A Randomized, Double-blind, Placebo-controlled, Parallel Group Trial Evaluating Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of BI 1291583 One Tablet Once Daily Over 12 Weeks Versus Placebo in Adult Patients With Cystic Fibrosis Bronchiectasis (Clairafly™)
Phase: PHASE2
Conditions: Cystic Fibrosis, Bronchiectasis
Sponsor: Boehringer Ingelheim

BI-VQD-12177_40-106_AD-03 (22.0)
TITLE PAGE
Clinical Trial Protocol
Document Number:
c40742178-04
EU Clinical Trial No.
2022-502835-21-00
Universal Trial Number
U1111-1291-2567
BI Trial No.
1397-0013 (ClairaflyTM)
BI Investigational
Medicinal Product(s)
BI 1291583
Title
A randomised, double-blind, placebo-controlled, parallel group trial 
evaluating safety, tolerability, pharmacodynamics and pharmacokinetics of 
BI 1291583 one tablet once daily over 12 weeks versus placebo in adult 
patients with cystic fibrosis bronchiectasis (ClairaflyTM)
Lay Title
A study to test how well BI 1291583 is tolerated by people with cystic 
fibrosis bronchiectasis (ClairaflyTM)
Clinical Phase
IIa
Clinical Trial Leader
Phone: 
Fax: 
Email: 
Coordinating 
Investigator
Phone: 
Fax: 
Email: 
Current Version and 
Date
Version 4.0, 21-Nov-2023
Original Protocol Date
Version 1.0, 09-May-2023
Page 1 of 125
Proprietary confidential information.
© 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written 
permission.
I 
Boehringer 
~111111/ lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original Protocol 
date
Version 1.0, 09-May-2023
Revision date
21 Nov 2023
BI trial number
EU CT number
Universal Trial 
Number
1397-0013 (ClairaflyTM)
2022-502835-21-00
U1111-1291-2567
Title of trial
A randomised, double-blind, placebo-controlled, parallel group 
trial evaluating safety, tolerability, pharmacodynamics and 
pharmacokinetics of BI 1291583 one tablet once daily over
12 weeks versus placebo in adult patients with cystic fibrosis 
bronchiectasis (ClairaflyTM)
Coordinating 
Investigator
Trial sites
Multi-centre trial conducted in approximately 7 countries
Clinical phase
IIa
Trial rationale
The intent of this profiling study is to assess safety, 
pharmacokinetics and pharmacodynamics of BI 1291583 in
patients with cystic fibrosis bronchiectasis (CFB).
 
Benefit-risk 
assessment and 
ethical 
considerations
The nature of the target and the mechanism of action of 
BI 1291583 is well understood. In the context of the unmet 
medical need and anticipated benefit of BI 1291583 for the study 
population, the benefit-risk evaluation of the compound, based 
upon the available preclinical and clinical information, is 
considered favorable.
Trial objectives
Primary objective: To investigate safety and tolerability of 5 mg 
BI 1291583 in patients with CFB following oral daily 
administration over 12 weeks.
Secondary objectives: To investigate pharmacodynamics (PD) and 
to assess the PK after the first dose and at steady state after 
multiple dosing of BI 1291583 5 mg qd
Trial endpoints
Primary endpoint: Occurrence of TEAEs up to 16 weeks from first 
drug administration

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Trial endpoints, 
cont.
Secondary endpoints: 

Relative change from baseline in Neutrophil elastase (NE)
activity in sputum at Week 8 after first drug administration

AUC over a dosing interval (AUCτ) for the first dose

Maximum concentration (Cmax) for the first dose

AUCτ at steady state (AUCτ,ss)

Cmax at steady state (Cmax,ss)
Trial design
Multi-center, randomised, placebo-controlled, double-blind, 
parallel group trial to evaluate safety, tolerability, PD and PK of
BI 1291583 5 mg p.o. qd over 12 weeks versus placebo in adult 
patients with CFB.
Total number of 
trial participants 
randomised
24 eligible patients
Number of trial 
participants per
treatment group
16 patients on BI 1291583 5 mg qd
8 patients on Placebo qd
Diagnosis,
main inclusion and 
exclusion criteria
Main Diagnosis
Cystic fibrosis bronchiectasis (CFB)
Main inclusion criterion
Adult patients of either sex with a diagnosis of CFB (confirmed by 
CT) treated or not treated with cystic fibrosis transmembrane 
conductance regulator (CFTR) modulator therapy (individual
standard of care)
Main exclusion criterion
Any acute infection requiring systemic or inhaled anti-infective 
therapy or clinically relevant respiratory infection within 4 weeks 
prior first trial drug intake
Test product
BI 1291583 
Dose and mode of 
administration
5 mg qd, p.o. (oral)
Comparator 
product
Matching placebo 
Dose and mode of 
administration
Not applicable, p.o. (oral)
Duration of treatment 12 weeks
Statistical methods
The primary endpoint and secondary endpoints will be evaluated 
using descriptive statistics. No confirmatory testing is performed 
and hence no null and alternative hypotheses are defined. All 
evaluations are to be considered exploratory.

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FLOW CHART
Trial Periods
Screening
Treatment
End 
of 
study
Visit
1
2
3
4
5
6 / 
EoT
1
7 / 
EoS1/
FU
Week
-6
0
1
4
8
12
16
Day
-42
1
8
29
57
85
113
Time window for visits [days]
≥7 d prior V2
-
±3
±3
±3
±3
+7
Informed consent2
X
Demographics
X
Medical history / proof of CFB
diagnosis
X
X
CT scan (proof of BE diagnosis)3
X
Review of in-/ exclusion criteria
X
X
Physical examination including 
skin
X
X
X
X
X
X
X
Vital signs, pulse rate, blood 
pressure, aural body temperature5
X
X
X
X
X
X
X
Height (only at Visit 1) /
body weight
X
X
X
Sputum collection at site 
(spontaneous or induced)6
X
X
X
X
X
X
Sputum collected at home 
(backup sample, if needed)7
(X)
X
X
X
X
P. aeruginosa sputum sample for 
culture8
X
X
Murray sputum colour chart
X
X
12-lead ECG
X
X
X
X
Panoramic radiography11
X
Safety laboratory tests (blood / 
urine samples)12
X
X
X
X
X
X
(X)
Pregnancy tests13
X
X
X
X
X
X
Cotinine (urine)
X
X
X
X
X
X
PK blood sample (profile)15
X
X
PK blood sample (trough)15
X
X
X
X
X

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Trial Periods
Screening
Treatment
End 
of 
study
Visit
1
2
3
4
5
6 / 
EoT
1
7 / 
EoS1/
FU
Week
-6
0
1
4
8
12
16
Day
-42
1
8
29
57
85
113
Time window for visits [days]
≥7 d prior V2
-
±3
±3
±3
±3
+7
All AEs/SAEs/AESIs; 
concomitant therapy
X
X
X
X
X
X
X
Pulmonary exacerbation review, 
eCRF documentation
X
X
X
X
X
X
IRT call/notification
X18
X
X
X
X
Randomisation
X19
Dispense trial medication20
X
X
X
Collect trial medication
X
X
X
Compliance / drug accountability
X
X
X
Completion of trial participant 
participation
X
1   Patients who completed treatment as planned will have an End of Treatment Visit (EOT) and a subsequent Follow up Visit 
after 28 (+7) days. The Follow-up Visit will be End of Study (EOS). Trial participants who discontinue trial treatment 
prematurely should undergo the EOT Visit as soon as possible and the EOS Visit 28 (+7) days thereafter.
2   Informed consent needs to be signed before any trial-related procedure is performed (before or at Visit 1).
3   CT scan not older than 5 years at randomisation. A new CT may be performed for the purpose of the study, if the patient 
is otherwise eligible. It has to be ensured that local regulatory requirements regarding radiation exposure are fulfilled.
4   
5   Measurements of vital signs should precede blood sampling and intake of trial medication.
6   Sputum samples will be used for NE activity and other biomarker assessment, details are provided in the ISF / lab 
manual.
7   All patients will be provided sputum containers for sputum collection at home in the morning of visit days, if possible. 
At V2 only applicable in case patient’s eligibility providing sputum sample at site already confirmed (see 
Section 5.4.1.3.2 for details).
8   P. aeruginosa culture from sputum samples will be performed at central lab.
9  
10

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11 A standard panoramic radiograph is required for baseline assessment of the periodontal status at the dentist, historical 
radiographs taken within 1 year prior to randomisation are acceptable. If a new radiograph needs to be performed within 
the scope of the trial, this should happen if the patient is otherwise eligible and, if applicable, in accordance with local 
regulations regarding radiation exposure.
12  Laboratory tests for safety monitoring: HBV and HCV tests to be performed only at Visit 1, 
      SARS-CoV-2 testing may be performed according to official local/national recommendations. At EOS, laboratory 
sample collection will be performed at the discretion of the investigator.
13  For WOCBP. At screening, a serum pregnancy test on β-HCG is performed. Urine dipstick pregnancy tests will be provided 
by central laboratory and should be performed at every visit (except at Visit 3).
14 
      (Note for Visit 1: fasting can only be asked for if informed consent was signed at least the day before V1)
15  PK trough samples will be taken at all visits just before drug administration. Date and exact clock time of drug
administration and blood sampling must be recorded in the eCRF. Further PK samples for PK profile will be taken at 
Baseline and at EOT according to PK sampling time schedule (Appendix 10.2, PK time schedule). Patients will receive a 
PK-card at Visit 2 to support the recording of the exact clock time of medication intake for the previous two doses 
preceding PK sampling at subsequent visits.
16 
17  
18  Screening has to be registered in the Interactive Response Technology (IRT) system at time of informed consent to 
trigger initial medication supply to the site. The use of CFTR modulator therapy (CFTR-MT) has to be entered via the 
IRT module (CFTR-MT yes / no).
19  Randomisation V2: At randomisation the use of CFTR-MT has to be confirmed as stratification factor via the IRT 
module (CFTR-MT yes / no).
20  Patients should be instructed not to take their trial medication at home on scheduled visit days but bring it to the site and 
take it after respective pre-dose procedures have been performed.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS AND DEFINITIONS...........................................................................11
1.
INTRODUCTION...............................................................................................15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
DRUG PROFILE................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................22
1.4
BENEFIT - RISK ASSESSMENT.....................................................................23
1.4.1
Benefits.................................................................................................................23
1.4.2
Risks .....................................................................................................................24
1.4.2.1
Risk related to the COVID-19 pandemic..............................................................27
1.4.3
Key safety data from clinical studies.................................................................28
1.4.4
Discussion.............................................................................................................29
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................32
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........32
2.1.1
Main objectives....................................................................................................32
2.1.2
Primary endpoint................................................................................................32
2.1.3
Secondary endpoint(s) ........................................................................................32
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................34
3.1
OVERALL TRIAL DESIGN.............................................................................34
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................35
3.3
SELECTION OF TRIAL POPULATION .......................................................37
3.3.1
Main diagnosis for trial entry ............................................................................38
3.3.2
Inclusion criteria .................................................................................................38
3.3.3
Exclusion criteria ................................................................................................39
3.3.4
Discontinuation of trial participants from treatment or assessments............41
3.3.4.1
Discontinuation of trial treatment .........................................................................42
3.3.4.2
Withdrawal of consent to trial participation .........................................................43
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................43
4.
TREATMENTS...................................................................................................44
4.1
INVESTIGATIONAL TREATMENTS ...........................................................44
4.1.1
Identity of the Investigational Medicinal Products..........................................44
4.1.2
Selection of doses in the trial..............................................................................44
4.1.3
Method of assigning trial participants to treatment groups ...........................45

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4.1.4
Drug assignment and administration of doses for each trial participant......45
4.1.5
Blinding and procedures for unblinding...........................................................46
4.1.5.1 
Blinding.................................................................................................................46
4.1.5.2
Emergency unblinding and breaking the code......................................................47
4.1.6
Packaging, labelling, and re-supply...................................................................47
4.1.7
Storage conditions...............................................................................................47
4.1.8
Drug accountability.............................................................................................48
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................48
4.2.1
Other treatments and emergency procedures..................................................48
4.2.1.1
Additional treatments............................................................................................49
4.2.2
Restrictions ..........................................................................................................49
4.2.2.1
Restrictions regarding concomitant treatment ......................................................49
4.2.2.2
Restrictions on diet and lifestyle...........................................................................51
4.2.2.3
Contraception requirements..................................................................................51
4.3
TREATMENT COMPLIANCE........................................................................52
5.
ASSESSMENTS..................................................................................................53
5.1
ASSESSMENT OF EFFICACY........................................................................53
5.1.1
Pulmonary exacerbation.....................................................................................53
5.1.2
Pulmonary function testing................................................................................53
5.2
ASSESSMENT OF SAFETY.............................................................................56
5.2.1
Physical examination ..........................................................................................56
5.2.2
Vital signs.............................................................................................................57
5.2.3
Safety laboratory parameters ............................................................................57
5.2.4
Electrocardiogram ..............................................................................................59
5.2.6
Assessment of adverse events.............................................................................61
5.2.6.1
Definitions of AEs ................................................................................................61
5.2.6.2
Adverse event collection and reporting ................................................................64
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................65
5.3.1
Assessment of pharmacokinetics .......................................................................65
5.3.2
Methods of sample collection .............................................................................66
5.3.4
Pharmacokinetic - pharmacodynamic relationship.........................................66
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................66
5.4.1
Pharmacodynamics, safety, and patient selection biomarkers.......................66
5.4.1.1
Baseline patient characterisation:..........................................................................66
5.4.1.2
Pharmacodynamic investigations..........................................................................67

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5.4.1.3
Methods and timing of sample collection..........................................................68
5.5
BIOBANKING ....................................................................................................71
5.5.1
Methods and timing of sample collection..........................................................71
5.6
OTHER ASSESSMENTS...................................................................................71
6.
INVESTIGATIONAL PLAN.............................................................................73
6.1
VISIT SCHEDULE.............................................................................................73
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................74
6.2.1
Screening period..................................................................................................74
6.2.2
Treatment period ................................................................................................76
6.2.3
Follow-up period and trial completion..............................................................77
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE......................................................................................................................79
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................79
7.2
PLANNED ANALYSES.....................................................................................79
7.2.1
General considerations .......................................................................................79
7.2.2
Handling of Intercurrent Events .......................................................................80
7.2.3
Primary objective analyses.................................................................................80
7.2.4
Secondary objective analyses.............................................................................81
7.2.4.1
Neutrophil elastase activity in sputum..................................................................81
7.2.4.2
Pharmacokinetic endpoints ...................................................................................81
7.2.7
Other Analyses ....................................................................................................82
7.2.8
Interim Analyses .................................................................................................82
7.3
HANDLING OF MISSING DATA ...................................................................83
7.4
RANDOMISATION ...........................................................................................83
7.5
DETERMINATION OF SAMPLE SIZE .........................................................83
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........85
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................85
8.2
DATA QUALITY ASSURANCE ......................................................................86
8.3
RECORDS...........................................................................................................86
8.3.1
Source documents ...............................................................................................86
8.3.2
Direct access to source data and documents.....................................................87
8.3.3
Storage period of records ...................................................................................88
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................88
8.5
STATEMENT OF CONFIDENTIALITY AND TRIAL PARTICIPANT 
PRIVACY ............................................................................................................88

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8.5.1
Collection, storage and future use of biological samples and 
corresponding data .............................................................................................89
8.6
TRIAL MILESTONES.......................................................................................89
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................90
9.
REFERENCES....................................................................................................92
9.1
PUBLISHED REFERENCES............................................................................92
9.2
UNPUBLISHED REFERENCES......................................................................96
10.
APPENDICES.....................................................................................................97
10.1
CREATININE CLEARANCE...........................................................................97
10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................98
10.3
EQUIVALENT DOSES OF CORTICOSTEROIDS.......................................99
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................118
11.1
GLOBAL AMENDMENT 1 ............................................................................118
11.2
GLOBAL AMENDMENT 2 ............................................................................121
11.3
GLOBAL AMENDMENT 3 ............................................................................123

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ABBREVIATIONS AND DEFINITIONS
AE
Adverse event
AESI
Adverse event of special interest
ALCOA
Attributable, legible, contemporaneous, original, accurate
ALT
Alanine aminotransferase
AMP
Auxiliary medicinal product
AST
Aspartate aminotransferase
ATS 
American Thoracic Society
AUC
Area under the curve
BE
Bronchiectasis
BI
Boehringer Ingelheim
bid
Bis in die, twice daily
BM
Biomarker
BP
Blood pressure
CA
Competent Authority
CAT
COPD Assessment Test
CatC
Cathepsin C
CatG
Cathepsin G
CF
Cystic fibrosis
cfu
Colony forming units
CFB
Cystic fibrosis bronchiectasis
CFTR
Cystic fibrosis transmembrane conductance regulator
CFTR-MT
CFTR modulator therapy
CI
Confidence interval
Cmax
Maximum plasma concentration
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical research associate
CRF
Case report form, paper or electronic (sometimes referred to as 
“eCRF”)
COVID-19
Coronavirus disease 2019
CRO
Contract Research Organisation
CT
Computed tomography

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CTCAE
Common Terminology Criteria for Adverse Events
CT Leader
Clinical trial leader
CT Manager
Clinical trial manager
CTP
Clinical trial protocol
CTR
Clinical trial report
DBL
Database lock
DILI
Drug induced liver injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DV
Deviation Domain
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
EoS
End of study (corresponds with end of trial)
EoT
End of treatment
ERS
European Respiratory Society
FU
Follow-up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HA
Health authority
IB
Investigator’s Brochure
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ICSR
Individual Case Safety Reports
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
IRT
Interactive response technology
ISF
Investigator site file

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IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LPLT
Last participant last treatment
LPLV
Last participant last visit
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed module with repeated measurements
MoA
Mode of Action
MRD
Multiple rising dose
NCFB
Non-cystic fibrosis bronchiectasis
NE
Neutrophil elastase
NOAEL
No observed adverse effect level
NSPs
Serine proteases released by neutrophils
OPU
Operative unit
p.o.
Per os (oral)
PD
Pharmacodynamics
PCD
Primary ciliary dyskinesia
PID
Primary immunodeficiency disorders
PK
Pharmacokinetics
PKS
Pharmacokinetic set
PR
Pulse rate
PTM
Planned time
PV
Pharmacovigilance
qd
Quaque die (once a day)
RA
Regulatory authority
RBC
Red blood cell
REML
Restricted maximum likelihood
REP
Residual effect period
RS
Randomised set
SAE
Serious adverse event

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SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SCS
Screening set
SoC
Standard of care
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment emergent AE
TIR
Treatment Information Release
t1/2
Half-life time
tmax
Timepoint of maximum plasma concentration
TMF
Trial master file
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WBC 
White blood cell
WHO
World Health Organisation
WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Bronchiectasis, a hallmark of cystic fibrosis (CF) lung disease, is a heterogenous lung disease 
characterised by abnormal and irreversible dilation of the airways caused by chronic 
infection, inflammation and airway obstruction. Patients suffer from high symptom burden 
(cough, production of large volumes of sputum, dyspnea, chronic fatigue, hemoptysis) and 
low quality of life. Recurrent exacerbations of bronchiectasis lead to worsened symptoms, 
hospitalisation, and increased mortality.
As CFB (cystic fibrosis bronchiectasis) was historically considered a pediatric disease, and 
NCFB (non-cystic fibrosis bronchiectasis) was considered a disease of adults, bronchiectasis 
research tended to consider CFB and NCFB as separate entities. Nowadays, the majority of 
CF patients are adults and NCFB is increasingly recognised and diagnosed in pediatric 
patient populations. Bronchiectasis is a neutrophilic airway disease in which serine proteases 
released by neutrophils (NSPs) are elevated and a major driver in the pathogenesis of 
bronchiectasis. 
 
Bronchiectasis, including bronchiectasis related to CF, is characterised by neutrophilic 
bronchial inflammation. NSPs, such as NE, cause structural damage to the airways, goblet 
cell metaplasia and mucus hypersecretion, impaired mucus clearance, and result in a vicious 
cycle of chronic airway infections, inflammation and progressive airway damage
[P13-15562]. Free airway NE is particularly high in patients with bronchiectasis and CF 
[R18-3357]. Damaged and dilated airways filled with mucus are an ideal growth medium, 
leading to chronic infection with pathogens such as Pseudomonas (P.) aeruginosa. 
Irreversibly dilated airways, goblet cell metaplasia, mucus hypersecretion and impaired 
mucus clearance leads to recurrent acute worsening of respiratory symptoms commonly 
associated with a drop in lung function, referred to as acute pulmonary exacerbations. 
Exacerbations are a hallmark of bronchiectasis, leading to further airway damage and 
increased mortality. Even though airway dilation is irreversible, its detrimental consequences 
might be mitigated and its progression may be slowed. There is currently no registered 
therapy that ameliorates neutrophilic inflammation and tissue destruction mediated by 
uncontrolled NSP activity in the airways of patients with bronchiectasis, including patients 
with underlying CF.
The relevance of NE for the pathophysiology of bronchiectasis has been confirmed in a 
number of studies. NE represents the most abundant elastase in the sputum of chronically 
inflamed airways in CFB and NCFB patients and is a key driver of tissue destruction 
independent of the underlying disease [R18-3357, R18-3321, R22-1286, R22-1285]. 
Sputum NE activity is a biomarker of disease severity and a predictor of risk for 
exacerbations in patients with bronchiectasis [P19-09060]. 

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The central role of neutrophilic inflammation driven by serine proteases is well described in 
both, CFB and NCFB [R19-3084]. Compared to NE, less evidence exists for proteinase 3 
(PR3) and Cathepsin G (CatG), but these two proteases are also assumed to make a relevant 
contribution to extracellular matrix protein degradation. Hence, suppressing all three NSPs by 
inhibition of CatC is expected to have a stronger beneficial impact on bronchiectasis, 
compared to direct reduction of, e.g., NE activity alone. 
As an effective airway host defence is absent in CFB and NCFB, P. aeruginosa can establish 
persistent bronchial infection in these patients, representing one of the most important 
pathogens across etiologies of bronchiectasis, and is associated with high mortality rates 
[R22-1343, R20-1169]. CFB and NCFB share a number of common characteristics, with 
NCFB already being the outcome of numerous etiologies of various origins. Underlying 
etiologies of NCFB range from other diseases such as primary ciliary dyskinesia (PCD), 
asthma, COPD, post infectious sequelae, primary immunodeficiency disorders (PID) and 
various autoimmune diseases such as inflammatory bowel disease or rheumatoid arthritis. 
Many patients have idiopathic bronchiectasis.
CF is an inherited life-threatening disease affecting the respiratory and gastrointestinal 
systems and characterised by respiratory manifestations, pancreatic exocrine insufficiency, 
and abnormally high sweat electrolytes. It affects more than 100,000 children and adults 
worldwide [R23-0768].
The gene responsible for the disease encodes a transmembrane protein called cystic fibrosis 
transmembrane conductance regulator (CFTR) that functions as an ion channel and is critical 
in the transport of anions (chloride and bicarbonate) and fluid across epithelial surfaces
[R15-5856]. In CF patients, CFTR malfunction results in abnormally thick, sticky mucus that 
clogs the bronchi and leads to chronic airway infection and inflammation resulting in 
progressive bronchiectasis. Almost all patients with CF have bronchiectasis by the time they 
reach adulthood, and respiratory failure is the main cause of death.
CF patients represent a subset of the global population afflicted with bronchiectasis. The 
incidence of bronchiectasis is increasing worldwide. Previously classified as a rare disease, 
NCFB is estimated at 53 to 566 cases per 100, 000 inhabitants, increasing with age and 
occurring more frequently in females than males [R21-3309, R21-3311]. CF makes up 10% 
of the total bronchiectasis population. Bronchiectasis is established in over 75% of CF 
patients and in most adults with this disease [R21-4488].
Standard therapy for adult and pediatric patients with CF includes pancreatic enzyme 
replacement, nutritional supplements, physiotherapy supported by airway clearance 
techniques and devices, antibiotics, anti-inflammatory therapies such as ibuprofen, inhaled 
drugs such as dornase alfa (Pulmozyme®), bronchodilators, inhaled hypertonic saline.
In patients with specific CFTR mutation types, CFTR modulators alone or in combination are 
SoC and offer substantial benefit to patients by restoring effectively the function of CFTR 
channels. 

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However, even with the majority of patients with CF responding to CFTR-MT, established 
bronchiectasis with significant structural damage is not reversible and inflammatory markers 
and NE remain elevated even in this patient population as seen with Ivacaftor monotherapy 
which is also CFTR-MT for patients with gating mutations [R22-3244]. A subset of patients 
treated with CFTR-MT (estimated 15 to 20%) still suffer from bronchiectasis symptoms and 
pulmonary exacerbations [R20-0582, R22-0627]. Some patients (approx. 10%) have CFTR 
genotypes that do not respond to CFTR-MT and a number of patients do not have access to 
CFTR-MT. All these subsets of patients continue to experience airway complications of 
bronchiectasis similar to patients with NCFB. Therefore, therapies that can reduce active 
serine proteases, could improve the clinical status of patients with bronchiectasis, including 
CFB and in conjunction with existing medications reduce the risk of bronchiectasis 
exacerbations, improve quality of life and potentially improve patient survival.
1.2
DRUG PROFILE
For a comprehensive description of the BI 1291583 profile, please refer to the current 
Investigator’s Brochure (IB) [c18711868].
Mechanism of action
Cathepsin C (CatC) is a cysteine protease which is exclusively responsible for the activation 
of all NSPs (NE, CatG, PR3) during myelopoiesis of neutrophils in the bone marrow
[R17-2915]. All three NSPs contribute to inflammation and tissue destruction. NE impairs 
ciliary function and promotes mucus secretion, it cleaves CXCR1, CD14, and CD16 on 
neutrophils and thus disables bacterial killing and impairs innate immunity. By crippling 
normal host opsonophagocytosis, bacterial persistence is promoted. Epithelial cells, induced 
by NE, release IL-8, which in turn recruits even more neutrophils that are unable to kill 
bacteria, i.e., excessive amounts of NE induce ineffective antibacterial defence [R18-3384]. 
Goblet cell metaplasia, mucus hypersecretion and impaired mucus clearance also contribute 
to an ineffective antibacterial defence.
BI 1291583 is a potent and highly selective inhibitor of CatC and is expected to improve the 
protease-antiprotease balance in the lungs of patients with chronic neutrophilic airway 
inflammation.
The anti-serine protease effects of CatC inhibition are not expected to be apparent in 
peripheral blood and non-myelogenic organs until several weeks after treatment is started, 
given the central nature of inhibition in the bone marrow and maturation time of 
inflammatory cell precursors in the bone marrow and subsequent release into the systemic 
circulation [R17-3119]. Inhibition of CatC is expected to decrease loading of active NE, 
CatG, and PR3 into neutrophils.
Reduction of NE, PR3 and CatG is expected to result in anti-inflammatory and tissue-
preserving effects. 

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Improving the protease-antiprotease balance is expected to reduce goblet cell metaplasia, 
mucus hypersecretion, symptoms of cough and sputum, frequency and severity of pulmonary 
exacerbations, and hospitalisation thereby improving health-related quality of life. Supporting 
this hypothesis, another CatC inhibitor, brensocatib, has demonstrated proof of concept in a 
Phase II trial in NCFB. In that trial, sputum NE activity was reduced from baseline over the 
24-week treatment period, and time to the first exacerbation was prolonged as compared with 
placebo. Patients exhibiting chronic airway infection with P. aeruginosa (30% of the overall 
trial population) benefitted equally from treatment [R21-0168] as patients that were not P. 
aeruginosa colonised. A PK study investigating brensocatib in patients with CF is completed. 
Similar levels of NE inhibition in blood might be reached by CatC inhibition in both NCFB 
and CF patients (clinicaltrials.gov identifier: NCT05090904; [R23-4200]).
Key pharmacokinetic and pharmacodynamic characteristics from clinical studies
In healthy subjects, following single dose administration of BI 1291583 (
 
 in SRD trial 1397-0001 and multiple-dose administration (
) 
in multiple rising dose (MRD) trials 1397-0002 and 1397-0011 and 1397-0003 Japanese 
healthy volunteers, BI 1291583 was readily absorbed with peak plasma concentration 
observed 6 h to 7 h post-dose. Pharmacokinetic steady state is reached within 14 days of 
dosing. Renal clearance is low. In a relative bioavailability food effect study (1397-0008), no 
food effect was observed. Exposure to BI 1291583 was slightly higher (less than 2-fold) in 
Japanese than in non-Japanese and within the exposure thresholds established in non-clinical 
studies.
The following 
human metabolites of BI 1291583 were identified and characterized:
The pharmacodynamic effects noted with CatC in MRD trials 1397-0002 and 1397-0011 
were dose dependent. Peripheral inhibition of CatC activity was noted at 6 h post-dose on the 
first day of dosing. With repeat dosing, maximum effects were observed by Day 7 to Day 10. 
Inhibition of peripheral CatC activity declined over 2 to 4 weeks after stopping treatment.
The duration of decline increased with dose.
The down-stream pharmacodynamic effects, for example inhibition of NE activity, were 
observed to commence after 20 days of dosing. Decreased PR3 was first demonstrated by 
Day 28.

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This delay in onset of down-stream effects in peripheral blood is expected and is caused by 
the lag due to maturation time of neutrophils in the bone marrow, prior to their release into 
the systemic circulation.
Drug-drug interactions
BI 1291583 is mainly metabolised by CYP3A4 and is a P-gp transporter substrate. In trial 
1397-0010, drug-drug interaction between BI 1291583 and itraconazole (a strong CYP3A4 
and Pg-P inhibitor) was investigated. BI 1291583 systemic exposures increased 
approximately 2-fold when co-administered with itraconazole. Chronic treatment with 
concomitant strong CYP3A4 and P-gp inhibitors and inducers should be avoided.
BI 1291583 may inhibit the P-gp transporter at dosages of 
 or greater at the site of first 
contact (relevant for P-gp mediated transport at the luminal surface of enterocytes). It may 
inhibit BCRP at doses 
. As the top dose to be administered in the current trial is
5 mg, there are no restrictions for concomitant therapies that are P-gp or BCRP substrates. 
For the metabolites described above, no interactions with P-gp or CYP450 isoenzymes could 
be observed.
Residual Effect Period
As described previously, with the downstream pharmacodynamic effects of BI 1291583, 
there is a lag period for onset and offset of pharmacodynamic effects (recovery of NE activity 
in the periphery for example). Based on clinical data from studies 1397-0002 and 1397-0011, 
the pharmacodynamic Residual Effect Period (REP) of BI 1291583 is 28 days. This is the 
period after which pharmacodynamic effects are expected to have reversed.
Data from non-clinical studies
The toxicology program of BI 1291583 to date includes repeat-dose studies up to 26 weeks in 
Wistar rats, 39 weeks in Göttingen minipigs, and up to 13 weeks in CD1-mice, embryo-fetal 
development studies in Wistar rats and rabbits, a standard battery of genotoxicity studies both 
in vivo and in vitro, an immunotoxicology study, and a phototoxicity study.
Reproductive toxicology studies to evaluate fertility and early embryonic development, and 
pre- and postnatal development, as well as carcinogenicity studies are planned. 
The multiples of exposure in minipigs were calculated compared to the total steady-state area 
under the curve (AUC) from time 0 to 24 hours (AUC0-24) (187 nM·h in Caucasian and 273 
nM h in Japanese) in humans at the top dose of 5 mg qd to be administered in this study. In 
rats, the multiples of exposure were calculated to the unbound AUC0-24 (26.6 and 38.8 nM·h
in Caucasians and Japanese, respectively) due to differences in protein binding between rats 
and humans. 
BI 1291583 induced findings considered to be related to phospholipidosis and/or lysosomal 
storage in all tested species, starting at 1.7-fold (1.1-fold in Japanese) and at 33-fold (23-fold 

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in Japanese) the expected AUC0-24 total/unbound, in the chronic toxicity studies in the 
minipig and rat, respectively. 
These findings were considered relevant to humans, however, sufficiently high multiples of 
exposure to degenerative changes [starting at 169-fold (Japanese: 117-fold) in the rat and 
170-fold (Japanese: 116-fold) in the minipig] and mortality [1,556-fold (Japanese: 1066-fold)
in the minipig] were achieved. In the chronic toxicity studies, minimal findings of 
phospholipidosis and lysosomal storage were observed at the no observed adverse effect level 
(NOAEL) in the rat [AUC0-24: 33-fold (Japanese: 23-fold)] and minipig [AUC0-24: 1.7-fold
(Japanese: 1.1-fold)] with a low incidence, severity and lack of additional degenerative 
changes and, therefore not considered adverse.
Findings considered to be related to altered bone remodelling were present in the minipig and 
in the rat and were considered potentially relevant to humans. In the minipig, immature 
woven bone formation and marrow cavity fibrosis were present after 4 and 13 weeks of 
administration at exposures equal or higher than 38-fold (Japanese: 26-fold) and absent at 8-
fold (Japanese 5-fold) the AUC0-24 total at the therapeutic dose. These findings were 
considered adverse. After 39-weeks of treatment in minipigs, minimally increased amount of 
bone (hyperostosis), composed of well-formed and mature lamellar bone, was present at 
exposures equal or higher than 10-fold (Japanese: 7-fold) the AUC0-24 total, but was not 
accompanied by any change in the bone biomechanical parameters at any dose levels. This 
finding was conservatively considered adverse.
In the 26-week study in the rat, minimally increased amount of bone (hyperostosis) was 
present at exposures equal to or higher than 169-fold (Japanese: 116-fold) and absent at 
33-fold (Japanese: 23-fold) the AUC0-24 unbound at the therapeutic dose and was 
accompanied by minimally decreased stiffness of the tibial diaphysis in males, at very high 
doses of BI 1291583 [resulting in exposures of 552-fold (Japanese: 379-fold) the AUC0-24
unbound at the expected human therapeutic dose], which was fully reversible after a 4-week 
recovery period. The minimally increased amount was conservatively considered adverse at 
all dose levels [c18711868].
For toxicological qualification, human metabolites of BI 1291583 were tested for 
pharmacological activity on the target (cathepsin C), for off-target effects (CEREP-87 
screen), for abuse potential (CEREP screen) and for genotoxicity. 
 
 
. However later study results showed that 
all human metabolites were also formed from BI 1291583 in preclinical species including the 
rat:
•
 do not show any pharmacological 
on- or off-target effects or relevant effects in binding assays for targets related to 
abuse potential. 
All four metabolites are non-genotoxic and were covered in rats and minipigs with 
comfortable safety margins

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•
does not show any pharmacological on- or off-target effects or relevant 
effects in binding assays for targets related to abuse potential. In vivo repeat-dose 
toxicity studies in Wistar rats up to 13 weeks showed no adverse findings up to the 
highest tested dose of 
, resulting in exposure multiples of 552-fold 
(Japanese: 415-fold) the AUC0-24h at the expected human therapeutic dose of BI 
1291583
•
was non-mutagenic and non-clastogenic in systemically exposed tissues 
(bone marrow and liver), but exerts a clastogenic, local effect at the direct site of 
contact (stomach). High exposure multiples comparing the concentration free of 
effects in the Comet assay in the rat stomach to the human concentration in the liver 
of patients in repeat dose trials administered 
 BI 1291583 qd (639- and 
285-fold) were achieved. The dose multiples were still 389-fold for repeated 
administration of
 qd of BI 1291583 to Japanese volunteers. Therefore, since 
clastogenicity is a threshold-related effect, the exposure to the metabolite is 
considered safe for patients with chronic administration in the current study
For 
 in silico assessments for the prediction of mutagenicity were negative. 
Testings for pharmacological activity on the target (CatC), for off-target effects (CEREP-87 
screen), for abuse potential (CEREP screen) and for genotoxicity are planned. Based on 
available data, 
 is covered within the general toxicity studies in rats and the 
embryofetal development toxicity studies. It is not expected to be pharmacologically active 
based on structure-activity relationship considerations.
Human teratogenicity/fetotoxicity for BI 1291583 and its metabolites was not demonstrated 
in the embryofetal development (EFD) toxicity study in Wistar rats and New Zealand White 
Rabbits:
•
In rats, a slight but dose dependent increase in the incidence of skeletal variations, 
affecting the sternebra (misshapen ossification site), ribs (misaligned costal cartilage) 
and pelvis (caudal shift in the position of the pelvic girdle) was observed. 
These variations occur naturally in control animals and at 
 the 
incidence of variations was within background data. At all dose levels, these minor 
variations were not considered adverse, since a variation is a change that occurs 
within the normal population under investigation and is unlikely to adversely affect 
survival or health. This might include a delay in growth or morphogenesis that has 
otherwise followed a normal pattern of development [R12-0355]. The NOAEL for 
maternal and embryo-fetal toxicity was therefore considered to be 100 mg/kg/day 
resulting in exposures of 788- fold and 538-fold to the expected human therapeutic 
dose of 5 mg in Caucasians and Japanese, respectively
•
In rabbits, markedly lower food intake was observed in the pregnant females at 
highest dose administered (100 mg/kg). This resulted in corresponding body weight 
losses or reduced body weight gains, an increase in mortality and lower fetal weights 
in animals surviving to scheduled necropsy. 

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Nonetheless, in the animals that survived there was no indication that BI 1291583 
induced malformations or structural variations in the fetuses. At 3 and 15 mg/kg/day, 
BI 1291583 was well tolerated. There was no maternal toxicity or effects on embryo 
fetal development. 
The NOAEL for maternal and embryo-fetal toxicity was considered to be
15 mg/kg/day resulting in exposures of 184- fold and 126-fold to the expected human 
therapeutic dose of 5 mg in Caucasians and Japanese, respectively.
In summary, the currently available toxicology data support the administration of BI 1291583 
up to 5 mg for an indefinite time period in humans with once daily oral administration.
For key safety data from clinical studies, please refer to Section 1.4.3.
For a more detailed description of the BI 1291583 profile, please refer to the current IB
[c18711868].
1.3
RATIONALE FOR PERFORMING THE TRIAL
No approved treatments are available to diminish inflammation and tissue destruction in 
patients with bronchiectasis (BE), a chronic lung disease with neutrophilic bronchial 
inflammation. There is a high unmet medical need to break the vicious cycle of recurrent 
severe infections and further airway damage.
will provide information on the efficacy, safety and optimal dosing regimen of 
BI 1291583 in preventing pulmonary exacerbations in patients with BE not related to CF. 
Approx. 240 BE patients, with a diagnosis confirmed by a CT scan, who are regular sputum 
producers and have had at least 2 pulmonary exacerbations in the previous year, (alternatively 
1 pulmonary exacerbation plus high symptom burden as measured by the SGRQ 
questionnaire, Appendix 10.4.1), will be enrolled in a 2:1:1:2 ratio to receive once-daily oral 
doses of 5 mg, 2.5 mg, 1 mg of BI 1291583 or placebo. Commonly used stable maintenance 
treatment will be allowed as background treatment. 
Trial 1397-0013 (ClairaflyTM) is mirroring the first 12 weeks of 
and is by that 
adding important information on safety and PK similarity across bronchiectasis patients with 
and without CF treated with BI 1291583 5 mg qd or placebo.
Downstream suppression of NE activity will be used to link clinical outcomes assessed in 
as established surrogate biomarker for exacerbations. 

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In order to be able to address future scientific questions, trial participants will be asked to 
voluntarily donate biospecimens for banking (please see Section 5.5). 
If the trial participant agrees, banked samples may be used for future biomarker research and 
drug development projects, e.g. to identify patients that are more likely to benefit from a 
treatment or experience an adverse event (AE), or to gain a mechanistic or genetic 
understanding of drug effects and thereby better match patients with therapies.
Agreement on this banking is not a requirement for study enrolment.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits 
BI 1291583 is a potent CatC inhibitor with an expected inhibition of 99% in the bone marrow 
for the dose included in this study and is expected to improve the protease-antiprotease 
balance in the lungs of patients with chronic neutrophilic airway inflammation. The central 
role of neutrophilic inflammation driven by serine proteases is well described in both, CFB 
and NCFB. A complex interplay between infection and inflammation feeds the pro-
inflammatory vicious cycle that drives the destruction of pulmonary architecture. 
Inflammatory immune cells (mainly activated macrophages and neutrophils) represent the 
major infiltrating population in disease conditions associated with BE and contribute 
significantly to tissue damage and BE generation.
Cell-derived proteases and reactive oxygen species represent key mediators and particularly 
the protease-antiprotease imbalance is considered as key pathogenic component in degrading 
extracellular matrix [R21-3308].
Treatment with BI 1291583, and hence suppression of NSPs, has the potential to provide 
significant benefit to patients by disrupting this vicious cycle. Associated benefits would be 
sustained tissue protection and reduced symptoms (e.g. cough, volumes of sputum), 
prolonged time to exacerbation and reduction in exacerbation frequency, as well as better 
maintained quality of life and potentially even a reduction in mortality. 
This premise has already been partially validated by the outcome of the Phase II study of the 
CatCi brensocatib in the NCFB WILLOW study [R21-0168].
Patients with CFB receiving the CatC inhibitor BI 1291583 in this ‘first-in-CF-patient’ trial 
may have a transient direct medical benefit from participation, as a treatment duration of
12 weeks is not expected to have a permanent impact on the long-term course of their 
disease. However, the NE pathway is anticipated to play an important role in bronchiectasis
as sputum NE activity was found to be a biomarker of disease severity and future risk of
exacerbations in patients with bronchiectasis [R18-3321]. For this trial, patients will be 
selected that have a history of pulmonary exacerbations, indicating that the targeted pathway 
is active. Considering the study treatment duration of 12 weeks, inhibition of NE activity may 
result in modulation of clinical efficacy endpoints. Some benefit in symptoms (e.g., sputum 

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volume, cough, mucus plugging), 
 might be expected with
administration over 12 weeks.
In patients treated with placebo, no benefit is expected beyond the general benefits of regular
medical assessment during participation in a clinical trial. All participants will have a close
safety monitoring of their health status throughout the trial.
1.4.2
Risks
Factors of risks may derive from knowledge regarding the mode of action (MoA), the nature 
of the target, findings in animal models / non-clinical safety studies, and findings from 
clinical studies. 
The clinical data of BI 1291583 showed an acceptable safety profile in healthy volunteers.
A Phase II trial in patients with 
 A Phase II trial 
with another CatC inhibitor, brensocatib, in NCFB showed that 24 weeks treatment resulted 
in a slightly increased occurrence of periodontal disease and skin exfoliation in patients 
receiving brensocatib compared to those with placebo [R21-0168]. Despite the increase of 
periodontal diseases in patients treated with brensocatib, there was no difference among each 
treatment group in the progression of periodontal disease observed. In addition, the incidence 
rates of hyperkeratosis (trial-defined skin event of interest) were comparable across different 
treatment groups. No elevated risk of infection was reported in clinical studies with 
brensocatib. The PK – safety evaluation of brensocatib showed no clinically relevant 
relationships between brensocatib exposure and the incidence of adverse events of special 
interest (AESIs) [R22-2961].
Potential effects of life-long and complete CatC inhibition can be learned from Papillon-
Lefèvre Syndrome (PLS), a rare genetic disease with loss of function mutations in both 
alleles of the CatC gene (see Table 1.4.2: 1).
Table 1.4.2: 1
Overview of trial related risks based on the mode of action (MoA), 
the nature of the target, findings in non-clinical safety studies and 
mitigation strategies
Possible or known 
risks of clinical 
relevance for this 
trial
Summary of data,
rationale for the risk
Mitigation strategy
Possible effects of 
CatC inhibition 
are 
- Hyperkeratosis
- Periodontitis, 
which might 
lead to alveolar 
bone resorption, 
Based on observations in 
patients with the rare 
genetic disease Papillon-
Lefèvre Syndrome (PLS), 
clinical signs and symptoms 
of life-long complete 
absence of CatC, are 
palmoplantar 
hyperkeratosis, severe 
- Exclusion of subjects with relevant 
immunodeficiency or receiving 
immunosuppressive medication or 
having an acute infection.
- Regular clinical and laboratory 
monitoring for infection.
- Exclusion of subjects having a history 
of hyperkeratosis on palms or soles. 

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Possible or known 
risks of clinical 
relevance for this 
trial
Summary of data,
rationale for the risk
Mitigation strategy
loss of 
deciduous and 
permanent teeth
- Susceptibility to 
infections
periodontitis, alveolar bone 
resorption, loss of deciduous 
and permanent teeth, and an 
increased susceptibility to 
infections [R17-3100]. The 
immune-deficiency in PLS 
patients is generally mild
[R17-3101]
- Close skin monitoring throughout the 
study (Flow Chart and
Section 5.2.5.2).
- Exclusion of subjects with moderate 
or severe periodontal disease. 
Requirement of dental examination 
for all subjects during screening. 
Subjects with signs of mild 
periodontal disease will receive 
standard periodontal care.
- Periodontal assessment at EOT and 
during the study at the discretion of 
the investigator 
- Discontinuation from trial treatment in 
case of severe periodontal AEs or 
deterioration 
(Flow Chart and Section 5.2.5.1).
A complete / near complete loss of 
CatC function is not expected
An independent Data Monitoring 
Committee (DMC) will periodically 
evaluate clinical trial safety data.
Effects on lung, 
liver, kidney and 
bone
In non-clinical studies, daily 
treatment with BI 1291583 
was associated with changes 
indicative of 
phospholipidosis / 
lysosomal storage in several 
tissues and organ systems. 
Most prominently affected 
organs were lung, liver, 
kidneys, and bone. Bone 
findings are possibly 
indicative of altered bone 
remodeling. 
Degenerative changes or 
changes in the clinical status 
of the animals were not 
observed at exposures 
targeted in clinical studies.
- Exclusion of subjects with a relevant 
concomitant disease assessed as 
clinically relevant by the investigator, 
particularly gastrointestinal, hepatic, 
renal, pulmonary, cardiovascular, 
metabolic, immunological, or 
hormonal disorders.
- Laboratory testing, including blood 
cell count, liver function, renal 
function, bone turnover biomarkers 
and urinalysis, as well as physical 
examination, will be used to monitor 
lungs, livers, bones, and kidneys.
The safety margins are sufficiently high 
in man from preclinical species where 
there were findings (see 
Section 1.2).
An independent DMC will periodically 
evaluate clinical trial safety data.

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Possible or known 
risks of clinical 
relevance for this 
trial
Summary of data,
rationale for the risk
Mitigation strategy
Reproductive
system
Genotoxicity for
BI 1291583 and the 
 
previously identified 
metabolites was not 
demonstrated in preclinical 
studies. The genotoxicity 
assessment has not yet been 
completed for the newly 
identified metabolite
. Data in humans 
are not available.
- Women who are pregnant or 
breastfeeding will be excluded.
- Women of child-bearing potential 
must be willing and able to use two 
medically approved methods of birth 
control, one barrier method plus one
highly effective non-barrier method
(Section 4.2.2.3).
- Men able to father a child must be 
willing and able to use male 
contraception (Section 4.2.2.3).
Drug-induced 
liver injury 
(DILI)
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators. 
Although not specifically 
expected with this molecule 
or mechanism, monitoring 
for DILI is standard in drug 
development.
- Timely detection, evaluation, and 
follow-up of laboratory alterations in 
selected liver laboratory parameters
(Section 5.2.6.1.4).
Blood sampling
Blood sampling is a standard 
clinical procedure. As with 
all blood sampling, there is a 
risk of mild pain, local 
irritation, or bruising (a black 
or blue mark) at the puncture 
site. Furthermore, there is a 
small risk of light-headedness 
and/or fainting. In rare cases, 
the puncture site can also 
become infected, or nerves 
may be damaged, inducing 
long-lasting abnormal 
sensations (paresthesia), 
impaired sensation of touch 
and persistent pain.
- Close clinical monitoring for AEs
- Selection of experienced sites and site 
staff
Lung function 
measurements 
Assessment of lung function 
is a standard clinical 
procedure that many of the 
patients will already have 
experienced. Risks and 
discomforts associated with 
lung function testing may 
include shortness of breath, 
- Close clinical monitoring for AEs
- Selection of experienced sites and site 
staff

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Possible or known 
risks of clinical 
relevance for this 
trial
Summary of data,
rationale for the risk
Mitigation strategy
dizziness, or headache during 
the breathing tests.
Administration of
4 doses of inhaled 
salbutamol / 
albuterol (total dose 
approx.
400 μg), used as 
Auxiliary Medicinal 
Product (AMP) in 
this trial
Post-bronchodilator 
pulmonary function test is a 
standard test. Most common 
side effects of salbutamol / 
albuterol 100 μg includes: 
palpitation, chest pain, fast 
heart rate, shakiness, 
nervousness, headache, 
dizziness, sore throat, and 
runny nose
- Patients with concomitant 
cardiovascular disease that in the 
opinion of the investigator may put the 
patient at risk by participating in the 
study are excluded.
- On-site use only and under direction of 
a healthcare provider.
- Close clinical monitoring for AEs
Sputum induction
Sputum induction is a simple 
and non-invasive procedure 
used for patients who are not 
able to provide a sputum 
sample spontaneously. The 
patient inhales nebulised iso-
or hypertonic saline solution, 
which could cause 
bronchoconstriction.
- Close clinical monitoring for AEs
- Selection of experienced sites and site 
staff
- Use of inhaled Salbutamol (Albuterol) is 
recommended before sputum induction 
if no Salbutamol (Albuterol) was 
administered within 4 hours at the visit 
for post-bronchodilator spirometry
Pandemic situations 
Travelling to site, being at 
site for assessments (standard 
risk in the current pandemic 
situation).
- On-site visits are reduced to a 
minimum.
- Testing and infection control will be 
done according local / national 
recommendations
- For possible additional modifications in 
pandemic situation see Section 6
1.4.2.1
Risk related to the COVID-19 pandemic
The available evidence does not suggest an increased risk of acquiring an infection with a 
viral pathogen targeting the airways, including SARS-CoV-2, nor of a particularly more 
severe clinical presentation in case of such an infection, with suppression of Cathepsin C. 
There is no evidence to suggest an increased risk of bacterial superinfection in case of 
COVID-19.
An increased risk of severe COVID-19 is possible in patients with CFB due to their 
underlying condition but is not supported for CF patients by registry data and is not expected 
based on the mechanism of action of BI 1291583.
CatC inhibition is not expected to reduce the efficacy of a COVID-19 vaccine to induce an 
immune response; and vice versa, vaccination is not expected to reduce the efficacy of the 
CatC inhibitor.

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1.4.3
Key safety data from clinical studies
The results of 6 Phase I trials show an acceptable safety profile in healthy volunteers at all 
doses tested, with no serious adverse events (SAEs), AE of special interest or death.
One subject treated with BI 1291583 (1 mg) discontinued treatment due to other significant 
AEs according to ICH E3 (PT ‘thrombophlebitis’ and ‘increased CRP’) which were assessed 
as non-drug-related. In the safety lab, vital signs and ECG data there were no clinically 
relevant findings. The most frequently reported adverse events (AEs) investigators 
considered drug-related are displayed in Table 1.4.3: 1. All AEs considered drug-related were 
mild to moderate and resolved.
Table 1.4.3: 1
Summary of AEs considered drug related by investigators across 
healthy volunteer trials performed 
Healthy volunteer trials performed
Summary of AEs considered drug related by 
investigators
1397-0001, single-rising-dose


54 healthy male subjects versus 
placebo. 40 subjects received BI 
1291583, 14 subjects received placebo
Ten subjects (25.0%) receiving BI 1291583 and
2 subjects (14.3%) receiving placebo had AEs that were 
assessed as drug-related by the investigator. Drug-related 
AEs reported for more than 1 subject overall in the 
BI 1291583 groups were headache (4 cases of mild or 
moderate intensity) and dry skin (3 cases of mild 
intensity).
1397-0008, food-effect cross-over trial

 of BI 1291583 once in the 
fasted state and once following a 
standard high-fat, high-calorie meal

12 healthy male subjects
No investigator-defined drug-related AEs were reported. 
1397-0010, drug-drug interaction trial 
(itraconazole)

Single dose of 
 alone, followed 
by 
together with multiple doses 
itraconazole 

14 healthy male subjects 
Investigator-defined drug-related AEs were reported in
4 subjects (28.6%). The drug-related AEs were diarrhea, 
dyspepsia, increased alanine aminotransferase, increased 
aspartate aminotransferase, decreased appetite, and 
thermohyperaesthesia. Each AE was reported in
1 subject (7.1%) only after BI 1291583 + itraconazole.
1397-0002 and 1397-0011, multiple-rising-
dose. 4 weeks treatment


48 healthy male and female subjects. 
36 subjects received BI 1291583,
12 subjects received placebo 
Six subjects (16.7%) receiving BI 1291583 and
3 subjects (25.0%) receiving placebo were reported with 
AEs that were assessed as drug-related by the 
investigators. The only drug-related event reported for 
more than 1 subject overall in the BI 1291583 groups 
was skin exfoliation (3 subjects, 8.3%), whereas in 
placebo it was reported in 1 subject (8.3%). Drug-related 
skin events were not reported more frequently for 
subjects treated with BI 1291583 than for subjects 
receiving placebo (13.9% vs. 16.7%, respectively). 

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Healthy volunteer trials performed
Summary of AEs considered drug related by 
investigators
1397-0003, Japanese single rising dose and 
multiple dose study

 single dose; 
24 healthy male subjects. 18 subjects 
received BI 1291583, 6 subjects 
received placebo

 once daily for 4 weeks; 
12 healthy male subjects. 

9 subjects received BI 1291583, 3 
subjects received placebo
Single-dose and multiple-doses in healthy Japanese 
subjects were well tolerated.
No AEs leading to treatment discontinuation, or AEs
defined by the investigator to be related to the study drug 
were reported.
For clinical assessment of bone turnover biomarkers, following the International 
Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry (IFCC) 
recommendations [R21-0018], CTX-I and P1NP were chosen as most sensitive reference 
markers for bone resorption and formation, respectively.
No effects on bone turnover biomarkers were seen in the 4-week MRD studies in humans at 
exposures up to twofold higher than will be tested in the Phase II trials, suggesting that 
repeat-dose administration of BI 1291583 is not associated with any clinically relevant 
changes in bone turnover. 
For a more detailed description of the BI 1291583 profile, please refer to the current IB for 
BI 1291583 [c18711868].
1.4.4
Discussion
The clinical data of BI 1291583 showed an acceptable safety profile in healthy volunteers at 
all doses tested, with no serious adverse events (SAEs) or adverse events of special interest 
(AESIs). No clinical data of BI 1291583 in patients are available to date. 
In a study investigating 24 weeks of treatment in patients with bronchiectasis with the CatC 
inhibitor brensocatib a significant prolongation in the time to first pulmonary exacerbation 
was reported, even in the 1/3 colonised with P. aeruginosa, suggesting that pharmacological 
inhibition of CatC may decrease the rate of bacterial airway infections in this population 

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[R21-0168]. The safety evaluation of brensocatib showed no clinically relevant relationships 
between brensocatib and AESIs or infections [R22-2961].
Twenty-four weeks treatment resulted in a slightly increased occurrence of periodontal 
disease but not progression, and skin exfoliation in patients receiving brensocatib compared 
to those with placebo, with no relationship to dose [R21-0168]. The mechanism of action of 
brensocatib is the same as for BI 1291583.
Based on the properties and the mode of action of BI 1291583, no specific safety concerns 
for patient with CF are expected:

No specific liability to the GI tract was identified in preclinical and clinical studies.
Based on the observation of no dependency of exposures on food (fasted versus high-
calory/high-fat meal), it is not expected that absorption will be affected by gastric pH 
or pancreatic exocrine insufficiency and the management thereof by using enzyme-
replacement therapy.

For CF patients an increased risk for periodontitis is not described.

The pathophysiology of CF specific aquagenic palmoplantar keratoderma is different 
to the skin lesion related to CatC inhibition and can be clinically distinguished from 
hyperkeratosis.

A treatment duration of 4 weeks (Phase I MRD trials, 9 healthy volunteers in each 
dose group), 12 weeks (ClairaflyTM, 18 patients with CF treated with BI 1291583,
5 mg) and at least 24 weeks (
, 80, 40 and 40 patients in respective dose 
groups) will provide relevant insights on the effect of BI 1291583 on bone 
biomarkers.

No specific risk for extrapulmonary infections is expected in CF patients. The 
migration of neutrophils to the site of infection is not affected by BI 1291583. 
Neutrophils that lack NSPs are still equipped with other microbicidal tools, such as 
myeloperoxidase and the α-defensin group of antimicrobial peptides.

No saftey concerns are attributed specifically to concomitant use of modulators and 
BI 1291583. BI 1291583 and its metabolites are not expected to affect 
pharmacokinetics of CFTR modulators. BI 1291583 and its metabolites are not 
inhibitors of Cyp3A4 and inhibition of P-gp may only occur at higher doses (≥9 mg) 
than are used in ClairaflyTM. BI 1291583 and its metabolites are not critically affected 
by concomitant use of CFTR modulators (except lumacaftor, see Section 4.2.2). 
Conservatively assessed, co-administration of a CFTR modulator containing Ivacaftor 
may lead to an increase in exposure to BI 1291583 of max. 30%. Based on pre-
clinical and clinical data to date, it is not expected that BI 1291583 will increase the 
risk of liver diseases as references the risk from modulator therapies.
A comprehensive safety analyses will also be performed based on all available data prior to 
Phase III, including 
, a Phase II study currently underway in patients with nCFB 
240 patients planned to be randomized (2:1:1:2) to BI 1291583
5 mg, 2.5 mg, 1 mg or placebo respectively).

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To mitigate the potential risk associated with a placebo-controlled trial in this patient 
population, usual SoC will be allowed as stable background treatment.
To ensure safety of trial participants, an independent DMC which includes experts also in the 
field of CF will conduct regular reviews of all unblinded safety data.
The nature of the target and the mechanism of action of BI 1291583 are well understood. In 
the context of the unmet medical need and anticipated benefit of BI 1291583, the benefit risk 
evaluation of the compound, based upon the available preclinical and clinical information, is 
considered favourable.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The aim of the trial is to investigate whether 5 mg qd of BI 1291583 (the expected human 
therapeutic dose) in patients with CF is safe and to assess PD and PK. Based on these data, an
across-trial comparison will be performed.
 
The primary objective, is to estimate the number and percentage of patients who have at least 
one treatment-emergent AE (TEAE) during the trial.
The secondary objective is to estimate the PD effect, at Week 8, after the first drug 
administration. The other secondary objective is to estimate the PK effect, after the first dose 
and at steady state, after multiple dosing of BI 1291583 5 mg qd.
All treatment effect estimations will be as randomised, including the effects of any changes 
of treatment.
2.1.2
Primary endpoint
The primary endpoint is to evaluate the occurrence of TEAEs, up to 16 weeks, from first drug 
administration.
2.1.3
Secondary endpoint(s)
The following secondary endpoints will be determined:

Relative change from baseline in NE activity, in sputum, at Week 8 after first drug 
administration (8 weeks was chosen as timepoint for this secondary endpoint to 
synchronise with potential cycling antibiotic use)

AUC, over a dosing interval (AUCτ), for the first dose

Maximum concentration (Cmax) for the first dose

AUCτ at steady state (AUCτ,ss)

Cmax at steady state (Cmax,ss)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a multi-centre, randomised, placebo-controlled, double-blind, parallel group, Phase IIa
clinical trial to investigate the safety, tolerability, PD and PK of 5 mg BI 1291583 (oral, qd)
in patients with CFB.
Approximately 24 eligible patients will be randomised in a 2:1 ratio to either BI 1291583 or 
placebo. Approximately 50% of patients will be treated with CFTR-MTs, for restricted 
CFTR-MT also refer to Section 4.2.2. The randomisation will be stratified based on whether 
the patient is on stable maintenance use of CFTR-MT or not (yes / no). The stratification 
should assure that sufficient patients are recruited within each treatment population.
Screening of patients into any single stratum will be closed in order to ensure that not more 
than 18 patients are randomised into that stratum. The rationale is to assess whether both 
treatment populations will fit into the NCFB population regardless of their background 
medication.
The design outline is depicted in Table 3.1: 1.
Table 3.1: 1 
Design outline
Design outline
R = Randomisation
The screening period may last up to maximal 6 weeks, the planned treatment period is
12 weeks, afterwards patients are followed up for additional 28 days (REP). SoC is allowed; 
however for an antibiotic cycling regimen, start days of a new cycle needs to be aligned with 
visit schedules. The visit schedule is shown in Figure 3.1: 1.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
Due to the fact that participating sites are experienced CF sites and considering a treatment 
duration of 12 weeks, patient loss to follow-up is assessed as minor risk. Patients who 
discontinue the trial early for whatever reason should perform EOT and EOS visit (refer to 
Section 6.2.3 and Flow Chart) and will not be replaced.
Placebo, q.d.
N = 8 
5 mg BI 1291583 q.d.
N = 16
R
CFTR-MT 
yes/no

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An independent Data Monitoring Committee will evaluate safety and efficacy data on a
continuous basis. For details please refer to Section 8.7.
Figure 3.1: 1
Visit schedule
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Since this trial evaluates BI 1291583 for 12 weeks and for the first time in a CF patient 
population, safety and tolerability is the primary objective. A randomised, double-blind, 
placebo-controlled, parallel group trial is considered the most robust design to assess safety, 
tolerability, pharmacodynamic and pharmacokinetics of BI 1291583. A double-blind concept 
was chosen to reduce the bias with regards to treatment-dependent effects as much as 
possible. Due to a close safety monitoring and the fact that no SoC treatments are restricted, 
this approach is considered acceptable for patients. A placebo group is included in order to 
reduce bias and to provide a comparator arm to reliably assess safety, tolerability, and 
pharmacodynamic effects of the trial medication.
Availability of clinical safety, efficacy and surrogate biomarker (i.e. free NE activity) data in 
a patient population with BE not related to CF [c35703911-05] are considered sufficient to 
evaluate their similarity in CF patients with BE. Detection of early signs of clinical efficacy 
and safety of BI 1291583 are expected over a 12-week treatment period.
Evaluation of NE inhibition at Week 8 (secondary endpoint) takes into account potential 
effects of maintenance cycling antibiotic treatment.
A2 
82 
A2 
82 
• • • • 
start treatment 
EOT 
Screening1 
12 weeks treatment 
* 
Visit 
Vl 
Week w -6 
M 
* Sputum collection at site 
1 Examination by Dentist 
2 Cycling Soc antibiotic treatment: 
EOS 
Follow Up1 
A is either first day 'on treatment' (or on treatment A); Bis either first day 'off treatment' (or on treatment B) 
R: Randomisation 
EOT: end of treatment visit 
EOS: end of study visit 

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Before initiating future trials including CF and NCF patients with BE within one study, the 
data from 
 and 1397-0013 (CFB) will be reviewed (Figure 3.2: 1).
Although there is no evidence that genetic defects causing CF directly lead to altered 
pharmacokinetics, differences in the PK of CFB patients compared to healthy volunteers 
could result from pathophysiological differences in the gastrointestinal tract which may 
impact absorption. In addition, higher volume of distribution and clearance were observed in 
CF patients potentially related to an altered body composition [R22-1342]. Deficiency of 
functional CFTR in CF leads to decreased ductal cell secretions of Cl−, water and HCO3−, 
which also lowers pH [R22-2965, R22-2966]. 
However, BI 1291583 exhibits moderate to high solubility over GI tract pH range. In 
combination with the high permeability found in CaCo-2 cells, BI 1291583 is classified as a 
BCS class I compound. These physico-chemical characteristics support an expectation of 
similar PK profiles across non-GI diseases. BI 1291583 at a dose level of 5 mg qd is fully 
soluble in the gastric volume irrespective of pH. No difference in relative bioavailability was 
observed in healthy volunteers under fed and fasted conditions (study 1397-0008, 
 
BI 1291583, high-fat and high caloric meal). Due to the absence of a pH dependent 
absorption, a difference in exposure for patients with CF is considered unlikely. The 
sampling regimen with two full profiles on Day 1 and at steady state on Day 85, allows to 
characterise the absorption as well as the initial elimination and distribution phase. Additional 
trough samples especially before steady state (before 2 weeks) will provide information on 
the accumulation profile of BI 1291583. Overall, trough samples serve a better 
characterisation of clearance in CF patients. Together with PK information from Phase I and 
Phase II studies, the PK sampling regimen may enable identification of covariate effects in 
case there are differences between the different study populations. 
A 28-days follow-up period without treatment covers the residual effect period during which 
BI 1291583 exposures are expected to return to levels below quantification and after which 
pharmacodynamic effects are expected to have reversed.
There is currently no approved pharmacotherapy available to treat the inflammatory 
component of BE in CF patients. Thus, no active control group is included in the trial. To 
mitigate the potential risk associated with a placebo-controlled trial in this patient population, 
usual SoC will be allowed as stable background treatment or in case of complications of CF.

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To ensure safety of trial participants, an independent DMC will conduct regular reviews of 
the trial safety data.
Given that not all patients with CF will benefit from modulator therapies and as inflammation 
with elevated free NE activity [R22-3244] will proceed particularly in established BE, 
patients with established CFB are likely to benefit from anti-inflammatory therapies 
irrespective of CFTR-MT. Therefore, there is a remaining unmet need for anti-inflammatory 
therapies in the management of CF lung disease [R22-1347]. Observational studies have 
shown that NE activity and other inflammation markers remain highly elevated in CFTR-MT
treated CF patients compared to healthy people [R20-0748].
The overall feasibility of the trial is considered possible, as experienced investigators will be 
selected who can ensure the required safety monitoring, have access to patients with CFB and 
are proficient in required trial procedures.
3.3
SELECTION OF TRIAL POPULATION
It is planned to enrol approximately 24 eligible adult patients of either sex with a diagnosis of 
CF and BE (confirmed by CT), treated or not treated with CFTR-MT (individual SoC) in the 
trial.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all
sites at the same time once a sufficient number of patients in both strata (CFTR-MT yes / no) 
has been screened. Screening of patients into any single stratum will be closed in order to 
ensure that not more than 18 patients are randomised into that stratum. Investigators will be 
notified about termination of screening and will then not be allowed to screen additional 
patients for this trial or in a specific stratum, respectively. Patients already in screening at this 
time will be allowed to continue to randomization, if eligible.
•
Re-tests during screening are allowed, for example, if a laboratory test has been 
cancelled by the central laboratory (e.g. for specimen not received or received beyond 
stability) or in case of a laboratory result that is considered to be a spurious result if 
compared to previously available laboratory results (at investigator’s discretion). 
The re-test should be carried out as soon as possible so the laboratory test results will 
be received within the planned visit windows. Re-tests may similarly be performed for 
other visits upon investigator’s discretion
•
Re-screening of patients will be permitted in circumstances where safety is not 
compromised and where the patient is expected to become eligible, as the screening 
failure was due to a transient, potentially reversible, condition. This could be, for 
example, a pulmonary exacerbation requiring use of i.v./oral/inhaled antibiotics.
A maximum of 2 re-screenings will be permitted. Upon re-screening, a new patient 
number will be assigned by the IRT. The previous patient number, with which the 
patient failed screening, will be recorded in the eCRF. The current approved version 
of the patient information and consent form should be signed again

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A log of all participants enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
Even for screen failure participants a minimum of information will be collected: participant
number, visit date, demographics, eligibility criteria, information on adverse events (if 
applicable), concomitant treatment relevant for the adverse event.
If retrospectively it is found that a trial participant has been entered in error (=did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 
contacted immediately. Based on an individual benefit-risk assessment a decision will be 
made whether continued trial participation is possible or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in adult male or female patients with a diagnosis of CF and BE, 
treated or not treated with CFTR-MT (individual SOC).
Please refer to Section 8.3.1 for the documentation requirements pertaining to the in- and 
exclusion criteria.
3.3.2
Inclusion criteria
1. Age of patients when signing the informed consent ≥18 years
2. Historical clinical diagnosis of CF (symptoms of CF and sweat chloride ≥60 mmol/L 
and/or 2 CF-causing CFTR mutations [R22-1344])
3. Investigator-confirmed diagnosis of BE by CT scan and clinical history consistent with 
BE (e.g., cough, chronic sputum production, recurrent respiratory infections). Subjects 
whose past chest CT records are not available will undergo a chest CT scan during 
Screening. Historical scans must not be older than 5 years
4. History of pulmonary exacerbations requiring antibiotic treatment. In the 12 months 
before Visit 1, patients must have had either:
a.
at least 2 exacerbations, or
b. at least 1 exacerbation and an
 at screening Visit 1
For patients on stable oral or inhaled antibiotics as chronic treatment for BE, at least one 
exacerbation must have occurred while on stable antibiotics (see Table 4.2.2.1: 1).
5. Patients must be able to provide spontaneous or induced sputum samples.
6. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.

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7. Male or female patients (also refer to Section 4.2.2.3).
Women of childbearing potential (WOCBP)1 must be ready and able to use a highly 
effective method of birth control per ICH M3 (R2) that results in a low failure rate of less 
than 1% per year when used consistently and correctly, as well as one barrier method.
A list of contraception methods meeting these criteria is provided in the patient 
information.
Men participating in this clinical trial must use male contraception (condom or sexual
abstinence) if their sexual partner is a WOCBP.
___________________________________________________________________________
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
3.3.3
Exclusion criteria
Laboratory and medical examination:
1. Moderate or severe liver disease (defined by Child-Pugh score B or C hepatic 
impairment) or AST and/or ALT > 3.0x ULN at Visit 1
2. Estimated glomerular filtration rate (eGFR) according to CKD-EPI formula < 30 mL/min 
at Visit 1
3. Absolute blood neutrophil count < 1,000/mm3 (equivalent to < 1000 cells/µL or <
109 cells/L) at Visit 1
4. Any findings in the medical examination (including BP, PR, or ECG) and/or laboratory 
value assessed at Visit 1 or during screening period that in the opinion of the investigator 
may put the patient at risk by participating in the trial
[Laboratory parameters from Visit 1 have to satisfy the laboratory threshold values as shown above. Visit 2 
laboratory results will be available only after randomisation. In case at Visit 2 the results do no longer 
satisfy the entry criteria, the investigator has to decide whether it is justified that the patient remains in the 
trial. The justification for decision needs to be documented.]
5. Positive serological tests for hepatitis B, hepatitis C (also confirmed with HCV RNA), or 
human immunodeficiency virus (HIV) infection, or known infection status
Concomitant diagnosis and therapy:
6. A current diagnosis of:
a. Hypogammaglobulinemia
b. Common variable immunodeficiency
c. α1-antitrypsin deficiency being treated with augmentation therapy
d. Allergic bronchopulmonary aspergillosis being treated or requiring treatment 
e. Tuberculosis or non-tuberculous mycobacterial infection being treated or requiring 
treatment according to local guidelines
[Laboratory tests (e.g. Quantiferon Gold test) may be performed at the discretion of the
investigator]

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f.
Palmoplantar keratosis; or keratoderma climactericum
g. Hypothyroidism, myxedema, chronic lymphedema with associated hyperkeratosis 
of the skin, acrocyanosis. If a subject has hypothyroidism but is treated and 
compensated, the subject is allowed into the trial
h. Psoriasis affecting palms and soles; or body surface area for psoriasis ≥10%
i.
Reactive arthritis (Reiter’s syndrome); keratoderma blennorrhagicum 
j.
Pityriasis rubra pilaris
k. Atopic dermatitis affecting palms and soles; or body surface area for atopic 
dermatitis ≥10%
l.
Active extensive verruca vulgaris, as per investigator’s discretion
m. Active fungal infection of hand and/or feet not adequately treated and responsive to 
antifungal therapy, as per investigator’s discretion
7. Any clinically relevant respiratory infection within 4 weeks prior Visit 2
8. Any acute infection requiring systemic or inhaled anti-infective therapy within 4 weeks 
prior Visit 2
9. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(including, but not limited to Burkholderia cenocepacia, Burkholderia dolosa, and 
Mycobacterium abscessus)
10. Any evidence of a concomitant disease, such as Papillon-Lefevre Syndrome, relevant 
pulmonary, gastrointestinal, hepatic, renal, cardiovascular, metabolic, immunological, 
hormonal disorders, or patients who are immunocompromised with a higher risk of 
invasive pneumococcal disease or other invasive opportunistic infections (such as 
histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis), that in the opinion of 
the investigator, may put the patient at risk by participating in the study
11. Received any live attenuated vaccine within 4 weeks prior Visit 2
12. Medical conditions associated with periodontal disease (to be evaluated by a periodontist 
or dentist):
a.
Any tooth that can potentially cause pain or infection as noted in the oral exam 
unless they are corrected before Visit 2 (e.g., pulp necrosis)
b. 2 or more teeth with pocket depth measurements ≥ 4 mm and bleeding or
≥ 5 mm due to periodontitis
c.
Class-3 mobility or Class-3 furcation involvement
d. Scheduled tooth extraction during the trial period
13. Patients who must or wish to continue the intake of restricted medications (see Table 
4.2.2.1: 1) or any drug considered likely to interfere with the safe conduct of the trial; 
patients who take / had taken Lumacaftor / Ivacaftor dual combination
(see Table 4.2.2.1: 1)
Others / general conditions:
14. Lung transplanted patients and patients with a planned transplantation while participating 
in the trial

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15. Major surgery (major according to the investigator’s assessment) performed within
6 weeks prior to randomisation or scheduled during trial period
16. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated in situ non-melanoma skin cancers or in 
situ carcinoma of uterine cervix
17. Current smokers, or stopped smoking only within 3 months of screening, or not willing 
to maintain non-smoking status for the duration of the trial
18. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled, i.e., chronic alcohol or drug abuse or any other condition 
that, in the investigator’s opinion, makes the patient an unreliable trial participant
19. Recent significant hemoptysis (≥300 mL or requiring blood transfusion) in the preceding 
4 weeks before Screening Visit 1 (and during screening phase)
20. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s) or receiving other 
investigational treatment(s)
21. Previous randomisation in this trial
22. Any vulnerable person (defined as: pregnant or breastfeeding women; women who plan
to become pregnant while in the trial; persons deprived of their liberty; minors; persons 
that may have insufficient power, intelligence, education, resources, strength, or other 
needed attributes to protect their own interests; or unable to explicitly give consent), as 
per local regulation
23. Contraindications to the class of drugs under study including known hypersensitivity to 
the drug or its excipients
24. History of any illness or clinical condition that in the opinion of the investigator might 
confound the study results
For study restrictions, refer to Section 4.2.2.
3.3.4
Discontinuation of trial participants from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole 
(withdrawal of consent) with very different implications, please see Sections 3.3.4.1, 3.3.4.2, 
and 3.3.4.3 below. 
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the 
explanation of the consequences of withdrawal. 
Discontinued patients will not be replaced.

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The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, the requirements for 
Adverse Event collection and reporting (see Section 5.2.6.2) should be considered.
3.3.4.1
Discontinuation of trial treatment
An individual trial participant will discontinue trial treatment if:

The patient wants to discontinue trial treatment. The patient will be asked to explain the 
reasons but has the right to refuse to answer

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, the safety of the 
patient cannot be guaranteed as he/she is not willing or able to adhere to the trial 
requirements in the future

The patient needs to take concomitant medication that interferes with the safety of the 
investigational medicinal product as evaluated by the investigator, if needed in 
consultation with the sponsor

The patient can no longer receive trial treatment for medical reasons as per judgement of 
the investigator

Serious or severe Drug Induced Liver Injury attributable to the trial drug (see 
Section 5.2.6.1.4)

Pregnancy

The patient experiences an AE where the PI considers that it is drug related (see 
Section 5.2.6) and evaluates that it is not in the best interest of the subject to continue in 
the study 

The investigator considers that treatment continuation is negatively impacting well-being 
and treatment discontinuation is in the best interest of the patient

Serious infections, e.g., life-threatening infections or infections requiring hospitalisation 
(except hospitalisations for exacerbations, where the investigator will evaluate whether it 
is in the best interest of the subject to continue in the trial)

The trial participant meets the following criteria of periodontal progression:
o
Severe periodontal findings, particularly if at least 3 teeth with pocket depth
≥6 mm (upon the average of 2 measures).
o
If at least 3 teeth have progressed (pocket depth increase ≥2 mm upon the average of 
2 measures). The Investigator and the dentist, in conjunction with the patient, upon 
thorough assessment of all available clinical data and taking into consideration the 
potential risks and benefits associated with administration of BI 1291583, may decide 
not to discontinue the trial medication. In such a case, continuation of treatment with 
trial medication should be discussed with the patient, and the decision and reasoning 
should be documented in the source data (see also Section 5.2.5.1).

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Even if the trial treatment is discontinued the trial participants remain in the trial and, given 
their agreement, will undergo the procedures for end of treatment visit and follow-up as 
outlined in the Flow Chart and Section 6.2.3.
If a patient becomes pregnant during the trial, the investigational product must be 
discontinued, and the patient should be followed up until birth or otherwise termination of the 
pregnancy.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all trial 
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
Trial participants may withdraw their consent to trial participation at any time without the 
need to justify the decision. If a trial participant wants to withdraw consent, the investigator 
should be involved in the discussion with the trial participant and explain the difference 
between trial treatment discontinuation and withdrawal of consent to trial participation, as 
well as explain the options for continued follow-up after trial treatment discontinuation;
please see Section 3.3.4.1.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New efficacy or safety information invalidating the earlier positive benefit-risk
assessment; please see Section 3.3.4.1
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate 
conduct of the trial
Further treatment and follow up of trial participants affected will occur as described in 
Section 3.3.4.1.
The investigator/the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 1291583 and placebo will be manufactured by Boehringer Ingelheim Pharma GmbH & 
Co. KG. The clinical trial supplies will be provided in bottles containing 20 tablets each. The 
tablets should be handled according to the labelled storage instructions and shelf life.
One tablet strength (5 mg) was prepared for clinical evaluation. In addition to the drug 
substance, the tablets contain the following standard pharmaceutical excipients in common 
amounts: mannitol, microcrystalline cellulose, hydroxypropylcellulose, crospovidone, and
magnesium stearate. Placebo tablets, apart from being devoid of the drug substance, also lack 
the excipients hydroxypropylcellulose and crospovidone, but are otherwise identical to 
BI 1291583 tablets.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the two test products are given below:
Table 4.1.1: 1
BI 1291583 5 mg tablets
Substance:
BI 1291583
Pharmaceutical formulation:
Tablets 
Unit strength:
5 mg
Posology:
qd
Method and route of administration:
Oral
Table 4.1.1: 2
Placebo tablets
Substance:
No substance (placebo to BI 1291583 5 mg)
Pharmaceutical formulation:
Tablets 
Unit strength:
matching placebo 
Posology:
qd
Method and route of administration:
Oral
4.1.2
Selection of doses in the trial
Based on MRD data, doses up 
 qd BI 1291583 were safe and well tolerated in healthy 
volunteers. With 5 mg qd dosing at a mean AUC0-24 of 187 nM·h, a plateau effect at 83.1% 
inhibition of CatC in blood was observed. BI 1291583 at its expected human therapeutic dose 
(5 mg qd) inhibited NE in a range from 67.2% up to 86.8% in blood of a healthy volunteer 
population which may translate to > 90% reduction of NE in sputum in NCFB patients and 
similar reduction levels in patients with CFB. Five mg qd represents the dose with the highest 
expected clinical benefit of reduced exacerbation risk in a BE patient population, and thus a 
favourable benefit/risk profile.

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4.1.3
Method of assigning trial participants to treatment groups
After the assessment of all in- and exclusion criteria, each eligible trial participant will be 
randomised to a treatment group according to a randomisation plan in a 2:1 ratio (verum / 
placebo), please see Section 7.4. This randomisation will be stratified according to SoC
CFTR-MT yes / no, assuming approx. 50% will be on CFTR-MT. Randomisation codes will 
be generated through a validated software and kept blinded to the trial team, sites and trial 
participants. Access to the codes will be controlled and documented. An Interactive Response 
Technology (IRT) system will be used to screen participants, create a participant number, 
perform drug assignment, manage initial/re-supply ordering of drug supplies and handle 
emergency unblinding.
4.1.4
Drug assignment and administration of doses for each trial participant
A double-blind design is required to keep the blind (see Section 4.1.5) of trial participants 
and investigators. Patients will receive bottles containing 20 tablets each of either active or 
placebo. Once a day, they will take one tablet for 12 weeks. 
The patients should swallow the trial medication unchewed together with a glass of water 
(~250 mL). Trial medication should be taken at the same time each morning (e.g., 8:00 am) 
during the treatment phase, within a time window of +/- 1 hour. Missed dose(s) will not be 
replaced. If a dose is missed by more than 12 hours, that dose should be skipped, and the next 
dose should be taken as scheduled.
No restrictions apply whether to take the medication with food or close to a meal as no food 
effect was observed in clinical Phase I.
On visit days, trial medication will be taken at the site from the new kits assigned at the 
respective visits, even if outside the normal schedule to accomplish assessments at the site. 
Patients will then return to their usual intake time. 
The last dose will be administered at EOT.
The investigational product should only be dispensed to participating patients by authorised 
personnel as documented in the ISF.
The kits will be used for treating the patient at visits at the site and at the respective time 
points at home in between site visits.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please 
see Section 6) physical visits to the sites may not be feasible or may need to be restricted to 
ensure participant safety. Based on a thorough assessment of benefits and risks, the 
investigator may still decide to continue the trial treatment. Where permitted by local law and 
regulations, trial medication may be shipped directly to the participants’ home.

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4.1.5
Blinding and procedures for unblinding
4.1.5.1 
Blinding
This trial is planned as double blinded. Table 4.1.5.1: 1 below summarises the 
masking/blinding level of individual functions, roles and responsibilities involved in the trial.
Table 4.1.5.1: 1
Blinding level of functions involved in the trial
Role/function
Timing of unblinding/receiving access to the treatment 
information (including rationale)
Patients
Blinded until data ready for final analysis
Investigator/site staff
Blinded until data ready for final analysis
Sponsor, clinical trial team
Blinded until data ready for final analysis
Independent Data Monitoring 
Committee (DMC)
Unblinded for periodic safety review. The release of the 
treatment information at individual time points will be 
documented.
Sponsor, independent evaluation 
team
Unblinded for optional interim PD/PK review. The release of 
the treatment information will be documented.
Bioanalytical staff
As requested for analysis of bioanalytical samples
During the time a role/function is blinded, the randomisation schemes and medication kit lists 
(i.e. the treatment information) are kept restricted by the global Randomisation Team per 
Sponsor Standard Operating Procedure (SOP), with the following exceptions:
The independent DMC (refer to Section 7.2.8) will periodically review unblinded data related 
to safety under conditions that ensure that patients, investigators and trial team will remain 
blinded. Respective documentation will be done according to sponsor SOPs.
A trial independent evaluation team will be appointed to support the optional interim PD/PK
analysis. Details on the interim PD/PK analysis will be described in a separate logistics and 
access plan, see also Section 7.2.8.
The responsible bioanalyst of the external bioanalytical laboratory will receive the
randomisation codes prior to last patient completed to allow for the exclusion from the
analyses of pharmacokinetic (PK) samples taken from placebo / comparator patients.
The Trial Bioanalyst may receive unblinding data from the external bioanalytical laboratory 
after the last patient completed the last visit but prior to official unblinding (TIR approval) of 
the trial for preparation of data transfer, e.g. check file structure prior to data upload and 
SDTM transformation and bioanalytical report writing.

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4.1.5.2
Emergency unblinding and breaking the code
Emergency unblinding will be available to the investigator via emergency service and via 
IRT. It must only be used in an emergency when the identity of the trial drug must be known 
to the investigator in order to provide appropriate medical treatment or otherwise assure 
safety of trial participants. The treatment allocation should not be disclosed to the sponsor 
unless this is explicitly requested. The reason for unblinding must be documented in the 
source documents and/or appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual trial participants during trial conduct. The 
access to the code will only be given to authorised PSPV representatives for processing in the 
Pharmacovigilance database and not be shared further.
To ensure patient’s safety during the trial, a fully external DMC, independent of the trial and 
project teams, will review periodically all available safety data. A DMC SAP which describes 
the analyses required for assessment by the DMC will be produced. Further details will be 
provided in a DMC charter.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
The label will be prepared according to regulation (EU) No 536/2014, Annex 6, Section D.8.,
omitting certain particulars with the following justifications: 

The investigator name was omitted from the label due to the IRT system.
Should local regulations outside the EU require these particulars they will be added to the 
country specific label text.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. Further 
information will be also provided in the ISF. A temperature log must be maintained for 
documentation. If the storage conditions at site are found to be outside the specified range, 
the Clinical Research Associate (CRA, as provided in the list of contacts) must be contacted
immediately.

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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor or 
delegate when the following requirements are fulfilled:

Approval of the clinical trial protocol (CTP) 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 CTP

If applicable per local regulations, availability of the proof of a medical license for the 
Principal Investigator

For USA: Availability of FDA Form 1572 (if applicable)
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Trial participants should be instructed 
to return unused investigational drug and empty medication kits (i.e. bottles).
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 trial participant, and the return to the sponsor or
warehouse/drug distribution centre or alternative disposal of unused products. If applicable,
the sponsor or warehouse/drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational medicinal product and trial 
participants. The investigator or designee will maintain records that document adequately that 
the trial participants were provided the doses specified by the CTP and reconcile all 
investigational medicinal products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the trial participant and that no remaining 
supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no specific special emergency procedures to be followed. Requirements regarding 
specific monitoring and potential action to be taken is described in Section 5.2.5.

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4.2.1.1
Additional treatments
Salbutamol / albuterol is being used to assess a further endpoint in the clinical trial 
(measurement of post-bronchodilator pulmonary function during spirometry) and hence is 
considered an auxiliary medicinal product (AMP). Its use is described in detail in 
Section 5.1.2.
The total dose of salbutamol / albuterol administered during each of the spirometric 
assessments (at the timepoints indicated in the Flow Chart) is approximately 400 µg
(delivered as four separate doses of approximately 100 µg by oral inhalation from a metered 
dose inhaler (MDI) at approximately 30 sec intervals).
This use of salbutamol / albuterol is in accordance with the American Thoracic Society 
(ATS)/European Respiratory Society (ERS) Technical Statement [R20-2419] on the conduct 
of spirometry and is a well-established standard.
For the AMP salbutamol / albuterol, the safety reference document for global safety reporting 
purpose is the ProAir HFA US prescribing information [R23-3789]. A version of the 
prescribing information / summary of product characteristics of the salbutamol / albuterol 
metered dose inhaler (MDI) product used for pulmonary function testing should be filed in 
the ISF.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
While enrolled in this trial, trial participants must not participate in another investigational 
drug or device trial or receive other investigational treatment(s). For details about restrictions 
regarding concomitant treatment, refer to Table 4.2.2.1: 1 below.
The medical management of acute exacerbations is not restricted.
To minimise variability not related to the investigational product, medications with potential 
effect on bone turnover biomarkers (e.g., medications to treat osteoporosis, heparin, selective 
estrogen receptor modulators, thiazolidinediones, Vitamin K antagonists, systemic 
ketoconazole, anti-convulsant, etc., a list of examples will be provided in the ISF) should be 
stable at baseline for > 4 weeks and continue to be stable throughout the trial, if possible.

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Table 4.2.2.1: 1 
Restrictions regarding concomitant treatment
Medication restrictions
Prior to 
randomisation
(Day 1,
Visit 2)
During 
treatment 
period
(12 weeks)
During REP 
(EOT +
28 days)
Drugs with effect on immune response
Immunosuppressants or other drugs with 
immunosuppressive effects that can increase 
the risk of infections (e.g., Methotrexate, 
Azathioprine, Cyclosporine, Tacrolimus, 
Mycophenolate, Rituximab, Tocilizumab, 
Mepolizumab, Lebrikizumab, Dupilumab, 
Benralizumab, Omalizumab, Leflunomide 
and similar)
NOT permitted 
within
3 months 
NOT permitted
NOT permitted
Oral corticosteroids defined as Prednisone 
>10 mg/day or equivalent (see 
Appendix 10.3)
NOT permitted 
within 2 weeks 
NOT 
permitted*
NOT 
permitted*
Medications that may cause palmoplantar keratoderma unless on stable treatment > 3 months 
prior randomisation without skin reactions
Tegafur/fluorouracil, Bleomycin, 
Hydroxyurea, Lithium, Venlafaxine, 
Quinacrine, Imatinib mesylate
NOT permitted 
within 4 weeks 
NOT permitted
NOT permitted
Antibiotic therapy, unless on stable treatment > 3 months prior randomization and to be continued 
throughout the trial, if possible
Maintenance dose/regimen for oral or inhaled 
antibiotics as chronic treatment for BE,
permanent or cycling#
(Seasonal use of antibiotic doses is not 
considered stable treatment)
NOT permitted 
within 4 weeks
NOT 
permitted*
Permitted*
CFTR-MT, unless on stable treatment > 3 months prior randomization
CFTR-MT maintenance dose/regimen for 
CFTR defect 
NOT permitted 
within
3 months
NOT permitted
NOT permitted
Lumacaftor / Ivacaftor dual combination
(as being a strong CYP3A4 inducer)
NOT permitted
NOT permitted
NOT permitted

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Medication restrictions
Prior to 
randomisation 
(Day 1,
Visit 2)
During 
treatment 
period
(12 weeks)
During REP 
(EOT +
28 days)
Maintenance therapy with bronchodilators is permitted except prior to pulmonary function tests 
as specified below
Short-acting bronchodilators (e.g., 
Salbutamol/Albuterol, Terbutaline, 
Ipratropium)
NOT permitted 
6 hours before 
PFT
NOT permitted 
6 hours before 
PFT
NOT permitted 
6 hours before 
PFT
Long-acting bid bronchodilators (e.g., 
Salmeterol, Formoterol, Theophylline)
NOT permitted 
12 hours before 
PFT
NOT permitted 
12 hours before 
PFT
NOT permitted 
12 hours before 
PFT
Long-acting qd bronchodilators. (e.g., 
Olodaterol, Indacaterol, Tiotropium, 
Tulobuterol, Theophylline)
NOT permitted 
24 hours before 
PFT
NOT permitted 
24 hours before 
PFT
NOT permitted 
24 hours before 
PFT
Other
Chronic use of strong CYP3A4 and P-gp 
inhibitors (e.g. clarithromycin, itraconazole, 
ketoconazole, ritonavir, and grapefruit) as 
well as strong CYP3A4 and/or P-gp
inducers (e.g. rifampicin and phenytoin)
NOT permitted 
within 4 weeks 
NOT permitted
NOT permitted
* Acute exacerbations should be treated according to best standard practice
# Defined as course of antibiotics leading to continuous exposure (e.g., every day, every other day or Week, 2 weeks on-
followed by 2 weeks off-treatment) For patients who are on a stable regimen of cycling antibiotics, every other month,
Visit 2 should occur on the Day 1 of an “On-cycle” (+3 days) whatever the antibiotic is. Further visits should then always
  occur on the same day of the monthly cycle (e.g., always on Day 1).
4.2.2.2
Restrictions on diet and lifestyle
Please refer to Sections 4.2.2.1 and 4.2.2.3, there are no further restrictions on diet and 
lifestyle.
4.2.2.3
Contraception requirements
The following measures are defined to prevent pregnancy during participation in the clinical 
trial:
Female patients
WOCBP, if their sexual partner is a man able to father a child, must use two medically 
approved methods of birth control throughout the trial and for a period of at least 9 months
after the last trial drug intake: one barrier method, and one highly effective non-barrier 
method. Accepted highly effective methods of birth control per ICH M3 (R2) that result in a 
low failure rate of less than 1% per year when used consistently and correctly:

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
Combined (estrogen and progestogen containing) hormonal birth control that prevents
ovulation (oral, intravaginal, transdermal)

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Sexual partner is vasectomised
Male patients
Men participating in this clinical trial, if their sexual partner is a WOCBP, must use a condom
from the first administration of trial medication until 6 months after the last administration of
trial medication. They should also agree to refrain from donating sperm for the same time
period.
Alternatively to the contraceptive methods described above, trial participants (male or 
WOCBP) must abstain from male-female sex. This is defined as being in line with the
preferred and usual lifestyle of the patient. Periodic abstinence, e.g., calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
4.3
TREATMENT COMPLIANCE
Trial participants are requested to bring all remaining trial medication including empty 
package material with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the sponsor or delegate.
Treatment compliance (%) =
Number of tablets actually taken 100
Number of tablets which should have been taken as 
directed by the investigator
If the number of doses taken is not between 80 to 120%, site staff will explain to the trial 
participant the importance of treatment compliance.

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Pulmonary exacerbation
The pulmonary exacerbation definition is following the definition that will be used to cross-
reference between patient groups (
 and 1397-0013 
ClairaflyTM) and 
. 
A pulmonary exacerbation in this study is defined as having 3 or more of the following 
symptoms for at least 48 hours resulting in a physician’s decision to prescribe antibiotics 
(oral or intravenous):

Increased cough

Increased sputum volume or change in sputum consistency

Increased sputum purulence

Increased breathlessness and/or decreased exercise tolerance

Fatigue and/or malaise

Hemoptysis
Further CF specific symptoms to allow for exacerbation evaluation according to Fuchs 
criteria [R02-1107] will be collected in the eCRF of all Phase II and Phase III trials ongoing 
or planned.
Subjects on chronic macrolide therapy whose only change in therapy is minor dose or 
frequency adjustment will not meet the definition of exacerbation.
Dose or frequency change of background antibiotic treatment of ≥ 2 fold when administered 
for ≥ 3 symptoms will meet the definition of exacerbation.
Severe pulmonary exacerbations are defined as exacerbations leading to hospitalisation 
and/or intravenous antibiotic administration.
“Onset of exacerbation” will be defined by the onset of first recorded symptom.
The “end of exacerbation” will be the end date of the related antibiotic treatment.
5.1.2
Pulmonary function testing
Pulmonary function will be assessed using standardized spirometry. Spirometry will be 
conducted at clinic visits using the site’s own equipment and procedures, which must meet 
2019 ATS/ERS criteria [R20-2419]. Spirometry will be conducted with the subject in a 
seated position. It is preferable that the same trained individual performs the PFTs for a given 
patient. 
The best of three efforts will be defined as the highest FEV1 and the highest FVC each 
obtained on any of three blows meeting the ATS criteria (with a maximum of eight attempts). 
The highest FEV1 and FVC will be selected regardless of whether they come from different 

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spirometric manoeuvres or from the same manoeuvre. As reference values the global lung 
function 2012 equations will be used [R15-0845]. On days of clinic visits, patients must 
refrain from strenuous activity at least 12 hours prior to PFTs. Patients should also avoid cold 
temperatures, environmental smoke, dust, or areas with strong odors (e.g., perfumes). If 
treated with bronchodilators, patients should not take their daily bronchodilator inhalation 
until after completion of the spirometry, refer to Table 4.2.2.1: 1.
PFTs should preferably be started after spontaneous sputum collection and approximately at 
the same time at visit days (e.g. always at 11:00 am) with an allowed time window of 1 hour.
In case sputum needs to be induced, this should happen after PFT.
Post-bronchodilator (salbutamol (albuterol)) testing:
Following the completion of three acceptable pre-bronchodilator forced expiratory 
maneuvers, salbutamol (albuterol) will be administered to each patient. After a gentle and 
incomplete expiration, a dose of approximately 100 µg of salbutamol (albuterol) is inhaled in 
one breath to total lung capacity. The breath is held for 5 – 10 sec before the patient exhales. 
Four separate doses (total dose approximately 400 µg) are delivered at approximately 30 sec 
intervals (this dose ensures that the response is high on the salbutamol (albuterol) dose-
response curve). Three to five additional, acceptable post-bronchodilator forced expiratory 
manoeuvre tests are recorded 15 – 30 minutes after the last dose of salbutamol (albuterol) is 
inhaled.
The absolute values of FEV1 and FVC will be reported in the eCRF. Further instructions 
regarding PFT measurements will be provided in the ISF.

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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
Flow Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, and skin.
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart.
Specific periodontal and dermal assessments have to be performed in this trial which are not 
part of standard physical examination, see Sections 5.2.5.1 and 5.2.5.2.
The results must be included in the source documents available at the site. 

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5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest and aural body 
temperature. 
The results must be included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2 . For the 
sampling time points, please refer to the Flow Chart.
Trial participants should be fasted, if possible, for the blood sampling for bone metabolism 
biomarkers.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF.
Instructions regarding sample collection, sample handling/processing, and sample shipping 
are provided in the Laboratory Manual / ISF.
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the trial participant concerned will be increased due to this 
additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor or delegate.
Table 5.2.3: 1
Safety laboratory tests 
Functional lab group
Test name
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes (RBC)
Reticulocyte count
Reticulocytes/Erythrocyte
White Blood Cells/Leucocytes (WBC)
Platelet Count/Thrombocytes (quant)
Automatic WBC differential, 
relative (per Leukocytes) and 
absolute 
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes

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Functional lab group
Test name
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin time – INR (International Normalised Ratio)
Fibrinogen
Enzymes
Aspartate aminotransferase (AST/GOT) 
Alanine aminotransferase (ALT/GPT)
Alkaline Phosphatase [AP]
Gamma-Glutamyl Transferase (GGT)
Creatine Kinase (CK)
Creatine Kinase Isoenzyme MB (CK-MB), if CK is elevated
Substrates
Creatinine
Total bilirubin
Direct bilirubin
Total protein
Albumin
C-Reactive Protein (CRP) 
Blood urea nitrogen (BUN)
Uric Acid
Total cholesterol
Triglycerides
Glucose
Electrolytes
Sodium
Potassium
Chloride
Calcium
Drug screening (urine)
Cotinine (except V3)
Serum Pregnancy test for WOCBP
at screening
Human Serum Chorionic Gonadotropin
Urine Pregnancy test (Dipstick) 
for WOCBP1
Human Chorionic Gonadotropin in urine
Urine analysis (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
Urine analysis
Urine albumin creatinine ratio
1 Urine pregnancy testing will be performed at site as indicated in the Flow Chart
eGFR will be analysed and calculated by the central laboratory at the same timepoints as 
other safety laboratory parameters (see in the Flow Chart), by using the CKD-EPI formula 
(see Appendix 10.1) and using an enzymatic assay for serum creatinine measurement, IDMS 
standardized.

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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which are planned during 
screening only but may be repeated as required. The investigator will use the exclusionary lab 
test results for the assessment of the participants’ eligibility for the trial. The lab results will 
not be reported to the sponsor.
Table 5.2.3: 2 Exclusionary laboratory tests
Functional lab group
Test name 
Infectious serology (blood)
Hepatitis B surface antigen (qual)*
Hepatitis B core antibody (qual)*
Hepatitis C antibodies (qual)
HIV-1 and HIV-2 antibody (qual)
* An HBV-DNA test should be conducted if Hepatitis B core antibody is positive and Hepatitis B surface antigen is negative.
**An HCV-RNA test should be performed if Hepatitis C antibodies result is positive to confirm if the infection is active. 
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flow Chart. 
The investigator or a designee will evaluate whether the ECG is normal or abnormal and 
assess clinical relevance. ECGs may be repeated for quality reasons and a repeated recording 
used for analysis. Additional ECGs may be recorded for safety reasons. Dated and signed 
printouts of ECG with findings should be documented in participant’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.2.5
Other safety parameters
5.2.5.1
Periodontal assessments
Before start of trial treatment
CFB patients will be, on average, significantly younger compared to NCFB patients and thus 
concomitant periodontal issues are expected to be rare. An increased susceptibility to 
periodontal disease is not described [R22-3121].
The entry criteria in the study have been specified to exclude subjects with underlying 
moderate or severe periodontal conditions.
All patients considered eligible are required to have a periodontal assessment by a trial-
designated local dentist during screening period, including parameters such as pocket depth, 
attachment loss, bleeding on probing etc. 
All patients should have a panoramic radiograph available at baseline (except if edentulous), 
as detailed in the Flow Chart.

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
Patients without teeth (edentulous)
The dentist will confirm the edentulous status and check for implants supporting a denture. 
Implant sites will be examined.
 

Patients with no or mild periodontitis
Defined as with pocket depth up to 3 mm or up to 4 mm (4 mm only if no bleeding on 
probing), will receive a professional plaque removal.
Details on the parameters to be assessed will be provided in the ISF.
5.2.5.2
Dermatological assessment
The entry criteria of the trial have been defined to exclude subjects with underlying 
dermatologic conditions that could impair the ability to detect a potential safety signal or 
might put the subject at increased risk.

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Treatment continuation or discontinuation decisions will be made by the investigator 
considering the dermatologist’s evaluation if applicable.
Forms to document skin assessments will be provided in the ISF, and data will be transferred 
into the eCRF.
5.2.6
Assessment of adverse events
Data and information necessary for the thorough assessment of AEs, SAEs, and AESIs will 
be reported to the sponsor via eCRF. This may include specific data and information not 
prospectively specified in this protocol.
5.2.6.1
Definitions of AEs
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a trial participant or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded on the appropriate eCRF(s) if applicable:

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
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 participant was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if more severe

Requires inpatient hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly/birth defect

Is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the participant and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 

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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 in Section 5.2.6.1.2. The latest list of “Always Serious AEs” can be found in the eDC 
system. A copy of the latest list of “Always Serious AEs” will be provided upon request. 
These events should always be reported as SAEs as described in Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 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 event 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 any 
of the following alerts (alterations) of hepatic laboratory parameters: 
For patients with normal transaminase levels (AST and ALT ≤1 x ULN) at baseline:

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

ALT and / or AST elevations ≥10-fold ULN.

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For patients with abnormal aminotransaminase levels between > 1 and < 3 x ULN at baseline:

An elevation of AST and / or ALT ≥3-fold the baseline value combined with an 
elevation of bilirubin ≥2-fold ULN or ≥2-fold the baseline value (if bilirubin is 
elevated at baseline), measured in the same blood sample, or in samples drawn within 
30 days of each other; or; 

Aminotransferase elevations ≥5-fold the baseline value.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary, in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Details on documentation and reporting are provided in the ISF.
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 judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, considering all relevant factors, including pattern of 
reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases and relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the trial drug

The event is known to be caused by or attributed to the drug class

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)

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
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 trial drug 
concerned)

Continuation of the event despite the withdrawal of the medication, considering 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
The investigator shall maintain and keep detailed records of all AEs in the participant files.
Per default, SAEs/AESIs should be reported via the eCRF in the EDC system. If the EDC 
system is not or no longer available (e.g. after database lock), the paper BI SAE form should 
be used; please see Section 5.2.6.2.2.
The following must be collected and documented:

From signing the informed consent onwards until the individual participant’s end of trial
(usually the End of Study (EoS) visit: all AEs (serious and non-serious) and all AESIs

After the individual participant’s end of trial: 
The investigator does not need to actively monitor the participant for new AEs but should 
only report any occurrence of cancer of new histology and trial drug related SAEs and 
trial drug related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call
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 AE or SAE eCRF pages to the sponsor’s unique entry point
immediately (within 24 hours of becoming aware of the event), the country specific process
will be described in the ISF. 

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The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone in addition. 
With receipt of any further information on these events, follow-up reports have to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual participant’s end of trial
must be followed up until they have resolved, have been assessed as “chronic” or “stable”, or 
no further information can be obtained.
Should the EDC system not be available for more than 24 hours, reporting must occur via the 
BI paper SAE forms.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a trial 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 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 Studies is to be completed. However, 
if a SAE and/or AESI is associated with the pregnancy it must be reported as described in 
Section 5.2.6.2.2.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Blood samples for assessment of BI 1291583 plasma PK will be collected as indicated in the 
Flow Chart and Table 10.2: 1. The exact date and actual 24-hour clock time of PK samples 
will be recorded in the CRF. The exact date and actual 24-hour clock time of doses 
administered at Visit 2 and Visit 6/EOT will be recorded in the CRF. The exact date and 
actual 24-hour clock time of doses administered in the 2 calendar days prior to all visits in 
Table 10.2: 1 will be recorded in the CRF. 

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The actual sampling times will be used for determination of pharmacokinetic parameters if 
available; otherwise, nominal times may be used.
5.3.2
Methods of sample collection
For the quantification of BI 1291583 plasma concentrations, blood samples will be collected 
as indicated in the Flow Chart. The actual sampling times and time of dosing will need to be 
recorded. Detailed instructions on sampling, preparation, processing, shipment and storage 
are provided in the laboratory manual. Plasma samples will be stored frozen at about -20°C or 
below at the participating sites, logistics CRO/central laboratory and bioanalytical laboratory. 
The samples will be shipped on dry ice.
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing. 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. Left-over PK samples will be discarded at the latest within
6 months of signature of the clinical trial report. 
5.3.4
Pharmacokinetic - pharmacodynamic relationship
The PK and PD data from this study may be used for an exploratory investigation of PK/PD 
relationship of BI 1291583.
5.4
ASSESSMENT OF BIOMARKER(S)
This section refers to exploratory biomarkers. Established biomarkers of efficacy and safety 
are described and discussed in Sections 5.1 and 5.2.
5.4.1
Pharmacodynamics, safety, and patient selection biomarkers
Biomarker assessments will be conducted for baseline patient characterisation as well as for 
pharmacodynamic investigations.
5.4.1.1
Baseline patient characterisation:

P. aeruginosa colonisation correlates with the frequency of pulmonary exacerbation.
P. aeruginosa sputum cfu (colony forming units) assessment will be done at central lab

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
Murray Colour Chart: Sputum purulence, reported to correlate to bacterial colonisation 
[R20-2792], will be assessed by use of the Murray sputum colour chart. 
The Murray colour chart is a tool for visual comparison of sputum colour, allowing to 
characterise sputum according to the three categories mucoid, mucopurulent, or purulent

NEATstik®: Semi-quantitative sputum NE activity based on point of care test performed 
at analysis lab [R19-3083] 
5.4.1.2
Pharmacodynamic investigations
Pharmacodynamic biomarkers will be assessed over time to characterise the mode of action 
of BI 1291583 in patients with CF for comparison with data from NCFB patients obtained in 
study 1397-0012 [c35703911-05]. 
NE activity
Sputum NE activity will be quantified to determine how target engagement in blood, 
demonstrated in healthy volunteer trials, translates into target engagement in patients’ sputum 
as surrogate for the target organ lung.

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5.4.1.3
Methods and timing of sample collection
5.4.1.3.1
Blood
Whole blood, serum and plasma samples will be collected. Detailed instructions on sampling, 
preparation, processing, shipment and storage are provided in the ISF / laboratory manual. 
For sampling timepoints see the Flow Chart.
5.4.1.3.2
Sputum
Sputum collection at site
Sputum collection on visits indicated in the Flow Chart should occur with active breathing 
techniques, supported by the site staff, if needed. In case of difficulties producing sputum and
no adequate sputum sample is produced spontaneously, induction of sputum is mandatory. 

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Recommendations for sputum induction will be provided in the ISF, however sites can also 
follow their own standards of saline inhalation or follow the standard operating procedure of 
the Cystic Fibrosis Therapeutics Development Network.
Sputum induction should only be performed after the pulmonary function test (details in 
Section 6.2.2). 
If a sputum sample cannot be obtained on the day of the visit, it is generally possible that the 
patient returns the next day to provide the sputum sample.
To assess patient’s eligibility for trial participation, at least one adequate sputum sample must 
be obtained at the site prior randomisation at V2 as indicated in the sputum decision tree for 
the screening period, Figure 5.4.1.3.2: 1.
Sputum collection at home
After having confirmed patient’s eligibility, the patient will be asked to collect spontaneous 
sputum accrued during the morning routine on visit days, if possible. This sample should be 
taken to the site in the provided collection containers and will serve as backup sample in case 
all attempts failed to obtain a sputum sample at site.
Sites will assess the quality of the backup sample macroscopically, including using the 
Murray Colour Chart.
A sputum decision tree for the treatment period is depicted in Figure 5.4.1.3.2: 2. This 
approach is also applicable for a patient, who could provide a sputum sample at the site prior 
to Visit 2.
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the ISF / laboratory manual. 

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Figure 5.4.1.3.2: 1
Sputum decision tree – screening period V1 – V2 / eligibility
___________________________________________________________________________
Figure 5.4.1.3.2: 2
Sputum decision tree – treatment period V4 – EOS; applicable for V2
only, if sputum sample already obtained at the site prior V2
Patient: able to provide
sputum sample at V1
(either spontaneously or induced)?
Patient: able to provide
sputum sample at site at later date
(either spontaneously or induced)?
Eligible
NOT
Eligible
Site will ask patient to return.
At least one sputum sample
must be provided on site.
Very last opportunity at V2
prior randomisation.
Eligible
yes
no
no
yes
Patient: able to provide
sputum sample at site visit
(either spontaneously or induced)?
Patient: able to return to site
the next day to provide a sample?
Next visit as planned
Use backup sample
Patients will be provided 
containers to collect a
backup sputum sample
(if possible) in the morning
before an on-site visit.
That sample should only be 
used if all measures to obtain
a sample at the site failed
and the patient is not able to 
return to the site next day.
New attempt
yes
no
no
yes
In case this 
attempt failed
as well
" 
L 
' 
" 
I 
,...._ _ 
______._ __ 
I _____ ____, 
~1 
17 
,. 
I 
I 
. I 

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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements.
Additional biomarker analysis may help to better characterise the patients and their disease 
course. This may support future drug developments by delivering in depth patient 
characterisation for patient selection as well as deliver detailed insights into the MoA of the 
CatC inhibition allowing for differentiation approaches.
To enable this, additional serum samples and a DNA sample will be taken. In case more
sputum could be collected than required for biomarker analyses and P. aeruginosa culture, an 
aliquot will be taken and transferred into the biobank. 
5.5.1
Methods and timing of sample collection
Blood will be drawn for optional serum and DNA banking at timepoints indicated in the 
Flow Chart. The analysis lab will take a sputum aliquot for biobanking purposes, if feasible.
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see the Flow Chart.
5.6
OTHER ASSESSMENTS
There are no other assessments planned.

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6.
INVESTIGATIONAL PLAN
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
execution of the investigational plan as per this clinical trial protocol may not be feasible. 
With the consent of the participant, the sponsor and investigator may agree on alternative, 
back-up or rescue methodology which may include but will not be limited to virtual trial 
participant visits and assessments, home healthcare nurse visits, direct-to-participant/direct-
from-participant shipments of trial treatment or bio-sample pick up from the participant’s 
home. The implementation of these measures will depend on participant’s consent, 
operational feasibility, local law and regulations. If alternative methodology is implemented, 
the deviations from the original plan will be precisely documented.
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. Each visit date
(with its window) up to EOS is to be counted from Day 1 (Visit 2). If any visit has to be 
rescheduled, subsequent visits should follow the original visit date schedule. Additional visits 
for the purpose of re-testing of laboratory parameters or AE monitoring may be included as 
deemed necessary by the investigator. All deviations from the original schedule of visits and 
procedures will be documented and the implications considered for the analysis of the trial 
data.
 This applies also to the randomisation visit (V2).
Measurement of vital signs should precede blood sampling and be assessed pre-dose at all
dosing visits.
If possible, blood sampling should always be performed at the same time of the day
 
Patients should be instructed not to take the trial medication at home on scheduled visit days 
but bring it to the site and take it after pre-dose procedures were performed.
Procedures that should be performed pre-dose are 
and safety assessment as AE and 
concomitant therapy collection, physical examination incl. vital signs and skin monitoring, 
ECG, and urine pregnancy test, if applicable. Also blood and urine sampling, incl. the pre-
dose PK sample, should precede intake of study medication.
Sputum collection and pulmonary function test may be performed after intake of study 
medication, considering operational aspects and that no immediate effect on the lung is 
expected.

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The order of the different trial procedures should be planned, taking into account the structure 
of the individual investigational site and following the requirements outlined in the clinical 
trial protocol and ISF/Lab Manual.
Visit days with full PK profile, i.e. V2 (randomisation visit) and EOT Visit, may be split over 
2 consecutive days, i.e. procedures as
 AE collection, physical examination and ECG 
could be completed the day before the main visit.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, patients will provide written informed consent in 
accordance with GCP and local legislation prior to enrolment in the study.
Patients will be asked to give informed consent to biobanking of specified sample types
DNA, serum and a sputum sample, if feasible. Participation to biobanking is voluntary and is 
not a prerequisite for participation in the trial.
Note: banking samples must not be taken prior to Visit 2.
Preferred order of procedures during trial visits, where applicable:
1.
)
2. AE and concomitant therapy collection, 
3. Physical examination including vital signs and skin monitoring
4. ECG
5. Urine pregnancy test (if applicable)
6. Blood and Urine sampling, including trough (predose) PK sampling, safety 
lab and biomarkers
7. Sputum sample collection (if spontaneous)
8. Pulmonary function test
spirometry should preferably happen after spontaneous sputum collection and at 
the same time of the day at each visit ± 60 min. 
9. Sputum sample collection (if induced) 
In case a patient does not expectorate sputum spontaneously, expectoration may
be triggered by pulmonary function testing. In case sputum needs to be induced, 
this should happen after PFT. If patient is exhausted, it may be considered to 
postpone sputum expectoration or lung function measurement to the next day.
10. Study medication administration
(may be done prior to 7. considering operational aspects, see above)
11. Post dose PK samples should be taken according to the time schedule provided 
in Appendix 10.2 after IMP intake. The exact time of sample collection is to be 
recorded in the eCRF.

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Patients will be asked to complete the 
 on his/her own in a quiet 
area/room before any other screening assessments. 
 will be completed 
at screening.
Inclusion and exclusion criteria have to be checked according to Section 3.3.
At the screening visit, patients have to donate a spontaneous or induced sputum sample at site 
(Section 5.4.1.3.2):

An appropriate part of the sputum sample will be taken for P. aeruginosa culture, if 
possible

Sputum colour will be characterised by use of the Murray Colour Chart

Samples will be sent frozen to the central lab for further processing
During the screening visit, demographic information will be collected. This includes: 

Age on the day of informed consent (in years)

Sex (male, female in order to describe the subject`s sex at birth) 

For women: if they are of childbearing potential, yes / no; in order to characterise the 
patient population and as a basis for contraception requirements 

Ethnicity and race in order to sufficiently characterise the patient population, to 
support possible subgroup analyses if needed, and to support the calculation of the 
kidney function via the CKD EPI formula unless not acceptable according to local 
regulations.
Further assessments/measurements at Screening include (see Flow Chart and Sections 5.2.1, 
5.2.2, 5.2.3, 5.2.4, 5.2.5, 5.2.6.2.3):

Relevant Baseline Conditions and Medical History (stable maintenance use of CFTR-
MT has to be entered as stratification criterion at screening and confirmed at 
randomisation)

Physical examination including vital signs (BP, PR, aural body temperature), height 
and body weight

12-lead ECG

Safety laboratory tests

Blood and urine sampling for biomarkers

Pregnancy testing in blood (if applicable)

Pulmonary function test

A CT must be available for confirmation of BE diagnosis at Visit 2. The scan may be 
historical (up to 5 years prior randomisation). If a new CT scan needs to be performed 
within the scope of the trial, this should happen (if a patient is otherwise eligible) 
during screening period before Visit 2. If applicable, accordance with local 
regulations regarding radiation exposure has to be ensured

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The Screening Visit 1 can cover a period of up to 6 weeks, e.g., to wait for appointment at 
dentist, or if washout or stabilisation of certain medication is required (see Section 4.2.2.1). If 
the screening period of 6 weeks has to be exceeded for unforeseen reasons (e.g. scheduling 
dentist’s appointment, infection) the sponsor has to be contacted immediately. In this case 
specific safety assessments have to be repeated prior V2 in an unscheduled visit (safety lab, 
physical examinations, vital signs, pregnancy testing, if applicable).
The Screening has to be registered in IRT to trigger the first medication shipment to the site.
In case eligibility of a patient is not confirmed, the patient will be registered as screen-failure. 
Re-screening would be allowed for screen-failed patients who are considered eligible at a 
later time point. Re-screening for a second time would be allowed if for independent reasons 
where one of these was an infection. These patients will receive a new patient number 
(Section 3.3).
6.2.2
Treatment period
When eligibility of the patient is confirmed, randomisation via IRT will be performed at 
Visit 2. 
Prerequisite for randomisation is information on stable maintenance use of CFTR-MT (yes / 
no) which will be used as stratification factor.
The treatment period is from Day 1 to Week 12.
At the beginning of each visit during treatment phase, investigator and site personnel should 
check the well-being of the patient as well as prepare for all required procedures during the 
visit, e.g. sputum sampling, PK sampling.
A sputum sample should be collected at site, either spontaneously or induced, see 
Section 5.4.1.3.2. Additionally, patients should be instructed at each visit to collect sputum 
accrued during the morning routine on visit days, if possible, and bring the sputum collection 
containers to the site.

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Information on dose assignment and drug administration by the patient is provided in
Section 4.1.4.
Procedures at the visits should be performed as described in the Flow Chart, see also details 
described above (Section 6.2.1), in Section 5 and in Lab Manuals/ISF.
Patients using bronchodilators should adhere to the following wash-out times before 
pulmonary function tests (for further details, refer to Table 4.2.2.1: 1):
24 hours for qd long acting bronchodilators, 

12 hours for bid long acting bronchodilators, and 

6 hours for short acting bronchodilators
For PK samples, the provided planned time according to the time schedule (Appendix 10.2) is 
approximate, the actual time when the samples were collected has to be documented. 
After completion of the treatment period, male subjects with WOCBP partners and WOCBP 
participants should be reminded to continue to use contraception after the last administration 
of trial medication as provided in Section 4.2.2.3.
6.2.3
Follow-up period and trial completion
Patients who completed treatment (as planned or premature) will have an End of Treatment 
(EOT) Visit and a subsequent Follow-up Visit after 28 (+ 7) days. The Follow-up Visit will 
be End of Study (EOS).
After the EOS (End of Trial) Visit any abnormal assessments or lab values, or ongoing AEs, 
will be followed up as medically required in the opinion of the investigator. For reporting of 
AEs after patient’s completion of the trial, please see Section 5.2.6.2.2.
Early treatment discontinuation
In case a patient has to permanently discontinue trial medication prematurely for whatever 
reason, discontinuation of treatment should be registered in IRT and documented in the 
eCRF. The patient should attend an EOT Visit and 28 (+ 7) days later a Follow-up Visit to 
ensure patient safety and data integrity.

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Treatment completion (EOT)
Treatment completion is defined as a patient having completed treatments until planned EOT
Visit (Week 12).
Trial completion (EOS)
For patients who completed treatment (as planned or premature), the trial completion 
(individual patient’s EOS) is achieved when the Follow-up Visit (EOS Visit) has taken place.
The EOS eCRF page has to be filled-in when the patient has ended the trial.
After the EOS Visit any abnormal assessments, abnormal lab values, or ongoing AEs, will be 
followed up as medically required in the opinion of the investigator.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The trial is designed to assess safety and tolerability of 5 mg qd of BI 1291583, in CF 
patients, and to investigate the pharmacokinetic properties and pharmacodynamic effects over 
a 12-week treatment period. All evaluations are to be considered exploratory.
 
. Analysis details will be included in a separate statistical 
analysis plan.
7.1
NULL AND ALTERNATIVE HYPOTHESES
The study is exploratory in nature and no confirmatory testing will be performed. Hence no 
null and alternative hypotheses are defined. Any confidence intervals or p-values provided are 
to be interpreted in the perspective of the exploratory character of the study. A justification of 
the sample size is provided in Section 7.5.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The following analysis sets will be defined for statistical analyses:

Screening set (SCS): This patient set includes all patients who signed informed 
consent. The SCS will be used for the analyses of patient disposition.

Randomised set (RS): This patient set includes all randomised patients. The RS will be 
used for the analyses of patient disposition.

Treated set (TS): This patient set includes all randomised patients who received at 
least one dose of trial medication. The TS is the main analysis set for the efficacy 
analyses, the safety analyses as well as for demographics and baseline characteristics 
and protocol deviations.

Pharmacokinetic set (PKS): This patient set includes all patients from the TS who 
provided at least one post-dose plasma BI 1291583 concentration that was not 
excluded due to a protocol deviation relevant to the evaluation of PK, or due to PK 
non-evaluability.
For all analyses, patients will be analysed according to planned treatment group. In case of 
patients receiving the wrong medication unintentionally (i.e., different to their planned 
treatment), the impact to study outcomes will be assessed with details specified in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(iPD) categories (including violations of the key inclusion and exclusion criteria, incorrect 
medication taken and any other deviations of the protocol deemed important) will be 
specified in the Protocol Deviation Domain.

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Protocol deviations will be identified no later than in the Report Planning Meeting, and the 
iPD categories will be updated as needed. All decisions concerning important protocol 
deviations will be made prior to database lock. 
Further analysis sets will be defined in the TSAP, if needed.
7.2.2
Handling of Intercurrent Events
The expected intercurrent events (ICEs) of interest in this trial are:

Treatment discontinuation

Initiation of macrolides during trial

Start of cyclic doses of antibiotic treatment during the trial

Initiation or Change of CFTR-MT during the trial
For the primary objective, intercurrent events will be handled by using the while-on-
treatment strategy, as defined in ICH E9(R1) [R21-0743]. Measurements, taken prior to the 
intercurrent event, will be used to assess treatment effect.
For the secondary objective, intercurrent events will be handled by using the treatment policy 
strategy, as defined in ICH E9(R1). Use of the “treatment policy” approach disregards the 
intercurrent event and uses measurements regardless of the occurrence of an intercurrent 
event. Additional details regarding intercurrent event handling strategy will be described in 
the TSAP.
7.2.3
Primary objective analyses
The primary endpoint as described in Section 2.1.2, will be derived according to BI 
standards. The analysis will be based on the TS and will be descriptive in nature. The number 
and proportion of patients, with at least one TEAE per treatment group, will be derived. 
TEAE is defined as all adverse events occurring between the start of treatment and the end of 
the REP (see Section 1.2). Adverse events that start before first drug intake and deteriorate
under treatment will also be considered as ‘treatment-emergent’.

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7.2.4
Secondary objective analyses
7.2.4.1
Neutrophil elastase activity in sputum
The biomarker endpoint as described in Section 2.1.3 will be analysed based on the TS. The 
analysis of this endpoint will be performed on log transformed data.
Baseline NE activity, in sputum, will be derived as the mean value of available valid samples 
of Screening and Week 0, prior to the first treatment intake. The change from baseline of NE 
activity, in sputum, at different visits (X) is calculated as:
ℎ	 
 		       =      −   		
The change from baseline, in NE activity in sputum, at Week 8, will be analysed by 
descriptive statistics and graphical representations across all visits. 
7.2.4.2
Pharmacokinetic endpoints
The PK parameters, described in Section 2.1.3, will be estimated using a population PK 
modelling approach. The PK endpoints (concentrations and parameters) will be reported 
descriptively, based on the PKS. For all patients, the following descriptive statistics will be 
calculated for plasma concentrations and PK parameters: number (N), arithmetic mean, 
standard deviation, minimum, median, maximum, arithmetic coefficient of variation, 
geometric mean, and the geometric coefficient of variation. The following statistics will 
additionally be provided for PK parameters: the 10th, 25th, 75th, and 90th percentiles.

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7.2.6
Safety analyses
All treated patients will be included in the safety analysis. In general, the safety analyses will 
be descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between the start of treatment and the end of the REP, a period of 28 days after 
the last dose of trial medication, will be assigned to the on-treatment period for evaluation.
Statistical analysis and reporting of AEs will concentrate on TEAEs (see Section 7.2.3).
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term, after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA), at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside of the 
reference range, as well as values defined as clinically relevant, will be summarised. 
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial, and at the end-of-trial evaluation, will be assessed 
with regard to possible changes compared with findings before start of treatment.
Clinically relevant abnormal findings of ECG will be reported and analysed as baseline 
conditions (at screening) or as AEs (during the trial).
7.2.7
Other Analyses
Other analyses are not planned. 
7.2.8
Interim Analyses
Given the exploratory nature of this study, the sponsor may choose to conduct an interim 
PD/PK analysis
 
. The decision to conduct an optional 
interim analysis, and the timing of the analysis, will be documented in the sponsor’s trial 
master file, in a logistics and access plan, prior to the conduct of the interim analysis. There is 
no plan to adjust sample size based on the interim analysis results. The interim analysis will 
be performed and interpreted, by an independent evaluation team of the sponsor, which is 
independent of the trial team. No interim report will be written. 
To ensure patient’s safety during the trial, a fully external DMC, independent of the trial and 
project teams, will review periodically all available safety data. A DMC SAP, which 
describes the analyses required for assessment by the DMC, will be produced. Further details 
will be provided in a DMC charter.

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7.3
HANDLING OF MISSING DATA
In general, missing data will not be imputed.
Primary endpoint
Missing or incomplete AE dates will be handled according to BI standard.
Secondary PK endpoints
Handling of missing PK data will be performed according to the Sponsor’s SOPs.
PK parameters, that cannot be reasonably calculated based on the available drug 
concentration-time data, will not be imputed.
7.4
RANDOMISATION
The randomisation will be stratified according to the use of SoC CFTR-MT (yes vs. no). 
Within each stratum, patients will be randomised, in a 2:1 ratio, to either receive BI 1291583
5 mg qd, or placebo.
BI will arrange for the randomisation and the packaging and labelling of trial medication. 
The randomisation list will be generated, using a validated system, which involves a pseudo-
random number generator, so that the resulting treatment will be both reproducible and non-
predictable. Specific parameters, used for the creation of the randomisation schedule (e.g.
block size or biasing coin probabilities), will be documented in the CTR. Access to the codes 
will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
For this exploratory trial, it is planned to include a total of 24 treated patients. Sixteen (16)
patients will receive BI 1291583, 5 mg qd, and 8 patients will receive placebo. The planned 
sample size is not based on a power calculation but is considered sufficient, for the 
exploratory evaluation of safety, tolerability of BI 1291583, as well as to investigate PD and 
PK properties. 
Apart from the safety assessment, NE inhibition, in sputum, is one of the main interests of the 
study to support further drug development decisions for BI 1291583. A variety of different 
effect sizes for % NE reduction were investigated, and Table 7.5: 1 shows the simulated 
operating characteristics of the design for different scenarios and sample sizes for the active 
arm. 

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With 16 (24) patients in the active group, there is approximately 65% (70%) probability to 
observe a % reduction in NE activity, in sputum, of at least 80% when the true effect size is 
90%. In contrast, if the true effect size is 40%, the probability to observe a % NE reduction of 
at least 80% would be 21%, for 16 patients in the active group, and 18% if there are
24 patients randomised, in the active group. If only 12 patients are evaluable for the 
assessment of % NE reduction at week 8 (e.g., due to dropouts) the increased uncertainty for 
a correct decision is considered acceptable.
Overall, a sample size of 16 patients, in the active group, is regarded as sufficient for the 
objectives of this trial.
Table 7.5: 1
Simulated probabilities for observing at least a given % reduction in 
NE activity, in sputum, at 8 weeks
Sample 
size
%Reduction
Probability to 
observe at least a 
70% reduction (%)
Probability to 
observe at least an
80% reduction (%)
Probability to 
observe at least a 
90% reduction (%)
12
95%
82.4%
75.5%
61.2%
90%
70.0%
61.5%
45.4%
80%
55.5%
45.7%
30.9%
70%
45.7%
37.7%
22.6%
50%
34.3%
25.9%
14.9%
40%
30.1%
23.2%
12.4%
16
95%
86.9%
80.1%
64.2%
90%
74.3%
64.7%
46.6%
80%
57.7%
47.2%
29.5%
70%
47.5%
36.7%
21.4%
50%
34.4%
24.0%
12.8%
40%
29.5%
21.1%
10.2%
24
95%
92.0%
86.0%
80.3%
90%
80.3%
70.3%
48.4%
80%
60.5%
47.9%
26.6%
70%
47.8%
35.3%
17.3%
50%
32.1%
21.2%
8.5%
40%
26.8%
18.0%
6.9%
Assumptions: SD= 2.15 (on a log10 scale).
Simulations were performed using R Version 4.0.2, with 10000 simulation runs per scenario.

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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 Harmonised Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
Regulation 536/2014 and other relevant regulations. Investigators and site staff must adhere 
to these principles. 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 treating physician of the trial participant.
The investigator will inform the sponsor or delegate 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 rule, no trial results should be published prior to finalisation of the CTR.
The certificate of insurance cover is made available to the investigator and the trial 
participants and is stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to 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 form 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 or the participant’s 
legally accepted representative.
The trial participant must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the trial participant’s own free will with 
the informed consent form after confirming that the trial participant understands the contents. 
The investigator or 
 delegate must sign (or place a seal on) and date the informed consent 

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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. 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, 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 trial participants will be provided by the sponsor. See Section 4.1.5.2 for 
rules about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial participant. 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 

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medical records. If this fails, a verbal history from the participant, documented in their 
medical records, would be acceptable.
If the trial participant is not compliant with the protocol, any corrective action e.g. re-training 
must be documented in the participant file.
For the CRF, data must be derived from source documents, for example:

Participant identification: sex, 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

Adverse events and outcome events (onset date (mandatory), and end date (if 
available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

Completion of participant’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it)

Prior to allocation of a trial 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

Data related to safety monitoring 
 
)
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 always be available for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor or delegate will also monitor compliance with the protocol and GCP.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war; please 
see Section 6), site access may be restricted, thus limiting the ability to perform standard site 

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monitoring activities on-site such as on-site source data review and source data verification. 
Therefore, some of these activities may be performed remotely or replaced by centralized 
monitoring to the extent possible, based on a documented risk assessment and in alignment 
with local regulations.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
SAE/AESI are processed in the global Safety Database and assessed for the company causal 
relationship as well as the expectedness of the event according to the reference safety 
information. Individual Case Safety Reports (ICSR) are subsequently reported according to 
local Regulations. 
Reporting suspected unexpected serious adverse reactions (SUSARs) to the EMA will be 
done via E2B transmission of ICSRs to the Eudravigilance CT Module.
8.5
STATEMENT OF CONFIDENTIALITY AND TRIAL PARTICIPANT
PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of trial participant data in accordance with the principles 7 and 12 of the WHO 
GCP handbook. 
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a participant identification number instead of the trial 
participant’s name. The code is only available at the site and must not be forwarded to the 
sponsor. In case participant’s records will be forwarded e.g. for SAE processing or 
adjudication committees, personal data that can identify the trial participant will be redacted 
by the site prior to forwarding. Access to the participant files and clinical data is strictly 
limited: personalised treatment data may be given to the trial participant’s personal physician 
or to other appropriate medical personnel responsible for the trial 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.

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A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs/IECs and trial 
participants will be informed as appropriate.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the separate biobanking 
informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The first act of recruitment represents the start of the trial and is defined as the date when 
the first trial 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 trial participant in the 
whole trial (“Last Participant Completed”).
The “Last Participant Last Treatment” (LPLT) date is defined as the date on which the last 
trial participant in the whole trial is administered the last dose of trial treatment (as scheduled 
per protocol or prematurely). Individual investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.

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The IEC/competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all trial participants have 
completed the trial in all countries (EU or non-EU) to incorporate and consider all data in the 
report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last trial 
participant (EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI). 
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A Data Monitoring Committee (DMC) is already in place 
 and 
will be extended for trial 1397-0013 (ClairaflyTM). Members of the DMC are independent of 
BI, they are physicians experienced in the treatment of the disease under investigation, in 
addition
 and a statistician. 
The DMC is responsible for routine evaluation of all safety data and efficacy data 
periodically as well as being alerted to blinded safety concerns noted by the sponsor for 
immediate evaluation. While DMC members may be unblinded, measures are in place to 
ensure the blinding for everyone else involved in the trial. Regular DMC meetings will be 
held at specified intervals. The DMC will recommend continuation, modification or 
termination of the trial as detailed in the DMC charter. 
DMC recommendations as well as the final BI decision will be reported to the appropriate 
Regulatory Authorities (RAs) / Health Authorities (HAs), IRBs / ECs, and to investigators as 
requested by local law. The tasks and responsibilities of the DMC are specified in a charter.
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 responsible for coordinating all required activities, in 
order to:

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries

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In the participating countries the trial will be performed by the respective local or regional 
BI-organisation (Operative Unit, OPU) in accordance with applicable regulations and BI 
SOPs, or by a Contract Research Organisation (CRO) based on a contract. The CRO will 
perform project management, clinical field monitoring, medical monitoring, and reporting.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, and IRT service will be used in this trial. Details will be 
provided in the IRT Manual and Laboratory Manual, available in the ISF.

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9.
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statistical principles for clinical trials: step 5 (17 February 2020, 
EMA/CHMP/ICH/436221/2017). 
https://www.ema.europa.eu/en/documetns/schientific-guideline/ich-e9-r1-
addendum-e stimands-sensitivity-anakysis-clinical-trials-guideline-
statistical-principles_e n.pdf (access date: 26 February 2021); European 
medicine Agency (EMA); 2020.
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Schaefer J, Griese M, Chandrasekaran R, Chotirmall S.H., Hartl D 
Pathogenesis, imaging and clinical characteristics of CF and non-CF 
bronchiectasis. BMC Pulm Med 2018; 18; 79.
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Ringshausen FC, Roux A de, Pletz MW, Hamalainen N, Welte T, 
Rademacher J. Bronchiectasis-associated hospitalizations in Germany, 2005 
- 2011: a population-based study of disease burden and trends. Plos One; 
2013; 8(8); e71109.
R21-3311
Kwak HJ, Moon JY, Choi YW, Kim TH, Sohn JW, Yoon JH, Shin DH, 
Park SS, Kim SH. High prevalence of bronchiectasis in adults: analysis of 
CT findings in a health screening program. Tohoku J Exp Med; 2010; 
222(4); 237-242.
R21-4488
Scotet V, L'Hostis C, Ferec C. The changing epidemiology of cystic 
fibrosis: incidence, survival and impact of the CFTR gene discovery. 
Genes; 2021; 11; 589.
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Griese M, Costa S, Linnemann RW, Mall MA, McKone EF, Polineni D, 
Quon BS, Ringshausen FC, Taylor-Cousar JL, Withers NJ, Moskowitz SM, 
Daines CL. Safety and efficacy of elexacaftor/tezacaftor/ivacaftor for 24 
weeks or longer in people with cystic fibrosis and one or more F508del 
alleles: interim results of an open-label phase 3 clinical trial. Am J Respir 
Crit Care Med 2021;203(3):381-385.
R22-1285
Cantin André M, Hartl D, Konstan MW, Chmiel JF. Inflammation in cystic 
fibrosis lung disease: Pathogenesis and therapy. Journal of Cystic Fibrosis 
14 (2015) 419–430.
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Voynow JA, Shinbashi M. Neutrophil Elastase and Chronic Lung Disease. 
Biomolecules 2021, 11, 1065. https://doi.org/10.3390/biom11081065.

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De Sutter P J, Gasthuys E, Van Braeckel E, Schelstraete P, Van Biervliet S, 
Van Bocxlaer J, Vermeulen, A. Pharmacokinetics in patients with cystic 
fibrosis: A systematic review of data published between 1999 and 2019. 
Clin Pharmackinet 2020; 59: 1551-1573.
R22-1343
Chalmers JD, Goeminne P, Aliberti S, McDonnell MJ, et al. The 
Bronchiectasis Severity Index. An International Derivation and Validation 
Study. American Journal of Respiratory and Critical Care Medicine 
Volume 189 Number 5, March 1 2014.
R22-1344
Farrell PM, White TB, Howenstine MS, Munck A, et al. Diagnosis of 
Cystic Fibrosis in Screened Populations. J Pediatr 2017; 181S: S33-44.
R22-1347
Keown K, Brown R, Doherty DF, Houston C, McKelvey M C, et al. 
Airway Inflammation and Host Responses in the Era of CFTR Modulators. 
Int. J. Mol. Sci. 2020, 21, 6379.
R22-2961
Chalmers JD, et al, Pharmacokinetic/Pharmacodynamic Evaluation of the 
Dipeptidyl Peptidase 1 Inhibitor Brensocatib for Non‑cystic Fibrosis 
Bronchiectasis, Clinical Pharmacokinetics, 
https://link.springer.com/article/10.1007/s40262-022-01147-w.
R22-2965
Wilschanski M, Durie PR. Patterns of GI disease in adulthood associated 
with mutations in the CFTR gene. Gut. 2007. 56:1153–63.
R22-2966
Taylor CJ, Aswani N. The pancreas in cystic fibrosis. Paediatric 
Respiratory Reviews. 2002. 3:77–81.
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Pawlaczyk-Kamienska T, Borysewicz-Lewicka M, Sniatala R, Batura-
Gabryel H, Cofta S. Dental and periodontal manifestations in patients with 
cystic fibrosis - a systematic review. J Cystic Fibros; 2019; 18; 762-771.
R22-3122
Gao Y, Leyah HA, Finch S, Lonergan M, Aliberti S, Soyza A de, Fardon 
TC, Tino G, Chalmers JD. Relationship between symptoms, exacerbations, 
and treatment response in bronchiectasis. Am J Respir Crit Care Med; 
2020; 201(12); 1499-1507.
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Tepper LA, Utens EMWJ, Caudri D, Bos AC, Gonzalez-Graniel K, 
Duivenvoorden HJ, Wiel ECW van der, Quittner AL, Tiddens HAWM. 
Impact of bronchiectasis and trapped air on quality of life and exacerbations 
in cystic fibrosis: Eur Respir J; 2013; 42; 371-379.
R22-3244
Harris JK, Wagner BD, Zemanick ET, Robertson CE, Stevens MJ, Heltshe 
SL, Rowe SM, Sagel SD, GOAL Investigators of the Cystic Fibrosis 
Foundation Therapeutics Development Network. Changes in airway 
microbiome and inflammation with ivacaftor treatment in patients with 
cystic fibrosis and the G551D mutation. Ann Am Thorac Soc; 2020; 17(2); 
212-220.

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Guo J, Garratt A, Hill A. Worldwide rates of diagnosis and effective 
treatment for cystic fibrosis. Journal of Cystic Fibrosis 21, (2022) 456-462.
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(U.S. prescribing information, revised: 9/2022)
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4b84-bada-84e4f04f5e62&type=pdf (access date 23 March 2023); 2022
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Konstan M, Flume P, Ramirez C, Li S, Teper A, Vergara M, Usansky H. 
Pharmacokinetics and safety of brensocatib in patients with cystic fibrosis. 
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9.2
UNPUBLISHED REFERENCES
c18711868
Investigator’s Brochure BI 1291583. Current Version.

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10.
APPENDICES
10.1
CREATININE CLEARANCE
Calculation Name
GFR CKD-EPI
Formula
Units
Decimal Places
Conventional:
Black or African American formulas:
Female with a serum creatinine value of ≤0.7 mg/dL
166 x (Serum Creatinine (mg/dL) / 0.7) -0.329 x (0.993)age
Female with a serum creatinine value of >0.7 mg/dL
166 x (Serum Creatinine (mg/dL) / 0.7) -1.209 x (0.993)age
Male with a serum creatinine value of ≤0.9 mg/dL
163 x (Serum Creatinine (mg/dL) / 0.9) -0.411 x (0.993)age
Male with a serum creatinine value of >0.9 mg/dL
163 x (Serum Creatinine (mg/dL) / 0.9) -1.209 x (0.993)age
White, American Indian, Alaska Native, Asian, Native Hawaiian, 
Other Pacific Islander, Other formulas:
Female with a serum creatinine value of ≤0.7 mg/dL
144 x (Serum Creatinine (mg/dL) / 0.7) -0.329 x (0.993)age
Female with a serum creatinine value of >0.7 mg/dL
144 x (Serum Creatinine (mg/dL) / 0.7) -1.209 x (0.993)age
Male with a serum creatinine value of ≤0.9 mg/dL
141 x (Serum Creatinine (mg/dL) / 0.9) -0.411 x (0.993)age
Male with a serum creatinine value of >0.9 mg/dL
141 x (Serum Creatinine (mg/dL) / 0.9) -1.209 x (0.993)age
Creatinine in mg/dL is rounded to 2 decimal places prior to applying 
the formula.
mL/min/
1.73m²
0
SI:
Serum creatinine in µmol/L will be rounded to zero decimal place and 
converted to mg/dL by multiplying by 0.01131. This creatinine value 
in mg/dL will be rounded to 1 decimal place. This creatinine result will 
be used in the GFR Conventional formulas listed above.
mL/min/
1.73m²
0
Limitations/Special 
Notes:
Age is truncated to a whole number prior to performing the calculation.

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10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
PK trough samples will be taken at all visits and additional blood samples for PK profiles will 
be taken at Visits 2 and EOT (see Table 10.2: 1 below). The PK analysis for this group will 
use a population PK approach. Therefore, samples do not have to be taken precisely at the 
planned time. Instead, they must be taken at any time during the sampling window that 
corresponds to the planned time in this table. 
Table 10.2: 1
Time schedule for PK blood sampling
Visit
Week
Day
Time Point [hh:min]
Event
Trough (T) e.g., clock time
2
0
1
Before drug administration 
PK Blood
T
07:55
0:00
Drug admin.
8:00
1:00 (±45 min)
PK Blood
9:00
3:30 (±1 h)
PK Blood
11:30
6:00 (±1 h) 
PK Blood
14:00
8:00 (±1 h) 
PK Blood
16:00
3
1
8
Before drug administration (-1 h)
PK Blood
T
4
4
29
Before drug administration (-1 h)
PK Blood
T
5
8
57
Before drug administration (-1 h)
PK Blood
T
6 /
EOT
12
85
Before drug administration (-1 h)
PK Blood
T
07:55
0:00
Drug admin.
8:00
1:00 (±45 min)
PK Blood
9:00
3:30 (±1 h)
PK Blood
11:30
6:00 (±1 h)
PK Blood
14:00
8:00 (±1 h) (optional)
PK Blood
16:00
I 

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10.3
EQUIVALENT DOSES OF CORTICOSTEROIDS
Table 10.3: 1 
Equivalent Doses of Corticosteroids
Drug
Equivalent dose (mg)
Conversion factor
Prednisone
10
x 1
Prednisolone
10
x 1
Triamcinolone
8
x 1.25
6-Methylprednisolone
8
x 1.25
Dexamethasone
2
x 5
Betamethasone
1.5
x 6.7
16-Methylprednisolone
12
x 0.8
Fluocortalon
10
x 1
Cloprednol
7.5-10
x 1.5-1.0
Deflazacort
12
x 0.8
Cortisol (hydrocortisone)
40
x 0.25
Cortisone
50
x 0.20

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
16 Jun 2023
EU CT number
2022-502835-21-00
BI Trial number
1397-0013 (ClairaflyTM)
BI Investigational Medicinal 
Product(s)
BI 1291583
Title of protocol
A randomised, double-blind, placebo-
controlled, parallel group trial evaluating 
safety, tolerability, pharmacodynamics 
and pharmacokinetics of BI 1291583 one 
tablet once daily over 12 weeks versus 
placebo in adult patients with cystic 
fibrosis bronchiectasis (ClairaflyTM)
Global Amendment due to urgent safety reasons
Global Amendment
Note: global amendment was needed prior to first clinical trial 
application submission.
X
Category
Section 
No.
Description
Section to be changed
Title page
Description of change
Typo (Berlin) corrected
Rationale for change
Typographical error 
Section to be changed
Abbreviations and Definitions
Description of change
Missing abbreviation (MoA) added
Rationale for change
Consistency
Section to be changed
1.2
Drug profile:
a) Key pharmacokinetic and 
pharmacodynamic characteristics from 
clinical studies 
b) Drug-drug interactions
c) Data from non-clinical studies
Description of change
a) & b) Added information about new 
pre-clinical toxicological data 
 
which was also identified as a major 
metabolite of BI 1291583.
c) Added new information about 
metabolite and deleted the following 

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paragraph:
 
covered within the general toxicity 
studies, including the embryofetal 
development toxicity studies. It is not 
expected to be pharmacologically active 
based on structure activity relationship 
considerations. In silico assessments for 
the prediction of mutagenicity were 
negative. The genotoxicity assessment 
has not yet been completed.”
Rationale for change
a), b), and c) New pre-clinical
toxicological data available
Section to be changed
1.4.2
Risks, Table 1.4.2: 1: Overview of trial 
related risks based on the mode of action 
(MoA), the nature of the target, findings 
in non-clinical safety studies and 
mitigation strategies
Description of change
Reproductive system: Summary of data 
and rationale for the risk: Updated 
wording that genotoxicity for 
BI 1291583 and its major metabolites 
was not demonstrated. Deletion of 
sentence “The genotoxicity assessment is 
still underway for the newly identified 
metabolite 
Mitigation strategy: Updated that 
WOCBP must be willing and able to use 
a highly effective method of birth 
control. Deletion of the requirement to 
use one barrier method in addition.
Deletion of sentence “Men able to father
a child must be willing and able to use 
male contraception.”
Rationale for change
Because of the negative outcome of the 
completed BI teratogenicity and 
genotoxicity studies, a double barrier 
method of contraception is not required. 
Contraception of male trial participants 
and female partners of male trial 
participants are not required.
Section to be changed
3.3.2
Inclusion criteria WOCBP (#7)
Description of change
Updated wording. Deletion of 
requirement to use one barrier method in 
addition for WOCBP. 

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Deletion of sentence “Men participating 
in this clinical trial must use male 
contraception (condom or sexual 
abstinence), if their sexual partner is a 
WOCBP.”
Rationale for change
Because of the negative outcome of the 
completed BI teratogenicity and 
genotoxicity studies, a double barrier 
method of contraception is not required. 
Contraception of male trial participants 
and female partners of male trial 
participants are not required.
Section to be changed
4.2.2.3
Contraception requirements
Description of change
Updated wording for WOCBP: Use of a 
highly effective method throughout the 
trial and for a period of at least 75 days 
after the last trial drug intake. Deletion of 
the requirements to use one barrier 
method in addition and to use 
contraception for at least 9 months. 
Deletion of the paragraph “Men
participating in this clinical trial, if their 
sexual partner is a WOCBP, must use 
condom from the first administration of 
trial medication until 6 months after the 
last administration of trial medication. 
They should also agree to refrain from 
donating sperm for the same time 
period.”
Rationale for change
Because of the negative outcome of the 
completed BI teratogenicity and 
genotoxicity studies, a double barrier 
method of contraception is not required. 
Contraception of male trial participants 
and female partners of male trial 
participants are not required.
Section to be changed
5.2.6.2.3
Pregnancy
Description of change
Deletion of the following paragraph: 
“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. 

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The ISF will contain the trial specific 
information and consent for the pregnant 
partner.”
Rationale for change
Contraception of male trial participants 
and female partners of male trial 
participants are not required. Systematic 
collection of pregnancy data in female 
partners of clinical trial participants is not 
required.  
Section to be changed
6.2.2
Treatment period
Description of change
Updated wording regarding reminder to 
continue to use contraception for 
WOCBP, reminder deleted for male 
subjects.
Rationale for change
Contraception of male trial participants 
and female partners of male trial 
participants are not required.
11.2
GLOBAL AMENDMENT 2
Date of amendment
17 Oct 2023
EU CT number
2022-502835-21-00
BI Trial number
1397-0013 (ClairaflyTM)
BI Investigational Medicinal 
Product(s)
BI 1291583
Title of protocol
A randomised, double-blind, placebo-
controlled, parallel group trial evaluating 
safety, tolerability, pharmacodynamics 
and pharmacokinetics of BI 1291583 one 
tablet once daily over 12 weeks versus 
placebo in adult patients with cystic 
fibrosis bronchiectasis (ClairaflyTM)
Global Amendment due to urgent safety reasons
Global Amendment.
X
Category
Section 
No.
Description
Section to be changed
1.4.4
Benefit/Risk assessment / Discussion
Description of change
Details added for the rationale of a
comprehensive safety analyses in 
conjunction 
 
, as there are no specific safety 
concerns due to the MoA and properties 
of BI 1291583 for patients with CF.

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Rationale for change
Request from regulators
Section to be changed
3.1
Overal trial design
Description of change
Justification added why patients who 
discontinue early won’t be replaced
Rationale for change
Request from regulators
Section to be changed
3.3.2
Inclusion Criteria
Description of change
#7: added “male or” female patients
Rationale for change
Clarification
Section to be changed
3.3.3
Exclusion Criteria
Description of change
#13: added “intake of Lumacaftor / 
Ivacaftor dual combination”
Rationale for change
Clarification
Section to be changed
3.3.3
Exclusion Criteria
Description of change
#22: rephrased (any vulnerable person as 
per local regulation)
Rationale for change
Clarification
Section to be changed
5.4.1.2
Pharmacodynamic investigations
Description of change
What will happen to samples after 
completion of the trial / destruction of 
samples: “Urine” added
Rationale for change
Clarification
Section to be changed
7.2.1
Planned Analysis / General 
considerations
Description of change
Clarification of data handling for patients 
who unintentionally received treatment 
not according to their randomization
Rationale for change
Request from regulators
Section to be changed
7.5
Determination of sample size
Description of change
Added additional simulated probabilities 
for sample size of 12
Rationale for change
Request from regulators
Section to be changed
8.1
Trial Approval, Patient Information, 
Informed Consent
Description of change
Reference to “participant’s legally 
accepted representative” deleted
Rationale for change
Request from regulators

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Section to be changed
8.4
Expedited reporting of Adverse Events
Description of change
Additional information on expedited 
reporting of adverse events added
Rationale for change
Request from regulators
Section to be changed
9
References
Description of change
Update safety reference document to 
most current version (ProAir HFA US)
Rationale for change
Currentness of references
11.3
GLOBAL AMENDMENT 3
Date of amendment
21 Nov 2023
EU CT number
2022-502835-21-00
BI Trial number
1397-0013 (ClairaflyTM)
BI Investigational Medicinal 
Product(s)
BI 1291583
Title of protocol
A randomised, double-blind, placebo-
controlled, parallel group trial evaluating 
safety, tolerability, pharmacodynamics 
and pharmacokinetics of BI 1291583 one 
tablet once daily over 12 weeks versus 
placebo in adult patients with cystic 
fibrosis bronchiectasis (ClairaflyTM)
Global Amendment due to urgent safety reasons
Global Amendment.
X
Category
Section 
No.
Description
Section to be changed
1.2
Drug Profile
Description of change
Information on recently detected 
metabolite 
 added and text 
rephrased accordingly
Rationale for change
Wording updated due to to recently 
detected, 
 
Section to be changed
1.2
Drug Profile
Description of change
Nomenclature of metabolites 
standardized, use of CD numbers instead 
of M numbers
Rationale for change
Alignment with nomenclature used in 
investigator’s brochure

Boehringer Ingelheim
21 Nov 2023
BI Trial No.: 1397-0013
c40742178-04                                       Clinical Trial Protocol
Page 124 of 125
Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-12177_40-106_AD-03 (22.0)
Section to be changed
1.2
Drug Profile
Description of change
Reference added (PK and safety of 
brensocatib in patients with CF)
Rationale for change
Results just recently published
Section to be changed
1.4.2
Risks - Table
Description of change
Reproductive system: information added 
and text rephrased
Genotoxicity for BI 1291583 and the 
 
previously identified metabolites was not 
demonstrated in preclinical studies. The 
genotoxicity assessment has not yet been 
completed for the 
 
. Data in humans 
are not available.
Mitigation strategy adapted: 
contraception requirements for WOCBP 
(2 methods) and men able to father a 
child
Rationale for change
Contraception requirements added due to 
recently detected, 
 
Section to be changed
3.3.2
Inclusion criteria
Description of change
Consecutive numbering of Inclusion 
Criteria
Rationale for change
Correction, formatting issue in previous 
version
Section to be changed
3.3.2
Inclusion Criteria
Description of change
#7: information on contraception 
requirements for male and WOCBP trial 
participants added
Rationale for change
Criterium updated due to to recently 
detected, 
 
Section to be changed
4.2.2.3
Contraception requirements
Description of change
Information updated: WOCBP, if their 
sexual partner is a man able to father a 
child, must use two medically approved 
methods of birth control throughout the 
trial and for a period of at least 9 months 
after last trial drug intake.

Boehringer Ingelheim
21 Nov 2023
BI Trial No.: 1397-0013
c40742178-04                                       Clinical Trial Protocol
Page 125 of 125
Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-12177_40-106_AD-03 (22.0)
Men participating in this clinical trial, if 
their sexual partner is a WOCBP, must 
use condom from the first administration 
of trial medication until 6 months after 
the last administration of trial 
medication.
Rationale for change
Requirements updated due to to recently 
detected, 
 
Section to be changed
5.2.6.2.3
Pregnancy
Description of change
Information added: 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.
Rationale for change
Detection of previously unidentified 
metabolite 
Section to be changed
6.2.2
Treatment period
Description of change
Reminder for male participants with 
WOCBP partners added, to continue use 
of contraception after last administration 
of trial medication
Rationale for change
Updated contraception requirements for 
male participants with WOCBP partners

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c40742178
4.0
clinical-trial-protocol-version-04
A randomised, double-blind, placebo-controlled, parallel group trial evaluating
safety, tolerability, pharmacodynamics and pharmacokinetics of BI 1291583 one
tablet once daily over 12 weeks versus placebo in adult patients with cystic fibrosis
bronchiectasis (ClairaflyTM)
Author-Statistician
21 Nov 2023 12:33 CET
Approval-Clinical Program 
21 Nov 2023 13:26 CET
Approval-Clinical Trial Leader
21 Nov 2023 13:35 CET
Verification-Paper Signature
Completion
22 Nov 2023 08:17 CET
Boehringer 
~11111~ lngelhein1 

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c40742178
4.0