Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: yes

Brief summary:
The main objective of the study is investigate the effect of escalating doses of oral tyramine on systolic blood pressure (SBP) at baseline and following an oral treatment with BI 1467335 up to 39 days at a low or high dose once daily compared to placebo and phenelzine (Nardil®) as positive control.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: BI 1467335 intervention 2: Placebo intervention 3: Phenelzine sulfate intervention 4: Tyramine
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet intervention 3: Film-coated tablet intervention 4: Capsules

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:
c24752093-05
EudraCT No.
2018-003965-32
BI Trial No.
1386-0016
BI Investigational
Medicinal Product
BI 1467335
Title
A phase I parallel group study in healthy subjects to evaluate the 
effect of multiple oral doses of BI 1467335 and phenelzine as 
positive control on blood pressure response to oral tyramine 
(double-blind, randomised, placebo-controlled design for 
BI 1467335 treatment groups, open label for phenelzine)
Lay Title
A study in healthy people to test how combining BI 1467335 and 
tyramine affects blood pressure
Clinical Phase
I
Clinical Trial Lead
Phone:
Fax:
Principal Investigator
Phone:
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 4))
Version and Date
Version: 5.0
Date: 13 February 2020
Page 1 of 75
Proprietary confidential information
© 2020 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
15 May 2019
Revision date
13 February 2020
BI trial number
1386-0016
Title of trial
A phase I parallel group study in healthy subjects to evaluate the effect of multiple 
oral doses of BI 1467335 and phenelzine as positive control on blood pressure 
response to oral tyramine (double-blind, randomised, placebo-controlled design for 
BI 1467335 treatment groups, open label for phenelzine)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
In-vitro tests revealed a reversible inhibition of MAO-A catalyzed kynuramine 
deamination by BI 1467335. The reversible inhibition of MAO-A was considered to 
be probably of remote clinical relevance, which nevertheless requires further 
clinical evaluation. Therefore, as long as no clinical data are available, in ongoing 
clinical studies with BI 1467335 it is recommended that as a precautionary measure 
subjects should refrain from tyramine-rich food while on treatment.
Study 1386-0016 will be conducted to confirm that multiple doses of BI 1467335 at 
therapeutic dose levels do not inhibit MAO-A activity in humans thus justifying to 
lift dietary restrictions.
Trial objective
To investigate the effect of escalating doses of oral tyramine on systolic blood 
pressure (SBP) at baseline and following an oral treatment with BI 1467335 up to 
39 days at a dose of 10 mg or 15 mg once daily compared to placebo and 
phenelzine as positive control.
Trial design
Double-blind, randomised, multiple-dose, placebo- controlled within BI 1467335 
dose groups, parallel group design.
Open label for phenelzine treatment group (positive control without placebo 
control).
BI 1467335 dose groups will not start before at least 8 subjects of the phenelzine 
treatment group have completed the trial.


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Trial endpoints:
Primary endpoint: 
Tyramine sensitivity factor (TSF), defined as ratio of the tyramine dose causing an 
increase of systolic blood pressure (SBP) G 30 mmHg for at least 3 consecutive
measurements (TYR30) at baseline and at steady state following multiple oral doses
of BI 1467335, placebo or phenelzine.
Secondary endpoints:
Not applicable.
Number of subjects 
total entered
62
each treatment
Dose Group 1 (BI 1467335 - 10 mg): 24 subjects (16 active + 8 placebo);
Dose Group 2 (BI 1467335 - 15 mg): 24 subjects (16 active + 8 placebo);
Dose Group 3 (phenelzine - 30 mg): 14 subjects (all active).
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male/female subjects, age of 18 to 45 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive); at least 30% of each gender to be included 
into each Dose Group
Test product
BI 1467335, film-coated tablets, 5 mg of free base
dose
10 mg (2 x 5 mg) QD and 15 mg (3 x 5 mg) QD
mode of admin.
Oral with 240 mL of water 
Reference product
Matching placebo to BI 1467335
dose
Not applicable
mode of admin.
Oral with 240 mL of water 
Comparator
Phenelzine (Nardil®), tablets, 15 mg 
dose
15 mg BID
mode of admin.
Oral with 240 mL of water 


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Challenge agent
Tyramine powder in capsules
dose
Baseline (Day -10 to Day -1, tyramine powder alone; each subject receives 
escalating doses, dose escalation to be stopped as soon as TYR30 has been 
obtained): 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg QD.
mode of admin.
At steady state (for BI 1467335 dose groups Day 29 up to Day 39 , for phenelzine 
dose group Day 8 to Day 19, tyramine powder in combination with assigned study 
treatment; tyramine dose escalation to be stopped as soon as TYR30 has been 
obtained): 5, 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg QD
An intermediate dose of 150 mg QD only in phenelzine group.
Oral with 240 mL of water
Duration of treatment
Baseline tyramine challenge up to 10 days (Day -10 to Day -1), tyramine challenge 
to be stopped individually as soon as baseline TYR30 has been established.
BI 1467335 or placebo will be administered from Day 1 up to Day 39 (treatment 
will be stopped as soon as individual TYR30 on treatment with BI 1467335 has 
been attained).
Phenelzine will be administered from Day 1 up to Day 19 (treatment will be 
stopped as soon as individual TYR30 on treatment with phenelzine has been 
attained).
From Day 8 (phenelzine) or Day 29 (BI 1467335 or placebo) onwards, tyramine 
challenge up to 12 days (Day 8 to Day 19 for phenelzine or Day 29 to Day 39 for 
BI 1467335 or placebo) concomitantly to the study medication.
Statistical methods
The primary endpoint tyramine sensitivity factor (ratio of TYR30 at steady state 
compared to TYR30 at baseline; TSF) will be compared between the different 
treatment arms (BI 1467335 10mg, 15mg, Placebo and Phenelzine).
The statistical model used will be an analysis of variance (ANOVA) model on the 
logarithmic scale including treatment as fixed effect.
Descriptive statistics for the primary endpoint TSF will be calculated.


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FLOW CHART (BI 1467335 OR PLACEBO)
Visit
Day
Planned time (relative to first 
drug administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
12-lead ECG
Monitoring of BP 7
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-31 to 
-13
Screening (SCR)1
x
x
x
2
-12
14:00
Admission to trial site
x5
-11
06:00
x2
x2
x2
07:25
M
08:00
First tyramine administration7
N
08:30
x
N
09:00
N
10:00
x
N
12:00
Lunch3
x
O
x
16:00
x
-10 
to -2
06:00
x2
x2
07:25
M
08:00
Tyramine administration7
N
08:30
x
N
09:00
N
10:00
x
N
12:00
Lunch3, discharge from trial site 
as soon as TYR30 achieved
x
O
x
16:00
x
3
-1
-18:00
14:00
Admission to trial site
x5
x
1
-0:30
07:30
Allocation to treatment
x2
x2
x2
x2
0:00
08:00
First drug administration, 
discharge from trial site
2
24:00
08:00
Drug administration9
3
48:00
08:00
Drug administration9
4
72:00
08:00
Drug administration9
5
96:00
08:00
Drug administration9
6
120:00
08:00
Drug administration9
126:00
14:00
Admission to trial site
x5
x
7
144:00
08:00
Drug administration
Dispense of study medication
Discharge
x2
x2
x2
8
168:00
08:00
Drug administration9
9
192:00
08:00
Drug administration9
10
216:00
08:00
Drug administration9
11
240:00
08:00
Drug administration9
12
264:00
08:00
Drug administration9
13
288:00
08:00
Drug administration9
294:00
14:00
Admission to trial site
x5
x


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Visit
Day
Planned time (relative to first 
drug administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
12-lead ECG
Monitoring of BP 7
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
3
14
312:00
08:00
Drug administration
Dispense of study medication
Discharge
x2
x2
x2
x2
15
336:00
08:00
Drug administration9
16
360:00
08:00
Drug administration9
17
384:00
08:00
Drug administration9
18
408:00
08:00
Drug administration9
19
432:00
08:00
Drug administration9
20
456:00
08:00
Drug administration9
462:00
14:00
Admission to trial site
x5
x
21
480:00
08:00
Drug administration
Dispense of study medication
Discharge
x2
x2
x2
22
504:00
08:00
Drug administration9
23
528:00
08:00
Drug administration9
24
552;00
08:00
Drug administration9
25
576:00
08:00
Drug administration9
582:00
14:00
Admission to trial site
Start of hospitalisation
x5
x
26
600:00
08:00
Drug administration
27
624:00
08:00
Drug administration
28
648:00
08:00
Drug administration
x2
x2
x2
x2
648:30
08:30
650:00
10:00
Light breakfast3
652:00
12:00
Lunch3
656:00
16:00
Snack (voluntary)3
658:00
18:00
Dinner3
660:00
20:00
x
x
29-39
670:00 -
920:00 
06:00
x2
x2
07:25
M
08:00
Drug + tyramine administration8
N
08:30
x
N
x
09:00
N
x
10:00
x
N
x
12:00
Lunch3, discharge from trial site 
as soon as TYR30 achieved
x
O
x
16:00
Snack (voluntary)3
x
4
41 to 51
End of trial (EoTrial)
examination4
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening and 
pregnancy test in females), demographics (including determination of body height and weight, smoking status and 
alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.


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2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, body weight, vital signs, ECG, safety 
laboratory (including pregnancy test in females), recording of AEs and concomitant therapies. 
5.
Only drug and alcohol screening in urine will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
From Day -11 to Day -2 escalating oral doses of tyramine from 10 to 700 mg /day will be administered. Baseline blood 
pressure prior to tyramine dosing defined as three consecutive measurements with a maximum range of 10 mmHg or, if a 
stable SBP will not be obtained within the 35 minutes, the mean of all 7 readings. Blood pressure monitoring continues 5 
minutes after tyramine administration and approximately every 5 minutes thereafter for at least 2 hours and then 
approximately every 15 minutes for an additional 2 hours. Tyramine dose escalation is to be terminated when the 
predefined target elevation in SBP is reached (i.e., SBP increased G30 mmHg from baseline for three consecutive 
measurements). Participants who do not attain the predefined target elevation in SBP within 4 hours after the maximum
tyramine dose (700 mg) on Day -2 or TYR30 is < 200 mg are screening failures. All other participants are going to be 
included in the study. 
8.
From Day 29 to Day 39 escalating oral doses of tyramine from 5 to 700 mg /day will be administered in Dose Groups 1 
and 2 (concomitantly with BI 1467335 or placebo),. The treatment is to be terminated once the participant reaches the 
predefined target elevation in SBP (i.e., SBP increased G30 mmHg from baseline for 3 consecutive measurements), and 
then the participant is allowed for discharge after an overnight stay at trial site.
9.
On Days 2 to 6, 8 to 13, 15 to 20 and 22 to 25, subjects are allowed to take their study medication at home if deemed
appropriate by the investigator. Compliance of medication intake will be monitored by subject diary and daily phone 
contact (e.g. text message) between subject and site. The scheduled time for drug intake throughout the study for 
subjects assigned to Dose Group 1 and 2 (BI 1467335 or placebo) is 08:00 (applies for intake at home and at the trial 
site).
10. A pharmacogenomic sample will be collected (see Section 5.6.2). If not possible at V3, this sample may also be 
collected during a later visit.
13. This sample to be taken directly prior to dosing of BI 1467335 or placebo.


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FLOW CHART (PHENELZINE)
Visit
Day
Planned time (relative to first 
drug administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
12-lead ECG
Monitoring of BP 7
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-31 to 
-13
Screening (SCR)1
x
x
x
2
-12
14:00
Admission to trial site
x5
-11
06:00
x2,10
x2
x2
07:25
M
08:00
First tyramine administration7
N
08:30
x
N
10:00
x
N
12:00
Lunch3
x
O
x
16:00
x
-10
to -2
06:00
x2
x2
07:25
M
08:00
Tyramine administration7
N
08:30
x
N
10:00
x
N
12:00
Lunch3, discharge from trial site as 
soon as TYR30 achieved
x
O
x
16:00
x
3
-1
-18:00
14:00
Admission to trial site
x5
x
1
-0:30
07:30
Allocation to treatment
x2, 10
x2
x2
x2
0:00
08:00
First drug administration
12:00
20:00
Drug administration
2
24:00
08:00
Drug administration
36:00
20:00
Drug administration
3
48:00
08:00
Drug administration
x2
x2
x2
60:00
20:00
Drug administration
4
72:00
08:00
Drug administration
84:00
20:00
Drug administration
5
96:00
08:00
Drug administration
108:00
20:00
Drug administration
6
120:00
08:00
Drug administration
132:00
20:00
Drug administration
7
144:00
08:00
Drug administration
x2
x2
x2
x2
156:00
20:00
Drug administration
8-19
166:00 -
440:00 
06:00
x2
x2
07:25
M
08:00
Drug + tyramine administration8
N
08:30
x
N
x
09:00
N
10:00
x
N
x
12:00
Lunch3; discharge from trial site as 
soon as TYR30 achieved
x
O
x


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Visit
Day
Planned time (relative to first 
drug administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
12-lead ECG
Monitoring of BP 7
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
16:00
Snack (voluntary)3
x
20:00
Drug administration 9
4
21 to 31
End of trial (EoTrial) examination4
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening and 
pregnancy test in females), demographics (including determination of body height and weight, smoking status and 
alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. .
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, body weight, vital signs, ECG, safety 
laboratory (including pregnancy test), recording of AEs and concomitant therapies. 
5.
Only drug and alcohol in urine screening will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
From Day -11 to Day -2 escalating oral doses of tyramine from 10 mg to 700 mg /day will be administered. Baseline 
blood pressure prior to tyramine dosing defined as three consecutive measurements with a maximum range of 10 mmHg 
or, if a stable SBP will not be obtained within the 35 minutes, the mean of all 7 readings. Blood pressure monitoring 
continues 5 minutes after tyramine administration and approximately every 5 minutes thereafter for at least 2 hours and 
then approximately every 15 minutes for an additional 2 hours. Tyramine dose escalation is to be terminated when the 
predefined target elevation in SBP is reached (i.e., SBP increased G30 mmHg from baseline for three consecutive 
measurements). Participants who do not attain the predefined target elevation in SBP within 4 hours after the maximum
tyramine dose (700 mg) on Day -2 are screening failures. All other participants are going to be included in the study. 
8.
From Day 8 to Day 19 escalating oral doses of tyramine from 5 mg to 700 mg /day will be administered in Dose Group 3 
(concomitantly with phenelzine). Tyramine will be administered only in the morning the respective study days. The 
treatment is to be terminated once the participant reaches the predefined target elevation in SBP (i.e., SBP increased 
G30 mmHg from baseline for 3 consecutive measurements), and then the participant is allowed for discharge after an 
overnight stay at trial site.
9.
Subjects are hospitalized during treatment period. Phenelzine will be administered BID, the scheduled time for drug 
intake throughout the study for subjects assigned to Dose Group 3 is about 08:00 and 20:00. On Day 19 only at 8:00 
Phenelzine will be given.
10. A pharmacogenomic sample will be collected (see Section 5.6.2). If not possible at V3, this sample may also be 
collected during a later visit.
12. Continuous cardiac telemetric monitoring (bedside monitor, Mortara Surveyor S12) from baseline up to 4 hour following 
tyramine administration.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART (BI 1467335 OR PLACEBO).................................................5
FLOW CHART (PHENELZINE).....................................................................8
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................18
1.2.1
BI 1467335 .............................................................................................18
1.2.2
Phenelzine (Nardil®) .............................................................................21
1.2.3
Tyramine................................................................................................21
1.2.4
Residual Effect Period..........................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.4
BENEFIT - RISK ASSESSMENT ...................................................................22
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 25
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......25
2.1.1
Main objectives......................................................................................25
2.1.2
Primary endpoint..................................................................................25
2.2.2.2
Safety and tolerability..............................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 27
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................27
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................28
3.3
SELECTION OF TRIAL POPULATION ......................................................28
3.3.1
Main diagnosis for trial entry..............................................................28
3.3.2
Inclusion criteria...................................................................................29
3.3.3
Exclusion criteria ..................................................................................29
3.3.4
Withdrawal of subjects from treatment or assessments ...................31
3.3.4.1
Discontinuation of trial treatment ............................................31
3.3.4.2
Withdrawal of consent to trial participation ............................32
3.3.4.3
Discontinuation of the trial by the sponsor..............................32
3.3.5
Replacement of subjects .......................................................................33


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4.
TREATMENTS........................................................................................ 34
4.1
INVESTIGATIONAL TREATMENTS ..........................................................34
4.1.1
Identity of BI Investigational Medicinal Products, reference
products and provoking agent.............................................................34
4.1.2
Selection of doses in the trial................................................................35
4.1.3
Method of assigning subjects to treatment groups ............................35
4.1.4
Drug assignment and administration of doses for each subject .......36
4.1.5
Blinding and procedures for unblinding ............................................37
4.1.6
Packaging, labelling, and re-supply ....................................................37
4.1.6.1
BI 1467335 or placebo.............................................................37
4.1.6.2
Phenelzine (Nardil®)................................................................37
4.1.6.3
Tyramine..................................................................................38
4.1.7
Storage conditions.................................................................................38
4.1.8
Drug accountability ..............................................................................38
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................39
4.2.1
Other treatments and emergency procedures....................................39
4.2.2
Restrictions............................................................................................39
4.2.2.1
Restrictions regarding concomitant treatment .........................39
4.2.2.2
Restrictions on diet and life style.............................................39
4.3
TREATMENT COMPLIANCE.......................................................................40
5.
ASSESSMENTS....................................................................................... 41
5.1
ASSESSMENT OF EFFICACY.......................................................................41
5.2
ASSESSMENT OF SAFETY............................................................................41
5.2.1
Physical examination ............................................................................41
5.2.2
Vital signs...............................................................................................41
5.2.3
Safety laboratory parameters..............................................................41
5.2.4
Electrocardiogram................................................................................44
5.2.5
Other safety parameters.......................................................................45
5.2.5.1
Continuous ECG monitoring ...................................................45
5.2.6
Assessment of adverse events...............................................................45
5.2.6.1
Definitions of adverse events...................................................45
Adverse event ............................................................45
5.2.6.1.1
Serious adverse event ................................................46
5.2.6.1.2
AEs considered ‘Always Serious’.............................46
5.2.6.1.3
Adverse events of special interest .............................46
5.2.6.1.4
Intensity (severity) of AEs.........................................47
5.2.6.1.5
Causal relationship of AEs ........................................47
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................48


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AE collection.............................................................48
5.2.6.2.1
AE reporting to the sponsor and timelines ................49
5.2.6.2.2
Information required..................................................49
5.2.6.2.3
Pregnancy ..................................................................49
5.2.6.2.4
5.6
OTHER ASSESSMENTS .................................................................................51
5.6.1
Tyramine challenge...............................................................................51
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................52
6.
INVESTIGATIONAL PLAN.................................................................. 54
6.1
VISIT SCHEDULE............................................................................................54
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................54
6.2.1
Screening period....................................................................................54
6.2.2
Treatment period ..................................................................................54
6.2.3
Follow-up period and trial completion ...............................................55
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 56
7.1
STATISTICAL DESIGN – MODEL ...............................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................56
7.3
PLANNED ANALYSES....................................................................................56
7.3.1
Primary endpoint analyses...................................................................57
7.3.2
Secondary endpoint analyses ...............................................................58
7.3.4
Safety analyses.......................................................................................58
7.4
INTERIM ANALYSES .....................................................................................59
7.5
HANDLING OF MISSING DATA ..................................................................59
7.5.1
Safety......................................................................................................59
7.6
RANDOMISATION ..........................................................................................60


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7.7
DETERMINATION OF SAMPLE SIZE ........................................................60
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 62
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................62
8.2
DATA QUALITY ASSURANCE .....................................................................63
8.3
RECORDS..........................................................................................................63
8.3.1
Source documents .................................................................................63
8.3.2
Direct access to source data and documents.......................................64
8.3.3
Storage period of records.....................................................................64
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................64
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......64
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................65
8.6
TRIAL MILESTONES .....................................................................................65
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................66
9.
REFERENCES......................................................................................... 67
9.1
PUBLISHED REFERENCES...........................................................................67
9.2
UNPUBLISHED REFERENCES.....................................................................68
10. APPENDICES .......................................................................................... 70
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 71
11.1
GLOBAL AMENDMENT 1 .............................................................................71
11.2
GLOBAL AMENDMENT 2 .............................................................................72
11.3
GLOBAL AMENDMENT 3 .............................................................................73
11.4
GLOBAL AMENDMENT 4 .............................................................................75


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
AMP
Auxiliary Medicinal Product
ANOVA
Analysis of variance
AOC3
Amine oxidase copper-containing 3
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CRA
Clinical Research Associates
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTCAE
Common Terminology Criteria for Adverse Events
CTM
Clinical trial manager)
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee


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IPD
Important protocol deviation
IQRM
Integrated risk and management plan
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
NPDR
Non-proliferative diabetic retinopathy
PD
Pharmacodynamic(s)
PP
Polypropylene
PR
Pulse rate
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
REP
Residual effect period
SAE
Serious adverse event
SBP
Systolic blood pressure
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
SSAO
Semi-carbazide-sensitive amine oxidase
ss
(at) steady state
T
Test product or treatment
TS
Treated set
TSAP
Trial statistical analysis plan
TSF
Tyramine sensitivity factor
ULN
Upper limit of normal


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US PI
US Package Insert
VAP-1
Vascular adhesion protein-1
XTC
Ecstasy


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Boehringer Ingelheim (BI) is developing BI 1467335 (formerly Pharmaxis PXS-4728A), an 
oral, small-molecule inhibitor of semi-carbazide-sensitive amine oxidase (SSAO), also 
known as vascular adhesion protein-1 (VAP-1) or amine oxidase copper-containing 3 
(AOC3), in the indication of non-alcoholic steatohepatitis (NASH) and, more recently, non-
proliferative diabetic retinopathy (NPDR).
NASH is characterised histologically by a high level of steatosis, ballooning of hepatocytes, 
and necroinflammation. NASH often leads to fibrosis which can progress to cirrhosis with a 
high risk of liver failure. AOC3 in liver sinusoidal endothelial cells is responsible for the firm 
adhesion and transmigration of leukocytes into the tissue and for the propagation of the 
inflammatory environment in steatohepatitis. Fibrotic regions of NASH liver sections are 
strongly positive for AOC3 immune reactivity [R15-5697]. The associated generation of 
peroxide during the course of amine oxidation is known to activate quiescent stellate cells 
supporting the differentiation into myofibroblasts, and fibrotic tissue generation. Therefore, 
targeting the inhibition of AOC3 enzymatic activity might be beneficial for patients with 
steatohepatitis and fibrosis in order to reduce the recruitment of leukocytes into the liver and 
reduce cytokine and oxygen stress dependent hepatocyte damage and activation of hepatic 
stellate cells.
With a prevalence of about 20 - 30% in the general population of Western countries, non-
alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease 
worldwide [R15-5365]. While simple hepatic steatosis can have a benign, non-progressive 
course, about 40% of patients with NAFLD progress to NASH. As the disease progresses, 
significant fibrosis develops in 37 - 41% of subjects within 15 years. In the United States, 
NASH is believed to be the most common cause of liver cirrhosis [R15-6070] which is 
estimated to be the 12th leading cause of death [R15-6057]. Patients with NASH are also at 
increased risk of hepatocellular carcinoma, even in the absence of cirrhosis [R15-5365]. By 
2023, about 13 million patients are projected to have NASH with advanced stages (i.e. G 
stage 3) of fibrosis (of those, 2.9 million in the US, 3.5 million in EU, 5 million in China). 
Individuals with advanced fibrosis are estimated to progress with a 4% annual event rate to 
cirrhosis. The risk of liver-related death in Western patients with NASH ranges from 10% 
over 13.7 years to 18% over 18.5 years [P13-02280].
To date, no approved therapy for liver fibrosis or effective disease modifying regimen for 
NASH is available, despite the strong interface with metabolic syndrome, obesity and Type 2 
diabetes mellitus. The current standard of care for NASH is weight loss through diet and 
exercise to improve insulin resistance and lower fat mass which is a clinically challenging 
goal to achieve and shows minimal impact on disease progression [R15-6044].
It should be noted that the potential therapeutic effect of BI 1467335 is not only evaluated in 
patients with NASH [c08980589] but also in patients with NPDR [c14141887].


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For a more detailed description of the BI 1467335 profile including a comprehensive 
overview of NPDR refer to the current Investigator’s Brochure (IB) [c04751792].
1.2
DRUG PROFILE
1.2.1
BI 1467335
BI 1467335 is a small molecule AOC3 inhibitor that exhibits both anti-inflammatory and 
anti-fibrotic characteristics in various animal models. AOC3 is a membrane bound adhesion 
protein that facilitates the binding of leukocytes to endothelial cells and the subsequent 
transmigration to sites of inflammation.
For a more detailed description of the BI 1467335 profile please refer to the current
Investigator’s Brochure (IB) [c04751792].
Non-clinical findings
Nonclinical pharmacology
In several disease related rodent models, resembling different aspects of NASH, BI 1467335 
showed reduced steatosis, inflammatory cell infiltrates and fibrotic area compared to control 
animals (Stelic Animal ModelTM mouse model), a reduction of stellate cell activation 
(Methionine-Choline deficient Diet model), and an (inconsistent) reduction of biomarkers for 
inflammation and fibrosis (carbon tetrachloride induced fibrosis model in mice and rats). 
However, the overall conclusion from these studies was that BI 1467335 demonstrated 
beneficial signals for NASH-related pathologies, including myofibroblast activation, necro-
inflammation, and fibrogenesis, supported by literature data on the potential role of AOC3 in 
NASH.
In a cardiovascular safety pharmacology study, male dogs received BI 1467335 single oral 
doses of 0, 6, 15 and 45 mg/kg with adequate recovery period between dose levels. While no 
effects were observed with single doses of 6 mg/kg, significant increases in QTc intervals 
were seen at doses G 15 mg/kg. All other safety pharmacology studies showed no BI 1467335 
related changes.
Toxicology
The NOAEL in rats orally exposed to BI 1467335 for 13 weeks was 12.5 mg/kg. This dose
corresponded to mean Cmax and AUC0-24h levels of 8430 nM and 65700 nM h, respectively, 
in rat. The NOAEL in dogs orally exposed to BI 1467335 for 13 weeks was 3 mg/kg. This 
dose corresponded to mean Cmax and AUC0-24h levels of 3000 nM and 25900 nM h, 
respectively, taken from females who the lowest plasma exposure at the NOAEL. This 
provides an adequate safety window between clinical exposure and exposure at NOAEL 
levels in animals. For further details, please refer to the current ‘Investigator’s Brochure (IB)’ 
[c04751792].
These findings are consistent with results of the 4 weeks toxicology studies in rats and dogs 
[n00244592, n00247850].
BI 1467335 does not present a genotoxic hazard.


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The available nonclinical safety data on embryo-fetal development in rats and rabbits support 
repeated oral administration of BI 1467335 to humans of non-childbearing potential for up to 
13 weeks duration. However, women of childbearing potential are only allowed to participate 
in clinical trials after testing negative for pregnancy and under adequate contraception with 
two methods, of which at least one is highly effective, during the trial.
The pharmacokinetic behavior of BI 1467335 in rats and dogs was characterised by rapid 
absorption, a low to moderate half-life and a predominantly over proportional increase of 
plasma exposure over dose. The in vitro plasma protein binding was low in all investigated 
species, with Y25% bound in human plasma. In vitro studies in cryopreserved human 
hepatocytes indicated a prevalence of oxidative O-dealkylation as primary metabolic 
pathway.
BI 1467335 inhibited MAO-B catalyzed kynuramine deamination with an IC50 of 1.04 ZM 
and MAO-A catalyzed kynuramine deamination with an IC50 of 74.4 ZM [n00257993]. Time 
dependent inhibition of MAO-B catalyzed kynuramine deamination by BI 1467335 was 
observed indicating an irreversible inhibition mechanism. Inhibition constants for irreversible 
enzyme inhibition were determined and resulted in an inhibition constant (KI) of 2.01 ZM 
and an inactivation rate constant (kinact) of 0.087 min-1 [n00259383].
A more detailed description is provided in the current Investigator’s Brochure (IB) 
[c04751792].
Clinical experience
A 4-week phase I study [c08854973] investigated safety, tolerability, PK and PD of multiple 
doses of 10 mg, 15 mg and 20 mg q.d. administered for 28 days. The study included 
36 healthy subjects (28 males, 8 females of non-childbearing potential) with 12 subjects 
assigned to one of three treatment groups with 9 subjects on active and 3 on placebo. 
Repeated doses of 10 mg, 15 mg or 20 mg BI 1467335 q.d. have been well tolerated with 
similar frequencies of AEs across all dose groups including placebo. The intensity of AEs 
was mainly mild (CTCAE grade 1), there were no SAEs. 
There were no noteworthy changes in vital signs or laboratory parameters. A centralized ECG 
evaluation did not show any relevant individual QT prolongation, i.e. QTcF increase of 
greater 60 ms from baseline or an absolute QT or QTc value greater than 500 ms. Both 
graphical and explorative systemic BI 1467335 exposure versus QTcF, QTcN, and HR 
analyses did not suggest relevant drug related signals [c16567028].
The safety observed after 4 weeks is in line with results of a preceding combined SRD and 
MRD study [c09036683] investigating single doses of 1-20 mg BI 1467335 (HCl, 
corresponding to 0.885 – 17.7 mg free base) and multiple doses (14 days) of 3 to 10 mg 
BI 1467335 HCl q.d. (corresponding to 2.66 to 8.85 mg free base). The data are also in line 
with a single dose study investigating the food effect of a tablet formulation at a dose of 
10 mg q.d. [c17150058].
Two further Phase I studies have been finally reported. These studies provide additional 
safety information to support the dose regimen of the planned study. 
Study 1386-0002 [c25844331] investigated the influence of moderate renal impairment on 
the pharmacokinetics of multiple doses in comparison to a matched control group with 


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normal renal function. The study included altogether 20 participants in the trial, 10 subjects 
with moderate renal impairment and 10 subjects with normal renal function. All subjects 
received 10 mg of BI 1467335 over 4 weeks. In the moderate group and in the normal group, 
2 of 10 subjects (20%) were reported with at least one treatment-emergent AE (TEAE). No 
AEs leading to discontinuation, no AEs of special interest, no other significant AEs 
(according to ICH E3), and no serious AEs were reported in this trial. Reported TEAEs were 
headache, vomiting, and pruritic rash. All TEAEs were resolved by the end of trial. There 
were no clinically relevant findings with respect to safety laboratory parameters, vital signs, 
body weight and ECG.
Study 1386-0011 [c23797175] explored the basic pharmacokinetics of BI 1467335, its 
metabolites, [14C]-radioactivity, including mass balance, excretion pathways and metabolism 
following a single oral dose of 10 mg [14C]BI 1467335 on Day 1 or on Day 28 following a 
preceding multiple dose treatment of 10 mg QD from Day 1 to Day 27. The study included 
16 healthy male subjects with 8 subjects receiving multiple doses. Subjects assigned to the 
multiple dose group continued treatment from Day 29 up to Day 39 (maximum duration). In 
the multiple dose part of the trial, 2 subjects were reported with drug-related headache. There 
were no SAEs, protocol-specified AESIs, or other significant AEs (according to ICH E3). 
Furthermore, there were no other clinically relevant findings with respect to safety laboratory 
parameters, ECG recordings, or vital signs.
Pharmacokinetics in healthy subjects
Following both single and multiple doses up to 20 mg, BI 1467335 displayed both time 
dependent and greater than dose proportional kinetics. Following once a day dosing, steady-
state was attained by Day 14 following 15 and 20 mg and attained around Day 28 following 
10 mg. Renal clearance of parent drug was independent of dose or study day.
Following both single and multiple doses up to 20 mg, Cmax and AUC0-24 of BI 1467335 
increased in a more than dose proportional manner on Days 1, 14 and 28. On Day 28, gMean 
AUC0-24 and Cmax values were approximately 7.9- and 3.5 fold -higher for the 20 mg dose 
group, (2940 nmol h/L and 255 nmol/L), compared to the 10 mg dose group, (373 
nmol h/L and 72.1 nmol/L). In comparison, the increase from 15 to 20 mg was less 
pronounced: AUC0-24 and Cmax on Day 28 was approximately 1.7 and 1.3-fold higher for the 
20 mg dose group (2940 nmol h/L and 255 nmol/L) compared to the 15 mg dose group 
(1720 nmol h/L and 189 nmol/L).
Following repeat oral dosing, BI 1467335 displayed time dependent kinetics. Systemic 
BI 1467335 exposures accumulated more than predicted from single oral dose kinetics. 
Quantifiable BI 1467335 concentrations could be measured in all subjects up to 8, 12 and 
24 h postdose for 10, 15 and 20 mg dose groups respectively on Day 1, and throughout the 
24 h dosing interval on Days 14 and 28 for all dose groups.
The observed apparent elimination half-life (gMean), during the dosing interval, for 
BI 1467335 was significantly shorter on Day 1 (<2 h for all dose groups) compared to 
Days 14 and 28, (<3 h following 10 mg, <7.6 h following 15 mg and 20 mg doses) which 
may represent different elimination phases.


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Despite the short apparent half-lives during the 24 h dosing interval, BI 1467335 exposures 
(depicted by Cmax and AUC0-24) significantly accumulated following q.d. dosing. For 10 mg 
q.d., Cmax increased by approximately 26-fold on Day 14 and 40-fold on Day 28 compared to 
Day 1 values, and AUC0-24 increased by approximately 70-fold on Day 14 and 159-fold on 
Day 28. For 15 mg q.d. dosing, Cmax increased by approximately 17-fold on Day 14 and 
19-fold on Day 28, and AUC0-24 increased by approximately 83-fold on Day 14 and 95-fold 
on Day 28. For 20 mg q.d. dosing, Cmax increased by approximately 11-fold on both Days 14 
and Day 28, and AUC0-24 increased by approximately 87-fold on Day 14 and 74-fold on 
Day 28.
Following 10 mg q.d., Cmax and AUC0-24 are approximately 54% and 124% higher 
respectively on Day 28 compared to that on Day 14, whereas following 15 mg and 20 mg 
q.d., Cmax and AUC0-24 values are comparable on Days 14 and 28 suggesting steady state is 
attained after 14 days. Following 10 mg q.d., Day 28 is predicted to be either close to or at 
steady state.
For a more detailed description of the BI 1467335 profile, please refer to the current 
Investigator’s Brochure (IB) [c04751792].
1.2.2
Phenelzine (Nardil®)
Phenelzine (Nardil®) is a non-selective and irreversible monoamine oxidase (MAO) inhibitor
and indicated in depressive disorders as second line treatment. As non-selective irreversible 
MAO-inhibitor phenelzine inhibits intestinal MAO A and therefore will serve positive 
control in the planned study. Phenelzine has been marketed for about 10 years with a well-
established safety profile derived from a large patient population. Phenelzine treatment is 
associated with a high incidence of common side effects, in particular in combination with 
other drugs such as sympathomimetic or serotoninergic agents. Common side effects are 
mainly related to CNS (e.g. dizziness, headache, drowsiness) or GI tract (e.g. constipation, 
dry mouth, GI disturbances). As an irreversible MAO inhibitor phenelzine increases the risk 
of hypertensive crisis after ingesting food with high tyramine concentration.
The intended dose of 15 mg BID (daily dose 30 mg) of the planned study is below the 
recommended therapeutic starting dose of 45 mg/day (maintenance dose between 60 mg and 
90 mg/day). 
For a more detailed description of the phenelzine profile, please refer to the current SmPCs
[R19-1594, R19-1659].
1.2.3
Tyramine 
Tyramine is a biogenic amine, naturally occurring in multiple foods and beverages and 
produced due to decarboxylation of the amino acid tyrosine (fermentation and decay). High 
amounts of tyramine are found e.g. in tap beer, yeast, aged meat, aged cheese or red wine. 
Under physiological conditions alimentary tyramine is degraded by MAO-A to prevent 
systemic uptake. Tyramine may act as an indirect sympathomimetic agent. Tyramine is a 
substrate for the noradrenaline transporter molecule situated in the plasma membrane of 
sympathetic nerves and adrenal medulla, as well as the vesicular transporter situated in the 


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membrane of storage vesicles. The initial transport of tyramine molecules into the neuron 
activates reverse transport of noradrenaline molecules situated in the cytoplasmic 
compartment just inside the plasma membrane, and tyramine releases monoamines stored in 
vesicular storage granules. This increased release of noradrenaline may lead to 
vasoconstriction and increase in blood pressure. Tyramine has also been reported to cause 
headache, hypertensive crisis and even stroke [R19-1599].
In a preceding tyramine challenge study [R18-2841] there was one report of a cardiovascular 
event requiring hospitalisation (coronary syndrome) which was considered by the investigator 
to be probably related to the tyramine challenge. Since this study included subjects up to an 
age of 70 years, this may have increased the risk to include a subject with an asymptomatic
coronary disease which became symptomatic after the tyramine related sympathomimetic 
stimulation. Therefore, in study 1386-0016 we will limit the upper age range to 45 years. This 
is considered to mitigate the risk of conducting the study in a subject with a hidden coronary 
disease. Furthermore, the shallow tyramine dose escalation, the stop of further dose 
escalation at TYR30, as well as the possibility to limit or stop tyramine related 
sympathomimetic effects by using a non-selective -blocker, should avoid overshooting 
sympathomimetic effects.
1.2.4
Residual Effect Period
The Residual Effect Period (REP) is the period after the last dose with measurable drug levels
and/or pharmacodynamics effects still likely to be present. The REP of BI 1467335 is not
known for this clinical trial. Therefore all AEs reported until the end of trial examination (last
per protocol contact) will be considered on treatment. This rule will be also applied for 
subjects treated with phenelzine.
1.3
RATIONALE FOR PERFORMING THE TRIAL
An observed inhibition of MAO-A catalyzed kynuramine deamination by BI 1467335 was 
shown to be reversible. Although the in-vitro finding of a reversible inhibition of MAO-A 
was considered to be of remote clinical relevance, subjects and patients in ongoing studies 
were nevertheless advised to avoid the consumption of tyramine-rich food while on treatment
with BI 1467335.
In case of a relevant MAO-A inhibition, dietary tyramine may escape from metabolic 
inactivation resulting in systemic noradrenergic effects, such as peripheral vasoconstriction, 
increase of systolic blood pressure or an increase of heart rate.
The planned study will be conducted as part of the overall risk assessment for treatment with 
BI 1467335 to conclusively demonstrate that multiple doses of BI 1467335 at therapeutic and 
supratherapeutic dose levels do not affect intestinal MAO-A activity in humans, thus 
excluding the necessity for dietary restrictions related to potential MAO-A inhibition.
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 further clinical development of


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BI 1467335 in upcoming phase II and III studies. 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 be 
approximately 500 mL and thus does 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.
As part of the screening procedure, subjects will receive increasing oral doses of up to 
700 mg tyramine. Under physiological conditions alimentary tyramine is completely 
inactivated by intestinal MAO-A, due to the limited amount of tyramine in food. For the 
challenge test, it is intended to exceed the individual intestinal MAO A capacity to achieve a 
systemic availability of oral tyramine. Tyramine acts as an indirect sympathomimetic agent 
by displacing noradrenaline from vesicles of adrenergic nerves. This leads to vasoconstriction 
and increase in blood pressure, and may cause headache and even hypertensive crisis 
[R19-1599]. Due to the design of the planned study with a shallow dose escalation, the stop
of further tyramine dosing at TYR30, and the possibility to counteract the sympathomimetic 
effects with a non-selective -blocker, the risk of overshooting sympathomimetic effects (in 
particular the risk for hypertensive crisis) is considered remote. This should be also true for 
the occurrence of cardiac events by only including young healthy subjects at the age of 
Y 45 years.
Drug-related risks and safety measures
BI 1467335
BI 1467335 could cause on-target toxicity as its anti-inflammatory effects may reduce the 
immune response and thus worsen infections. However, a deleterious effect relating to a 
reduction in leukocyte or lymphocyte migration was not seen in any of the preclinical models
and also not in patients or subjects exposed to BI 1467335.
The human safety and tolerability profile in male and female healthy subjects was 
satisfactory for multiple doses given over 28 consecutive days of up to 20 mg of BI 1467335 
in study 1386.8 (see Section 1.2). There were no deaths or other serious adverse events. 
Adverse events, mostly reported as mild (CTCAE grade 1), had no apparent dose or exposure 
relationship. In view of the non-proportional increase of exposure there is an about 5-fold 
safety margin between the highest exposure at 20 mg q.d. and the exposure with 15 mg of 
BI 1467335 q.d. of the planned study.
It should be highlighted that the safety profile across all phase I studies was comparable. 
There were in particular no SAEs or reports of possibly dose limiting AEs.


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Phenelzine (Nardil®)
Subjects may receive as positive control phenelzine for up to 19 days. The selected doses of 
15 mg BID is below the recommended starting dose of 15 mg TID. The subjects to be 
included in the study will comply with the precautions or contraindications for phenelzine 
treatment (e.g. hepatic disease, alcoholism, diabetes mellitus, asthma, hyperthyroidism etc.).
Common side effects of phenelzine are related to CNS, gastrointestinal tract and may also 
include postural hypotension and edema [R19-1594, R19-1659]. Subjects will be closely 
monitored for the occurrence of adverse events, with discontinuation of treatment in case of 
possibly drug related AEs of severe intensity.
DILI
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.
Summary of benefit-risk assessment
In previous trials in healthy subjects, multiple oral doses of up to 20 mg BI 1467335 were 
safe and well-tolerated. Because of the non-proportional increase of the exposure, this results 
in a huge safety margin between the exposure at the already tested maximum doses and the 
maximum dose of 15 mg of BI 1467335 in the planned study.
The treatment with phenelzine for up to 19 days using a dose regimen of 15 mg BID (daily 
dose 30 mg) is below the recommended starting dose and, based on a vast body of clinical 
experience, considered to be safe. However, as precautious measure subjects assigned to 
phenelzine treatment will be hospitalized while on treatment.
The trial design is optimized to collect relevant information on intestinal MAO-A activity
upon treatment with BI 1467335 without exposing participating volunteers to undue risk.
There is always the potential of serious adverse events (SAEs) occurring with intake of any 
trial medication. Risks to subjects will be minimized and addressed by eligibility criteria, 
safety laboratory examinations, ECG and vital sign measurements, in-house observation 
periods, and verbal communication concerning AEs.
If the investigator should have any clinical concern, the safety of the subjects will be of 
paramount importance. The investigator has the discretion to remove subjects from the study 
should there be any safety concerns or if the subject’s wellbeing is at jeopardy.


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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 the study is investigate the effect of escalating doses of oral tyramine 
on systolic blood pressure (SBP) at baseline and following an oral treatment with BI 1467335 
up to 39 days at a dose of 10 mg or 15 mg once daily compared to placebo and phenelzine 
(Nardil®) as positive control.
Further objectives are the exploratory evaluation of pharmacokinetics and the evaluation of 
safety and tolerability.
2.1.2
Primary endpoint
Primary endpoint of the study is the tyramine sensitivity factor (TSF), defined as ratio of the 
tyramine dose causing an increase of systolic blood pressure (SBP) G 30 mmHg for at least 3 
consecutive measurements (TYR30) at baseline and at steady state following multiple oral 
doses of BI 1467335, placebo or phenelzine.


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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 1467335 and phenelzine (Nardil®) will be assessed based on:
#
Adverse events (including clinically relevant findings from the physical examination)
#
Safety laboratory tests
#
12-lead ECG
#
Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
In total, 62 healthy male and female subjects are planned to participate in this multiple dose 
study.
The primary outcome of the study will be the tyramine sensitivity factor (TSF), which is 
defined as the ratio of the tyramine dose causing an increase in systolic blood pressure (SBP) 
G 30 mmHg for at least 3 consecutive measurements (TYR30) at baseline and following a 
treatment of 28 days with BI 1467335 or placebo QD, or 7 days with phenelzine BID. A 
treatment duration of 28 days is required for BI 1467335 to reach steady state, whereas 
7 days is considered sufficient for phenelzine.
As part of the screening procedure subjects will be challenged with escalating oral doses of 
tyramine. Tyramine doses will be escalated from 10 mg to 700 mg QD (25, 50, 100, 200, 
300, 400, 500, 600, 700 mg) on a daily basis. For each subject, the tyramine dose escalation 
will be stopped when an increase of systolic blood pressure (SBP) G 30 mmHg for at least 3 
consecutive measurements is measured (i.e. TYR30). Participants who will not attain the 
predefined target elevation in SBP within 4 hours after the highest tyramine dose (700 mg) 
will not be included in the study.
Subjects considered eligible to enter the study will be assigned to one of three dose groups. 
The three dose groups to be evaluated are outlined in Table 3.1: 1.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
BI 1467335
BI 1467335
Phenelzine
(Nardil®)
Daily dose (mg)
10
15
30
Posology
1-0-0
1-0-0
1-0-1
Treatment duration
Up to Day 39
Up to Day 39
Up to Day 19
Number of subjects
24
24
14
Subjects receiving placebo
8
8
0
Subjects receiving active drug
16
16
14
Dose Group 1 and 2 consists of 24 subjects each, with 16 subjects per dose group assigned to 
BI 1467335 (active drug) and 8 subjects assigned to placebo. Both BI 1467335 dose groups 
will be conducted according to a double-blind, randomised, multiple-dose, placebo-
controlled within dose groups, parallel group design.
Dose Group 3 will be conducted open-label with no placebo control, and consists of 
14 subjects receiving the same treatment of phenelzine as positive control (comparator).


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From Day 29, for the BI treatment and placebo arms, and Day 8 for the phenelzine arm, 
tyramine challenge will be repeated with escalating doses from 5 mg to 700 mg until TYR30 
has been established. Concomitant to the tyramine challenge subjects will continue with the 
intake of their assigned medication, resulting in a maximum treatment duration of up to 19 
days (on Day 19 intake of phenelzine only in the morning) for the phenelzine dose group and 
up to 39 days for the BI 1467335 dose groups.
The study will start with subjects of the phenelzine group. After completion of at least 8 
subjects of the phenelzine group, subjects of all dose groups may enter the study.
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
In both BI 1467335 dose groups, double-blind conditions regarding the subject’s treatment 
(active drug or placebo) are maintained within each dose group. Although the current dose 
level will be known to subjects and investigators, the risk of an observer bias with regard to
dose dependent effects and the primary endpoint (TSF) is considered low. The use of placebo 
will allow estimating the impact of individual factors on the results of the tyramine challenge.
Phenelzine as an unselective MAO-inhibitor was consistently shown to increase TSF
[R18-2841] and phenelzine was therefore selected as positive control. Because of the 
expected pronounced effect on TSF a reliable blinding of the phenelzine treatment is 
considered not applicable, and therefore this dose group will be conducted open label. The 
anticipated effects on TSF in the phenelzine treatment group will serve as a benchmark to 
conclude about effects on TSF in the BI 1467335 dose groups. As a validation of study 
conduct, the study will start with subjects of the phenelzine group, before subjects of the 
BI 1467335 dose groups may enter the study.
Dosing duration for BI 1467335 and phenelzine is considered sufficient to achieve steady-
state drug exposure and to exclude transient effects.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 62 healthy male and female subjects (at least 30% of each sex) 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 
2.
Age of 18 to 45 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 before the first 
administration of trial medication until 30 days after trial completion:
-
Use of adequate contraception, e.g. any of the following methods plus condom:
implants, injectables, combined oral or vaginal contraceptives, intrauterine device
(in case of oral contraceptives start of contraception at least 30 days before 
administration of trial medication)
-
Sexually abstinent
-
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 33,4 U/L and estradiol 
below 71,6 pmol/L is confirmatory)
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, with their 
partner, they must comply with the contraceptive requirements detailed above.
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 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 assessed as clinically relevant by the investigator


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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
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)
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 20 g per day for females and 30 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 
23. Use of MAO inhibitors within 90 days before tyramine dosing
24. Use of fluoxetine within 5 weeks before tyramine dosing
25. Use of over-the-counter sympathomimetic or grapefruit products within 7 days before 
tyramine dosing
26. Subject has a known intolerability to tyramine-containing foods
27. At screening, no increase of systolic blood pressure > 30 mmHg during tyramine 
challenge at the highest tested dose of 700 mg tyramine


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Female subjects will not be allowed to participate, if any of the following apply:
28. Positive pregnancy test, pregnancy, or plans to become pregnant within 30 days after 
study completion
29. Lactation
For study restrictions, refer to Section 4.2.2.
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 1.2.4), 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.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.6.2.4.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. 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
3.
The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4.
The subject can no longer receive trial treatment for medical reasons (such as 
pregnancy, surgery, adverse events, or diseases)


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5.
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
6.
The subject experiences a serious adverse reaction which is considered at least possibly 
related to the IMP administration
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 
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 t any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals
2. 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
3. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate conduct 
of the trial
4.
The sponsor decides to discontinue the further development of the investigational 
product
5.
Severe non-serious adverse reactions (i.e. severe non-serious adverse events considered 
as, at least, possibly related to the IMP administration) in two subjects in the same dose 
group, independent of within or not within the same system-organ-class.
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).


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3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the clinical trial lead together with the trial 
pharmacokineticist and the trial statistician are to decide if and how many subjects will be 
replaced. Replacement of subjects should always be done in mutual agreement with the 
principal investigator. A replacement subject will be assigned a unique study 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
The investigational product BI 1467335 or placebo has been manufactured by BI Pharma 
GmbH & Co. KG. BI 1467335 doses will be calculated as a free base of the BI 1467335 salt,
with 10 mg BI 1467335 free base equals to 11.3 mg BI 1467335 HCl salt and 15 mg BI 
1467335 free base equals to 16.95 mg BI 1467335 HCl salt.
Phenelzine (Nardil®) is as a non-selective MAO-inhibitor and approved for the treatment of 
major depressive disorder. Nardil® will be used as positive control.
The provoking agent tyramine has been manufactured by 
4.1.1
Identity of BI Investigational Medicinal Products, reference products and 
provoking agent 
The characteristics of the test product is given below:
Substance:
BI 1467335
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology:
2-0-0 / 3-0-0
Route of administration:
oral
Duration of use:
up to 39 days
The characteristics of the reference product (placebo) is given below:
Reference 
Substance:
Placebo matching in size and weight to 5 mg tablet
Pharmaceutical formulation: Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
2-0-0 / 3-0-0
Route of administration:
oral
Duration of use:
up to 39 days


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Competitor
Substance:
Phenelzine sulfate
Pharmaceutical formulation: Film-coated tablet
Source:
Erfa Canada Inc. [Nardil®]
Unit strength:
15 mg 
Posology:
1-0-1, on Day 19 1-0-0
Route of administration:
oral
Duration of use:
up to 19 days (Day 19 QD)
The characteristics of the provoking agent tyramine (NIMP) is given below:
Substance:
Tyramine (quality food grade)
Pharmaceutical formulation: Capsules
Source:
Unit strength:
5 mg to 160 mg
Posology:
1-0-0 
Route of administration:
oral
Duration of use:
up to 22 days (screening 10 days, at steady state 12 days)
4.1.2
Selection of doses in the trial
An oral dose of 10 mg corresponds to the maximum dose tested in ongoing phase II studies 
[c08980589]. The oral dose of 15 mg BI 1467335 (calculated as free base) is below the 
already tested highest oral dose of 20 mg of BI 1467335 for 4 weeks in healthy subjects. In 
healthy volunteers, this dose was safe and well-tolerated (Section 1.2).
A daily dose of 30 mg phenelzine, a dose below the initial starting dose in patients, was 
shown to provide a sufficient effect on TSF in healthy subjects [R18-2841].
The tyramine dose from 5 mg to 700 mg is based on published information indicating that a 
sufficient number of otherwise eligible subjects should attain TYR30.
In summary, the selected doses and the duration of the various treatments are considered 
adequate for the objectives of the current trial.
4.1.3
Method of assigning subjects to treatment groups
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 3). For this purpose, numbers of the randomisation 
list will be allocated to the subjects. Subjects are then assigned to a treatment sequence
according to the randomisation list.
The randomisation list will be provided to the trial site in advance.


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Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a parallel-group multiple dose study. 
All subjects assigned to Dose Group 1 and 2 (BI 1467335 or placebo) will receive the 
treatments in a double-blind fashion. The treatments to be evaluated are outlined in Table 
4.1.4: 1 below.
Table 4.1.4: 1
Dosage and treatment schedule (BI 1467335 or placebo)
Treatment
Substance
Formulation
Unit strength
Dosage
Total daily dose
T (Test)
BI 1467335
Film-coated 
tablet
5 mg
2 tablets (5 mg) q.d. for 
up to 39 days
10 mg 
T (Test)
BI 1467335
Film-coated 
tablet
5 mg
3 tablets (5 mg) qd for 
up to 39 days
15 mg 
R (Reference)
Placebo
Film-coated 
tablet
n.a.
n.a., dose regimen as 
Test treatment
n.a.
All subjects assigned to Dose Group 3 (phenelzine) will receive the treatments in an open 
fashion. The treatment to be evaluated is outlined in Table 4.1.4: 2 below.
Table 4.1.4: 2
Dosage and treatment schedule (phenelzine)
Treatment
Substance
Formulation
Unit strength
Dosage
Total daily dose
C 
(Competitor)
Phenelzine 
sulfate 
(Nardil®)
Film-coated 
tablet
15 mg
1 tablet (15 mg) BID for 
up to 18 days, QD on 
Day 19
30 mg
All subject participating in the study will undergo a tyramine challenge receiving escalating 
daily doses of 5 mg to 700 mg tyramine as capsules (see Section 5.6.1). Tyramine intake will 
be done under fasting conditions (10 h prior to dosing) because of an established food effect.
In principal, the so-called four-eye principle (two-person rule) should be applied for 
administration of trial medication at the study site, while intake under ambulatory conditions 
will be monitored by phone contacts (e.g. text message) between study site and subject. For 
the purpose of four-eye principle, one authorised employee of the trial site should witness the 
administration of trial medication, and – if applicable – its preparation (e.g. reconstitution), if 
correct dosage cannot be ensured otherwise.


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4.1.5
Blinding and procedures for unblinding
For Dose Group 1 and 2, the trial is designed double-blind. Neither subject nor investigator 
will be aware of the trial treatments. For the blinded segment of this trial the investigator will 
be supplied with a set of sealed envelopes containing the medication codes. The envelopes 
will be kept unopened at the study site until the end of data collection or, in an emergency 
requiring the investigator to know a subject’s treatment allocation, opened with appropriate 
documentation. At the trial close-out visit, all envelopes will be collected. Persons directly 
involved in the clinical conduct of the trial will not have access to the treatment allocation 
prior to database lock.
At the trial site, access to the randomisation schedule is restricted to unblinded pharmacists 
and pharmacy staff members. Access to the codes will be controlled and documented by a 
signed confidentiality statement, which will be stored in the TMF. Persons directly involved 
in the clinical conduct of the trial will not have access to the treatment allocation prior to 
database lock.
For Dose Group 3, the 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 for Dose Group 3 will not be provided, because the 
dose of trial medication is known to investigators and subjects.
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical trial lead, clinical monitor, data 
manager, statistician, bioanalyst, pharmacokineticist, pharmacokinetic analyst, 
pharmacometrician, drug metabolism scientist as well as dedicated CRO personnel). The 
objective of the trial is not expected to be affected.
4.1.6
Packaging, labelling, and re-supply
4.1.6.1
BI 1467335 or placebo
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packaging and the description of the label, refer to the ISF.
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.
4.1.6.2
Phenelzine (Nardil®)
The marketed product will be used for the study. Handling of the compound will be assumed 
by
 local pharmacy.


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4.1.6.3
Tyramine
Tyramine (as capsule) will be used as challenging agent.
will ensure that the 
challenging agent will be of appropriate quality for the purposes of the trial, taking into 
account, among other things, the source of the raw materials and any repackaging.
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
after 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 all unused or partially used drug supplies have been 
returned by the clinical trial subject and that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.


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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, 
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 except for hormonal contraceptives or ovary 
hormone replacement. However, in case of AEs subjects will be treated as necessary 
including concomitant or rescue therapies.
All concomitant or rescue therapies will be recorded (including time of intake on study days) 
on the appropriate pages of the CRF. Limited amounts of paracetamol are allowed when 
prescribed by a 
 physician.
Since BI 1467335 demonstrated in vitro to be an irreversible inhibitor of monoamine oxidase 
B (MAO-B), any concomitant medication should be only used after consultation and 
approval of the medical investigator. This is also true for phenelzine as an irreversible 
inhibitor of MAO-A and MAO-B.
If required subjects will be kept under constant supervision at the trial centre or transferred to 
hospital until all results of the evaluations have returned to a medically acceptable level.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. In addition, subjects are required to refrain from smoking while 
hospitalized.
For fasting times before drug administration, see Section 4.1.4. For fasting times before 
safety laboratory investigations see Section 5.2.3. Because of the known food effect, intake of 
tyramine will be conducted under fasted conditions. During tyramine challenge as well as on 
Day 28 (PK assessment) starting from 1 hour before until 2 h after drug administration fluid 
intake is not allowed except from the 240 mL water administered with the drug intake. 
Poppy-seed containing products should not be consumed starting 2 days before first tyramine 
challenge on Day -10 until discharge from the trial. 
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products including St. John's wort (Hypericum perforatum) are not permitted starting 7 


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days before the first administration of trial medication (i.e. Day -10) until after the last PK 
sample is collected.
Alcoholic beverages are not allowed 48 hours before start of tyramine challenge, before 
administration of the compound, before each admission and during the clinic period. During 
ambulatory phases alcohol consumption is restricted to 24 units a week.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed at days of inhouse confinement.
Subjects should be advised to avoid foods containing a very large amount of tyramine 
(especially found in fermented food). These include for example aged cheese, aged meats, 
soybean products (soy sauce), red wine, tap (draft) beer, St John’s Wort, pickled herring, 
sauerkraut (fermented cabbage), and tryptophan supplements.
Excessive physical activity (such as competitive sport) should be avoided starting 4 days 
before the first administration of trial medication (i.e. Day -10) until the end of trial 
examination.
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 monitored by either administration of all trial medication in the study 
centre under supervision of the investigating physician or a designee or during ambulatory 
periods by daily phone contact (e.g. text message) between study site and subject. The 
measured plasma concentrations of trial medication will provide additional confirmation of 
compliance.
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, relevant medical history and concomitant therapy, review of 
inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests
(including drug screening and pregnancy test in females), and a physical examination. At the 
end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory tests
(including pregnancy test in females), and a physical examination including determination of 
weight.
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 
(Carescape VC150, GE Medical Systems) 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. 


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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.
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
X
Automated relative
WBC 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Manual differential 
WBC (if automatic
relative WBC is 
abnormal and 
considered clinically 
relevant by the 
investigator), 
according to local 
procedure
Neut. Poly (segs); Neut. Poly (segs); Neutrophils Bands;  
Neutrophils Bands; Eosinophils/Leukocytes; Eosinophils; 
Basophils/ Leukocytes; Basophils; Monocytes/ Leukocytes; 
Monocytes; Lymphocytes/Leukocytes; Lymphocytes.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase (total)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
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
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
X
X
X
Urinalysis1 (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine haemoglobin (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
X
X
X
X
X
X
X
X
X
Urine sediment1
(microscopic 
examination if 
haemoglobin, 
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 and Visit 2 screening examination, Day -11) 
B: parameters to be determined at Visit 3 on Day 1, 14, 28 for Dose Group 1 and 2,
     parameters to be determined at Visit 3 on Day 1, 7 for Dose Group 3
     (for time points refer to Flow Chart)
C: parameters to be determined at Visit 4 (end of trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be repeated throughout the study (see Flow Chart).


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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
XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Alcohol
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Pregnancy test (serum)
Beta human chorionic gonadotropin (beta-HCG)
Postmenopausal Status (blood)
FSH, estradiol
The results of the drug screening and alcohol test will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at the safety 
laboratory of 
 
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (Mortara ELI 250c) at the time points given in the 
Flow Chart.
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. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven.
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.


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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
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous bedside 
monitoring (Mortara Surveyor S12) predose and about 4 h following tyramine administration.
This continuous ECG monitoring supports the early detection of adverse events such as
clinically relevant bradycardia, tachycardia, or arrhythmia at the trial site. Beyond this
clinical evaluation at the trial site, no further data collection or analyses will be performed 
based on continuous ECG monitoring.
ECG data from continuous ECG recording will not transferred to the clinical trial database. 
Abnormal findings during continuous ECG recording will be recorded as AEs if judged 
clinically relevant by the Investigator.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
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.


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Serious adverse event
5.2.6.1.2
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
#
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
AEs considered ‘Always Serious’
5.2.6.1.3
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 Section 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. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
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.


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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 G10 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 via 
eDC. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure 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.
Intensity (severity) of AEs
5.2.6.1.5
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.
Causal relationship of AEs
5.2.6.1.6
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)


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
#
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
#
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger
#
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)
#
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
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.


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#
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.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax 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.
Information required
5.2.6.2.3
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.
Pregnancy
5.2.6.2.4
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.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires 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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5.6
OTHER ASSESSMENTS
5.6.1
Tyramine challenge
Tyramin challenge will be conducted predose (Day -10 to Day -1) and during steady state 
(Day 8 to Day 19 for Dose Group 3, Day 29 to Day 39 for Dose Groups 1 and 2).
Before start of the tyramine challenge, subjects have rested for at least 5 min in a supine 
position. Systolic and diastolic blood pressures (BP) will be measured by a blood pressure 
monitor (Mortara Surveyor S12). Blood pressure will be measured approximately every 5
minutes during the 35 minutes preceding tyramine administration to determine the baseline 
SBP, i.e. mean of 3 consecutive measurements with a maximum range of 10 mmHg. If a 
stable SBP will not be obtained within the 35 minutes, the mean of all 7 readings will be used 
as the baseline value. 
After baseline SBP has been established, fasted subjects will receive a single oral dose of 
tyramine. Tyramine doses will be escalated from 10 mg to 700 mg QD (10, 25, 50, 100, 200, 
300, 400, 500, 600, and 700) on a daily basis. After each tyramine administration blood 
pressure will be again measured beginning 5 minutes after tyramine dosing and 
approximately every 5 minutes thereafter for at least 2 hours and then approximately every 
15 minutes for additional 2 hours. For each subject, the tyramine dose escalation will be 
stopped when an increase of systolic blood pressure (SBP) G 30 mmHg for at least 3 
consecutive measurements is measured (i.e. TYR30). Participants who will not attain the 
predefined target elevation in SBP within 4 hours after the highest tyramine dose (700 mg) 
will not be included in the study.
At steady state the tyramine challenge test will be repeated, starting with a lower tyramine 
dose of 5 mg in all dose groups. Further tyramine dose escalation is identical to the predose 
regimen, apart from an intermediate dose of 150 mg only exclusively in the phenelzine group. 
Subjects will continue with their assigned treatment (BI 1467335 or placebo, or phenelzine) 
which is administered simultaneously to the tyramine dose. For each subject, the tyramine 
dose escalation will be stopped as soon as TYR30 has been established (increase of SBP G 30 
mmHg for at least 3 consecutive measurements). In none of the subjects the tyramine dose 
will exceed 700 mg, even if TYR30 has still not been established.


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5.7
APPROPRIATENESS OF MEASUREMENTS
Tyrosine sensitivity factor (TSF) was shown to be a suitable tool for the assessment of drug 
induced MAO-A inhibition and has been considered appropriate for risk assessment (R18-
2841, R19-1593).


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All further measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety 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.


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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 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
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.
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, and physical examination, refer to Sections 5.2.3 to 5.2.6. For the tyramine challenge 
(Visit 2, hospitalisation from Day -12 up to Day -2; see Flowchart), results of this test are 
mandatory for final inclusion.
6.2.2
Treatment period
Dose Group 1 and 2 (BI 1467335 or placebo)
Each subject will receive a single dose of BI 1467335 or placebo from Day 1 to Day 28.
On Days 2 to 6, 8 to 14, 15 to 20 and 22 to 25, subjects are allowed to take their study 
medication at home if deemed appropriate by the investigator. On Day 6, Day 13, Day 20 and 
Day 25 participants will be admitted to the trial site and, due to assessments and dispensing 
of study medication in the morning of the next day, will overnight at the trial site. From the 
evening of Day 25, subjects will stay hospitalized. Tyramine challenge will start from Day 
29, with a maximum duration up to Day 39. As long as individual TYR30 has not been 
established subjects will continue their assigned study treatment (BI 1467335 or placebo).


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After TYR30 has been established, further treatment will be stopped and subjects are 
discharged from the study site.
Dose Group 3 (phenelzine)
Subjects will be hospitalized during the complete treatment period , no ambulatory intake of 
study medication is planned. Each subject will receive 15 mg phenelzine BID (daily dose 
30 mg) from Day 1 to Day 7. Tyramine challenge will start from Day 8, and will not exceed 
Day 19. Subjects will continue treatment with phenelzine up to TYR30 has been established. 
After TYR30 has been established, further treatment will be stopped and subjects are 
discharged from the study site.
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 Sections 5.2.2 to 5.2.5. Subjects who 
discontinue treatment before the end of the planned treatment period should undergo the
EoTrial Visit.
All abnormal values (including laboratory parameters) 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 main objective of this trial is to compare the primary endpoint tyramine sensitivity factor 
(ratio of TYR30 at steady state compared to TYR30 at baseline) as listed in Section 2.1.2
between the different treatment arms (BI 1467335 10mg, 15mg, Placebo and Phenelzine). 
The trial will be evaluated statistically by use of a linear model for the logarithmically 
transformed endpoint.
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 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The TSF between the treatments BI 1467335 10mg (T1), BI 1467335 15mg (T2), placebo (R) 
and Phenelzine (C) will be compared. Ratios of geometric means (T1/R), (T2/R) and (C/R), 
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.
#
Per protocol analysis set (PPS): This set includes all subjects in the treated set (TS) 
who provide at least one endpoint that was defined as primary and was not excluded 
due to a protocol violation relevant. Descriptive and model based analyses of the 
primary endpoint will be based on the PPS.


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Adherence to the protocol will be assessed by the trial team. Important protocol deviations
(IPD) categories will be suggested in the IQRM, IPDs will be identified no later than in the 
Report Planning Meeting, and the IPD categories will be updated as needed.
7.3.1
Primary endpoint analyses
Primary analyses
Descriptive statistics for the primary endpoint TSF will be presented.
The statistical model used for the analysis of the primary endpoint will be an analysis of 
variance (ANOVA) model on the logarithmic scale for each treatment relative to placebo. 
That is, the TSF will be log-transformed (natural logarithm) prior to fitting the ANOVA


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model. This model will include the fixed effect treatment (T1 and T2: treatment group, R: 
placebo, C: Phenelzine). The model is described by the following equation:
yk =  + %k + ek, where
yk = logarithm of response measured on treatment k,
 = the overall mean,
%k = the kth treatment effect, k = 1, 2, …,
ek = the random error term,
where e ~ N0,   i.i.d..
Point estimates for the ratios of the geometric means (T1/R), (T2/R) and (C/R) and
corresponding two-sided 90% confidence intervals (CIs) will be provided.
For TSF the difference between the expected means for log(test)-log(reference) 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.
7.3.2
Secondary endpoint analyses
Not applicable, the study does not evaluate secondary endpoints.
7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. 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.


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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 1.2.4) 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 
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. However, an informal exploratory analysis of TSF in the open 
label phenelzine group may be conducted if considered necessary.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.


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7.6
RANDOMISATION
Subjects within BI 1467335 dose groups (including Placebo) will be randomised stratified by 
gender to one of the 3 treatment arms in a 1:1:1 ratio. Subjects within the phenelzine 
treatment group (positive control without placebo control) will not be randomised. The block 
size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 62 subjects in the trial, because this sample size 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 coefficient of variation (gCV) for phenelzine [R18-2841] was roughly 86% for
the tyramine sensitivity factor.
For various assumptions around the gCV of 86%, 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.


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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 (N=32)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
80.0
1.67
100
60.06
166.50
80.0
1.67
150
90.09
249.75
80.0
1.67
175
105.11
291.37
80.0
1.67
200
120.12
333.00
80.0
1.67
600
360.36
998.99
86.0
1.72
100
58.31
171.49
86.0
1.72
150
87.47
257.23
86.0
1.72
175
102.05
300.10
86.0
1.72
200
116.63
342.98
86.0
1.72
600
349.88
1028.93
*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( ) ± #),
with e being the ratio (T/R) on original scale and f the distance from the estimate e 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 3.5.1.


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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 directive 
2001/20/EC, 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 his delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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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. See Section 4.1.5 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records 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 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 Clinical Trial Manager (CTM),
Clinical Research Associates (CRA), and investigators of participating trial sites
The trial medication (BI 1467335 or placebo) will be provided by the Clinical Trial Supplies 
Unit, BI Pharma GmbH & Co. KG, Biberach, Germany. Phenelzine treatment will be based 
on the marketed product (Nardil®), supply and distribution is managed by 
 
 
 
will also provide the challenging agent tyramine.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
The analyses of BI 1467335 concentrations in plasma will be performed at a suitable CRO.
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
P13-02280
Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment 
of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 
2012;10(8):837-858.
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pd f;2010.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R15-5365
Weston CJ, Shepherd EL, Claridge LC, Rantakari P, Curbishley SM, 
Tomlinson JW, Hubscher SG, Reynolds GM, Aalto K, Anstee QM, 
Jalkanen S, Salmi M, Smith DJ, Day CP, Adams DH. Vascular adhesion 
protein-1 promotes liver inflammation and drives hepatic fibrosis. J Clin 
Invest 2015;125(2):501-520.
R15-5697
Karim S, Liaskou E, Fear J, Garg A, Reynolds G, Claridge L, Adams DH,
Newsome PN, Lalor PF. Dysregulated hepatic expression of glucose
transporters in chronic disease: contribution of semicarbazide-sensitive 
amine oxidase to hepatic glucose uptake. Am J Physiol 
2014;307(12):G1180-G1190.
R15-6044
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K,
Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic
fatty liver disease: practice guideline by the American Association for the 
Study of Liver Diseases, American College of Gastroenterology, and the 
American Gastroenterological Association. Hepatology 2012;55(6):2005-
2023.
R15-6057
Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital
Stat Rep 2013;61(4):1-117.
R15-6070
Dharel N, Fuchs M. Nonalcoholic fatty liver disease - a major public health 
challenge for the 21st century. JSM Gastroenterol Hepatol 2014;2(2):1018.
R18-2841
Goren T, Adar L, Sasson N, Weiss YM. Clinical pharmacology tyramine 
challenge study to determine the selectivity of the monoamine oxidase type 
B (MAO-B) inhibitor rasagiline. J Clin Pharmacol 2010;50:1420-1428.
R19-1593
Marquet A, Kupas K, Johne A, Astruc B, Patat A, Kroesser S, et al. The 
effect of safinamide, a novel drug for Parkinson's disease, on pressor 
response to oral tyramine: a randomized, double-blind, clinical trial. Clin 
Pharmacol Ther 2012;924(4):450-457.


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R19-1594
Nardil tablets (Kyowa Kirin) (summary of product characteristics, updated 
06-Mar-2017). https://www.medicines.org.uk/emc/product/228/smpc/print 
(access date: 9 May 2019); 2017.
R19-1599
Anderson MC, Hasan F, McCrodden JM, Tipton KF. Monoamine oxidase 
inhibitors and the cheese effect. Neurochem Res 1993;18(11):1145-1149.
R19-1659
Nardil phenelzine sulfate tablets 15 mg (ERFA Canada) (product 
monograph, updated 11-Dec-2015); 2015.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c04751792
Investigator's 
Brochure: BI 1467335 in NASH and NPDR, 29.05.2018.
c08854973
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses of BI 1467335 in healthy 
male and female subjects (double-blind, randomised, placebo-controlled 
within dose groups), 1386.8, 05.10.2016.
c08980589
A multi-centre, double-blind, parallel-group, 
randomised, placebo controlled phase II a study to investigate safety, 
tolerability, pharmacodynamics, and pharmacokinetics of different doses of 
orally administered BI 1467335 during a 12-week treatment period 
compared to placebo in patients with clinical evidence of NASH, 1386.4,
12.09.2018.
c09036683
Single ascending dose and multiple ascending dose phase 1 
study of PXS-4728A administered orally in healthy adult males,
PXS-4728A-101, 13.11.2015.
c14141887
A Randomized, double-masked, placebo-controlled exploratory 
study to evaluate safety, tolerability, pharmacodynamics and 
pharmacokinetics of Orally administered BI 1467335 for 12 weeks with a 
12 week follow up period in patients with Non-proliferative diabetic 
retinopathy without center-involved diabetic macular edema (ROBIN 
study), 1386.12, 11.04.2019.
c16567028
Preliminary analysis 10+15 mg appendix 2, 
1386.8, 28.03.2017.
c17150058
Relative bioavailability of a 
BI 1467335 tablet compared to a BI 1467335 oral solution and the effect of 
food on the bioavailability of the tablet following oral administration (a 
randomised, open-label, single dose, three-way crossover trial in helathy 
male subjects, 1386.17, 09.11.2017.


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c23797175
A phase I, open-label, single and 
multiple dose trial to investigate metabolism and pharmacokinetics of 
[14C]BI 1467335 administered as oral solution in healthy male volunteers,
1386.11, 12.04.2019.
c25844331
Pharmacokinetics, safety and 
tolerability after multiple dose administration of BI 1467335 in subjects 
with moderate renal impairment and subjects with normal renal function 
(a mono-centric, open-label study in matched-group design), 1386-0002,
15.04.2019.
n00244592
BI 1467335: 4-week oral (gavage)
supplementary toxicity study in Sprague Dawley rats, 15B108, 06.07.2016.
n00247850
A Four-Week Oral Repeat Dose Toxicity and Toxicokinetic Study 
of PXS-4728A in Beagle Dogs, 53703-13-825, 04.11.2014.
n00257993
In vitro inhibition of MAO-A and MAO-B 
catalyzed kynuramine deamination by BI 1467335, A437/17LU, B6034, 
31.08.2017.
n00259383
Irreversible in vitro inhibition of MAO-B 
catalyzed kynuramine deamination by BI 1467335, A442/17LU, B6114, 
01.12.2017.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
27 June 2019
EudraCT number
EU number
2018-003965-32
BI Trial number
1386-0016
BI Investigational Medicinal 
Product(s)
BI 1467335
Title of protocol
A phase I parallel group study in healthy subjects to 
evaluate the effect of multiple oral doses of BI 
1467335 and phenelzine as positive control on blood 
pressure response to oral tyramine (double-blind, 
randomised, placebo-controlled design for BI 
1467335 treatment groups, open label for 
phenelzine)
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
Synopsis, Flow Chart and Section 5.6.1, Tyramine 
challenge
Description of change
In the phenelzine dose group the tyramine challenge 
test at steady state will include an intermediate dose 
of 150 mg.
Rationale for change
Treatment with the non-selective MAO inhibitor 
phenelzine is expected to significantly increase the 
TSF. Published data suggest, that subjects treated 
with phenelzine may have at steady state TYR30 
values between 100 and 200 mg. In these subjects an 
intermediate dose of 150 mg is considered to 
mitigate the risk of overshooting sympathomimetic 
effects.
With this amendment we have also corrected a few 
inconsistencies throughout the protocol. 


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11.2
GLOBAL AMENDMENT 2
Date of amendment
16 July 2019
EudraCT number
EU number
2018-003965-32
BI Trial number
1386-0016
BI Investigational Medicinal 
Product(s)
BI 1467335
Title of protocol
A phase I parallel group study in healthy subjects to 
evaluate the effect of multiple oral doses of BI 
1467335 and phenelzine as positive control on blood 
pressure response to oral tyramine (double-blind, 
randomised, placebo-controlled design for BI 
1467335 treatment groups, open label for 
phenelzine)
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
Flow charts,
Sections 1.4, 3.1, 4.1, 5.2.5.1, 5.6.1
Description of change
In the phenelzine group tyramine challenge may be 
conducted up to Day 19 instead of Day 18, this has 
been corrected throughout the protocol.
Addition of foot notes in the flow chart of the
BI 1467335 dose groups to further specify collection 
of predose PK and tyramine samples at steady state.
The blood pressure monitoring during the tyramine 
challenge test will be conducted with the device 
Mortara Surveyor S12 instead of Carescape VC 150.
Section 5.2.5.1 (assessment of vital signs) was 
removed, as this was already described in a previous 
section (section 5.2.2).
Rationale for change
This amendment corrects minor inconsistencies, 
mainly related to the tyramine challenge test.
In addition, redundant information was deleted.


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11.3
GLOBAL AMENDMENT 3
Date of amendment
02 September 2019
EudraCT number
EU number
2018-003965-32
BI Trial number
1386-0016
BI Investigational Medicinal 
Product(s)
BI 1467335
Title of protocol
A phase I parallel group study in healthy subjects to 
evaluate the effect of multiple oral doses of BI 
1467335 and phenelzine as positive control on blood 
pressure response to oral tyramine (double-blind, 
randomised, placebo-controlled design for BI 
1467335 treatment groups, open label for 
phenelzine)
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 (Phenelzine), footnote 9
2. Section 3.1 Overall Trial Design and Plan
3. Section 4.1.1 Identity of BI IMPs, reference 
products and provoking agent
4. Section 4.1.3 Method of assigning subjects to 
treatment groups
5. Section 4.1.4 Drug assignment and administration 
of doses for each subject, Table 4.1.4: 2
6. Section 4.1.5 Blinding and procedures of 
unblinding
Description of change
1. – 3. On day 19 Phenelzine will be given only 
at 8:00
4. Randomisation list will be provided to unblended 
pharmacist
5. On day 19 Phenelzine will be given only at 8:00
6. Unblinding of pharmacist to optimize a potential 
replacement subject to the correct assignment of 
study medication


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Rationale for change
1. Clarification of inconsistencies between Flow
chart and text body
2. - 6. Optimization of drug assignment


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11.4
GLOBAL AMENDMENT 4
Date of amendment
13 February 2020
EudraCT number
EU number
2018-003965-32
BI Trial number
1386-0016
BI Investigational Medicinal 
Product(s)
BI 1467335
Title of protocol
A phase I parallel group study in healthy subjects to 
evaluate the effect of multiple oral doses of 
BI 1467335 and phenelzine as positive control on 
blood pressure response to oral tyramine (double-
blind, randomised, placebo-controlled design for 
BI 1467335 treatment groups, open label for 
phenelzine)
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 and Synopsis: 
Name of Principal Investigator
Description of change
Name of Principal Investigator changed
Rationale for change
Delegation to a new Principal Investigator


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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c31618226-01
BI Trial No.:
1386-0016
Title:
A phase I parallel group study in healthy subjects to evaluate the
effect of multiple oral doses of BI 1467335 and phenelzine as
positive control on blood pressure response to oral tyramine
(double-blind, randomised, placebo-controlled design for BI 
1467335 treatment groups, open label for phenelzine)
Including revised protocol version 5 [c24752093-05]
Investigational
Product:
BI 1467335
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
16 JUL 2020 SIGNED
Version:
1
Page 1 of 21
Proprietary confidential information
2020 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.


Boehringer Ingelheim
TSAP for BI Trial No: 1386-0016
Page 2 of 21
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINT .......................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoints......................................................................................8
5.2.2
Secondary endpoints.............................................................................................8
5.3.2
Safety parameters .................................................................................................8
5.4
OTHER VARIABLES..........................................................................................8
5.4.1
Demographic and other baseline characteristics ...............................................8
5.4.2
Treatment compliance and treatment exposure ................................................8
6.
GENERAL ANALYSIS DEFINITIONS ............................................................9
6.1
TREATMENTS.....................................................................................................9
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................10
6.3
SUBJECT SETS ANALYSED...........................................................................11
6.5
POOLING OF CENTRES .................................................................................12
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................12
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................12
7.
PLANNED ANALYSIS......................................................................................13
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........13
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................14
7.3
TREATMENT COMPLIANCE........................................................................14
7.4
PRIMARY ENDPOINTS...................................................................................14
7.4.1
Primary analysis of the primary endpoint........................................................14
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoint ................................................................................................14
7.5
SECONDARY ENDPOINTS.............................................................................15
7.5.1
Key secondary endpoints....................................................................................15
7.5.2
Secondary endpoints...........................................................................................15
7.6.2
Safety parameters ...............................................................................................15
7.7
EXTENT OF EXPOSURE.................................................................................15
7.8
SAFETY ANALYSIS..........................................................................................16


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7.8.1
Adverse Events ....................................................................................................16
7.8.2
Laboratory data ..................................................................................................17
7.8.3
Vital signs.............................................................................................................17
7.8.4
ECG......................................................................................................................18
7.8.5
Others...................................................................................................................18
8.
REFERENCES....................................................................................................19
10.
HISTORY TABLE..............................................................................................21


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs, vital signs and safety 
laboratory data ....................................................................................................9
Table 6.2: 1
Handling of IPDs..............................................................................................11
Table 6.3: 1
Subject sets analyzed........................................................................................11
Table 10: 1
History table .....................................................................................................21


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
BI 
Boehringer Ingelheim
BP
Blood pressure
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important protocol deviations
IQRMP
Integrated quality and risk management plan
MedDRA
Medical Dictionary For Regulatory Activities
PD
Protocol deviation
PPS
Per protocol set
PR
Pulse rate
RAGe
Report appendix generator
SAE
Serious adverse event
SBP
Systolic blood pressure
SD
Standard deviation
SOC
System Organ Class
TS
Treated set
TSF
Tyramine sensitivity factor
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 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 will be stored in a trial database within Medidata Rave system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), 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, 
Certara USA Inc., Princeton, NJ, USA).


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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.
While the CTP lists both the ANOVA and the descriptive analyses of the primary endpoint as 
part of the primary analysis, this TSAP focusses on the ANOVA as primary analysis and 
declares the descriptive analyses as exploratory analyses.
Assessment of COVID-19 Impact
Due to the study interruption caused by the Covid-19 pandemic the decision was made to stop 
the study prematurely. This decision was based on the fact that the data from the 10 mg BI 
group was thought to be sufficient to adequately address the main study objective.
The study was permanently discontinued while the 15mg BI 1467335 group was still ongoing, 
due to lock down of the side. None of the subjects in the 15mg BI 1467335 group completed 
the tyramine challenge at visit 3. Therefore, TYR30 at steady state and the primary endpoint 
TSF are not available for the 15mg BI 1467335 group. As a consequence, the ratio of 15mg 
BI 1467335 (T2)/Placebo (R) (primary analysis of primary endpoint) can not be calculated.
For safety evaluation all data will be used.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint is the tyramine sensitivity factor (TSF), ratio of TYR30 at baseline and 
steady state, as defined in CTP Section 2.1.2.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Not applicable.
5.3.2
Safety parameters
Safety and tolerability of BI 1467335 and phenelzine will be assessed based on further safety 
parameters defined in Section 2.2.2.2 of the CTP:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure [BP], pulse rate [PR])
5.4
OTHER VARIABLES
5.4.1
Demographic and other baseline characteristics
CTP: At screening, the medical examination will include demographics, height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests (including drug screening and pregnancy test in females), and a physical 
examination.
Body mass index will be calculated as weight [kg] / height [m]2.
5.4.2
Treatment compliance and treatment exposure
Treatment compliance will not be analysed as a specific endpoint, cf. Section 4.3 of the CTP.
Treatment exposure is defined as the total dose and number of doses of BI 1467335, 
phenelzine and tyramine per subject.


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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.
All subjects will start by undergoing a "baseline" tyramine challenge receiving escalating 
daily doses of 5-700 mg tyramine until baseline TYR30 is reached. Baseline TYR30 is the 
tyramine dose causing an increase of systolic BP (SBP) ≥ 30 mmHg for at least 3 consecutive 
measurements compared with baseline SBP (baseline SBP is defined in Section 6.6).
Each subject is then planned to be treated with multiple doses of 10 mg or 15 mg BI 1467335 
or matching placebo up to 39 days or with phenelzine up to 19 days. Treatment is to be 
stopped once TYR30 at steady state is achieved. Therefore, starting on Day 29 for 
BI 1467335 and placebo arms and on Day 8 for phenelzine, the tyramine challenge is to be 
repeated until TYR30 at steady state is reached.
For statistical analyses of AEs the following separate analysis phases will be defined for each 
subject:
Table 6.1: 1
Analysis phases for statistical analysis of AEs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of tyramine
during Visit 2
On-treatment
Tyramine screening 
challenge
Tyr screening
Date/time of first 
administration of tyramine 
during Visit 2
Date/time of first 
administration of BI 
1467335, placebo or 
phenelzine respectively
On-treatment
BI,
Placebo or
phenelzine
Placebo,
10 mg BI,
15 mg BI or
Phen,
respectively
Date/time of first 
administration of BI 
1467335, placebo or 
phenelzine respectively
Date/time of first 
administration of tyramine 
during Visit 3 or
12:00 a.m. on day after last 
contact date whatever comes 
first
On-treatment
BI + tyramine,
Placebo + tyramine 
or
phenelzine + 
tyramine
Placebo + Tyr,
10 mg BI + Tyr,
15 mg BI + Tyr or
Phen + Tyr
respectively
Date/time of first 
administration of tyramine 
during Visit 3
12:00 a.m. on day after last 
contact date
AE displays in CTR Section 15.3, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 will 
present results for the on-treatment phase only.
In AE tables in CTR Section 15.3 (but not in Appendix 16.1.13.1.8.2 and Appendix 
16.1.13.1.8.3 AE tables), the following totals will be provided in addition: 

"Total on-trt", defined as the total over all on-treatment phases

“Total BI + Tyr", defined as the total over all on-treatment phases involving BI + Tyr


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
"Total BI", defined as the total over all on-treatment phases involving BI
Vital signs and safety laboratory data will be analysed by treatment group (Placebo, Phen, 10 
mg BI, 15 mg BI). Actual treatments displayed in addition will be based on the analysis 
phases of AEs (see Table 6.1: 1).
In summaries of disposition, demographics and baseline characteristics, a “Total” (across the 
treatment groups Placebo, 10 mg BI, 15 mg BI and Phen) will be presented additionally.
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 (RPM). At this meeting, it will be 
decided whether a discrepant data value can be used in the 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 
integrated quality and risk management plan (IQRMP). If the data show other IPDs, the 
definition in the IQRMP will be supplemented accordingly by the time of the RPM.
IPDs will be summarized and listed. Table 6.2: 1 below specifies which kind of IPDs could 
potentially lead to exclusion from which analysis set. The decision on exclusion of subjects 
from analysis sets will be made at the latest at the RPM, 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 RPM.


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Table 6.2: 1
Handling of IPDs
IPD code
IPD Category & Brief Description
Excluded from which analysis set
A1
Inclusion criteria not met
PPS
A2
Exclusion criteria not met
PPS
B1
Informed consent not available/not 
done
TS, PKS
B2
Informed consent too late
None
C1
Non-compliance
PPS, PKS
C2
Incorrect intake of trial medication
PPS, PKS
C3
Incorrect trial medication taken
PPS, PKS
D1
Prohibited medication use
PPS
D2
Improper washout of prohibited 
concomitant medication
PPS
E1
Certain violations of procedures used to 
measure primary endpoint data
PPS
F1
Certain violations of time schedule used 
to measure primary endpoint data
PPS
G1
PDs affecting safety and rights of 
subjects
None
6.3
SUBJECT SETS ANALYSED
Subject sets will be used as defined in the CTP, Section 7.3.
Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PPS
Primary endpoint
X
Safety parameters & 
treatment exposure
X
Demographic/baseline 
endpoints
X


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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
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) will 
be reported in the CTR as far as their data are available. All withdrawals will be documented 
and the reason for withdrawal reported in the CTR.
CTP: It is not planned to impute missing values for safety parameters.
One exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline is defined as the last available value assessed prior to first BI 1467335, placebo or 
phenelzine administration.
"Baseline" SBP used for comparison of TYR30 is defined as follows: Consider all SBP values 
within 35 min before tyramine administration on each tyramine testing day. If the SBP of the 
last 3 of these measurements are within a range of 10 mmHg, the mean of these 3 SBP values 
will be defined as baseline. If they are not within a range of 10 mmHg, the mean of all SBP 
values within 35 min before first tyramine administration will be defined as baseline. Baseline 
SBP is calculated prior to each tyramine testing day.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the 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 treatment group
subject number and visit (if visit 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
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.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.


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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.
A medication will be considered concomitant, if it

is ongoing at the time of first 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.
Only descriptive statistics are planned for this section of the CTR.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analyzed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoint
Primary analysis of the primary endpoint will be performed as defined in Sections 7.3.1 of the 
CTP.
The statistical model for the primary analysis defined in the CTP is an analysis of variance 
(ANOVA) model on the logarithmic scale including "treatment" as fixed effect. The model 
will include all three treatments at the same time, i.e., including data from treatments T1, C 
and R in the same analysis. The difference in TSF will be estimated by the ratios of the 
geometric means of 

10 mg BI 1467335 (T1)/ Placebo (R)

Phenelzine (C)/ Placebo (R)
of the primary endpoint.
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint
The primary endpoint will also be assessed descriptively. Summary statistics, by treatment, 
will be presented for TSF, TYR30 at baseline and TYR30 at steady state.


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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
This section is not applicable as no secondary endpoint has been specified in the protocol.
7.6.2
Safety parameters
Safety endpoints and tolerability will be analysed as described in Section 7.8 of this TSAP.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
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). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to screening, on-treatment or follow-up phases 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 other significant AEs according to ICH E3 (8) and for the class of 
AESIs.
CTP: 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) AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
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, subjects 
with AESIs and subjects with other significant AEs (according to ICH E3 (8)). 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.


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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).
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.
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).
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM at the latest. It is the Investigator's responsibility to 
decide whether a lab value is clinically significant abnormal or not. Standard or project-
specific rules for flagging clinically significant values in an automated manner will not be 
applied in this study.
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 and 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 


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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).
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.
Data from the BP monitoring will be listed. In addition, the maximum increase in SBP at 
TYR30 at screening and steady state will be analyzed descriptively. The maximum increase is 
defined as the highest change from the three SBP measurements used to attain TYR30, 
compared to the baseline SBP value used to calculate TYR30.
7.8.4
ECG
Relevant ECG 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 ECG findings will be prepared.
7.8.5
Others
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.


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8.
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 Trialss, current version
2
001-MCS-40-413_1.0: "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
6
KM Asset BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse 
Event 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: "Display and Analysis of Laboratory Data", 
current version; KMED


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
16-JUL-2020
None
This is the final TSAP