Pharmacokinetics, Safety and Tolerability of BI 1015550 Following Oral Administration in Male and Female Participants With Different Degrees of Renal Impairment (Severe and Moderate) as Compared With Individually Matched Male and Female Participants With Normal Renal Function (an Open-label, Non-randomised, Single Dose, Parallel, Individual-matched Design Trial)
Phase: PHASE1
Conditions: Renal Insufficiency, Healthy
Sponsor: Boehringer Ingelheim



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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
25 Nov 2022
Revision date
10 Jan 2023
BI trial number
1305-0025
Title of trial
Pharmacokinetics, safety and tolerability of BI 1015550 following oral 
administration in male and female participants with different degrees of renal 
impairment (severe and moderate) as compared with individually matched male and 
female participants with normal renal function (an open-label, non-randomised, 
single dose, parallel, individual-matched design trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
In this trial, pharmacokinetics, safety, and tolerability of BI 1015550 single oral 
dose in participants with different degrees of renal impairment compared to 
individually matched participants with normal renal function will be assessed.
Trial objective(s)
To investigate the effect of severe and moderate renal impairment on the 
pharmacokinetics of BI 1015550
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of BI 1015550
Secondary endpoints: AUC0-! of BI 1015550
Trial design
Open-label, non-randomised, single dose, parallel, individual-matched design
Number of participants 
total entered
32*
* additional participants may be included to ensure that the study objectives are 
reached
on treatment
∀Group 1: 8 participants with severe renal impairment 
∀Group 2: 8 participants with normal renal function matching Group 1 **
∀Group 3: 8 participants with moderate renal impairment
∀Group 4: 8 participants with normal renal function matching Group 3**
** Each participant with normal renal function may be matched to multiple 
participants with renal impairment across groups (i.e., Group 1 and Group 3) and 
can be matched to only 1 participant within a renal impairment group. Thus, a 
participant with normal renal function may be in Group 2 as well as in Group 4 and 
the total sample size may be 24 to 32 participants.

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Diagnosis
Participants with renal impairment (severe and moderate) and participants with 
normal renal function (matched controls to the participants with renal impairment)
Main inclusion criteria
Male/female participants (at least 25% of each gender), age of 18-79 years
(inclusive), body mass index (BMI) of 18.5 to 35.0 kg/m2 (inclusive) with renal 
impairment (severe, moderate) based on assessment of eGFR and not requiring 
dialysis:
∀
Moderate renal impairment: 30-59 mL/min/1.73m²
∀
Severe renal impairment: 15-29 mL/min/1.73m²
Participants with normal (≥90 mL/min/1.73m2) renal function age of 18-79 years
(inclusive), BMI of 18.5 to 35 kg/m2 (inclusive) – individually matched by age (± 
10 years), gender, weight (± 15%) and race to the participants with renal 
impairment.
Test product
BI 1015550 tablet, iCF
dose
18 mg
mode of 
administration
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
Single dose
Statistical methods
To assess the effect of renal impairment on the primary and secondary 
pharmacokinetic endpoints of BI 1015550, the relative bioavailability will be 
estimated by the ratios of the geometric means of the respective pairwise 
comparison of interest, i.e., for each renal impairment group vs. the respective 
control group. 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 for any 
comparison of interest. The statistical model will be an analysis of variance 
(ANOVA) on the logarithmic scale including the fixed effect ‘degree of renal 
impairment’ and the random effect ‘matched pair’.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory 8
PK blood 9
PK urine 10
Suicidality assessment 14
12-lead ECG 11
Vital signs (BP, PR) 12
Questioning for AEs and 
concomitant therapy 6
1
-21 to -2
Screening (SCR)1
A
x
x
x
2
-1
-24:00
08:00
Admission to trial site13
B5
x13,15
x
1
-2:00
06:00
x2
x2,7
x2
x2
x2
x2
0:00
08:00
Drug administration
▲
0:30
08:30
x
│
0:45
08:45
x
│
1:00
09:00
x
│
x
x
x
1:15
09:15
x
│
1:30
09:30
x
│
1:45
09:45
x
│
2:00
10:00
240 mL fluid intake (snack for 
participants with diabetes)
x
│
x
x
x
2:30
10:30
x
│
3:00
11:00
x
│
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
┼
x
x
x
6:00
14:00
x
│
8:00
16:00
Snack (voluntary)3
x
┼
x
x
x
10:00
18:00
x
│
11:00
19:00
Dinner3
│
12:00
20:00
x
┼
14:00
22:00
x
│
x
2
24:00
08:00
x
┼
x
x
x
36:00
20:00
x
┼
x
3
48:00
08:00
x
┼
│
x
4
72:00
08:00
Breakfast (voluntary),
discharge from trial site
B
x
┼
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
┼
x
6
120:00
08:00
Ambulatory visit
x
▼
x
7
144:00
08:00
Ambulatory visit
x
x
x
3
8 to 14
End of study (EoS) examination4
C
x
x
x
x
1.
Participant must be informed and written informed consent obtained prior to starting any screening procedures. 
Screening procedures include physical examination (including assessment of suicidal ideation and behaviour using the 
C-SSRS questionnaire), check of vital signs, ECG, safety laboratory (including eGFR, drug screening, alcohol breath 
test, serology, and SARS-CoV-2 PCR test, serum pregnancy test in WOCBP, and HbA1c determination in participants 
with diabetes), demographics (including determination of body height and weight, smoking status and alcohol history), 
relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 2 h prior to drug administration.

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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 (including 
assessment of suicidal ideation and behaviour using the C-SSRS questionnaire), body weight, vital signs, ECG, safety 
laboratory (including urine pregnancy test in WOCBP), recording of AEs and concomitant therapies.
5.
In addition: urine drug screening, alcohol breath test, SARS-CoV-2 antigen test, as well as serum pregnancy test in 
WOCBP
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.
A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96 and 96-
120 h.
8.
Letters A, B and C define different sets of safety laboratory examinations (for details refer to Section 5.2.3).
9.
For details of PK blood sampling, refer to Section 5.3.2.1.
10. For details of PK urine sampling, refer to Section 5.3.2.2.
11. For details of 12-lead ECG, refer to Section 5.2.4.
12. For details of vital signs evaluation, refer to Section 5.2.2.
13. Including assessment of body temperature (if needed due to the current status of the pandemic).
14. For details of suicidality assessment, refer to Section 5.2.5.1.
15. Including measurement of body weight at this time point.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS AND DEFINITIONS..................................................... 10
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................14
1.2.1
BI 1015550 .............................................................................................14
1.2.1.1
Non-clinical pharmacokinetics ................................................14
1.2.1.2
Non-clinical safety pharmacology and toxicology ..................15
1.2.1.3
Clinical pharmacokinetics........................................................16
1.2.1.4
Clinical safety and efficacy......................................................18
1.2.2
Residual Effect Period..........................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................20
1.4
BENEFIT - RISK ASSESSMENT ...................................................................20
1.4.1
Benefits...................................................................................................20
1.4.2
Risks .......................................................................................................21
1.4.3
Discussion...............................................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......26
2.1.1
Main objectives......................................................................................26
2.1.2
Primary endpoints ................................................................................26
2.1.3
Secondary endpoint ..............................................................................26
2.2.2.3
Safety and tolerability..............................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 28
3.1
OVERALL TRIAL DESIGN............................................................................28
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................28
3.3
SELECTION OF TRIAL POPULATION ......................................................29
3.3.1
Main diagnosis for trial entry..............................................................29
3.3.2
Inclusion criteria...................................................................................30
3.3.2.1
Inclusion criteria applying to all participants...........................30

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3.3.2.2
Inclusion criteria applying only to participants with impaired 
renal function ...........................................................................30
3.3.2.3
Inclusion criteria applying only to participants with normal 
renal function ...........................................................................31
3.3.3
Exclusion criteria ..................................................................................31
3.3.3.1
Exclusion criteria applying to all participants .........................31
3.3.3.2
Exclusion criteria applying only to participants with renal 
impairment...............................................................................33
3.3.3.3
Exclusion criteria applying only to matched participants with 
normal renal function...............................................................34
3.3.4
Withdrawal of participants from treatment or assessments.............34
3.3.4.1
Withdrawal from trial treatment ..............................................35
3.3.4.2
Withdrawal of consent to trial participation ............................36
3.3.4.3
Discontinuation of the trial by the sponsor..............................36
3.3.5
Replacement of participants ................................................................36
4.
TREATMENTS........................................................................................ 38
4.1
INVESTIGATIONAL TREATMENTS ..........................................................38
4.1.1
Identity of the Investigational Medicinal Products ...........................38
4.1.2
Selection of doses in the trial................................................................38
4.1.3
Method of assigning participants to treatment groups .....................38
4.1.4
Drug assignment and administration of doses for each 
participant .............................................................................................38
4.1.5
Blinding and procedures for unblinding ............................................39
4.1.6
Packaging, labelling, and re-supply ....................................................39
4.1.7
Storage conditions.................................................................................39
4.1.8
Drug accountability ..............................................................................40
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................40
4.2.1
Other treatments and emergency procedures....................................40
4.2.2
Restrictions............................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment .........................41
4.2.2.2
Restrictions on diet and life style.............................................41
4.2.2.3
Contraception requirements.....................................................41
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
ASSESSMENTS....................................................................................... 43
5.1
ASSESSMENT OF EFFICACY.......................................................................43
5.2
ASSESSMENT OF SAFETY............................................................................43
5.2.1
Physical examination ............................................................................43
5.2.2
Vital signs...............................................................................................43
5.2.3
Safety laboratory parameters..............................................................43
5.2.4
Electrocardiogram................................................................................47
5.2.5
Other safety parameters.......................................................................47

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5.2.5.1
Suicidality assessment .............................................................47
5.2.6
Assessment of adverse events...............................................................48
5.2.6.1
Definitions of adverse events...................................................48
5.2.6.1.1 Adverse event ............................................................48
5.2.6.1.2 Serious adverse event ................................................48
5.2.6.1.3 AEs considered ‘Always Serious’.............................49
5.2.6.1.4 Adverse events of special interest .............................49
5.2.6.1.5 Intensity (severity) of AEs.........................................50
5.2.6.1.6 Causal relationship of AEs ........................................50
5.2.6.2
Adverse event collection and reporting ...................................51
5.2.6.2.1 AE collection.............................................................51
5.2.6.2.2 AE reporting to the sponsor and timelines ................52
5.2.6.2.3 Pregnancy ..................................................................53
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................53
5.3.1
Assessment of pharmacokinetics .........................................................53
5.3.2
Methods of sample collection...............................................................53
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................53
5.3.2.2
Urine sampling for pharmacokinetic analysis..........................54
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................55
5.4
ASSESSMENT OF BIOMARKERS................................................................55
5.5
BIOBANKING ...................................................................................................55
5.6
OTHER ASSESSMENTS .................................................................................56
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................56
6.
INVESTIGATIONAL PLAN.................................................................. 57
6.1
VISIT SCHEDULE............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................57
6.2.1
Screening period....................................................................................57
6.2.2
Treatment period ..................................................................................58
6.2.3
Follow-up period and trial completion ...............................................58
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 59
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................59
7.2
PLANNED ANALYSES....................................................................................59
7.2.1
General considerations.........................................................................59
7.2.1.1
Analysis sets.............................................................................59
7.2.1.2
Pharmacokinetics.....................................................................59

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7.2.2
Primary endpoint analyses...................................................................60
7.2.3
Secondary endpoint analyses ...............................................................61
7.2.5
Safety analyses.......................................................................................61
7.2.6
Interim analyses ....................................................................................62
7.3
HANDLING OF MISSING DATA ..................................................................62
7.3.1
Safety......................................................................................................62
7.3.2
Pharmacokinetics..................................................................................62
7.4
RANDOMISATION ..........................................................................................63
7.5
DETERMINATION OF SAMPLE SIZE ........................................................63
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 64
8.1
TRIAL APPROVAL, PARTICIPANT INFORMATION, INFORMED 
CONSENT ..........................................................................................................64
8.2
DATA QUALITY ASSURANCE .....................................................................65
8.3
RECORDS..........................................................................................................65
8.3.1
Source documents .................................................................................65
8.3.2
Direct access to source data and documents.......................................66
8.3.3
Storage period of records.....................................................................66
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................67
8.5
STATEMENT OF CONFIDENTIALITY AND PARTICIPANT 
PRIVACY ...........................................................................................................67
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................67
8.6
TRIAL MILESTONES .....................................................................................67
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................68
9.
REFERENCES......................................................................................... 70
9.1
PUBLISHED REFERENCES...........................................................................70
9.2
UNPUBLISHED REFERENCES.....................................................................71
10. APPENDICES .......................................................................................... 73
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................73
10.2
LISTING RESTRICTED CONCOMITANT MEDICATION......................79
10.2.1 Strong CYP3A4 inhibitors ...................................................................79
10.2.2 Combinations of CYP 3A4 inhibitors .................................................79
10.3
CKD-EPI FORMULA.......................................................................................80
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 81
11.1
GLOBAL AMENDMENT 1 .............................................................................81

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ILD
Interstitial lung disease
IPD
Important protocol deviation
IPF
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
IUS
Intrauterine hormone-releasing system
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LOAEL
Lowest Observed Adverse Effect Level
MACE
Major Adverse Cardiovascular Events
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NOAEL
No Adverse Effect Level
NOEL
No observable effect level
PCR 
Polymerase chain reaction
PDE4 
Phosphodiesterase 4
PDEi 
Phosphodiesterase inhibitor
PE
Polyethylene
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
REP
Residual effect period
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus type 2
SOP
Standard operating procedure
SRD
Single-rising dose
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TMF
Trial master file

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intensity, with the exception of CRP increase which was of moderate intensity and led to 
discontinuation of the participant [c02191718].
No severe, serious, fatal AEs, nor SUSARS have been reported in the healthy volunteer 
studies. No dose-dependency was observed.
In patients with IPF, two clinical studies have been completed with BI 1015550: a Phase Ic 
MRD study in patients without background antifibrotic treatment (1305-0012 [c25085412]) 
and a proof-of-clinical principle Phase II study in patients stratified by background 
antifibrotic treatment (1305-0013 [c37065416]).
Overall, in Phase Ic and II trials in patients with IPF, BI 1015550 at a dose of 18 mg bid for 
up to 12 weeks showed acceptable safety and tolerability, both in patients without or with 
background antifibrotic treatment (nintedanib or pirfenidone). The most common AEs were 
GI events (more specifically diarrhoea), which were reported with a higher frequency under 
BI 1015550 treatment (vs. placebo) and in patients with background antifibrotic treatment.
In the Phase II trial which investigated treatment with BI 1015550 18 mg bid for 12 weeks in 
patients with IPF, diarrhoea was the most common AE leading to discontinuation of 
treatment and all AEs leading to discontinuation were reported in the BI 1015550 group. The 
frequency of SAEs in patients was numerically higher in placebo-treated patients, which was 
driven by placebo-treated patients without antifibrotic background treatment. Two patients 
with IPF treated with BI 1015550 had fatal AEs: one case of COVID-19 pneumonia and one 
case of suspected condition aggravated/suspected vasculitis; in both cases, risk factors were 
present. One AESI was reported (the fatal AE of suspected vasculitis), and evaluation by an 
external, independent Data Monitoring Committee could neither confirm the diagnosis of 
vasculitis, nor a causal relationship with BI 1015550. There were no AESIs of hepatic injury. 
No relevant patterns, clusters or imbalances were observed for any of the other safety topics 
of interest, including depression, anxiety, malignancies, insomnia, major adverse cardiac 
events, or tachyarrhythmia. No clinically relevant changes in vital signs (including body 
weight) or ECG parameters (including QTc) were observed. No changes in the C-SSRS and 
no AEs of suicidal ideation or behaviour were reported during trial treatment.
Clinical efficacy
In the proof-of-clinical principle Phase II trial, a relevant treatment effect in favour of 
BI 1015550 18 mg bid was observed on the primary efficacy endpoint, the change from
baseline in FVC at 12 weeks. Treatment with BI 1015550 prevented a decline in FVC in 
patients with IPF, irrespective of background antifibrotic treatment, in contrast to the placebo 
groups in which a marked decline in FVC was observed. Thus, treatment with BI 1015550 at 
18 mg twice daily preserved lung function in patients with IPF over 12 weeks.
For a more detailed description of BI 1015550 profile, please refer to the current IB 
[c02094779].
1.2.2
Residual Effect Period
This is the period after the last 
dose during which measurable drug levels and/or pharmacodynamic effects are still likely to 
be present.

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∀
Participant’s withdrawal 
criteria in case of new-onset 
suicidal behaviour or any 
suicidal ideation of type 4 or 
5 in the C-SSRS.
Severe infections
including, serious,
opportunistic and
mycobacterium
tuberculosis infections
∀
Inhibition of the immune response
due to the anti-inflammatory mode 
of action of BI 1015550 potentially
increases the risk of severe and
serious infections.
∀
Serious infections were balanced
between placebo and BI 1015550 
in Phase II trial.
∀
 was more 
frequently reported under treatment 
with BI 1015550 in Phase Ic/II but 
not in Phase I trials and the 
numbers were very small.
∀
Screening procedures for 
infections are defined for this 
trial. Participants with any 
relevant chronic or acute
infections are excluded from 
the trial
∀
Treatment of infections 
should be initiated promptly 
according to standards of care
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
∀
Participants will stay under 
close medical surveillance 
during the whole period of 
72 h after 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.
∀
Participants with a recent 
history of malignancy within 
5 years will be excluded from 
participation in this trial
Gastrointestinal 
disorders (e.g., 
diarrhoea, nausea, 
vomiting, abdominal 
pain)
∀
Vomiting and diarrhoea 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 participants 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 

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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 in general 
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, 
participants 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 active 
infection.
In case of severe COVID-19 infection during the conduct of the trial, treatment with BI 
1015550 will not be started which is also applicable for any other active infection. 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 participants 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 participant from further trial procedures to avoid undue risks to 
other participants 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.
1.4.3
Discussion
The nature of the target and the mechanism of action of BI 1015550 is well understood.
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, ECG, C-SSRS, safety 
laboratory, and AE monitoring with a special focus on vasculitis assessment has been 
implemented.
Taking into account these safety measures, potential risks to participants with normal renal 
function and those with impaired renal function 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 effect of severe and moderate renal 
impairment on the PK of BI 1015550 following oral administration.
2.1.2
Primary endpoints
The following PK parameters will be determined for BI 1015550:
∀
AUC0-tz (area under the concentration-time curve of BI 1015550 in plasma over the 
time interval from 0 to the last quantifiable data point)
∀
Cmax (maximum measured concentration of BI 1015550 in plasma)
2.1.3
Secondary endpoint
The following PK parameter will be determined for BI 1015550:
∀
AUC0-∞(area under the concentration-time curve of BI 1015550 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)
∀
Safety laboratory tests
∀
Assessment of suicidal ideation and behaviour (C-SSRS)
∀
12-lead ECG
∀
Vital signs (BP, pulse rate)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as a non-randomised, parallel matched-group design trial in 
participants with renal impairment (severe and moderate) and participants with normal renal 
function (matched controls to the participants with renal impairment). The treatment will be 
one 18 mg BI 1015550 tablet administered to participants in the fasting state. For details,
refer to Section 4.1.
∀
Group 1: 8 participants with severe renal impairment and not requiring dialysis
∀
Group 2: 8* participants with normal renal function matching Group 1
∀
Group 3: 8 participants with moderate renal impairment 
∀
Group 4: 8* participants with normal renal function matching Group 3
*Each participant with normal renal function may be matched to multiple participants with 
renal impairment across groups (i.e., Group 1 and Group 3) and can be matched to only 
1 participant within a renal impairment group. Thus, a participant with normal renal function 
may be in Group 2 as well as in Group 4.
Matching criteria of the participants with normal renal function to the participants with renal 
impairment:
∀
Age (± 10 years)
∀
Gender
∀
Weight (± 15%)
∀
Race
Each group will contain at least 25% participants (i.e., 2) of each gender.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
Definition of trial start and end are given in Section 8.6.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
From preclinical and clinical data (see Section 1.2.1), no clinically relevant increase in 
exposure to BI 1015550 in patients with impaired renal function is expected.
The group size of 8 participants is considered sufficient for the exploratory evaluation of PK. 
The assignment of individually matched control participants with normal renal function is a 
useful method to control for other factors which may influence the PK of BI 1015550 in a 
renal impaired population. 
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma and urine concentrations of the analyte. Furthermore, all 
participants will receive the same dose, and participants will be stratified to the groups 
according to their renal function.

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The PK of BI 1015550 are dose-linear and time-independent, therefore, a single dose study is 
considered adequate to meet the objectives of the trial.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 male and female participants with severe or moderate renal impairment 
(at least 25% of each gender per group) and up to 16 individually matched male and female 
control participants with normal renal function will enter the trial.
The control participants with normal renal function will be recruited from the volunteers' pool 
of the trial site. Participants with renal impairment will be recruited in cooperation with 
nephrological centres.
Participants will be assigned to one of the renal function groups (moderate renal impairment, 
severe renal impairment, normal renal function) based on their eGFR according to CKD-EPI
(see Appendix 10.3). The assessment of renal function and assignment to the renal function 
groups will be conducted by the investigators at the screening examination. In addition, 
participants with normal renal function will be assigned to a group according to their match 
to a participant with renal impairment (Table 3.3: 1).
Table 3.3: 1
Overview of group stratification
Group
Renal function
eGFR 
(mL/min/1.73 m2)
Number of 
participants
1
Severe impairment
15 – 29
8
2
Normal renal function
≥90
8*
3
Moderate impairment
30 – 59
8
4
Normal renal function
≥90
8*
* Each participant with normal renal function may be matched to multiple participants with renal impairment 
across groups (i.e., Group 1 and Group 3) and can be matched to only 1 participant within a renal impairment 
group. Thus, a participant with normal renal function may be in Group 2 as well as in Group 4.
Participants with normal renal function will be matched individually to a participant with 
impaired renal function by age (± 10 years), weight (± 15%), race, and gender. One 
participant with normal renal function may be matched to multiple participants with renal 
impairment across different groups and can be matched to only 1 participant with renal 
impairment within a group.
A log of all participants 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 participants with impaired renal function and matched control 
participants with normal renal function.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.

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3.3.2
Inclusion criteria
Participants will only be included in the trial if they meet the following criteria:
3.3.2.1
Inclusion criteria applying to all participants
1. Male or female participants
2. Age of 18-79 years (inclusive)
3. BMI of 18.5 to 35.0 kg/m2 (inclusive)
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
5. Male participants are not required to use contraception
6. WOCBP are allowed to participate provided they use a highly effective contraception 
from at least 30 days before the administration of trial medication until 7 days after trial 
completion. 
Of note, oral hormonal contraceptives are not considered as highly effective in this study 
due to the potential CYP3A induction by BI 1015550. Therefore, the following methods 
of contraception are considered adequate for female participants of childbearing potential:
-
Use of combined (oestrogen and progestogen containing) hormonal 
contraception that prevents ovulation (oral, intravaginal or transdermal), plus 
condom
-
Use of progestogen-only hormonal contraception that inhibits ovulation (only 
injectables or implants), plus condom
-
Use of intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS)
-
Sexually abstinent
-
A vasectomised sexual partner who received medical assessment of the 
surgical success (documented absence of sperm) and provided that partner is the 
sole sexual partner of the trial participant.
Female participants are not considered to be of childbearing potential if they are 
either surgically sterilised (including hysterectomy) or postmenopausal, defined as 
no menses for 1 year without an alternative medical cause (in questionable cases,
a blood sample with levels of FSH above 40 U/L and oestradiol below 30 ng/L is 
confirmatory).
3.3.2.2
Inclusion criteria applying only to participants with impaired renal function
In addition to the inclusion criteria given in Section 3.3.2.1, participants with impaired renal 
function must fulfil the following criteria:
7. Renal impairment based on assessment of eGFR at screening (moderate renal 
impairment: 30-59 mL/min/1.73m2, severe renal impairment: 15-29 mL/min/1.73m2); 
participants do not require dialysis and are not anticipated to require haemodialysis or 

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renal transplantation, and are anticipated to have renal function appropriate to moderate 
or severe renal impairment for the duration of the study
8. Chronic renal impairment > 12 months (documented renal impairment indicated by 
reduced eGFR for more than 12 months until screening)
9. Absence of clinically significant abnormalities, as based on a complete medical history 
including a full physical examination, clinical laboratory tests, vital signs (BP, PR) and 
12-lead ECG at both screening and check-in visits, with the exception of findings that in 
the opinion of the investigator are consistent with participant’s renal impairment.
10. Medication and/or treatment regimens must have been stable (i.e., no dose adjustments) 
for at least 4 weeks prior to the screening period and should be kept stable until study 
completion. 
Fluctuating treatment regimens may be considered for inclusion on a case-by-case basis if 
the underlying disease is under control in the opinion of the investigator and must be 
agreed to by both the investigator and the Sponsor.
3.3.2.3
Inclusion criteria applying only to participants with normal renal function
In addition to the inclusion criteria given in Section 3.3.2.1, participants with normal renal 
function must fulfil the following criteria:
11. Individually matched to participants with renal impairment according to sex, age, and 
weight and race
12. eGFR > 90 mL/min/1.73m2
13. Absence of clinically significant abnormalities identified by a detailed medical history, 
full physical examination, vital signs and 12-lead ECG at both screening and check-in 
visits
14. Absence of clinically significant abnormalities identified by a laboratory test at screening 
visit
3.3.3
Exclusion criteria
3.3.3.1
Exclusion criteria applying to all participants
Participants will not be allowed to participate, if any of the following general criteria apply:
1. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
2. Cholecystectomy or other surgery of the GI tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
3. Diseases of the CNS (including but not limited to any kind of seizures or stroke), and 
other relevant neurological or psychiatric disorders (including but not limited to major 
depressive disorder)
4. History of relevant orthostatic hypotension, fainting spells, or blackouts
5. Relevant chronic or acute infections

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6. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or 
squamous cell carcinoma in situ of the skin or in situ carcinoma of uterine cervix
7. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients)
8. Use of drugs within 30 days (or 5 of their half-lives, whichever is longer) of planned
administration of trial medication that might reasonably influence the results of the trial 
(including drugs that cause QT/QTc interval prolongation)
9. Intake of an investigational drug in another clinical trial within 60 days (multiple dose 
trials) / 30 days (single dose trials) or 5 half-lives (whichever is longer) of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
10. Smoker (more than 15 cigarettes or 5 cigars or 5 pipes per day)
11. Inability to refrain from smoking on specified trial days
12. Alcohol abuse (consumption of more than 10 g per day for females and 20 g per day for
males)
13. Drug abuse or positive drug screening
14. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
15. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
16. Inability to comply with the dietary regimen of the trial site
17. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
18. Participant is assessed as unsuitable for inclusion by the investigator, for instance,
because the participant is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study
19. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
20. For female participants: Lactation, pregnancy, or plans to become pregnant during the 
trial or within 7 days after trial completion, or positive pregnancy test
21. Active vasculitis, unstable or uncontrolled within 8 weeks prior to Visit 1 or during the 
screening period.
22. History of vasculitis
23. Relevant immunodeficiency
24. Patients with active tuberculosis at Visit 1 or medical history of incompletely treated 
tuberculosis

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25. Any suicidal behaviour in the past 2 years (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
26. Any suicidal ideation of type 4 or 5 on the C-SSRS in the past 3 months or at Visit 1 
and/or Day 1 predose (i.e. active suicidal thought with method and intent but without 
specific plan; or active suicidal thought with method, intent and plan)
27. Cardiovascular diseases, any of the following:
a. Severe hypertension within 3 months of Visit 1
b. Myocardial infarction, stroke or transient ischaemic attack within 6 months of Visit 1
c. Unstable cardiac angina within 6 months of Visit 1
3.3.3.2
Exclusion criteria applying only to participants with renal impairment
In addition to the exclusion criteria listed in Section 3.3.3.1, participants with renal 
impairment fulfilling any of the following criteria will not be included into the trial:
28. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 480 ms in males or repeatedly greater than 500 ms in females) or any other 
relevant ECG finding at screening
29. Acute renal failure or active nephritis
30. Nephrotic syndrome
31. Impaired hepatic function, including relevant increases in liver enzymes indicating liver 
disease
32. Relevant diseases for which it can be assumed that the absorption of the study drugs will 
not be normal (i.e., relevant malabsorption, chronic diarrhoea)
33. Participant under dialysis or planned to start dialysis during participation in the study
34. History of myocardial infarction, cerebrovascular accident or severe arrhythmia within 
the 6 months prior to the screening visit
35. History of vascular surgery or intervention (e.g., coronary artery bypass, percutaneous 
transluminal angioplasty etc.) less than 6 months prior to dosing
36. Congestive heart failure of New York Heart Association grade III or IV, severe 
arrhythmia requiring antiarrhythmic treatment
37. History of clinically significant aortic or pulmonary valve stenosis, or renal artery 
stenosis
38. Any other disease or condition which could influence the physiological metabolic 
turnover (e.g., endocrine diseases, severe infections)
39. Significant uncorrected rhythm or conduction disturbances such as a second-or third 
degree AV block without a cardiac pacemaker, marked QTc prolongation (such as QTc 
intervals that are repeatedly greater than 480 ms in males or repeatedly greater than 
500 ms in females at screening), or episodes of sustained ventricular tachycardia
40. Resting supine systolic BP below 99 or above 179mmHg and resting supine diastolic BP 
below 50 or above 100 mmHg at screening visit

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41. Resting supine HR equal to or below 50 bpm or above 90 bpm, at screening visit
42. Haemoglobin <9 g/dL
43. Serum albumin <30 g/L
44. Platelet count <100 x 109/L
45. Other clinically relevant deviations in clinical chemistry (especially liver enzymes) or 
haematology
46. Participants with diabetes mellitus with a fasting blood glucose >220 mg/dL or glycated 
haemoglobin (HbA1c) >10%
3.3.3.3
Exclusion criteria applying only to matched participants with normal renal 
function
In addition to the exclusion criteria listed in Section 3.3.3.1, participants with renal 
impairment fulfilling any of the following criteria will not be included into the trial:
47. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
48. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males or repeatedly greater than 470 ms in females) or any other 
relevant ECG finding at screening
49. Repeated measurement of systolic BP outside the range of 90 to 140 mmHg (for 
participants older than 60 years: 90 to 150 mmHg), diastolic BP outside the range of 50 to 
90 mmHg, or pulse rate outside the range of 50 to 90 bpm
50. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
51. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of participants from treatment or assessments
Participants 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 participant is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this participant will not be entered in the case report form (CRF) 
and will not be reported in the clinical trial report (CTR).
If a participant 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.

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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 1.2.2, the 
discontinued participant 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 participant.
3.3.4.1
Withdrawal from trial treatment
An individual participant will be withdrawn from trial treatment if:
1. The participant wants to withdraw from trial treatment. The participant will be asked to 
explain the reasons but has the right to refuse to answer
2. The participant 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 
participant cannot be guaranteed as he / she is not willing or able to adhere to the trial
requirements in the future.
3. The participant needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4. The participant can no longer receive trial treatment for medical reasons (such as 
pregnancy, surgery, AEs, or diseases)
5. The participant has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of 
total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be 
followed up according to the DILI checklist provided in the ISF
6. The participant exhibits suicidality, in the clinical judgment of the investigator or 
according to the following criteria:
∀
any suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behaviour)
∀
any suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal thought 
with intent but without specific plan, or active suicidal thought with plan and 
intent)
7. If any of the following AEs is reported, the treatment has to be discontinued:
-
Severe or serious infections, opportunistic or mycobacterium tuberculosis infections
-
Malignancies
-
Vasculitis
Of note, depending on the current status of the COVID-19 pandemic, all participants 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 participant (refer to Section 1.4.2).
In addition to these criteria, the investigator may discontinue participants at any time based 
on his or her clinical judgment.

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If it is known that a participant becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the participant is to be removed from the trial. 
The participant is to be followed until she has given birth or until the end of the pregnancy. 
The participant’s data are to be collected until the end of the trial (last visit of last participant) 
and reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.6.2.3.
If new efficacy or safety information becomes available, BI will review the benefit-risk-
assessment and, if needed, pause or discontinue the trial treatment for all participants or take 
any other appropriate action to guarantee the safety of the trial participants.
3.3.4.2
Withdrawal of consent to trial participation
Participants may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a participant wants to withdraw consent, the investigator should be 
involved in the discussion with the participant and explain the options for continued follow-
up after trial treatment discontinuation.
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, SAEs, or any safety information invalidating the earlier 
positive benefit-risk-assessment (see Section 3.3.4.1)
5. More than 50% of the participants show drug-related and clinically relevant AEs of 
moderate intensity, or if more than two participants have drug-related severe non-serious 
adverse events, or if at least one drug-related SAE is reported
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 participants
In case more than 2 participants in any group do not complete the trial (including participants 
non-evaluable for PK), additional participants may be enrolled and treated in this respective 
trial group, i.e. “replaced”, if considered necessary to reach the objective of the trial.
Participants who withdraw or are withdrawn from treatment or assessments because of a
drug-related AEs will not be replaced. The Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many participants will 
be replaced. The total number of replacements may not exceed 1/3 of the total number of 

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evaluable participants anticipated to complete the trial. A replacement participant will be 
assigned a unique trial participant number. In case of enrolment of additional participants, the 
trial site should ensure the requirements for distribution of gender (‘at least 25% of each 
gender within each group’) are still met within the comprising group of further on treated and 
additionally enrolled participants.

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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 (iCF)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
18 mg
Posology:
1-0-0
Mode of administration:
Oral
4.1.2
Selection of doses in the trial
The dose selected for this trial is one of the standard clinical doses (see Section 1.2).
4.1.3
Method of assigning participants to treatment groups
There is only one treatment investigated in this trial.
Participants with renal impairment and matching control participants will be assigned to 
treatment groups according to their renal function (Section 3.1).
Groups 3 and 4 will only be conducted if the effect of severe renal impairment on the PK of 
BI 1015550 is obvious, as described in Section 3.1.
Once a participant number has been assigned, it cannot be reassigned to any other participant.
All participants may be treated in one cohort, i.e. all participants may receive treatment on the 
same calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), 
the group may be split into several cohorts as required. For discussion of trial-associated risks 
and safety measures, see Section 1.4).
4.1.4
Drug assignment and administration of doses for each participant
This is a non-randomised, open-label, individual-matched parallel design trial. All 
participants will receive the same active treatment. The treatments to be evaluated are 
summarised in Table 4.1.4: 1 below.

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Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T (Test)
BI 1015550
Film-coated 
tablet
18 mg
1 tablet (18 mg) as single dose
18 mg
Administration of trial medication will be performed after participants have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. The investigator (or 
authorised designee) will administer the trial medication as an oral dose together with about 
240 mL of water to participants who are in a sitting/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.
Participants will be kept under close medical surveillance until 72 h after drug administration. 
During the first 4 h after drug administration, participants are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture), except for 
examinations and assessments.
4.1.5
Blinding and procedures for unblinding
This non-randomised open-label Phase I trial will be handled in an open fashion throughout. 
There will be only one treatment, so the treatment assignment will be available to all involved 
parties.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of GMP.
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the participant information form. The EudraCT number is indicated on 
the title page of this protocol as well as on the participant information and informed consent
forms.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
CRA (as provided in the list of contacts) is to be contacted immediately.

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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB / ethics committee
∀
Availability of a signed and dated clinical trial contract between the sponsor or 
delegate and the investigational site
∀
Approval/notification of the regulatory authority, e.g. competent authority
∀
Availability of the curriculum vitae of the Principal investigator
∀
Availability of a signed and dated clinical trial protocol 
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial participants. 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 participant, 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 
participants. The investigator or designee will maintain records that document adequately that 
the participants 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, participants 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.

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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed except for hormonal contraceptives or ovary 
hormone replacement. Medications considered as exclusion criteria are also restricted during 
the trial.
In participants with renal impairment, contraceptives as well as concomitant medication for 
the treatment of the renal disorder or other concomitant diseases are allowed.
Strong CYP3A inhibitors are restricted medications in all trial participants due to potential 
DDI (see Appendix 10.2).
Short-term use of ibuprofen and acetylsalicylic acid is acceptable for symptomatic treatment 
of AEs, if necessary.
All concomitant or rescue therapies will be recorded (including time of intake on trial days) 
on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the participants will be instructed not to consume any foods 
or drinks other than those provided by the staff. Standardised meals will be served at the 
times indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake. Only 
participants with diabetes will receive a snack at 2 h post dose, if necessary.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
participants). From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements are not permitted from 7 days before the administration of trial 
medication until after the last PK sample is collected.
Products containing St. John's wort (Hypericum perforatum) are not permitted from 30 days 
before the administration of trial medication until after the last PK sample is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) not allowed from 24 h before administration of trial medication until the end of in-
house confinement at the trial site.
Smoking is not allowed from 10 h before until 8 h after administration of trial medication.
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.
4.2.2.3
Contraception requirements
If WOCBP are included in the trial, adequate contraception is to be maintained throughout 
the course of the trial (see Section 3.3.2 for the definition of adequate measures).

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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 
and/or urinary excretion of trial medication will provide additional confirmation of 
compliance.
Participants 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, concomitant therapies, and C-SSRS scale. 
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, a physical examination including determination of body weight, recording of AEs, 
concomitant therapies, and C-SSRS scale.
5.2.2
Vital signs
Systolic and diastolic BP as well as PR or HR (HR is considered to be equal to PR) will be 
measured by a BP monitor (Dinamap Pro care DPC220x,
 
 at the times indicated in the Flow Chart, after participants have rested for at least 
5 min in a supine position. All recordings should be made using the same type of BP
recording instrument on the same arm, if possible.
Body temperature will be monitored as part of vital signs assessment if still needed due to the 
current status of the pandemic. Body temperature will not be entered into the eCRF.
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 participants 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
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
HbA1c (only in participants with diabetes)
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
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
--
--
--
--
X
X
X
--
Enzymes
AST (Aspartate aminotransferase) /GOT, SGOT 
ALT (Alanine aminotransferase) /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase (CK]
Creatine Kinase Isoenzyme MB (only if CK is elevated]
Lactic Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
Free T3 - Triiodothyronine 
Free T4 – Thyroxine
FSH (if applicable)
Oestradiol (if applicable)
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
Substrates
Glucose (Plasma)
Creatinine
eGFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant) 
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X *
X
X
X
X
--
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)
Magnesium
X
X
X
X
X
X
X
X
X
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, or nitrite 
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 2 on Day -1 and 4 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (EoS examination)
* eGFR/CKD-EPI only on Day -1
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 pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
the treatment period, and as part of the end of trial examination. Drug screening will be 
performed at screening and prior to treatment.

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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 HR at rest and to assure high quality recordings, the site personnel will 
be instructed to assure a relaxed and quiet environment, so that all participants are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after participants 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.
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 participant 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
Prospective monitoring will be conducted throughout this trial using the C-SSRS.
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation. It does 
not give a global score but provides some categorical and some severity information 
specifically for behaviour and ideation.
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 participant’s suicidal ideation type 4 to 5 within the preceding 3 months or at Visit 1 
or any suicidal behaviour in the past 2 years. The lifetime history of suicidal ideation and 
behaviour will also be recorded.
After Visit 1, the assessment ‘since last visit’ will be performed at each clinic visit (‘since last 
visit’ version).
Appendix 10.1 provides details how the C-SSRS will be assessed.
C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.2.

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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 participant 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.
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 behaviour 
must be reported as separate SAEs by the investigator.
For ‘self-injurious behaviour, 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 AE as defined 
in the protocol, and if it is considered an AE then it must be reported accordingly.
Adverse event report for diarrhoea events
In case of events of diarrhoea, the following definitions should be followed:
∀
Diarrhoea is defined as at least 3 loose or liquid stools per day (WHO definition)
∀
Diarrhoea episode = 2 diarrhoea episodes are separated by at least 7 days without any 
diarrhoea
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

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∀
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 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
∀
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 participants showing these 
lab abnormalities need to be followed up according to the ‘DILI checklist’ provided in 

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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.
∀
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), 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].
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.

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Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug
∀
The event is known to be caused by or attributed to the drug class
∀
A plausible time to onset of the event relative to the time of drug exposure
∀
Evidence that the event is reproducible when the drug is re-introduced
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger
∀
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 participant’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently.
Participants will be required to report spontaneously any AEs. In addition, each participant
will be regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, participants 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.

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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 participant’s end of 
trial (the 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 participants discontinue from the 
trial due to screening failures prior to administration of any trial medication. In 
these cases, the participants’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.
∀
After the individual participant’s end of trial:
o
The investigator does not need to actively monitor the participant 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 participant’s end of 
trial, must be followed up until they have resolved, have been sufficiently characterised (e.g. 
as ‘chronic’ or ‘stable’), or no further information can be obtained.

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5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a participant has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 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 PK, blood and urine samples will be collected at the time points / time 
intervals indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of PK parameters.
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 1015550 and 
 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 within 1 h after blood draw. Two plasma 
aliquots will be obtained and stored in polypropylene tubes. The first aliquot should contain 
at least 0.5 mL of plasma. The remaining plasma will be transferred into a second 
polypropylene tube. The process from blood collection until transfer of plasma aliquots into 
the freezer should be completed within 2 h, with interim storage of blood samples and 
aliquots at room temperature. The time each aliquot was placed in the freezer will be 
documented. Until transfer on dry ice to the analytical laboratory, the aliquots will be stored 
upright at approximately -20°C or below at the trial site. The second aliquot will be 

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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 barcode, BI trial number, participant
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
Urine sampling for pharmacokinetic analysis
A blank urine sample will be collected before administration of trial medication (ref. Flow 
Chart) and two 0.5 mL aliquots will be retained to check for analytical interference by 
concomitant or rescue medication.
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
3-L polyethylene (PE) containers and stored in the cooler. Participants are told to empty their 
bladders at the end of each sampling interval.
Due to the known adsorption (its metabolites) to the container wall and instability of the 
metabolites, 115.2 g citric acid and 30 mL of 20% Tween 20 solution will be added to the 3-L
container prior to the start of urine sampling. The weight of the empty container including 
citric acid will be determined, 30 mL of 20% Tween 20 will be added, and the weight of the 
container at the end of each sampling interval will be determined. (however, no correction for 
the specific gravity of urine is done, i.e. 1 L is defined to be equal to 1 kg). Two 0.5 mL 
aliquots will be stored in polypropylene (PP) tubes for bioanalytical measurements. If more 
than one collection container is used in a sampling interval, the contents of all containers 
have to be mixed before aliquots are prepared. Mixing should be done by transferring the 
entire content of all collection containers into a Single PE/PP or glass container, and stirring 
the mixed fractions for about I min (manually or using a stir bar or other stirring device made 
of PE, PP, Teflon or glass). 
Generally, the collection container should be shaken upon addition of every urine fraction to 
ensure proper distribution of Tween and urine. 
At a minimum, the sample tube labels should list barcode, BI trial number, subject number, 
visit, and planned collection time. Further information, such as matrix and analyte may also 
be provided. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at
approximately -20%C +/- 5°C or below at the trial site. The second aliquot will be transferred
after the bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical 
laboratory, the urine samples will be stored at approximately -20°C or below until analysis.
After analysis, the urine samples may be used for further methodological investigations (e.g. 
for stability testing, assessment of metabolites) or to address Health Authority questions 

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regarding the results/methodology. However, only data related to the analyte and/or its 
metabolite(s) 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 has been archived.
5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between PK and pharmacodynamic parameters is planned for 
this trial.
5.4
ASSESSMENT OF BIOMARKERS
Not applicable.
5.5
BIOBANKING
Not applicable.

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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 participants’ safety and to determine PK parameters in an 
appropriate way. The scheduled measurements will allow monitoring of changes in vital
signs, standard laboratory values, suicidal risk 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 PK 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 2 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, and laboratory tests will be ± 30 min during the inhouse period, and 
± 2 h for ambulatory visits.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the procedures due to its inconvenience to the participant and possible influence on 
physiological parameters.
For planned blood sampling times and urine collection intervals, 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 PK parameters.
To allow for a streamlined operational conduct of trials at trial site, the following flexibility 
as regards time-windows for PK sampling times will be allowed:
∀
Predose: within 2 h prior to drug administration
∀
Postdose:
-
From dosing until 2 h: ± 2 min;
-
>2 h until 4 h: ± 5 min;
-
>4 h until 72 h: ± 15 min;
-
>72:00: ± 60 min
If a participant 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 participants 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, and physical examination, refer to Sections 5.2.1 to 5.2.5.

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6.2.2
Treatment period
On Day -1 of the treatment period, trial participants will be admitted to the trial site. They 
will be kept under close medical surveillance for at least 72 h following drug administration
on Day 1. The participants will then be allowed to leave the trial site on Day 4 after formal 
assessment and confirmation of their fitness. On all other trial days, participants will come to 
the trial site for ambulatory visits.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining participant’s written informed consent until the end of trial
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Participants who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a participant’s EoS Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
To assess the effect of renal impairment on the PK of BI 1015550, the relative bioavailability 
will be estimated by the ratios of the geometric means of the respective pairwise comparison 
of interest for the primary and secondary endpoints, i.e., for each renal impairment group vs. 
the respective control group. Additionally, their 2-sided 90% 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 participants 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 participants in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and that was not excluded due to a protocol deviation relevant to the 
evaluation of PK or due to PK non-evaluability (as specified in Section 7.2.1.2). Thus, 
a participant will be included in the PKS, even if he/she contributes only one PK 
parameter 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 PK parameters listed in Section 2.1 and 2.2.2 for drug BI 1015550 and 
 will be 
calculated according to the relevant BI internal procedures.
Plasma and urine concentration data and parameters of a participant will be included in the 
statistical 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 participant’s data will be documented in the CTR.

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Important protocol deviations may be
∀
Incorrect dose of trial medication taken
∀
Use of restricted medications
Plasma and urine concentrations and/or parameters of a participant will be considered as non-
evaluable, if for example
∀
The participant experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the participants 
experiencing emesis),
∀
A predose concentration is >5% Cmax value of that participant
∀
Missing samples/concentration data at important phases of PK disposition curve
Plasma/urine concentration data and parameters of a participant which are flagged for 
exclusion will be reported with its individual values but will not be included in the statistical 
analyses. 
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. Concentrations used in the PK calculations 
will be in the same format provided in the bioanalytical report, (that is, to the same number of 
decimal places provided in the bioanalytical report).
7.2.2
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an ANOVA 
model on the logarithmic scale. That is, the PK endpoints will be log-transformed (natural 
logarithm) prior to fitting the ANOVA model. This model will include effects accounting for 
the following sources of variation: ‘degree of renal impairment” as a fixed effect as well as
‘matched pair’ as random effect.
The model is described by the following equation:
yik = & + si + ∃k + eik, where
yik = logarithm of response measured for the degree of renal impairment k and
matched pair i,
& = the overall mean,
si = the effect associated with the ith matched pair, m = 1, 2, …, 8
∃k = the effect associated with the kth degree of renal impairment, k = 1 for normal 
renal function (control) and k=2, 3 for moderate, severe renal impaired respectively,
eik = the random error associated with the degree of renal impairment k for matched 
pair i
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and si, eik are independent random variables
(note that the indices ‘B’ and ‘W’ correspond to ‘between’ and ’within’ matched pair 
variability, respectively).

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The model described above will be fitted separately for the two renal impaired groups, i.e., 
one model for the participants with severe renal impairment and their matched controls and 
one model for the participants with moderate renal impairment and their matched controls.
For the evaluation of each primary endpoint, the difference between the expected mean for
log response of renal impaired group k (k=2, 3) – log response of normal control group
(k=1) will be estimated by the difference in the corresponding adjusted means (Least Squares 
Means). Additionally, their two-sided 90% CIs will be calculated based on the residual error 
from the ANOVA and quantiles from the t-distribution. These quantities will then be back-
transformed to the original scale to provide the point estimate and 90% CIs for each endpoint.
Further exploratory analyses
In addition to the model-based approach all parameters will be calculated and analysed 
descriptively.
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.
7.2.5
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
participants (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.
Groups 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 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 the intake of trial medication will be 
assigned to the screening period, those between intake of trial medication and end of REP 
(see Section 1.2.2) will be assigned to the treatment period. Events occurring after the REP 
but prior to EoS examination date will be assigned to ’follow-up’. 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 database lock of the trial
will be reported to Pharmacovigilance only and will not be captured in the trial database.

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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.
C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.2 and will be 
summarised as such. Results of the C-SSRS will be provided as listing.
Previous and concomitant therapies will be presented per group without consideration of time 
intervals and treatment periods.
In general, unless otherwise specified in the TSAP, the last non-missing measurement prior to 
study treatment will be used as baseline for safety variables.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No formal interim analysis is planned.
A preliminary, exploratory analyses of all available or specific data (e.g. safety, PK) may be 
performed prior to final database lock to inform other activities during the development of 
BI 1015550. In case of preliminary assessment of PK data, the PK parameters will be 
calculated according to the relevant BI internal procedure. In contrast to the final PK 
calculations, the preliminary analysis will be based on planned sampling times rather than on 
actual times, regardless of whether actual times were within the time windows. Therefore, 
minor deviations may occur between preliminary and final results. The possible preliminary 
PK analysis will provide individual and gMean concentration profiles and summary statistics 
of PK parameters per group. No inferential statistical preliminary analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.

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7.4
RANDOMISATION
The trial will not be randomised, thus this section is not applicable.
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to include a maximum of 32 participants in the trial: 8 participants with severe 
renal impairment, 8 participants with moderate renal impairment and up to 16 matched 
control participants with normal renal function will be treated. Note, one participant with 
normal renal function may match a participant in only one or in both groups with renal 
impaired participants. The matching criteria are described in Section 3.1.
The planned sample size is not based on a power calculation, but is considered sufficient to 
detect major differences between the different groups of participants with renal impairment 
and the respective control group containing participants with normal renal function.

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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 participant’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial participants 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 participants and are stored in the ISF.
8.1
TRIAL APPROVAL, PARTICIPANT 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 participant’s participation in the trial, written informed consent must be obtained 
from each participant 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 participant-information form retained by the investigator 
as part of the trial records. A signed copy of the informed consent and any additional 
participant information must be given to each participant.
The participant must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the participant’s own free will with the 
informed consent form after confirming that the participant understands the contents. The 
investigator or his / her 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 participant 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 participants 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 participant 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 participant 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 participant, 
documented in their medical records, would be acceptable.
Before providing any copy of participants’ source documents to the sponsor, the investigator 
must ensure that all participant identifiers (e.g., participant’s name, initials, address, phone 
number, and social security number) have properly been removed or redacted to ensure 
participant confidentiality.
If the participant is not compliant with the protocol, any corrective action (e.g. re-training) 
must be documented in the participant file.

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For the CRF, data must be derived from source documents, for example:
∀
Participant identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Participant participation in the trial (substance, trial number, participant number, date 
participant was informed)
∀
Dates of participant’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 participant’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)
∀
Prior to allocation of a participant 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 participant or 
testing conducted specific for a protocol) to support inclusion/exclusion criteria does 
not make the participant eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g.
FDA). They may review all CRFs and informed consents. The accuracy of the data will be 
verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor 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 PARTICIPANT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of participant data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual participant 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 participant’s personal physician or to other 
appropriate medical personnel responsible for the participant’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 participant in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last participant in the whole 
trial (‘Last Participant Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.

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Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state.
A final report of the clinical trial data will be written only after all participants have 
completed the trial in all countries (EU or non-EU), so that all data can be incorporated and 
considered in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last participant
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI web portal 
Clinergize to access documents provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial activities, in order to
∀
Manage the trial in accordance with applicable regulations and internal SOPs
∀
Direct the clinical trial team in the preparation, conduct, and reporting of the trial
∀
Ensure appropriate training and information of local Clinical Trial Managers
(CT Managers), CRAs, and investigators of participating trial sites
The trial medication will be provided by the 
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
.
Analyses of BI 1015550 and 
concentrations in plasma and urine will be performed 
at
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.

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Data management and statistical evaluation will be done by BI, or a contract research
organisation appointed 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
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.
P20-01299
Wong AW, Ryerson CJ, Guler SA. Progression of fibrosing interstitial lung 
disease. Respir Res 2020; 21(1):32.
P22-03204
Raghu G, Remy-Jardin M, Richeldi L, et al. American Thoracic Society, 
European Respiratory Society, Japanese Respiratory Society, Asociacion 
Latinoamericana de Torax. Idiopathic pulmonary fibrosis (an update) and 
progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT 
clinical practice guideline. Am J Respir Crit Care Med 2022;205(9):e18-
e47
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI). A new equation to 
estimate glomerular filtration rate. Ann Intern Med. 2009 May 
5;150(9):604-12
R13-4387
Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure 
Work Group. KDIGO 2012 clinical practice guideline for the evaluation 
and management of chronic kidney disease. Kidney Int Suppl; 2013 
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

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R19-0854
Kolb M, Vasakova M. The natural history of progressive fibrosing 
interstitial lung diseases. Respir Res 2019; 20(1):57.
R22-3783
European Medicines Agency. Committee for Medicinal Products for 
Human use (CHMP): guideline on the evaluation of the pharmacokinetics 
of medicinal products in patients with decreased renal function (17 
December 2015, EMA/CHMP/83874/2014). 2015
R22-3784
Food and Drug Administration. Guidance for industry: pharmacokinetics in 
patients with impaired renal function - study design, data analysis, and 
impact on dosing: draft guidance (this guidance document is being 
distributed for comment purposes only.) (September 2020, clinical 
pharmacology, revision 2). 2020.
9.2
UNPUBLISHED REFERENCES
c02094779
 
 Investigator's Brochure BI 1015550 for 
1305.P3, current version.
c02191718
Safety, tolerability and pharmacokinetics of multiple rising oral doses of BI 
1015550 powder for oral solution in healthy male volunteers q.d. or bid for 
14 days (a randomised, double-blind, placebo-controlled within dose groups 
Phase I trial). 1305.2.
c20307414
Relative bioavailability of BI 1015550 following oral administration under 
fed and fasted conditions in healthy male subjects. 1305-0020.
c22991937
Safety, tolerability and pharmacokinetics of single and multiple rising oral 
doses of BI 1015550 in healthy subjects. 1305-0011.
c24902949
Relative bioavailability of a single oral dose of BI 1015550 when 
administered alone or in combination with multiple oral doses of 
itraconazole in healthy male subjects. 1305-0015.
c25085412
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 
1015550 in patients with idiopathic pulmonary fibrosis (IPF) on no 
background anti-fibrotic therapy. 1305-0012.
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

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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.

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10.2
LISTING RESTRICTED CONCOMITANT MEDICATION
10.2.1
Strong CYP3A4 inhibitors
∀
boceprevir
∀
ceritinib
∀
clarithromycin
∀
cobicistat
∀
conivaptan
∀
diltiazem
∀
idelalisib
∀
indinavir
∀
itraconazole
∀
ketoconazole oral administration
∀
LCL161
∀
mifepristone
∀
mibefradil
∀
nefazodone
∀
nelfinafir
∀
posaconazole
∀
ribociclib
∀
ritonavir
∀
saquinavir
∀
telaprevir
∀
telithromycin
∀
troleandomycin
∀
VIEKIRA PAK2
∀
voriconazole
10.2.2
Combinations of CYP 3A4 inhibitors
∀
danoprevir/ritonavir
∀
elvitegravir/ritonavir

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∀
indinavir/ritonavir
∀
lopinavir/ritonavir
∀
paritaprevir/ritonavir/ombitasvir/dasbuvir
∀
saquinavir/ritonavir
∀
tipranavir/ritonavir
10.3
CKD-EPI FORMULA
eGFR (mL/min/1.73m2) = 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if 
female] x 1.159 [if Black]
-
SCr (standardized serum creatinine) = mg/dL
-
κ = 0.7 (females) or 0.9 (males)
-
α = -0.329 (females) or -0.411 (males)
-
min = indicates the minimum of SCr/κ or 1
-
max = indicates the maximum of SCr/κ or 1
-
age = years
See references [R12-1392, R13-4387].

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
10 Jan 2023
EudraCT number
EU number
2022-003080-18
BI Trial number
1305-0025
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
Pharmacokinetics, safety and tolerability of 
BI 1015550 following oral administration in male 
and female participants with different degrees of 
renal impairment (severe and moderate) as 
compared with individually matched male and 
female participants with normal renal function (an 
open-label, non-randomised, single dose, parallel, 
individual-matched design trial)
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1. Synopsis 
2. Section 3.3.2.1 Inclusion Citeria No. 2
Description of change
1. Inclusion Criteria no. 2 Age changed to 18-
79 years inclusive in Synopis and section 
3.3.2.1
Rationale for change
1. BfArM Request

 
 
 
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