The Effect of Multiple Oral Doses of BI 1015550 on Metabolism of Midazolam Administered Orally in Healthy Male Subjects (Open-label, Two-period Fixed Sequence Design Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim



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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
04 Aug 2022
Revision date
23 Sep 2022
BI trial number
1305-0033
Title of trial
The effect of multiple oral doses of BI 1015550 on metabolism of midazolam 
administered orally in healthy male subjects (open-label, two-period fixed sequence 
design trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
In order to assess the potential impact of steady state BI 1015550 on CYP3A 
clinically, the effect of BI 1015550 on the midazolam pharmacokinetics will be 
evaluated. Midazolam is a recommended substrate of CYP3A4.
Trial objective
The main objective is to investigate the induction effect of multiple oral doses of 
18 mg of BI 1015550 bid (twice daily) on the pharmacokinetics of a single oral 
dose of midazolam
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of midazolam
Secondary endpoints: AUC0-∞of midazolam
Trial design
Open-label, two-period fixed sequence design trial
Number of subjects 
total entered
15
on each treatment
15
Diagnosis
Not applicable
Main inclusion criteria
Healthy male subjects, age of 18 to 55 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product 1
BI 1015550, 18 mg film-coated tablets
dose
18 mg bid (= 2 x 1 tablet of BI 1015550)
mode of admin.
Oral with 240 mL of water
Test product 2
Midazolam-
2 mg/ml oral solution
dose
2 mg single dose (= 1 x 1 ml of midazolam) 
mode of admin.
Oral with 240 mL of water 

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Duration of treatment
Treatment Reference (R):
1 x 1 ml midazolam solution on Day 1 of period 1
Treatment Test (T):
1 tablet of BI 1015550 twice daily (bid) for 13 days (Day -13 to Day -1 of period 2) 
and only the morning dose (qd) on Day 1 of period 2 together with 1 ml midazolam 
oral solution
Statistical methods
The effect of steady state BI 1015550 on metabolism of midazolam will be 
estimated by the ratios of the geometric means (T/R) for the primary and secondary 
endpoints. Additionally, their two-sided 90% confidence intervals (CIs) will be 
provided. This method corresponds to the two one-sided t-test procedure, each at a 
5% significance level. Since the main focus is on estimation and not testing, a 
formal hypothesis test and associated acceptance range is not specified. The 
statistical model will be an analysis of variance (ANOVA) on the logarithmic scale 
including effects for ‘subject’ and ‘treatment’, with ‘subject’ as random and 
‘treatment’ as fixed effect. CIs will be calculated based on the residual error from 
the ANOVA.
Descriptive statistics will be calculated for all endpoints.

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Period
Visit
Day
Planned time (relative to 
midazolam intake [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood BI 101555011
PK blood Midazolam11
Depression, Anxiety and
Suicidality assessment15
ECG12
Vital signs (BP, PR, body 
weight)13
Questioning for AEs and 
concomitant therapy 6
-108:00
20:00
BI 1015550 administration
-4
-96:00
08:00
BI 1015550 administration
x2,18
-84:00
20:00
BI 1015550 administration
-3
-72:00
08:00
BI 1015550 administration
x8
x2
x2,18
-60:00
20:00
BI 1015550 administration
-2
-48:00
08:00
BI 1015550 administration
x2,18
-36:00
20:00
BI 1015550 administration
-1
-24:00
08:00
BI 1015550 administration
x8
x2
x2,18
-12:00
20:00
BI 1015550 administration
1
0:00
08:00
BI 1015550 + midazolam 
administration
B2
x8
x8
x2
x2
x2,17
x2,18
0:30
08:30
x
x
1:00
09:00
x
x
1:30
09:30
x
x
2:00
10:00
240 mL fluid intake
x
x
3:00
11:00
x
x
4:00
12:00
240 mL fluid intake, Lunch3
x
x
6:00
14:00
x
x
8:00
16:00
Snack (voluntary)3
x
x
10:00
18:00
x
x
11:00
19:00
Dinner
12:00
20:00
x
x
2
24:00
08:00
Breakfast3, discharge from 
trial site
x
x
x2
x2
x2,17
x2,18
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
x
x
5
96:00
08:00
Ambulatory visit
x
x
6
120:00
08:00
Ambulatory visit
x
x
FU
4
8-15
End of study (EoS) 
examination4
C
x
x
x
x18
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, depression & anxiety assessment, suicidality assessment, check of vital signs,
ECG, safety laboratory (including drug screening), 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 3 h prior to drug administration (or 
within 3 h prior to discharge on Day 2 of Visit 3).
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination, depression & 
anxiety assessment, suicidality assessment, vital signs, ECG, safety laboratory, recording of AEs and concomitant 
therapies.
5.
Urine drug screening and alcohol breath test 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.
Letters A, B and C define different sets of safety laboratory examinations (for details refer to Section 5.2.3).
8.
To be done within 30 min prior to dosing of BI 1015550.
9.
Admission to trial site in the preceding evening is possible and should not be later than 10 h prior to drug 
administration.

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10. At discretion of the investigator or designee, subjects may stay on Day 1 of Visit 2 overnight at the trial site, and on the 
next day proceed to Day -13 of Visit 3.
11. For details of PK blood sampling, refer to Section 5.3.2.
12. For details of 12-lead ECG, refer to Section 5.2.4.
13. For details of vital signs evaluation, refer to Section 5.2.2.
15. For details of suicidality assessment, depression and anxiety assessment, refer to Section 5.2.5.1 and 5.2.5.2.
16. PCR test for SARS-COV-2/ COVID-19 will be performed (if needed due to the current status of the pandemic) at 
screening and shortly (within 72 hours) before admission to trial site in each treatment period (or only before admission 
in Treatment Period 1 if point 10 (see above) is applied and a subject stays at the trial site overnight and not discharged 
between treatment periods).
17. Including assessment of body temperature (if needed due to the current status of the pandemic).
18. Vasculitis assessment: the investigator shall watch out for events suspicious of vasculitis without alternate cause, refer 
to Section 5.2.5.3.
19. Measurement of body weight is not required at the indicated time point.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS AND DEFINITIONS..................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................14
1.2.1
BI 1015550 .............................................................................................14
1.2.1.4
Clinical safety and efficacy......................................................18
1.2.2
Midazolam .............................................................................................20
1.2.3
Residual Effect Period..........................................................................20
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................20
1.4
BENEFIT - RISK ASSESSMENT ...................................................................21
1.4.1
Benefits...................................................................................................21
1.4.2
Risks .......................................................................................................21
1.4.3
Discussion...............................................................................................28
1.4.3.1
Preclinical and clinical experience with BI 1015550 ..............28
1.4.3.2
Clinical experience with other PDE4 inhibitors ......................29
1.4.3.3
Overall assessment...................................................................30
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 31
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......31
2.1.1
Main objectives......................................................................................31
2.1.2
Primary endpoints ................................................................................31
2.1.3
Secondary endpoint ..............................................................................31
2.2.2.3
Safety and tolerability..............................................................33
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 34
3.1
OVERALL TRIAL DESIGN............................................................................34
3.2
DISCUSSION OF TRIAL DESIGN.................................................................34
3.3
SELECTION OF TRIAL POPULATION ......................................................35

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3.3.1
Main diagnosis for trial entry..............................................................35
3.3.2
Inclusion criteria...................................................................................35
3.3.3
Exclusion criteria ..................................................................................35
3.3.4
Withdrawal of subjects from treatment or assessments ...................37
3.3.4.1
Withdrawal from trial treatment ..............................................37
3.3.4.2
Withdrawal of consent to trial participation ............................38
3.3.4.3
Discontinuation of the trial by the sponsor..............................39
3.3.5
Replacement of subjects .......................................................................39
4.
TREATMENTS........................................................................................ 40
4.1
INVESTIGATIONAL TREATMENTS ..........................................................40
4.1.1
Identity of the Investigational Medicinal Products ...........................40
4.1.2
Selection of doses in the trial and dose modifications........................40
4.1.3
Method of assigning subjects to treatment groups ............................41
4.1.4
Drug assignment and administration of doses for each subject .......41
4.1.5
Blinding and procedures for unblinding ............................................42
4.1.6
Packaging, labelling, and re-supply ....................................................42
4.1.7
Storage conditions.................................................................................42
4.1.8
Drug accountability ..............................................................................42
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................43
4.2.1
Other treatments and emergency procedures....................................43
4.2.2
Restrictions............................................................................................44
4.2.2.1
Restrictions regarding concomitant treatment .........................44
4.2.2.2
Restrictions on diet and life style.............................................44
4.3
TREATMENT COMPLIANCE.......................................................................44
5.
ASSESSMENTS....................................................................................... 45
5.1
ASSESSMENT OF EFFICACY.......................................................................45
5.2
ASSESSMENT OF SAFETY............................................................................45
5.2.1
Physical examination ............................................................................45
5.2.2
Vital signs...............................................................................................45
5.2.3
Safety laboratory parameters..............................................................45
5.2.4
Electrocardiogram................................................................................49
5.2.5
Other safety parameters.......................................................................49
5.2.5.1
Suicidality assessment .............................................................49
5.2.5.2
Depression and anxiety............................................................50
5.2.5.3
Vasculitis assessment...............................................................51
5.2.6
Assessment of adverse events...............................................................51
5.2.6.1
Definitions of adverse events...................................................51

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7.2.1.2
Pharmacokinetics.....................................................................63
7.2.2
Primary endpoint analyses...................................................................64
7.2.3
Secondary endpoint analyses ...............................................................65
7.2.5
Safety analyses.......................................................................................66
7.2.6
Interim analyses ....................................................................................67
7.3
HANDLING OF MISSING DATA ..................................................................67
7.3.1
Safety......................................................................................................67
7.3.2
Pharmacokinetics..................................................................................67
7.4
RANDOMISATION ..........................................................................................67
7.5
DETERMINATION OF SAMPLE SIZE ........................................................67
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 69
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................69
8.2
DATA QUALITY ASSURANCE .....................................................................70
8.3
RECORDS..........................................................................................................70
8.3.1
Source documents .................................................................................70
8.3.2
Direct access to source data and documents.......................................71
8.3.3
Storage period of records.....................................................................71
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................72
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......72
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................72
8.6
TRIAL MILESTONES .....................................................................................72
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................73
9.
REFERENCES......................................................................................... 75
9.1
PUBLISHED REFERENCES...........................................................................75
9.2
UNPUBLISHED REFERENCES.....................................................................78
10. APPENDICES .......................................................................................... 80
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................80
10.2
HOSPITAL ANXIETY AND DEPRESSION SCALE...................................86
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 87
11.1
GLOBAL AMENDMENT 1 .............................................................................87

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DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EFD
Embryo-fetal development
EoS
End of Study (synonym for End of Trial)
ESR
Erythrocyte Sedimentation Rate
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FEED
Fertility and early embryonic development
FU
Follow-up
FVC
Forced vital capacity
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
ICH
International Council for Harmonisation
IGRA
Interferon Gamma Release Assays
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
IPD
Important protocol deviation
IPF
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LOAEL
Lowest observed adverse effect Level
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NOAEL
No observed adverse effect level
NOEL
No observable effect level

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1.2.1.4
Clinical safety and efficacy
BI 1015550 has been investigated in a total of 9 clinical studies: 8 Phase I trials (seven trials 
in healthy subjects and one in patients with IPF), and a proof-of-clinical principle Phase II 
trial in patients with IPF. Overall, 146 healthy volunteers and 107 patients with IPF have 
been exposed to BI 1015550.
BI 1015550 was well tolerated following single dose administration up to 48 mg in healthy 
volunteers and following multiple administrations up to 18 mg bid over a treatment period of 
up to 12 weeks in patients.

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To date, no side effects have been identified for BI 1015550. Potential side effects of 
BI 1015550 will be under continuous evaluation during clinical development. Vasculitis and 
foetal loss are considered as important potential risk based only on non-clinical findings. The 
risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs and from preclinical and clinical data of 
compounds with a comparable mode of action. For adverse events reported during clinical 
trials with BI 1015550 please refer to Section 1.2.1.
Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or 
known risks of 
clinical relevance 
Summary of data, rationale for the 
risk
Mitigation strategy
Investigational Medicinal Product: BI 1015550
Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Major Adverse 
Cardiovascular 
Events (MACE) 
and 
tachyarrhythmia
#
Important potential risk for 
marketed PDE4 inhibitor 
apremilast.
#
In preclinical studies with 
BI 1015550 no adverse 
cardiovascular findings detected
(focal myocardial degeneration or 
necrosis in monkeys were with no 
apparent vascular changes).
#
In clinical trials with BI 1015550 
no relevant findings were observed.
#
These risks will be addressed by 
careful safety monitoring and safety 
measures such as close clinical 
monitoring for AEs; regular 
monitoring of vital signs and ECG 
assessments
#
Subjects will stay under close 
medical surveillance during the 
whole period of treatment with 
BI 1015550
Malignancies
Inhibition of the immune response 
with an immunomodulatory drug 
may potentially impair immune 
defences and thus, theoretically 
decrease immune defence against 
malignancies.
#
Subjects with a recent history of 
malignancy within 5 years will be 
excluded from participation in this 
trial
#
In case of occurrence of malignant 
neoplasm other than appropriately 
treated basal cell carcinoma or 
squamous cell carcinoma of the skin 
or in situ carcinoma of uterine 
cervix, the investigator should 
discontinue trial treatment
#
Diagnostics and treatment have to 
be initiated according to local 
standard of care.
Gastrointestinal
disorders (e.g., 
diarrhoea, 
nausea, 
vomiting, 
abdominal pain)
#
Vomiting and diarrhea are 
important dose-limiting side effects 
of marketed oral PDE-4 inhibitors.
#
In Phase II study of BI 1015550, 
diarrhoea was the most frequently 
reported AE.
#
Increased awareness of symptoms
#
Careful monitoring of hydration in 
subjects with diarrhoea 
recommended
#
Symptomatic treatment if required.
Drug-induced 
liver injury
(DILI)
Rare but severe event, thus under 
constant surveillance by sponsors and 
regulators.
#
Timely detection, evaluation, and 
follow-up of laboratory alterations 
in selected liver laboratory 
parameters to ensure subjects´ safety
#
Increased awareness and expedited 
reporting (AESI).

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Investigational Medicinal Product: Midazolam
CNS-related 
effects
In line with its target indication the 
therapeutic use of midazolam will 
cause sedative effects
#
The investigated dose of midazolam 
is 2 mg which is lower than the 
adult therapeutic dose (7.5 – 15 mg)
#
Subjects are under close monitoring 
at the site
#
Prior discharge the subject will be 
assessed by the investigator 
including its ability to drive and 
operate machines. If required the in-
house period will be extended until 
the subject has completely 
recovered.
Trial procedures
Bruising and, in 
rare cases, 
phlebitis, or 
nerve injury, 
potentially 
resulting in 
paraesthesia, 
reduced 
sensibility, 
and/or pain 
General risk by venepuncture for 
blood sampling, acceptable in the 
framework of trial participation.
Medical expertise of the trial site 
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
BI 1015550 is not recognized as high-risk compound, and patients with IPF exposed to 
BI 1015550 18 mg bid over up to 12 weeks demonstrated acceptable safety and tolerability.
However, so far this dose level has not been tested in healthy volunteers, and safety data in 
healthy subjects is available up to 12 mg bid over 2 weeks only (also with acceptable safety 
and tolerability). Thus, the following general safety measures will be applied in order to 
minimize the risk to the healthy volunteers.
#
15 subjects will be divided in 3 cohorts (5 subjects per cohort). First BI 1015550 
administrations in each cohort will be separated by at least 72 hours
#
Stringent in- and exclusion criteria define a relatively homogenous population and 
exclude subjects that might be at increased risk for adverse events (see Section 3.3).
#
Extensive safety laboratory examinations
#
Treatment duration with BI 1015550 is limited to 2 weeks

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#
Hospitalisation during the whole duration of treatment with BI 1015550
Considerations on male contraception requirements:
The exposure through seminal fluid to sexual partners of males receiving BI 1015550 is 
expected to be minimal. At a plasma BI 1015550 Cmax of 460 nM following an 18 mg bid 
dose, the worst-case seminal fluid level is anticipated to be 460 nM. Assuming a seminal 
fluid volume of 5 mL, a worst-case 100% absorption from the vagina, and a plasma volume 
of 3.5L, the resultant plasma concentration in the woman would be 0.66 nM. This 
concentration is approximately 3,500-fold below the most conservative maximum plasma 
level of 2,300 nM at the NOAEL in rats in a fertility and early embryonic development study 
[n00290709], and in EFD studies in rats and rabbits. This large safety margin, the absence of 
dysmorphogenesis in two species, and lack of genotoxicity suggest that barrier methods of 
contraception should not be required for a male administered BI 1015550 [c39775503].
Considerations on COVID-19:
Generally, in healthy volunteers' population, the risk of severe COVID-19 infection is not 
higher, and study participation would not increase the risk of becoming infected with SARS-
CoV-2 beyond the potential risk associated with any need for the study participant to leave 
their home for study related activities. The appropriate risk minimisation measures will be 
taken in accordance with the public health precautions if needed due to the current status of 
the pandemic.
Based on the pharmacological mechanism and existing non-clinical and clinical data, there is
no indication that treatment with BI 1015550 may increase the risk of infection including
SARS-CoV-2 infection. Even though an increased risk of SARS-CoV-2 infection -or of a 
more severe COVID-19 disease in case of such an infection appears unlikely, subjects with 
active or recent (i.e. within the 4 weeks prior to screening) SARS CoV-2 infection should not 
be included in the trial which is also applicable for any other relevant acute infection 
(exclusion criterion No. 9).
In case of severe COVID-19 infection during the conduct of the trial, treatment with
BI 1015550 has to be interrupted which is also applicable for any other relevant acute 
infection (criterion of withdrawal from trial treatment No. 9). The appropriate diagnostic and 
treatment measures will be taken in accordance with the public health precautions.
Of note, depending on the current status of the COVID-19 pandemic, all subjects with 
confirmed SARS CoV-2 infection will be handled in accordance with local guidance and 
SOPs meaning that any confirmed SARS CoV-2 infection during the conduct of the trial will 
lead to withdrawal of the subject from further trial treatment and/or trial procedures to avoid 
undue risks to other subjects at the trial site and the site personnel. The appropriate diagnostic 
and treatment measures will be taken in accordance with the public health precautions. If 
feasible, the EoS examination to be performed as early as possible after the SARS CoV-2 
infection is resolved.

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the observed effects in non-clinical species, two PDE4 inhibitors (apremilast and roflumilast) 
have been successfully marketed and vascular injury has not been documented in humans.
Also, both marketed PDE4i (roflumilast, apremilast) have demonstrated adverse effects in 
reproductive toxicity studies that namely fertility and fetal loss and are labelled accordingly 
[R17-0915, R17-0919].
In healthy volunteers’ studies, in which 146 subjects received BI 1015550, up to a 48 mg 
single-dose and 12 mg bid multiple-dose appeared to show acceptable safety and tolerability.
So far, a dose of 18 mg bid has not been tested in healthy volunteers. However, patients with 
IPF demonstrated acceptable safety and tolerability at the dose of 18 mg bid (proposed 
therapeutic dose): 10 patients over up to 12 weeks in trial 1305-0012 [c25085412] and 97 
patients over 12 weeks in trial 1305-0013 [c37065416].
1.4.3.2
Clinical experience with other PDE4 inhibitors
Non-selective PDE4 inhibitors have been approved for chronic obstructive pulmonary disease 
(COPD) with chronic bronchitis and a history of exacerbations (roflumilast), and for 
moderate to severe plaque psoriasis and active psoriatic arthritis (apremilast).
Roflumilast has been tested in Phase III studies for asthma and apremilast in Phase III studies 
for active Behcet’s disease. No other PDE4 inhibitor has been tested in IPF.
Cilomilast
Cilomilast was the first PDE4 inhibitor developed for the maintenance of lung function 
(forced expiratory volume in one second (FEV1)) in patients with COPD but failed to 
demonstrate efficacy to support approval of the drug. Cilomilast non-clinical findings include 
mesenteric arteritis in rats. In the clinical program the frequency of GI AEs was high. Fecal 
occult blood testing was benign with unremarkable colonoscopy findings in the few patients 
with blood in the stool. Lack of approval was based on inadequate evidence of efficacy rather 
than any safety concern [P06-08316].
Roflumilast
Only one PDE4 inhibitor, roflumilast (Daxas® in EU, Daliresp® in US), has received 
marketing authorization by regulatory agencies for a respiratory indication, COPD.
More than 5,000 patients with COPD were included in the “COPD Safety Pool” of the large 
roflumilast clinical development program. The most frequently reported AEs associated with 
the treatment with roflumilast were diarrhoea, weight loss, nausea, abdominal pain and 
headache followed by insomnia, dizziness and decreased appetite.
The most common AEs leading to withdrawal in approximately 14% of the patients treated 
with roflumilast were nausea, diarrhoea and headache. The rate of withdrawal due to AEs 
among patients receiving placebo was 9%.
The mechanism of weight loss, which was observed in approximately 7% of the patients 
receiving roflumilast, is not fully understood [R10-1555].
Clinical manifestation of mesenteric vasculitis was not reported in these clinical studies. The 
SmPCs of Daxas®/Daliresp®, recommend the close monitoring of patient’s body weight and 
its cautious use in patients with previous or existing psychiatric symptoms or if concomitant 

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treatment with other medicinal products, which are likely to cause psychiatric events, is 
intended. The above events were not observed with cilomilast, hence not clearly defined as 
class effects.
Apremilast
One PDE4 inhibitor for treatment of active psoriatic arthritis (Otezla®) has been approved by 
the FDA on March 2014, in September 2014 for moderate to severe plaque psoriasis and in 
July 2019 for the treatment of oral ulcers associated with Behçet’s disease.
Otezla® has been evaluated in 1493 patients with active psoriatic arthritis in three 
randomised placebo-controlled studies [R17-1427].
The most common adverse reactions were diarrhoea, headache and nausea, followed by 
vomiting, upper respiratory tract infection, nasopharyngitis and abdominal pain. 
The most common adverse reactions leading to discontinuation were diarrhoea (1.8%), 
nausea (1.8%) and headache (1.2%).
The proportion of patients with psoriatic arthritis who discontinued treatment due to any 
adverse reaction was 4.6% for patients taking Otezla® 30 mg twice daily and 1.2% for 
placebo-treated patients.
The product information of Otezla® recommends the close monitoring of patient’s body 
weight and its cautious use in patients with history of depression and/or suicidal thoughts or 
behaviour [R14-1795].
BI 137882
One previous selective inhibitor of PDE4 B, BI 137882 has been tested in 40 healthy 
volunteers [U10-3777] at Boehringer Ingelheim. Most frequently reported drug-related AEs 
were oropharyngeal pain and headache. The oropharyngeal pain was considered to be related 
to the solution for reconstitution. Most AEs were mild in intensity. AEs of moderate intensity 
were reported in 5 patients; most frequent was headache. A fatal event, not considered related 
to study medication, occurred in a 25-year-old volunteer 8 days following administration of a 
single dose. The cause of death was myocarditis, in retrospect considered pre-existing with an 
additional finding of pre-existing Hashimoto thyroiditis [U11-2788].
1.4.3.3
Overall assessment
BI 1015550 is an oral preferential inhibitor of the PDE4B with broad anti-inflammatory and
antifibrotic activities. Based on its mode of action, as well as available preclinical and clinical 
data, BI 1015550 is hypothesised to have complementary activity to current therapies in IPF 
and other forms of progressive pulmonary fibrosis.
In the current trial, adequate safety monitoring including vital signs, safety laboratory, 
suicidality assessment, depression & anxiety assessment and adverse events monitoring with 
a special focus on vasculitis assessment has been implemented. Taking into account these 
safety measures, potential risks to healthy participants are considered to be low and 
outweighed by the benefit of a successful clinical development of BI 1015550 in the context 
of the unmet medical need.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the induction effect of multiple oral doses of 
18 mg bid of BI 1015550 on the pharmacokinetics of the sensitive CYP3A4 substrate 
midazolam.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for midazolam:
#
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)
#
Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for midazolam:
#
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

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2.2.2.3
Safety and tolerability
Safety and tolerability of BI 1015550 will be assessed based on:
#
Adverse events (including clinically relevant findings from the physical examination
and vasculitis assessment)
#
Suicidality assessment (C-SSRS), Hospitality anxiety and depression score (HADS)
#
Safety laboratory tests
#
12-lead ECG
#
Vital signs (blood pressure, pulse rate, body weight)

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induction the biomarkers of induction (see Section 2.2.2.2) will be determined. For the victim 
drug midazolam, a single dose is sufficient.
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analyte.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 15 healthy male subjects will enter the trial. 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 trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1.
Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests without any clinically significant abnormalities
2.
Age of 18 to 55 years (inclusive)
3.
BMI of 18.5 to 29.9 kg/m2 (inclusive)
4.
Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
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 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance, in particular, hepatic parameters (ALT, AST, total bilirubin) or renal 
parameters (creatinine) exceeding the ULN or estimated GFR is below 
90 ml/min/1.73m2 after repeated measurements

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4.
Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
5.
Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders
6.
Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or simple hernia 
repair)
7.
Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8.
History of relevant orthostatic hypotension, fainting spells, or blackouts
9.
Relevant chronic or acute infections, including but not limited to SARS-CoV 2, viral 
hepatitis and HIV
10.
Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal cell carcinoma of the skin, in 
situ squamous cell carcinoma of the skin
11.
History of relevant allergy or hypersensitivity (including allergy to the trial medication
or its excipients) 
12.
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)
13.
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
14.
Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15.
Inability to refrain from smoking on specified trial days
16.
Alcohol abuse (consumption of more than 24 g per day)
17.
Drug abuse or positive drug screening
18.
Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
19.
Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
20.
Inability to comply with the dietary regimen of the trial site
21.
A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males) or any other relevant ECG finding at screening
22.
A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)

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23.
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 
24.
During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
25.
Concomitant intake of amprenavir, indinavir, nelfinavir, ritonavir, itraconazole or 
ketoconazole
26.
According to C-SSRS questionnaire at screening: any suicidal ideation type 2-5 in the 
past 12 months or any lifetime history of suicidal behaviour 
27.
Acute or chronic severe depression defined as HADS subscore >14 at Visit 1 and/or 
Day -13 of Visit 3
28.
History of vasculitis
29.
Relevant immunodeficiency
30.
Subjects with positive TB test at Visit 1 unless they have completed treatment for active 
or latent tuberculosis in line with local guidelines
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may 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, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.3, the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer

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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, the safety of the 
subject cannot be guaranteed as he / she 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 surgery, 
adverse events (AEs), or diseases), in particular, if an AE of severe intensity or a 
serious adverse event (SAE) occurs
5.
The subject has an elevation of AST and/or ALT ≥3-fold ULN
6.
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
7.
Suicidal ideation (type 2-5) or any suicidal behaviour based on C-SSRS questionnaires 
during the trial
8.
Subjects with a BMI<18,5 kg/m2 that experience an additional, unexplained and 
clinically significant (>10%) weight loss during trial treatment
9. If any of the following adverse events is reported, the treatment has to be discontinued:
-
Severe or serious infections, opportunistic or mycobacterium tuberculosis 
infections
-
Malignancies 
-
Vasculitis
-
A new onset of severe depression as defined by a HADS subscore >14.
Of note, depending on the current status of the COVID-19 pandemic, all subjects with 
confirmed SARS CoV-2 infection will be handled in accordance with local guidance and 
SOPs meaning that any confirmed SARS CoV-2 infection during the conduct of the trial will 
lead to discontinuation of the subject (refer to Section 1.4.2).
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects.
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.

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3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately):
1.
Failure to meet expected enrolment goals overall or at a particular trial site
2.
The sponsor decides to discontinue the further development of the investigational 
products
3.
Deviation from GCP, or the CTP, or the contract with BI impairing the appropriate
conduct of the trial
4.
New toxicological findings, serious adverse events, or any safety information
invalidating the earlier positive benefit-risk-assessment (see Section 3.3.4.1)
5.
More than 50% of the subjects show drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least one drug-related serious adverse event or 
one severe non-serious adverse drug reaction is reported. If a relationship between AE 
and drug is at least reasonably possible (i.e. the relationship cannot be ruled out), it is to 
be considered as drug-related (see Section 5.2.6.1.6).
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 3 subjects do not complete the trial (including subjects non- evaluable for 
PK), subjects may be replaced if considered necessary to reach the objective of the trial.
Subjects who withdraw or are withdrawn from treatment or assessments because of a drug-
related adverse event will not be replaced. The Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. The total number of replacements may not exceed 1/3 of the total number of 
evaluable subjects anticipated to complete the trial. A replacement subject will be assigned a 
unique trial subject number and will receive both treatments per trial protocol.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 1015550
Pharmaceutical formulation: Film-coated tablets
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
18 mg
Posology:
1 – 0 – 1
Mode of administration:
Oral
Duration of use:
13 days bid (twice daily on Days -13 to -1 of Period 2) and 
1 day qd (once daily, only morning dose on Day 1 of Period 2)
The characteristics of the reference product are given below:
Name:
Midazolam-
2 mg/ml Lösung
Substance:
Midazolam
Pharmaceutical formulation: Oral solution
Source:
Unit strength:
2 mg/mL
Posology:
1 mL – 0 – 0
Mode of administration:
Oral
Duration of use:
Single dose on Day 1 of Period 1 and Period 2
4.1.2
Selection of doses in the trial and dose modifications
BI 1015550:
18 mg bid of BI 1015550 is the therapeutic dose that is used in clinical drug development.
Midazolam:
The clinically recommended dose for adults is 7.5 mg to 15 mg. For safety reasons a dose of 
2 mg has been selected for this trial. Considering the pre-clinical data, an increase of 
exposure is not expected with combined drug intake.

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4.1.3
Method of assigning subjects to treatment groups
Prior to the start of the study, subjects willing to participate will be recruited to cohorts 
according to their temporal availability. There is only one treatment sequence investigated in 
this trial, and each subject will be allocated to the treatment sequence R-T. The subjects will 
be allocated to a trial subject number on a first-come, first-served basis prior to first 
administration of trial medication (midazolam) in the morning of Day 1 of Visit 2.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
For safety reasons (see Section 1.4.2), 15 subjects will be divided in 3 cohorts (5 subjects per 
cohort). First BI 1015550 administrations in each cohort will be separated by at least 72 hours 
which is expected to cover the period of highest risk / peak effect. Within each cohort
subjects can be dosed as close as 5 min apart.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a non-randomised trial with 2 periods. All subjects will receive the 2 treatments 
in a fixed order. The treatments to be evaluated are summarised in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total daily 
dose
R (Reference)
Midazolam
Oral solution
2 mg/mL
1 mL (D1 V2)
2 mg
T (Test)
BI 1015550
Midazolam
Tablet
Oral solution
18 mg
2 mg/mL
1 tablet bid for 13 days (D-13 to 
D-1 V3) and 
1 tablet qd (D1 V3)
1 mL (D1 V3)
36 mg 
18 mg
2 mg
Administration of midazolam in both treatment periods and BI 1015550 (morning doses) will 
be performed after subjects have fasted overnight; fasting is to start no later than 10 h before 
the scheduled dosing. The evening dose of BI 1015550 will be administered approximately 
12 h after the morning dose on Days -13 to -1 in Period 2, no special fasting requirement 
applies. No evening dose of BI 1015550 will be given on Day 1 of Period 2.
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
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. On Day 1 of Period 2 both midazolam and BI 1015550 will be administered 
together (midazolam to be given first).
Subjects will be kept under close medical surveillance until 12 h after midazolam 
administration in Period 1 and starting from the first BI 1015550 administration until 24 h 
after the last dose administration in Period 2.

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Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. 
At the time of disposal of remaining trial medication, the investigator or designee must verify 
that no remaining supplies are in the investigator’s possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
Vasculitis
In case of events suspicious for vasculitis, trial treatment will be discontinued. A thorough 
work-up has to be initiated including at least but not limited to
#
appropriate imaging, including angiography
#
biopsy if possible
#
appropriate laboratory screening, including measurements of vasculitis markers at the 
local lab, see Section 5.2.3. In addition, an analysis of the previously collected and 
stored samples will need to be requested and considered.
#
thorough documentation of all reported symptoms
Referral to a vasculitis expert is recommended. If required, vasculitis treatment should be 
initiated according to standard of care.

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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on trial days) on the appropriate pages of the CRF.
For treatment of headache, one of the most frequent AEs in clinical studies with BI 1015550
(see Section 1.2.1.4), if necessary, short-term use of ibuprofen or paracetamol is acceptable.
Another common AE, diarrhoea, can be treated symptomatically with loperamide.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. 
On Day 1 of both treatment periods and Day -13 of Treatment Period 1, standardised meals 
will be served at the times indicated in the Flow Chart. No food is allowed for at least 4 h 
after drug intake. Starting from 1 h before drug intake until lunch, fluid intake is restricted to 
240 mL of water administered with the drug, and an additional 240 mL of water at 2 h and 
4 h post-dose (mandatory for all subjects). From lunch until 12 h post-dose, total fluid intake 
is restricted to 2000 mL. On the other days during in-house confinement, meals could be 
served after drug administration (if applicable) and no restriction with regards to fluid intake 
applies.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each trial period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed during in-house confinement at the trial site on Day 1 of Period 1 
and Days -13 and 1 of Period 2.
Smoking is not allowed during in-house confinement.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or to solarium radiation should be avoided during the entire trial.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. 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 (alcohol history not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, a physical 
examination, assessment of suicidal ideation and behaviour using the C-SSRS 
(‘baseline/screening scale’), and assessment of anxiety and depression using the HADS. 
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, physical examination including determination of body weight, and assessment of 
suicidal ideation, behaviour using C-SSRS (‘since last visit scale’), and assessment of anxiety 
and depression using the HADS.
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) or pulse rate will be measured by a blood pressure 
monitor (Dinamap Pro 100, 
) 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. Measurement of body weight will be performed as well at the times 
indicated in the Flow Chart. Further, body temperature will be monitored as part of vital signs 
assessment if still needed due to the current status of the pandemic.
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 to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
Reticulocytes/Erythrocyte
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.; 
Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time - Quick
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X 
X
X
X
X 
X
X
X
X 
X
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
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 
Free T3 - Triiodothyronine 
Free T4 – Thyroxine 
X
X
X
--
--
--
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
Albumin (Protein Electrophoresis) 
Alpha-1-Globulin (Protein Electrophoresis) 
Alpha-2-Globulin (Protein Electrophoresis) 
Beta-Globulin (Protein Electrophoresis) 
Gamma-Globulin (Protein Electrophoresis) 
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
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
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal in 
urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 3 on Days -13, -10, -6 and 1 (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 and COVID-19, it is planned to perform these tests during 
screening only. Drug screening will be performed at screening and prior to each treatment 
period.

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SureStep ML 10 Scr Test Device; 
, or comparable test 
systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4).
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 
 at the times provided in the Flow Chart. 
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 trial procedures scheduled
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists).
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 (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the subject will be removed from 
the trial and will receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Suicidality assessment
Based on the FDA guidance on prospective assessment of suicidality [R12-4395] suicidal 
ideation and behaviour (SIB) will be proactively evaluated as part of the drug development. 
This also refers to clinical trials in healthy volunteers with multiple dose administration of the 
IMP. 
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation. It does 

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not give a global score, but provides some categorical and some severity information 
specifically for behaviour and ideation [R08-1147].
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsellor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behaviour, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and 
behaviour will also be recorded. See Section 10.1 for the original English C-SSRS. For this 
trial, the paper version of the respective German translation will be used. 
After the screening visit, the ‘since last visit’ version is used for the suicidality assessment at 
the time points indicated in the Flow Chart.
The investigator is to review all reports for plausibility and clinical relevance. Doubtful 
reports may be repeated or reports may be validated by a consulting psychiatrist. If there is a 
confirmed report of suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the 
investigator is to immediately interview the subject during the clinic visit, and/or is to consult 
a psychiatrist. If the report is confirmed, appropriate actions for the subject’s safety have to 
be initiated.
There are following types of suicidal ideation and behaviour [R12-4395]:
Suicidal ideation
1. Passive 
2. Active: nonspecific – no method, intent or plan 
3. Active: method, but no intent or plan 
4. Active: method and intent, but no plan 
5. Active: method, intent, and plan 
Suicidal behaviour
1. Completed suicide
2. Suicide attempt
3. Interrupted attempt
4. Aborted attempt
5. Preparatory actions toward imminent suicidal behaviours.
For details regarding AE reporting see Section 5.2.6.2.3
5.2.5.2
Depression and anxiety
Prospective monitoring using the Hospital Anxiety and Depression Scale (HADS). 

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This questionnaire is patient friendly and easy to use and takes less than 5 minutes for 
completion. The questionnaire comprises seven questions for anxiety and seven questions for 
depression that are scored separately. Cut-off scores are available for quantification: The 
HADS questionnaire has been validated in many languages, countries and settings including 
general practice and community settings and is one of the tools recommended by National 
Institute for Health and Care Excellence (NICE) for diagnosis of depression and anxiety and 
is included in the American Thoracic Society’s list of patient reported outcome measures for 
use in ILD [R22-1857, R22-1856]. The HADS (Appendix 10.2) will be self- administered.
For details regarding AE reporting see Section 5.2.6.1.4 and 5.2.6.2.3.
5.2.5.3
Vasculitis assessment
The investigator should monitor for any signs and symptoms of vasculitis at all times and 
specifically as part of the AE questioning at the time points indicated in the Flow Chart. 
In case of (suspected) events of vasculitis, further work-up and management as outlined in 
Section 4.2.1 has to be followed, including biopsy, appropriate imaging/angiography, 
laboratory measures (e.g. ESR, additional lab sample for immunological and further 
inflammation markers, see Section 5.2.3).
For details regarding AE reporting see section 5.2.6.1.4. and 5.2.6.2.3.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
#
Worsening of the underlying disease or of other pre-existing conditions 
#
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Adverse event report for diarrhoea events
In case of events of diarrhoea the following definitions should be followed:
Diarrhoea is defined ≥3 loose/liquid stools per day (WHO definition)

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5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
#
Results in death 
#
Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 
#
Requires inpatient hospitalisation, or prolongation of existing hospitalisation
#
Results in persistent or significant disability or incapacity 
#
Is a congenital anomaly/birth defect 
#
Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology 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’.
SAE reporting in case of Suicidal Risk assessed by the C-SSRS:
All C-SSRS reports of suicidal ideation type 4 and 5 and all reports of suicidal behavior must
be reported as separate SAEs by the investigator.
For ‘self-injurious behavior, no suicidal intent’ (type 11) standard AE/SAE reporting rules
are to be applied.
For each negative report (Suicidal ideation type 1, 2, or 3) after the start of the trial, the
investigator is to decide based on clinical judgement whether it represents an adverse event
(AE) as defined in the protocol, and if it is considered an AE then it must be reported
accordingly.

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5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
#
Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure 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.
#
Vasculitis events
In this trial protocol vasculitis is defined as any event term included in the MedDRA 
SMQ Vasculitis (broad). This includes clinical and pathological features related to 
primary or secondary vasculitis syndromes and involving any type, size, and location 
of blood vessels. 
The investigator should monitor for any signs and symptoms of vasculitis at all times 
and specifically as part of the AE questioning. 
In case of (suspected) events of vasculitis, further work-up and management as 
outlined in Section 4.2.1 has to be followed, including biopsy, appropriate 
imaging/angiography, laboratory measures (e.g. ESR, additional lab sample for 
immunological and further inflammation markers).
#
Serious infections, opportunistic or mycobacterium tuberculosis infections. 
These include Pneumocystis jirovecii, BK virus disease including polyomavirus-
associated nephropathy (PVAN), Cytomegalovirus (CMV), post-transplant 
lymphoproliferative disorder (Epstein–Barr virus [EBV]), progressive multifocal 
leucoencephalopathy, bartonellosis (disseminated only), blastomycosis, 
toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), 

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candidiasis (invasive or pharyngeal), cryptococcosis, other invasive fungi 
(mucormycosis (zygomycosis, rhizopus, mucor, lichtheimia), 
Scedosporium/Pseudallescheria boydii, fusarium), legionellosis, Listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), HBV reactivation, herpes simplex 
(invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, Penicillium marneffei, Sporothrix 
schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), Trypanosoma cruzi infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), HCV progression [R17-2617]
#
New onset of severe depression, defined as HADS subscore >14
#
New onset of severe anxiety, defined as HADS subscore >14
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. An AE for which a causal relationship to the trial treatment is at least reasonably
possible (i.e. the relationship cannot be ruled out) is to be classified as drug-related.
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
#
There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned
#
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs. 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
(the End of Study (EoS) visit): 
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 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 new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 
24 hours of becoming aware of the event, the country specific reporting process will be 
provided in the ISF. The same timeline applies if follow-up information becomes available. 
On specific occasions, the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and send the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
AE reporting from depression, anxiety & suicidality assessment
All reports of suicidal ideation type 4 and 5 and all reports of suicidal behaviour (based on 
C-SSRS questionnaire during the trial, see Section 5.2.5.1), must be reported as separate 
SAEs by the investigator. 
Suicidal ideation type of 1, 2 or 3 based on C-SSRS questionnaire, see Section 5.2.5.1 and 
signs and symptoms of depression & anxiety based on Hospital Anxiety and Depression 
Scale (HADS) questionnaire, see Section 5.2.5.2, may fulfil AE definition, see 5.2.6.1 and 
have to be collected & reported as AEs. All HADS and C-SSRS reports should be reviewed 
by the Investigator for clinical relevance and determination if an AE report is warranted.
New onset of severe depression, defined as HADS subscore >14 and new onset of severe 
anxiety, defined as HADS subscore >14 must be reported as AESIs, see Section 5.2.6.1.4.
The Investigator should check any AE resulting from C-SSRS questionnaire with the list of 
Always Serious AEs (see Section 5.2.6.1.3) and any AEs resulting from HADS questionnaire 
if AESI criteria are met (see Section 5.2.6.1.4).

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5.2.6.2.4
Pregnancy
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, potential drug exposure during 
pregnancy must be reported. This requires written consent of the pregnant partner. Reporting 
and consenting must be in line with local regulations. The ISF will contain the trial specific 
information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis of midazolam
For quantification of midazolam concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 60 min with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.

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At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After analysis, the plasma samples may be used for further methodological investigations
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.
5.3.2.2
Blood sampling for pharmacokinetic analysis of BI 1015550
For quantification of BI 1015550 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 60 min with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After analysis, the plasma samples may be used for further methodological investigations 
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.

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5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
biomarker parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an orally administered drug, 
and are widely used in clinical trials. The pharmacokinetic parameters and measurements 
outlined in Section 5.3 are generally used assessments of drug exposure.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, ECG, AE questioning, depression & anxiety assessment, suicidality 
assessment and laboratory tests will be ± 60 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
ECG recordings have to be done first. Furthermore, if several measurements including 
venepuncture are scheduled for the same time, venepuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological
parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, suicidality assessment, depression & anxiety assessment and physical examination, 
refer to Sections 5.2.1 to 5.2.5.
In accordance with the Flow Chart, duration of screening period is up to 21 days (Day -21 to 
Day -1 of Visit 1). However, the final review of eligibility criteria is conducted in the 
morning of Day 1 of Visit 2 prior to predose blood sampling and first drug administration.
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Day 1 of Visit 2, Reference 
Treatment (R)), and Days -13 to 1 of Visit 3 (Test Treatment(T)).
On Day 1 of Visit 2, trial participants will be admitted to the trial site (admission in the 
preceding evening is also possible) and kept under close medical surveillance for at least 12 h

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of midazolam under steady state exposure of BI 1015550 (Test)
compared with midazolam alone (Reference) will be estimated by the ratios of the geometric 
means (test/reference), and their corresponding 2-sided 90% confidence intervals (CIs) will 
be provided. This method corresponds to the two one-sided t-test procedure, each at the 5% 
significance level. Since the main focus is on estimation and not testing, a formal hypothesis 
test and associated acceptance range is not specified.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:
#
Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.
# Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the IPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for drug midazolam and 
BI 1015550 will be calculated according to the relevant BI internal procedures. 
Plasma 
 concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol deviation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Important protocol deviations may be

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∀k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
7.2.3
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures and will be assessed statistically using the same methods as described 
for the primary endpoints.

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7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.3. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between first trial medication intake and end of REP 
(see Section 1.2.3) will be assigned to the treatment period. Events occurring after the REP 
but prior to next intake or end of trial termination date will be assigned to ’follow-up’. In case 
of two or more treatments, the follow-up will be summarized according to the previous 
treatment. These assignments including the corresponding time intervals will be defined in 
detail in the TSAP. Note that AEs occurring after the last per protocol contact but entered 
before unblinding the trial 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. 

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Table 7.5: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a two-period fixed sequence design 
trial (N=12 evaluable subjects)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
10
1.10
80
72.55
88.22
10
1.10
100
90.68
110.28
10
1.10
125
113.35
137.84
10
1.10
150
136.02
165.41
15
1.16
80
69.11
92.60
15
1.16
100
86.39
115.75
15
1.16
125
107.99
144.69
15
1.16
150
129.59
173.63
20
1.21
80
65.88
97.15
20
1.21
100
82.35
121.43
20
1.21
125
102.94
151.79
20
1.21
150
123.53
182.15
25
1.27
80
62.84
101.85
25
1.27
100
78.55
127.31
25
1.27
125
98.19
159.13
25
1.27
150
117.83
190.96
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(∃T)/exp(∃R).
The expected 90% confidence interval limits in the table were derived by
CI limit !!"#,$%&"# = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 4.0.1.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC and other relevant regulations. Investigators and site staff must adhere to these 
principles. Deviation from the protocol, the principles of ICH GCP or applicable regulations 
will be treated as ‘protocol deviation’.
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 finalisation 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 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.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable.
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.

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For the CRF, data must be derived from source documents, for example:
#
Subject identification: gender, 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
#
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.

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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the 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, storage and 
future use of biological samples and clinical data, in particular
#
Sample and data usage have to be in accordance with the informed consent
#
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage 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 (e.g. 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 ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.

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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
P04-00210
Galteau MM, Shamsa F. Urinary 6beta-hydroxycortisol: a validated test
for evaluating drug induction or drug inhibition mediated through CYP3A 
in humans and in animals. Eur J Clin Pharmacol 2003;59(10):713-733.
P06-08316
Giembycz MA. An update and appraisal of the cilomilast phase III clinical 
development programme for chronic obstructive pulmonary disease. Br J 
Clin Pharmacol 2006; 62(2):138-152.
P10-00100
Turpault S, Brian W, Horn R van, Santoni A, Poitiers F, Donazzolo Y, 
Boulenc X. Pharmacokinetic assessment of a five-probe cocktail for CYPs 
1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 2009;68(6):928-935.
P11-07084
Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic 
pulmonary fibrosis: evidence-based guidelines for diagnosis and 
management. Am J Respir Crit Care Med 2011;183(6):788-824
P12-05791
U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER). 
Guidance for industry: drug interaction studies - study design, data 
analysis, implications for dosing, and labeling recommendations (draft 
guidance, February 2012 (this guidance document is being distributed for 
comment purposes only)). Website: 
fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gu
idances/ucm292362.pdf (access date: 14 May 2012) ; U.S. Department of 
Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER); 2012.
P15-07539
Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT 
clinical practice guideline: treatment of idiopathic pulmonary fibrosis: an 
update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 
2015; 192(2): e3-e19.
P17-10582
Flaherty KR, Brown KK, Wells AU, et al. Design of the PF-ILD trial: a 
double-blind, randomised, placebo-controlled phase III trial of nintedanib 
in patients with progressive fibrosing interstitial lung disease. BMJ Open 
Respir Res 2017; 4: e000212.
P18-04729
Wells AU, Brown KK, Flaherty KR, et al. IPF Consensus Working Group. 
What's in a name? That which we call IPF, by any other name would act 
the same. Eur Respir J 2018; 51:1800692.
P18-06345
Sisson TH, Christensen PJ, Muraki Y, et al. Phosphodiesterase 4 inhibition 
reduces lung fibrosis following targeted type II alveolar epithelial cell 
injury. Physiol Rep 2018; 6(12): e13753.
P19-01738
Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases: 
knowns and unknowns. Eur Respir Rev 2019; 28:180100.

Boehringer Ingelheim
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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-13 (7 0) / Saved on: 22 Jun 2021
P20-01299
Wong AW, Ryerson CJ, Guler SA. Progression of fibrosing interstitial 
lung disease. Respir Res 2020; 21(1):32.
R07-0090
Tran JQ, Kovacs SJ, McIntosh TS, Davis HM, Martin DE. Morning spot 
and 24-hour urinary 6 beta-hydroxycortisol to cortisol ratios: 
intraindividual variability and correlation under basal conditions and 
conditions of CYP 3A4 induction. J Clin Pharmacol 1999;39:487-494
R08-1147
Posner K. State of the science: measurement of suicidal adverse events and 
the Columbia Suicide Severity Rating Scale. 47th NCDEU Ann Mtg, Boca 
Raton, 11 - 14 Jun 2007. 2007:15
R09-0156
Dietsch GN, DiPalma CR, Eyre RJ, et al. Characterization of the 
inflammatory response to a highly selective PDE4 inhibitor in the rat and 
the identification of biomarkers that correlate with toxicity. Toxicol Pathol 
2006; 34:39-51.
R10-1555
Daxas (roflumilast) in chronic obstructive pulmonary disease, NDA 22-
522, FDA Advisory Committee briefing document presented to: 
Pulmonary-Allergy Drugs Advisory Committee (briefing book, April 7, 
2010). Website: 
fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmo
nary -AllergyDrugsAdvisoryCommittee/ucm207376.htm (access date: 23 
November 2010) ; Jersey City: Forest Research Institute; 2010.
R10-1559
Giembycz MA. Life after PDE4: overcoming adverse events with dual 
specificity phosphodiesterase inhibitors. Curr Opin Pharmacol 2005; 
5:238-244.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R12-4395
Guidance for industry: suicidal ideation and behavior: prospective 
assessment of occurrence in clinical trials (draft guidance, August 2012). 
Website: 
fda.gov/downloads/Drugs/GuidanceRegulatoryInformation/Guidances/UC
M22 5130.pdf (access date: 5 October 2012); 2012.
R14-1795
Otezla (apremilast) tablets, for oral use (Celgene). U.S. prescribing 
information, revised: Mar 2014.
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide. 
http://www.statsols.com/wp-
content/uploads/2013/10/nQ70_version2_manual.pdf 
(access date: 20 March 2015) ; Los Angeles: Statistical Solutions; 2007.
R17-0158
Korkmaz S, Maupoil V, Sobry C, et al. An increased regional blood flow 
precedes mesenteric inflammation in rats treated by a phosphodiesterase 4 
inhibitor. Toxicol Sci 2009; 107(1):298-305.

Boehringer Ingelheim
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R17-0915
Daxas (roflumilast 500 mcg tablets: pharmacology/toxicology review of 
NDA 22-522, Center for Drug Evaluation and Research, FDA. Website: 
accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000PharmR.p
df (access date: 06 Apr 2022); Jersey City: Forest Research Institute, 2011.
R17-0916
Losco PE, Evans EW, Barat SA, et al. The toxicity of SCH 351591, a 
novel phosphodiesterase-4 inhibitor, in cynomolgus monkeys. Toxicol 
Pathol 2004; 32(3):295-308.
R17-0919
Otezla (apremilast) (Celgene): pharmacology/toxicology NDA/BLA 
review and evaluation, application number: 205437Orig1s000. Website: 
accessdata.fda.gov/drugsatfda_docs/nda/2014/205437Orig1s000PharmR.p
df (access date: 06 Apr 2022); Department of Health and Human Services, 
Public Health Service, Food and Drug Administration, Center for Drug 
Evaluation and Research (2014).
R17-1427
Otezla 10 mg, 20 mg, 30 mg film-coated tablets, Otezla 30 mg film-coated 
tablets (Celgene) (summary for product characteristics, manufacturer 
responsible for batch release, conditions or restrictions regarding supply 
and use, other conditions and requirements of the marketing authorisation, 
conditions or restrictions with regard to the safe and effective use of the 
medicinal product, labelling and package leaflet (first published 
16/02/2015). Website:ec.europa.eu/health/documents/community-
register/2015/20150115130395/anx _130395_en.pdf (access date: 19 April 
2017);2015.
R17-2617
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen 
P, et al. Opportunistic infections and biologic therapies in immune-
mediated inflammatory diseases: consensus recommendations for 
infection reporting during clinical trials and postmarketing surveillance. 
Ann Rheum Dis 2015;74:2107-2116.
R17-3022
Halama B, Hohmann N, Burhenne J, Weiss J, Mikus G, Haefeli WE, et al. 
A nanogram dose of the CYP3A probe substrate midazolam to evaluate 
drug interactions. Clin Pharmacol Ther 2013;93(6):564-571.
R18-1244
Richter W, Xie M, Scheitrum C, et al. Conserved expression and functions 
of PDE4 in rodent and human heart. Basic Res Cardiol 2011; 106:249-
262.
R18-1245
Bian H, Zhang J, Wu P, et al. Differential type 4 cAMP-specific 
phosphodiesterase (PDE4) expression and functional sensitivity to PDE4 
inhibitors among rats, monkeys and humans. Biochem Pharmacol 2004; 
68:2229-2236.
R19-0854
Kolb M, Vasakova M. The natural history of progressive fibrosing 
interstitial lung diseases. Respir Res 2019; 20(1):57.
R22-1856
Stern AF. The hospital anxiety and depression scale. Occup Med (Oxf) 
2014;64:393-394.

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c36151567
A Phase I, open-label, non-randomized, single-dose, single-arm, single-
period study to investigate the metabolism and pharmacokinetics of [C-14]-
labelled BI 1015550 after oral administration in healthy male subjects. 
1305-0016.
c37065416
A randomised, double-blind, placebo-controlled parallel group study in IPF 
patients over 12 weeks evaluating efficacy, safety and tolerability of BI 
1015550 taken orally. 1305-0013.
c39775503
 Assessment of requirement for male contraception. Memo. 09 
June 2022
n00201897
In vitro determination of BI 1015550 protein binding in human and animal 
plasma and in human serum albumin and α1-acid glycoprotein solutions. 
(DM-11-1046).
n00201905
In vitro blood cell partitioning of 14C-BI 1015550 in rat, Göttingen 
minipig, and human blood. (DM-11-1045).
n00261666
BI 1015550: Metabolite profiling in plasma after multiple oral 
administration to healthy volunteers and metabolite exposure determination 
in human and the relevant toxicity species.
n00290709
A fertility and early embryonic development to implantation study of BI 
1015550 by oral gavage in male and female rats. CRL study no. 9001829, 
BI no. 21R070.
U10-3777
 Investigator Brochure BI 137882 BS. 02 November 
2011.
U11-2788
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 
137882 in healthy male volunteers (A randomised, single-blind, placebo-
controlled phase I study). 1306.1.

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10.2
HOSPITAL ANXIETY AND DEPRESSION SCALE

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
23 Sep 2022
EudraCT number
EU number
2022-002249-16
BI Trial number
1305-0033
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
The effect of multiple oral doses of BI 1015550 on 
metabolism of midazolam administered orally in 
healthy male subjects (open-label, two-period fixed 
sequence design trial)
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1.   1.2.1
2.   1.3
3.   2.2.2.1
4.   3.3.2
5.   3.3.3
6.   3.3.4
7.   3.3.5
8.   5.2.3: 1
9.   5.2.6.1.6
10. 7.5: 1
11. 8.1
12. 8.6
Description of change
1. Rationale for twice daily dosing added.
2. Rationale for performing the trial substantiated.
3. Further PK endpoints clarified.
4. Inclusion criteria clarified.
5. Exclusion criteria clarified.
6. Criteria of withdrawal from trial treatment 
clarified.
7. Trial discontinuation criteria clarified.
8. GFR added to Routine laboratory tests.
9. Causal relationship of AEs clarified.

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10. Confidence intervals clarified.
11. Reference to legally authorized representatives 
deleted.
12. End of study milestone clarified.
Rationale for change
1-2. Request from the ethics committee
4-8, 10-11. Request from the competent authority
3, 5, 7. Correction of typos and mistakes

 
 
 
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