Conditions: Healthy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: yes

Brief summary:
The main objective of this trial is to investigate the relative bioavailability of a single dose of bupropion when given alone (Reference) compared with co-administration (Test) with BI 1358894 in healthy volunteers.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Elontril intervention 2: BI 1358894
Intervention descriptions: intervention 1: Tablet intervention 2: Film coated tablet

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c34402516-04
EudraCT No.
2020-006052-40
BI Trial No.
1402-0018
BI Investigational
Medicinal Product
BI 1358894
Title
An open-label, two-period fixed sequence trial to evaluate the 
effect of multiple doses of BI 1358894 on the pharmacokinetics 
of bupropion in healthy volunteers
Lay Title
A study in healthy men and women to test whether BI 1358894
influences the amount of bupropion in the blood
Clinical Phase
I
Clinical Trial Leader
Phone: 
Fax: 
Principal 
Investigator
Phone: 
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 3))
Version and Date
Version: 4.0
Date: 29 July 2021
Page 1 of 75
Proprietary confidential information
© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
06 April 2021
Revision date
29 Jul 2021
BI trial number
1402-0018
Title of trial
An open-label, two-period fixed sequence trial to evaluate the effect of multiple
doses of BI 1358894 on the pharmacokinetics of bupropion in healthy volunteers
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
To investigate the influence of BI 1358894 on the activity of CYP2B6 by using
probe drug bupropion, recommended as sensitive substrate for the CYP2B6 
enzyme.
Trial objectives
To assess the influence of BI 1358894 on the pharmacokinetics of CYP2B6 probe 
drug bupropion when given as an oral single dose together with multiple oral doses 
of BI 1358894 (Test, T), as compared to when given alone as oral single dose 
(Reference, R).
Trial design
Open-label, two-period, fixed sequence
Trial endpoints:
Primary endpoints: AUC0-tz and Cmax of Bupropion
Secondary endpoints: AUC o-∞of Bupropion
Number of subjects 
total entered
18 
each treatment
18 
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male/female subjects, age of 18 to 55 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Test product 1
BI 1358894 50 mg tablets;
dose
mode of admin.
100 mg q.d. over 19 days in treatment T 
Oral administration under fed conditions with 240 mL of water


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Test product 2
Bupropion SR tablet (Elontril®)
dose
150 mg sustained release tablet, 2 single doses in Treatments T and R
mode of admin.
Oral administration under fed conditions with 240 mL of water
Duration of treatment
Reference Treatment (R): Bupropion alone in Period 1 (Visit 2)
Single dose of 150 mg bupropion hydrochloride (Day 1).
Test Treatment (T): Bupropion plus BI 1358894 in Period 2 (Visit 3)
Multiple doses of 100 mg BI 1358894 administered once daily on 19 days (Day -14
to Day 5) combined with a single dose of 150 mg bupropion hydrochloride (Day 1) 
on the 15th day of BI 1358894 treatment
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints.
Additionally, the two-sided 90% confidence interval (CIs) will be provided. This 
method corresponds to the two one-sided t-tests procedure, each at a 5% 
significance level. Since the main focus is on estimation and not testing, a formal 
hypothesis test and associated acceptance range is not specified. The statistical 
model will be an analysis of variance (ANOVA) on the logarithmic scale including 
effects for ‘subjects’ and ‘treatment’. CIs will be calculated based on the residual 
error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART PERIOD R
Visit
Day
Planned Time [h:min] 
relative to Bupropion
Approximate  clock 
time of actual day1
[h:min]
Event and comment
PK plasma for 
Bupropion 
and metabolites6
Clinical laboratory 
tests 2
Vital signs (BP, PR), 
ECG3
Physical /Neurological 
Examination
Questioning  for AEs 
and concomitant 
therapy 7
1
-21 
to -1
Informed consent, screening 9
A12
X
X
X
2
-1
-24:00
Admission to trial site
B12,13,14
X
1
-3:00
X11
X
X
X
0:00
08:00 Administration of 150 mg 
Bupropion4
1:00
09:00
X
2:00
10:00 240 mL fluid intake
X
3:00
11:00
X
4:00
12:00 240 mL fluid intake thereafter 
Lunch8
X
X
5:00
13:00
X
6:00
14:00
X
7:00
15:00
X
8:00
16:00 Snack (voluntary) 8
X
10:00
18:00
X
11:00
19:00 Dinner
12:00
20:00
X
X
2
24:00
08:00 Breakfast8
X
B
X
X
X
24:30
08:30 Discharge from trial site
3
48:00
08:00 Ambulatory visit
X
X
4
72:00
08:00 Ambulatory visit
X
X
5
96:00
08:00 Ambulatory visit
X
X
6
120:00
08:00 Ambulatory visit
X
B12
X


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FLOW CHART PERIOD T
Visit
Day
Planned Time [h:min] relative to
Bupropion
Approximate  clock time 
of actual day1 [h:min]
Event and comment
PK (plasma) for
BI 1358894 6
Clinical laboratory tests 2
PK (plasma) for Bupropion 
and metabolites6
Vital signs (BP, PR) ECG3
Physical /Neurological 
Examination
Questioning  for AEs and 
concomitant therapy 7
3
-14
-336:00
08:00
10:00
Administration of 100 mg 
BI 13588944,5
Discharge
X15
X13,
14,15,
16
X15
X15
X
X
-13
-312:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X
-12
-288:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X
-11
-264:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X
-10
-240:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X
-9
-216:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X
-8
-192:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X
-7
-168:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X
-6
-144:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X15
B
X
-5
-120:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X


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Visit
Day
Planned Time [h:min] relative to 
Bupropion
Approximate  clock time 
of actual day1 [h:min]
Event and comment
PK (plasma) for
BI 1358894 6
Clinical laboratory tests 2
PK (plasma) for Bupropion 
and metabolites6
Vital signs (BP, PR) ECG3
Physical /Neurological 
Examination
Questioning  for AEs and 
concomitant therapy 7
-4
-96:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X15
X
-3
-72:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X15
X
-2
-48:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X15
X
-1
-24:00
08:00 Admission to trial site
Administration of 100 mg 
BI 13588944
X15
B12
X
X
1
-0:30
07:30
X
X
X
X
0:00
08:00 Administration of 150 mg 
Bupropion4 and 
Administration of 100 mg 
BI 13588944
1:00
09:00
X
3
2:00
10:00 240 mL fluid intake
X
3:00
11:00
X
4:00
12:00 240 mL fluid intake, 
thereafter Lunch8
X
X
5:00
13:00
X
6:00
14:00
X
7:00
15:00
X
8:00
16:00 Snack (voluntary) 8
X
10:00
18:00
X
X
11:00
19:00 Dinner
12:00
20:00
X
X
2
24:00
08:00 Administration of 100 mg 
BI 13588944
Discharge
X15
X
X
X


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Visit
Day
Planned Time [h:min] relative to 
Bupropion
Approximate  clock time 
of actual day1 [h:min]
Event and comment
PK (plasma) for
BI 1358894 6
Clinical laboratory tests 2
PK (plasma) for Bupropion 
and metabolites6
Vital signs (BP, PR) ECG3
Physical /Neurological 
Examination
Questioning  for AEs and 
concomitant therapy 7
3
48:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X15
X
X
4
72:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X15
X
X
5
96:00
08:00 Ambulatory visit
Administration of 100 mg 
BI 13588944
X15
X
X
6
120:00
08:00 Ambulatory visit
X
B
X
X
X
4
19
End-of-study examination10
C13
X
X
X
1
Actual clock time depends on the time of dosing
2
As specified in Section 5.2.3 of this protocol
3
As specified in Section 5.2.2 and 5.2.4 of this protocol
4
Within 30 min following continental breakfast
5
First BI 1358894 administration followed by a 2 hour post-administration in-house observation period
6
As specified in Section 5.3 of this protocol
7
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at 
the time points indicated in the Flow Chart above
8
If several actions are indicated at the same time point, the intake of meals will be the last measure
9
Screening includes subject information, informed consent, physical and neurological examination, check of 
vital signs, ECG, safety laboratory (including drug and virus screening, and including serum pregnancy 
test in female subjects of childbearing potential), demographics (including determination of body height 
and weight, smoking status and alcohol history), relevant medical history, concomitant therapy, review of 
inclusion/exclusion criteria and suicidality assessment (C-SSRS).
10
End-of-trial (EOT) examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies, neurological examination and suicidality assessment (C-
SSRS). The EOT assessments will be performed on Day 19 at earliest.
11
Including one blood sample for pharmacogenetic analyses (section 5.6.1)
12
SARS-CoV-2 PCR test will be performed at screening, and shortly (within 72 hours) before admission to
the site
13
Urine pregnancy for WOCBP
14
Urine drug screening and alcohol breath test
15
Before study drug administration
16
At this timepoint, no safety lab B taken.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART PERIOD R ..............................................................................4
FLOW CHART PERIOD T...............................................................................5
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................16
1.2.1
BI 1358894 .............................................................................................16
1.2.2
Bupropion..............................................................................................18
1.2.3
Residual Effect Period..........................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................19
1.4
BENEFIT - RISK ASSESSMENT ...................................................................19
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......22
2.1.1
Main objectives......................................................................................22
2.1.2
Primary endpoints ................................................................................22
2.1.3
Secondary endpoint ..............................................................................22
2.2.1.2
Safety and tolerability..............................................................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 24
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................24
3.3.1
Main diagnosis for trial entry..............................................................24
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................25
3.3.4
Withdrawal of subjects from treatment or assessments ...................27
3.3.4.1
Discontinuation of trial treatment............................................27
3.3.4.2
Withdrawal of consent to trial participation ............................27
3.3.4.3
Discontinuation of the trial by the sponsor..............................28
3.3.5
Replacement of subjects .......................................................................28
4.
TREATMENTS........................................................................................ 29


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4.1
INVESTIGATIONAL TREATMENTS ..........................................................29
4.1.1
Identity of the Investigational Medicinal Products ...........................29
4.1.2
Selection of doses in the trial................................................................29
4.1.3
Method of assigning subjects to treatment groups ............................30
4.1.4
Drug assignment and administration of doses for each subject .......30
4.1.5
Blinding and procedures for unblinding ............................................31
4.1.6
Packaging, labelling, and re-supply ....................................................31
4.1.7
Storage conditions.................................................................................32
4.1.8
Drug accountability ..............................................................................32
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................32
4.2.1
Other treatments and emergency procedures....................................32
4.2.2
Restrictions............................................................................................33
4.2.2.1
Restrictions regarding concomitant treatment .........................33
4.2.2.2
Restrictions on diet and life style.............................................33
4.3
TREATMENT COMPLIANCE.......................................................................33
5.
ASSESSMENTS....................................................................................... 35
5.1
ASSESSMENT OF EFFICACY.......................................................................35
5.2
ASSESSMENT OF SAFETY............................................................................35
5.2.1
Physical examination ............................................................................35
5.2.2
Vital signs...............................................................................................35
5.2.3
Safety laboratory parameters..............................................................35
5.2.4
Electrocardiogram................................................................................38
5.2.5
Other safety parameters.......................................................................39
5.2.5.1
Suicidality assessment .............................................................39
5.2.4.2
Neurological examination........................................................39
5.2.6
Assessment of adverse events...............................................................40
5.2.6.1
Definitions of adverse events...................................................40
5.2.6.1.1 Adverse event ............................................................40
5.2.6.1.2 Serious adverse event ................................................40
5.2.6.1.3 AEs considered ‘Always Serious’.............................41
5.2.6.1.4 Adverse events of special interest .............................41
5.2.6.1.5 Intensity (severity) of AEs.........................................42
5.2.6.1.6 Causal relationship of AEs ........................................42
5.2.6.2
Adverse event collection and reporting ...................................43
5.2.6.2.1 AE collection.............................................................43
5.2.6.2.2 AE reporting to the sponsor and timelines ................44
5.2.6.2.3 Information required..................................................44
5.2.6.2.4 Pregnancy ..................................................................44
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................45
5.3.1
Assessment of pharmacokinetics .........................................................45
5.3.2
Methods of sample collection...............................................................45


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5.3.2.1
Blood sampling for pharmacokinetic analysis.........................45
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................46
5.4
ASSEMENT OF BIOMARKER ......................................................................46
5.5
BIOBANKING ...................................................................................................46
5.6
OTHER ASSESSMENTS .................................................................................46
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................47
6.
INVESTIGATIONAL PLAN.................................................................. 48
6.1
VISIT SCHEDULE............................................................................................48
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................48
6.2.1
Screening period....................................................................................48
6.2.2
Treatment periods.................................................................................48
6.2.3
Follow-up period and trial completion ...............................................49
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 50
7.1
STATISTICAL DESIGN – MODEL ...............................................................50
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................50
7.3
PLANNED ANALYSES....................................................................................50
7.3.1
Primary endpoint analyses...................................................................51
7.3.2
Secondary endpoint analyses ...............................................................52
7.3.4
Safety analyses.......................................................................................53
7.4
INTERIM ANALYSES .....................................................................................54
7.5
HANDLING OF MISSING DATA ..................................................................54
7.5.1
Safety......................................................................................................54
7.5.2
Pharmacokinetics..................................................................................54
7.6
RANDOMISATION ..........................................................................................54
7.7
DETERMINATION OF SAMPLE SIZE ........................................................55
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 56
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................56
8.2
DATA QUALITY ASSURANCE .....................................................................57
8.3
RECORDS..........................................................................................................57
8.3.1
Source documents .................................................................................57
8.3.2
Direct access to source data and documents.......................................58
8.3.3
Storage period of records.....................................................................58
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................58


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8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......58
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................59
8.6
TRIAL MILESTONES .....................................................................................59
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................60
9.
REFERENCES......................................................................................... 61
9.1
PUBLISHED REFERENCES...........................................................................61
9.2
UNPUBLISHED REFERENCES.....................................................................62
10. APPENDICES .......................................................................................... 64
10.1
COLUMBA-SUICIDE SEVERITY RATING SCALE..................................64
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 70
11.1
GLOBAL AMENDMENT 1 .............................................................................70
11.2
GLOBAL AMENDMENT 2 .............................................................................71
11.3
GLOBAL AMEDNMENT 3 .............................................................................74


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ALDH
Aldehyde dehydrogenase
ANOVA
Analysis of variance
AO
Aldehyde oxidase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
Borderline personality disorder
bpm
Beats per minute
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular 
administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CML
Clinical Monitor Local
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as 
‘eCRF’)
CRP
C-reactive proteins
C-SSRS
Columbia-Suicidal Severity Rating Scale
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P450
DDI
Drug-drug interaction
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 


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EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
ESR
Erythrocyte sedimentation rate
EudraCT
European Clinical Trials Database
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GLP
Good Laboratory Practice
gMean
Geometric mean
HCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus infection
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDD
Major depressive disorder
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
No observed adverse effect level
PCR
Polimerase chain reaction
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
PT
Preferred Term
q.d.
Quaque die
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
RAUC0-∞, M/P
Ratio of metabolite AUC0-∞to parent AUC0-∞
RAUC0-tz, M/P
Ratio of metabolite AUC0-tz to parent AUC0-tz
REP
Residual effect period
SAE
Serious adverse event


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SIB
Suicidal Ideation and Behavior
SmPC
Summary of Product Characteristics
SOC
System Organ Class level of MedDRA
SOP
Standard operating procedure
T
Test product or treatment
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of 
the analyte in plasma
TRPC
Transient receptor potential canonical
TS
Treated set
TSAP
Trial statistical analysis plan
tz
Time of last measurable concentration of the analyte in plasma
UGT
UDP-Glucuronosyltransferase
ULN
Upper limit of normal
VAS
Visual Analogue Scale
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WOCBP
Women of Childbearing Potential
XTC
Ecstasy 


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1.
INTRODUCTION
BI 1358894, an oral, small-molecule inhibitor of a transient receptor potential cation channel, 
subfamily C, members 4 and 5 (TRPC 4/5) is being developed for major depressive disorder 
(MDD) and borderline personality disorder (BPD). 
1.1
MEDICAL BACKGROUND
Major depressive disorder is a debilitating disease characterized by low mood and often by 
low self-esteem, low energy, and a loss of interest. It can strongly impact a person’s life and
health, including significantly increased risk of suicidality, and is difficult to treat, even with 
systematic antidepressant strategies. In the National Institute of Mental Health funded 
STAR*D trial of >4000 patients with nonpsychotic depression, about 30% of the patients did 
not reach remission after 4 different medications [P06-11895] and continued to experience 
residual symptoms [R16-5475] that significantly impacted the patients’ quality of life 
[R06-2872]. 
Borderline personality disorder (BPD) is a chronic mental disorder with an estimated 
prevalence of around 2% in the general community [R16-5476] and severely impaired quality 
of life [R16-5474]. The main symptom clusters of BPD include impulsive-behavioural 
dyscontrol, cognitive-perceptual symptoms, disturbed interpersonal relations, and affective 
instability. Patients with BPD have high rates of deliberate self-harm and a rate of completed 
suicide that is 50 times higher than in the general population [R16-5477]. Even the presence 
of a single diagnostic feature of BPD is predictive for poor functioning and psychiatric illness 
burden [R16-5483]. Treatment guidelines recommend psychotherapy as the mainstay of 
treatment, but pharmacotherapy is commonly used as an adjunctive, symptom-targeted 
component of treatment. However, no drug is approved for the treatment of BPD.
TRPC4 and TRPC5 form ion channels that are involved in the regulation of neuronal 
excitability. They are most highly expressed in the amygdala, frontal cortex, hippocampus, 
and hypothalamus [R15-3888, R16-5350], which are involved in modulation and processing 
of emotion and affect. Pre-clinically, treatment with BI 1358894 has shown diminished fear 
and anxiety and increased social interaction without impairing other brain functions such as 
learning and memory behaviours. 
It is hypothesized that in patients with affective disorders, an overactive amygdala is a major 
contributor to attentional bias to negative stimuli, pessimistic thoughts, and anxiety 
[R16-5473] and there is growing evidence supporting the role of amygdala in the emotion 
processing disturbances observed in patients with BPD [R16-5472]. Therefore, treatment 
with BI 1358894 has the potential to improve affective symptoms and emotion control in 
patients with MDD and BPD.


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1.2
DRUG PROFILE
1.2.1
BI 1358894


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For a more detailed description of the BI 1358894 profile, please refer to the current 
Investigator’s Brochure (IB) [c10354149].
1.2.2
Bupropion
Potential inductive effects of BI 1358894 on CYP2B6 will be investigated using the probe
substrate bupropion.
Bupropion is used as antidepressant and smoking cessation aid. It acts as selective inhibitor
of neuronal reuptake of noradrenalin and dopamine. The mechanism by which it helps in
smoking cessation is unknown.
After oral administration of a 150 mg bupropion extended release tablet (as used in this trial),
tmax was observed at approximately 2.5-3 h. Bupropion is extensively metabolised with only
0.5% excreted unchanged in either faeces or urine. Hydroxybupropion, threohydrobupropion
and erythrohydrobupropion are active metabolites. Only the formation of hydroxybupropion
is catalysed via CYP2B6.
Based on a mouse antitetrabenazine model, hydroxybupropion is approximately 50% as 
active as bupropion, and threohydrobupropion and erythrohydrobupropion are approximately
20% as active as bupropion [P06-00643]. Plasma Cmax and AUC of the main metabolite
hydroxybupropion are approximately 3- and 14-fold higher than for bupropion, respectively.
tmax of hydroxybupropion is reached approximately 6 h after administration of a single dose
of bupropion [R21-0979].
Clinically, bupropion is used as a racemate, and disposition is stereoselective. CYP2B6
catalyzes hydroxylation of both enantiomers, R-bupropion and S-bupropion, to
R,R-hydroxybupropion and S,S-hydroxybupropion, respectively. The rate of S-bupropion 
hydroxylation has been reported to exceed R-bupropion hydroxylation by
approximately 1.5- to 3-fold. Interestingly, S,S-hydroxybupropion plasma concentration is 
formation-rate limited, whereas R,R-hydroxybupropion is elimination-rate limited [R14-
3843]. Therefore, both plasma concentration of S,S-hydroxybupropion and the
metabolite-to-parent ratio of S,S-hydroxybupropion to S-bupropion may be used as
parameters for CYP2B6 activity in addition to plasma concentrations of bupropion or
S-bupropion.
Mean plasma t1/2 of bupropion, hydroxybupropion, threohydrobupropion, and
erythrohydrobupropion is approximately 20, 20, 37, and 33 h, respectively [R21-0979].
Maximal daily dose of bupropion is 300 mg. Recommended treatment duration is 7-9 weeks 
for smoking cessation or >6 months for treatment of depression.
The most frequent side effects of bupropion are psychiatric or neurologic reactions such as
sleep disorders (especially when taken in the evening), agitation, anxiety, depression,
concentration disorders, headache or dizziness, moreover hypersensitivity reactions such as 
urticaria, skin reactions such as exanthema, pruritus or increased sweating, or fever, or
gastrointestinal symptoms such as dry mouth, nausea, vomiting, or obstipation. Moreover,
bupropion dose-dependently increases the risk of cerebral seizures (at doses of up to 300 mg
bupropion hydrochloride the frequency of cerebral seizure is reported as 0.1%).
Use of bupropion is contraindicated in patients with cerebral seizure, bulimia, anorexia, or a
bipolar mood disorder in the medical history.
Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency
(EMA) recommend the use of bupropion as in vivo probe drug for CYP2B6 in DDI trials
[P12-05791, P15-06991]. The EMA guideline specifically recommends the investigation of


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S-bupropion (hydroxylation) as in vivo marker for CYP2B6 activity.
For further details, see the current version of SmPC [R21-0979].
1.2.3
Residual Effect Period
Based on an effective half-life of 50 to 70 h the Residual Effect Period (REP) of BI 1358894 
is 14 days. The Residual Effect Period (REP) of bupropion is 5 days. This is the period after 
the last dose with measurable drug levels and/or pharmacodynamic effects is still likely to be 
present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Based on in vitro data, BI 1358894 is a potential inducer of CYP2B6 at anticipated human 
therapeutic exposure levels. However, the predictive value of in vitro data is limited, and the 
probability of DDIs can be entirely assessed only with in vivo data in humans. Therefore, this 
trial is aimed to investigate the influence of BI 1358894 on the activity of CYP2B6 by using 
drug recommended by both the FDA [P12-05791] and EMA [P15-06991] as in vivo probes.
Results of this DDI trial will provide a general signal of potentially important DDI upon
which further exploration can be based.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 1358894. The 
assessment of the drug-drug-interaction (DDI) potential of BI 1358894 will contribute to a 
safe clinical use of this TRPC 4/5-inhibitor in patients with MDD or BPD that often have to 
use multiple co-medications. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
In a comprehensive package of safety pharmacology, genetic toxicology, general toxicology,


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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. 
The single and multiple dose administrations of up to 200 mg BI 1358894 under fasted and 
fed conditions has been well tolerated by healthy subjects.
For details on treatment related risks, refer to CTP section 1.2 and the IB, version 6 
[c10354149].
While there are no precedent clinical data implicating association between TRPC4/5
antagonism and Suicidal Ideation and Behavior (SIB), in the interest of ensuring participant
safety, trial participants will be proactively screened and monitored for SIB in accordance 
with available regulatory guidance.
Because psychoactive drugs may impair thinking, judgment, and/or motor skills, participants
should be cautioned about operating machinery, including automobiles, until they are 
reasonably certain that the study medication does not adversely affect their ability to engage 
in such activities. It is recommended that participants should exercise caution when driving or 
operating machinery.
Participants will be closely monitored during the trial participation (including safety 
laboratory, AE monitoring, physical and neurological examinations) to ensure that any 
occurring events are detected and any necessary actions taken.
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.
Therefore, no undue risk is expected from the multiple dose administration of 100 mg BI 
1358894 over 19 days to healthy subjects planned for this trial.
Risks related to bupropion administration
The dose of bupropion administered in the current trial (two single doses of 150 mg extended
release tablets separated by a bupropion free interval of 21 days) corresponds to the starting
dose given in therapy. AEs will be appropriately monitored and could be adequately treated if
necessary because the subjects will be hospitalized at the trial site under close medical 
surveillance for 24 h after bupropion administration. Subjects with contraindications for the
use of bupropion will be excluded from participation (see Section 3).
Single doses of 150 mg bupropion have been well tolerated by healthy volunteers in previous
DDI trials. Due to the supposed CYP2B6 induction mediated by BI 1358894, plasma 
concentrations of bupropion and its metabolites may be decreased. Thus no undue risk is 
expected to healthy subjects from the combined administration of BI 1358894 and bupropion 
in this trial.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also section 5.2.6.1.4, adverse events of special interest.


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If the investigator should have any clinical concern, the safety of subjects will be of upmost 
importance. The Investigator has the discretion to remove subjects from the trial should there 
be any safety concerns, or if the subjects wellbeing is at jeopardy. 
Taken together, the risk of study participation is considered to be minimal and justified when 
compared to the potential benefit of a successful clinical development of BI 1358894 for 
patients with MDD and BPD.


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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 investigate the relative bioavailability of a single dose of 
bupropion when given alone (Reference) compared with co-administration (Test) on the 15th 
day of a 19-day treatment with BI 1358894 (100 mg once daily) following oral
administration in healthy volunteers.
The assessment of safety and tolerability will be additional objectives of this trial.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for bupropion when 
administered alone and co-administered at BI 1358894 steady state:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for bupropion when 
administered alone and co-administered at BI 1358894 steady state:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to infinity)


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2.2.1.2
Safety and tolerability
Safety and tolerability of BI 1358894 and bupropion will be assessed based on:  

Adverse events (including clinically relevant findings from the physical/neurological 
examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The trial is designed to assess effects of BI 1358894 on CYP2B6 activity after
achievement of steady-state concentrations of BI 1358894.
The trial will be performed as an open-label, two period fixed sequence trial in healthy male 
and female volunteers enrolled at a single site. Eighteen subjects will receive the following 
oral treatments (for details refer to Section 4.1.):

150 mg bupropion hydrochloride as single dose on Day 1 of Visits 2 and 3

100 mg BI 1358894 as daily doses over 19 days from Day -14 to Day 5 of Visit 3
There will be an interval of 21 days between the single-dose administrations of 
the CYP2B6 probe, bupropion (Day 1 of Visits 2 and 3).
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
Because of the long (50-70 hours) half-life of BI 1358894, a fixed-sequence design was 
selected, in which BI 1358894 is administered in the second study period only. 
For relative bioavailability trials, the crossover design is preferred because of its efficiency:
since each subject serves as his/her own control, the comparison between treatments is based
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments (R94-1529).
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory.
Dosing durations are long enough to reliably achieve steady-state drug exposures.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 18 healthy male and female will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.


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3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male or female subjects according to the assessment of the investigator, as based 
on a complete medical history including a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Male subjects, or female subjects who meet any of the following criteria from at least 30 
days before the first administration of trial medication until 30 days after trial completion:

Sexually abstinent

Use of adequate contraception, e.g. any of the following methods plus condom:
implants, injectables, intrauterine device

A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)

Surgically sterilised (including hysterectomy)

Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in
questionable cases a blood sample with levels of FSH above 40 U/L and estradiol 
below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including safety laboratory, BP, PR or ECG)
deviating from normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections


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10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation, or vaccination of any kind requiring re-vaccination during the course of the 
trial)
12. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day for
males)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or 
any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
Female subjects will not be allowed to participate, if any of the following apply:
23. Positive pregnancy test
24. Lactation
In addition, the following trial-specific exclusion criteria apply:
25. A history of cerebral seizure
26. A history of bipolar mood disorder, bulimia or anorexia
27. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
28. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
For study restrictions, refer to Section 4.2.2.


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3.3.4
Withdrawal of subjects from treatment or assessments
Subjects 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.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.3), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:

The subject wants to discontinue trial treatment, without the need to justify the decision

The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.

The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment

The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases). The subject will discontinue trial treatment if he or she 
shows one drug-related adverse event of severe intensity or one drug-related serious 
adverse event. 

The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF

In addition to these criteria, the investigator may discontinue subjects at any time based 
on his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 


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involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site

New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported

Violation of GCP, or the CTP, or the contract with BI impairing the appropriate conduct 
of the trial-

The sponsor decides to discontinue the further development of the investigational product
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 2 subjects do not complete the trial the Clinical Trial Leader together with 
the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects 
will be replaced. A replacement subject will be assigned a unique trial subject number, and 
will be assigned to the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Product 1:
Substance:
BI 1358894
Pharmaceutical formulation: Film coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg
Posology:
2-0-0
Route of administration:
oral
Duration of use:
Multiple doses from Day -14 to Day 5 of Visit 3 (19 days in 
total)
The characteristics of the reference product are given below:
Name:
Elontril
Substance:
Bupropion hydrochloride
Pharmaceutical formulation: Tablet
Source:
Unit strength:
150 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
Single doses on Days 1 of Visit 2 and Visit 3
Bupropion will be obtained from a public pharmacy.
4.1.2
Selection of doses in the trial
In this trial, multiple daily doses of 100 mg of BI 1358894 are planned, and are considered to
be safe for administration to healthy subjects. Doses of 100 mg are on the upper end of the 
expected efficacious dose-range likely to be used in clinical practice.


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The doses of bupropion are standard clinical doses. Single doses of 150 mg have been used in 
previous DDI trials with healthy volunteers [P10-12978, U07-1865, c03050404].
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment sequence investigated in this trial, and each subject will be
allocated to the same treatment sequence (R-T). The subjects will be allocated to a study
subject number by first come first serve prior to first administration of trial medication in the 
morning of Day 1 of Visit 2. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
4.1.4
Drug assignment and administration of doses for each subject
This is an open-label, two-period, fixed-sequence trial. All subjects will receive the 2 
treatments in fixed order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit 
strength
Dosage
Total 
dose
T (Test)
BI 
13588941
Tablet
50 mg
2 tablets (100 mg) doses on 
days-14 to Day 5 (19 days) of 
Visit 3
1900 mg
Bupropion1 Tablet
150 mg 
1 tablet (150 mg) single dose 
on day 1 Visit 3
150 mg
R
(Reference)
Bupropion1 Tablet
150 mg
1 tablet (150 mg) single dose 
on day 1 Visit 2
150 mg
1 Drug administration after a standard continental breakfast 
The trial medications will be administered to the subjects as an oral dose together with about 
240 mL of water under supervision of the investigating physician or an authorised designee. 
Administration of BI 1358894 will be performed in the morning of Days -14 to day 5 of Visit 
3, and administration of Bupropion will be performed on Days 1 of Visits 2 and 3 following a 
standard continental breakfast.
The consumption of the continental breakfast should occur within 30 minutes prior to dosing. 
PK blood samples should be taken before the study drug administration, whereas the safety 
laboratory samples should be taken as the first morning sample after an overnight fast. 
To ensure a dosing interval of 24 hours (treatment T, Visit 3), the administration of 
BI 1358894 should take place at the same time every day. For BI 1358894 administration on 
Days -1 and 2, a deviation of no more than +/-15 min is allowed, whereas on ambulatory 
visits, a deviation of no more than +/- 60 min is allowed. The first BI 1358894 administration 
will be followed by a 2-hour post administration in-house observation period.


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Table 4.1.4: 2 Composition of the standard continental breakfast as an example
Ingredients
kcal
1 bread roll
164
15 g butter 
113
1 slice of Gouda cheese (approximately 40g)
146
1 slice of meat (approximately 20g)
33
1 cup of decaffeinated coffee or tea (without sugar)
2
Sum1
458
1
The total caloric content is supplied approximately as following: approx. 88 kcal as protein, approx. 133 kcal 
as carbohydrate, and approx. 237 kcal as fat.
Subjects will be kept under close medical surveillance until 24 h following drug 
administration of Bupropion. During the first 5 h after Bupropion administration, they are not 
allowed to lie down (i.e. no declination of the upper body of more than 45 degrees from
upright posture).
The single dose Bupropion in Period Reference and the single dose of Bupropion in Period
Test are to be separated by a washout period of at least 7 days. There will be 14 days follow-
up period after the last BI 1358894 administration.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
BI 1358894 will be provided by BI. It will be packaged and labelled in accordance with local 
law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
Bupropion tablets will be obtained by the clinical trial site from a public pharmacy. The drug 
will be dispensed out of the original, unmodified packages.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
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 subject, and the disposal of unused products.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 subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed locally by the trial site upon written authorisation of 
the clinical trial leader. Receipt, usage and disposal of trial medication must be documented 
on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 


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kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the fluid served with 
breakfast (see Table 4.1.4: 2), the water administered with the drug, and an additional 
240 mL of water at 2 h and 4 h post-dose (mandatory for all subjects). From lunch until 24 h 
post-dose, total fluid intake is restricted to 3000 mL on day 1 Visits 2 and 3.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each study period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before until 24 h after each administration of trial 
medication on Visits 2 and 3.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Poppy-seeds containing foods should not be consumed starting 3 days before the first drug 
administration in order to avoid false-positive results in the drug screen.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial (see Section 3.3.2 for the definition of 
adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.


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Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported),
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG, laboratory tests, suicidality assessment and a 
physical examination including neurological exam. At the end of trial examination, it will 
include review of vital signs, 12-lead ECG, laboratory tests, suicidality assessment and a 
physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap, 
) at the times indicated in the Flow 
Chart, after subjects have rested for at least 5 min in a supine position. All recordings should 
be made using the same type of blood pressure recording instrument on the same arm, if 
possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
Reticulocytes/Erythrocyte
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
X
--
--
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
--
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
--
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands; Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
--
--
--
--
--
--
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Lactic Dehydrogenase
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
X
X
X
X
X
X
X
X
X
X
X
--
--
--
X
X
X
X
X
--
--
Hormones
Thyroid Stimulating Hormone
Follicle Stimulating Hormone1
X
X
--
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
eGFR (CKD-EPI for creatinine)
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
--
X
--
X
X
--
--
--
--
--
X
X
--
X
X
--
--
--
--
--


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Electrolytes
Sodium
Potassium
Calcium
X
X
X
--
--
--
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visits 2 and 3 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 4 (end of trial examination)
1
Only for post-menopausal females if needed
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results might not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
each treatment period, and as part of the end of trial examination. Drug screening will be 
performed at screening and prior to each treatment period.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
COVID 19 infection1
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
SARS-CoV-2 virus PCR test
Pregnancy test (urine)3
Pregnancy test (serum at 
screening only)2
Beta human chorionic gonadotropin (beta-HCG)
1
Will be performed at screening, and shortly (within 72 hours) before admission to the site as per Flow 
Chart.
2
Only for female subjects of childbearing potential.
3
Only for female subjects of childbearing potential. Before start of the study drugs, on Day -1 Visit 2, 
and day -14 Visit 3 and EOT.
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
6820, 
) will be performed prior to each treatment period, and 
may be repeated at any time during the study at the discretion of an investigator or designee. 
The results will not be included in the CTR
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of 
drug screening and pregnancy tests. These tests will be performed at the trial site using 
SureStepTM Multi-Drug Test (
) and hcG urine test (
), respectively, or 
comparable test systems.
SARS-CoV-2 testing will be performed at the local lab mentioned above or at site.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 
) at the times provided in the Flow Chart.


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To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). Precise electrode placement will be marked with an 
indelible mark on the skin to allow reproducible placement throughout the study.
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Suicidality assessment
Suicidality assessment to further evaluate the psychological status of the subject will be 
performed at screening and follow up visits using the Columbia Suicidal Severity Rating 
scale (C-SSRS). The C-SSRS is a brief measure which is designed to assess severity and 
change of suicidality by integrating both behaviour and ideation. The C-SSRS was designed 
to address the need for a summary measure to track change in the severity of suicidality 
across both clinical settings and treatment trials.
The original C-SSRS is shown in Appendix 10.1.
5.2.4.2
Neurological examination
As a general additional safety measure, a physical neurological examination will be
performed at the time points specified in the respective Flow Chart.
The neurological examination will include the following assessments:

General level of arousal

Orientation

Eye movement

Pupil size and pupil reactivity

Reflexes

Assessment of muscle strength


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
Gait

Romberg test

Tremor

Point-to-point movements

Sensitivity
Documentation, Assessment, and Reporting:
Results will be documented in source data at the clinical trial site and assessed for clinical
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant
findings of the neurological examination will be reported as Adverse Events (during the trial)
or as baseline conditions (at screening).
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
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  

Requires prolongation of existing hospitalisation


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
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 
upon appropriate medical judgment 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
5.2.6.1.3
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further 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, an electronic data 
capture system which allows the entry of trial data at the trial site. Adverse events of special 
interest
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
eDC. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 


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etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger


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
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.


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5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions the 
Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax 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.
5.2.6.2.3
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
5.2.6.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of 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 Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
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 Trials 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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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 1358894 concentrations in plasma, 3 mL of blood will be drawn
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 2 h, with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
For quantification of bupropion (and relevant bupropion metabolite) plasma concentrations,
4.9 mL of blood will be taken into K2-EDTA-Gel blood drawing tubes per time point.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. 
Two plasma aliquots will be obtained from each blood sample and stored in polypropylene 
tubes. For analysis of bupropion (and bupropion metabolite) plasma concentrations, the first 
aliquot should contain at least 0.8 mL of plasma.
The process from blood collection until transfer of plasma aliquots into the freezer should be
completed within 60 min for bupropion samples, with interim storage of blood samples in ice 
water before centrifugation. Centrifugation of bupropion samples should start within 45 min 
after blood withdrawal. In the time interval between centrifugation and storage in the freezer, 
bupropion samples should be cooled, e.g. by use of cryo blocks, to avoid conversion between 
the S- and R-enantiomers.
The time each aliquot was placed in the freezer will be documented. Until transfer on dry ice 
to the analytical laboratory, bupropion aliquots will be stored upright at approximately -70°C 
or below at the trial site. The second aliquot will be transferred to the analytical laboratory 
after the bioanalyst has acknowledged safe arrival of the first aliquot. 


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At the analytical laboratory, the plasma samples will be stored appropriately until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations. However, only data related to the study will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the CTR is archived.
5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSEMENT OF BIOMARKER
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS


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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.4 are 
generally used assessments of drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 of Visit 2 are to be performed and completed within a 3 h-period 
prior to the trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests 
will be ± 30 min on Day 1, ± 45 min from 24 hours onwards, and ± 60 min from 119 hours 
onwards.
For ambulatory administration of BI 1358894 of Visit 3, a time window of ± 60 min will be 
allowed, whereas for BI 1358894 administrations on Days -1 and 2 of Visit 3, a deviation of 
no more than +/- 15 min is allowed.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, physical examination and neurological examination including suicidality assessment, 
refer to Section 5.2.
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days 1 to 6 in period 1, day
–14 to 6 in period 2). At least 6 days will separate drug administrations in the first and second 
treatment periods.


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On Day -1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit, at least 14 days after last administration of BI 1358894 or 5 days 
after last administration of Bupropion (as applicable).
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The primary objective of this trial is to investigate whether there is a drug-drug interaction
between BI 1358894 (as the perpetrator) and the CYP2B6 probe drug bupropion. Hence, the 
relative bioavailability of bupropion given as single dose without BI 1358894 (Reference R) 
and given as single dose at steady state of BI 1358894 (Test T) is analysed on the basis of the 
primary and secondary pharmacokinetic endpoints, as listed in Section 2.1.2 and 2.1.3. The 
trial is designed to allow intra-subject comparisons and will be evaluated statistically by use 
of a linear model for logarithmically transformed PK endpoints.
The assessment of safety and tolerability is a further objective of this trial, and will be
evaluated by descriptive statistics for the parameters specified in Section 2.2.1.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of bupropion given alone and at steady state of BI 1358894 will 
be estimated by the ratios of the geometric means (test/reference), and their corresponding 2-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to the two 
one-sided t-test procedure, each at the 5% significance level. Since the main focus is on 
estimation and not testing, a formal hypothesis test and associated acceptance range is not 
specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment.
Descriptive and model based analyses of PK parameters will be based on the PKS.


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Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IPD specification file prior to trial initiation, IPDs 
will be identified no later than in the Report Planning Meeting, and the IPD categories will be 
updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug Bupropion will be calculated 
according to the to the relevant BI internal procedures.
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A predose bupropion concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
7.3.1
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subjects and treatment. The effect 
'subjects' will be considered as random, whereas the other effects will be considered as fixed. 
The model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response measured on subject m receiving treatment k,


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= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
k = the kth treatment effect, k = 1, 2
ekm = the random error associated with the mth subject who received
treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally, their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
‘subjects’ considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures and will be assessed statistically using the same methods as described 
for the primary endpoints.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.1.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first trial medication intake and end of 
REP (see Section 1.2.3) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
In case of two or more treatments, the follow-up will be summarized according to the 
previous treatment. These assignments including the corresponding time intervals will be 
defined in detail in the TSAP. Note that AEs occurring after the last per protocol contact but 


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entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures.
PK parameters that cannot be reasonably calculated based on the available drug
concentration-time data will not be imputed.
7.6
RANDOMISATION
In this trial subjects receive all treatments in the same order, thus no randomisation for the 
treatment assignment is performed (see also Section 4.1.3).
The sponsor will arrange for the randomisation as well as packaging and labelling of BI 
1358894 medication. 


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7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 18 subjects in the trial, accounting for up to 2 non-PK 
evaluable subjects. This sample size is not based on a power calculation but is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (test/reference) can be expected with 
95% probability. Precision is defined as the ratio of upper CI limit to the relative BA 
estimate. Note that the precision is independent of the actual ratio of geometric means.
The observed intra-individual coefficient of variation (gCV) for 
bupropion in a previous trial [c03050404] was about 19% for total bupropion, for both Cmax 
and AUC0-tz.
For various assumptions around this gCV, Table 7.7: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (test/reference). For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios T/R of geometric means.
Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in two period fixed sequence design
(N=16)
gCV [%]
Precision upper 
CL / relative BA
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
15.0
1.127
50
44.38
56.34
15.0
1.127
75
66.56
84.51
15.0
1.127
100
88.75
112.68
15.0
1.127
125
110.94
140.84
20.0
1.172
50
42.67
58.58
20.0
1.172
75
64.01
87.88
20.0
1.172
100
85.35
117.17
20.0
1.172
125
106.68
146.46
25.0
1.218
50
41.06
60.89
25.0
1.218
75
61.59
91.33
25.0
1.218
100
82.12
121.77
25.0
1.218
125
102.65
152.22
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit)**+,,-./+, = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 4.0.1.


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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
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects 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 general rule, no trial results should be published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT 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 a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. 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 for each trial subject that include 
all observations and other data pertinent to the investigation. 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.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication


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
Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject 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 Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 


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Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for 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 EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 


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A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
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).
The trial will be conducted at 
, 
, under the supervision of the Principal Investigator. Relevant documentation on the 
participating (Principal) Investigators (e.g. their curricula vitae) will be filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
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 local clinical monitors (CML), Clinical 
Research Associates, and investigators of participating trial sites
The trial medication BI 1358894 will be provided by the 
 
. Bupropion will be obtained by the clinical 
trial site from a public pharmacy.
Safety laboratory tests will be performed by the local laboratory of the trial site 
(
).
Analyses of BI 1358894 concentrations in plasma will be performed at 
.
Analyses of Bupropion, S-Bupropion, R-Bupropion and metabolites S,S-Hydroxybupropion 
and R,R-Hydroxybupropion-concentrations in plasma will be performed at 
, 
.
Pharmacogenomic samples will be sent to and analysed by 
, 
. 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
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
P06-00643
Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive 
disorder: pharmacokinetic and formulation considerations. Clin Ther 2005; 
27(11):1685-1695
P06-11895
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, 
Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath 
PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and 
longer-term outcomes in depressed outpatients requiring one or several 
treatment steps: a STAR*D report. Am J Psychiatry 2006 ; 163(11) ; 1905-
1917. 
P10-12978
Park J, Vousden M, Brittain C, McConn DJ, Iavarone L, Ascher J, 
Sutherland SM, Muir KT. Dose-related reduction in bupropion plasma 
concentrations by ritonavir. J Clin Pharmacol 2010 ; 50(10) ; 1180-1187.
P12-05791
U.S. Department of Health and Human Services Food and Drug 
Administration. Center for Drug Evaluation and Research (CDER). 
Guidance for industry: drug interaction studies - study design, data analysis, 
implications for dosing, and labeling recommendations (draft guidance, 
February 2012 (this guidance document is being distributed for comment 
purposes only)). 
Website: fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guidances/ucm292362.pdf (access date: 14 May 2012); U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER); 2012.
P15-06991
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions (21 
June 2012, CPMP/EWP/560/95/rev. 1 corr. 2). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guid 
eline/2012/0 7/WC500129606.pdf (access date: 8 July 2015); London: 
European Medicines Agency (EMA); 2012.
R06-2872
Trivedi MH, Rush AJ, Wisniewski SR, Warden D, McKinney W, Downing 
M, Berman SR, Farabaugh A, Luther JF, Nierenberg AA, Callan JA, 
Sackeim HA. Factors associated with health-related quality of life among 
outpatients with major depressive disorder: a STAR*D report. J Clin 
Psychiatry 2006 ; 67(2) ; 185-195. 
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R14-3843
Kharasch ED, Mitchell D, Coles R. Stereoselective bupropion 
hydroxylation as an in vivo phenotypic probe for cytochrome P4502B6 
(CYP2B6) activity. J Clin Pharmacol 2008;48(4):464-474.


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R15-3888
Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao 
GL, Tsvetkov E, Rodig SJ, Veer A van't, Meloni EG, Carlezon WA, 
Bolshakov VY, Clapham DE. Essential role for TRPC5 in amygdala 
function and fear-related behavior. Cell 2009 ; 137(4) ; 761-772.
R16-5350
Fowler MA, Sidiropoulou K, Ozkan ED, Phillips CW, Cooper DC. 
Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent 
brain. Plos One 2007 ; 2(6) ; e573 
R16-5472
Koenigsberg HW, Denny BT, Fan J, Liu X, Guerreri S, Mayson SJ, et al.
The neural correlates of anomalous habituation to negative emotional 
pictures in borderline and avoidant personality disorder patients. Am J 
Psychiatry 2014 ; 171(1) ; 82-90. 
R16-5473
Mandell D, Siegle G, Shutt L, Feldmiller J, Thase ME. Neural substrates of 
trait ruminations in depression. J Abnorm Psychol 2014 ; 123(1) ; 35-48. 
R16-5474
IsHak WW, Elbau I, Ismail A, Delaloye S, Ha K, Bolotaulo NI, et al.
Quality of life in borderline personality disorder. Harvard Rev Psychiatry 
2013 ; 21(3) ; 138-150. 
R16-5475
McClintock SM, Husain MM, Wisniewski SR, Nierenberg AA, Stewart 
JW, Trivedi MH, et al. Residual symptoms in depressed outpatients who 
respond by 50 % but do not remit to antidepressant medication. J Clin 
Psychopharmacol 2011 ; 31(2) ; 180-186. 
R16-5476
Links PS, Heslegrave R, Reekum R van. Prospective follow-up study of 
borderline personality disorder: prognosis, prediction of outcome, and axis 
II comorbidity. Can J Psychiatry 1998 ; 43(3) ; 265-270. 
R16-5477
Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Pfohl B, Widiger TA.
The borderline diagnosis II: biology, genetics, and clinical course. Biol 
Psychiatry 2002 ; 51(12) ; 951-963. 
R16-5483
Ellison WD, Rosenstein L, Chelminski I, Dalrymple K, Zimmerman M.
The clinical significance of single features of borderline personality 
disorder: anger, affective instability, impulsivity, and chronic emptiness in 
psychiatric outpatients. J Personal Disord 2016 ; 30(2) ; 261-270. 
R21-0979
Elontril 150mg and 300mg Tabletten Fachinformation (October 2020)
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
c03050404
. The effect of multiple doses 
of BI 187004 on the single-dose pharmacokinetics of repaglinide and 
bupropion following oral administration in healthy male subjects (an open-
label, one sequence trial). Clinical Trial Report. 1307.20. 23 Oct 2015.
c10354149
. Investigator's Brochure BI 1358894 in Major Depressive 
Disorder and Borderline Personality Disorder. Current Version.


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U07-1865
. An 
open, randomised two-period cross-over trial to evaluate the effect of 
multiple doses of flibanserin on the steady-state pharmacokinetics of 
bupropion. Clinical Trial Report. 511.88. 06 Jun 2008. 


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10.
APPENDICES
10.1
COLUMBA-SUICIDE SEVERITY RATING SCALE


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
27 May 2021
EudraCT number
2020-006052-40
BI Trial number
1402-0018
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
An open-label, two-period fixed sequence trial to 
evaluate the effect of multiple doses of BI 1358894 
on the pharmacokinetics of bupropion in healthy 
volunteers
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Title page
2. Flow Chart
3. Section 3.3.3
4. Section 3.3.4.1
Description of change
1. CT Leader change from 
 to 
 implemented
2. Formatting corrected: In Flow Chart “Period T” 
header is now formatted as header to ensure it is 
displayed on all pages of this flow chart
3. Content and format:

Content: Exclusion limit for alcohol 
consumption in exclusion criterion 15 
lowered to more than 24 or 12 g/d in men or 
women, respectively

Format: “Female subjects will not be allowed 
to participate, if any of the following apply:” 
is not an independent exclusion criterion but, 
as indicated by the “:” a header/explanation 
for the subsequent two criteria
4. Treatment discontinuation criterion for 
individual subjects for medical reasons specified 
that a drug-related severe or serious AE in a 
subject requires treatment discontinuation in the 
respective subject


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Rationale for change
1. CT Leader has changed
2. Formatting correction avoids mistakes
3. Content change requested by IEC/CA. 
Formatting correction needed for 
implementation.
4. Specification of treatment discontinuation 
criterion requested by IEC/CA.
11.2
GLOBAL AMENDMENT 2
Date of amendment
23 Jun 2021
EudraCT number
2020-006052-40
BI Trial number
1402-0018
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
An open-label, two-period fixed sequence trial to 
evaluate the effect of multiple doses of BI 1358894 
on the pharmacokinetics of bupropion in healthy 
volunteers
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Flow Chart
2. Section 4.1.4
3. Section 5.2.3
4. Section 6.1
5. Section 8.7
Description of change
1. Flow Chart:
1.1.
Explanation added to footnote 9 that 
screening includes serum pregnancy test in 
females of childbearing potential
1.2.
Addition of footnote 13 to Visit 2, Day -1; 
deletion of footnote 13 at Visit 2, Day 6, 
and addition of footnote 13 to Visit 3, Day -
14
1.3.
New footnote 14 “Urine drug screening and 
alcohol breath test”; added to Visit 2, Day -
1 and Visit 3, Day -14 
1.4.
New footnote 15 “Before study drug 
administration”; added to Visit 3, Day -14, 


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08:00 (PK sample BI 1358894, clinical 
laboratory, vital signs, 
physical/neurological examination), and to 
Visit 3, Days -6, -4, -3, -2, -1, 2, 3, 4, and 5 
(PK sample BI 1358894) 
1.5.
Addition of “Ambulatory visit” to 
ambulatory appointments at Visit 3 and 
addition of “Discharge” to timepoint +24 h 
at Visit 3
1.6.
Combination of the two rows at identical 
timepoint Visit 3, -24:00 h to one single 
row and deletion of the redundant AE 
questioning
1.7.
Deletion of the two timepoints without 
activities (Visit 3, planned time 0:15 and 
0:30) and deletion of the empty rows (Visit 
3, between planned times 1:00 and 2:00 and 
between planned times 3:00 and 4:00)
1.8.
Addition of 240 mL fluid intake at planned 
times +2:00 and +4:00 h at Visit 3 and 
Lunch moved from planned time +5:00 h to 
planned time +4:00 h at Visit 3
1.9.
Correction of links in footnote 3 from 
Sections 5.2.1 and 5.2.2 to 5.2.2 and 5.2.4
1.10. New footnote 16 “At this timepoint, no 
safety lab B taken” added to newly
introduced “X” in clinical laboratory 
column at Visit 3, Day -14
2. Section 4.1.4:
2.1. Table 4.1.4: 1: Already available footnote 1 
(“drug administration after a standard 
continental breakfast”) added also to 
“Bupropion” (previously only with BI 
1358894).
2.2. Section 4.1.4, text part: Clarification that 
the described time window of +/- 15 min 
applies to BI 1358894 administration on 
Days -1 and 2, and added that for 
ambulatory administration of BI 1358894 a 
time window of +/- 60 min applies.
3. Section 5.2.3: 
3.1. Table 5.2.3: 1: Addition of “--“ when 
parameter is not measured in the respective 
laboratory set
3.2. Table 5.2.3: 2: Specification that urine 
pregnancy test applies only to female 


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subjects of childbearing potential
3.3. Section 5.2.3, text (2nd paragraph): 
Deletion of hyperlink to Section 10
4. Section 6.1: Clarification that a time window of 
+/- 60 min applies to ambulatory BI 1358894 
administration, and that for administration of BI 
1358894 on Days -1 and 2, a time window of +/-
15 min applies.
Rationale for change
1. Changes to Flow Chart:
1.1.
Serum pregnancy test in women of 
childbearing potential at screening is 
described in Section 5.2.3; has now been 
added to Flow Chart for consistency
1.2.
Urine pregnancy test prior to each treatment 
period is described in Section 5.2.3 
including exact timepoints; has now been 
corrected in / added to Flow Chart for 
consistency
1.3.
Alcohol breath test and urine drug 
screening are planned prior to each 
treatment period as per Section 5.2.3; has 
now been added to Flow Chart for 
consistency
1.4.
New footnote 15 to describe order of events 
for clarity and consistency with Section 
4.1.4
1.5.
Clarification of ambulatory appointments
and discharge timepoints for consistency 
with Sections 1.4, 4.1.4, and 6.2.2
1.6.
Formatting at Visit 3 timepoint -24:00 h has 
been corrected for clarity; at this timepoint 
there were two AE questionings, the 
duplicate was deleted because illogical.
1.7.
Deletion of timepoints without activities 
and of empty rows because these activity-
empty lines are not needed (meaningless) 
and deletion makes Flow Chart clearer
1.8.
Fluid intake on Day 1 of Visit 3 added and 
lunch moved from +5:00 to +4:00 h at Visit 
3 for consistency with Day 1 of Visit 2 and 
for consistency with Section 4.2.2 
1.9.
Links in Flow Chart footnote 3 referred to 
wrong Sections. This has now been 


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corrected.
1.10. Footnote 16 added to clarify that the newly 
introduced “X” in clinical laboratory 
column does not introduce a new safety lab 
B at Visit 3 Day -14.
2. Changes to Section 4.1.4:
2.1. Table 4.1.4: 1: Footnote 1 was missing for 
Bupropion and has now been added; 
administration of all study drugs after food 
is described as such in the Flow Chart and 
in the text of Section 4.1.4.
2.2. Section 4.1.4, text part: Specification of 
time windows for BI 1358894 
administrations for clarification and 
alignment between conflicting statements in 
Sections 4.1.4 and 6.1.
3. Section 5.2.3: 
3.1. Table 5.2.3: 1: Addition of “--“ when the 
parameter is not a part of the respective set 
to improve readability of the table.
3.2. Table 5.2.3: 2: Specification that urine 
pregnancy test applies only to females of 
childbearing potential for consistency with 
Flow Chart footnote 13 and for consistency 
with text in Section 5.2.3.
3.3. Section 5.2.3, text, 2nd paragraph: Deletion 
of hyperlink to the appendix because text 
refers to ISF Section 10 and not to Section 
10 of the protocol 
4. Section 6.1: Specification of time windows for 
BI 1358894 administrations for clarification and 
alignment between conflicting statements in 
Sections 4.1.4 and 6.1.
11.3
GLOBAL AMEDNMENT 3
Date of amendment
29 Jul 2021
EudraCT number
2020-006052-40
BI Trial number
1402-0018
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
An open-label, two-period fixed sequence trial to 


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evaluate the effect of multiple doses of BI 1358894 
on the pharmacokinetics of bupropion in healthy 
volunteers
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Title Page
Description of change
Clinical Trial Leader change from 
to 
 implemented
Rationale for change
Change in Clinical Trial Leader


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34402516
4.0
clinical-trial-protocol-version-04
An open-label, two-period fixed sequence trial to evaluate the effect of multiple
doses of BI 1358894 on the pharmacokinetics of bupropion in healthy volunteers
Approval-Team Member Medicine
29 Jul 2021 21:38 CEST
Author-Trial Statistician
30 Jul 2021 10:41 CEST
Approval-Clinical Trial Leader
30 Jul 2021 13:00 CEST
Verification-Paper Signature
Completion
04 Aug 2021 08:13 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34402516
4.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c36732863-01
BI Trial No.:
1402-0018
Title:
An open-label, two-period fixed sequence trial to evaluate the
effect of multiple doses of BI 1358894 on the pharmacokinetics of 
bupropion in healthy volunteers
Revised Protocol # 04
Investigational
Product:
BI 1358894
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
13 OCT 2021 SIGNED
Version:
1
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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
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINT .................................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
5.3.1
Safety parameters .................................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.4
PRIMARY ENDPOINTS...................................................................................17
7.4.1
Primary analysis of the primary endpoints......................................................17
7.4.2
Further exploratory analyses of the primary endpoints .................................19
7.5
SECONDARY ENDPOINTS.............................................................................19
7.5.1
Key secondary endpoints....................................................................................19
7.5.2
Secondary endpoints...........................................................................................19
7.5.2.1
Secondary endpoint analysis.................................................................................19
7.6.1
Safety parameters ...............................................................................................19


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7.8
SAFETY ANALYSIS..........................................................................................20
7.8.1
Adverse Events ....................................................................................................20
7.8.2
Laboratory data ..................................................................................................21
7.8.3
Vital signs.............................................................................................................22
7.8.4
ECG......................................................................................................................23
7.8.5
Others...................................................................................................................23
7.8.5.1
Physical examination ............................................................................................23
7.8.5.2
Neurological examination.....................................................................................23
7.8.5.3
Body weight ..........................................................................................................23
7.8.5.4
Suicidality assessment (C-SSRS)..........................................................................23
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............24
9.
REFERENCES....................................................................................................25
11.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data and vital signs .......................................................12
Table 6.3: 1
Subject sets analyzed........................................................................................14
Table 11: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis data set
AE
Adverse Event
AESI
Adverse event of special interest
ANOVA
Analysis of variance
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity
AUC0-tz 
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BI 
Boehringer Ingelheim
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
COVID
Coronavirus disease
CRF
Case Report Form, paper or electronic (sometimes referred to as
‘eCRF’)
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
C-SSRS
Columbia-Suicidal Severity Rating Scale
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
EudraCT
European Clinical Trials Database
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important protocol deviations
kg
kilogram
m
meter
MedDRA
Medical Dictionary For Regulatory Activities
PD
Protocol deviations


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Term
Definition / description
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
PR
Pulse rate
RAGe
Report appendix generator
REP
Residual Effect Period
RPM
Report Planning Meeting
SAE
Serious adverse event
SD
Standard Deviation
SDL 
Subject Data Listing
SOC
System Organ Class
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to 
include detailed procedures for executing the statistical analysis of the primary variables and 
other data.
This TSAP assumes familiarity with the CTP and its 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 revised 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, 
randomisation.
Study data as collected in the eCRF will be stored in a trial database within the RAVE EDC
system. All study data also including external data will then be uploaded to the CDR data 
warehouse.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints are PK endpoints of bupropion when administered alone and co-
administered at BI 1358894 steady state, as defined in Section 2.1.2 of the CTP. 

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoint
Secondary endpoint is a PK endpoint of bupropion when administered alone and co-
administered at BI 1358894 steady state, as defined in Section 2.1.3 of the CTP.

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
5.3.1
Safety parameters
Safety and tolerability of BI 1358894 and bupropion will be assessed based on further safety 
parameters defined in Section 2.2.1.2 of the CTP:

AEs (including clinically relevant findings from the physical/neurological examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment
groups, and selection of doses cf. Section 4 of the CTP.
In trial period R (Reference Period) subjects will receive bupropion alone (Reference 
treatment R) whereas in trial period T (Test Period) bupropion plus BI 1358894 (Test 
treatment T) will be administered. 
In trial period R, each subject will receive:

150 mg bupropion hydrochloride administered as sustained release tablet in fed state 
In trial period T, each subject will receive: 

Multiple doses of 100 mg BI 1358894 administered once daily on 19 days (Day -14 to 
Day 5) as tablets in fed state combined with a single dose of 150 mg bupropion
hydrochloride on the 15th day of BI 1358894 treatment (Day 1).
CTP Section 1.2.3: The Residual Effect Period (REP) of BI 1358894 is 14 days. The 
Residual Effect Period (REP) of bupropion is 5 days. This is the period after the last dose 
with measurable drug levels and/or pharmacodynamic effects is still likely to be present. 
For statistical analysis of AEs, the following analysis phases are defined for each subject. 
Analysis phases for active treatments are defined separately for Period R and Period T.


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Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data and vital signs
Study analysis 
phase
Label
Start
End
Screening1
Screening
Date of informed consent
Date/time of first administration 
of Bupropion
On treatment
Bupropion
Date/time of first
administration of Bupropion
Date/time of first administration 
of Bupropion + REP (5 days * 
24 h) or 12:00 a.m. on day after 
subject’s end of trial termination 
date, whichever occurs earlier.
Follow-up
F/U Bupropion
Date/time of first 
administration of Bupropion + 
REP (5 days * 24 h)
Date/time of first administration 
of BI 1358894 or 12:00 a.m. on 
day after subject’s end of trial 
termination date, whichever 
occurs earlier.
On treatment
BI 1358894
Date/time of first 
administration of BI 1358894 
Date/time of administration of 
Bupropion (Visit 3) or date/time 
of last administration of BI 
1358894 + REP (14 days * 24 h) 
or 12:00 a.m. on day after 
subject’s end of trial termination 
date, whichever occurs earlier.
On treatment
BI 1358894 + 
Bupropion
Date/time of administration of 
Bupropion at Day 1, Visit 3 
Date/time of administration of 
Bupropion (Visit 3) + REP (5 
days *24 h) or 12:00 a.m. on day 
after subject’s end of trial 
termination date, whichever 
occurs earlier.
On treatment
BI 1358894
Date/time of administration of 
Bupropion (Visit 3) + REP (5 
days * 24 h)
Date/time of last administration 
of BI 1358894 + REP (14 days * 
24 h) or 12:00 a.m. on day after 
subject’s end of trial termination 
date, whichever occurs earlier.
Follow-up
F/U BI 1358894
Date/time of last administration 
of BI 1358894 + REP (14 days 
* 24 h)
12:00 a.m. on day after trial 
termination date
1 See Section 6.7 for definition of baseline, which will be used in the statistical analyses of safety laboratory data and vital 
signs.
AE summary tables will present results for the on-treatment phase only. All AEs will be 
listed.
CTP Section 7.3.4: Note that AEs occurring after the last per protocol contact but entered 
before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.


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The following AE tables will be provided in the report:

Section 15.3, Appendix 16.1.13.1.8.1 and 16.1.13.1.8.2 of the CTR displays
In these displays, the on-treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening will not be included in this analysis.
In Section 15 AE tables (but not in Appendix 16.1.13.1.8.1 and Appendix 16.1.13.1.8.2 AE 
tables), the following totals will be provided in addition:

"Total Bupropion", defined as the total over all on-treatment phases involving 
bupropion

"Total BI", defined as the total over all on-treatment phases involving BI

"Total on-trt", defined as the total over all on-treatment phases involving BI and 
bupropion
Listings of AEs presented in Section 15.4 will display results for the screening, on-treatment 
phases, and follow-up phases (labelled with the name of the study treatment (short label)).
Safety laboratory data and vital signs will be analyzed based on treatments in the respective 
treatment period (Period R: Bupropion; Period T: BI + Bupropion) with clear differentiation 
between baseline (cf. Section 6.7) and on-treatment measurements. Measurements will be 
considered on-treatment, if they were taken within the on-treatment phases as defined in 
Table 6.1: 1.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting. At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important PD (IPD). For definition of IPDs, and for the process of 
identification of these, refer to the BI reference document "Identify and Manage Important 
Protocol Deviations (IPD)" (2).
If any IPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. Categories which are considered to be IPDs in this trial are defined in the 
DV domain template. If the data show other IPDs, the definition in the DV domain template
will be supplemented accordingly by the time of the Report Planning Meeting.
IPDs will be summarized and listed. Which kind of IPDs could potentially lead to exclusion 
from which analysis set is specified in the DV domain template. The decision on exclusion of 
subjects from analysis sets will be made at the latest at the Report Planning Meeting, after 
discussion of exceptional cases and implications for analyses. If the data show other IPDs, 
this table will be supplemented accordingly by the time of the Report Planning Meeting.


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Non-important COVID-19 related PDs will only be listed.
6.3
SUBJECT SETS ANALYSED
The treated set (TS) and pharmacokinetic parameter analysis set (PKS) will be used as 
defined in the CTP, Section 7.3.
Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PKS
Disposition
X
iPDs
X
Primary PK endpoints
X
Secondary PK endpoint 
X
Further PK endpoints 
X
Safety parameters 
X
Demographic/baseline 
characteristics
X
Treatment exposure
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
CTP Section 3.3.4: “If a subject is removed or withdraws from the trial prior to the first 
administration of trial medication, the data of this subject will not be entered in the case 
report form (CRF) and will not be reported in the clinical trial report (CTR). If a subject is 
removed or withdraws from the trial after the first administration of trial medication, this will 
be documented and the reason for discontinuation must be recorded in the CRF. In addition, 
the data will be included in the CRF and will be reported in the CTR.”
CTP Section 7.5.1: “It is not planned to impute missing values for safety parameters.”
One exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).


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Missing data and outliers of PK data are handled according to BI standards (4) and (5).
CTP: “Pharmacokinetic parameters that cannot be reasonably calculated based on the 
available drug concentration-time data will not be imputed.”
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For all parameters the last non-missing value determined prior to the very first study drug 
administration (bupropion or BI 1358894) will be defined as baseline.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the Report Planning Meeting (RPM).


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6).
The individual values of all subjects will be listed. Listings will be sorted by subject number, 
visit and time point (if visit/ time point is applicable in the respective listing). AE listings will 
be sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
Only descriptive statistics are planned for this section of the CTR.
CTP Section 7.3.4: Previous and concomitant therapies will be presented per treatment 
group without consideration of time intervals and treatment periods.
A medication will be considered concomitant to a treatment period, if it

is ongoing at the time of study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoints
CTP Section 7.3.1: The statistical model used for the analysis of the primary endpoints will 
be an analysis of variance (ANOVA) model on the logarithmic scale. That is, the PK 
endpoints will be log-transformed (natural logarithm) prior to fitting the ANOVA model. This 
model will include effects accounting for the following sources of variation: subjects and 
treatment. The effect 'subjects' will be considered as random, whereas the other effects will 
be considered as fixed. The model is described by the following equation:
ykm
=+ sm+ k+ ekm, where
ykm
= logarithm of response measured on subject m receiving treatment k,

= the overall mean,


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sm
= the effect associated with the mth subject, m=1,2,…,n
k
= the kth treatment effect, k = 1, 2
ekm
= the random error associated with the mth subject who received treatment k,
where sm ~ N(0, σB 2) i.i.d., ekm ~ N(0, σW 2) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will
then be back-transformed to the original scale to provide the point estimate and 90% CIs for
each endpoint.
The analysis of primary endpoints will be based on the PKS.
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for
exclusion, i.e. with APEXC equal to "Included".
CTP Section 7.3: Plasma concentration data and parameters of a subject will be included in 
the statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol deviation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the 
value will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.


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Further details are given in “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies” (4) and “Description of Analytical Transfer Files and PK/PD 
Data Files” (5).
7.4.2
Further exploratory analyses of the primary endpoints
CTP Section 7.3.1: The same statistical model as stated above will be repeated for the 
primary endpoints but with 'subjects' considered as fixed effect.
CTP Section 7.3.1: In addition to the model based approach all parameters will be 
calculated and analysed descriptively.
The analysis of primary endpoints will be based on the PKS.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.
7.5.2.1
Secondary endpoint analysis
CTP Section 7.3.2: The secondary endpoints (refer to Section 2.1.3) will be calculated 
according to the relevant BI internal procedures and will be assessed statistically using the 
same methods as described for the primary endpoints.
Exclusion of PK parameter and exclusion of plasma concentrations are handled as described 
in Section 7.4.1.
7.6.1
Safety parameters
Safety endpoints and tolerability will be analysed as described in Section 7.8 of this TSAP.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
CTP Section 7.3.4: For all analysis, the treatment actually administered (= treatment at 
onset) to the subject will be used.  
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 


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The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to screening or on-treatment periods as defined in Section 6.1. 
AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of AESIs.
CTP Section 5.2.6.1.4: 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 transaminase) and/or ALT (alanine 
transaminase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold ULN 
measured in the same blood sample, or 
○
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted).
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs and
subjects with AESIs. AEs will also be summarized by maximum intensity.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards "Display and Analysis of Laboratory Data" (9).


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Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented by treatment.
Unscheduled measurements of laboratory data will be assumed to be repeat measurements of 
the most recent scheduled measurement (e.g. for follow-up or confirmation of a particular 
value). Therefore, unscheduled measurements will be assigned to the planned time point of 
the previous scheduled measurement. Descriptive statistics will be calculated by planned time 
point based on the worst value of the subject at that planned time point (or assigned to that 
planned time point).
Clinically significant abnormal laboratory values are only those identified either in the 
Investigator's comments or at the Report Planning Meeting at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as possibly clinically significant values will be highlighted in the listings.
Possibly clinically significant laboratory values will be listed in Section 15.4.1.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Unscheduled measurements of vital signs will be assigned to planned time points in the same 
way as described above for laboratory data. However, for vital signs, descriptive statistics 
will be calculated by planned time point based on the last value of the subject at that planned 
time point (or assigned to that planned time point). If the time of measurement is missing for 
a scheduled post-baseline measurement, the scheduled measurement will be used in 
calculation of descriptive statistics (as time difference between scheduled and unscheduled 
cannot be assessed). Unscheduled measurements assigned to planned time point -336:00 will 
only be used in calculation of descriptive statistics if the measurement is taken before 
administration of first dose of BI 1358894 as it is planned for this time point.
If the time of measurement is missing for an unscheduled measurement, this measurement 
will be listed but will be ignored for the calculation of descriptive statistics.


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Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.4
ECG
Abnormal findings in ECG will be reported as baseline conditions (at screening) or as AEs 
(during the trial) if judged clinically relevant by the investigator, and will be analyzed as such.
No separate listing or analysis of ECG data will be prepared.
7.8.5
Others
7.8.5.1
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.
7.8.5.2
Neurological examination
Clinically relevant findings of the neurological examination will be reported as baseline 
conditions (at Screening) or as AEs (during the trial) and will be summarized as such. No 
separate listing or analysis of physical examination findings will be prepared.
7.8.5.3
Body weight 
Since body weight is only assessed at screening it will only be listed.
7.8.5.4
Suicidality assessment (C-SSRS) 
Suicidality monitoring will be performed at screening and follow-up visits as described in 
Section 5.2.5.1 of the CTP. Results for subjects who answered any question with 'Yes' will be 
listed.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database at trial initiation.


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9.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of 
Clinical Trials, current version
2
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE 
dates", current version; KMED
4
BI-KMED-TMCP-MAN-0014: "Noncompartmental PK/PD Analyses of Clinical 
Studies", current version; KMED 
5
BI-KMED-TMCP-MAN-0010: "Description of Analytical Transfer Files, PK/PD 
Data Files and ADA files", current version; KMED
6
KM Asset BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials 
and Project Summaries", current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0066: "Analysis and Presentation of AE data from 
clinical trials", current version; KMED
8
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
9
KM Asset BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of 
Laboratory Data", current version; KMED


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