half-life of 50 to 70 hours. Accumulation ratios for 
Cmax ranged from 1.6 to 1.8 and for AUC from 2.3 to 2.6.
Drug interactions
Based on in vitro Cytochrome (CYP) inhibition data and in perspective with clinical BI 
1358894 exposure data, no restriction of concomitant therapy with sensitive substrates of 
CYP enzymes were defined. No restrictions of concomitant therapy were defined based on in 
vitro UGT inhibition data of BI 1358894.


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BI 1358894 is not inhibiting or inducing CYP3A as was shown with the CYP3A sensitive 
substrate midazolam. There was no clinically relevant effect on the midazolam exposure 
when co-administered after single or multiple BI 1358894 doses compared with midazolam 
administration alone. Comedications, which are sensitive substrates of CYP3A, are not 
restricted.
Furthermore, absence of a clinically relevant induction of CYP3A by BI 1358894 is 
considered surrogate of absence of relevant induction of CYP2C family due to the shared
PXR dependent induction mechanism. Hence, sensitive drugs metabolised by the CYP2C 
family are also not restricted.
In vitro BI 1358894 induced CYP2B6, therefore a DDI study was performed with a CYP2B6 
substrate. As no clinically relevant induction was seen, there are no restrictions on the use of 
comedications for sensitive substrates of CYP2B6.
A drug interaction effect of BI 1358894 was observed with a strong CYP3A4 inhibitor. 
Coadministration with the strong CYP3A4 inhibitor itraconazole increased BI 1358894 total 
exposure (<2-fold). As the increase is less than 2-fold, there are no restrictions for the use of 
concomitant CYP3A4 inhibitors. 
In vitro data show that BI 1358894 is metabolised by UGTs and CYP3A4. In vivo data on 
metabolites was collected in the SRD and the MRD study. Human plasma was taken in both 
studies and analysed for human metabolites. The human plasma in both the SRD and the 
MRD study contained mainly the main metabolite, i.e. the carboxylic acid metabolite. Yet 
contained only minor amounts of other metabolites. Under steady state conditions, on day 14, 
for the 50 mg dose, only 1.6% glucuronide metabolite was found, which is formed via UGT 
enzymes. Since this is only a minor metabolic pathway, inhibitors of UGT enzymes can be 
included as concomitant therapy.
Strong CYP3A4 inducers are excluded from concomitant therapy due to potential lowering of 
BI 1358894 exposure.
Initial results from the DDI study 1402-0009 indicate that BI 1358894 has a weak drug 
interaction effect on drug transporter substrates. BI 1358894 may cause mild inhibition on P-
gp (probe substrate dabigatran, 1.2-fold mean increase in AUC and Cmax). The mild 
inhibition was assessed as clinically not relevant. Hence, the use of substrates for the drug 
transporters P-gp is not restricted. However, results from 1402-0009 suggest a mild to 
moderate interaction with Breast Cancer Resistance Protein (BCRP)/OATP1B1/OATP1B3, 
which results in an increase of rosuvastatin levels (1.8-fold mean increase in AUC and Cmax) 
when concomitantly taken with BI 1358894. The interaction could affect BCRP and Organic 
Anion Transporting Polypeptide (OATP) channels and could impact all statins, since these 
transporters play a significant and general role in statin metabolism. If statins are 
concomitantly used during the trial, the highest dose of the statin should not be taken together 
with the investigational compound. Patients concomitantly taking statins in this trial should 
be monitored for statin related toxicity including myopathy.


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Residual Effect Period
The Residual Effect Period (REP) of BI 1358894 is 28 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
For a more detailed description of the BI 1358894 profile, please refer to section 1.4 and the 
current Investigator’s Brochure (IB). For the most frequently reported adverse events refer to 
table 1.4.2:1.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Currently the only generally approved medication for treatment of PTSD are the selective 
serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. These medications produce 
reduction in symptom severity rather than symptom remission, do not treat all symptoms, and 
have a relatively low usage in patients with PTSD. Currently most national guidelines 
recommend psychotherapy as first line treatment for PTSD in adults and medications to be 
used as second line treatment. Thus there is a significant unmet medical need for more 
efficacious medications for first-line treatment of PTSD.
TRPC4/5 channels modulate the excitability of the amygdala/cortico-limbic system. As a 
TRPC4/5 inhibitor, the therapeutic concept of BI 1358894 is to decrease amygdala 
hyperreactivity and thus decrease emotional reactivity, emotional dysregulation, and affective 
instability across a range of psychiatric disorders where these are prominent symptoms. 
Clinical evidence supporting the therapeutic concept was demonstrated in an fMRI study in 
patients with MDD, where BI 1358894 produced a significant and robust decrease in the 
Blood-oxygenation-level-dependent (BOLD) activation of the amygdala in an emotional face 
task. In an emotional scene task the BOLD signal was also significantly and robustly reduced 
in amygdala and additional brain areas. BI 1358894 is currently being tested in Phase II 
clinical trials in patients with MDD and BoPD. Thus the MoA of this compound in principle 
holds significant potential benefit for individuals with PTSD.
For the PTSD patient trial population, a cut-point on the CAPS-5 of ≥ 30 was selected with 
the following rationale: In literature, the cut-point on the CAPS-5 of ≥ 30 has been postulated 
to represent a reasonable lower score representing moderate PTSD, being roughly in the 
middle of the moderate severity range (23-34) [R21-0830]. The cutoff criteria for CAPS-5 
were largely extrapolated from the empirically derived severity score ranges determined in 
the CAPS version based on DSM-IV (CAPS-IV), adjusting for the changes in the number of 
symptoms and the new metric for CAPS-5 item severities. The cutoff criterion of ≥ 30 is also 
acknowledged by PTSD experts to be clinically meaningful in terms of selecting for 
moderate severity of PTSD. It is further supported by evidence on the PCL-5 suggesting that
our selected cut-off on CAPS-5 of ≥ 30 is a reasonable cut-off for inclusion of patients in a 
treatment intervention trial.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see Section 5.7). If the patient agrees, banked 
samples may be used for future biomarker research and drug development projects, e.g. to 
identify patients that are more likely to benefit from a treatment or experience an adverse 
event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby 
better match patients with therapies.


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1.4
BENEFIT - RISK ASSESSMENT
The overall safety profile of BI 1358894 is outlined in the current IB c10354149.
1.4.1
Benefits
This is an experimental drug at an early stage of testing and therefore an individual benefit 
cannot be guaranteed. Potential efficacy has been demonstrated in pre-clinical and PoCP data.
1.4.2
Risks
In a comprehensive package of safety pharmacology, genetic toxicology, general toxicology, 
and nonclinical studies, BI 1358894 was demonstrated to be safe in humans for up to 13 
weeks. Based on the mode of action, the pharmacological target, non-clinical toxicology data 
and clinical data, BI 1358894 is not considered a high-risk compound for clinical studies. As 
in other clinical trials, trial patients are exposed to the risks related to the exposure to the trial 
medication and to the risks of the trial procedures.
In one completed pivotal embryo-fetal development study in Goettingen minipigs, embryo-
fetal development toxicity was identified (decreased number of implantations, increased 
number of early resorptions, decreased fetal weight, skeletal malformations) at relevant
human exposure levels. Maternal toxicity was not seen at human relevant doses. The NOAEL 
shows that the findings are relevant for the maximum dose (125 mg once daily) tested in the 
ongoing clinical trials.
Therefore, a risk for teratogenicity in humans cannot be excluded. To mitigate this risk, 
women of childbearing potential (WOCBP) who are heterosexually active must agree and 
adhere to contraceptive measures consisting of one highly effective method of birth control 
per ICH M3 (R2) that results in a low failure rate of less than 1% plus one additional barrier 
method during the treatment and follow-up period of the trial. Pregnancy testing has to be 
performed at every site visit. 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 1 (including phone visits).
While there are no precedent clinical data implicating association between TRPC4/5 
antagonism and Suicidal Ideation and Behavior (SIB), in the interest of ensuring patient 
safety, trial patients will be proactively screened and monitored throughout the trial for SIB 
in accordance with available regulatory guidance.
Because psychoactive drugs may impair thinking, judgment, and/or motor skills, patients 
should be cautioned about operating machinery, including automobiles, until they are 
reasonably certain that the study medication does not adversely affect their ability to engage 
in such activities. It is recommended that patients should exercise caution when driving or 
operating machinery.
Patients will be closely monitored during the trial participation (including AE monitoring 
beyond clinic visits and assessment of suicidal ideation during clinic visits) to ensure that 


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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.
The trial will be monitored by an external Data Monitoring Committee (DMC), independent 
from the sponsor; refer to section 8.7 for further DMC details.
BI 1358894 is a highly specific inhibitor of TRPC 4/5 channels, which are predominantly 
located in the CNS. All investigation into distribution and function of TRPC 4/5 (preclinical 
and clinical) so far have not identified any interference with the immune system, the 
respiratory system or the cardio-vascular system.
For the Phase II trial, the benefit-risk for the trial patients treated with BI 1358894 remain 
unchanged in relation to the COVID-19 pandemic since:

The mode of action does not appear to have a substantial effect on clinically relevant 
organs (e.g. respiratory or cardiovascular system) critically affected by COVID-19

There is currently no evidence that intake of BI 1358894 leads to immunosuppression

There is currently no evidence that their underlying disease (PTSD) makes the patients at 
higher risk to SARS-CoV-2 infection or to develop severe COVID-19

The PTSD 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 or patients participating in these studies will not differ from 
the current general risk for humans of SARS-CoV 2 infection with all its potential 
consequences. A specific SARS-CoV 2 PCR (Polymerase Chain Reaction) serving as a tool 
for inclusion or exclusion of trial patients during the screening phase is not foreseen, since it 
is not believed that study substance or comparator imply an elevated risk for the patient to 
develop COVID-19. It is also not believed that a SARS-CoV2 infection or clinical apparent 
COVID-19 impacts the activity of the investigational or comparator compound.
There is no restriction for trial patients to receive vaccination against COVID-19 during or 
after the study treatment period.
As part of the screening safety procedures, every patient will be assessed thoroughly, and 
individual benefit-risk assessments are made prior to study entrance and during the study by 
the investigator in respect of SARS-CoV2 infection. The investigators will take the totality of 
information related to each single patient, including but not limited to physical exam, vitals, 
ECG, safety labs, etc., and the local COVID-19 situation into consideration when performing 
the individual benefit-risk assessment. Considering all aspects, the investigator will decide 
upon each 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 CTP section 1.2 and the IB.


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Table 1.4.2:1 Overview over trial related risks
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Investigational Medicinal Product - BI 1358894
Most commonly reported 
AEs in Phase I were:

Headache

Dizziness

Orthostatic intolerance

Fatigue

Disturbance in attention

Dyspepsia

Nasopharyngitis
All reported AEs were of 
mild or moderate intensity. 
None of the patients 
experienced any serious 
SAE or relevant alterations 
in laboratory parameters, 
vital signs, and ECG. 
Refer to IB for more details
Management of symptoms, 
evaluation, and follow-up 
as needed to ensure patient 
safety, per investigators 
clinical judgment.
Concomitant use of:

Strong inducers of 
CYP3A4

Strong inhibitors of 
CYP3A4
Based on current non-
clinical and BI 1358894 
drug-drug interactions data, 
use of certain concomitant 
medications may increase or 
decrease such medications 
or BI 1358894. 
Refer to the investigator site 
file (ISF) for more 
information on restricted 
mediations.
Patients on these 
medications will be 
excluded from trial and use 
of these drugs will be 
restricted during the 
treatment period. If such 
medication is used during 
the trial for some reason, 
Investigator should stop 
either this medication or 
IMP per the clinical 
judgment.


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Table 1.4.2:1 Overview over trial related risks (cont.)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Investigational Medicinal Product - BI 1358894
Concomitant use of:
Statins
Drug-drug interactions 
suggest a minor to moderate 
increase in rosuvastatin 
levels when concomitantly 
taken with BI 1358894. This 
interaction takes place on an 
OATP transporter level and 
is expected to affect all 
statins.
Patients on statins should be 
monitored for statin-related 
toxicity including signs of 
myopathy, weakness, 
muscle pain, etc. along with 
clinical lab results. If statins 
are concomitantly used 
during the trial, the highest 
dose of the statin should not 
be taken together with the 
investigational compound. 
If patient in this trial is on 
the highest recommended 
statin dose, investigator 
should consider changing 
the statin dose to the next 
lower dose recommended 
for the respective statin if 
appropriate.
Drug-induced liver injury 
(DILI)
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators.
Timely detection, 
evaluation, and follow-up of 
laboratory alterations in 
selected liver laboratory 
parameters to ensure patient 
safety.


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Table 1.4.2:1 Overview over trial related risks (cont.)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Embryo-fetal development 
toxicity
Decreased number of 
implantations, early 
resorptions, decreased fetal 
weight, skeletal 
malformations in minipigs 
at relevant human exposure 
levels. Thus, a risk for 
teratogenicity in humans 
cannot be excluded.
WOCBP must adhere to 
contraceptive measures 
consisting of one highly 
effective method of birth 
control per ICH M3 (R2) 
during the treatment and 
follow-up period. Sexual 
abstinence as a 
contraceptive method will 
not be allowed for WOCBP 
who are heterosexually 
active. 
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.
Pregnancy testing must be 
performed at every site 
visit. 
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 
1 (including phone visits).
Refer to section 4.2.2.3 for 
more details regarding 
contraception counseling.


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Table 1.4.2:1 Overview over trial related risks (cont.)
BI 1358894 – Placebo

Worsening of PTSD

Occurrence or increase of 
suicidality
Even though mitigation 
measures are applied, this 
cannot be completely ruled 
out
Patients will remain on their 
stable treatment with an SSRI
and psychotherapy, where 
applicable. Placebo is 
adjunctive to this treatment.
Frequency of clinic visits with 
suicidality assessments are 
optimized.
Suicidal patients will be 
excluded form trial 
participation (refer to section
3.3.4.1)


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Table 1.4.2:1 Overview over trial related risks (cont.)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
General risk of psychoactive drugs

Impair thinking, 
judgment, and/or motor 
skills 
Psychoactive drugs are 
known to potentially cause 
unwanted side effect on 
brain function.   
Patients should be cautioned 
about operating machinery, 
including automobiles, until 
they are reasonably certain 
that the study medication 
does not adversely affect 
their ability to engage in 
such activities.
Trial procedures

General discomfort

Blood draw
The potential risks of a 
blood draw include fainting 
and pain, bruising, swelling, 
or rarely infection where the 
needle is inserted.
In rare cases a nerve may be 
damaged, inducing long-
lasting abnormal sensations 
(paraesthesia), impaired 
sensation of touch and 
persistent pain.
The total volume of blood 
withdrawal per patient 
during the trial will be 
approximately up to 220 mL 
over 16 weeks. This amount 
may be exceeded if 
additional unscheduled (in 
case of necessary safety 
follow-up) monitoring of 
laboratory results is needed.
Management of discomfort, 
evaluation, and follow-up as 
needed to ensure patient 
safety.
No health-related risk is 
expected from this blood 
withdrawal.


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Table 1.4.2:1 Overview over trial related risks (cont.)
Other risks

Hypersensitivity and 
allergic reactions
As with all drugs, the 
potential for 
hypersensitivity and allergic 
reactions has to be taken 
into consideration when BI 
1358894 is administered.
First dose of BI 1358894 
administered on site, with 
safety clinic visit at Week 1. 
Monitoring and 
management of symptoms 
and treatment as needed, 
including discontinuation of 
trial treatment as per 
investigators clinical 
judgment.


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1.4.3
Discussion
Considering this patient population, and the need to adequately monitor suicidality, frequent 
clinic and phone visits, which include C-SSRS assessments, are planned in this trial to 
monitor patients.
Additionally, all patients will be allowed to continue antidepressants and other psychiatric 
medications (i.e. non-benzodiazepine anxiolytics) if on stable treatment at the time of trial 
entry and throughout the whole trial performance. Considering the mechanism of action of 
BI 1358894 and the adverse events reported in clinical trials to date, there is no undue risk 
related to stopping the trial drug during the treatment period or at the end of the treatment 
period, nor any major risk related to potential aggravation of the side effect profile/s of the 
background medication/s.
After patients have completed trial participation, they should return to treatment as prescribed 
by their treating physicians.
Embryo-fetal development toxicity has been identified in a pre-clinical study in minipigs at 
relevant human exposure levels. Therefore, a risk for teratogenicity in humans cannot be 
excluded. It is of high importance that WOCBP strictly adhere to contraceptive measures 
consisting of one highly effective method of birth control per ICH M3 (R2) that results in a 
low failure rate of less than 1% plus one additional barrier method during the treatment and 
follow-up period of the study. Sexual abstinence as a contraceptive method will not be 
allowed for WOCBP who are heterosexually active. Pregnancy testing has to be performed at 
every site visit. Additionally, WOCBP will be repeatedly counselled with regard to the need 
for contraception at all visits as per Flow Chart 1 (including phone visits).
Considering the acceptable and manageable safety profile of BI 1358894 as demonstrated in 
nonclinical and toxicology studies, good tolerability in clinical studies performed to date,  
close monitoring (including the above-mentioned risk mitigation activities to minimize the 
risk of pregnancy during the trial) planned during the trial visits and the involvement of an 
independent external DMC, the potential risks to the patients will be minimized and 
outweighed by a potential therapeutic benefit of the trial drug and more effective treatment 
for patients with PTSD.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to provide proof of concept (PoC) of orally administered BI 
1358894 125mg after eight weeks treatment in patients with PTSD compared to placebo.
2.1.2
Primary endpoint(s)
Change from baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total 
severity score at Week 8
2.1.3
Secondary endpoint(s)
CAPS-5
-
Response defined as ≥30% CAPS-5 reduction from baseline at Week 8
-
Response defined as ≥50% CAPS-5 reduction from baseline at Week 8
PCL-5
-
Change from baseline on the PTSD Checklist for DSM-5 total score at Week 8


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2.2.3
Safety
Safety will be assessed descriptively 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, 8-week-treatment, multicenter, randomized, double blind, placebo-
controlled, parallel-group trial in patients with Post-Traumatic Stress Disorder (PTSD). In 
total, approximately 286 male and female patients with PTSD meeting the entry criteria are 
planned to be randomized into this trial.
V = Visit, W = Week, EOT = End of Treatment, EOS = End of study, = Telephonic Visit
Figure 3.1: 1 Trial design
Patients are enrolled into the trial after informed written consent has been obtained. Eligible 
patients will be randomized to double-blind treatment with either placebo (approx. n=143) or 
BI 1358894 at 125 mg QD (approx. n=143). Total treatment duration will be eight weeks, 
refer to Figure 3.1: 1.
After the completion of the 8-week double-blind treatment period or following early 
discontinuation of the trial at any timepoint, patients will complete the 4-week follow-up 
period with the end of study (EOS) visit. All (S)AEs, including those persisting after 
individual patient’s end of study must be followed up until they have resolved, have been 
assessed as “chronic” or “stable”, or no further information can be obtained. Individual 
patient participation is concluded when the patient has completed their last planned visit (end 
of study visit) (refer to sections 3.3.4.1 and 3.3.4.2).
An interim analysis is planned when the 120th evaluable patient completes the Week 8 visit. 
The purpose of this interim analysis is for internal planning of the PTSD indication with 
BI 1358894. Please refer to section 7.2.8


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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 trial. This design is 
appropriate for providing proof-of-concept and assessing the safety and efficacy of 
BI 1358894 compared to placebo in patients with PTSD. It is important to have a placebo 
control to address potential confounding factors. This is acceptable as patients will remain on 
their stable background treatment and the duration of the placebo treatment will be limited to 
8 weeks.
The design of the trial will provide efficacy and safety of BI 1358895 on PTSD patients to 
support proof of concept. 
Data at Week 8 will provide evidence of efficacy and safety of BI 1358894 compared to 
placebo. In addition, safety data will also be obtained through the end of observation period 
(early drug discontinuation date / EOT+28+2 days). Exploratory outcomes from Ecological 
Momentary Assessments (EcMAs) are intended to assess the disease status in the patients’ 
natural environments. Collectively, this information will help facilitate the design of the 
Phase III program.
BI 1358894 is regarded as a first in class compound, hence, it was decided to include the 
review of data by an Independent Data Monitoring Committee (DMC), independent from the 
sponsor, to review the trial data as a general safety measure. The purpose of the DMC is to 
ensure that the safety of the patients participating in this trial is maintained by monitoring for 
possible untoward harmful effects or unexpected frequency of adverse safety events of trial 
drugs based on emerging data.
The DMC will evaluate and analyse accrued patient data in order to recommend whether the 
trial or program should continue, be modified or stopped for safety concerns. 
The DMC will review pertinent trial data, including SAEs, AEs and laboratory data. DMC 
meeting frequency and logistics will be specified in a separate DMC Charter.
3.3
SELECTION OF TRIAL POPULATION
A total of approximately 286 patients is planned to be randomized into the trial. It is planned 
that about 70 trial centers in 10 countries will be participating in this trial to ensure a 
sufficient number of patients are randomized.
It is expected that approximately 4-10 patients will be randomized at each trial center. If 
enrolment is delayed, additional sites may be recruited. To avoid differential center influence 
on trial 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 enrolment status and 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 


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notified when the appropriate number of patients has been screened and screening is 
complete, and will not be allowed to recruit additional patients for this trial. Patients already 
in screening at this time will be allowed to continue to randomisation, if eligible.
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 retrospectively it is found that a patient has been randomized < in error (=did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 
contacted immediately. Based on an individual benefit-risk assessment a decision will be 
made whether continued trial participation is possible or not.
Retesting
Retesting applies in situations when the issue can be resolved within the screening period of 
28 days.For example patients that are testing positive on urine drug screen for cannabis or 
opioids at Visit 1 can be retested once (consider long half-life of cannabis) within the 
screening period of 28 days, if there is a reasonable explanation and expectation that the 
patient is not a regular user and will not test positive again on retest or has stable treatment 
with medically prescribed opioids, both at the discretion of the investigator.
In case of retesting, the patient will keep the same patient number. The results of all retests
should be available within the 28 days of screening period. Once retests are available and 
negative for the retested parameter/eligibility confirmed, and in case all other eligibility 
criteria are met, the patient can be randomized on the planned Visit 2 date.
Rescreening of patients
Rescreening of a patient can be done once, if there is a reasonable explanation and 
expectation that the patient may have become eligible.
Potential reasons for rescreening could be: 

Active infection with SARS-CoV-2 

Suicidality once the required exclusion period is over

Clinically significant findings per Investigators judgement 

Restricted medications like CYPs/ alternative or traditional medicine 

Positive urine drug test at screening visit, if longer wash-out period needed
Background therapy must be stable prior to re-screening.
For other potential reasons, please contact the clinical trial leader (CTL).
In case of re-screening, the patient will receive a new patient number. The patient must sign 
the current, approved version of the informed consent before any study specific procedures 
are performed. 

If rescreening is done within 12 weeks of screening, all procedures except CTQ, Life 
Events Checklist and extended Criterion A (as part of the Screening PCL-5) must be 
repeated. The exceptions above only apply if these assessments are not the reason for 
rescreening.

If the rescreening is done more than 12 weeks after the screening, all procedures as 
shown in the Flow Chart 1 and Flow Chart 2 for Visit 1 must be repeated. 


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For all re-screened patients, the screening period will be again 28 days as per protocol. In 
case all eligibility criteria are met during these repeated screening procedures, the patient can 
be randomized on the newly planned Visit 2 date.
3.3.1
Main diagnosis for trial entry
Patients with an established diagnosis of Post-Traumatic Stress Disorder confirmed at the 
time of screening by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) will be 
evaluated for eligibility for the study. 
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Established diagnosis of Post-Traumatic Stress Disorder (PTSD) corresponding to DSM-
5 criteria.
2. Time since index event according to Life Events Checklist / CAPS-5 Criterion A at least 
3 months before screening visit.
3. PTSD must be the clinically pre-dominant disorder, as per investigator´s judgement. 
Other comorbid psychiatric disorders are allowed, unless specifically excluded in the 
exclusion criteria. 
4. A total severity score of ≥ 33 on the PCL-5 at the screening visit.
5. Moderate to severe PTSD confirmed by CAPS-5 range ≥ 30 confirmed at screening visit. 
6. Male or female patients, 18 to 65 years of age, both inclusively at the time of informed 
consent.
7. Women who are of child-bearing potential (WOCBP)1 must be 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 result in a low failure rate of less 
than 1%, plus one additional barrier method. 
A list of contraception methods meeting these criteria and instructions on the duration of 
their use is provided in section 4.2.2.3.
8. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
  
A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal occlusion/ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause.
3.3.3
Exclusion criteria
1. Corresponding to DSM-5, had ever met diagnostic criteria for schizophrenia, 
schizoaffective disorder, schizophreniform disorder, bipolar disorder, delusional disorder, 
brief psychotic disorder or any other psychotic disorder as well as MDD with psychotic 
features as assessed by the MINI at the time of screening.
2. Any psychiatric or non-psychiatric medical condition likely to negatively impact trial 
participation as per the judgement of the investigator.


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3. Acute stress disorder or significant traumatic event within 3 months prior to the screening 
visit.
4. Use of stimulant medications within 3 months prior to the screening visit (Attention 
Deficit Hyperactivity Disorder (ADHD) diagnosis alone is not exclusionary)
5. Severe traumatic brain injury (life-time) or moderate traumatic brain injury within the last 
2 years prior to screening visit or 3 months for mild traumatic brain injury, based on the 
Ohio State University TBI Identification Method Short Form. Or history of traumatic 
brain injury that would impact ability to complete trial assessments or procedures 
according to investigator.
6. Current treatment with trauma focused therapy (i.e. CPT, PE, EMDR).
A psychotherapy in type, intensity and/or frequency other than trauma focused therapy is 
allowed if stable within the last 8 weeks prior to screening and not anticipated to change 
during the entire course of the trial. Long-term psychotherapy is permitted as long as 
patients are not in an exposure phase during the trial.
7. Diagnosis of a current moderate or severe alcohol use disorder according to MINI within 
3 months prior to screening visit (mild alcohol use disorder (AUD) and patients in early 
remission = criterion not met for between 3 & 12 months are allowed).
8. Diagnosis of a substance use disorder (non-alcohol) according to MINI within 12 months 
prior to screening visit. Caffeine and nicotine are allowed.
9. Positive urine drug screen at the screening visit. Exception: stable opioid-treatment with 
medically prescribed opioids. Please refer to section 3.3 Retesting for retesting options 
within the screening period.
10. Any suicidal behavior in the past 12 months prior to screening (per investigator 
judgement including an actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behavior) and during the screening period. 
11. Any suicidal ideation of type 4 or 5 in the Columbia Suicide Severity Rating Scale (C-
SSRS) in the past 3 months prior to screening or at screening or baseline visit (i.e. active 
suicidal thought with method and intent but without specific plan, or active suicidal 
thought with method, intent and plan). 
12. Treatment with benzodiazepines is allowed if stable in dose and frequency of use for at 
least 2 months prior to randomization visit (please refer to section 4.2.2). Note: PRN- use 
is not permitted.
13. Antipsychotics, antidepressants and other psychiatric medication are allowed if stable in 
dose and frequency of use for at least 2 months prior to randomization visit (please refer 
to section 4.2.2)
14. Any use of restricted medications within 7 days prior to randomization visit (refer to 
section 4.2.2).
15. Patients who must or wish to continue the intake of restricted medications or any drug 
considered likely to interfere with the safe conduct of the trial. 
16. Use of alternative medicine (e.g. Chinese traditional medicine, herbal medication, St. 
John’s wort, etc.) during the entire course of the trial.
17. History of seizure disorders, stroke, brain tumor or any other major neurological illness 
that can impact participation in the trial. 
18. 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.
19. Positive result for ongoing Hepatitis B or C infection.


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20. Known hypersensitivity to any of the excipients of BI 1358894 or the matching placebos. 
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 5 half-lives of the investigational 
medicinal product).
22. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening.
23. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
24. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled.
25. Considered by the investigator, for any other reason, to be an unsuitable candidate for the 
trial.
26. Patients who are currently and during the course of the trial confined to an institution by 
court or administrative order.
27. Patients who are currently involved in any ongoing legal processes related to the index 
traumatic event (e.g. lawsuit or criminal prosecution).
28. Patients currently using NightwareTM Digital Therapeutic tool.
29. In-patients are generally excluded, however in-patients who are admittedon a voluntary 
basis in an open-ward (i.e. "residential ward") and are non-suicidal are allowed.
30. 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.
31. Symptomatic/unstable/uncontrolled or clinically relevant concomitant disease or 
condition (e.g. renal failure, hepatic dysfunction, cardiovascular disease, etc.) that would 
jeopardize the patient´s safety while participating in the trial or capability to participate in 
the trial, based on investigator´s discretion.
3.3.4
Discontinuation 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.
However, if the patient agrees, they should stay in the trial: even if continued trial treatment 
is not possible, they should attend further trial visits to ensure their safety and to collect 
important trial data.
After premature study drug discontinuation, patients will be asked to further attend scheduled 
trial visits unless they withdraw consent to participate in the study. 
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 options for early discontinuation and explanation of the consequences in 
case of withdrawals.


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The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see section 5.4.6.2).
3.3.4.1
Discontinuation of trial treatment
Ideally, the patient should attend all remaining visits and perform all study related procedures 
according to Flow Chart 1, Flow Chart 2 and section 6.2.2 An early EoT (eEOT) Visit shall 
be conducted within 7 days of the last dose of trial medication for patients who agree to 
conduct regularly scheduled visits after premature drug discontinuation (if consistent with the 
planned visit schedule, the eEOT can replace the next regularly scheduled clinic visit). After 
this early EOT visit, patients should be followed up according to the regularly scheduled visit 
for both clinic and phone visits including Visit 10 and should be encouraged to complete the 
EOS Visit 28+2 days after the drug discontinuation date. All procedures should be 
completed, with the exception of trial drug procedures and PK collections. If a regular 
planned visit is completed prior to the initially planned Visit10 (early drug discontinuation 
date + 28+2 days), no additional FUP Visit may be needed. However, end of study 
participation (EOS) must be completed.
If the patient does not agree to return for all remaining scheduled visits, the patient should be 
encouraged to return at least for an early EoT (eEOT) Visit within 7 days of the last dose of 
trial medication, for the regularly scheduled Visit 10 and EOS. If EOS visit (early drug 
discontinuation date + 28 +2 days) can be completed prior to the date of the planned Visit 10, 
no additional FUP Visit may be needed. However, end of study participation (EOS) must be 
completed. 
Should the patient not agree to any further clinic visits, at least phone contacts should occur 
at the scheduled visit time points, should that not be acceptable, a phone contact at the end of 
the planned observation period (i.e. 12 weeks after start of treatment or 4 weeks after last 
dose) should occur to collect the most relevant information: vital status (please see section 
5.4.6.2.1) adverse events, or last contact date in case of lost to follow-up. 
Patients who refuse all of the above are considered to have fully withdrawn consent to 
participate in the trial. In this case, the patient does not need to justify the decision and should 
be withdrawn from the trial and all follow-up assessments (please refer to section 3.3.4.2).
Withdrawal from the trial of an individual patient may be considered also in case of 
administrative reasons, such as but not limited to multiple important protocol violations and 
persistent non-compliance. No patient should be withdrawn from the trial before discussion 
with the sponsor.
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment. The patient will be asked to explain the 
reasons but has the right to refuse to answer.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 


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patient cannot be guaranteed as he/she is not willing or able to adhere to the trial 
requirements in the future. 

The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment; refer to the ISF.

The patient undergoes an ECT.

Patient receives Ketamine /S-Ketamine treatment during the course of the trial.

The patient can no longer receive trial treatment for serious medical reasons (such as 
surgery, adverse events, other diseases, or pregnancy), per investigator’s clinical 
judgement. In case of a temporary reason, trial treatment should be restarted if medically 
justified.

Pregnancy occurs during the trial. (Once a patient has been enrolled in the clinical trial 
and has taken trial medication, the investigator must report any drug exposure during 
pregnancy which occurred in a female trial patient to the Sponsor immediately (within 24 
hours) by means of Part A of the Pregnancy Monitoring Form to the Sponsor’s unique 
entry point).

The patient must discontinue treatment with trial medication if the patient develops 
suicidal ideation of type 4 or 5 in the C-SSRS (i.e., active suicidal thought with intent but 
without specific plan, active suicidal thought with plan and intent) or suicidal behaviour 
(i.e. actual attempt, interrupted attempt, aborted attempt or preparatory acts or behavior).
In addition to these criteria, the physician may discontinue treatment at any time based on his 
or her clinical judgment. For all patients the reason for withdrawal from trial treatment (e.g. 
AEs) must be recorded in the CRF. These data will be included in the trial database and 
reported.
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 ensure the safety of the trial patients.
Even if the trial treatment is discontinued, the patients 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 1, Flow Chart 2 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:


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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.
Further treatment and follow up of patients affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 1358894 film-coated tablets are manufactured by BI Pharma GmbH & Co. KG, Germany. 
Placebos, matching BI 1358894 film-coated tablets, are manufactured by BI Pharma GmbH 
& Co. KG, Germany and 
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1:1 BI 1358894
Substance:
BI 1358894
Pharmaceutical formulation:
Film-coated Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, 
Germany
Unit strength:
25 mg, 50 mg
Posology:
QD
Mode of administration:
Per os
Table 4.1.1:2 Placebo matching BI 1358894
Substance:
Placebo matching BI 1358894
Pharmaceutical formulation:
Film-coated Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, 
Germany;
Unit strength:
N.A.
Posology:
QD 
Method and route of administration:
Per os
4.1.2
Selection of doses in the trial and dose modifications
The dose of 125 mg BI 1358894, once daily, is selected for this trial based on the results of
the PK and safety data obtained in the trials 1402-0001 (Single Rising Dose (SRD) and Food
Effect), 1402-0002 (Multiple Rising Dose (MRD)), and 1402-0010 (rel Bioavailability (BA);
formulation selection) combined with the preclinical efficacy data.
In the SRD trial, single dose levels up to 100 mg were well tolerated. In the MRD trial,
multiple dose levels up to 200 mg were well tolerated. The 125 mg was selected to account
for potential larger variability in PK in Phase II due to a more heterogeneous population that
is expected compared to Phase I. This dose is expected to deliver a 5-fold concentration of
the target C16,ss in 49.8 % to 96.6 % of patients depending on the food condition.
Therefore it is concluded that the dose of 125 mg once daily has an acceptable safety margin


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and potential efficacious dose for BI 1358894.
BI 1358894 was tested in several Phase I studies:

evaluation of safety, tolerability and PK after single and multiple dose

evaluation of relative bioavailability under fasted and fed conditions of different solid 
oral formulations

evaluation of drug-drug interaction with strong index CYP3A4 inhibitor

evaluation of physiological response and circuit engagement in a Cholecystokinin
Tetrapeptide (CCK-4) challenge in healthy volunteers

evaluation of physiological response and circuit engagement in a functional MRI 
study in depressed patients after single dose
BI 1358894 was safe and well tolerated up to the highest dose tested (200 mg under fed
conditions) after a single dose (after a high calorie/high fat breakfast) as well as after 14 day
qd dosing (after continental breakfast). BI 1358894 (single dose of 100 mg administered
under fed conditions) also demonstrated physiological response by attenuation of CCK-4
induced panic symptoms, attenuation of CCK-4 induced stress hormone elevation 
(Adrenocorticotropic hormone (ACTH) and Cortisol) and reduction in the score of the 
emotional Visual Analogue Scale (VAS).
Within preclinical research, the forced swim test in mice was evaluated to test potentially
efficacious concentrations. This test resulted in an EC50 of 77 nM (and a corresponding
EC90 of 165 nM). This target concentration of 77 nM BI 1358894 total plasma concentration
was set as the minimal concentration to be reached at 16 h after dosing under steady state
conditions for prediction of an estimated therapeutic dose in humans.
Pharmacokinetic data of BI 1358894 from the SRD, MRD and relative BA study for
formulation finding and food effect assessment were integrated into a Population PK model
in order to predict steady state exposure of the solid oral formulation selected for Phase II
under fasted and high calorie high fat conditions. The predictions under different food
conditions should indicate the range of exposures to be expected under different food
conditions, with fasted and high calorie high fat conditions representing the extremes of
potential exposures. It is expected that a standard breakfast would lead to exposures that lie
somewhere in-between those predicted. Of note, exposure of BI 1358894 increases less than
dose-proportionally. The current Pop PK model over predicts Cmax, hence, predicted exposure
may be higher than exposures to be observed in Phase II.
Repeat-dose toxicity testing with daily administration for 13 weeks revealed a NOAEL of
1000 mg/kg/day in rats. This NOAEL is considered to represent the most relevant NOAEL
for repeat-dose toxicity testing in rats, as detailed in the IB [c10354149]. This dose resulted 
in maximum plasma levels and exposures that represented sufficient multiples of the same
parameters as predicted for a 125 mg dose in humans and fed conditions. Cmax and AUC0-24h
at the NOAEL in rats are also higher than the 95th percentile of the respective parameter at
the maximum dose of BI 1358894 in Phase II under fed conditions (for details see IB).
Repeat dose toxicity testing for up to 13 weeks in dogs revealed an overall NOAEL of 
30 mg/kg/day, as described in detail in the IB [c10354149]. This dose resulted in maximum


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plasma levels and exposures (AUC0-24h) representing sufficient multiples of the same
parameter at a 125 mg dose in humans and fed conditions. Cmax and AUC0-24h at the NOAEL
in dogs were also higher than the 95th percentile of the prediction of the respective parameter
at the maximum dose of BI 1358894 in Phase II under fed conditions (for details see IB
[c10354149].
In conclusion, results of repeat-dose toxicity testing support the conduct of Phase II clinical
trials at the 125 mg dose once daily at fasted or fed conditions and for a maximum duration of
treatment of 13 weeks.
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomized 
to treatment groups according to a randomisation plan at Visit 2 via Interactive Response 
Technology (IRT). Note that the medication number is different from the patient number (the 
latter is generated during screening via the IRT System). To facilitate the use of the IRT, the 
Investigator will receive all necessary instructions.
Patients will be randomly assigned with an allocation ratio of 1:1 to the following treatment 
groups:

125 mg BI 1358894

Placebo matching BI 1358894
Patient assignment to the treatment groups will be determined by a computer-generated 
random sequence. Randomization sequence will be generated using validated randomisation 
software. Access to the randomization code will be controlled and documented.
Randomization into each treatment group will be stratified by:
- presence of significant childhood trauma (YES/NO, according to investigator´s judgement, 
assessed by CTQ at screening visit)
The kit(s) corresponding to the assigned medication number(s) should be given to the patient
and entered in the eCRF. Using this procedure, relevant parties will be blinded to the 
treatment group assignment.
4.1.4
Drug assignment and administration of doses for each patient
The medication assignment will be provided through IRT. The assigned medication 
number(s) must be entered in the eCRF, and the corresponding medication kit(s) must be 
given to the patient. The duration of treatment is 8 weeks. The last dose of trial medication 
should be taken on the day before the EOT Visit. Dosing per treatment assignment is noted in 
Table 4.1.4:1.
At Visit 2, after randomization, patients will receive medication kits for the double-blind 
treatment period. The morning dose of trial medication will be taken at the trial site under 
supervision of the investigator or site staff. Patients will bring trial medication (used/unused 
blister and covering packages) to site visits for compliance check (V4/V6/V8/V10). At visits 
V4, V6 and V8, patients will return used/unused medication kits and receive new supplies.


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Each trial medication kit contains supplies for 14 days of treatment. For the first trial 
medication kit supplies, participants will receive two kits (one kit for the 14 treatment days 
plus a reserve kit), and all following re-supplies will be one kit of BI 1358894 or matching 
placebo.
Patients should be instructed not to take their trial medication in the morning of Visits 2, 4, 6, 
8, as patients will be dosed at the site after pre-dose PK sampling. For patients who complete 
the treatment period, the last dose of trial medication should be taken on the day before the 
EOT Visit (V10). Patients who fail to do so should have the visit rescheduled as soon as 
possible, ideally on the following day.
Patients should be instructed to take the BI 1358894 tablets or matching placebos orally with 
water and in a consistent way, i.e., either with or without food every morning at 
approximately the same time. If a morning dose is missed by more than 12 hours, that dose 
should be skipped and the next dose should be taken as scheduled. On days prior to a visit, 
the morning dose should be taken approximately 24 hours before the planned morning dose at 
the clinic visit. A dose reduction of BI 1358894 is not possible.
Table 4.1.4:1
Dosage and treatment schedule 
25mg film-
coated tablet
50mg film-
coated tablet
PBO matching 25mg 
film-coated tablet
PBO matching 50mg 
film-coated tablet
Dose group
Number of tablets to be taken daily – in the morning ☼
Placebo
0
0
1
2
125 mg
1
2
0
0
During the COVID-19 pandemic, there might be situations that would not allow a patient to 
come to the site for the study visit. If the investigator judges it as acceptable and safe to 
continue trial medication, trial medication might be shipped from the site to the patient (for 
more details see section 6.1 and 10.3). 
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators and everyone involved in trial conduct or analysis or with any other 
interest in this double-blind trial will remain blinded with regards to the randomized 
treatment assignments until the time specified in the database lock process, with the 
exceptions described in this section below and in section 7.2.8.
The access to the randomisation code will be kept restricted until its release for analysis.
The randomisation codes will be provided to bioanalytics prior to last patient completed to 
allow for the exclusion from the analyses of pharmacokinetic (PK) samples taken from 
placebo patients. Bioanalytics will not disclose the randomisation code or the results of their 
measurements until the trial is officially unblinded.


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Dedicated database snapshots (no partial DBL) will be generated prior to DBL to allow for 
development and refinement of population PK and exposure-response models (“Fast-track” 
PK and PK/PD analysis). 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 the first database snapshot for ‘fast-track’ 
PK/PD analyses.
No formal interim report will be generated. Final PK and PK/PD analyses will be reported 
once after availability of data from DBL.
The access to the randomisation code will be kept restricted until its release for analysis.
The randomisation codes will be provided to bioanalytics before the last patient completed 
the trial to exclude placebo or comparator samples from the PK analysis. Bioanalytics will 
not disclose the randomisation code or the results of their measurements until the database 
lock.
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 patients. 
The reason for unblinding must be documented in the source documents and/or appropriate 
CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (as provided in the list of contacts) must be contacted immediately.


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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor or 
delegate when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor or deligate
and the investigational site,

Approval / notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Please refer to section 5.4.5.1 for handling patients with positive report of suicidal ideation 
and/or behavior.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The following restrictions for comedications are defined for this trial: 

Strong inhibitors of CYP3A4 

Strong inducers of CYP3A4 (please refer to the ISF)
A list of restricted concomitant medications and drugs with potential pharmacokinetic 
interactions with the trial compound BI 1358894 can be found in the ISF. The list is not 


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comprehensive. For example, drugs that are solely indicated for diseases that are excluded in 
this trial - like cancer drugs - may not be listed.
Use of ECT and Ketamine/S-Ketamine are restricted during the study, and would lead to 
study discontinuation (refer to section 3.3.4.1).
Patients on statins should be monitored for statin-related toxicity including signs of 
myopathy, weakness, muscle pain, etc. along with clinical lab results. If statins are 
concomitantly used during the trial, the highest dose should not be taken together with the 
investigational compound. If a patient in this trial is on the highest recommended statin dose, 
investigator should consider changing the statin dose to the next lower dose recommended for 
the respective statin if appropriate.
Please note:

Investigators may use their clinical discretion to wash out (at least 3 half-lives of 
referenced medication) the restricted medications during the screening period. The patient 
must adhere to the screening visit dose of the allowed background medication for the 
entire duration of the trial. 

Patients who are on stable treatment with low-dose antipsychotics for treatment of 
insomnia or similar for at least 2 months prior to randomization should continue without 
change for the entire trial duration. Antipsychotic treatment for psychiatric symptoms is 
disallowed.

Patients who are on stable treatment with ongoing antidepressants for at least 2 months 
prior to randomization should continue without change for the entire trial duration.

Patients who are on stable treatment with ongoing benzodiazepine (including Z- drugs) or 
non-benzodiazepine hypnotics for at least 2 months prior to randomization should 
continue without change for the entire trial duration. 
For patients who are not on current treatment with benzodiazepine (including Z-drugs) or 
non-benzodiazepine hypnotics at the time of screening, the protocol will allow 
concomitant use of non-benzodiazepine-, non-Z-drug hypnotics at lowest dose of the 
compound as noted in the Summary of Product Characteristic (or SmPC) during the trial.

Patients who are on stable treatment with medically prescribed opioids (except fentanyl)
for at least 2 months prior to randomization should continue without change for the entire 
trial duration. Short-term opioid therapy up to 4 weeks per time, for example with cough 
syrup or pain killer, is allowed (except fentanyl).

In case of AEs, any treatment deemed necessary per the clinical judgment of investigator 
for the management of AEs considering patient safety is allowed.
For further guidance investigators are referred to the actual Investigator´s Brochure or may 
contact the sponsor.


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4.2.2.2
Restrictions on diet and life style
In general, patients should keep their usual habits throughout the trial for diet and exercise, as 
well as nicotine, alcohol and caffeine intake. It should be within acceptable daily amounts in 
discretion of the investigator and not be drastically changed throughout the trial conduct. 
Note the following restrictions:

Use of traditional medicine (e.g. Chinese traditional medicine, herbal medication, St. 
John’s wort, etc.) during treatment period.

Patients should not abuse alcohol or drugs during the trial. A urine drug screen will be 
performed at selected trial visits (see Flow Chart 1). For a list of drugs assessed by the 
urine drug screen please refer to table 5.4.3: 1.

Patients should not enter or modify a smoking-cessation program during the conduct of 
the trial.

It is recommended that patients should exercise caution when driving or operating 
machinery until they are reasonably certain that the study medication does not adversely 
affect their ability to engage in such activities.
Patients do not have to come fasted to any trial visit.
4.2.2.3
Contraception requirements
Women of childbearing potential (WOCBP - for the definition please refer to section 3.3.2)
must use two methods of contraception, which include one highly effective methods of birth 
control per ICH M3 (R2) that result in a low failure rate of less than 1%, plus one additional 
barrier method. Contraception must be used during the treatment and follow-up period. 
Women of child-bearing potential must agree to periodic pregnancy testing during 
participation in the trial. If a urine pregnancy test is positive, a serum test needs to be 
performed for confirmation.
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
1 (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.


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Acceptable forms of contraception are:
One of the highly effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1%:

Use of hormonal methods of contraception associated with inhibition of ovulation
o
a. combined (estrogen and progestogen containing) hormonal contraception:

oral

intravaginal

transdermal
o
b. progestogen-only hormonal contraception:

oral

injectable

Implantable

Placement of intrauterine device (IUD) or intrauterine hormone releasing system (IUS)

Bilateral tubal occlusion or ligation

Vasectomy (with appropriate post-vasectomy documentation of the absence of sperm in 
the ejaculate and provided that male partner is the sole sexual partner of the WOCBP trial 
patient)

Complete sexual abstinence when this is in line with the preferred and usual lifestyle of 
the study patient. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal (coitus interruptus) are not acceptable methods of 
contraception) - (in this specific case the barrier methods as mentioned below, are not 
applicable). Sexual abstinence as a contraceptive method will not be allowed for WOCBP 
who are heterosexually active.
plus one of the barrier methods:

Male or female condom with or without spermicide

Cap, diaphragm or sponge with spermicide
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on non-missing tablet counts, treatment compliance will be calculated as shown in the 
formula below. Compliance will be verified by the CRA authorised by the sponsor or 
delegate.
Treatment compliance (%) =
Number of doses actually taken 100
     Number of doses which should have been taken as 
directed by the investigator


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The potential for trial drug abuse will be closely monitored. Events including overdose, 
misuse, lost and unaccounted for medication must be thoroughly documented in the patient’s 
source and on the appropriate eCRFs. Furthermore, if the treatment compliance is less than 
80% or greater than 100%, site staff should discuss and document the reasons on the eCRFs. 
Site staff will explain to the patient the importance of treatment compliance.
Additionally, as an exploratory approach, the intake of the trial drug at clinic visits and at 
home will be monitored by the patient with a smartphone app (see section 5.8.3). The 
identification of the tablet shapes and sizes, time and day, the patient face-ID, and the drug 
intake process will be captured in selfie mode of the smartphone camera, by the patient. The 
face of the patient will be anonymized by the managing software of the vendor before the 
data are submitted to the vendor for potential further analysis.


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5.
ASSESSMENTS
5.1
CONFIRMATION OF DIAGNOSIS
Eligibility of patients for the trial will be evaluated using the Clinician-Administered PTSD 
Scale for DSM-5 (CAPS-5) during screening for confirmation of the diagnosis of Post-
Traumatic Stress Disorder (PTSD). To exclude patients with other psychiatric disorders as 
described in the exclusion criteria, the Mini International Neuropsychiatric Interview will be 
performed.
The CAPS-5 and MINI will be audio recorded at the screening visit 1 and the recordings will 
be reviewed by an independent external clinical reviewer from 
.
MINI - Mini International Neuropsychiatric Interview
The MINI is a structured diagnostic interview designed to provide a brief standardised 
evaluation of mental health disorders in line with DSM-5 criteria [R07-1303, R07-1261, R07-
1263, R07-1262]. Each of the independent 17 diagnostic modules consists of screening and a 
series of secondary questions to be answered with “yes” or “no” responses. If the patient 
answers “no” to a screening question, the clinician starts asking questions from the next 
module. A clinician can use the MINI after a short training session. It takes approximately 20 
minutes to administer the MINI.
In this study, the MINI for psychotic disorders studies (English verison 7.0.2 for DSM-5) 
customized for Boehringer Ingelheim International will be used. The customization comprises
the following two modifications:

Module Y “Borderline Personality Disorder” will be added to the MINI to assess comorbid 
BoPD.

Module B “suicidality” will not be administered, all evaluations in relation to suicidality 
will be performed with the C-SSRS (please refer to section 5.4.5.1).
The Ohio State University TBI Identification Method Short Form will be used to assess any 
history of traumatic brain injury for patients.
OSU TBI-ID-SF – Ohio State University TBI Identification Method Short Form
The Ohio State University TBI Identification Method Short Form (OSU-TBI-ID-SF) is a 
structured clinical interview designed to detect lifetime history of exposure to TBI [R21-
2334, R21-2333]. Multiple dimensions of history are available, including number of injuries 
without or with loss of consciousness; duration of loss of consciousness from none, < 30 
minutes, 30 minutes to 24 hours to > 24 hours; age at (first) TBI, worst injury and repeated 
injuries.
A scoring system is used to quantify these dimensions and to categorize the likelihood of TBI 
exposure as: improbable - possible - mild - moderate - severe TBI. 
It takes approximately 5 minutes to complete and score the OSU TBI-ID-SF.


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5.2
ASSESSMENT OF EFFICACY
5.2.1
Clinician administered assessments
In addition to confirmation of PTSD diagnosis, using the CAPS-5 past month version, the 
CAPS-5 past week version will be used to assess PTSD total symptom severity as well as 
cluster symptom severity at Baseline and during the course of the trial.
CAPS-5 - Clinician-Administered PTSD Scale for DSM-5
The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a 30-item structured 
interview designed to make a current and lifetime diagnosis of PTSD evaluating the past 
month period as well as to assess PTSD symptoms over the past month or past week,
depending on the version used. [R21-2327, R21-0830, R21-2548].
In addition to assessing the 20 DSM-5 PTSD symptoms, questions target the onset and 
duration of symptoms, subjective distress, impact of symptoms on social and occupational 
functioning, improvement in symptoms since a previous CAPS administration, overall 
response validity, overall PTSD severity, and specifications for the dissociative subtype 
(depersonalization and derealization). Administration requires identification of an index 
traumatic event to serve as the basis for symptom inquiry.
Each of the 20 symptom items is rated on a 5-point severity rating scale ranging from 0 
(absent) to 4 (extreme/incapacitating) with a single severity score combining information 
about frequency/amount and intensity according to detailed scoring rules. A CAPS-5 total 
symptom severity score is yield by summing individual item scores. The total severity score 
ranges from 0 to 80 with higher scores indicating higher symptom severity.
CAPS-5 symptom cluster severity scores are yield by summing individual item scores 
pertaining to the following clusters (sometimes also referred to as domain): Criterion B (re-
experiencing), Criterion C (avoidance), Criterion D (negative alterations in cognitions and 
mood) and Criterion E (hyperarousal). A symptom cluster can also be calculated for 
dissociation by summing scores for items 29 and 30.
Two formats of the CAPS-5 measure will be used in this trial:

CAPS-5 past month version for confirmation of PTSD diagnosis and evaluation of 
eligibility (for screening visit only) [R21-2327].

CAPS-5 past week version for efficacy measurement (all subsequent trial visits) [R21-
2548].
The CAPS was designed to be administered by trained clinicians. The full interview takes 45-
60 minutes to administer.


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Categorization of index traumatic event
Investigators will be asked to categorize the index traumatic event as determined in CAPS-5 
Criterion A at screeening visit according to the following categories:
Table 5.2.1:1
Index traumatic event categorization criteria
Category
Response options
Type of trauma
Interpersonal
e.g. abuse, rape, hostage situation, assault, physical dispute, domestic 
violence
General
e.g. natural catastrophe, accident, (terrorist) attack, war
Combat trauma (only for veterans/military-associated personnel) 
e.g. hand-to-hand combat
Frequency
Isolated
Multiple (≥2) unrelated
Recurrent/chronic (same or similar trauma experienced repeatedly)
e.g. sexual abuse in the same context, domestic violence
Exposure level
In-person “First-hand” including witnessed
Learned about it
A separate assessment with the patient is not requested. Investigators will review CAPS-5 
Criterion A, Life Event Checklist and Extended Criterion A, as well as medical reocrds to 
decide on the categorization of the index traumatic event per their clinical judgement 
according to the criteria outlined above in Table 5.2.1: 1.
The index traumatic event, determined during the screening visit is to be referred to for all 
CAPS-5 and PCL-5 (incl. EcMA) assessments during the patient’s treatment period.
The categorization will be documented in the patient records and the eCRF.


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CGI-S/C - Clinical Global Impression Severity/Change Scale
The Clinical Global Impression Severity Scale (CGI-S) is a single item rating scale designed 
to measure the clinician's impression of the severity of illness exhibited by a patient that takes 
into account all available information, including knowledge of the patient's history, 
psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the 
patient's ability to function. The CGI-S evaluates the severity of psychopathology on a seven-
point scale [R03-0520, R19-1932]. 
The CGI-S question states “Considering your total clinical experience with this particular 
population, how ill is the patient at this time (at the visit and over the course of the past 7 
days) (Note that the subject’s illness is the disease under study; in this case, Post-Traumatic 
Stress Disorder – NOT other conditions/co-morbidities.)”, 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.
In the Flow Chart 2 this is referred to as CGI-S (total). 
In addition, domain level CGI-S versions covering DSM-5/CAPS-5 domains (intrusion 
symptoms, persistent avoidance, negative alterations in cognitions and mood and alterations 
in arousal and reactivity) assessing clinicians’ impression on domain level severity at this 
time (at the visit and over the course of the past 7 days) will be performed.The domain level 
CGI-S are rated on the following five-point scale: 1=none; 2=mild; 3=moderate; 4=severe
and 5=very severe.
In the Flow Chart 2 this is referred to as CGI-S (domain). 
The Clinical Global Impression Change Scale (CGI-C) is a single item rating scale designed 
to measure the clinician's impression of change of the patient’s condition since start of 
medication intake [R03-0520].
The CGI-C question states “Please choose the response that best describes the overall change 
in the patient’s condition since he/she started taking the study medication. (Note that the 
subject’s illness is the disease under study; in this case, Post-Traumatic Stress Disorder –
NOT other conditions/co-morbidities.)” and is rated on the balanced five-point scale: much 
better, a little better, no change, a little worse, much worse. 
The CGI-S/C is to be completed by a trained clinician and takes 5-10 minutes each to 
complete. 
5.2.2
Patient Reported Outcomes
All Patient Reported Outcomes will be completed by the patient using the rater station/tablet 
provided by the vendor.


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PCL-5 - PTSD Checklist for DSM-5
The PTSD Checklist for DSM-5 (PCL-5) is a 20-item patient-reported assessment designed 
to measure the presence and severity of PTSD symptoms. Items on the PCL-5 correspond 
with DSM-5 criteria for PTSD. The PCL-5 is intended to assess patient symptoms in the past 
month [R21-1742, R21-1740, R21-2336, R21-2341, R21-2340]. Each item is rated on a five-
point Likert scale, from 0 (not at all) to 4 (extremely). A total severity score can be yield by 
summing up individual item scores, and ranges from 0 to 80 with higher scores indicating 
higher severity. 
In addition, cluster severity scores can be calculated for Criterion B (re-experiencing, 
Criterion C (avoidance), Criterion D (negative alterations in cognitions and mood), Criterion 
E (hyperarousal).
Two formats of the PCL-5 measure will be used in this trial:
•
PCL-5 with Life Event Checklist (LEC-5) and extended Criterion A assessment (for 
screening visit only; as separate assessments) [R21-2326]
•
PCL-5 without Criterion A component (for all subsequent trial visits)
It takes approximately 5-10 minutes to complete the PCL-5.
CTQ - Childhood Trauma Questionnaire
The Childhood Trauma Questionnaire (CTQ)1 is a 28-item patient-reported assessment 
designed to measure five types of maltreatment: 1) emotional abuse, 2) physical abuse, 3) 
sexual abuse, 4) emotional neglect, and 5) physical neglect, and includes three items to screen 
for false-negative trauma reports [R21-2335, R21-2324, R21-2323]. 
Each item is rated on a five-point scale, from: never true to very often true. Scoring results in 
a classification of the level of maltreatment (None, Low, Moderate and Severe) for each of 
the five domains. 
It takes approximately 10 minutes to complete the CTQ.
PGI-S/C - Patient Global Impression Severity/Change Scale
The Patient Global Impression Severity Scale (PGI-S) is a single item patient-reported 
assessment designed to measure the patient’s impression of the severity of their illness on a 
five-point scale. The Patient Global Impression Change Scale (PGI-C) is a single item 
patient-reported assessment designed to measure the patient’s impression of change of their 
illness since start of medication intake [R03-0520].
                                                
1Bernstein, D., & Fink, L. (1998). Childhood Trauma Questionnaire: A retrospective self-report. San Antonio, TX: The 
Psychological Corporation


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The PGI-S question states “Please choose the response below that best describes the overall 
severity of your Post-Traumatic Stress Disorder over the past week (Select one response)” 
1=None, 2=Mild, 3=Moderate, 4=Severe, 5=Very severe.
The PGI-C states “Please choose the response below that best describes the overall change in 
your Post-Traumatic Stress Disorder (PTSD) since you started taking the study medication”
and is rated on the balanced five-point scale: much better, a little better, no change, a little 
worse, much worse. 
It takes approximately 5 minutes each to complete the PGI-S and PGI-C.
STAI - The State-Trait Anxiety Inventory
The State-Trait Anxiety Inventory (STAI) for adults has been used extensively in research 
and clinical practice. It comprises separate self-report scales for measuring state and trait 
anxiety. The S-Anxiety scale (STAI Form Y-1) consists of twenty statements that evaluate 
how respondents feel “right now, at this moment.” The T-Anxiety scale (STAI Form Y-2) 
consists of twenty statements that assess how people generally feel [R98-0762].
Each STAI item is rated on a four-point scale, from 1 (not at all) to 4 (very much so). A 
rating of 4 indicates the presence of a high level of anxiety for ten S-Anxiety items and 
eleven T-Anxiety items (e.g., “I feel frightened,” “I feel upset”). A high rating indicates the 
absence of anxiety for the remaining ten S-Anxiety items and nine T-Anxiety items (e.g., “I 
feel calm,” “I feel relaxed”). 
A total score for the S-Anxiety and T-Anxiety scales is yield by summing the weighted 20 
item scores per scale. Scores for the S-Anxiety and the T-Anxiety scale range each from 20 to 
80 with higher scores indicating greater anxiety.
It takes approximately 10 minutes to complete the STAI-S and STAI-T. 
PHQ-9 - Patient Health Questionnaire-9
The Patient Health Questionnaire-9 (PHQ-9) is a 9-item patient-reported assessment designed 
to be used for screening, diagnosing, monitoring and measuring the severity of depression
[R12-3115]. 
Each of the nine items is rated on a four-point scale (0, 1, 2, 3) for the period of the last two 
weeks. A total score is yield by summing up individual item scores, and ranges from 0-27 
with higher scores indicting higher symptom severity. Depression Severity is assessed as: 
none (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), or severe (20-27).
It takes approximately 5 minutes to complete the PHQ-9.


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DERS-16 - Difficulties in Emotion Regulation Scale – 16 item
The Difficulties in Emotion Regulation Scale (DERS) is a 16-item patient-reported 
assessment designed to measure emotion regulation difficulties [R19-1172, R19-1186, R19-
1171] in the following five dimensions: 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).
Each of the 16 items is rated on a five-point Likert scale, from 1=almost never (0-10%); 
2=sometimes (11-35%); 3=about half the time (36-65%); 4=most of the time (66-90%), to 
5=almost always (91-100%).
A total score is yield by summing up individual item scores, and ranges from 16-80 with 
higher scores reflecting greater levels of emotion dysregulation. 
It takes approximately 5-8 minutes to complete the DERS-16.
PSQI - Pittsburgh Sleep Quality Index
The Pittsburgh Sleep Quality Index (PSQI)2 is a 19-item patient-reported assessment 
designed to measure sleep quality over the past month grouped into seven components of 
sleep quality. The seven components comprise subjective sleep quality; sleep latency; sleep 
duration, habitual sleep efficiency; sleep disturbances; use of sleeping medication; daytime 
dysfunction [R00-0292].
Each of the seven components is rated on a four-point scale (0, 1, 2, 3) transforming patient 
responses to the 19 individual items into ratings based on a specific scoring algorithm.
In addition to the seven component scores, a global PSQI score is yield by summing up 
individual component scores, and ranges from 0-21 with higher scores indicting worse sleep 
quality
It takes approximately 5-10 minutes to complete and 5 min to score the PSQI.
SDS - The Sheehan Disability Scale
The Sheehan Disability Scale (SDS) is a patient-reported assessment of disability and 
functional impairment. The SDS is a composite of three self-rated items and two items on the 
days (lost and unproductive) due to the impairment. It is designed to assess functional 
impairment in three major life domains: work, social life/leisure activities, and family 
life/home responsibilities [P08-11546, R20-1844].
                                                
2 The Pittsburgh Sleep Quality Index: A New Instrument for Psychiatric Practice and Research (Authors Daniel J. Buysse, 
Charles F. Reynolds III, Timothy H. Monk, Susan R. Berman, and David J Kupfer, © 1989 and 2010, University of 
Pittsburgh. All rights reserved.)


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Each item is rated on a 10-point visual analogue scale using spatiovisual, numeric and verbal 
descriptive anchors simultaneously to assess disability. A total score is yield by summing up 
individual item scores, and ranges from 0 (unimpaired) to 30 (highly impaired). 
It takes approximately 3-5 minutes to complete the SDS.
EQ-5D-5L - The Euro Qol -5 Dimensions -5 Levels
The Euro Quality of Life -5 Dimensions -5 Levels is a standardized patient-reported 
instrument for use as a measure of health outcome. The EQ-5D-5L consists of the EQ-5D-5L 
descriptive system and the EQ Visual Analogue scale (EQ VAS). 
The EQ-5D-5L descriptive system comprises 5 dimensions of health (mobility, self care, 
usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, and extreme problems. The 
EQ VAS records the patient’s self-rated health status on a vertical visual analogue scale 
graduated from 0 (worst) to 100 (best health the patient can imagine)[R12-1920]. 
It is a generic measure, rather than disease-specific, and is therefore applicable to a wide 
range of health conditions and treatments. It provides a simple descriptive profile and a single 
index value for health status.
It takes approximately 5 minutes to complete the EQ-5D-5L.
5.3
RATER QUALIFICATION
Rater training and qualification on clinical outcome assessments for the purpose of this trial 
will be managed by the vendor as per vendor qualification methodology that has been agreed 
with the sponsor.
The vendor will manage rater training and qualification via evaluating the rater’s experience
and scoring performance, tracking required training, and collecting documentation of training 
and qualification. New raters joining the trial will be trained and qualified with the same 
defined Rater Training and Qualification Program using the vendor Learning Platform
The MINI, CAPS-5, CGI-S and CGI-C must be administered by a psychiatrist, psychologist 
or other clinician demonstrating adequate experience in patients with Post-Traumatic Stress 
Disorder and relevant Comorbidities. Exceptional situations will be reviewed on a case by 
case basis.
The C-SSRS must be administered by a trained staff member with a valid C-SSRS Training 
Certificate. 
All raters for the trial will be trained on the handling of all Clinician administered
assessments that they will be administering and Placebo Response Mitigation (except the C-
SSRS). In addition, each rater will complete a scale specific training before considered 
qualified for rating a patient on the respective scale in the context of the trial.


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For raters, handling Patient Reported Outcomes throughout the trial (i.e. PCL-5 including 
Criterion A and Life Events Checklist, CTQ, PGI-S, PGI-C, STAI, PHQ-9, DERS-16, PSQI, 
SDS and EQ-5D-5L), the completion of a PRO scales training is obligatory. 
The vendor will provide a Site Status Memo indicating the status for all raters who have 
completed the Rater Training and Qualification Program as well are Follow-up requirements
(C-SSRS Certificate will be filed separately).
No patient is allowed to be rated before the Site Status Memo confirming the Qualified status 
for the rater is filed in the ISF.
For each individual patient, the same qualified rater should rate the patient throughout the 
trial, if at all possible. In case of unforeseen circumstances, a qualified back-up rater must be 
available throughout the trial.
5.4
ASSESSMENT OF SAFETY
5.4.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow
Chart 1. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin.
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart 1.
The results must be included in the source documents available at the site. 
5.4.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart 1, prior to blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must be 
included in the source documents available at the site.
5.4.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.4.3:1. For the sampling time 
points please see Flow Chart 1. The total volume of blood withdrawal per patient during the 
trial will be approximately up to 200 mL over 16 weeks. This amount may be exceeded if 
additional unscheduled (in case of necessary safety follow-up) monitoring of laboratory 
results is needed.
Analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the lab manual, except in cases where the ESR will be done locally in which case 
the ESR results will be recorded in the CRF.
Patients do not have to be fasted for the blood sampling for the safety laboratory. 


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Instructions regarding sample collection, sample handling / processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to section 5.4.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see section 5.4.6.1 and the DILI Checklist provided in the ISF and 
electronic data capturing (eDC) system. The amount of blood taken from the patient 
concerned will be increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
Table 5.4.3:1 
Safety laboratory tests
Category
Test name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)
Red Blood Cell Count/ Erythrocytes
Erythrocyte sedimentation rate (ESR) either assessed 
centrally or locally*
Reticulocyte Count
White Blood Cells / Leucocytes
Platelet Count/ Thrombocytes
MCV, MCH, RDW, MCHC
Diff. Automatic
Neutrophils (relative and absolute count)
Eosinophils (relative and absolute count)
Basophils (relative and absolute count)
Monocytes (relative and absolute count)
Lymphocytes (relative and absolute count)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes


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Table 5.4.3:1 
Safety laboratory tests (cont.)
Chemistry
Albumin
AST(GOT)
ALT(GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Lipase
Chemistry Amylase
Calcium
Sodium
Urea (Blood Urea Nitrogen (BUN))
Potassium
Glucose
Creatinine
Bilirubin Total, fractionated if increased
Protein, Total
C-Reactive Protein
Cholesterol, total
Triglycerides
TSH (Reflex testing for fT3 and fT4 if TSH is > 
ULN)
Testosteron1
LH1
FSH1
Folate
Estimated Glomerular Filtration Rate (eGFR) using 
the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation


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Table 5.4.3:1 
Safety laboratory tests (cont.)
Urine (dipstick) Pregnancy test (only for female 
patients of childbearing potential - test done at all 
clinic visits beginning with Visit 1A)
Human Chorionic Gonadotropin in the urine
Serum Pregnancy test (only for female patients of 
childbearing potential) at screening or if urine 
pregnancy test is positive) 
Human Serum Chorionic Gonadotropin 
Urinalysis (dipstick), with microscopic examination if 
urine analysis is abnormal
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Blood
Leukocyte Esterase
Urine pH
Urinalysis
Albumin (quantitative)
Creatinine
Drug screening (urine)
Cannabis
Benzodiazepine
Barbiturates
Opiates
Cocaine
Amphetamines
Methadone
PCP
Infections screening2
Hepatitis B Surface Antigen (qualitative) 
Hepatitis C Antibody (qualitative)
Hepatitis C Virus (HCV) RNA – only if Hepatitis C 
antibodies (qualitative) are positive
1 Males only
2 At screening only
*In this protocol, ESR testing is used solely for the collection of data for analysis purpose at the end of the trial, per FDA’s 
recommendation. The ESR Testing results are not intended to be used as Safety Parameter or for medical management 
decisions. For medical management decisions of Safety relevant inflammation parameter, the CRP test should be used.
For assessment of the kidney function, the formula of the estimated glomerular filtration rate 
(eGFR) CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) will be used. This 
requires that ethnicity need to be captured. See details in the ISF.
If blood sampling for central lab at the trial site is not possible, safety lab analyses can be 
performed at a local lab. The results of the lab tests must be transferred to the investigator 
who ensures medical review and documents a clinically relevant safety issue as an adverse 
event (please refer to section 10.3).


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Minimum required safety lab parameters include liver enzymes and Bilirubin, haematology 
including differential test, blood glucose, sodium, potassium, creatinine, urea (BUN) and 
eGFR. It is important that always the reference values of the local lab are also provided.
5.4.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart 1. Twelve-lead ECGs (I, 
II, III, aVR, aVL, aVF, V1 – V6) will be recorded using equipment provided by a central 
ECG vendor. The ECGs will be recorded for at least 10-second duration after the patients 
have rested for at least 5 minutes in a supine position and prior to lab sampling. Electrode 
placement will be performed according to the method of Einthoven/Goldberger (ankles and 
wrists). At all-time points indicated in the Flow Chart 1, single ECGs will be recorded. ECG 
recordings at planned time points may be repeated for quality reasons like alternating current 
artefacts, muscle movements and electrode dislocation. In this case the repeated ECG 
recordings will be used if quality was better.
The investigator or a designee will evaluate whether the ECG is normal or abnormal and 
whether it is clinically significant, if abnormal. The electronic version of the ECG is regarded 
as source data. Dated and signed printouts will be stored in the 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 (in accordance with the central ECG report) noticed at screening (Visit 1) should be 
reported as baseline condition. Clinically relevant abnormal findings noticed at subsequent 
assessments will be reported as AEs and followed up and/or treated as medically appropriate 
until normal or stable condition.
All ECGs will be transmitted electronically to the central ECG vendor in order to enable a 
centralized and independent re-evaluation of all 12-lead ECGs. A centralized and 
independent re-evaluation will be done. Abnormalities detected during this centralized ECG 
evaluation will not necessarily qualify as AE.
Central evaluation on individual ECG level will be performed by the vendor and a report will 
be provided to the site. Decisions on eligibility for the trial and treatment or further follow-up 
of any findings are in the responsibility of the investigator, based on the central ECG report. 
5.4.5
Other safety parameters
5.4.5.1
Assessment of Suicidality
C-SSRS - Columbia-Suicide Severity Rating Scale
Suicidal risk 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.


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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 multinational clinical trials. The C-SSRS will be 
administered first at screening (Visit 1) (using the ‘Baseline / Screening’ version) with the 
aim to exclude patients with active moderate or severe symptomatology within a specified 
time prior to screening (i.e. 3 months for suicidal ideation and 1 year for suicidal behavior). 
The lifetime history of suicidal ideation and behavior will also be recorded.
After screening (Visit 1) the assessment ‘since last visit’ will be performed at each trial visit
i.e. clinic and phone visits as per Flow Chart 2 (‘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 patient’s safety have to be initiated.
An experienced clinician can use the C-SSRS after a short training session. It takes 
approximately 5 minutes to administer and rate the C-SSRS. At a minimum, the interview 
consists of 2 screening questions related to suicidal ideation and 4 related to suicidal 
behavior, and may be expanded to up to 17 items in case of positive responses. Freetext 
entries are allowed; the investigator has to directly evaluate the scale and write a report.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior during 
the course of trial participation 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 report of suicidal ideation type 1, 2 or 3, after start of the trial, the investigator is to 
decide based on clinical judgment whether it represents an AE as defined in the protocol, and 
if it is considered an AE, then it must be reported accordingly. Please note that 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 5.4.6.1.3).
Any lifetime history of suicidal ideation, self-injurious behavior, no suicidal intent’ or 
suicidal behavior at the screening visit that is not an exclusion criterion, should be considered
as baseline condition/medical history.
5.4.6
Assessment of adverse events
5.4.6.1
Definitions of AEs 
5.4.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.


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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
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.
5.4.6.1.2
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 hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.4.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency (EMA) 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 5.4.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.4.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.


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5.4.6.1.4
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 5.4.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold 
ULN measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN.

These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the 
ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
No other AESIs have been defined for this trial.
5.4.6.1.5
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.
5.4.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, 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 trial drug.

The event is known to be caused by or attributed to the drug class.


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
A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size (ES) 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 trial 
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.

There is an alternative explanation, e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned.

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.4.6.2
Adverse event collection and reporting
5.4.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial
(= the End of Study (EoS) 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 drug related SAEs and trial drug 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 5.4.6.2.2), but 
not on the CRF.
Vital Status Data Collection
Patients who discontinue trial treatment 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 any occurrence of cancer, report all deaths / fatal AEs regardless of 


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relationship, and trial drug related SAEs and trial drug related AESIs the investigator 
becomes aware of. 
5.4.6.2.2
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 to the sponsor’s unique entry point within 24 
hours of becoming aware of the event, the country specific process will be specified 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 the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual 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.
5.4.6.2.3
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 patient 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 patient 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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5.6
ASSESSMENT OF BIOMARKER(S)
This section refers to exploratory biomarkers. Established biomarkers of efficacy and safety 
are described and discussed in sections 5.2 and 5.4.
5.7
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.
5.7.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see Flow Chart 1.
Approximately 45.5 mL blood will be drawn for DNA, Plasma and Serum banking purposes.
5.8
OTHER ASSESSMENTS


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5.8.2
Speech recording
For use in future exploratory investigations, voluntary speech record samples will be 
collected after separate speech recording informed consent has been given in accordance with 
local ethical and regulatory requirements. Participation in the speech sampling is not a 
prerequisite for participation in the trial.
Speech records, along with related information on communication and mental state, will be 
collected with a tool on the tablet/rater station. The tablet/rater station will lead the patient
through a set of speech elicitation tasks designed to assess motor and cognitive function as 
well as affect. Acoustic and language-level features will be extracted from the speech data 
and will be used to examine changes in speech and language features for each patient over 
time. 
These data may be combined with data from other trials of psychiatric indications to explore 
possible association between speech parameters and clinical parameters.


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Speech record collection will occur at the time points indicated in the Flow Chart2.
Instructions for recording are provided in a speech analysis procedures manual, filed in the 
ISF.
Note: All speech sampling tasks may not be available in all countries/languages and will 
therefore be implemented as available per country.
5.8.3
Medication Adherence and Reminder System
In addition to the regular calculation of treatment compliance as described in section 4.3, 
medication adherence will be monitored using a medication adherence monitoring platform. 
 
 
time and day, the patient face-ID, and the drug intake process will be captured in selfie mode 
of the smartphone camera, by the patient. In addition, built-in reminders and a 
communication system allow real-time intervention in case of drug interruptions.
These measures will not supersede or replace the physician and/or prescribed medication 
protocol of the patients. The platform encourages adherence to the predefined protocol but 
does not change the medication protocol of the patients; thus, use of this platform presents 
minimal risk to the patients. Use of the platform will be required for all patients in the trial.
Non-compliance with the system will not lead to patient discontinuation, however patients 
should be encouraged to be fully compliant.
Registration in the 

In most countries, the platform may be downloaded as an application on the patient’s
personal smartphone. If a patient does not own a smartphone or prefers not to use his/ her 
personal smartphone, one of the backup provisioned devices should be provided. In some 
countries, all participants will use a provisioned device. Patients will receive the 
application along with a training during visit 1A (please refer to Flow Chart2 and section 
6.2).

At Visit 2 patients will begin using the platform to monitor study drug intake.
Ongoing use and monitoring of medication adherence

Patients should use the application to record each intake of study medication 
throughout the trial. Patients will follow a series of prescribed steps in front of the 
front-facing webcam to confirm their ingestion of the medication by video and audio.

When at home, patients will receive a medication reminder at a time within a 
predefined window. This notification reminds patients to take their medication dose 
while using the platform

Site personnel are expected to check the 
on an ongoing basis
(minimum once per week) to ensure consistent medication adherence throughout the 
study. In cases of missed doses or pending data, site personnel should follow up with 
the patient as soon as possible to assess the reason for non-adherence and reinforce 


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the importance of complying with the study drug dosing schedule. The 
aforementioned contact/intervention is expected to be logged in the dashboard.

If the patient reports that a dose was taken but not logged in the application, site 
personnel should reclassify this dose to “site reported” using the dashboard.
5.8.4
Verification of current and past research study status of trial patient
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 
patient, in this study, must have their current study status checked by utilizing the system of 
the vendor 
 This is a mandatory process, local amendments will be 
prepared as applicable.
Following proper informed consent and after issuing a study patient number, each patient will 
be checked in the 
 database, as indicated in the Flow Chart 1. Partial 
identifiers will be utilized. This will include checking a valid form of picture ID when 
available.
The first 3 letters of the first and last name will be entered along with the middle initial, Date 
of Birth (DOB), Sex, and last 5 digits of that ID. If the research patient is a Verification 
Success he/she may proceed in the study. Verification Failures status will not be permitted to 
screen without follow-up investigation and documentation of final decision . The duplicate 
patient check will be performed only after approval is received in accordance with local 
regulations.
5.9
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 on race will be collected because this demographic information is required for 
the calculation of eGFR (CKD-EPI formula) (please refer to section 6.2.1).


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6.
INVESTIGATIONAL PLAN
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue 
methodology.
The implementation of these measures will depend on patient’s consent, operational 
feasibility, local law and regulations. If alternative methodology is implemented, the 
deviations from the original plan will be precisely documented.
6.1
VISIT SCHEDULE
All patients have to adhere to the visit schedule as specified in the Flow Chart 1 and Flow 
Chart 2. Each visit date (with its window) is to be counted from Day 1. If any visit has to be 
rescheduled, subsequent visits should follow the original visit date schedule. Additional visits 
for the purpose of re-testing of laboratory parameters or AE monitoring may be included as 
deemed necessary by the investigator.
During the COVID-19 pandemic, there might be situations when patients might not be able to 
come to the site for the scheduled visit. This might be e.g. due to restrictions set by 
authorities or by the investigator site/institution, because the 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
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Trial procedures to be performed at each visit are listed in the Flow Chart 1 and Flow Chart 
2. Additional details regarding visit procedures are provided below.
The following requirements for the conduct of the PTSD assessments need to be followed:
•
The site staff must be properly trained on all trial procedures and training documentation 
filed in the ISF.
•
At all visits, following screening, it must be reiterated that WOCBP must  use the 
appropriate methods of contraception.
•
Qualification, training, remediation (if needed) and central reading of the scales will be 
provided by a specialized vendor. The training standards and standards for the conduct of 
the assessments will be defined for each assessment individually and can be found in the 
ISF; It is the responsibility of the Principal Investigator at the site to ensure that all 
members of the site staff involved in the PTSD assessments undergo qualification and 
training by the vendor (please also refer to section 5.3).
•
The CAPS-5 and CGI-S/C assessments should preferentially be done by the same rater 
for a given patient throughout the study period.


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•
For each individual patient, the same qualified rater should rate the patient throughout the 
trial, if at all possible. In case of unforeseen circumstances, a qualified back-up rater must 
be available throughout the trial.
•
Results of the MINI, CAPS-5, PCL-5 (including Life Events Checklist), OSU TBI-ID-SF
and C-SSRS assessments at screening are part of the eligibility evaluation.
•
The CAPS-5 rater should review the LEC and Extended Criterion A upon completion by 
the patient before the patient completes the PCL-5 to identify the index traumatic event to
be referred to during patient’s PCL-5 completion and the CAPS-5 administration. It is 
essential that the referenced index traumatic event is consistent for PCL-5 and CAPS-5 
assessments.
•
All MINI and CAPS-5 administrations will be audio recorded for central review by the 
vendor for quality assurance.
•
During the assessments, patients are allowed to take short breaks as needed, in the 
judgement of the rater/investigator 
•
The Baseline/screening scale of the C-SSRS will be administered for eligibility 
confirmation and the follow-up scale at all visits for assessment of suicidality.
Order of Assessments and Procedures at Screening Visit
At the screening visit, all clinical examinations and procedures (Flow Chart 1) should be 
performed first, followed by the clinical outcome assessments (Flow Chart 2) in the below 
order. Blood draws are preferably done after clinical outcome assessments but may be done 
as part of the clinical examination and procedures (Flow Chart 1) as per investigator’s 
discretion.
The following clinical outcome assessments 1. to 5. must be in the specific order: 
1. Life Events Checklist (as part of PCL-5)
2. Extended Criterion A (as part of PCL-5)
3. PCL-5
4. CAPS-5 (in consideration of LEC and Extended Criterion A as part of PCL-5)
5. MINI
Assessments/procedures 6. to 8. should preferably be performed in the below order:
6. OSU TBI-ID-SF
7. C-SSRS
8. CTQ
6.2.1
Screening Visit and Screening Period
No trial procedures should be done unless the patient has consented to taking part in the trial. 
Prior to any trial related procedure, the patient information and informed consent may also be 
done at an extra visit but at a maximum up to 2 weeks before V1. 
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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As duplicate enrolment imposes a risk for poor quality and safety, each patient in the trial 
following proper informed consent and after issuing a study patient number must have their 
study status checked by utilizing the system of the vendor “
 The 
duplicate patient check will be performed only after approval is received in accordance with 
local regulations. Please refer to section 5.8.4 for details.
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.
Screening period
The Screening period, i.e. the phase before the first administration of the trial drug, starts at 
Visit 1 (screening visit). The Screening period may last up to a maximum of 28 days but 
should be kept as short as possible.
Within the screening period, screening procedures may be extended to more than one 
physical visit in exceptional situations to reduce patient burden (ahead and in addition to 
planned Visit 1A). 
In such a case, the clinical assessments (Flow Chart 1) should be done on the first day and the 
clinical outcome assessments (Flow Chart 2) preferably on the following day but no longer 
than 3 days after completing the clinical assessments. Exceptional situations must be
discussed and agreed upfront with the Clinical Trial Manager.
Splitting of required procedures for a visit over more than one day is only allowed for Visit 1. 
The screening visit date to be entered into the eCRF is the first day of visit 1, i.e. the day all 
clinical assessments are performed.
EcMA and medication adherence assessment
Eligibility of patients is to be confirmed (i.e. all results received from the screening Visit) 
before Visit 1A is scheduled. Visit 1A must be scheduled at minimum 8 days prior to Visit 2 
to allow for 7 days of EcMA assessments (please refer to Flow Chart 1 and 2). 
During the Visit 1A, patients must be trained on the EcMA and adherence assessment 
according to vendor’s instructions. Patient may choose to download the app or will be 
provided with the loaner smartphone to use during the trial. The adherence assessments will 
start with the first administration of the trial drug at randomization.
In case Visit 2 is delayed after patient completes EcMA assessments, the EcMA assessment 
does not need to be repeated. 
An informational video for placebo response risk mitigation will also be shown to the patient 
during Visit 1A. The video intends 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 


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randomly assigned to placebo, and stresses the importance of reporting all symptoms, be they 
positive or negative or neutral
Optional
Informed Consent for sample biobanking of plasma and serum for biochemical markers and 
DNA; this separate consent must be obtained prior to the collection of the respective blood 
samples.
Informed consent for speech recording. Participation in the sampling of speech recordings is 
voluntary and only allowed after the patient has given separate consent prior to the collection 
of the respective speech records.
Atraining video for speech recordings will be shown to the patient after having agreed to 
participate and having provided informed consent. The first speech recording should be 
performed at the Visit 1A already. 
Infection screening
In case of positive hepatitis B surface antigen (qualitative), the patient will be excluded from 
the trial. 
In case of positive hepatitis C antibody (qualitative), a hepatitis C RNA will be performed. If 
hepatitis C infection is confirmed by hepatitis C RNA, the patient will be excluded from the 
trial. 
Demographics and Baseline Conditions
During the screening visit, demographics information will be collected. 
This includes: 

Age on the day of informed consent (in years)

Sex (male, female in order to describe the patient`s sex at birth), 

Questions on potential disability payments related to PTSD

For women: of childbearing potential yes / no in order to characterize the patient 
population and as a basis for contraception requirements 

Ethnicity and race in order to sufficiently characterize the patient population, to 
support possible subgroup analyses if needed unless not acceptable according to local 
regulations.
Information on race will be collected because this demographic information is required for 
the calculation of eGFR (CKD-EPI formula). Blood pressure should always be measured 
before any blood samples are taken. 
Any abnormal condition of clinical significance identified during physical examination, vital 
signs, 12 lead ECG and/or laboratory assessment should be recorded as a baseline condition.
Any diagnoses identified through MINI questionnaire must be recorded as baseline 
conditions.


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Any lifetime history of suicidal ideation, self-injurious behavior, no suicidal intent’ or 
suicidal behavior at the screening visit that is not an exclusion criterion, should be considered
as baseline condition/medical history.
Medical History
In order to collect previous medical reports to keep records of exact dates/diagnoses of 
relevant medical history or prior medication, up to three documented attempts at different 
days should be made and documented.
Additional details regarding headaches need to be recorded in CRFs for all headaches that 
occurred up to 3 months prior to the screening visit. Please refer to the current CRFs for 
information that needs to be collected.
Additional details regarding concomitant psychotherapy at screening need to be recorded in 
CRFs. Please refer to the current CRFs for information that needs to be collected. During the 
treatment, the question whether there were any significant changes in psychotherapy will be 
recorded in eCRFs only at clinic visits.
Concomitant treatments which are restricted before and during trial participation, , are listed 
in the ISF. Patients will be instructed to continue allowed background medication without 
changes and to adhere to their administration algorithm.
Substance use, e.g., nicotine, alcohol, caffeine at screening and at subsequent clinic visits. 
Please refer to the current CRFs for details about substance use to be collected.
Eligibility Review
A central clinical review by an external clinical reviewer (i.e., 
 clinical 
reviewer) will be performed to ensure patient eligibility based on the audio recording of the 
MINI administration and CAPS-5 data and audio recording, at the screening visit.
Any uncertainty raised by the external clinical reviewer of these scales related to 
inclusion/exclusion criteria will be discussed with the investigator/rater in order to establish 
confidence in the diagnosis and level of symptom severity. Patients for whom 
diagnostic/severity agreement between the investigator/study center clinician and the vendor 
clinician(s) cannot be reached, may not be appropriate for study participation and should not 
be enrolled. 
For eligibility documentation purpose, 
 will send a Subject Eligibility 
Notification to the site indicating one of the three following scenarios: a) the central reviewer 
had no comments to the assessment/rating, b) a discussion was held between the central 
reviewer and the site rater and a mutual agreement with respect to patient eligibility was 
reached or c), the discussion did not lead to an agreement and the patient should not be 
randomized.
Rescreening
For patients who fail screening, a rescreening may be done only once based on investigator 
judgement and prior permission from sponsor. Patient who are re-screened need to be re-


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consented and will be given a new patient number. All the study procedures for screening 
(Visit 1) must be repeated.
Please see Section 3.3 for further details regarding re-screening.
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.
Order of Assessments and Procedures during Treatment  period
After the screening visit, is it up to investigator’s discretion whether clinical outcome 
assessments (Flow Chart 2) or all clinical examinations and procedures (Flow Chart 1) are 
performed first, but for each individual patient, the entire order of all assesments and 
procedures (Flow Chart 1 & 2) should be kept consistent throughout the course of the trial, if 
at all possible.
ECG and vital signs should always be measured before any blood samples are taken. Other 
clinical examinations and procedures can be performed in any order.
All clinical outcome assessments should be completed in the order described below.
Order of clinical outcome assessments
All clinical outcome assessments to be performed per visit are listed in Flow Chart 2.

PCL-5 must be performed first, 

followed by CAPS-5, 

CGI-S (total and domain),

CGI-C 

and C-SSRS, as applicable per visit schedule.
Remaining patient reported outcome assessments as per Flow Chart 2 including optional 
speech recordings may be performed in the preferred order provided in the ISF (and as 
presented on the tablet) after IMP intake and before 


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Meal intake routine will be documented in the eCRF at visits with 
 
Visit 2 (Randomization)
At the start of Visit 2, it should be ensured that all Visit 1 and Visit 1A procedures have been 
successfully completed within the past 28 days and eligibility has been confirmed.
Pandemic restrictions
The patient will be presented with questions to evaluate the impact of COVID-19 pandemic 
restrictions. The assessment period will be aligned with the CAPS-5 recall period (i.e. past 
week).
Randomization should not be performed in case of a positive urine pregnancy test (to be 
completed locally on-site using kits provided by central lab). In this case, a serum pregnancy 
test will be performed by the central lab for confirmation.
Upon randomization via the IRT, medication kit will be dispensed. Trial medication is 
administered after 
The first dose should be taken at the clinic after all Visit 2 assessments and procedures are 
completed, except for remaining patient reported clinical outcome assessments including 
optional speech recordings as described above, and followed by 
. Samples for optional plasma/serum and DNA biobanking will be collected if Informed 
Consent is provided. A sample for DNA biobanking is preferentially collected at Visit 2 but 
can be collected at another time point thereafter.
Trial drug kits will be dispensed for home administration.
Visit 4, Visit 6, Visit 8
Patients should not take trial medication before coming to the clinic. This is because patients 
will be dosed at the clinic. When applicable, dosing should occur after safety lab samples and 
 samples are taken if applicable (please refer to Appendix 10.2).
Pandemic restrictions
At Visit 6, the patient will be presented with questions to evaluate the impact of COVID-19 
pandemic restrictions. The assessment period will be aligned with the CAPS-5 recall period 
(i.e. past week).
Phone visits
Visit 3, Visit 5, Visit 7 and Visit 9 will be conducted by phone or by video call, if in line with 
local regulation.
At Visit 9, patients will be instructed to take the last dose of study medication on the day 
before the EOT visit. 


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Visit 10 / End of Treatment (EOT) Visit
For patients completing the 8-week treatment, this visit will be EOT visit. For patients who 
discontinue study treatment prematurely and continue with study visits, this visit at Week 8 
will be their Visit 10.
EOT visit represents the end of the treatment period. Last study drug administration will be 
on the day before EOT visit. The overall duration of the anticipated treatment period 
(Randomization to EOT) should not be less than 56 days; therefore the EOT visit is 
scheduled at Day 57 with a visit window of up to +2 days.
Patients prematurely discontinuing study drug
If the trial drug intake needs to be permanently stopped for any reason prior to the scheduled 
Week 8 visit, an Early End of treatment Visit (eEOT) visit will be completed instead of the 
planned treatment period visit within 7 days of the last dose of trail medication. See Flow
Chart 1 and section 3.3.4 for further details regarding discontinuation of patients from 
treatment or assessments.
Pandemic restrictions
At Visit 10 or EOT repectively, the patient will be presented with  questions to evaluate the 
impact of COVID-19 pandemic restrictions. The assessment period will be aligned with the 
CAPS-5 recall period (i.e. past week).
6.2.3
Follow-up period and trial completion
For all patients who had at least one dose of trial medication, the follow-up visit will be 
performed as described in section 3.3.4.1 and 3.3.4.2.
If the last day of trial drug intake is different from the day prior to the EOT visit, the date of 
the last day of trial drug intake will be used for calculation of the FUP/EOS visit date.
Patients who finish the randomized treatment period according to the protocol, will return to 
the clinic for the end of study (EOS) Visit 11. Trial completion is defined as patients having 
reached the EOS visit within the specified window per the Flow Chart 1. The trial completion 
page in the eCRF has to be entered.
For all randomized patients, termination of trial medication and trial completion must be 
recorded on the corresponding eCRFs.
Should it be not possible for the patient to attend a follow up visit at the trial site, a visit out 
of time window should be performed as soon as possible; if a visit at the site is not possible at 
all, at least a phone contact should occur at the scheduled follow-up visit time point (please 
refer to section 3.3.4.1 and 5.4.6.2.1).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
This trial is designed to assess the effects of BI 1358894 and placebo on patients with PTSD. 
There will be no formal hypothesis testing performed. Inference concerning the efficacy of 
BI 1358894 will be assessed based on the estimated mean difference(s) between the treatment 
and placebo arm on the change from baseline to Week 8 in CAPS-5 total score, as well as 
other efficacy endpoints.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The following patient analysis sets are defined for this trial:

Full Analysis Set (FAS): includes all randomized patients who received at least one 
dose of trial medication during the trial and had a baseline and at least one post-
baseline observation for the primary or secondary endpoints. The FAS is used for 
efficacy analyses and patients in FAS are analysed under the randomized trial 
medication. 

Treated Set (TS): includes all patients who signed informed consent and were treated 
with at least one dose of the trial medication. Patients in TS are analyzed under the 
actual trial medication received at randomization. The TS is used for safety analyses 
as well as demographics and baseline characteristics.
Data from patients who were screened but not randomized will be listed but not included in 
any summary or inferential statistics.
In general, baseline values are the last measurements taken prior to the first administration of 
trial medication at randomization (Visit 2), (see Flow Chart 1). Further details (e.g., the 
handling of randomized patients that receive the wrong treatment) will be provided in the 
TSAP.
7.2.2
Handling of Intercurrent Events
In the analyses of the primary endpoint, the following intercurrent events (ICEs) are of 
interest:
1. Change in background CNS active medication (e.g., non-SSRI antidepressant, 
anxiolytics)
2. Change in pharmacological therapy (SSRI)
3. Change in drug test result from negative to positive (Cannabis, Benzodiazepine, 
Barbiturates, Opiates, Cocaine, Amphetamines, Methadone, PCP)
4. Change in non-pharmacological therapy – trauma-focused psychotherapy


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5. Change in non-pharmacological therapy – all other cognitive/behavioral therapy
(CBT) (e.g., any other kind of psychotherapy, nicotine withdrawal therapy, diet, etc.)
6. Withdrawal of study medication due to investigator assessed drug-related adverse 
events (e.g., headache)
7. Withdrawal of study medication due to perceived lack of efficacy or disease 
worsening
8. Withdrawal of study medication due to other adverse events
9. Withdrawal of study medication due to any other reasons
Table 7.2.2 :1 Handling rules for Intercurrent events
ICE
Primary 
Estimand
Supplementary 
Estimand 
Handling rules 
for ICEs
1-4
Treatment 
policy
Treatment 
policy
5
Treatment 
policy
Treatment 
policy
6-7
Hypothetical
Treatment 
policy
8-9
Hypothetical
Hypothetical
The primary estimand estimates the treatment effect when changes to background CNS active 
medication, pharmacological SSRI therapies and non-pharmacological therapies (ICEs 1-5) are 
considered to be part of the treatment effect, but changes to randomized treatment (ICEs 6-9) 
are not considered to be part of the treatment effect of interest. ICEs are therefore handled by a 
hybrid estimand that combines the treatment policy and hypothetical approaches, where ICEs 
1-5 are handled using the treatment policy approach, and measurements taken after the 
occurrences of these ICEs are included in the primary analysis; ICEs 6-9 are handled using the 
hypothetical approach, and measurements after their occurrences are therefore censored in the 
primary analysis.


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Regardless of the occurrence of ICEs, every attempt will be made to follow all patients until
the end of the planned study period.
7.2.3
Primary objective analyses
The primary analysis of the primary efficacy endpoint uses the Full Analysis Set. Intercurrent 
events are handled as specified in Section 7.2.2 above and missing data as a result from the 
strategy (including both actual missing outcomes and excluded outcomes) will be handled 
using a mixed effects model with repeated measures (MMRM) under the assumption of 
missing at random (MAR). For change from baseline to Week 8 in CAPS-5 total score, a 
restricted maximum likelihood (REML) based approach using MMRM will be conducted to 
compare the adjusted mean between BI 1358894 125mg QD vs. placebo QD. The MMRM 
includes the fixed categorical effects of treatment at each visit, fixed categorical effects of the 
stratification factor of presence of significant childhood trauma (yes vs. no), and the fixed 
continuous covariates of time since index event (in years) and baseline CAPS-5 total score at 
each visit. Patient is treated as random effect. Visit will be treated as the repeated measure 
with an unstructured covariance structure used to model the within-patient measurements. 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. The point estimates of the adjusted mean difference between 
treatment arms at each visit, together with the corresponding two-sided 95% confidence 
intervals and p-values will be presented. The p-values and 95% confidence intervals are 
considered descriptive statistics. The primary treatment comparison will be the contrast 
between treatment and placebo at Week 8.
Procedures to follow if the MMRM analysis fails to converge will be described in the Trial 
Statistical Analysis Plan.
7.2.4
Secondary objective analyses
For the continuous efficacy endpoint of change from baseline on the PTSD Checklist for 
DSM-5 (PCL-5) total score at Week 8, the same strategy for handling the intercurrent events 
in the primary estimand analysis and a similar MMRM analysis used for the primary efficacy 
endpoint will be conducted to obtain the adjusted mean treatment effect between BI and 
placebo in terms of change from baseline to Week 8. This MMRM model includes the 
discrete fixed effects of treatment at each visit, fixed categorical covariate of the stratification 
factor of presence of significant childhood trauma (yes vs. no), and continuous fixed effects 


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of time since index event (in years) and the corresponding baseline endpoint value at each 
visit. Visit will be treated as the repeated measure with an unstructured covariance structure 
to model the within-subject measurements. Subjects will be considered as a random effect. 
The primary treatment comparison is the contrast between treatment and placebo at Week 8.
A logistic regression adjusted for treatment and stratification factor of presence of significant 
childhood trauma (yes vs. no) will be used for binary endpoints.
7.2.6
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. 
All treated patients will be included in the safety analysis and will be summarized under the 
actual trial medication received at randomization. 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. To this end, all adverse events occurring between the start of treatment and 
the end of the residual effect period will be considered ‘treatment-emergent’. The residual 
effect period is defined as 28 days after the last dose of trial medication. 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 most updated version of the
MedDRA at the time of reporting.
Frequency tables for all adverse events, protocol-specified adverse event of special interest 
(AESI), serious adverse event (SAE), adverse event leading to death, adverse event leading to 
discontinuation, investigator assessed drug-related adverse event and serious related adverse 
event will be generated for treatment-emergent adverse events. In addition, summary 
statistics and descriptive analyses will be conducted for other safety parameters that are 
assessed using dedicated scales, including suicidality as assessed by C-SSRS. 


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Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. 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 trial and at the end-of-trial evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment.
For more details, please refer to the TSAP.
7.2.7
Other Analyses
7.2.8
Interim Analyses
An interim analysis is planned when the 120th evaluable patient completes the preplanned 
treatment period. Here, an evaluable subject is one that has remained in the study, and has at 
least one change from baseline CAPS-5 severity score. 
The purpose of this interim analysis is for internal planning of the PTSD indication with BI 
1358894. PoC could be established and the trial may be stopped early if at the interim 
analysis an impressive standardized effect size is observed. The decision to stop or continue 
the trial will be made by BI based on the totality of evidence - to also include observations 
from secondary objectives and the safety profile. An independent team will be formed to 
perform this analysis. Details will be specified in an interim analysis logistic plan.  
The same MMRM model and estimands used on the primary endpoint, will be used for this 
interim analysis. When the 120th evaluable patient has completed the preplanned treatment 
period, the analysis will be performed on the change from baseline to Week 8 in CAPS-5. 
Based on this observed standardized effect size of the change in CAPS-5 at Week 8 at 
interim, along with evidence from secondary objectives, as well as the observed safety 
profile, a team decision will be made to either stop the trial early for efficacy, and potentially 
claim the achievement of PoC in this indication, or continue enrolling patients until the 
maximum recruitment target of 200 evaluable patients is reached (assuming a drop-out rate of 
30%, this is equivalent to a total sample size of 286 randomized patients, please refer to 


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Section 7.5 for more details on the sample size justification). Detailed efficacy boundary at 
interim will be specified in a separate document. 
During the conduct of the interim analysis, recruitment into the trial will continue. If the trial 
is stopped at interim, there will be a final analysis of the complete data set that will include 
all the patients that were enrolled during the conduct of the interim analysis period. In order 
to support the double-blinded conduct of the trial, the trial team will be kept blinded to the 
individual patients’ treatment group assignment at interim. A separate team will perform the 
interim analysis. Details will be specified in a separate logistic plan.
More details about the interim analysis and final analysis will be specified in the TSAP and 
(or) in the interim logistic plan.
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at the specific time points under patients’ 
consent, even for subjects who terminated trial medication prematurely. For the primary 
analysis in the primary estimand, missing data will not be imputed. The MMRM analysis will 
handle missing data based on a likelihood method under the “missing at random” assumption. 
Please refer to section 3.3.4 for patient retention strategy to minimize missing data. For more 
details regarding missing data handling, please refer to the TSAP.
7.4
RANDOMISATION
Eligible patients will be randomised in equal ratio to BI 1358894 125mg arm and the placebo 
arm. The randomisation will be implemented in blocks to achieve balanced allocation to each 
treatment arm. In addition, randomisation will be stratified by presence of significant 
childhood trauma (yes vs. no), according to investigator´s judgement, assessed by CTQ at 
screening visit).
The randomization will be conducted via an interactive response technology (IRT). BI will 
arrange for the randomization and the packaging and labelling of trial medication. The 
randomization list will be generated using a validated system, which involves a
pseudorandom number generator so that the resulting treatment will be both reproducible and 
nonpredictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to randomize a maximum of 286 patients in this trial, since this sample size is 
considered sufficient to provide a reasonable chance to achieve the aims of this trial (Please 
refer to Table 7.5: 1 for more details). Assuming an early study drop-out rate of 30%, this is 
equivalent to a total of 200 evaluable patients. 
An interim analysis to potentially stop the trial due to efficacy will take place when the 120th
evaluable patient (about 172 patients randomized, assuming an early drop-out rate of 30%) 
has completed the 8-week treatment duration. If the trial is not stopped at interim, then 
patient enrolment will continue to the pre-planned maximum of 286 patients (200 evaluable 
patients). 


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The sample size calculation is based on a target SES of BI 1358894 vs. placebo of 0.35 for 
the primary endpoint. Recent research on drugs for the PTSD indication suggest that an 
estimated standardized ES around 0.38 – 0.53 could be expected (assuming equal variances 
of the treatment and the placebo groups) [R21-1623]. The assumed SES of 0.35 is based on 
the expectation that BI 1358894 has competitive efficacy with other drugs under 
development.
Based on these sample sizes, the probabilities of observing a (1) ES >= 0.5 at interim, and (2) 
ES <0.5 at interim, and ES < 0.25, between 0.25 and 0.32, or >= 0.32 at the final stage with 
200 evaluable patients are presented in Table 7.5: 1. The estimated ES is between treatment 
and placebo on the change from baseline to Week 8 in CAPS-5 total score. In addition, the 
overall probability of observing an ES >=0.5 at interim or observing a standard ES of at least 
0.32 at the final stage are presented in Table 7.5: 1.
Table 7.5: 1 Probabilities of observing a standardized ES at different stages of the study for 
treatment relative to placebo under different scenarios (60 and 100 
evaluable patients per arm at interim, and at final analysis stage, 
respectively).
True standardized ES
Probabilities
0.53
0.46
0.35
0.25
0.15
0.1
P(observed SES >= 0.5 at 
interim) 
0.579
0.422
0.204
0.081
0.028
0.015
P(obs SES < 0.5 at interim & 
final obs SES >= 0.32)
0.356
0.424
0.395
0.241
0.093
0.048
P(obs SES < 0.5 at interim & 
final obs ES < 0.25)
0.024
0.066
0.230
0.488
0.755
0.854
P(obs SES < 0.5 at interim & 
0.25 <= final obs ES < 0.32)
0.041
0.088
0.171
0.190
0.124
0.084
P(observed SES >= 0.5 at 
interim or observed SES > 
0.32 at final)
0.935
0.846
0.599
0.322
0.121
0.063
The calculation was performed using R studio version 3.5.1, based on 10000 simulations.
Hence, under the truly positive scenario of true standardized ES = 0.53, the probability of 
observing ES >= 0.5 at interim is 57.9%, and the probability of observing a standardized ES 
>= 0.5 at interim, or observing a standardized ES >= 0.32 at the final analysis stage is 93.5%. 
Assuming the true standardized effect size is 0.35, there is a 20.4% probability to observe a 
standardized ES between the treatment and placebo arm to be >= 0.5 at interim, and an 
overall 59.9% probability to observe a standardized ES >= 0.5 at interim, or to observe a 
standardized ES of at least 0.32 at the final analysis stage. And an overall 77% probability to 
observe a standardized ES >= 0.5 at interim, or to observe a standardized ES of at least 0.25 


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at the final analysis stage. On the other hand, assuming the true standardized effect size is 
only 0.1, there is an 85.4% probability of observing an ES < 0.5 at interim and observing an 
ES < 0.25 at the final analysis stage. And the overall probability of observing a standardized 
ES >= 0.5 at interim or observing a standardized ES >= 0.32 at the final analysis stage is 
6.3%.


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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 and/or EU regulation 536/2014, and other relevant regulations. Investigators and 
site staff must adhere to these principles. Deviation from the protocol, the principles of ICH 
GCP or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor or delegate 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 finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient according to ICH-GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional patient-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional patient
information must be given to each patient 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 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial patient protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, 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.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
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.
The electronic version of the ECG is regarded as source data. Dated and signed printouts will
be stored in the patient’s medical file.
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 one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.


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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)

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 (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of 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 patient 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 CRF and all source 
documents / data, including progress notes, copies of laboratory and medical test results, 
which must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor or delegate will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
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 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:
Personalised 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 patients 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 Informed Consent 
Form (ICF) is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay / equipment validation depending on 
the intended use of the biomarker data

Samples and / or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first 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 


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termination of the trial is defined as the premature termination of the trial due to any reason 
before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all 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 DMC will evaluate safety data.
The DMC will receive urgent significant safety concerns including severe infections, 
suicidality reports and DILI, for immediate evaluation. While DMC members may be 
unblinded, measures are in place to ensure the blinding for everyone else involved in the trial 
conduct. Regular DMC meetings will be held at specified intervals. The DMC will 
recommend continuation, modification or termination of the trial as detailed in the DMC 
charter. DMC recommendations as well as the final BI decision will be reported to the 
appropriate Regulatory Authorities (RAs)/Health Authorities (HAs), IRBs/ECs, and to 
investigators as requested by local law. The tasks and responsibilities of the DMC are 
specified in a charter.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF.
Vendors will be used in this trial for central laboratory services, IRT, central ECG services, 
Clinician-rated Outcome (ClinRO)/PRO scales assessments including, medication intake 
monitoring, EcMAs, speech recordings and duplicate checks. Details will be provided in the 
respective manuals available in the ISF.
Bioanalysis of BI 1358894 is done by 
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.


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BI has appointed a Clinical Trial Leader responsible for coordinating all required activities, in 
order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
In the participating countries the trial will be performed by the respective local or regional 
BI-organisation (Operating Unit, OPU) in accordance with applicable regulations and BI 
SOPs, or by a Contract Research Organisation (CRO) based on a contract. The CRO will 
perform project management, clinical field monitoring, medical monitoring, and reporting.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, 
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Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: validity of a brief 
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of EQ-5D (EQ-5D-5L), Qual Life Res 2011 ; 20; 1727-1736.
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GL, Tsvetkov E, Rodig SJ, Veer A van't, Meloni EG, Carlezon WA, 
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function and fear-related behavior. Cell 2009 ; 137(4) ; 761-772.
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trait ruminations in depression. J Abnorm Psychol 2014 ; 123(1) ; 35-48.
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research tool in clinical practice. Psychiatry (Edgemont) 2007;4(7):28-37.
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PTSD Scale for DSM-5 (CAPS-5): Development and initial psychometric 
evaluation in military Veterans. Psychological Assessment, 30, 383-395. 
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DJ, Karam EG, Meron Ruscio A, Benjet C, Scott K, Atwoli L, Petukhova 
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Ciutan M, de Girolamo G, Degenhardt L, Gureje O, Haro JM, Huang Y, 
Kawakami N, Lee S, NavarroMateu F, Pennell BE, Piazza M, Sampson N, 
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(2017) Posttraumatic stress disorder in the world mental health surveys. 
Psychol Med 47:2260–2274
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CW, 
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Friedman MJ (2013) National estimates of exposure to traumatic events and 
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multicenter randomized clinical trial of the safety and efficacy of TNX-102 
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American College of Neuropsychopharmacology, ACNP 2016.
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P., Schnurr, P. P., & Keane, T. M. (2015). Psychometric properties of the 
PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders-
Fifth Edition (PCL-5) in Veterans. Psychological Assessment, 28, 1379-
1391. doi:10.1037/pas0000254
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L. (2015). The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5): 
Development and initial psychometric evaluation. Journal of Traumatic 
Stress, 28, 489-498. doi:10.1002/jts.22059
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al, It is time to address the crisis in the pharmacotherapy of posttraumatic 
stress disorder: a consensus statement of the PTSD Psychopharmacology 
Working Group, Biol Psychiatry 2017 ; 82; e51-e59.
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Steenkamp MM, Litz BT, Hoge CW, Marmar CR, Psychotherapy for 
military-related PTSD: a review of randomized clinical trials, JAMA 2015 ; 
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R21-2323
Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, 
et al. Development and validation of a brief screening version of the 
childhood trauma questionnaire. Child Abuse Negl (2003) 27(2):169–90 
R21-2324
Bernstein DP, Ahluvalia T, Pogge D, Handelsman L. Validity of the 
Childhood Trauma Questionnaire in an adolescent psychiatric population. J 
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Watson, David, and Lee Anna Clark. The PANAS-X: Manual for the 
Positive and Negative Affect Schedule - Expanded Form. University of 
Iowa, 1994. Web.
R21-2326
Weathers, F. W., Blake, D. D., Schnurr, P. P., Kaloupek, D. G., Marx, B.
P., & Keane, T. M. (2013). The Life Events Checklist for DSM-5 (LEC-5) 
– Extended. [Measurement instrument]. Available from 
https://www.ptsd.va.gov 
R21-2327
Weathers, F.W., Blake, D.D., Schnurr, P.P., Kaloupek, D.G., Marx, B.P., & 
Keane, T.M. (2013). The Clinician-Administered PTSD Scale for DSM-
5 (CAPS-5). [Assessment] Available from www.ptsd.va.gov.
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Bogner, J.A., Corrigan, J.D. (2009). Reliability and validity of the OSU TBI 
Identification Method with Prisoners. Journal of Head Trauma 
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Corrigan, J.D., Bogner, J.A. (2007). Initial reliability and validity of the 
OSU TBI Identification Method. Journal of Head Trauma Rehabilitation, 
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Bernstein DP, Fink L, Handelsman L et al. (1994), Initial reliability 
and validity of a new retrospective measure of child abuse and neglect. Am 
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Dondanville, K. A., Hall-Clark, B., Foa, E. B., Young-McCaughan, S., 
Yarvis, J., Hembree, E. A., Mintz, J., Peterson, A. L., & Litz, B. T. (2016). 
Psychometric analysis of the PTSD Checklist-5 (PCL-5) among treatment-
seeking military service members. Psychological Assessment, 28, 1392-
1403. doi:10.1037/pas0000260
R21-2340
Weathers, F.W., Litz, B.T., Keane, T.M., Palmieri, P.A., Marx, B.P., & 
Schnurr, P.P. (2013). The PTSD Checklist for DSM-5 (PCL-5). Scale 
available from the National Center for PTSD at www.ptsd.va.gov.


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R21-2341 
Weathers, F.W., Litz, B.T., Keane, T.M., Palmieri, P.A., Marx, B.P., & 
Schnurr, P.P. (2013). The PTSD Checklist for DSM-5 (PCL-5). Scale 
available from the National Center for PTSD at www.ptsd.va.gov. 
PCL5_Standard_form_week
R21-2342
Weathers, F.W., Litz, B.T., Keane, T.M., Palmieri, P.A., Marx, B.P., & 
Schnurr, P.P. (2013). The PTSD Checklist for DSM-5 (PCL-5). Scale 
available from the National Center for PTSD at www.ptsd.va.gov. 
PCL5_Standard_form-month
R21-2548
Weathers, F. W., Blake, D. D., Schnurr, P. P., Kaloupek, D. G., Marx, B. 
P., & Keane, T. M. (2015). The Clinician-Administered PTSD Scale for 
DSM-5 (CAPS-5) – Past Week [Measurement instrument]. Available from 
https://www.ptsd.va.gov/
R98-0762
Spielberger CD. Manual for the state-trait anxiety inventory. Palo Alto: 
Consulting Psychologists Press; 1983.
9.2
UNPUBLISHED REFERENCES
c10354149
Investigator’s Brochure 1402.P1 & 1402.P2


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
Refer to ISF.


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10.3
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF
RESTRICTIONS DUE TO COVID-19
As mentioned in section 6.1, 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 patient safety and appropriate trial continuation based on a thorough 
benefit-risk assessment (see section 1.4.2).
Under these circumstances, the below modifications can be considered. 
Safety lab, other laboratory tests
If taking blood samples for central lab is not possible, blood analysis for safety lab can be 
done in a local lab. The results of the lab tests are to be reported and transferred to the 
investigator, who has to ensure medical review and proper documentation. 
Safety lab parameters should at least include liver enzymes and Bilirubin, haematology 
including differential test, blood glucose, sodium, potassium, creatinine, urea (BUN) and 
eGFR. It is important that always the reference values of the local lab are also provided. 
Dispensation of Trial medication (IMP)
If a participant is not able to come to visit 4, visit 6 or visit 8 as planned and the investigator 
considers it acceptable and save for participant to continue with IMP, IMP can be shipped 
from site directly to the participant (if legally acceptable according to local regulations).
If home visits by trial staff members or e.g. “Home Healthcare Nurse” are possible, further 
assessments can be done like e.g. vital signs, blood draw for safety lab and biomarkers as 
well as collection of urine samples to be sent to central lab, or compliance check.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
03 May 2022
EudraCT number/EU number
2021-003154-23
BI Trial number
1402-0030
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 8-week-treatment, multicenter, 
randomized, double-blind, placebo-controlled, 
parallel group trial to evaluate the efficacy, 
tolerability and safety of orally administered BI 
1358894 in patients with Post-Traumatic Stress 
Disorder (PTSD)
Global Amendment due to urgent 
safety reasons
X
Global Amendment
1
Sections to be changed
Flow Chart 1; Flow Chart 1 footnote 8; Table 
5.4.3:1
Description of change
Added pregnancy test at EOS visit, corrected 
footnote text and table 5.4.3:1 to include 
pregnancy test at V1A as required by Flow 
Chart 1
Rationale for change
New safety information.
Sections to be changed
Flow Chart 1; Section 4.2.2.3; Section 6.2


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Description of change
Flow Chart 1
The following text was added:
Informed consent 4 (including informed 
consents for patient’s duplicate check5, 
optional biobanking and speech recording;
counseling about the need of contraception)
Section 4.2.2.3
The following text was added:
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. 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 1 (including phone visits).
Complete sexual abstinence when this is in line 
with the preferred and usual lifestyle of the 
study patient. When there is complete sexual 
abstinence, the patient refrains from any sort of 
sexual activity that could involve the spill of an 
ejaculate, even if the spill does not occur. 
(Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and 
withdrawal (coitus interruptus) are not 
acceptable methods of contraception).
Was changed to:
Complete sexual abstinence when this is in line 
with the preferred and usual lifestyle of the 
study patient. (Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal (coitus 
interruptus) are not acceptable methods of 
contraception) - (in this specific case the 
barrier methods as mentioned below, are not 
applicable). Sexual abstinence as a 


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contraceptive method will not be allowed for 
WOCBP who are heterosexually active.
6.2
The following was added:
At all visits, following screening, it must be 
reiterated that WOCBP must use the 
appropriate methods of contraception.


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Rationale for change
New safety information.
Sections to be changed
Flow Chart 1, footnote 5; section 5.8.4
Description of change
Flow Chart 1, footnote 5
The following was added:
Registration of patient by site staff in the 
system is only required 
during the Screening Visit; no further action 
for the site staff during the course of the study.
Section 5.8.4
If the research patient is a Verification Success 
he/she may proceed in the study. Verification 
Failures status will not be permitted to screen 
without sponsor approval.
Was changed to:
If the research patient is a Verification Success 
he/she may proceed in the study. Verification 
Failures status will not be permitted to screen 
without follow-up investigation and 
documentation of final decision.
Rationale for change
Clarification of process.
Sections to be changed
Flow Chart 1, footnote 12


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Description of change
Collection of biobanking samples is optional. 
Samples will be collected at Visit 2 (serum, 
plasma and deoxyribonucleic acid (DNA) 
samples) and EOT/Early EOT, respectively 
(serum, plasma only). Patients are required to 
sign a separate informed consent for 
biobanking. Samples will be stored at a 
biobanking facility for future research
Was changed to:
Collection of biobanking samples is optional. 
Samples must be collected at Visit 2 (serum, 
plasma samples) and EOT/Early EOT, 
respectively (serum, plasma only). Patients are 
required to sign a separate informed consent 
for biobanking. Samples will be stored at a 
biobanking facility for future research
Rationale for change
Clarification
Sections to be changed
Flow Chart 2, section 6.2.1
Description of change
Patient informational video speech recording
Was changed to:
Patient training video speech recording
Rationale for change
Clarify that purpose of the video is the training 
of patients on the assessment.
Sections to be changed
Section 1.2 


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Description of change
The following text was added:
Oral administration of BI 1358894 to the 
pregnant Goettingen minipigs throughout 
organogenesis was associated with 
developmental effects including lower embryo-
fetal survival (due to a reduced number of 
intrauterine implantations and an increased 
number of early resorptions) and decreased 
fetal weights, compared to control. In addition, 
there were higher incidences of skeletal 
malformations and/or variations. The NOAEL 
for embryo-fetal development (100 mg/kg/day) 
corresponded to a mean Cmax of 1,980 nmol/L 
and a mean AUC0-24h of 31,300 nmol∙h/L of 
BI 1358894, therefore providing safety 
margins of 1.4 and 1.6, respectively (compared 
with the predicted exposure at the human dose 
of 125 mg).
Rationale for change
New safety information
Sections to be changed
Section 1.2
Description of change
Overall, 217 healthy volunteers and 73 patients 
with MDD had been exposed to BI 1358894 in 
7 Phase I clinical trials, which were completed 
at the time of CTP writing.  
Was changed to:
Overall, 211 healthy volunteers and 23 patients 
with MDD had been exposed to BI 1358894 in 
8 Phase I clinical trials. 
Rationale for change
Update in  numbers of participants in clincial 
studies for alignment with current 
Investigator’s Brochure Version 7.
Sections to be changed
Section 1.4.2 


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Description of change
The following text was added:
In one completed pivotal embryo-fetal 
development study in Goettingen minipigs, 
embryo-fetal development toxicity was 
identified (decreased number of implantations, 
increased number of early resorptions, 
decreased fetal weight, skeletal malformations) 
at relevant human exposure levels. Maternal 
toxicity was not seen at human relevant doses. 
The NOAEL shows that the findings are 
relevant for the maximum dose (125 mg once 
daily) tested in the ongoing clinical trials.
Therefore, a risk for teratogenicity in humans 
cannot be excluded. To mitigate this risk, 
women of childbearing potential (WOCBP) 
who are heterosexually active must agree and 
adhere to contraceptive measures consisting of 
one highly effective method of birth control 
per ICH M3 (R2) that results in a low failure 
rate of less than 1% plus one additional barrier 
method during the treatment and follow-up 
period of the trial. Pregnancy testing has to be 
performed at every site visit. Additionally, 
investigators must counsel WOCBP with 
regard to the importance of contraception at all 
visits as per Flow Chart 1 (including phone 
visits).
Rationale for change
New safety information
Sections to be changed
Table 1.4.2:1


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Description of change
The following was added to the table:
Embryo-fetal development toxicity
Decreased number of implantations, early 
resorptions, decreased fetal weight, skeletal 
malformations in minipigs at relevant human 
exposure levels. Thus, a risk for teratogenicity 
in humans cannot be excluded.
WOCBP must adhere to contraceptive 
measures consisting of one highly effective 
method of birth control per ICH M3 (R2) 
during the treatment and follow-up period. 
Sexual abstinence as a contraceptive method 
will not be allowed for WOCBP who are 
heterosexually active. 
Pregnancy testing must be performed at every 
site visit. 
Investigators must counsel WOCBP with 
regard to the need for contraception at all visits 
as per Flow Chart 1 (including phone visits).
Rationale for change
New safety information
Sections to be changed
Section 1.4.3


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Description of change
The following text was added:
Embryo-fetal development toxicity has been 
identified in a pre-clinical study in minipigs at 
relevant human exposure levels. Therefore, a 
risk for teratogenicity in humans cannot be 
excluded. It is of high importance that WOCBP 
strictly adhere to contraceptive measures 
consisting of one highly effective method of 
birth control per ICH M3 (R2) that results in a 
low failure rate of less than 1% plus one 
additional barrier method during the treatment 
and follow-up period of the study. Sexual 
abstinence as a contraceptive method will not 
be allowed for WOCBP who are 
heterosexually active. Pregnancy testing has to 
be performed at every site visit. Additionally, 
WOCBP will be repeatedly counselled with 
regard to the need for contraception at all visits 
as per Flow Chart 1 (including phone visits).
Considering the acceptable and manageable 
safety profile of BI 1358894 as demonstrated 
in nonclinical and toxicology studies and the 
good tolerability in clinical studies performed 
to date together with the close monitoring…
Was changed to:
Considering the acceptable and manageable 
safety profile of BI 1358894 as demonstrated 
in nonclinical and toxicology studies, good 
tolerability in clinical studies performed to 
date, close monitoring (including the above-
mentioned risk mitigation activities to 
minimize the risk of pregnancy during the trial) 
planned during the study visits …
Rationale for change
New safety information
Sections to be changed
Section 3.3


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Description of change
Retesting applies in situations when the issue 
can be resolved within the screening period of 
28 days. For example patients are testing 
positive on urine drug screen for cannabis or 
opioids at Visit 1. These patients can be re-
tested once (consider long half-life of 
cannabis) within the screening period of 28 
days, if there is a reasonable explanation and 
expectation that the patient is not a regular user 
and will not test positive again on re-test or has 
stable treatment with medically prescribed 
opioids, both at the discretion of the 
investigator.
In case of retesting, the patient will keep the 
same patient number. The results of all retests 
should be available within the 28 days of 
screening period. Once retests are available 
and negative for the retested parameter and in 
case all other eligibility criteria are met, the 
patient can be randomized on the planned Visit 
2 date.
Was changed to:
Retesting applies in situations when the issue 
can be resolved within the screening period of 
28 days, for example patients that are testing 
positive on urine drug screen for cannabis or 
opioids at Visit 1 can be retested once 
(consider long half-life of cannabis) within the 
screening period of 28 days, if there is a 
reasonable explanation and expectation that the 
patient is not a regular user and will not test 
positive again on retest or has stable treatment 
with medically prescribed opioids, both at the 
discretion of the investigator. 
In case of retesting, the patient will keep the 
same patient number. The results of all retests 
should be available within the 28 days of 
screening period. Once retests are available 
and negative for the retested 
parameter/eligibility confirmed, and in case all 
other eligibility criteria are met, the patient can 
be randomized on the planned Visit 2 date.


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The following was added:
The exceptions above only apply if these 
assessments are not the reason for rescreening.
Rationale for change
Clarification of procedures for retesting and 
rescreening.
Sections to be changed
Section 3.3.3
Description of change
Exclusion Criterion #26
Patients who were confined to an institution by 
court or administrative order.
Was changed to:
Patients who are currently and during the 
course of the trial confined to an institution by 
court or administrative order.
Rationale for change
Clarification
Sections to be changed
Section 3.3.3
Description of change
Exclusion Criterion #29
In-patients are generally excluded, however in-
patients who are committed on a voluntary 
basis in an open-ward (i.e. "residental ward") 
and are non-suicidal are allowed.
Was changed to:
In-patients are generally excluded, however in-
patients who are admitted on a voluntary basis 
in an open-ward (i.e. "residential ward") and 
are non-suicidal are allowed.
Rationale for change
Clarification
Sections to be changed
Section 3.3.4.1; 6.2.3; Flow Chart 1&2 visit 
description; Flow Chart 1 footnote **


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Description of change
Section 3.3.4.1
After this early EOT visit, patients should be 
followed up according to the regularly 
scheduled visit for both clinic and phone visits 
until Visit 10 and should be encouraged to 
complete the EOS Visit 28+2 days after the 
drug discontinuation date. All procedures 
should be completed, with the exception of 
trial drug procedures and PK collections. If a 
regular planned visit is completed prior to the 
initially planned Visit10 (early drug 
discontinuation date + 28+2 days), no 
additional FUP is needed. However, end of 
study participation must be completed.
If the patient does not agree to return for all 
remaining scheduled visits, the patient should 
be encouraged to return at least for an early 
EoT (eEOT) Visit within 7 days of the last 
dose of trial medication, for the regularly 
scheduled Visit 10 and EOS. If EOS visit 
(early drug discontinuation date + 28 +2 days) 
can be completed prior to the date of the 
planned Visit 10, no additional FUP is needed. 
However, end of study participation must be 
completed. 
Was changed to:
After this early EOT visit, patients should be 
followed up according to the regularly 
scheduled visit for both clinic and phone visits 
including Visit 10 and should be encouraged to 
complete the FUP/EOS Visit 28+2 days after 
the drug discontinuation date. All procedures 
should be completed, with the exception of 
trial drug procedures and PK collections. If a 
regular planned visit is completed prior to the 
initially planned Visit10 (early drug 
discontinuation date + 28+2 days), no 
additional FUP Visit may be needed. However, 
end of study participation (EOS) must be 
completed.


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If the patient does not agree to return for all 
remaining scheduled visits, the patient should 
be encouraged to return at least for an early
EoT (eEOT) Visit within 7 days of the last 
dose of trial medication, for the regularly 
scheduled Visit 10 and EOS. If EOS visit 
(early drug discontinuation date + 28 +2 days) 
can be completed prior to the date of the 
planned Visit 10, no additional FUP Visit may 
be needed. However, end of study participation 
(EOS) must be completed.
Section 6.2.3
If the last day of trial drug intake is different 
from the day prior to the EOT visit, the date of 
the last day of trial drug intake will be used for 
calculation of the EOS visit date.
Was changed to:
If the last day of trial drug intake is different 
from the day prior to the EOT visit, the date of 
the last day of trial drug intake will be used for 
calculation of the FUP/EOS visit date.
Flow Chart 1&2
The following was added to V11 visit 
description:
Follow-up Visit (FUP) / 
Flow Chart 1, Footnote**
After this early EOT visit, patients should be 
followed up according to the regularly 
scheduled visit for both clinic and phone visits 
until Visit 10 and should be encouraged to 
complete the FUP Visit 28+2 days after the 
drug discontinuation date
All procedures should be completed, with the 
exception of trial drug procedures and PK 
collections. If a regular planned visit is 
completed prior to the initially planned Visit10 
(early drug discontinuation date + 28+2 days), 


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no additional FUP is needed. However, end of 
study participation must be completed.
If the patient does not agree to return for all 
remaining scheduled visits, the patient should 
be encouraged to return at least for an early 
EoT (eEOT) Visit within 7 days of the last 
dose of trial medication, for the regularly 
scheduled Visit 10 and FUP. If FUP visit (early 
drug discontinuation date + 28 +2 days) can be 
completed prior to the date of the planned Visit 
10, no additional FUP is needed. However, end 
of study participation must be completed.
Was changed to:
After this early EOT visit, patients should be 
followed up according to the regularly 
scheduled visit for both clinic and phone visits 
including Visit 10 and should be encouraged to 
complete the FUP Visit 28+2 days after the 
drug discontinuation date
All procedures should be completed, with the 
exception of trial drug procedures and PK 
collections. If a regular planned visit is 
completed prior to the initially planned Visit10 
(early drug discontinuation date + 28+2 days), 
no additional FUP Visit may be needed. 
However, end of study participation (EOS) 
must be completed.
If the patient does not agree to return for all 
remaining scheduled visits, the patient should 
be encouraged to return at least for an early 
EoT (eEOT) Visit within 7 days of the last 
dose of trial medication, for the regularly 
scheduled Visit 10 and FUP. If FUP visit (early 
drug discontinuation date + 28 +2 days) can be 
completed prior to the date of the planned Visit 
10, no additional FUP Visit may be needed. 
However, end of study participation (EOS) 
must be completed.


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Rationale for change
Clarification
Sections to be changed
Section 4.2.2.1
Description of change
For patients who are not on current treatment 
with benzodiazepine (including Z-drugs) or 
non-benzodiazepine hypnotics at the time of 
screening, the protocol will allow concomitant 
use of non-benzodiazepine-, non-Z-drug 
hypnotics during the trial at dose equivalent to 
≤ 1.0 mg lorazepam per day.
Was changed to:
For patients who are not on current treatment 
with benzodiazepine (including Z-drugs) or 
non-benzodiazepine hypnotics at the time of 
screening, the protocol will allow concomitant 
use of non-benzodiazepine-, non-Z-drug 
hypnotics at lowest dose of the compound as 
noted in the Summary of Product 
Characteristic (or SmPC) during the trial.
Rationale for change
Removal of lorazepam dose equivalent as this 
is not applicable in this trial for concomitant 
use started during the trial. 
Sections to be changed
Table 5.4.3:1 
Description of change
Hepatitis C Vaccine 
Was changed to:
Hepatitis C Virus
Rationale for change
Correction of term. 
Sections to be changed
Section 5.4.5.1


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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 
5.4.6.1.3).
Rationale for change
Reference to “Always serious adverse event 
list” added for clarification. 
Sections to be changed
Section 6.2
Description of change
The following text was added:
The CAPS-5 rater should review the LEC and 
Extended Criterion A upon completion by the 
patient before the patient completes the PCL-5 
to identify the index traumatic event to be 
referred to during patient’s PCL-5 completion 
and the CAPS-5 administration. It is essential 
that the referenced index traumatic event is 
consistent for PCL-5 and CAPS-5 assessments.
CTQ was added to listed assessments.
Rationale for change
Clarification of process.
Sections to be changed
Section 6.2.1


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Description of change
Concomitant treatments which are allowed or 
restricted before and during trial participation, 
including required washout durations, are listed 
in the ISF. Patients will be instructed to 
continue allowed/required background 
medication without changes and to adhere to 
their administration algorithm.
Was changed to:
Concomitant treatments which are restricted 
before and during trial participation, are listed 
in the ISF. Patients will be instructed to 
continue allowed background medication 
without changes and to adhere to their 
administration algorithm.
Rationale for change
Correction to remove not applicable text. 
Sections to be changed
Section 8.1
Description of change
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.
Was changed to:
Prior to patient participation in the trial, written 
informed consent must be obtained from each 
patient according to ICH-GCP and to the 
regulatory and legal requirements of the 
participating country.
Rationale for change
Legal accepted representatives are not 
applicable for this trial.
Sections to be changed
Throughout the document 
Description of change
Typos, formatting and duplicate wording  
corrected and paragraph moved within section
Rationale for change
Administrative changes to increase clarity, 
quality and readability.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
26 Sep 2022
EudraCT number/EU number
2021-003154-23
BI Trial number
1402-0030
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 8-week-treatment, multicenter, 
randomized, double-blind, placebo-controlled, 
parallel group trial to evaluate the efficacy, 
tolerability and safety of orally administered BI 
1358894 in patients with Post-Traumatic Stress 
Disorder (PTSD)
Global Amendment due to urgent 
safety reasons
N/A
Global Amendment
2
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
To follow an FDA request and to ensure that 
the investigator confirms the contraception 
requirement with the patient.
Section to be changed
Flow Chart 1 footnote 16
Description of change
Contraception counseling for WOCB
Was changed to:
Contraception counseling for WOCB16
16 This must include confirmation from the patient that she is 
using required contraception consistently and 
appropriately. Counseling and contraception confirmation 


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must be recorded in CRFs Refer to section 4.2.2.3 for 
more details regarding contraception counseling.
Rationale for change
To follow an FDA request and to reinforce that 
contraception counseling is done at every visit 
and documented. 
Section to be changed
Section 1.4.2 
Description of change
Additionally, investigators must counsel 
WOCBP with regard to the importance of 
contraception at all visits as per Flow Chart 
(including phone visits).
Was changed to:
Additionally, investigators must counsel 
WOCBP with regard to the importance of 
contraception and confirmation of appropriate 
contraception use at all visits as per Flow Chart 
(including phone visits).
Rationale for change
To follow an FDA request and to reinforce that 
contraception counseling is done at every visit 
and documented.
Section to be changed
Table 1.4.2: 1
Description of change
Embryo-fetal development toxicity
Section was updated:
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.
Pregnancy testing must be performed at every 
site visit. 
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 1 (including phone 
visits).
Refer to section 4.2.2.3 for more details 
regarding contraception counseling.


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Rationale for change
To follow an FDA request and to reinforce that 
contraception counseling is done at every visit 
and documented.
Section to be changed
Section 3.3.2
Description of change
7. Women who are of child-bearing potential 
(WOCBP)1 must be able and willing to use 
two methods of contraception which include 
one highly effective method of birth control 
per ICH M3 (R2) that result in a low failure 
rate of less than 1%, plus one additional 
barrier method. 
Was changed to:
7. Women who are of child-bearing 
potential (WOCBP)1 must be 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 result in a low failure rate of 
less than 1%, plus one additional barrier 
method. 
Rationale for change
To follow an FDA request and to ensure that 
the investigator confirms the contraception 
requirement with the patient.
Section to be changed
4.2.2.3
Description of change
Section was updated:
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.


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The importance of continuing with their chosen 
forms of birth control during study conduct 
will be emphasized to mitigate this risk and it 
must be reiterated at all visits as per Flow 
Chart 1 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.
Rationale for change
To follow an FDA request and to reinforce that 
contraception counseling is done at every visit 
and documented. Also to provide guidance for 
investigators on contraception rules.


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Sections to be changed
Flow Chart 1 & 2
Description of change
Description
-28 days to 0
V1A anytime up to day -7
Was changed to: 
-28 days
V1A anytime up to 8 days before V2
Rationale for change
Clarifcation of screening period definition.
Sections to be changed
Section 5.8.1, Figure 5.8.1.1:1


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Description of change
Section 5.8.1
A daily/weekly diary design beginning 7 days 
prior to the randomization visit and then over
the 8-week treatment period will be used.
Was changed to:
A daily/weekly diary design for 7 days prior to 
the randomization visit and then over
the 8-week treatment period will be used.
Figure 5.8.1.1:1
Visit 1A
up to day -7
Was changed to:
Visit 1A min. 8 days prior V2
56 days
Day 2 (the day after V2) to Day 56 (day before 
V10)
Was changed to:
55 days (+2)
Day 2 (the day after V2) to Day 56 (+2) (day 
before V10)
Rationale for change
Clarification of assessment period definition.
Figure 5.8.1.1.:1 was updated to be aligned 
screening period clarification and EcMA 
PANAS daily was corrected.
Sections to be changed
Footnotes Flow Chart 1 & 2, section 6.2, 
section 6.2.2


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Description of change
Footnote to Flow Chart 1 & 2:
At the screening visit, all clinical examinations 
and assessments as per Flow Chart 1 will be 
performed first, except for the blood draws, 
followed by PCL-5,CAPS-5 and MINI, 
followed by the other scale administrations, 
listed in Flow Chart 2.The order of assessments 
is described in detail in section 6.2.
For all further clinical visits, scale 
administrations should be done first, followed 
by the clinical examinations and assessments 
(Flow Chart 1) Please refer to section 6.2 for 
further details.
Was changed to:
At the screening visit, all clinical examinations 
and procedures  as per Flow Chart 1 should be 
performed first, followed by PCL-5 (version 
comprising LEC, Extended Criterion A and 
PCL5),CAPS-5 and MINI, followed by the 
other clinical outcome assessments, listed in 
Flow Chart 2. Blood draws are preferably done 
after clinical outcome assessments. The order 
of assessments and procedures is described in 
detail in section 6.2.
For all further clinical visits, please refer to 
section 6.2.2 for details on order of 
assessments and procedures.
The following text was removed:
All baseline assessments must be performed 
prior to the first intake of the trial medication.
Section 6.2:
Order of Assessments at Screening Visit
At the screening visit, all clinical examinations 
and assessment (Flow Chart 1) should be 
performed first except for the blood draws, 
followed by the clinical outcome 
measurements (Flow Chart 2) in the following 
order. 


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The following assessments 1. to 5. must be in 
the specific order: 
1. Life Events Checklist (as part of PCL-5)
2. Extended Criterion A (as part of PCL-5)
3. PCL-5
4. CAPS-5 (in consideration of LEC and 
Extended Criterion A as part of PCL-5)
5. MINI
Assessments/procedures 6. to 8. should 
preferably be performed in the below order:
6. OSU TBI-ID-SF
7. C-SSRS
8. CTQ
Was changed to:


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Order of Assessments and Procedures at 
Screening Visit
At the screening visit, all clinical examinations 
and procedures (Flow Chart 1) should be 
performed first, followed by the clinical 
outcome assessments (Flow Chart 2) in the 
below order. Blood draws are preferably done 
after clinical outcome assessments but may be 
done as part of the clinical examination and 
procedures (Flow Chart 1) as per investigator’s 
discretion.
The following clinical outcome assessments 1. 
to 5. must be in the specific order: 
1. Life Events Checklist (as part of PCL-5)
2. Extended Criterion A (as part of PCL-5)
3. PCL-5
4. CAPS-5 (in consideration of LEC and 
Extended Criterion A as part of PCL-5)
5. MINI
Assessments/procedures 6. to 8. should 
preferably be performed in the below order:
6. OSU TBI-ID-SF
7. C-SSRS
8. CTQ
The following text was removed:
After the screening visit, the scales should be 
performed first (Flow Chart 2), followed by the 
other clinical examinations (Flow Chart 1). All 
scales should be completed in the order 
described in section 6.2.2 below.
Section 6.2.2
Order of assessments
All clinical outcome assessments to be 
performed per visit are listed in Flow Chart 2.
PCL-5 should be performed first, followed by 
CAPS-5, CGI-S (total and domain) and CGI-C 
as applicable per visit schedule. For the 
remaining clinical outcome assessments, a 


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preferred order will be provided in the ISF. 
Clinical examinations (Flow Chart 1) should be 
performed after clinical outcome assessments 
(Flow Chart 2). ECG and blood pressure 
should always be measured before any blood 
samples are taken. Other assessments can be 
performed in any order. 
Was changed to:
Order of Assessments and Procedures during 
Treatment  period
After the screening visit, is it up to 
investigator’s discretion whether clinical 
outcome assessments (Flow Chart 2) or all 
clinical examinations and procedures (Flow 
Chart 1) are performed first, but for each 
individual patient, the entire order of all 
assesments and procedures (Flow Chart 1 & 2) 
should be kept consistent throughout the course 
of the trial, if at all possible.
ECG and vital signs should always be 
measured before any blood samples are taken. 
Other clinical examinations and procedures can 
be performed in any order.
All clinical outcome assessments should be 
completed in the order described below.
Order of clinical outcome assessments
All clinical outcome assessments to be 
performed per visit are listed in Flow Chart 2.

PCL-5 must be performed first, 

followed by CAPS-5, 

CGI-S (total and domain), 

CGI-C 

and C-SSRS, as applicable per visit 
schedule.
Remaining patient reported outcome 
assessments as per Flow Chart 2 including 
optional speech recordings may be performed 
in the preferred order provided in the ISF (and 
as presented on the tablet) after IMP intake and 
before PK post-dose blood sampling.


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The following text was removed:
For the remaining clinical outcome 
assessments, a preferred order will be provided 
in the ISF. Clinical examinations (Flow Chart 
1) should be performed after clinical outcome 
assessments (Flow Chart 2). ECG and blood 
pressure should always be measured before any 
blood samples are taken. Other assessments 
can be performed in any order. 
Rationale for change
Operational relief and reduction of patient and 
site burden.
Sections to be changed
Section 1.2
Description of change
In vitro BI 1358894 induced CYP2B6, 
therefore comedications which are sensitive 
substrates of CYP2B6 are excluded.
Was changed to:
In vitro BI 1358894 induced CYP2B6, 
therefore a DDI study was performed with a 
CYP2B6 substrate. As no clinically relevant 
induction was seen, there are no restrictions on 
the use of comedications for sensitive 
substrates of CYP2B6.
Rationale for change
New information available from a clinical DDI 
study with bupropion (see IB v9)
Sections to be changed
Table 1.4.2: 1 section  4.2.2.1
Description of change
The following text was removed:
Sensitive substrates of CYP2B6
Rationale for change
New information available from a clinical DDI 
study with bupropion (see IB v9)


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11.3
GLOBAL AMENDMENT 3
Date of amendment
18 JAN 2023
EudraCT number/EU number
2021-003154-23
BI Trial number
1402-0030
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 8-week-treatment, multicenter, 
randomized, double-blind, placebo-controlled, 
parallel group trial to evaluate the efficacy, 
tolerability and safety of orally administered BI 
1358894 in patients with Post-Traumatic Stress 
Disorder (PTSD)
Global Amendment due to urgent 
safety reasons
N/A
Global Amendment
3
Section to be changed
Flow Chart 1 & 2 Footnote 1
Description of change
Eligibility of patients should be confirmed 
before Visit 1A is scheduled. Visit 1A must be 
scheduled at minimum 8 days (day -7) prior to 
V2 to allow for 7 days of EcMA assessments 
before randomization. The randomization visit 
V2 should be planned shortly (preferably 
within the same week) after completion of the 
7 day EcMA baseline assessment period.
Was changed to:
Eligibility of patients is to be confirmed before 
Visit 1A is scheduled. Visit 1A must be 
scheduled at minimum 8 days prior to V2 to 
allow for 7 days of EcMA assessments before 
randomization. The randomization visit V2 
should be planned shortly (preferably within 
the same week) after completion of the 7 day 
EcMA baseline assessment period.
Rationale for change
Clarification of process
Section to be changed
3.3.3
Description of change
Exclusion Criterion 9: Positive urine drug 
screen at the screening visit. Exception: stable 


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opioid-treatment with medically prescribed 
opioids. Please refer to section 3.3 Retesting 
for retesting options within the screening 
period.
Was amended with:
Please refer to section 3.3 Retesting for 
retesting options within the screening period.
Rationale for change
Reference section added for clarification
Section to be changed
5.2.1
Description of change
The following text has been added:
Categorization of index traumatic event
Investigators will be asked to categorize the 
index traumatic event as determined in CAPS-
5 Criterion A at screeening visit according to 
the following categories:
A separate assessment with the patient is not 
requested. Investigators will review CAPS-5 
Criterion A, Life Event Checklist and 
Extended Criterion A, as well as medical 
reocrds to decide on the categorization of the 
index traumatic event per their clinical 
judgement according to the criteria outlined 
above in Table 5.2.1: 1.
The index traumatic event, determined during 
the screening visit is to be referred to for all 
CAPS-5 and PCL-5 (incl. EcMA) assessments 
during the patient’s treatment period.
The categorization will be documented in the 
patient records and the eCRF.
Table 5.2.1:1 was added:
Table 5.2.1:1 Index traumatic event 
categorization criteria
Category
Response options
Type of 
trauma
Interpersonal
e.g. abuse, rape, hostage situation, 
assault, physical dispute, domestic 
violence


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General
e.g. natural catastrophe, accident, 
(terrorist) attack, war
Combat trauma (only for 
veterans/military-associated 
personnel) e.g. hand-to-hand 
combat
Frequency
Isolated 
Multiple (≥2) unrelated
Recurrent/chronic (same or 
similar trauma experienced 
repeatedly)
e.g. sexual abuse in the same 
context, domestic violence
Exposure 
level
In-person “First-hand” 
including witnessed
Learned about it
Rationale for change
Trauma type categorization was added
Section to be changed
5.4.5.1 Assessment of Suicidality
6.2.1 Screening Visit and Screening Period
Description of change
Any lifetime history of suicidal ideation, self-
injurious behavior, no suicidal intent’ or 
suicidal behavior at the screening visit that is 
not an exclusion criterion, should be recorded 
as baseline condition/medical history in the 
eCRF.
Was changed to:
Any lifetime history of suicidal ideation, self-
injurious behavior, no suicidal intent’ or 
suicidal behavior at the screening visit that is 
not an exclusion criterion, should be 
considered as baseline condition/medical 
history.
Rationale for change
Administrative change to reduce site burden
Section to be changed
6.2.1 Screening period and Eligibility Review
Description of change
Screening period
Eligibility of patients should be confirmed (i.e. 
all results received from the screening Visit) 
before Visit 1A is scheduled.


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Was changed to:
Eligibility of patients is to be confirmed (i.e. all 
results received from the screening Visit) 
before Visit 1A is scheduled.
Eligibility Review
For documentation purpose, 
 
will send a Subject Eligibility Notification to 
the site (...)
Was changed to:
For eligibility documentation purpose, 
 
 will send a Subject Eligibility 
Notification to the site (...)
Rationale for change
Clarification and alignment with updated Flow 
Chart 1& 2 Footnote 1
Section to be changed
Throughout the document 
Description of change
Typos and formatting corrected 
Rationale for change
Administrative changes to increase consistency 
and quality.
.


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11.4
GLOBAL AMENDMENT 4
Date of amendment
09 JUN 2023
EudraCT number/EU number
2021-003154-23
BI Trial number
1402-0030
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
A Phase II, 8-week-treatment, multicenter, 
randomized, double-blind, placebo-controlled, 
parallel group trial to evaluate the efficacy, 
tolerability and safety of orally administered BI 
1358894 in patients with Post-Traumatic Stress 
Disorder (PTSD)
Global Amendment due to urgent 
safety reasons
N/A
Global Amendment
4
Section to be changed
3.3.3
Exclusion criteria
Description of change
18.
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.
Was changed to:
18.
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.
Rationale for change
Clarification.
Section to be changed
5.4.3
Safety laboratory parameters
Description of change
All analyses will be performed by a central 
laboratory, the respective reference ranges will 
be
provided in the lab manual.
Was changed to:


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Analyses will be performed by a central 
laboratory, the respective reference ranges will 
be provided in the lab manual,
except in cases where the ESR will be done 
locally in which case the ESR results will be 
recorded in the CRF.
Rationale for change
Process updated to implement local ESR 
assessment.
Section to be changed
Table 5.4.3:1 Safety laboratory tests
Description of change
Cross reference (*) added for Erythrocyte 
sedimentation rate (ESR) that ESR will be 
assessed either centrally or locally and
the ESR Testing results are not intended to be 
used as Safety Parameter or for medical 
management decisions. For medical 
management decisions of Safety relevant 
inflammation parameter, the CRP test should 
be used. 
Rationale for change
In this protocol, ESR testing is used solely for 
the collection of data for analysis purpose at 
the end of the trial, per FDA’s 
recommendation. The ESR Testing results are 
not intended to be used as Safety Parameter or 
for medical management decisions. For 
medical management decisions of Safety 
relevant inflammation parameter, the CRP test 
should be used. 
Section to be changed
Table 5.4.3:1 Safety laboratory tests
Description of change
Added Reflex testing (once technically 
implemented) for fT3 and fT4 if TSH > ULN
Rationale for change
Alignment with sister trial
Section to be changed
6.2.1
Screening Visit and Screening Period
Demographics and Baseline Conditions
Description of change
Gender identity removed from the 
demographics information collection
Rationale for change
Gender identity information not collected in 
this trial.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34993667
5.0
clinical-trial-protocol-version-05
A Phase II, 8-week-treatment, multicenter, randomized, double-blind,
placebo-controlled, parallel group trial to evaluate the efficacy, tolerability and safety
of orally administered BI 1358894 in patients with Post-Traumatic Stress Disorder
(PTSD)
Approval-Clinical Program 
09 Jun 2023 16:01 CEST
Author-Clinical Trial Leader
12 Jun 2023 13:03 CEST
Approval-Biostatistics
12 Jun 2023 14:57 CEST
Verification-Paper Signature
Completion
12 Jun 2023 15:04 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34993667
5.0

SAP_001.pdf: 
ABCD
BI-VQD-12681_50-415_AD-01 (4.0)
TRIAL STATISTICAL ANALYSIS PLAN
TITLE PAGE
Document No.:
c42059532-01
BI Trial No.:
1402.0030
Title:
A Phase II, 8-week-treatment, multicenter, randomized, double-     
blind, placebo-controlled, parallel group trial to evaluate the
efficacy, tolerability, and safety of orally administered BI 1358894
in patients with Post-Traumatic Stress Disorder (PTSD)
Clinical Trial Protocol c34993667-01
Investigational
Product(s):
BI 1358894
Responsible trial 
statistician(s):
Phone: 
Date of statistical 
analysis plan:
21 JUNE 2023 
Version:
1.0
Page 1 of 38
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
5.
ENDPOINTS(S).....................................................................................................9
5.1
PRIMARY ENDPOINT(S)...................................................................................9
5.2
SECONDARY ENDPOINT(S).............................................................................9
5.2.1
Key secondary endpoint(s) ...................................................................................9
5.2.2
Secondary endpoint(s)...........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................11
6.1
TREATMENT(S) ................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................11
6.3
INTERCURRENT EVENTS..............................................................................12
6.4
SUBJECT SETS ANALYSED ...........................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................16
7.
PLANNED ANALYSIS ......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........18
7.2
CONCOMITANT DISEASES AND MEDICATION......................................18
7.3
TREATMENT COMPLIANCE ........................................................................19
7.3.1
CRF Compliance .................................................................................................19
7.3.2
Video Confirmed 
................................................................20
7.4
PRIMARY OBJECTIVE ANALYSIS ..............................................................21
7.4.1
Main analysis .......................................................................................................21
7.5
SECONDARY OBJECTIVE ANALYSIS ........................................................23
7.5.1
Key secondary objective analysis.......................................................................23
7.5.2
Secondary objective analysis..............................................................................23
7.7
EXTENT OF EXPOSURE .................................................................................24
7.8
SAFETY ANALYSIS..........................................................................................24
7.8.1
Adverse Events ....................................................................................................24
7.8.2
Laboratory data...................................................................................................26
7.8.3
Vital signs.............................................................................................................26


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7.8.4
ECG ......................................................................................................................26
7.9
OTHER ANALYSIS ...........................................................................................26
7.9.3
Interim Analyses..................................................................................................27
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............29
9.
REFERENCES ....................................................................................................30
11.
HISTORY TABLE..............................................................................................38


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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
Handling rules for Intercurrent events..............................................................13
Table 6.4: 1 Subject sets analyzed ...........................................................................................15
Table 6.7: 1
Planned and actual study days..........................................................................16
Table 7.9.3:1 Interim Analysis Package .................................................................................27
Table 11: 1
History table .....................................................................................................38


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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
CAPS-5
Clinician-Administered PTSD Scale for DSM-5
CGI-S
Clinical Global Impression – Severity
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
DERS-16
Difficulties in Emotion Regulation Scale – 16 item
DV
Protocol Deviations
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


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Term
Definition / description
IVRS
Integrated Voice Response System
LLT
Lowest Level Term
MCPMod
Multiple Comparison Procedures and Modelling
MMRM
Mixed effects Model Repeated Measures
MQRM
Medical Quality Review Meeting
MRI
Magnetic Resonance Imaging
OAA
Overall 
Adherence
PCL-5
PTSD Checklist for DSM-5
PGI-I
Patient Global Impression – Improvement
PGI-S
Patient Global Impression Severity Scale
PHQ-9
Patient Health Questionnaire - 9 items
PK
Pharmacokinetics
PKS
PK parameter analysis set
PPS
Per Protocol Set
PSQI
Pittsburgh Sleep Quality Index
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
SOC
System Organ Class
SDS
The Sheehan Disability Scale
SS
Screened Set
STD
Standard Deviation
STAI
The State-Trait Anxiety Inventory for Adults
TMF
Trial Master File
TOM
Trial Oversight Meeting
TS
Treated Set


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Term
Definition / description
TSAP
Trial Statistical Analysis Plan
UDAEC
User-defined AE categories
ULN
Upper Limit of Normal
VAS
Visual Analog Scale
WHO
World Health Organisation
3.
INTRODUCTION
The purpose of this TSAP is to provide analysis specifications that is to be reported in the 
final CTR. Also included in this TSAP are analysis specifications for an interim analysis, the 
results of which are to be reported in a synoptic report that is separate from the final CTR.
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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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
Change from baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total
severity score at Week 8
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)
CAPS-5
- Response defined as ≥30% CAPS-5 reduction from baseline at Week 8
- Response defined as ≥50% CAPS-5 reduction from baseline at Week 8
PCL-5
- Change from baseline on the PTSD Checklist for DSM-5 total score at Week 8


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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 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
be used in analyses and/or whether it must be queried in the clinical database. Each CTP 
deviation must be assessed to determine whether it is an important Protocol Deviation (iPD). 
For definition of iPDs, and for the process of identification of these, refer to the current BI 
reference document "Identify and Manage Important Protocol Deviations (iPD)" (3). 


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Generally, a protocol deviation is considered as an iPD if it affects the rights or safety of the 
study subjects, or if it can potentially influence the primary outcome measurement(s) in a non-
negligible way. If any iPDs are identified, they are to be summarized into categories and will 
be captured in the RPM/DBLM/MQRM minutes via an accompanying DV domain 
specifications Excel spreadsheet (4). The following table contains the categories which are 
iPDs in this trial. If the data presents additional iPDs (e.g., based on monitor visits to the 
sites), then the DV domain specifications will be supplemented accordingly at TOMs or 
RPMs or through team review of the manual PD log. 
The decision whether a subject will be excluded from the analysis will be made at the final 
RPM prior to Database Lock (DBL). The documentation of the iPD categories and how to 
handle iPDs in the analysis are listed in the DV domain specifications and stored within the 
Trial Master File (TMF) in Electronic Document Management System (EDMS). iPDs will be 
summarized and listed for the treated set.
6.3
INTERCURRENT EVENTS
The following intercurrent events (ICEs) are of interest:
1. Change in background CNS active medication (e.g., non-SSRI antidepressant, 
anxiolytics)
2. Change in pharmacological therapy (SSRI)
3. Change in drug test result from negative to positive (Benzodiazepine, Barbiturates, 
Opiates, Cocaine, Amphetamines, Methadone, PCP)
4. Change in non-pharmacological therapy – trauma-focused psychotherapy
5. Change in non-pharmacological therapy – all other cognitive/behavioral therapy 
(CBT) (e.g., any other kind of psychotherapy, nicotine withdrawal therapy, diet, etc.)
6. Withdrawal of study medication due to investigator assessed drug-related adverse 
events (e.g., headache)
7. Withdrawal of study medication due to perceived lack of efficacy or disease 
worsening
8. Withdrawal of study medication due to other adverse events
9. Withdrawal of study medication due to any other reasons.
Table 6.3:1 lists the handling of the ICEs for the primary estimand and supplementary 
estimand. 


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Table 6.3:1
Handling rules for Intercurrent events
ICE
Primary
Estimand
Supplementary
Estimand
Handling rules 
for ICEs
1-4
Treatment
policy
Treatment
policy
5
Treatment
policy
Treatment
policy
6-7
Hypothetical
Treatment
policy
8-9
Hypothetical
Hypothetical
From the table above we see that that primary estimand estimates the treatment effect when 
changes to background CNS active medication, pharmacological SSRI therapies and non-
pharmacological therapies (ICEs 1-5) are part of the treatment effect, but changes to 
randomized treatment (ICEs 6-9) are not considered to be part of the treatment effect of 
interest. ICEs are therefore handled by a hybrid estimand that combines the treatment policy 
and hypothetical approaches, where ICEs 1-5 are handled using the treatment policy 
approach, thus measurements taken after the occurrences of these ICEs are included in the 
primary analysis. 
However, ICEs 6-9 are handled using the hypothetical approach, where measurements after 
their occurrences are therefore censored in the primary analysis. Therefore, this analysis 
(ICEs 6-9) 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.
6.4
SUBJECT SETS ANALYSED
The following analysis sets are defined for this trial:
-
Screened Set (SS): consists of all subjects who signed informed consent.
-
Treated Set (TS):  consists of all subjects that have been randomized and that received 
at least one administration of study drug. The TS will be the main analysis set for the 
evaluation of safety. Subjects are analysed according to the actual received treatment.
-
Full analysis set (FAS): consists of all subjects in TS that have a baseline and at least 
one evaluable post-baseline measurement for the primary endpoint. This is the main 
analysis set for the evaluation of efficacy data.
-
Per protocol set (PPS):  This is a subset of FAS, for subjects with adequate protocol 
compliance. It consists of all subjects in FAS without any important protocol 
deviations that impact efficacy assessments. 


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-
Adherent set (AS):  consists of all subjects in FAS that are at least 60% overall 
 
adherent to study medication. See Section 7.3.2 for further information.
-
 


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Table 6.4: 1 Subject sets analyzed
Subject set
Class of analyses
TS
SS
FAS
PPS
PKS
AS
Primary and secondary endpoints, compliance 
X
X*
Further endpoints (
X
Disposition
X
 
X
Safety variables and iPDs
X
Demographics, baseline characteristics, exposure
X
(X)
Primary endpoint adjusted for overall study 
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 treated subjects with no post randomization data for the primary endpoint.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing data are not explicitly imputed and remain missing for all main analyses. For 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 CAPS-5 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 
 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. 
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 – Day 2


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3
8
Day 3 – Day 12
4
15
Day 13 – Day 19
5
22
Day 20 – Day 26
6
29
Day 27 – Day 33
7
36
Day 34 – Day 40
8
43
Day 41 – Day 47
9
50
Day 48 – Day 52
10/EOT
57 for completed 
subjects
Day 53 – 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 31, it will be mapped to Visit 6. 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 CAPS-5 at Day 46, it 
will be mapped to Visit 8.
End of 
Trial
EOT + 28 days
[stopdt + 8 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’s no visit window mapping for C-SSRS given that it is collected every week throughout 
the study.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
Clinical Trials and Project Summaries" (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 clinical trial 
report as a frequency-distribution.  
For categorical data, tabulations of frequencies will include all defined categories even if 
there is no count in a category. Tabulations of frequencies will display the number of 
observations in a category as well as the percentage (%) relative to the number of 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 standard 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 
treatment group, System Organ Class (SOC) and Preferred Term (PT). Concomitant diseases 


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which are present at start of the study will be descriptively summarized by treatment, except 
for suicidal ideation, suicidal behavior and non-suicidal self-injurious behavior-. -These shall 
be removed from the concomitant diseases (baseline condition/medical history) and will be 
presented as a separate stand-alone table(s).  
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 2, 4, 6, and 8(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%, 
at Weeks 2, 4, 6, and 8, then the cumulative treatment compliance percent = (.80*2 + .81*2 
+ .82*2 + .83*2)/8*100 = 81.5%.
For early discontinued subject: if a subject’s observed treatment compliance rates are 80% at
Week 2, 81% at Week 4, 50% at eEOT, then the cumulative treatment compliance rate = 
(0.80*2 + 0.81*2 + 0.5*((eEOT date – drug start date + 1)/7 – 4))/((eEOT date – drug start 
date + 1)/7) * 100% = 63.6% if the quantity (eEOT date – drug start date + 1) is assumed to 
be 36 days. In the example above the last regular visit is Week 4, so 4 is subtracted because 
there is compliance for the first 4 weeks. If the last regular visit is Week 2, then the ‘4’ that’s 
being subtracted would change to 2 to account for having compliance up through 2 weeks.
If at a particular visit a participant did not return the trial drug kits, then the compliance at that 
visit is zero.


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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 
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% of planned", 
-
"80 to <100% of planned",
-
">=100% of planned",
-
missing.
7.3.2
Video Confirmed 
First, we define overall 
(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 3 times 56. Or, in other words:
-
OAA = [[(Sum of all tablet adherence) – (total number of red, orange, and yellow 
alerts)]/ 3*Treatment duration] *100,
o
Treatment duration is the number of days on treatment = treatment end date -
treatment start date +1

It is equal to 56 for subjects that adhere to the protocol. 
o
3 is the number of tablets per dose.
Tablet adherence is the successful administration of a pill as captured by 
 Red 
alerts are tablet administrations for which the 
 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 
For subjects that discontinue treatment early, 56, 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 6.4, the Adherent set (AS) consists of all subjects in FAS that achieved 
an OAA of at least 60%.


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7.4
PRIMARY OBJECTIVE ANALYSIS
7.4.1
Main analysis 
The primary endpoint is the change from baseline to Week 8 in CAPS-5 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 analysis of the primary 
endpoint will use a hybrid estimand that combines the treatment policy and hypothetical 
estimands as detailed in Section 6.3.
MMRM analysis
The change from baseline in CAPS-5 total score at Week 8 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, and the 
stratification indicator of presence of significant childhood trauma (yes vs. no), the continuous 
fixed covariates of baseline CAPS-5 total severity score and time since index event (in years) 
and the treatment-by-visit interaction. Patient is considered as a random effect. Visit will be 
treated as a repeated measure with an unstructured covariance matrix used to model 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. FAS is used for the primary analysis of the primary efficacy endpoint.
More specifically, the change in CAPS-5 total score from baseline (Visit 2), at Visits 2, 6, and 
10 (Weeks 0, 4, and 8) will be evaluated using an MMRM accounting for the following 
sources of variation: ‘treatment’, ‘visit’, ‘presence of significant childhood trauma (yes vs.no), 
time since index event (in years) and ‘baseline CAPS-5 total score’ as continuous covariates, 
and treatment-by-visit interaction, 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 time_since_index base / ddfm=kr s CL;
REPEATED visit / subject= subject type=un r rcorr;
LSMEANS visit*trt / pdiff=all om cl alpha=0.05 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.


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7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary objective analysis
Logistic regression analysis
The binary secondary endpoints of CAPS-5 response (defined as ≥30% CAPS-5 reduction 
from baseline at Week 8 and defined as ≥50% CAPS-5 reduction from baseline at Week 8)
will each 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 and presence 
of significant childhood trauma (yes vs. no). 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 treatment 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.  
The secondary endpoint of change from baseline in PTSD Checklist for DSM-5 (PCL-5) total
severity score at Week 8 will be analyzed using an MMRM model like that described for the 
primary analysis of the primary endpoint to obtain the adjusted change from baseline at Week 
8 for BI active arm versus placebo.


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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 weeks”, “>8 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 7.2.6 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 (8). 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:

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 (5,8).
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 


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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 (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold   
ULN measured in the same blood draw sample, or
-
aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN.
-
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the 
ISF.
Refer to CTP Section 5.4.6.1.4 for details.
Other significant AE (according to ICH E3)
According to ICH E3 (9), 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)
-
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.


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AEs suggestive of abuse potential 
In support of an evaluation of human abuse potential, user-defined AE categories (UDAEC) 
are defined in Section 10.4. 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
(10).  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.
7.9
OTHER ANALYSIS
This section mainly refers to CTP Section 7.2.7 Other Analyses.


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7.9.3
Interim Analyses
An interim analysis is planned when the 120th evaluable subject completes the planned
treatment period. An evaluable subject is one that has remained in the study, and has at
least one change from baseline CAPS-5 severity score. The purpose of this interim analysis is 
for internal planning of the PTSD indication with BI 1358894. PoC will be evaluated. The 
decision to stop or continue the trial will be made by BI based on the totality of evidence - to 
also include observations from secondary objectives and the safety profile. An independent 
team will be formed to perform this analysis. Details on whom has access to unblinded data
will be specified in an interim analysis logistic plan. Table 7.9.3:1 provides the scope of 
analysis for the interim analysis package.
Table 7.9.3:1 Interim Analysis Package
Demographics, Disposition and Baseline conditions
1. Baseline demographic tables (include HA/migraines)
2. Comorbidities
3. Concomitant medications – Background therapies
4. Disposition Table
Primary and secondary endpoints
5. Change from baseline in Clinician-Administered PTSD Scale for DSM-5 
(CAPS-5) total severity score at Week 8
6. Response defined as ≥30% CAPS-5 reduction from baseline at Week 8
7. Response defined as ≥50% CAPS-5 reduction from baseline at Week 8
8. Change from baseline on the PTSD Checklist for DSM-5 total score at 
Week 8
Standard safety
9. Overall summary of patients with AEs
10. Frequency of patients with AEs
11. Frequency of patients with AEs leading to drug discontinuation
12. Frequency of patients with serious AEs 
13. Frequency of patients with AEs leading to death
14. Suicidality as assessed by C-SSRS
15. AEs suggestive of abuse potential


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Exploratory
16. Change from baseline in Pittsburgh Sleep Quality Index (PSQI) global 
scores over time
17. Change from baseline in the Difficulties in Emotion Regulation Scale 
(DERS-16) total score at Week 8
18. Change from baseline in the State Trait Anxiety Inventory (STAI) State and 
Trait version at Week 8. Specifically, the change from baseline in the STAI-
S and STAI-T at Week 8. 
19. Change from baseline in CGI-S at Week 8 
The very first part of Table 7.9.3:1, ‘Demographics, Disposition and Baseline conditions’ will 
be analyzed as stated in Sections 7.1-7.4. The subsequent analyses that pertain to ‘Primary 
and secondary endpoints’ will be analyzed via the methods discussed in Sections 7.4.1 and 
7.5.2. Standard safety will be evaluated according to the methods described in Section 7.8.
And lastly, Table 7.9.3:1 ends with a set of ‘Exploratory’ analyses that will be analyzed 
descriptively, hence the change from baseline at Week 8, as well as the percent change from 
baseline (across treatment arms and for the total) will be provided.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
This section details the planned time point at which the database will be declared ready for 
analysis. Further details regarding the timing and disclosure of the interim analyses will be 
specified in the Logistics and Access plan.
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 8.
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, Group “Clinical Operations”, 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, Group “Biostatistics & Data 
Sciences”, 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.
BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event Data from
Clinical Trials", current version; IDEA for CON.
9.
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.
10. BI-KMED-BDS-HTG-0042: "How to Guide: Handling, Display and Analysis of
Laboratory Data", current version; IDEA for CON.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
21-JUNE-23
None
This is the final TSAP.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c42059532
1.0
8-01-tsap-core
A Phase II, 8-week-treatment, multicenter, randomized, double-blind,
placebo-controlled, parallel group trial to evaluate the efficacy, tolerability, and
safety of orally administered BI 1358894 in patients with Post-Traumatic Stress
Disorder (PTSD)
Approval-Biostatistics
21 Jun 2023 18:20 CEST
Approval-Clinical Program 
21 Jun 2023 19:45 CEST
Approval
22 Jun 2023 15:05 CEST
Approval-Clinical Trial Leader
22 Jun 2023 17:25 CEST
Approval-Medical Writer
22 Jun 2023 20:55 CEST
Author-Clinical Pharmacokineticist
23 Jun 2023 08:06 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c42059532
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