Clinical trial NCT04656275
Conditions: Non-cystic Fibrosis Bronchiectasis
Sponsor: Boehringer Ingelheim
Start date: 2021-03-04; Completion date: 2022-01-19
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with non-cystic fibrosis bronchiectasis. The main purpose of this study is to find out how a medicine called BI 1323495 is tolerated by people with non-cystic bronchiectasis.

The study tests 2 different doses of BI 1323495. Some of the participants get placebo. It is decided by chance who gets BI 1323495 and who gets placebo. Participants take BI 1323495 or placebo as tablets twice a day for 3 months. Placebo tablets look like BI 1323495 tablets but do not contain any medicine. Participants can also continue taking standard medicines for noncystic bronchiectasis throughout the study.

Participants are in the study for about 4 months. During this time, the participants visit the study site about 11 times and get about 2 phone calls. At the visits, doctors check the health of the participants and note any health problems that could have been caused by BI 1323495.

Detailed description:

Arms: arm 1: Part 1 arm 2: Part 2 arm 3: Placebo
Interventions: intervention 1: BI 1323495 intervention 2: Placebo
Intervention descriptions: intervention 1: BI 1323495 intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
TITLE PAGE
Document Number:
c31693972-02
EudraCT No.
EU Trial No.
2019-003853-27
Boehringer 
Ingelheim (BI)
Trial No.
1405-0008
BI Investigational
Medicinal Product(s)
BI 1323495
Title
Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
different oral doses of BI 1323495 versus placebo in patients 
with non-cystic fibrosis bronchiectasis (randomised, double-
blind, placebo-controlled, parallel group trial)
Lay Title
A study in patients with non-cystic fibrosis bronchiectasis to test 
how well different doses of BI 1323495 are tolerated and how 
BI 1323495 affects biomarkers of inflammation
Clinical Phase
Phase Ic
Clinical Trial Leader
Phone: 
Fax: 
Coordinating 
Investigator
Version and Date
Version: 2.0
Date: 22 Apr 2021
Page 1 of 111


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Proprietary confidential information.
2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
17 Sep 2020
Revision date
22 Apr 2021
BI trial number
1405-0008
Title of trial
Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
different multiple oral doses of BI 1323495 versus placebo in patients 
with non-cystic fibrosis bronchiectasis (randomised, double-blind, 
placebo-controlled, parallel group trial)
Coordinating 
Investigator
Trial site(s)
Multi-centre trial conducted in 2 countries
Clinical phase
Phase Ic
Trial rationale
After establishing safety and tolerability in healthy volunteers, the 
trial is intended to confirm the safety and tolerability of multiple 
doses of BI 1323495 in a population of patients with non-cystic 
fibrosis bronchiectasis (nCFB), and to assess the inhibition of 
neutrophil elastase (NE) in blood and sputum. 
Trial objective(s)
The main objectives of this trial are to compare safety and tolerability 
of different doses of BI 1323495 with placebo and to assess 
pharmacodynamics of BI 1323495 in sputum and in blood as well as 
early signs of clinical efficacy of BI 1323495 in patients with nCFB. 
Trial endpoints
Primary endpoint: The safety and tolerability of BI 1323495 will be 
assessed based on the occurrence of drug-related adverse events.
Secondary endpoints: 

Change from baseline to week 12 in absolute NE activity in 
sputum

Change from baseline to week 12 in neutrophil cell count in 
sputum

Change from baseline to week 12 in NE activity in whole blood 
after stimulation with zymosan, normalized to neutrophil cell 
counts

Change from baseline to week 12 in post-bronchodilator forced 
expiratory volume in one second (FEV1)
Trial design
Multicentre, randomised, double-blind (patient and investigator 
blinded), placebo-controlled, parallel group trial over 12 weeks
treatment
Total number of patients
randomised
36 patients in Parts A and B
Number of patients on 
each treatment

9 patients on placebo (in total in Parts A and B)

9 patients on BI 1323495 30mg bid in Part A

18 patients on BI 1323495 150 mg qd in Part B
Diagnosis
Proven and documented diagnosis of bronchiectasis not related to 
cystic fibrosis
Main in- and exclusion 

18 years to 80 years (inclusive), male and female (not of 


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criteria
childbearing potential) subjects

Clinical history consistent with nCFB and proven and 
documented diagnosis of bronchiectasis by CT and dilated 
airways compatible with bronchiectasis at initial diagnosis

Regular daily sputum producers with a history of chronic 
expectoration who are able to provide a valid sputum sample 
during screening (SCR)

Sputum neutrophil elastase positive based on point-of-care test 
(NEATstik® score ≥ 6 or equivalent) assessment at baseline

UDP-glucuronosyltransferase 2B17 (UGT2B17) extensive 
metabolizer (EM) (genotypes *1/*1 or *1/*2)

Stable regimen of standard nCFB treatment allowed

No concomitant diagnosis of pulmonary disease other than 
bronchiectasis, chronic obstructive pulmonary disease (COPD), 
or asthma
Test product(s)
BI 1323495 film-coated tablets (tablet strengths 10 and 50 mg)
dose
In Part A: 60 mg daily (30 mg bid). In Part B: 150 mg qd
mode of 
administration
Oral (p.o.) within 30 minutes of a meal containing a fat component
Comparator product(s)
Matching placebo
dose
Not applicable
mode of
administration
Oral (p.o.) within 30 minutes of a meal containing a fat component
Duration of treatment
84 days: In Part A, 83 days twice daily (bid) and single dose on day 
84; in Part B, 84 days once daily (qd)
Statistical methods
The primary and secondary endpoints will be evaluated using 
descriptive statistics.


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MAIN FLOW CHART
Trial Periods
Screening1
Run-in
(Baseline -
BSL)
Randomised Treatment Period
Follow-
up (FUP)
Visit2
1
2a
BSL
2b
BSL
33
415
5
6
PK Day
716
8
9a
9b
10 EoT / 
early EoT4
11 FUP / 
EoS
Week 
-4
-1
0
1
2
4
6
8
11
12
14
Day 
-27
-6
-2
1
8
15
29
43
57
78
82
84
98
Time window for visits (days)
+14
+2
+1
±0
±3
±3
±3
±3
±3
+3
+1
+3
±4
Informed consent
X
Demographics
X
Medical history including 
Smoking status and alcohol 
history
X
Testing for UGT2B17 genotype
X
Physical examination
X
X
X
X
X
Height (only at V1)/ body weight
X
X
X
X
X
Vital signs: pulse rate (PR), 
blood pressure (BP), aural body 
temperature
X
X
X
X
X
X
X
Laboratory tests (blood/urine)
X13
X
X
X
X
X
X
X
12-Lead Electrocardiogram 
(ECG) (single ECG, may be 
repeated by investigator 
judgement)
X
X
X
X
X
X
Pregnancy test in women 
(serum S / urine U)
X (S)
X (U)5
X (U)5
X (U)5
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Review of in-/exclusion criteria
X
X
X
X
Randomisation
X


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Trial Periods
Screening1
Run-in
(Baseline -
BSL)
Randomised Treatment Period
Follow-
up (FUP)
Visit2
1
2a
BSL
2b
BSL
33
415
5
6
PK Day
716
8
9a
9b
10 EoT / 
early EoT4
11 FUP / 
EoS
IRT call/notification12
X
X
X
X
X
X
Administer trial drugs at site6
X
X
Dispense trial drugs for home6
X
X
X
X
PK blood sampling (see Sample 
and Assessment Flow Chart)
X
X
X
X
Lung questionnaires
(QoL-B; SGRQ; CASA-Q)
X
X
X
Sputum (collected at site)7, 14
X17
X
X
X
X
X
X
X
X
X
X
24h Sputum (collected at home)8
X
X
X
Murray sputum colour chart
X
X
X
NEATstik® (NE determination)
X
X
X
Blood sample for biomarkers, 
pharmacodynamic (PD)
X
X
X
X
X
X
X
Zymosan stimulation in whole 
blood
X
X
X
X
X
X
X
Cotinine test
X
X
X
X
X
X
X
Serum banking sample 
(optional)9
X
X
X
X
X
X
X
Urine banking sample (otional)9
X
Pulmonary Function Test 
(PFT)10
X
X
X
X
X
X
All AEs/SAEs/AESIs11
X
X
X
X
X
X
X
X
X
X
X
X
X
Compliance check
(medication)
X
X
X
X
Completion of patient 
participation
X


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1.
Informed consent needs to be signed before any procedure related to this trial is performed (before or at Visit 1).
2.
Timing of sampling and assessments: see Sample and Assessment Flow Chart.
3.
Day of Randomisation / Day of first intake of randomised medication.
4.
Patients who discontinue trial treatment prematurely should undergo an early End of Treatment (EoT) visit as soon as possible (study procedures will be the same as 
for Visit 10 (EoT) except no treatment will be administered). Follow up Visit (End of Study (EoS)) will be 14 days +/- 4 days thereafter.
5.
Serum pregnancy test is to be performed if urine test positive and no Investigational Medicinal Product (IMP) to be given until negative result confirmed.
6.
Following first drug administration in Part A, evening and morning dose should be taken with a 12 h time interval (e.g. 20:00 h and 08:00 h) approximately at the 
same time each day during the treatment phase, within a time window of +/- 1 hour. In Part B, the once-daily dose should be taken approximately at the same time 
each morning during the treatment phase. Drug should be taken 15-30 min after food intake including a fat component (like yogurt, milk, cheese or sausage). As an 
exemption, at Visit 3 and Visit 6, drug administration will happen at the site outside the normal schedule. Patients will then go back to their usual evening/morning 
interval (Part A) or once-daily interval (Part B), respectively. At Visit 3, patient will receive a reserve kit in case medication gets lost or the patients comes back to 
the next visit after more than 2 weeks. The morning drug administration date/time is collected on the eCRF for all Visits 3 to 10 (except Visit 4).
7.
 
8.
Sputum containers for 24h sputum collection will be provided to the patient at Visit 2b, Visit 5 and Visit 9b.
9.
Collection of biobanking samples is optional and requires a separate informed consent form (ICF).
10. If treated with bronchodilators, wash-out of 24 hours for qd long acting, 12 hours for bid long acting, and 8 hours for short acting bronchodilators should be 
observed before pulmonary function tests. Screening PFT would also be accepted without wash-out in case consent was only signed on the same day.
11. After the EoS visit (=individual patient’s end of the trial) the investigator should report only any cancers of new histology and relapse of existing cancer, trial 
treatment related adverse events (AEs), serious adverse events (SAEs) and trial treatment related adverse events of special interest (AESIs) of which the investigator 
may become aware of and only via the BI SAE form, please see Section 5.2.6.2.1.
12. Screening has to be registered in the Interactive Response Technology (IRT) at time of informed consent to trigger initial medication supply to the site.
13. Polymerase Chain Reaction (PCR) Test on SARS-CoV-2 to be performed only at Screening.
14. Left over volume of sputum samples may be used for optional biobanking see Section 5.5.
15. Visit 4 will be conducted as a phone call with the patient.
16. Visit 7 will be conducted as a phone call and blood for safety lab will be collected at a local lab or by a flying nurse.
17. Sputum collection for check of inclusion criterion #7


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SAMPLE AND ASSESSMENT FLOW CHART
Visit
Day
Window
Planned time (relative to 
last drug administration
[h:min]1
Approximate clock time of 
actual day [h:min]1
Event and comment
Safety laboratory
12-lead ECG2, Vital signs
PKblood3
Blood for PD readouts
Biobanking sample
Lung questionnaires4
Sputum collection5
Pulmonary function test6
24 h Sputum
Murray colour chart
NEATstik®
V1
-27
+14
08:00
Screening visit
08:30
Safety
X7
X
09:00
Sputum collection for inclusion check
X
11:00
Pulmonary function
X
V2a
-6
+2
09:00
Sputum collection incl NEATstik®
X
X
V2b
-2
+1
08:00
Blood PD, serum and urine banking8
X
X
08:30
Questionnaires 
X
09:00
Sputum collection incl Murray chart and NEATstik®
X
X
X
11:00
Pulmonary function
X
V3
1
-02:30
08:00
Hand over of 24h sputum collected at home, safety, baseline PK and 
blood PD, serum banking8
X7
X
X
X
X
X
-02:00
08:30
Sputum collection incl. Murray chart
X
X
00:00
10:30
First drug administration
06:00
16:30
Safety
X
X
06:30
17:00
Discharge from trial site9; at home: Follow daily drug posology10
V5
15
±3
08:00
Drug intake at home. At site: safety, blood PD, PK, serum banking8
X
X
X
X
X
09:00
Sputum
X
11:00
Pulmonary function
X


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Visit
Day
Window
Planned time (relative to 
last drug administration
[h:min]1
Approximate clock time of 
actual day [h:min]1
Event and comment
Safety laboratory
12-lead ECG2, Vital signs
PKblood3
Blood for PD readouts
Biobanking sample
Lung questionnaires4
Sputum collection5
Pulmonary function test6
24 h Sputum
Murray colour chart
NEATstik®
V6
29
±3
-1:30
08:00
No drug intake at home. At site: safety, trough PK, blood PD, hand 
over of 24h sputum collected at home, serum banking8
X
X
X
X
X
X
-0:30
08:30
Sputum collection
X
0:00
10:30
Drug administration at site
1:00
11:30
PK
X
2:00
12:30
PK
X
4:00
14:30
PK
X
6:00
16:30
Safety, PK, Blood PD
X
X
X
X
17:00
Discharge from trial site9; at home: Follow daily drug posology10
V7
43
±3
8:00
Safety blood collected at a local lab or by a flying nurse
X
V8
57
±3
08:00
Safety, blood PD, serum banking8
X
X
X
X
08:30
Questionnaires
X
09:00
Sputum collection
X
11:00
Pulmonary function
X
V9a
78
+3
08:00
Sputum collection
X
V9b
82
+1
08:00
Sputum collection
X
V10
84
+5
08:00
Last drug administration at home; EoT site visit: Hand over of 24h 
sputum collected at home, safety, blood PD, PK, serum banking8
X
X
X
X
X
X
08:30
Questionnaires
X
09:00
Sputum collection incl. Murray chart, NEATstik®
X
X
X


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Visit
Day
Window
Planned time (relative to 
last drug administration
[h:min]1
Approximate clock time of 
actual day [h:min]1
Event and comment
Safety laboratory
12-lead ECG2, Vital signs
PKblood3
Blood for PD readouts
Biobanking sample
Lung questionnaires4
Sputum collection5
Pulmonary function test6
24 h Sputum
Murray colour chart
NEATstik®
11:00
Pulmonary function
X
V11
98
±5
08:30
Safety, blood PD, serum banking8
X
X11
X
X
09:00
Sputum collection
X
11:00
Pulmonary function
X
1.
The time is approximate; a deviation from the scheduled time of the day of ± 120 minutes is acceptable. The relative time deviations from time of administration 
should be kept as minimal as possible and should be below ± 15 minutes for PK measurements. The exact time of sample collection should be collected in electronic 
Case Report Form (eCRF). 
2.
ECG recordings are performed as single ECGs (no central ECG lab). The ECG recording may be repeated by investigator judgment for medical or quality reasons.
3.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) including addition of blood samples and visits 
as long as the total blood volume taken does not exceed 500 mL per subject.
4.
Self-reported outcome questionnaires include: Quality of Life Questionnaire-Bronchiectasis, QOL-B; St. George's Respiratory Questionnaire, SGRQ; Cough and 
sputum assessment questionnaire, CASA-Q. Questionnaires should be done in a quiet place prior to the lung-related visit procedures. 
5.
Sputum collection should occur during a 2h timeframe with active breathing techniques. Study nurse / physiotherapist needs to be available to support patient in 
performing active cycle of breathing technique in case of difficulties producing sputum. Next step will be Oscillating Positive Expiratory Pressure (OPEP), if despite 
breathing technique still no sputum is being produced. Patients who produce an adequate sputum sample do not have to undergo these supportive measures. In case 
no adequate sputum sample is produced spontaneously, induction of sputum with isotonic, or subsequently hypertonic saline is mandatory. If sputum samples do not 
meet the quality criteria as directly assessed at the site, re-sampling at the next day is generally possible.
6.
If treated with bronchodilators, wash-out of 24 hours for qd long acting, 12 hours for bid long acting, and 8 hours for short acting bronchodilators should be 
observed before pulmonary function tests.
7.
Including urine drug screening and alcohol breath test
8.
Collection of biobanking samples is optional. Participating patients are required to give informed consent specifically for biobanking. Samples will be stored at a 
biobanking facility for future research. 


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9.
Discharge is not mandatory and always at discretion of the investigator. Patient in-house stay may be extended at any time if deemed clinically necessary. The 
subjects are only allowed to leave the trial site after formal assessment and confirmation of their fitness by the investigator or 
 designee.
10. Following first drug administration in Part A, evening and morning dose should be taken with a 12 h time interval (e.g. 20:00 h and 08:00 h) approximately at the 
same time each day during the treatment phase, within a time window of +/- 1 hour. In Part B, the once-daily dose should be taken approximately at the same time 
each morning during the treatment phase. Drug should be taken 15-30 min after food intake including a fat component (like yogurt, milk, cheese or sausage). As an 
exemption, at Visit 3 and Visit 6, drug administration will happen at the site outside the normal schedule. Patients will then go back to their usual evening/morning 
interval (Part A) or once-daily interval (Part B), respectively.
11. At V11, only Vital Signs need to be assessed


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................3
MAIN FLOW CHART............................................................................................................5
SAMPLE AND ASSESSMENT FLOW CHART.................................................................8
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................16
1.
INTRODUCTION...............................................................................................21
1.1
MEDICAL BACKGROUND.............................................................................21
1.2
DRUG PROFILE................................................................................................21
1.2.1
Mode of action.....................................................................................................22
1.2.2
Data from non-clinical and toxicology studies .................................................22
1.2.2.1
Non-clinical pharmacology...................................................................................22
1.2.2.2
Non-clinical pharmacokinetics .............................................................................23
1.2.2.3
Drug interactions...................................................................................................23
1.2.2.4
Toxicology ............................................................................................................24
1.2.3
Data from clinical studies...................................................................................24
1.2.3.1
Clinical pharmacokinetics.....................................................................................25
1.2.3.2
Clinical Pharmacodynamics..................................................................................28
1.2.3.3
Clinical safety .......................................................................................................29
1.2.4
Residual Effect Period ........................................................................................33
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................33
1.4
BENEFIT - RISK ASSESSMENT.....................................................................34
1.4.1
Benefits.................................................................................................................34
1.4.2
Risks .....................................................................................................................34
1.4.2.1
Risk related to the COVID-19 pandemic..............................................................38
1.4.3
Discussion.............................................................................................................40
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................41
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........41
2.1.1
Main objectives....................................................................................................41
2.1.2
Primary endpoint(s)............................................................................................41
2.1.3
Secondary endpoint(s) ........................................................................................41
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................44
3.1
OVERALL TRIAL DESIGN.............................................................................44


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................46
3.3
SELECTION OF TRIAL POPULATION .......................................................47
3.3.1
Main diagnosis for trial entry ............................................................................48
3.3.2
Inclusion criteria .................................................................................................48
3.3.3
Exclusion criteria ................................................................................................49
3.3.4
Withdrawal of patients from treatment or assessments..................................51
3.3.4.1
Discontinuation of trial treatment .........................................................................51
3.3.4.2
Withdrawal of consent to trial participation .........................................................52
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................52
3.3.5
Replacement of patients......................................................................................52
4.
TREATMENTS...................................................................................................53
4.1
INVESTIGATIONAL TREATMENTS ...........................................................53
4.1.1
Identity of the Investigational Medicinal Products..........................................53
4.1.2
Selection of doses in the trial and dose modifications......................................54
4.1.3
Method of assigning patients to treatment groups...........................................54
4.1.4
Drug assignment and administration of doses for each patient......................54
4.1.5
Blinding and procedures for unblinding...........................................................55
4.1.5.1
Blinding.................................................................................................................55
4.1.5.2
Unblinding and breaking the code ........................................................................56
4.1.6
Packaging, labelling, and re-supply...................................................................56
4.1.7
Storage conditions...............................................................................................57
4.1.8
Drug accountability.............................................................................................57
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................57
4.2.1
Other treatments and emergency procedures..................................................57
4.2.2
Restrictions ..........................................................................................................58
4.2.2.1
Restrictions regarding concomitant treatment ......................................................58
4.2.2.2
Restrictions on vaccinations..................................................................................58
4.2.2.3
Restrictions on diet and life style..........................................................................58
4.2.2.4
Contraception requirements..................................................................................59
4.3
TREATMENT COMPLIANCE........................................................................59
5.
ASSESSMENTS..................................................................................................60
5.1
ASSESSMENT OF EFFICACY........................................................................60
5.1.1
Spirometry (PFT)................................................................................................60
5.1.2
24h-sputum weight..............................................................................................61
5.1.3
Patient Reported Outcomes ...............................................................................61
5.2
ASSESSMENT OF SAFETY.............................................................................62
5.2.1
Physical examination ..........................................................................................62
5.2.2
Vital signs.............................................................................................................62
5.2.3
Safety laboratory parameters ............................................................................62
5.2.4
Electrocardiogram ..............................................................................................65
5.2.5
Other safety parameters.....................................................................................65
5.2.6
Assessment of adverse events.............................................................................66
5.2.6.1
Definitions of AEs ................................................................................................66


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5.2.6.1.1
Adverse event........................................................................................................66
5.2.6.1.2
Serious adverse event............................................................................................66
5.2.6.1.3
AEs considered “Always Serious”........................................................................66
5.2.6.1.4
Adverse events of special interest.........................................................................67
5.2.6.1.5
Intensity (severity) of AEs....................................................................................67
5.2.6.1.6
Causal relationship of AEs....................................................................................67
5.2.6.2
Adverse event collection and reporting ................................................................68
5.2.6.2.1
AE Collection........................................................................................................68
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................69
5.2.6.2.3
Pregnancy..............................................................................................................69
5.2.6.2.4
Exemptions to SAE reporting ...............................................................................69
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................70
5.3.1
Assessment of pharmacokinetics .......................................................................70
5.3.2
Methods of sample collection .............................................................................70
5.3.2.1
Plasma sampling for pharmacokinetic analysis ....................................................70
5.3.2.2
Sputum sampling for pharmacokinetic analysis ...................................................70
5.5
BIOBANKING ....................................................................................................73
5.5.1
Methods and timing of sample collection..........................................................73
5.6
OTHER ASSESSMENTS...................................................................................73
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................73
6.
INVESTIGATIONAL PLAN.............................................................................75
6.1
VISIT SCHEDULE.............................................................................................75
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................75
6.2.1
Screening and run-in period ..............................................................................75
6.2.2
Treatment period ................................................................................................76
6.2.3
Follow-up period and trial completion..............................................................77
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................78
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................78
7.2
PLANNED ANALYSES.....................................................................................78
7.2.1
General considerations .......................................................................................78
7.2.2
Primary endpoint analyses.................................................................................79
7.2.3
Secondary endpoint analyses .............................................................................80
7.2.5
Safety analyses.....................................................................................................81
7.2.7
Interim Analyses .................................................................................................82
7.3
HANDLING OF MISSING DATA ...................................................................83
7.4
RANDOMISATION ...........................................................................................83


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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 ...................................................................................87
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................87
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........88
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................88
8.6
TRIAL MILESTONES.......................................................................................88
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................89
9.
REFERENCES....................................................................................................90
9.1
PUBLISHED REFERENCES............................................................................90
9.2
UNPUBLISHED REFERENCES......................................................................91
10.
APPENDICES.....................................................................................................93
10.1
INSTRUCTIONS FOR USE..............................................................................93
10.1.1
Quality of Life Questionnaire-Bronchiectasis, QOL-B ...................................93
10.1.2
St. George's Respiratory Questionnaire, SGRQ..............................................98
10.1.3
Cough and sputum assessment questionnaire, CASA-Q...............................104
10.2
PHARMACOKINETIC METHODS AND ANALYSES..............................109
10.3
TRIAL BIOMARKER PLAN..........................................................................109
10.4
VISIT MODIFICATION IN EXCEPTIONAL CIRCUMSTANCES .........109
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................110
11.1
GLOBAL AMENDMENT 1 ............................................................................110


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ABBREVIATIONS
A1AT
Alpha-1 antitrypsin
ABPA
Allergic Bronchopulmonary Aspergillosis
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AP
Alkaline Phosphatase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
AUC
Area under the Curve
BCRP
Breast Cancer Resistance Protein
BE
bronchiectasis
BI
Boehringer Ingelheim
bid
bis in die (twice daily)
BP
Blood Pressure
BSL
Baseline
CA
Competent Authority
CASA-Q
Cough and Sputum Assessment Questionnaire
CatC
Cathepsin C
CF
Cystic Fibrosis
CK
Creatine Kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CK-MB
Creatine Kinase Isoenzyme MB
Cmax
Maximum Plasma Concentration
COPD
Chronic Obstructive Pulmonary Disease
COVID-19
Coronavirus-associated disease 2019
Cpre,N
Predose concentration of the analyte in plasma immediately before 
administration of the Nth dose
CRA
Clinical Research Associate
CRO
Clinical Research Organization 


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CRP
C-Reactive Protein
CT
Computed Tomography
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CXCR1
C-X-C motif chemokine receptor 1
CYP
Cytochrome P450
DDI
Drug-drug interaction
DILI
Drug Induced Liver Injury
DMARDS
Disease-modifying Anti-rheumatic Drugs
DV
Deviation
e. g.
exempli gratia (for example)
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Effective Dose
eDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EM
Extensive Metabolizer(s)
EoS
End of Study
EoT
End of Treatment
ERS
European Respiratory Society
FDA
U.S. Food and Drug Administration
FEV1
Forced Expiratory Volume in one second
FSH
Follicle Stimulating Hormone
FUP
Follow-up
g
gram
GCP
Good Clinical Practice
gCV
Geometric Coefficient of Variation
GFR
Glomerular Filtration Rate


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GGT
Gamma-Glutamyl Transferase
GLDH
Glutamate Dehydrogenase
GLI
Global Lung Initiative
GLP
Good Laboratory Practice
gMean
Geometric mean value
GMP
Good Manufacturing Practice
gRT
global Randomisation Team
GSH
Glutathione
h
hour(s)
hERG
human Ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
i. e.
id est (that is)
i. v.
intravenous
IB
Investigator’s Brochure
IC50
Concentration at which 50% Inhibition of Target Occurs
IC90
Concentration at which 90% inhibition of target occurs
IC95
Concentration at which 95% inhibition of target occurs
ICF
Informed Consent Form
iCS
Inhaled Corticosteriods
IEC
Independent Ethics Committee
IgG
Immunglobulin G
IGRA
interferon gamma release assay
IL-1β
Interleukin-1ß
IL-8
Interleukin-8
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
iPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator Site File
ISO
International Organization for Standardization
kg
kilogram
LABA
Long Acting Beta Agonists


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LAMA
Long Acting Muscarinic Agonists
LC-MS/MS
liquid chromatography tandem mass spectrometry
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
milligram
min
minute(s)
mL
millilitre
mm
minute(s)
MMRM
Mixed Model for Repeated Measurements
MoA
Mode of Action
MRD
Multiple Rising Dose
mRNA
Messenger ribonucleic acid
NA
Not applicable
nCFB
Non-Cystic Fibrosis Bronchiectasis
NE
Neutrophil Elastase
nM
Nanomolar
NOAEL
No Observed Adverse Effect Level
NSAID
Non-Steroidal Anti-Inflammatory Drug
NTM
Nontuberculous Mycobacteria
OATP1B1
Organic anion transporting polypeptide 1B1
OPEP
Oscillating Positive Expiratory Pressure
OPU
Operating Unit
p.o.
per os (oral)
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic(s)
PFT
Pulmonary Function Test
P-gp
P-Glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set
PLS
Papillon-Lefèvre syndrome
PM
Poor Metabolizer(s)
PR
Pulse Rate
PR3
proteinase 3


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qd
once daily (quaque die)
QOL-B
Quality of Life Questionnaire - Bronchiectasis
RA,Cmax
Accumulation ratio for Cmax at steady state versus after the first dose
RA,AUCτ
Accumulation ratio for AUCτ at steady state versus after the first 
dose
RBC
Red Blood Cell Count
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
RS
Randomised Set
SAE
Serious Adverse Event
SCR
Screening
SCS
Screened Set
SGRQ
St. George’s Respiratory Questionnaire
SOP
Standard Operating Procedure
SP-D
Surfactant-Protein D
SRD
Single Rising Dose
SS
Steady State
SUSAR
Suspected Unexpected Serious Adverse Reaction
tmax
Timepoint of Maximum Plasma Concentration
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UDP
Uridine diphosphate
UGT2B17
UDP-glucuronosyltransferase 2B17
UGT2B7
UDP-Glucuronosyltransferase 2B7
ULN
Upper Limit of Normal
URTI
Upper Respiratory Tract Infection
WBC
White Blood Cells
WOCBP
Woman of Childbearing Potential
λz(,ss)
Terminal rate constant in plasma


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1.
INTRODUCTION
BI 1323495 is an oral, reversible inhibitor of neutrophil elastase (NE) under clinical 
development in chronic lung diseases with neutrophilic inflammation of the lower airways as 
a main feature, such as COPD, cystic fibrosis (CF), and nCFB.
1.1
MEDICAL BACKGROUND
There is a high unmet medical need in chronic lung diseases with neutrophilic airway 
inflammation as a main feature, such as non-cystic fibrosis bronchiectasis (nCFB).
nCFB is a chronic lung disease caused by a number of pathological insults and characterised 
by predominantly neutrophilic inflammation. Proteases released by neutrophils, such as 
neutrophil elastase, cause structural damage to the airways. This leads to irreversibly dilated 
airways, mucus gland hyperplasia, and impaired mucus clearance, and results in a vicious 
cycle of recurrent severe infections and further airway damage [P13-15562]. About 50 to 70 
per 100,000 are affected by nCFB [R19-3085, R20-1159]. Patients with nCFB typically 
suffer from chronic cough, sputum production, frequent respiratory infections and impaired 
lung function. They have a substantial burden due to frequent pulmonary exacerbations that 
cause hospital stays and unscheduled outpatient visits, and a significant morbidity, and are 
associated with increased mortality [R19-3087, R19-3082, P19-09060, R20-2791]. There is a 
high medical need for the development of drugs targeting the neutrophilic inflammation of 
nCFB, as currently there are no approved pharmacological therapies for nCFB. Current 
pharmacological management options centre around as-needed antibiotics to treat pulmonary 
exacerbations and off-label administration of bronchodilators, and/or inhaled corticosteroids. 
Under pathophysiological conditions, dysfunctional activation of neutrophils leads to release 
of neutrophil serine proteases, such as neutrophil elastase (NE), that are not adequately 
inhibited by endogenous anti-proteases. This leads to inflammation, excessive proteolysis of 
the lung connective tissue, damage to the airways [R19-3378, R19-3084, R19-3080, R16-
2239], increase mucus production in lung epithelial cells [R17-2928], and delay of the 
resolution phase of chronic lung inflammation [R17-2929]. Of note, NE proteolytic activity 
as well as extracellular matrix turnover markers have been associated with disease severity 
and clinically relevant outcomes in this disease [R18-3321]. Inhibition of NE by an orally 
available inhibitor is expected to result in reduced distal airway destruction related to damage 
to pulmonary elastin and other extracellular matrix proteins, in anti-inflammatory [R17-
2929], as well as in anti-mucus hypersecretory effects [P02-06423, R17-2928].
1.2
DRUG PROFILE
In this trial, the investigational medicinal product BI 1323495, an inhibitor of NE, will be 
administered. The sections below summarize the drug profile of BI 1323495. For details, 
refer to the current version of the Investigators’s Brochure (IB) [c21238478-05].


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1.2.1
Mode of action
BI 1323495 is a highly selective and reversible inhibitor of the enzymatic activity of 
neutrophil elastase (NE). NE is produced and stored in neutrophil granules and released in 
large quantities after activation. Excess activity of NE in the lung of COPD patients results in 
the degradation of several extracellular matrix proteins, an increased activation of other 
proteases (e.g. MMP9), and further inactivation of endogenous protease inhibitors (e.g., 
TIMP1, elafin). This leads to the destruction of alveolar septa and hence emphysema 
development, as well as potentiation and propagation of inflammation. By inhibiting NE, 
BI 1323495 is expected to slow the development of emphysema.
In CF, NE is known to impair antibacterial defense by cleavage of C-X-C motif chemokine 
receptor 1 (CXCR1), CD14, and CD16 on neutrophils and to promote bacterial persistence by 
crippling normal host opsonophagocytotic mechanisms [R18-3357]. The same processes are 
assumed to contribute to impaired antibacterial defense in nCFB. BI 1323495 is expected to 
reduce the deleterious effects of NE in the highly inflamed airways. This will result in a 
reduction in airway inflammation and its associated tissue destruction, in improved 
mucociliary clearance, as well as in improved bacterial killing capacity of neutrophils in the 
airways. Together, these effects are expected to result in a reduction in the frequency and 
severity of pulmonary exacerbations that are a hallmark of both nCFB and CF. The benefits 
of this therapeutic approach are assumed to be independent of concomitant therapies of a 
patient.
1.2.2
Data from non-clinical and toxicology studies
1.2.2.1
Non-clinical pharmacology
Due to sequence differences between human and other species’ NE, compounds targeting the 
S1 pocket are expected to show a different activity on the isolated human enzyme compared 
to other species. Therefore, the inhibition of isolated NE derived from different species 
(mouse, rat, dog, cynomolgus monkey) by BI 1323495 was measured. Half maximal 
inhibitory concentrations (IC50) are summarized in the following table.
Table 1.2.2.1: 1
Comparison of potency between mouse, rat, cynomolgus monkey, 
and human
Molecular potency (IC50)
Nanomolar (nM)
Mouse
21
Rat
16
Cynomolgus monkey
3
Human
0.4
BI 1323495 exhibits > 4000x selectivity versus the related neutrophil serine proteases 
Cathepsin G (CatG) and proteinase 3 (PR3) and has no activity against 44 tested unrelated 
receptors, transporters, and enzymes up to a concentration of 10 μM. BI 1323495 inhibits NE 
in plasma from zymosan-stimulated human blood with an IC50 of 1 nM and inhibits the 
degradation of insoluble elastin by human NE.


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The in-vivo activity of BI 1323495 was measured in an NE-induced lung damage model in 
mice. In this model, the intratracheal application of human NE results in a specific acute lung 
injury, which was attenuated by BI 1323495 in a dose-dependent manner with an effective 
dose at 50% reduction (ED50) of 1.9 mg/kg.
BI 1323495 inhibited hERG (human Ether-à-go-go-Related Gene) current with an IC50 of 80 
μM. The cardiovascular and central nervous systems were unaffected. In rats, a transient 
increase in mean respiratory rate (30-90 min postdose) of 26-59 % and minute volume (30-90 
min and 180 min postdose) of 15-27 % was observed at 900 mg/kg compared to vehicle-
treated control animals.
1.2.2.2
Non-clinical pharmacokinetics
Plasma protein binding of BI 1323495 was low and similar in all investigated animal species 
and humans with bound fractions ranging between 47.4 % and 59.6 %. Based on quantitative 
whole-body autoradiography in rats, distribution from whole blood into tissues was moderate. 
The half-lives in ocular tissues and skin were very similar to half-lives in plasma. BI 1323495 
was metabolized in vitro in human hepatocytes by glucuronidation by UDP-
Glucuronosyltransferase 2B7 (UGT2B7) and UGT2B17 and via various phase I 
biotransformations by Cytochrome P450 (CYP) 3A4. Non-enzymatic formation of a cysteine 
adduct was observed. The in vitro ratio of metabolism via glucuronidation to oxidation was in 
the range of 7:1 to 2:1. The predominant metabolite in rat plasma after oral administration 
was an oxidative metabolite in male rat. In female rats the cleavage product of BI 1323495 
glutathione (GSH) conjugate was the predominant metabolite in plasma. These gender-
related differences were also observed in excreta with respect to formation of sulfate 
conjugate that was observed only in female faeces.
The main route of elimination was via faeces (90 % and 88 % of the oral and intravenous 
dose, respectively). Urinary excretion was also relevant following oral administration (4 % of 
the dose in male rats and 10.5 % of the dose in female rats) and intravenous administration 
(6.7 % of the dose in males and 7.8 % of the dose in females). 
1.2.2.3
Drug interactions
BI 1323495 is not expected to inhibit hepatic CYP 1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 
and 3A4 up to a maximum plasma concentration (Cmax) of 87µM.
The induction potential of BI 1323495 was investigated on messenger ribonucleic acid 
(mRNA) level. Based on these results, BI 1323495 has the potential to induce CYP3A4 at 
Cmax,ss levels of 20 nM, CYP2C8 at 191 nM, CYP2B6 at 369 nM, and CYP2C9 at 678 nM. 
Based on current PK results of the multiple rising dose (MRD) trial, geometric mean value
(gMean) Cmax,ss levels of the 30 mg bid dose are ~100 nM, but at a higher dose, Cmax,ss is 
predicted to increase to up to 447 nM for 300 mg BI 1323495 bid. However, a midazolam 
arm was included into the MRD trial for dose groups ≥ 70 mg bid BI 1323495 to investigate 
the induction potential in humans. A microdose of midazolam (75 µg) was administered 
orally at day -1 before start of treatment with BI 1323495 (reference) and at day 11 (test). 


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No signs of induction of CYP3A4 was detected within the 70 mg bid BI 1323495 based on 
Midazoam and its metabolite 1-OH Midazolam. The results for dose groups above 70 mg are 
not yet available (data on file). Hence co-administration of drugs that are sensitive substrates 
of CYP3A4, including hormonal contraceptives are at the moment allowed for doses ≤ 70 mg 
bid BI 1323495. 
In vitro assessment showed that BI 1323495 has the potential to inhibit the gastrointestinal 
transporters P-Glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) at single 
doses higher than 32 mg and 120 mg, respectively. In addition, the renal transporter MATE2-
K may be inhibited at exposures higher than 0.12µM. There is also a likelihood that the 
hepatic transporter organic anion transporting polypeptide 1B1 (OATP1B1) may be inhibited 
at doses higher than 150 mg of BI 1323495.
1.2.2.4
Toxicology
The toxicology program of BI 1323495 to date includes repeat-dose toxicity trials up to 13 
weeks in Wistar rats and cynomolgus monkeys, the complete standard battery of genotoxicity 
trials, and the in vitro phototoxicity assay. Pivotal trials were performed in compliance with 
GLP (Good Laboratory Practice). General and safety pharmacology trials included in vitro 
hERG potassium channel trials, cardiovascular assessments in conscious cynomolgus 
monkeys, effects on the central nervous system and respiratory system in rats.
The 4- and 13-week trials resulted in no observed adverse effect levels (NOAEL) in rat or 
cynomolgus monkey of 300 and 200 (males)/600 (females) mg/kg/day or 250 and 300 
mg/kg/day, respectively. The associated mean exposures combined for males and females 
from the 4-week trials were 33,000 and 54,700 nM (Cmax) and 179,000 and 471,000 nM·h 
(area under the curve (AUC)0-24), respectively. At higher exposures above the NOAEL, BI 
1323495 was associated with findings in the liver and kidneys in the rat in the 4-week study 
while only kidney findings were confirmed in the 13-week rat study, showing reversibility 
within 8 weeks of recovery. Changes in the immune system were seen in the monkey at the 
NOAEL and below. They were mild in extent and reversible.
Based on these non-clinical toxicology assessments, exposure caps not to be exceeded in 
human trials were set to 1,900 nM and 11,500 nM*h for Cmax and AUC0-24, respectively. 
These exposure boundaries were defined to provide safety factors of 16 and 10 to the Cmax,ss 
of 30,900 nM and AUC0-24,ss of 115,000 nM*h, respectively that were observed at the 
NOAEL in rats in the 4 week toxicity study at 300 mg/kg, when – as the most conservative 
approach – the lower exposure observed in female rats were taken as reference.
For a detailed description of the non-clinical toxicology of BI 1323495, please refer to the 
current Investigator’s Brochure (IB) [c21238478-05].
1.2.3
Data from clinical studies
At the time of preparing this trial protocol, three Phase I trials with administration of single 
doses of BI 1323495 to healthy male volunteers have been completed. 


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The single-rising dose trial 1405-0001 was the first-in-man trial. Trial 1405-0007 investigated 
the relative bioavailability of single doses of BI 1323495 once administered in the fasted state 
and once administered following a high-fat, high-calorie meal. Trial 1405-0009 investigated 
the drug-drug interaction (DDI) with the strong CYP3A / P-gp inhibitor itraconazole.
Two clinical trials are completed and are in the reporting phase at the time of completing 
CTP amendment no 1: The multiple-rising dose trial 1405-0002 assessed the safety and 
tolerability as well as CYP3A4 induction potential of multiple twice daily (bid) or once daily 
(qd) doses of BI 1323495 in healthy subjects. Trial 1405-0015 assessed the effect of single 
doses of BI 1323495 on various transporter proteins in healthy male subjects.
1.2.3.1
Clinical pharmacokinetics
BI 1323495 exposure levels were found to be associated with a genetic polymorphism of 
uridine diphosphate (UDP)-glucuronosyltransferase 2B17 (UGT2B17). This metabolizing 
enzyme glucuronidates BI 1323495, predominantly in enterocytes, but also in the liver. Two 
common alleles exist: The *1 allele contains the full enzyme-encoding sequence which is, 
however, completely deleted in the *2 allele. Hence, *2/*2-homozygous individuals do not 
express UGT2B17 and do not glucuronidate BI 1323495 via this pathway (poor metabolizers, 
PMs). Carriers of at least one *1 allele are extensive metabolizers (EMs). In EMs, 
BI 1323495 is glucuronidated upon intestinal absorption and eliminated during the first 
passage through the liver/bile system. As the orally administered dose is only partially 
absorbed as the non-glucuronidated parent molecule, systemic exposure levels are low. In 
PMs, in contrast, most of the orally administered dose of BI 1323495 is absorbed non-
glucuronidated, resulting in higher systemic exposures. After the first-pass metabolism, the 
same pharmacokinetic properties apply to all genotypes. The effect of this UGT2B17 
polymorphism on the exposure of other drugs predominantly metabolized via this enzyme has 
been described [R19-1806]. The UGT2B17 polymorphism is unequally distributed among 
different ethnic groups. In Caucasian populations, the *2/*2 genotype is present in less than 
15%, whereas in Asian populations, the *2/*2 genotype predominates (>80% of the 
population) [R19-1805].
In the single rising dose (SRD) trial 1405-0001, AUCs and Cmax were increased in PMs, 
compared with EMs [c26492551]. gMean plasma exposure increased in a less than dose-
proportional manner. Multiple plasma concentration peaks were observed in the profiles of 
nearly all subjects treated. The terminal half-life was similar over all dose groups, except for 
being longer in the 600 mg dose group. 
The most prominent metabolites within the 200 mg dose group of the SRD in UGT2B17 
*1/*1 and *1/*2 subjects, were the glucuronide of BI 1323495 (CD 7545) and an oxidative 
metabolite (M517(1)). In UGT *2/*2 subjects, only minor amounts of the glucuronide
(CD 7545) were found in plasma. Comparable exposure of oxidative metabolites was found 
in both groups. Minor amounts of an additional oxidated and glucuronidated metabolite were 
additionally identified.
In clinical trial 1405-0002, the pharmacokinetics and pharmacodynamics of multiple rising 
oral doses of BI 1323495 were investigated. Preliminary PK data of the 10 mg, 30 mg, 


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70 mg, 120 mg, and 150 mg bid dose levels in Extensive Metabolizers, and the 10 and 30 mg 
bid dose levels in Poor Metabolizers are shown in Table 1.2.3.1: 1.
Pharmacokinetics after multiple doses in UGT2B17 Extensive Metabolizers (EMs)
The exposure to BI 1323495, based on Cmax and AUC at steady state, increased less than 
dose-proportionally from 10 to 30 mg bid and from 70 to 120 mg bid. However, the exposure 
to BI 1323495 increased more than dose-proportionally from the 30 to 70 mg bid dose. This 
over-proportional increase was caused by an increase in accumulation from 2-fold based on 
AUC in the 30 mg bid DG to ~3.5-fold for doses ≥ 70 mg bid. The exposure to BI 1323495 
was comparable between 70 mg bid and 150 mg bid. This was interpreted to be caused by 
usage of a higher tablet strength (150 mg) with unfavourable dissolution properties. The 
exposure at steady state of 120 mg administered once daily was between the exposure of 30 
and 70 mg given twice daily, as the accumulation ratio was lower as for the bid treatments. 
The exposure values in UGT2B17 EMs showed considerable inter-individual variability. 
Preliminary PK results do not indicate an obvious effect of gender on the pharmacokinetics of 
BI 1323495. No obvious effects of genotype (*1/*1 versus *1/*2 EMs) on the 
pharmacokinetics of BI 1323495 was observed in the completed dose groups.
Pharmacokinetics after multiple doses in UGT2B17 Poor Metabolizers (PMs)
The inter-individual variability was considerably lower in PMs as compared to EMs. 
Exposure to BI 1323495 at steady state was approximately ~3- to 5-fold higher based on
Cmax and AUC in PMs as compared to EMs. The accumulation ratios at 10 mg bid and 30 
mg bid were comparable between both PMs and EMs at the same dose level. However, the 
exposure after the first dose of 30 mg in PMs was twice as high as the one after the first dose 
of 70 mg bid DG in EMs. At 30 mg bid in PMs, less high accumulation was observed than in 
the higher dose groups in the EMs. This suggests that UGT2B17 metabolism plays a role in 
the unexpectedly high accumulation behavior in EMs. Steady state exposure upon 30 mg bid 
DG in PMs was comparable to the one observed with 70 mg bid in EMs. For further details 
refer to the IB (c21238478-05).
Based on a preliminary Pop PK model analysis that includes pharmacokinetic data from the 
SRD (1405-0001) and food effect (1405-0007) trials and preliminary data from the MRD
(1405-0002) trial, sex was not a statistically significant covariate, meaning that females so far 
did not show relevant higher exposure as compared to male volunteers (1405-0002 data on 
file).


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Table 1.2.3.1: 1
Preliminary selected gMean PK parameters of BI 1323495 at steady 
state in healthy volunteers under fed conditions in UGT2B17 EMs 
(genotypes *1/*2, *1/*1) and UGT2B17 PMs (*2/*2) in trial 1405-
0002 (data on file)
Cmax,ss
[nmol/L]
RACmax
AUCτ,ss [nmol·h/L]
RAAUCτ
N
gMean 
(gCV%)
gMean 
(min-max
gMean 
(gCV%)
gMean 
(min-max)
UGT2B17 EMs (*1/*2, *1/*1)
10 mg bid
9
37.5
(49.6)
1.59
(0.914 – 2.45)
237
(60.9)
2.00
(1.47 – 2.84)
30 mg bid
8
64.4
(78.7)
1.06
(0.684 – 1.99)
475
(86.2)
1.96
(1.14 – 2.47)
70 mg bid
8
281
(48.0)
2.31
(1.44 – 6.06)
2500
(59.4)
3.56
(2.18 – 6.37)
120 mg bid
9
362
(77.7)
2.38
(1.62 – 2.92)
2850
(69.3)
2.98
(2.21 – 3.71)
150 mg bid 
8
265
(46.0)
2.55
(1.71 – 7.57)
2080
(41.6)
3.45
(1.96 – 7.70)
120 mg qd
164
(48.7)
1.32
(0.828-2.68)
1960
(56.2)
1.50
(1.02-2.64)
UGT2B17 PMs (*2/*2)
10 mg bid
5
109
(27.7)
1.59
(0.914 – 2.45)
740
(22.4)
1.71
(1.28 – 2.26)
30 mg bid
6
300
(32.6)
1.06
(0.684 – 1.99)
2380
(28.1)
1.81
(1.47 – 2.26)
In the food effect trial 1405-0007, administration of 100 mg BI 1323495 together with a high-
fat, high-calorie meal increased the exposure 2.4-fold and 1.7-fold based on Cmax and AUC, 
respectively, versus fasted conditions. The maximum plasma concentrations were reached 
earlier in the fed state (median timepoint of maximum plasma concentration (tmax) 2.00) as 
compared to the fasted state (median tmax 3.52 h). The food effect was not different in poor 
metabolizers as compared to extensive metabolizers.


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The DDI trial 1405-0009 investigated the effects of multiple doses of itraconazole – a strong 
CYP3A4 and P-gp inhibitor – on the relative bioavailability of a single dose of 10 mg BI 
1323495 in EMs. Itraconazole caused a modest increase in exposure to BI 1323495 in gMean 
AUC0-∞and Cmax of ~1.7-fold and ~1.4-fold, respectively. Therefore, concomitant treatment 
with strong CYP3A4 / P-gp inhibitors should be avoided in EMs. In PMs, the effect of 
CYP3A4 / P-gp inhibition has not yet been assessed.
In a DDI trial (1405-0015) the effects of a single dose of 300 mg BI 1323495 on the PK of 
Rosuvastatin (10 mg) and Dabigatran (75 mg) were tested in 14 healthy subjects each. 
Rosuvastatin is a sensitive substrate of BCRP and OATP1B1, while Dabigatran is a sensitive 
substrate for P-gp.  Co-administration with BI 1323495 increased the Cmax (1.14-fold) and 
AUC (1.05-fold) of Rosuvastatin only slightly, with the upper boundary of the 90% 
confidence interval (CI) within or only slightly above (Cmax) above 125%. Co-
administration with BI 1323495 increased the AUC (1.09-fold) and Cmax (1.08-fold) of 
dabigatran only slightly with the upper boundary of the 90% CI still within 125%. Hence, BI 
1323495 appears not to have a clinically relevant effect on BCRP, OATP1B1 and P-gp
(c33366190-01).
1.2.3.2
Clinical Pharmacodynamics
In human single and multiple rising dose studies, ex-vivo peripheral blood enzymatic activity 
of NE following zymosan-induced release of enzyme-containing granules was quantified as a 
marker of the pharmacodynamic effect (direct target engagement). Enzymatic activity was 
calculated as percent inhibition from individual baseline values corrected for neutrophil count 
for each time point. 
In the SRD trial 1405-0001, after fitting an Emax model to plasma concentration against % 
inhibition of NE, IC50, IC90, and IC95 values were estimated to 3.6 nM, 33 nM, and 69 nM, 
respectively, with a maximum inhibition of 100% achieved (c26492551).
c26492551In the MRD trial 1405-0002, peripheral blood NE activity was evaluated only in 
the extensive metabolizers (EMs). Based on a preliminary evaluation, all subjects achieved a 
maximum % inhibition of at least 90% in doses higher than 10 mg bid. In Table 1.2.3.2: 1, % 
inhibition of NE (at trough and after dosing) is summarized per dose level.   


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Table 1.2.3.2: 1 
Preliminary assessment of peripheral blood % inhibition of NE (at 
trough and after dosing at steady state) in healthy volunteers that are
UGT2B17 EMs (genotypes *1/*2, *1/*1) in trial 1405-002 (data on 
file)
% inhibition of NE
(at trough)
% inhibition of NE
(after dosing)
N
Median
(Range)
N
Median
(Range)
Placebo
16
-3.1 (-41.3 – 36.6)
17
-9.1 (-41.4 – 36.9)
BID dosing
10 mg
8
81.0 (61.2 – 94.5)
8
90.0 (85.4 – 95.4)
30 mg
8
91.8 (80.4 – 93.4)
8
95.1 (90.0 – 99.0) 
70 mg
8
98.5 (96.4 – 99.5)
7
98.6 (97.4 – 99.7)
120 mg
9
98.0 (96.8 – 99.1)
9
98.7 (98.4 – 99.6) 
150 mg
8
97.3 (95.0 – 99.0)
8
98.3 (93.6 – 99.8)
QD dosing
120 mg 
9
93.1 (86.1 – 95.4)
9
98.0 (95.0 – 98.3)
1.2.3.3
Clinical safety
In the single-rising dose trial 1405-0001, 48 healthy male subjects received single oral doses 
of BI 1323495 of 10 mg to 600 mg, and 15 were administered placebo. The observed 
exposures did not reach the exposure safety caps of AUC0-24 (11,500 nM*h) and Cmax (1,900 
nM) – even not on an individual level – that had been predefined based on animal toxicity 
data. BI 1323495 was well tolerated, with no clinically relevant changes in safety lab, ECG, 
and vital signs observed. Treatment-emergent Adverse Events (AEs) were reported in 16 of 
the 48 subjects (33.3%) treated with BI 1323495 and 2 of the 15 subjects (13.3%) treated 
with placebo. Investigator-defined drug related AEs were reported for 11 (22.9%) of the 48 
subjects dosed with BI 1323495 and 1 (6.7%) of the 15 subjects dosed with placebo. Most 
frequent drug related AEs were headache, reported by 6 (12.5%), and diarrhea, reported by 2 
(4.2%). There was no relationship between the occurrence of AEs and dose. 3 AEs in subjects 
receiving BI 1323495 were judged as moderate in intensity, all other AEs were classified as 
mild. No severe or serious AEs were reported. Among the subjects receiving single doses of 
BI 1323495, 7 were UGT2B17 *2/*2 homozygous. Of these 7 subjects, 3 reported AEs 
(42.9%), which included one case of mild transient elevation of alanine aminotransferase
(ALT) and glutamate dehydrogenase (GLDH) in a subject having received a single dose of 
300 mg.


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In the food effect trial 1405-0007, 12 healthy male subjects received single oral doses of 
BI 1323495 of 100 mg under fasted and fed (high calorie, high fat meal) conditions. Of these, 
11 subjects completed the trial according to trial protocol. 
During the study, 5 AEs were observed in 5 subjects while on treatment. One on-treatment 
AE of headache was considered drug-related. No serious AEs or other significant AEs were 
reported. One severe AE of influenza led to discontinuation and was not considered drug 
related.
In the DDI trial 1405-0009, a total of 14 healthy male subjects were administered single 
doses of 100 mg, once alone and once in combination with itraconazole. AEs were reported 
in 6 of the 14 subjects (42.9%) treated with BI 1323495. Investigator-defined drug related 
AEs were reported for 2 (14.3%) of the 14 subjects, both diarrhea and occurring while treated 
with BI 1323495 in combination with itraconazole. No severe or serious AEs were reported.
MRD trial 1405-0002 investigated the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple bid oral doses of BI 1323495 in healthy subjects that are 
UGT2B17 EMs or PMs. One additional dose group with 120 mg qd oral doses of BI 1323495 
in UGT2B17 EMs was also conducted. The following represents a summary of the clinical 
safety data of 6 dose groups in EMs and 2 dose groups in PMs. In the six completed EM dose 
groups, 27 male healthy subjects and 18 female healthy subjects (not of child-bearing 
potential or using adequate contraception methods) received multiple bid doses of BI 
1323495 of 10 mg, 30 mg, 70 mg, 120 mg, or 150 mg over 10.5 days, and 6 male healthy 
subjects and 3 female healthy subjects received multiple qd doses of 120 mg BI 1323495 
over 11 days. In the two completed PM dose groups, 6 male healthy subjects and 5 female 
healthy subjects received multiple twice daily doses of BI 1323495 of 10 mg or 30 mg over 
10.5 days. 22 (16 males, 6 females) healthy EM or PM subjects received placebo.
Two subjects in the 120 mg bid dose group and one subject in the 150 mg bid dose group had 
AUC exposures exceeding the pre-defined exposure cap of AUC0-24 (11,500 nM*h); no 
subject exceeded the predefined exposure cap for Cmax (1,900 nM). One subject in the 70 
mg dose group had increased blood pressure, and one subject in the 150 mg dose group had a 
prolongation of the QTcB interval, both considered drug related by the investigator. In the 
other subjects, multiple bid or qd doses of BI 1323495 were associated with no clinically 
relevant changes in safety lab, ECG, and vital signs observed. No deaths or serious AEs were 
reported in this trial. Any AEs were reported in 42 (65%) of the 65 subjects treated with BI 
1323495, and 11 (50%) of the 22 subjects treated with placebo.
Investigator-defined drug-related AEs were reported for 12 (18.5%) of 65 subjects treated 
with BI 1323495 and 1 (4.5%) of 22 subjects receiving placebo. Headache of mild intensity 
was the most frequently reported drug related AE (by 6 subjects treated with BI 1323495).
Abdominal pain was reported by 3 subjects treated with BI 1323495, the 
furthergastrointestinal events abdominal pain diarrhea and flatulence each in 2 subjects 
treated with BI 1323495 and CK elevation was reported for 1 subject. No other drug related 
AEs were reported in more than one subject treated with BI 1323495. One subject in the 
placebo group had an AE of severe intensity (abdominal discomfort) that was considered 
related. One EM subject in the 30 mg dose group had an AE of severe intensity (headache; 
not considered related to study medication). All other reported AEs were of mild or moderate 


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intensity. Overall, three AEs led to treatment discontinuation: One each in the EM dose 
groups 30 mg bid (nausea/vomiting, moderate, not considered related), 70 mg bid (blood 
pressure increased, moderate, considered related), and 150 mg bid (electrocardiogram QT 
prolonged, mild, considered related). There was no apparent relationship of the occurrence of 
AEs with dose. An overview on AEs judged related by the investigator is presented in Table 
1.2.3.3: 1. In summary, multiple doses of BI 1323495 investigated so far in clinical trials with 
healthy subjects were safe and well tolerated.


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Table 1.2.3.3: 1: Drug-related AEs reported in MRD trial 1405-0002
System Organ Class
Placebo
BI 1323495
Preferred Term
Extensive metabolizers
(EMs)
Poor metabolizers (PMs)
Total on 
BI 1323495
Total on 
treatment
10 mg 
bid
30 mg 
bid
70 mg 
bid
120 mg 
bid
150 mg 
bid
120 mg 
qd
10 mg
30 mg
Number of subjects, N (%)
22 
(100)
9 (100)
9 (100)
9 (100)
9 (100)
9 (100)
9 (100)
5 (100)
6 (100)
65 (100)
87 (100)
Total with any drug related AEs
1 (4.5)
2 (22.2)
3 (33.3)
1 (11.1)
2 (22.2)
4 (44.4)
0 (0)
0 (0)
1 (16.7)
11(16.9)
12 (13.8)
Gastrointestinal disorders/
Abdominal discomfort
1 (4.5)
1 (1.1)
Abdominal pain
1 (4.5)
1 (11.1)
1 (16.7)
2 (3.1)
3 (3.4)
Abdominal pain (upper)
1 (11.1)
1 (1.5)
1 (1.1)
Diarrhea
1 (11.1)
1 (11.1)
2 (3.1)
2 (2.3)
Flatulence
1 (11.1)
1 (11.1)
2 (3.1)
2 (2.3)
Investigations/
Blood pressure increased
1 (11.1)
1 (1.5)
1 (1.1)
CK elevation
1 (11.1)
1 (1.5)
1 (1.1)
Electrocardiogram QT prolonged
1 (11.1)
1 (1.5)
1 (1.1)
Electrocardiogram PR shortened
1 (11.1)
1 (1.5)
1 (1.1)
Nervous system disorders/
Headache
1 (11.1)
3 (33.3)
1 (11.1)
1 (11.1)
6 (9.2)
6 (6.9)
Syncope
1 (11.1)
1 (1.5)
1 (1.1)


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In the ongoing DDI study 1405-0015, 14 healthy male subjects were administered single 
doses of rosuvastatin, and of BI 1323495 300 mg in combination with rosuvastatin. Any AEs 
were reported in 5 of the 14 subjects (35.7%) while treated with BI 1323495 and rosuvastatin, 
and in 4 of the 14 subjects (28.6%) while treated with rosuvastatin alone. Investigator-defined 
drug related AEs were reported for 2 (14.3%) of the 14 subjects, both while treated with 
rosuvastatin alone. No severe or serious AEs were reported.
1.2.4
Residual Effect Period
The Residual Effect Period (REP) of BI 1323495 is assumed to be 7 days, equivalent to 5 
times the half-life of 30 h (at the highest dose group of the SRD trial, 600 mg). This is the 
period after the last dose with measurable drug levels and/or pharmacodynamic effects still 
likely to be present.
For a more detailed description of the drug profile of BI 1323495, please refer to the current 
IB [c21238478-05].
1.3
RATIONALE FOR PERFORMING THE TRIAL
In this trial, for the first time the effects of multiple doses of BI 1323495 will be assessed in 
patients. The main purpose of the trial is to investigate whether the targeted 
pharmacodynamic effect of inhibition of neutrophil elastase (NE) activity is achieved with 
one or more dose levels that are associated with favourable pharmacokinetic, safety, and 
tolerability profiles over a 12 week treatmen period. This will be done in a population of 
nCFB patients that are UGT2B17 EMs.
Whilst BI 1323495 has the potential for development in several inflammatory airway 
diseases, nCFB patients were selected to be the study population, as their condition represents 
an inflammatory state characterized by accumulation of neutrophils and high NE activity in 
sputum. Furthermore – as one of the hallmarks of the disease – nCFB patients regularly 
produce a sufficient volume of spontaneous sputum which therefore can be collected non-
invasively [R18-3321]. nCFB patients will be selected that have detectable NE activity in 
sputum at baseline [R19-3080, R19-3083]. A 12 week trial is considered an adequate 
duration to allow the assessment of safety/tolerability and the quantification of the inhibitory 
effect on NE activity in sputum, to assess further inflammatory and tissue-destruction 
biomarkers, and to collect data on clinical outcomes.
Results of this trial are intended to provide the basis for a planned further clinical 
development of BI 1323495 for patients with COPD, CF, and/or nCFB. Particularly, the 
results will help to define an appropriate dosing regimen for future studies with this 
compound.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see Section 5.4). If the patient 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.


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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Patients with nCFB receiving the NE inhibitor BI 1323495 that participate in this ‘first-in-
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 have an important role in nCFB, as 
sputum NE activity was found to be a biomarker of disease severity and future risk of 
exacerbations in patients with bronchiectasis [R18-3321], and patients will be selected that 
have elevated NE activity in sputum indicating that the targeted pathway is active. 
Considering the study duration of 12 weeks, inhibition of NE activity may result in 
modulation of clinical efficacy endpoints. Some benefit in symptoms (e.g., sputum volume, 
cough, mucus plugging), quality of life, and lung function 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.
The major expected benefit is that results from the 1405-0008 trial will guide further clinical 
development activities of the NE inhibitor BI 1323495, such as Phase II and III studies for 
treatment of patients with COPD, CF, and/or nCFB. As a high proportion of patients with 
bronchiectasis have a concomitant diagnosis of COPD [R19-3085], such nCFB patients might 
especially benefit from further clinical development of BI 1323495.
1.4.2
Risks
Factors of risk may derive from particular knowledge (or the lack thereof) regarding the 
mode of action (MoA), the nature of the target, findings in animal models / non-clinical 
safety studies, findings from clinical studies, or drug-induced liver injury, and are referenced 
in detail in the latest version of the Investigator’s Brochure of BI 1323495 [c21238478-05].


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Table 1.4.2:1 Overview over trial related risks
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: BI 1323495
Infection
A mildly increased risk of 
bacterial infection has been 
reported in patients with 
Papillon-Lefèvre syndrome 
(genetic deficiency for 
Cathepsin C, the enzyme 
activating NE in neutrophil 
precursor cells in the bone 
marrow). These patients have 
life-long complete deficiency 
of active neutrophil serine 
proteases (NE, Cathepsin G, 
Proteinase 3).
No elevated risk of infection 
was reported in previous 
clinical studies with other 
inhibitors of NE.
Exclusion of patients with 
relevant immunodeficiency
or receiving 
immunomodulatory 
medication, or of patients 
having an acute infection.
Requirement of vaccination 
against Streptococcus 
pneumoniae in accordance 
with national vaccination 
recommendations.
Regular clinical and 
laboratory monitoring for 
infection.
Effects on the liver
Non-clinical toxicity studies 
at exposures high above those 
expected in humans revealed 
effects on the liver, indicated 
by increases in liver enzymes 
(aspartate aminotransferase
(AST), ALT or GLDH) and 
an increase in total bilirubin 
in rats, accompanied by 
biliary hyperplasia in female 
rats in the 4 week studies. 
These findings were not seen 
in the 13-week toxicity 
studies although male rats 
achieved high exposures. The 
drug exposure was much 
higher in these animals than 
those expected in man.
Subjects with clinically 
relevant impairment of liver 
function, based on 
laboratory assessment 
regarding liver 
aminotransferases, alkaline 
phosphatase (AP), gamma 
glutamyl transferase, 
bilirubin, serum albumin, 
and International 
Normalized Ration (INR), 
are excluded from 
participation in this trial. 
Liver aminotransferases, 
alkaline phosphatase, 
gamma-glutamyl 
transferase, as well as total 
and direct bilirubin are 
monitored as part of the 
standard safety laboratory 
assessments.


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Table 1.4.2:1 Overview over trial related risks (cont’d)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Effects on the kidneys
At exposures high above 
those expected in humans, 
effects on the kidneys were 
observed in 2- and 4-week
non-clinical toxicity studies. 
These were accompanied by 
increases in creatinine levels 
and changes in blood urea. In 
the 13-week study, tubular 
degeneration was seen in male 
rats at the highest dose tested 
but recovered fully within the 
8 week recovery period.
In the cynomolgus monkey 
toxicology studies no effects 
on the kidney were seen.
Patients with a clinically 
relevant, at least moderate
impairment in kidney 
function will be excluded 
from participation in this 
trial.
Serum creatinine, urea, and 
electrolyte levels will be 
assessed and Glomerular 
Filtration Rate (GFR) be 
estimated according to the 
CKD-EPI (Chronic Kidney
Disease Epidemiology 
Collaboration) equation as 
part of the safety laboratory 
assessments.
Coagulation pathway
In rats, an increase in 
fibrinogen (not considered 
toxicologically relevant) was 
observed. A reduction in 
platelet counts was observed 
in both rats and cynomolgus 
monkeys at exposures high 
above those expected in 
humans. This was
accompanied by minor 
increases in prothrombin time 
in male rats. No bleeding 
events occurred.
Patients with a known 
coagulopathy or abnormal 
coagulation laboratory 
parameters at screening, or 
patients who within 10 days 
prior to administration of 
trial medication used any 
drug that could inhibit 
coagulation will be 
excluded, except for low-
dose acetylsalicylic acid 
(aspirin) and NSAID.
Platelet count, prothrombin 
time and activated partial 
thromboplastin time (aPTT) 
will be measured as part of 
the standard safety 
laboratory assessments and 
concomitant drugs that 
inhibit platelet aggregation 
or coagulation will be 
prohibited.


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Table 1.4.2:1 Overview over trial related risks (cont’d)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Reproductive system
The risk to embryo-fetal 
development has not yet been 
assessed, and no data are 
available from its use in 
pregnant or breastfeeding 
women.
Women of child-bearing 
potential are excluded from 
participating in this trial, 
which also includes women 
that are pregnant or 
breastfeeding.
Men able to father a child 
must be willing and able to 
use highly effective 
methods of birth control.
Drug-induced liver injury
(DILI)
Rare but severe event, thus 
under constant surveillance by 
sponsors and regulators.
Timely detection,
evaluation, and follow-up of 
laboratory alterations in 
selected liver laboratory 
parameters to ensure 
patients´ safety.
Trial procedures
Blood sampling
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 (FEV1)
Risks and discomforts 
associated with lung function 
testing may include shortness 
of breath, dizziness, or 
headache during the breathing 
tests.
-
close clinical monitoring 
for AEs
-
selection of experienced 
sites and site staff


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Table 1.4.2:1 Overview over trial related risks (cont’d)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Other risks
Placebo
If the patient is randomised 
to receive a placebo, no 
clinical benefit from 
treatment with study 
medication is expected.
Study medication will be 
administered add-on to 
standard of care, ensuring 
that no relevant treatments 
are being withheld from 
patients. 
Risk related to Pandemic 
situations COVID-19
(Coronavirus-associated 
disease 2019)
Travelling to site, being at site 
for assessments, increased 
infection risk for lung 
function testing
Instead of site visits at
Day 8 and Day 43, phone 
visits will be conducted. A
flying nurse and local safety 
lab structure will be used to 
maintain control of safety of 
a patient and at the same 
time avoid risk of SARS-
CoV-2 exposition at site. 
To evaluate and implement 
the option of sputum 
collection at patient’s home 
as a fall-back scenario.
Possible modifications in 
pandemic situation as 
described in Section 6.1 and 
in Appendix 10.4.
1.4.2.1
Risk related to the COVID-19 pandemic
Patients with chronic respiratory diseases, such as non-CF bronchiectasis, are generally 
assumed to be at a higher risk of experiencing severe COVID-19, although this has not been 
seen clinically to date. A systematic evaluation of the risk for this particular patient 
population has currently not yet been published. An overview [R20-2485] of a limited 
number of cases reported in several national CF patient registries indicates no relevant 
increased risk for patients with cystic fibrosis, which shares many pathophysiological and 
clinical features with non-CF bronchiectasis (such as, e.g., mucus plugging of the airways 
and chronic colonization with pathogenic bacteria).
A theoretical risk of treatment with BI 1323495 and the associated suppression of NE activity 
may be an increase in the probability of contracting COVID-19 or of experiencing severe 
disease in case of such an infection, either by the virus itself or secondary bacterial infection. 
A thorough assessment has been conducted to evaluate whether the mechanism of action of 


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BI 1323495 to inhibit NE may suggest such an increased risk. The key aspects of the 
assessment are summarised below. The full written documentation of this assessment (BI 
1323495: Benefit-Risk assessment in context of COVID-19 infection) will be filed in the 
Trial Master File (TMF).
NE is an important component of the innate immune system, targeting proteins and virulence 
factors of various bacteria and thereby helping to fend off bacterial infections. However, it is 
only one among a large number of antimicrobial mechanisms of which neutrophils make use 
to kill bacterial pathogens. A specific role for neutrophils in the protection agains viral 
pathogens is not assumed.
The phenotype of patients with Papillon-Lefèvre syndrome (PLS), who completely lack 
functional neutrophil serine proteases (including NE) due to complete deficiency for 
Cathepsin C, is well described. No increased risk of viral infections has been reported in PLS 
patients. Likewise, no such risk has been documented in previous clinical trials in healthy 
subjects or in patients with respiratory diseases, including non-CF bronchiectasis, upon 
treatment with inhibitors of NE or inhibitors of the mechanistically related cathepsin C
(CatC) (referenced in the Investigator’s Brochure [c21238478-05]). Therefore, suppression of 
NE activity upon treatment with BI 1323495 is not expected to be associated with an 
increased risk of acquiring an infection with a viral pathogen targeting the airways, e.g., 
SARS-CoV-2, nor of a particularly severe clinical presentation in case of such an infection.
Currently available evidence does also not suggest an increased risk of secondary bacterial
infection in case of COVID-19 upon treatment with BI 1323495. Suppression of NE
represents a limited intervention into the overall armamentarium available to neutrophils to 
control bacterial infections. Furthermore, high levels of active NE have even been reported to 
impair antibacterial defense by cleavage of CXCR1, CD14, or CD16 on neutrophils, and by 
cleavage of opsonins from target bacteria, thereby impairing phagocytosis. Consistent with 
these considerations, studies investigating the effects of CatC or NE inhibitors in healthy 
subjects or patients with various respiratory diseases, including non-CF bronchiectasis, have 
not revealed an increased risk of bacterial infections, nor of aggravated clinical courses of 
influenza infections, or complications thereof by secondary bacterial infections.
NE inhibition by treatment with BI 1323495 is not expected to affect the benefit/risk ratio of 
a COVID-19 vaccine, and vice versa. A decision regarding vaccination of a subject 
participating in trial 1405-0008 must be taken based on an individual benefit-risk assessment 
by the investigator after thorough discussion with the subject. This assessment is to consider 
the approved label of the respective vaccine according to its summary of product 
characteristics as well as the provisions given in the CTP, including the time point when the 
vaccination should be given or a potential delay of the vaccination or the study treatment.
Based on these considerations, the benefit/risk assessment for the administration of
BI 1323495 to patients with non-CF bronchiectasis remains unaltered also in face of the 
COVID-19 pandemic.
Risk mitigation:


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Despite no increased risk of SARS-CoV-2 infection – or of a more severe COVID-19 disease
in case of such an infection – is assumed upon treatment with BI 1323495, an individual 
withdrawal criterion that treatment with BI 1323495 is to be discontinued in case of 
laboratory-confirmed COVID-19 infection has been defined. General protective measures to 
limit the risk of acquiring a SARS-CoV-2 infection, e.g., wearing gown, mask, and gloves; 
social distancing, etc., will be taken care of by each site in accordance with 
local/regional/national regulations.
1.4.3
Discussion
The BI 1323495 preclinical and clinical data, the clinical information from competitor 
compounds with the same MoA, as well as the implemented safety measures in this study, 
establish an acceptable risk profile to allow dosing of nCFB patients over 12 weeks.
The trial may only demonstrate efficacy in an exploratory fashion, and any direct benefit to 
patients receiving active treatment may be limited to a transient improvement of symptoms. 
However, the selected patient population and trial duration may allow detecting an early 
efficacy signal. Considering the medical need for the development of an effective treatment 
to slow the progression of airway inflammation and subsequent disease worsening, the 
Sponsor considers that the potential long-term benefits for patients with nCFB and other 
respiratory diseases associated with high levels of neutrophilic airway inflammation (COPD, 
CF) support the clinical development of BI 1323495.
Potential risks for the subject in relation to the current COVID-19 pandemic situation have 
been evaluated. With regard to study treatment, no relevant negative impact is expected on 
the patients’ health condition (e.g., increased susceptibility to viral / secondary bacterial 
infections, immune suppression, or impaired lung function). The number of scheduled site 
visits represents the minimum required for achieving the study goals. Appropriate cautionary 
measures will be set up at each site to minimize risk of infection with SARS-CoV-2 due to 
trial-related procedures. For the very unlikely case that despite all implemented measures a 
COVID-19 case occurs in a trial subject while in the study, a withdrawal criterion in case of 
laboratory-confirmed COVID-19 disease has been defined. The local/regional/national 
pandemic situation will be continuously evaluated while the study is ongoing, and – if needed 
– changes to the situation will be addressed by amendments to the Clinical Trial Protocol 
(CTP) to implement additional risk mitigation measures. 
A periodic safety review will be conducted to ensure the safety and wellbeing of trial 
participants.
In summary, based on these considerations, the benefit/risk assessment for the administration 
of BI 1323495 to nCFB patients is considered to remain positive also in face of the current 
COVID-19 pandemic.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of this trial is to compare safety and tolerability of different doses of
BI 1323495 with placebo in patients with nCFB based on the proportions of patients with 
drug-related adverse events after 12 weeks of different doses of BI 1323495 or placebo on an 
on-treatment basis. 
The secondary objective is to assess pharmacodynamics of BI 1323495 in sputum and in 
blood as well as early signs of clinical efficacy of BI 1323495, mainly focused on the change 
from baseline to week 12 in NE activity in sputum for each treatment, assuming that patients 
remain on treatment for 12 weeks without the use of prohibited medication (for details refer 
to Section 4.2). 
2.1.2
Primary endpoint(s)
The safety and tolerability of BI 1323495 will be assessed based on the occurrence of drug-
related adverse events after 12 weeks of treatment. The timeframe for the primary endpoint is 
from the first drug administration until end of the REP (Section 1.2.4) after the last drug 
administration.
2.1.3
Secondary endpoint(s)
The following secondary endpoints will be determined:

Change from baseline to week 12 in absolute NE activity in sputum

Change from baseline to week 12 in neutrophil cell count in sputum

Change from baseline to week 12 in NE activity in whole blood after stimulation with 
zymosan, normalized to neutrophil counts

Change from baseline to week 12 in absolute post-bronchodilator forced expiratory 
volume in one second, FEV1


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This Phase Ic trial consists of two trial parts (Part A and Part B). Each part is designed as 
multi-centre randomised, placebo controlled parallel study investigating different doses of 
BI 1323495 (orally, bid or qd) in patients with nCFB. Patients and investigators will remain 
blinded during the entire trial, the sponsor will be unblinded (for details refer to Section 
4.1.5).
In both trial parts, the study consists of a 2 to 4 week screening period including a 1 week 
baseline period, a 12 weeks randomised treatment period, and a 2 week follow-up period. 
Overall, each patient’s participation in the trial is estimated to last a total of approximately 
16-18 weeks.
As described in Figure 3.1: 1 below, patients will be enrolled (screened) in the trial (Visit 1) 
once the appropriate informed consent has been given. Determination of UGT2B17 genotype 
will be performed at screening to assess the eligibility of a patient to this trial that only allows 
participation of EMs (expected to constitute >85% in the Caucasian population). A point-of 
care assay (NEATstik®, 
) will be used to select patients with high sputum NE 
activity at baseline (NEATstik® score ≥ 6). During the baseline period (Visits 2a, b and Visit 
3 before treatment), patients have to donate two to three valid sputum samples.
At Visit 3, patients who successfully completed the screening visit and baseline period and 
still comply with the in- and exclusion criteria and have been clinically stable during the 
previous run-in period, will be randomised and allocated to treatment.
Subsequent visits (Visits 4, 5, 6, 7, 8, 10) primarily address safety, tolerability, and 
pharmacodynamics of BI 1323495, with an additional focus on pharmacokinetics of 
BI 1323495 at steady state (Visit 6). The last treatment week (Visits 9a and b and Visit 10 = 
End of Treatment) will again focus on the collection of two to three valid sputum samples to 
assess pharmacodynamics of BI 1323495.
After the completion of the 12 week treatment period, or in case of early treatment 
discontinuation, patients will be followed up for an additional 2 weeks. The patient’s 
participation is concluded when they have undergone the last planned visit (i.e. Visit 11 = 
Follow-up Visit = end of study visit, EoS). No overnight stationary visits are planned unless 
preferred by the patient or required by the investigator for operational reasons.


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Figure 3.1: 1 Schematic overview of the trial periods and visit schedule
As described in Figure 3.1:.2 below, the trial consists of two trial parts, Part A and Part B. In 
Part A, patients will be randomised to receive either 30 mg bid BI 1323495 or placebo bid. 
This dose was confirmed to be safely tolerated upon an assessment of clinical safety during 
an earlier stage of the healthy volunteer multiple-rising dose trial 1405-0002. The sponsor 
will review available safety data periodically throughout the trial.
Part B will start if the following conditions are fulfilled: 1) the active dose for Part B has been 
defined; and 2) periodic safety review up to this point has not revealed any concerns.
Completion of Part A is not a prerequisite to start Part B. In Part B, patients will be 
randomised to receive either 150 mg qd of BI 1323495 or placebo qd. Doses up to 150 mg 
bid (total daily dose: 300 mg BI 1323495) were tolerated safely in the healthy volunteer 
multiple-rising dose trial 1405-0002.
It is planned to include, in total, 36 patients with non-CF bronchiectasis in trial Parts A and 
B: 12 patients in Part A (3:1 randomisation, active:placebo) and 24 patients in Part B (3:1 
randomisation, active:placebo). 
Figure 3.1: 2 Overview of trial design
An unscheduled safety review meeting can be requested anytime by the Principal Investigator 
(or an authorised deputy) or the sponsor of the study (for instance, due to occurrence of any 
unforeseen adverse events).


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Since this trial evaluates BI 1323495 for 12 weeks (compared to 10.5 days – for bid dose 
groups, or 11 days – for the qd dose group in the healthy volunteer MRD trial) and for the 
first time in a patient population up to a higher age, safety and tolerability is the 
recommended primary objective for assessing a new drug in patients with nCFB. Due to its 
mechanism of action, a 12-week treatment period is considered sufficient to evaluate the PK 
and PD, and to potentially obtain an early sign of clinical efficacy of BI 1323495. A 2-week
follow-up period without treatment is considered to be sufficient, as this covers twice the 
residual effect period during which BI 1323495 exposures are expected to return to not 
quantifiable levels and pharmacodynamic effects (inhibition of NE) are expected to have 
fully reversed. 
Each trial part has a parallel-group, randomised, double-blind and placebo-controlled design 
as this is considered the most appropriate design to assess safety and efficacy of different 
doses of BI 1323495. In this trial, a double-blind (patient and investigator blinded, sponsor 
unblinded - for details refer to Section 4.1.5) concept was chosen to reduce the bias with 
regard to treatment-dependent effects as much as possible. Due to a close safety monitoring,
this approach is considered acceptable for patients. A placebo group is included in order to 
control for safety, tolerability, and pharmacodynamic effects of the trial medication.
Only UGT2B17 extensive metabolizers will be included in this study to reduce PK 
variability. A dose of 30 mg bid BI 1323495 has been shown to be safely tolerated and was 
associated with a median level of >90% inhibition of NE at trough in blood of a healthy 
volunteer population of UGT2B17 EMs. Of note, in addition, according to preliminary
pharmacometric simulations, a dose of 30 mg bid is predicted to remain within the exposure 
boundaries defined based on the results of the non-clinical toxicity studies even in UGT2B17 
PMs who are expected to have BI 1323495 exposures exceeding those in EMs. Therefore, 
this dose level might be compatible later in clinical development with a mixed population of 
both PMs and EMs (beyond the scope of this trial). As such, this dose could be a therapeutic
dose for EMs and PMs alike.
Total daily doses exceeding the dose of 150 mg qd to be investigated in Part B were
confirmed to be safe and tolerated in the MRD trial in healthy volunteers, and at 150 mg qd it 
is not expected that exposures in individual patients may exceed exposure boundaries that 
were predefined based on the NOAEL in animal toxicity studies. This dose is expected to 
achieve the maximal pharmacodynamic effect. A dose associated with a pharmacodynamic 
effect approaching complete suppression of NE activity in blood is considered important as 
previous trials with other NE inhibitors have failed to achieve a high level of NE suppression 
in the airways despite adequate suppression in blood. 
Based on information collected during the conduct of Parts A and B of this trial, it may be 
decided by the sponsor that important additional insights could be obtained from an 
additional part to introduce a third (intermediate or lower) dose level. This may be addressed 
in a subsequent substantial amendment.


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The start of each trial part is chosen to efficiently evaluate the overall trial objectives given 
the staggered availability of data from the MRD trial 1405-0002 and represents a careful and 
safety conscious approach to the treatment of nCFB patients with BI 1323495. Periodic 
analyses of trial data (for details see Section 7.2.7) will provide valuable results based on the 
actual study population. 
A total sample size of up to 36 patients, with N=12 in Part A and N=24 in Part B, is 
considered sufficient to assess the main objectives of this exploratory trial.
The final analysis of this trial will be based on data from all trial parts, resulting in a sample 
size of possibly 9 - 18 patients per treatment group. Data from patients treated with placebo 
from both trial parts will be pooled for the purpose of comparison with the two active 
treatment groups. The potential risk for bias due to combined analysis is thereby seen as low, 
as the unblinded periodic analysis results will not be shared with the staff at trial sites. Also, 
the time lag between the investigations of a specific treatment group from one trial part to the 
other is not expected to introduce bias in the data.
The overall feasibility of the trial is considered given, as experienced investigators will be 
selected that have both, access to nCFB patients as well as sputum handling proficiency.
3.3
SELECTION OF TRIAL POPULATION
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 has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial. A sufficient number of patients with nCFB will be screened from 
approximately 10 to 15 sites in two countries. nCFB patients who are regular daily producers 
of sputum with detectable NE activity levels will be the study population as 1) bronchiectasis 
(BE) represents an inflammatory state characterized by accumulation of neutrophils and 
associated proteases in the airways, and 2) a sufficient volume of spontaneous sputum can 
reproducibly be collected. It is expected that 2 to 5 patients will be randomised at each trial 
site. If enrolment is delayed, additional sites may be recruited.
Reasons for screening failures will be collected in the eCRF. The re-screening of patients will 
be permitted in circumstances where safety is not compromised and in which the patient is 
expected to become eligible as the screening failure was due to a transient, potentially 
reversible, condition. In such case, the patient should be declared as a screening failure in the 
eCRF and IRT with their original patient number. Upon re-screening, a new patient number 
will be assigned by the IRT. The old patient number, with which the patient failed screening, 
will be recorded in the eCRF and the already determined UGT2B17 genotype copied from 
the old eCRF. The current approved version of the information sheet and consent form should 
be signed again. One re-screening per patient will be allowed.
In case of pulmonary exacerbation requiring use of i.v./oral/inhaled antibiotics or 
hospitalization prior to the randomisation visit, the patient should be declared as a screening 
failure and a re-screening may be considered when the patient becomes eligible again. 


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Re-testing for eligibility criteria is only to be performed for a laboratory test that has been 
cancelled by the central laboratory (e.g. for specimen not received or received beyond 
stability) or for a laboratory result thought to be a spurious result if compared to previously 
available laboratory results. The re-test should be carried out as soon as possible so the 
laboratory test results will be received within the next planned visit windows in order to 
avoid protocol window violations.
A log of all patients 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. If a patient was randomised in error (does not meet all 
inclusion criteria or meets one or more exclusion criteria before randomisation), the sponsor 
should be contacted immediately.
3.3.1
Main diagnosis for trial entry
The key in- and exclusion criteria were selected to allow the enrolment of the preferred target 
population, i.e., patients of a broad age range that have clinically stable nCF bronchiectasis 
with regular daily sputum production and detectable NE activity in sputum. Eligibility will be 
confirmed at screening and baseline. The screening for detectable NE activity is considered 
crucial to reduce the potentially high variability in regard to sputum NE activity and ensure a 
trial population in which a treatment response to NE inhibition can be expected [R19-3080].
Concomitant maintenance treatment for the management of nCFB is allowed, except for 
strong CYP 3A4 inhibitors (a specified list of not-allowed comedications will be provided in 
ISF).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. 18 years to 80 years (inclusive) at the time of informed consent signature, male and 
female (not of childbearing potential) subjects.
For ‘female not of childbearing potential’ at least one of the following criteria must be 
fulfilled:

Permanently sterile (permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy; tubal ligation is not a method of 
permanent sterilisation)

Postmenopausal, defined as at least 1 year of spontaneous amenorrhea without an 
alternative medical cause (in questionable cases a blood sample with Follicle 
Stimulating Hormone (FSH) above 40 U/L and estradiol below 30 ng/L is 
confirmatory).


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Men must be vasectomised with documented absence of sperm or use male contraception 
(condom or sexual abstinence) from the first administration of trial medication until 30 
days after the last administration of trial medication if their sexual partner is a woman of 
childbearing potential (WOCBP).
2. Clinical history consistent with nCFB (cough, chronic sputum production and/or recurrent 
respiratory infections) and proven and documented diagnosis of bronchiectasis by 
computed tomography (CT) scan including dilated airways compatible with 
bronchiectasis at initial diagnosis. Bronchiectasis of various etiologies will be allowed, 
with exclusion criteria as below.
3. Vaccination against Streptococcus pneumoniae in accordance with national vaccination 
recommendations.
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with Good Clinical Practice (GCP) and local legislation.
5. FEV1 ≥30 % predicted (post-bronchodilator) at Screening Visit 1.
6. Stable (i.e., no dose change) regimen of standard nCFB treatment (including – but not 
limited to – hypertonic inhalation solutions, mucolytics, Long Acting Muscarinic 
Agonists (LAMA)/ Long Acting Beta Agonists (LABA) / inhaled corticosteriods (iCS), 
oral antibiotic maintenance regimen, and physiotherapy), if applicable, administered at 
least for 4 weeks prior to Screening Visit 1 and throughout the run-in period.
7. Regular daily sputum producers with a history of chronic expectoration who are able to 
provide a typical bronchiectasis sputum sample at Screening Visit 1.
8. Sputum neutrophil elastase positive based on point of care test (NEATstik® score ≥ 6) 
assessment at Visit 2a and Visit 2b.
9. Subjects genotyped as UGT2B17 extensive metabolizers prior to randomisation, i.e., 
carrying at least one functional allele of the UGT2B17 gene (*1/*1 or *1/*2).
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following criteria apply:
1.
Any finding in the medical examination (including BP, PR, or ECG) and/or laboratory 
value and/or any evidence of a concomitant disease assessed as clinically relevant by the 
investigator.
2.
Concomitant diagnosis of pulmonary disease other than bronchiectasis, COPD, or 
asthma.
3.
A current diagnosis of CF, primary immunodeficiency, active ABPA (Allergic 
Bronchopulmonary Aspergillosis) (defined by receipt of corticosteroids, anti-fungal 
treatment or monoclonal antibody treatment), or alpha-1 antitrypsin (A1AT) deficiency
as underlying disease. 
4.
A history or current immunodeficiency or are currently being treated (or are planned to 
be treated) with immunomodulatory drugs (except for iCS or low-dose oral 
corticosteroids), including disease-modifying anti-rheumatic drugs (DMARDs), and/or 
Immunglobulin G (IgG) treatments. Other medication that is excluded will be provided
in the ISF. On the day of the site visit with lung function measurement, no 
bronchodilators should be used until after completion of lung function assessment (see 
restrictions in Section 4.2.2.1). 


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5.
Any acute infections defined as infections requiring antibiotic therapy, or Upper 
Respiratory Tract Infection (URTI). Are currently being treated (or are planned to be 
treated) for a nontuberculous mycobacterial (NTM) lung infection or tuberculosis.
6.
A history of invasive pneumococcal disease.
7.
Inhaled antibiotic treatment or cycling oral antibiotic treatment with changed dose 
regimen 4 weeks prior to Screening Visit 1. 
8.
A treatment for a pulmonary exacerbation 4 weeks prior to Screening Visit 1.
9.
Systemic corticosteroids at >10°mg/day prednisolone equivalent within 4 weeks prior to 
Screening Visit 1.
10. History and/or presence of tuberculosis or positive result for interferon gamma release 
assay (IGRA) (i.e., QuantiFERON TB-Gold); positive results for Hepatitis B antigen, 
Hepatitis C antibodies and/or human immunodeficiency virus (HIV) 1 antigen or HIV1/2 
antibodies.
11. Any documented active or suspected malignancy or history of malignancy including lung 
cancer within 5 years prior to Screening Visit 1, except appropriately treated basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin or in situ carcinoma of 
uterine cervix.
12. Current smokers or or ex-smokers who stopped smoking less than three months ago or 
are not willing to maintain nicotin-abstinence during the trial if stopped smoking more 
than three months ago. 
13. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled, i.e. any condition that, in the investigator’s opinion, 
makes the patient an unreliable trial participant.
14. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for 
males) and/or drug abuse in the opinion of the investigator or positive drug screening.
15. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial.
16. Recent significant hemoptysis (≥300 mL or requiring blood transfusion) in the preceding 
4 weeks before Screening Visit 1 (and during the run-in period).
17. Intake of an investigational drug in another clinical trial within 60 days, or within 5 half-
lives of the investigational drug (whichever is longer), of planned administration of 
investigational drug in the current trial, or concurrent participation in another clinical 
trial in which investigational drug is administered.
18. Major surgery (major according to the investigator’s assessment) performed within 6 
weeks prior to randomisation or planned within 3 months after screening, e.g. hip 
replacement.
19. Current or history of relevant kidney, urinary tract diseases or abnormalities (e.g. 
nephrolithiasis, hydronephrosis, acute or chronic nephritis, renal injury, renal failure), 
according to investigator judgement.
20. Estimated glomerular filtration rate (eGFR) according to CKD-EPI formula < 60 mL/min 
at Screening Visit 1.
21. Known clinically relevant impairment of liver function or clinically relevant laboratory 
abnormality at the Screening Visit 1 regarding liver aminotransferases, alkaline 
phosphatase, gamma glutamyl transferase, bilirubin, serum albumin, as judged by the 
investigator. 
22. Known coagulopathy or abnormal coagulation laboratory parameters at screening, or 
subjects who, within 10 days prior to administration of trial medication, used any drug 


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that could reasonably inhibit coagulation, except for low-dose acetylsalicylic acid 
(aspirin) or NSAID.
23. Laboratory confirmed SARS-CoV-2 infection (PCR positive) within 4 weeks prior to 
Screening Visit 1.
24. Household contact with an individual with confirmed SARS-CoV-2 infection within 4 
weeks prior to Screening Visit 1. 
25. History of allergy/hypersensitivity to the systemically administered trial medication 
agent or its excipients.
3.3.4
Withdrawal of patients 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 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial.
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.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and eCRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Sections 5.2.6.2.1 and 
5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy). The subject shows an elevation of AST 
and/or ALT ≥3-fold upper limit of normal (ULN) combined with an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the ‘DILI checklist’ provided in the ISF.

The subject experiences an infection with SARS-CoV-2 (as confirmed by PCR Test, see 
Section 5.2.3) or an infection other than pulmonary exacerbation which requires systemic 
antibiotic treatment.In case a patient needs to take concomitant medication that interferes 
with the investigational medicinal product or other trial treatment (see Section 4.2.2), it will 
be decided on a case-by-case basis after consultation with the Sponsor whether or not 
discontinuation of trial treatment is required.
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 patients 
or take any other appropriate action to guarantee the safety of the trial patients. 


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Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flow Chart and Section 6.2.3.
Additional patients may be recruited, if early treatment discontinuation is due to non-safety 
related reasons (e.g. unable to continue protocol defined visits due to personal reason), or due 
to COVID-19 given the prevalence of the coronavirus in the community. In all cases, 
recruitment of additional patients should only occur if the patient discontinued treatment prior 
to week 12, and must first be discussed and agreed upon with the sponsor.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site.

New efficacy or safety information, toxicological findings or serious adverse events
invalidating the earlier positive benefit-risk-assessment, please see Section 3.3.4.1.

Deviations from GCP, the trial protocol, or the contract impairing the appropriate 
conduct of the trial.

The sponsor decides to discontinue the further development of the investigational 
product.
Further follow up of patients 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).
3.3.5
Replacement of patients
Patients with premature treatment discontinuation will not be replaced as all safety data 
captured from treated patients will be evaluated. In certain cases of premature treatment 
discontinuation, the recruitment of additional patients may be considered, see Section 3.3.4.1
for details.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products used in this trial, BI 1323495 and placebo, are manufactured by 
Boehringer Ingelheim Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
Film-coated tablets of 2 dosage strengths and matching placebo tablets were developed for 
oral administration: 10°mg (14 x 6.8 mm oval) and 50°mg (11 x 5.5 mm oval.
Table 4.1.1: 1 Test product BI 1323495
Substance:
BI 1323495
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg or 50 mg 
Posology:
bid for 12 weeks in Part A and qd for 12 weeks in 
Part B
Method and route of administration:
Oral, as tablets 
Further details are given in the Investigator’s Brochure [c21238478-05].
Matching placebo tablets have been developed, containing mannitol, microcrystalline 
cellulose, and magnesium stearate. 


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Table 4.1.1: 2 Placebo
Substance:
No substance (placebo)
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
No strength, matched to active test drug
Posology:
bid for 12 weeks in Part A and qd for 12 weeks in 
Part B
Method and route of administration:
Oral, as tablets 
The clinical trial supplies will be provided in blisters. The tablets should be handled 
according to the labelled storage instructions and shelf life.
4.1.2
Selection of doses in the trial and dose modifications
The 30 mg bid dose of BI 1323495 is a confirmed safe and tolerated dose after multiple 
dosing in healthy volunteers and could potentially be a therapeutic dose that is applicable for 
both, EMs and PMs, and will thus be tested in Part A. In the MRD trial 1405-0002, with 
30 mg bid in EMs, median trough NE inhibition at steady state exceeded 90% which is 
considered a PD effect size potentially associated with a clinical benefit if maintained long 
term (Table 1.2.3.2: 1). The 150 mg qd dose of BI 1323495 selected for Part B was based on 
safety/tolerability data from higher dose groups of the healthy volunteer MRD study and is 
anticipated to reach the maximal safely achievable PD effect. This dose was selected to 
ensure that exposures will not exceed a gMean value that was observed and safely tolerated 
in the MRD trial 1405-0002, and to not exceed exposure boundaries that were predefined 
based on animal toxicity studies (see Section 1.2.2.4). Doses will be administered with food 
containing a fat component.
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised 
to treatment groups according to a randomisation plan in a 3:1 ratio at visit 3 via Interactive 
Response Technology (IRT). Note that the medication number is different from the patient 
number (the latter is generated during screening via the IRT System).
4.1.4
Drug assignment and administration of doses for each patient
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of units for 
placebo corresponds to the number of units of the respective dose group of the active 
substance.


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Trial medication will be dispensed in a double-blinded manner to patients. That means, 
investigators and patients will not know if a patient is assigned to BI 1323495 or placebo.
Table 4.1.4: 1 Dosage and treatment schedule for the treatment phase
Treatment
Substance
Formulation
Unit strength
Dosage
Total daily dose
Part A
BI 1323495
Tablet, film coated
10 mg
3 tablets bid
60 mg
Part B
BI 1323495
Tablet, film coated
50 mg
3 tablets qd
150 mg
Subjects should take the study drug while in a standing or sitting position, as an oral dose 
together with about 240 mL of water. Drug should be taken 15-30 min after food intake 
including a fat component (like yogurt, milk, cheese or sausage).
Following first drug administration in Part A, evening and morning dose should be taken with 
a 12 h time interval (e.g. 20:00 h and 08:00 h) approximately at the same time each day 
during the treatment phase, within a time window of +/- 1 hour. In Part B, the once-daily dose 
should be taken approximately at the same time each morning during the treatment phase. 
Missed dose(s) will not be replaced.
As an exemption, at Visit 3 and Visit 6, drug administration will happen at the site outside the 
normal schedule for practical reasons to accomplish assessments. Patients will then return to 
their usual evening/morning interval (Part A) or thertheir usual morning interval (Part B), 
respectively.
All patients will be dispensed the trial medication consisting in total of 7 medication kits. 
Dispensing will be done during the trial stepwise via the IRT system at Visit 3, Visit 5, Visit 
6 and Visit 8. During the above-mentioned visits, 1 medication kit will be assigned by the 
IRT system. At Visit 6 and Visit 8, 2 kits will be dispensed to cover the 4 weeks duration 
until EoT visit. In addition, a patient will receive 1 kit as a reserve at Visit 3 in case 
medication gets lost or the patients comes back to the next visit after more than 2 or 4 weeks, 
respectively. 
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 vists.
During the COVID-19 pandemic, physical visits to the sites may need to be cancelled to 
ensure patient safety. Based on a thorough assessment of the benefits and risks, the 
investigator may still decide to continue the trial treatment, and trial medication may be 
shipped to the patient’s home if acceptable according to local laws and regulations (for more 
details see Section 6.1).
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The table below summarizes the masking /blinding level of individual functions involved in 
the trial.


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Table 4.1.5.1: 1
Blinding 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 (incl. clinical 
trial/project team), and 
database
After individual patient has been allocated to treatment.
Periodic safety review and descriptive analyses of 
selected PK and PD endpoints will be performed during 
the trial conduct (see Section 7.2.7). The release of the 
treatment information at the individual time points will 
be documented accordingly.
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 (gRT) 
per Sponsor Standard Operating Procedure (SOP).
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation 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 reason for unblinding must be documented in the source documents and/or 
appropriate eCRF 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 patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
Prior to completion of treatment allocation in each trial part, an in dividual patient unblinding 
by the sponsor may occur, in case during the periodic safety review an AESI or any other 
relevant AE has occurred, that needs a more detailed investigation and is crucial for 
continuation or modification of the trial.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated Clinical 
Research Organization (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.
For details of packaging and the description of the label, refer to the ISF.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA) (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
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 patient, 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
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor <and/or> appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient 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 special emergency procedures to be followed.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
All concomitant therapies will be recorded (including time of intake on study days) on the 
appropriate pages of the eCRF.
The use of certain medications, e.g. listed under the exclusion criteria (Section 3.3.3) is 
restricted during the trial. Details with regard to its use are provided in the ISF.
Drugs that are strong inhibitors of CYP3A4 have to be avoided for Part B, since a modest 
effect of the strong CYP3A4 inhibitor itraconazole on the PK of BI 1323495 in UGT2B17 
EMs has been observed (see Section 1.2.3.1).
Excluded concomitant medications that might be of relevance in the population of this trial
are provided in the ISF, including a detailed list of strong CYP3A4 inhibitors.
If treated with bronchodilators, wash-out of 24 hours for qd long acting, 12 hours for bid long 
acting, and 8 hours for short acting bronchodilators should be observed before pulmonary 
function tests.
4.2.2.2
Restrictions on vaccinations
Live or live-attenuated vaccine should be avoided during the trial. Vaccination against 
COVID-19 should have been completed (administration of both doses for those vaccinations 
in which two injections separated by several weeks are required) at least 4 weeks prior to 
screening. In case a patient, during his/her participation in this trial, is being offered COVID-
19 vaccination, this is considered – in principle – possible. Vaccination reactions (such as 
fever, chills, fatigue, pain or swelling at the injection site) have frequently been reported 
during the first 48 hours after vaccination against COVID-19. Therefore, vaccination should 
occur at least 48 hours prior to a study visit, and the time of its administration should be 
carefully documented on the concomitant medication page of the eCRF, to avoid 1) potential 
interference of a vaccination reaction with study procedures and data collection, and 2) to 
facilitate the differentiation of potentially vaccination-associated AEs from potentially IMP-
related AEs.
4.2.2.3
Restrictions on diet and life style
Drug should be taken 15-30 min after intake of food including a fat component like yogurt, 
milk, butter, cheese, or sausage. On PK day at Visit 6, a meal with a fat component will be 
provided by the site prior to drug administration.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample is collected.


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Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed during in-house confinement.
For more details on food effects please refer to Section 1.2.3.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
4.2.2.4
Contraception requirements
Trial participation is allowed for male and female (not of childbearing potential) subjects. 
For ‘female not of childbearing potential’ at least one of the following criteria must be 
fulfilled:

Permanently sterile (permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy; tubal ligation is not a method of permanent 
sterilisation)

Postmenopausal, defined as at least 1 year of spontaneous amenorrhea without an 
alternative medical cause (in questionable cases a blood sample with FSH above 40 U/L 
and estradiol below 30 ng/L is confirmatory).
Men must be vasectomised with documented absence of sperm or use male contraception 
(condom or sexual abstinence) from the first administration of trial medication until 30 days 
after the last administration of trial medication if their sexual partner is a woman of 
childbearing potential (WOCBP). 
4.3
TREATMENT COMPLIANCE
Patients 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.
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 80-120%, site staff will explain to the patient the 
importance of treatment compliance


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Spirometry (PFT)
Pulmonary function will be assessed using standardised spirometry equipment which will be 
provided centrally with supplies of pre-calibrated disposable flow sensors. These sensors 
meet International Organization for Standardization (ISO) 26782 standards, but with a 
maximum permissible accuracy error of ±2.5%, in accordance with the American Thoracic 
Society (ATS)/European Respiratory Society (ERS) Technical Statement [R20-2419]. As
such there is no need to conduct daily calibration prior to use. Only these spirometers are to 
be used for this trial. Spirometry performance will be centrally overread.
Description of COVID-19 precautionary measures upon conduct of spirometry testing will be 
provided in the ISF.
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 subject. The best of three efforts will 
be defined as the highest FEV1 obtained on any of three blows meeting the 2019 ATS/ERS
criteria (with a maximum of eight attempts). Predicted normal values will be calculated 
according to GLI (Global Lung Initiative).
On days of clinic visits, patients must refrain from strenuous activity at least 12 hours prior to 
pulmonary function testing. Patients should also avoid cold temperatures, environmental 
smoke, dust, or areas with strong odours (e.g. perfumes). If treated with bronchodilators, 
patients should not take their daily bronchodilator inhalation until after completion of the 
spirometry.
At Visit 1, the PFT should be started 11:00 am as outlined in the Flow Chart. At each 
following site visit, PFT will always start at approximately the same time of the day.
Post-bronchodilator (salbutamol (albuterol)) testing:
Following the completion of three acceptable pre-bronchodilator forced expiratory 
manoeuvers, salbutamol (albuterol) will be administered to each subject. 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 subject 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 force expiratory 
manoeuver tests are recorded 15 – 30 minutes after the last dose of salbutamol (albuterol) is 
inhaled.


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During the study, a central quality control center will receive the data of spirometry 
measurements electronically to ensure that the sites maintain the same standard throughout 
the study. The central quality center will review the spirometry measurement data and report 
to the sponsor on data quality and, if required, actions to be taken.
Further instructions regarding FVC measurements will be provided in the ISF.
5.1.2
24h-sputum weight
Patients will be asked to collect spontaneous sputum into a pre-weighted container at home 
over 24 hours and seal it in the collection container on days before hand-over of 24 hour 
sputum is indicated in the Flow Chart. The collection of the sputum has to be done over the 
24 hours preceeding the handover at the site. At the site the sputum weight will be 
determined. More details about the procedure will be provided in the ISF.
5.1.3
Patient Reported Outcomes 
Patient questionnaires will be completed at the time points indicated in the Flow Chart. 
Questionnaires will be completed in random order by the patient alone in a quite room. The 
questionnaire will be paper-based and available in the local language (provided in the ISF).

Quality of Life Questionnaire-Bronchiectasis, QOL-B
The Quality of Life-Bronchiectasis (QOL-B), a self-administered, patient-reported outcome 
measure assessing symptoms, functioning and health-related quality of life for patients with 
non-cystic fibrosis (CF) bronchiectasis, contains 37 items on 8 scales (Respiratory 
Symptoms, Physical, Role, Emotional and Social Functioning, Vitality, Health Perceptions 
and Treatment Burden).
Details of the QOL-B are provided in Appendix 10.1.1.

St. George's Respiratory Questionnaire, SGRQ
The SGRQ [R96-0686] is designed to measure health impairment in patients with COPD. It 
is divided into two parts. Part 1 produce the Symptoms score, and Part 2 the Activity and 
Impacts scores. A Total score is also produced.
Part 1 (Questions 1 to 8) covers the patient’s recollection of their symptoms over a preceding 
period that may range from 1 month to 1 year. It is not designed to be an accurate 
epidemiological tool; its purpose is to assess the patient’s perception of their recent 
respiratory problems. The original version was validated using a 12-month recall period. A 
3-month recall period has been used very satisfactorily. In summary, the 3-month and 1-year 
versions provide the best properties, with no specific advantages to either.
Part 2 (questions 9 to 16) addresses the patients’ current state (i.e. how they are these days). 
The activity score just measures disturbances to patient’s daily physical activity. The Impacts 
score covers a wide range of disturbances of psycho-social function. Validation studies 


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showed that this component relates in part to respiratory symptoms, but it also correlates 
quite strongly with exercise performance (6-minute walk test), breathlessness in daily life 
(MRC breathlessness score) and disturbances of mood (anxiety and depression). The Impacts 
score is, therefore, the broadest component of the questionnaires, covering the whole range of 
disturbances that respiratory patients experience in their lives.
Details of the SGRQ are provided in Appendix 10.1.2.

Cough and sputum assessment questionnaire, CASA-Q
The CASA-Q is a self-administered questionnaire that assesses cough and sputum based on 
their frequency, severity, and impact on daily activities in the previous 7 days. The CASA-Q 
contains four domains: cough symptoms, cough impact, sputum symptoms, and sputum 
impact. Each domain contains three to eight items, each of which is answered in five 
categories from “never” to “always” for frequency and from “not at all” to “a lot/extremely” 
for intensity. 
Details of the CASA-Q are provided in Appendix 10.1.3.
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.
The results must be included in the source documents available at the site. 
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 (BP) and pulse rate (PR) (electronically or 
by palpation count for 1 minute) in a seated position after 5 minutes of rest. 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 Table 5.2.3: 1 and exclusionary 
laboratory tests in Table 5.2.3: 2. For the sampling time points please see the Flow Chart.


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All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the 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 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
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
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin time – INR (International Normalized 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


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Table 5.2.3: 1 
Safety laboratory tests (cont’d)
Functional lab group
Test name
Substrates
Creatinine
GFR/ CKD-EPI
Total bilirubin
Direct bilirubin
Total protein
Albumin
C-Reactive Protein (CRP) 
Uric Acid
Urea
Total cholesterol
Triglycerides
Electrolytes
Sodium
Potassium
Chloride
Calcium
Urinalysis
Urine nitrite (qual)
Urine protein (qual)
Urine glucose (qual)
Urine ketone (qual)
Urobilinogen (qual)
Urine bilirubin (qual)
Urine leucocyte esterase (qual)
Urine blood (qual)
Urine RBC/erythrocytes
Urine WBC/leucocytes
Urine pH
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 results will not be entered in the 
eCRF/database and will not be reported in the Clinical Trial Report (CTR). Pregnancy testing 
in women will be performed at screening, prior to treatment start, and as part of the end of 
study examination. Drug screening will be performed at screening and prior to treatment 
start. Cotinine will be assessed at different time points and results will be transferred to the 
database.


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Table 5.2.3: 2 Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine
Cotinine
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qual)
Hepatitis B core antibody (qual)
Hepatitis C antibodies (qual)
HIV-1 and HIV-2 antibody (qual)
Immunology*
Interferon-ɣ release assay to tuberculosis (qualitative), e.g. 
QuantiFERON®-TB-Gold Test
Molecular Diagnostics
PCR test for detection of SARS-CoV-2 according to official 
local/national recommendations
*Test results already available for a subject do not have to be repeated, if assessment took place within 4 weeks before 
randomisation 
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
prior to treatment, and may be repeated at any time during the study at the discretion of an 
investigator or designee. The results will not be included in the final report.
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 patient’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
Not applicable.


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5.2.6
Assessment of adverse events
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 patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the eCRF and BI SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:

results in death,

is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe,

requires inpatient hospitalisation 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 patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.


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The latest list of “Always Serious AEs” can be found in the electronic Data Capture (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 relapse 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 events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

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 draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
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.
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 whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 


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Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
investigator:

From signing the informed consent onwards until the individual patient’s end of trial (the 
End of Study (EoS) visit):
All AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
The investigator does not need to actively monitor the patient for new AEs but should 
only report any occurrence of cancer and trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form (see 
Section 5.2.6.2.2), but not on the eCRF.


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5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’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.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient 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 Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical 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 Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.6.2.4
Exemptions to SAE reporting
No exemptions are defined.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples and sputum will be collected at the 
time points indicated in the Flow Chart. The actual sampling times will be recorded and used 
for determination of pharmacokinetic parameters.
5.3.2
Methods of sample collection
5.3.2.1
Plasma sampling for pharmacokinetic analysis
The planned PK analyses of BI 1323495 and its metabolite CD 7545 will require blood 
sampling at the time points indicated in the Flow Chart. Correct, complete and legible 
documentation of drug administrations and blood sampling times as well as adequate 
handling and identification of PK samples are mandatory to obtain data of adequate quality 
for the PK analysis.
In order to allow the sample identification, the sample tube labels should list at a minimum 
the following information: BI trial number, patient number, visit, matrix and planned 
sampling time.
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the CTR is archived.
5.3.2.2
Sputum sampling for pharmacokinetic analysis
Spontaneous sputum will be collected as indicated in the Flow Chart. In case no adequate 
sputum sample is produced spontaneously, induction of sputum with isotonic, or 
subsequently hypertonic saline is mandatory. If sputum samples do not meet the quality 
criteria as directly assessed at the site, re-sampling at the next day is generally possible.
Whether the BI 1323495 and CD 7545 concentrations in sputum will be measured depends 
on the amount of sputum expectorated at the clinical sites as the measurements for the 
secondary endpoints in sputum take precedence over PK analysis (further details will be 
provided in the lab manual). Hence, it might be that not at all visits with sputum collection 
PK samples are taken.
Correct, complete and legible documentation of drug administrations and sputum sampling 
times as well as adequate handling and identification of sputum PK samples are mandatory to 
obtain data of adequate quality for the sputum PK analysis.


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In order to allow the sputum sample identification, the sample tube labels should list at a 
minimum the following information: BI trial number, patient number, visit, matrix and 
planned sampling time.
After completion of the trial, the sputum samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 
investigations.
The left over sputum samples will be transferred to the biobank after completion of these 
analysis but no later than 5 years after signature of the CTR (see Section 5.5).


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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.
5.5.1
Methods and timing of sample collection
Approximately 60 mL blood will be drawn per patient for serum banking and spot urine will 
be collected at timepoints indicated in the Flow Chart. 
In addition left over sputum volume (see Section 5.3.2.2 and 5.4) will be used for banking 
purposes.
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see Flow Chart.
5.6
OTHER ASSESSMENTS
 
 
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 


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in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The study scheme, including all visits, is shown in Section 3.1, Figure 3.1: 1.
Screening Visit 1 will be done at least 7 days prior to Baseline (BSL) Visit 2a. During BSL 
(V2a, V2b, V3), there will be a minimum of two and up to three valid sputum samples within 
indicated timeframes. The End of Treatment (EoT) Visit 10 will be done 12 weeks after 
randomisation. Prior to EoT, during V9 and V10, i.e. Day 78-82 and EoT, two to three valid
sputum samples will be obtained within seven days.
The acceptable time windows for screening, for measurements and assessments are provided 
in the main Flow Chart and are also described in the Section 6.2 below.
The Sample and Assessment Flow Chart provides sputum, PK and PD details for timing of 
sampling as well as conduct of lung function meassurements and questionnaires. Planned 
blood sampling times should be adhered to as closely as possible.
The acceptable deviation from the scheduled time for vital signs, ECG, PK and laboratory 
tests will be ± 15 min. The exact times of trial visit assessments and measurements outside 
the permitted time windows will be documented in the eCRF.
If a patient misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
In exceptional circumstances during COVID-19 pandemic, when it is impossible to conduct 
study visits at the study site, study visits may be performed at patient’s home or remotely (via 
telephone and/or internet based means of communication). Visits may also be performed as a 
hybrid of home and remote visit. All home/remote visits need to be discussed with and 
authorised by the sponsor’s trial team. The trial team’s decision will be based on a thorough 
benefit-risk evaluation.
The procedures performed during a home/remote visit may be adjusted as compared to a 
regular visit, as detailed in Appendix 10.4
All COVID-19 related deviations from the original schedule of visits and procedures will be 
documented and the implications considered for the analysis of the trial data.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period
Screening Period


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After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol use, relevant medical history and concomitant therapy, review of 
inclusion and exclusion criteria, review of vital signs (BP, PR, aural body temperature), 12-
lead ECG, pregnancy testing, laboratory tests (including UGT2B17 genotyping), sputum 
collection, lung function and a physical examination. For information regarding physical 
examination, vital signs, laboratory tests and ECG refer to Sections 5.2.1, 5.2.2, 5.2.3 and 
5.2.4.
Genotyping for UGT2B17 will be performed in all trial patients (for details, see Section 5.4).
The Screening Visit 1 can cover a period of up to 4 weeks, e.g. to wait for laboratory results, 
or if washout of certain restricted medication is required (see Section 4.2.2.1).
During the baseline period (Visits 2a, b and Visit 3 before treatment), patients have to donate 
two to three valid sputum samples.
6.2.2
Treatment period
After Visit 3 with first drug administration, patients will visit the site after 2, 4, 8, 11 and 12 
weeks. Visit 4 after 1 week of treatment start will be conducted as a phone call with the 
patient. At Visit 7, 6 weeks after treatment start, the patient will be contacted via phone, and 
blood collection for safety laboratory will be done via a local lab or a flying nurse.
Following first drug administration in Part A, the evening and the morning dose should be 
taken with a 12 h time interval (e.g. 20:00 h and 08:00 h) approximately at the same time 
each day during the treatment phase, within a time window of +/- 1 hour. In Part B, the once-
daily dose should be taken approximately at the same time each morning during the treatment 
phase. Drug should be taken 15-30 min after food intake including a fat component (like 
yogurt, milk, cheese or sausage). As an exemption, at Visit 3 and Visit 6, drug administration 
will happen at the site outside the normal schedule. Patients will then go back to their usual 
evening/morning interval (Part A) or once-daily interval (Part B), respectively. On PK day at 
Visit 6, patients will stay at site for the reason of medical surveillance. 
The provided time according the Sample and Assessment Flow Chart is approximate; i.e. a 
deviation from the scheduled time of the day of ± 120 minutes is acceptable. The relative 
time deviations from time of administration should be kept as minimal as possible and should 
be below ± 15 minutes for PK measurements on PK days. The exact time of sample 
collection should be collected in electronic Case Report Form (eCRF). Patient questionnaires 
will be completed by the patient alone in a quite room.
Sputum collection should occur during a 2h timeframe with active breathing techniques or 
equivalent manouvres, if necessary. Study nurse / physiotherapist needs to be available to 
support patient in performing active cycle of breathing technique in case of difficulties 
producing sputum. Next step will be Oscillating Positive Expiratory Pressure (OPEP), if 
despite breathing technique still no sputum is being produced. Patients who produce an 
adequate sputum sample do not have to undergo these supportive measures. In case no 


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adequate sputum sample is produced spontaneously, induction of sputum with isotonic, or 
subsequently hypertonic saline is mandatory. If sputum samples do not meet the quality 
criteria as directly assessed at the site, re-sampling at the next day is generally possible. An 
instruction on sputum handling will be provided to the site in the ISF.
If treated with bronchodilators, wash-out of 24 hours for qd long acting, 12 hours for bid long 
acting, and 8 hours for short acting bronchodilators should be observed before pulmonary 
function tests.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart.
AEs and concomitant therapy will be assessed continuously from screening until the end 
ofstudy.
6.2.3
Follow-up period and trial completion
End of Study assessments must be conducted at least 7 days after the last trial drug intake, i.e. 
after the REP for BI 1323495.
For AE assessment, laboratory tests, recording of ECG and vital signs, sputum collection, 
lung function and physical examination during the End of Study Visit, see Section 5.2.
Patients who discontinue treatment before the end of the planned treatment period should also 
undergo the EoT Visit, at least 7 days after the last trial drug intake.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoT Visit must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Male subjects with ‘women of childbearing potential’ (WOCBP) partner will be reminded to 
use male contraception (condom or sexual abstinence) during the trial until 30 days after the 
last administration of trial medication.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The primary objective of this trial is stated in Section 2.1 and the associated endpoint will be 
evaluated using descriptive statistics.
The secondary endpoints, see Section 2.1, will be assessed using descriptive analysis. If 
considered valueable, an inferential analysis will be performed in an exploratory fashion, i.e. 
no hypothesis is stated and no adjustment for multiplicity will be applied.
 
 
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
Standard statistical parameters (number of non-missing values, mean, standard deviation
(SD), median, quartiles, minimum, and maximum) or frequency tables will be presented
where appropriate.
Analysis sets
Statistical analyses will be based on the following analysis sets:

Screened set (SCS): This patient set includes all patients that signed informed consent.
The SCS will be used for disposition.

Randomised Set (RS): This patient set includes all randomised patients. The RS will also 
be used for disposition.

Treated set (TS): The treated set includes all patients who were randomised and received
at least one dose of study drug. The treatment assignment will be determined based on the 
first actual treatment the patients received. The TS will be used for safety analyses and 
evaluation of biomarker and clinical assessments. 

 
 


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Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be specified in the Domain Deviation (DV). Protocol deviations will be 
identified no later than in the Report Planning Meeting, and the iPD categories will be 
updated as needed.
7.2.2
Primary endpoint analyses
The primary endpoint, see Section 2.1.2, will be derived according to BI standards and the 
proportion of patients with at least one drug-related AE per treatment group will be derived. 
The analysis will be based on the TS and will be descriptive in nature.


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7.2.3
Secondary endpoint analyses
The analysis of the secondary endpoints, see Section 2.1.3, will be based on the TS. 
Data from of all timepoints except those that were sampled within 15 days after the end of an 
exacerbation will be included in the analysis.
The ‘baseline’ and ‘after 12 weeks’ value of parameters that are measured more than once for 
these time points, see Sample and Assessment Flow Chart, will be derived as the mean of the 
available valid samples at each of these time points.
The change from baseline of NE activity in sputum at the different visits (X) is calculated as:
cfb in NE activity at Visit X = NE activity at Visit X – NE activity at baseline.
For the derivation of the change from baseline of NE activity in blood, the NE activity in 
blood at each visit will first be normalized to neutrophil counts
and then the change from baseline is determined analog to the NE activity in sputum above.
The secondary endpoints will be primarily analysed by descriptive statistics and graphical 
representations across all visits.


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7.2.5
Safety analyses
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 start of treatment and end of the REP, a period of 7 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation. For all 
analyses the treatment actually administered (= treatment at onset) to the patient will be used 
(any deviations from the randomised treatment will be discussed in the minutes of the
Report Planning Meeting).
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP, see Section 1.2.4. Adverse events that start before first drug intake and deteriorate 
under treatment will also be considered as ‘treatment-emergent’.
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.


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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 the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
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 to findings before start of treatment.
Clinically relevant abnormal findings in ECG will be reported either as baseline condition (at 
screening) or otherwise as AEs.
 
 
7.2.7
Interim Analyses
No formal interim analysis will be performed and no interim report is to be written.
A periodic unblinded safety review will be conducted by the sponsor to monitor safety and 
tolerability. Therefor descriptive and graphical presentations of the primary endpoint and 
further safety assessments will be created.
 
 
 
 
 
 
 
 


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7.3
HANDLING OF MISSING DATA
In general, missing data will not be imputed.
Safety
It is not planned to impute missing values for safety parameters.
Secondary biomarker endpoints
No imputation will be applied
 
7.4
RANDOMISATION
In trial Part A (N=12), patients will be randomised in a 3:1 ratio to receive either 30 mg bid 
BI 1323495 or placebo bid. In Part B (N=24), patients will be randomised in a 3:1 ratio to 
receive either 150 mg qd of BI 1323495 or placebo qd. 
The randomisation of patients to the treatment groups will be performed via an interactive 
response technology (IRT). 
BI will arrange for the randomisation, 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. The block size will be documented in the Clinical Trial Report (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 36 treated patients in Part A 
(N=12) and B (N=24). The planned sample size is not based on a power calculation. In Part A 
and B combined, 9 patients in total will receive placebo, 9 patients will receive 30 mg bid BI 
1323495 and 18 patients will receive 150 mg qd. The selected sample size per dose group is
considered sufficient to explore safety and tolerability of BI 1323495 
 
 
 
 


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC and other relevant regulations. Investigators and site staff must adhere to these 
principles. Deviation from the protocol, the principles of ICH GCP or applicable regulations 
as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients 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 Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, 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 patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.


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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 subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
eCRFs for individual patients 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 patient. 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 eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient 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. Before sending or uploading those copies, the investigator must ensure that 
all patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the eCRF, data must be derived from source documents, for example:


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
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’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 patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient 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 patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. U.S. Food and Drug Administration (FDA)). They may review all eCRFs and informed 
consents. The accuracy of the data will be verified by direct comparison with the source 
documents described in Section 8.3.1. The sponsor will also monitor compliance with the 
protocol and GCP.
8.3.3
Storage period of records
Trial site(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. 


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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). Early termination of the trial is defined as the premature 
termination of the trial due to any reason before the end of the trial as specified in this 
protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.


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A final report of the clinical trial data will be written only after all patients 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 patient
(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 periodic unblinded safety review will be conducted by the sponsor to monitor safety and 
tolerability. Therefor descriptive and graphical presentations of the primary endpoint and 
further safety assessments will be created.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required 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.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
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, a central spirometry service and an IRT vendor will be used in 
this trial. Details will be provided in the IRT Manual, the Spirometry Manual and Central 
Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P02-06423
Kohri K, Ueki IF, Nadel JA. Neutrophil elastase induces mucin production 
by ligand-dependent epidermal growth factor receptor activation. Am J 
Physiol 2002:283(3, Part 1):L531-L540
P13-15562
McShane PJ, Naureckas ET, Tino G, Strek ME.Non-cystic fibrosis 
bronchiectasis. Am J Respir Crit Care Med 2013. 188(6):647-656
P19-09060
Diel R, Chalmers JD, Rabe KF, Nienhaus A, Loddenkemper R, 
Ringshausen FC.Economic burden of bronchiectasis in Germany. Eur 
Respir J 2019. 53:1802033
R16-2239
Elborn JS, Perrett J, Forsman-Semb K, Marks-Konczalik J, Gunawardena 
K, Entwistle N.Efficacy, safety and effect on biomarkers of AZD9668 in 
cystic fibrosis. Eur Respir J 2012. 40(4):969-976
R17-2928
Park JA, He F, Martin LD, Li Y, Chorley BN, Adler KB.Human neutrophil 
elastase induces hypersecretion of mucin from well-differentiated human 
bronchial epithelial cells in vitro via a protein kinase Cdelta-mediated 
mechanism. Am J Pathol 2005. 167(3):651-661
R17-2929
Vago JP, Tavares LP, Sugimoto MA, Lima GLN, Galvao I, Caiux TR de, et 
al.Proresolving actions of synthetic and natural protease inhibitors are 
mediated by annexin A1. J Immunol 2016. 196(4):1922-1932
R18-2172
Bonett D, Wright T, Sample size requirements for estimating Pearson, 
Kendall and Spearman correlations. Psychometrika 2000. 65: 23-28
R18-3321
Chalmers JD, Moffitt KL, Suarez-Cuartin G, Sibila O, Finch S, Furrie E, et 
al.Neutrophil elastase activity is associated with exacerbations and lung 
function decline in bronchiectasis. Am J Respir Crit Care Med 2017. 
195(10):1384-1393
R18-3357
Hartl D, Latzin P, Hordijk P, Marcos V, Rudolph C, Woischnik M, et al. 
Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic 
fibrosis lung disease. Nature Med. 2007; 13, 1423-1430
R19-1805
Xue et al., Adaptive Evolution of UGT2B17 Copy-Number Variation. Am. 
J. Hum. Genet. 2008; 83: 337–346
R19-1806
Wang et al, UGT2B17 Genetic Polymorphisms dramatically affect the 
pharmacokinetics of MK-7246 in healthy patients in a fist-in-human study, 
Nature 2012; 92: 96-102
R19-3080
Keir HR, Fong CJ, Crichton ML, Barth P, Chevalier E, Brady G, et 
al.Personalised anti-inflammatory therapy for bronchiectasis and cystic 
fibrosis: selecting patients for controlled trials of neutrophil elastase 
inhibition. ERJ Open Res 2019. 5:00252-2018
R19-3082
Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE, 
Loebinger MR, et al.European Respiratory Society guidelines for the 
management of adult bronchiectasis. Eur Respir J 2017. 50(3):1700629


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Shoemark A, Cant E, Carreto L, Smith A, Oriano M, Keir HR, et al.A 
point-of-care neutrophil elastase activity assay identifies bronchiectasis 
severity, airway infection and risk of exacerbation. Eur Respir J 2019. 
53(6):1900303
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Jasper AE, McIver WJ, Sapey E, Walton GM . Understanding the role of 
neutrophils in chronic inflammatory airway disease. F1000Research. 
2019.8.557-574
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Ringshausen, F. C., A. de Roux, R. Diel, D. Hohmann, T. Welte, and J.
Rademacher. 2015. 'Bronchiectasis in Germany: a population-based 
estimation of disease prevalence', Eur Respir J, 46: 1805-1807
R19-3087
Quint JK, Millett ERC, Joshi M, Navaratnam V, Thomas SL, Hurst JR, et 
al.Changes in the incidence, prevalence and mortality of bronchiectasis in 
the UK from 2004 to 2013: a population-based cohort study. Eur Respir J 
2016. 47(1):186-193
R19-3378
King PT.The role of the immune response in the pathogenesis of 
bronchiectasis. Biomed Res Int 2018. 2018:6802637
R20-1159
Henkle, E., B. Chan, J. R. Curtis, T. R. Aksamit, C. L. Daley, and K. L. 
Winthrop. 2018. 'Characteristics and Health-care Utilization History of 
Patients With Bronchiectasis in US Medicare Enrollees With Prescription 
Drug Plans, 2006 to 2014', Chest, 154: 1311-1320
R20-2419
Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall 
GL, et al, American Thoracic Society, European Respiratory Society. 
Standardization of spirometry 2019 update: an official American Thoracic 
Society and European Respiratory Society technical statement. Am J Respir 
Crit Care Med 2019; 200(8); e70-e88
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Cosgriff R, et al. A multinational report to characterise SARS-CoV-2 
infection in people with cystic fibrosis. J. Cyst. Fibr. Journal of Cystic 
Fibrosis 2020. 19: 355-358
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Finklea JD, Khan G, Thomas S, et al. Predictors of mortality in hospitalized 
patients with acute exacerbation of bronchiectasis. Respir Med 2010; 104: 
816–821
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Murray MP, Pentland JL, Turnbull K, MacQuarrie S, Hill AT. Sputum 
colour: a useful clinical tool in non-cystic fibrosis bronchiectasis. Eur. 
Respir. J. 2009; 34: 361-364
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Jones PW, Quirk FH. A self-complete measure of health status for chronic 
airflow limitation. Am Rev Respir Dis 1992; 145; 1321-1327
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c21238478-05
 
 Investigator: Brochure BI 1323495 
COPD. 1405.P1., Current Version
c26492551
. Clinical Trial Report 1405-
0001. 04 Nov 2019


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c33366190-01
. Clinical Trial Report 1405-
0015.


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
10.1.1
Quality of Life Questionnaire-Bronchiectasis, QOL-B


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Table 10.1.1: 1 Quality of Life Questionnaire-Bronchiectasis, QOL-B


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Table 10.1.1: 1 Quality of Life Questionnaire-Bronchiectasis, QOL-B (cont’d)


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Table 10.1.1: 1 Quality of Life Questionna)ire-Bronchiectasis, QOL-B (cont’d)


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Table 10.1.1: 1 Quality of Life Questionnaire-Bronchiectasis, QOL-B (cont’d)


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10.1.2
St. George's Respiratory Questionnaire, SGRQ
Table 10.1.2: 1 St. George's Respiratory Questionnaire, SGRQ


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Table 10.1.2: 1 St. George's Respiratory Questionnaire, SGRQ (cont’d)


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Table 10.1.2: 1 St. George's Respiratory Questionnaire, SGRQ (cont’d)


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Table 10.1.2: 1 St. George's Respiratory Questionnaire, SGRQ (cont’d)


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Table 10.1.2: 1 St. George's Respiratory Questionnaire, SGRQ (cont’d)


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Table 10.1.2: 1 St. George's Respiratory Questionnaire, SGRQ (cont’d)


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10.1.3
Cough and sputum assessment questionnaire, CASA-Q
Table 10.1.3.: 1 Cough and sputum assessment questionnaire, CASA-Q


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Table 10.1.3.: 1 Cough and sputum assessment questionnaire, CASA-Q  (cont’d)


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Table 10.1.3.: 1 Cough and sputum assessment questionnaire, CASA-Q (cont’d)


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Table 10.1.3.: 1 Cough and sputum assessment questionnaire, CASA-Q (cont’d)


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Table 10.1.3.: 1 Cough and sputum assessment questionnaire, CASA-Q (cont’d)


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10.2
PHARMACOKINETIC METHODS AND ANALYSES
Not applicable
10.3
TRIAL BIOMARKER PLAN
Not applicable
10.4
VISIT MODIFICATION IN EXCEPTIONAL CIRCUMSTANCES
INITIAL / STANDARD
MODIFIED or ADDED 
Face-to-face patient visit 
performed by a 
physician/under the 
responsibility of a physician on 
site.
Phone call or home visit performed by the investigational 
site physician/under the responsibility of the 
investigational site physician to ensure the wellbeing of a 
patient and to collect at least: Adverse Events and
Concomitant Treatments.
Regular on-site safety lab test 
using central lab kits:

Haematology, 
Biochemistry, Electrolytes, 
Coagulation, Urinalysis as 
per Flow Chart.

At visits indicated in the 
Flow Chart, safety lab
samples can be collected at 
local labs by using central 
lab kits)

The results of the lab tests are to be reported and 
transferred to the investigator, who has to ensure 
medical review and proper documentation.

Decision whether to continue BI 1323495 treatment 
should be made based on an individual risk 
assessment for that individual patient and weigh up 
the benefits of an extended lab interval to maximum 
2 weeks (3 weeks at the end of the treatment period) 
versus an interruption of treatment. The sponsor
shoud be contacted for a joint decision.

Medical decision has to be documented in patient’s 
source notes.
Dispensation of study 
treatment on site

Site to patient IMP shipments

Patients must consent to providing contact details for 
shipping purposes 

Patients should retain all unused IMP and packaging 
and return it when they are able to return to the site.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
22 Apr 2021
EudraCT number
EU number
2019-003853-27
BI Trial number
1405-0008
BI Investigational Medicinal 
Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of different oral doses of BI 
1323495 versus placebo in patients with non-cystic 
fibrosis bronchiectasis (randomised, double-blind, 
placebo-controlled, parallel group trial)
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Synopsis, Flowcharts, 2.1, 3.2, 4.1, 6.2, 7.4, 7.5
Description of change
Additional information and requirements for 
dosing of Part B, 150 mg qd in the morning was 
added
Rationale for change
Implementation of dosing for Part B
Section to be changed
Flowchart
Description of change
Explanation of visit procedures in more detail
Rationale for change
Correction. Visit 3 is no PK day, documentation of 
IMP administration in eCRF, timepoints of 
zymosan stimulation, compliance check of IMP 
only
Section to be changed
1.2.3, 4.2.2
Description of change
Due to new results being available from SRD study 
1405-0001 and MRD study 1405-0002, updated 
information is added to this protocol, i.e. to 
substantiate the 150 mg qd dosing in Part B and to 
add new safety information
Rationale for change
Add addition PK and PD data
Section to be changed
1.4.2, 4.2.2
Description of change
Added that requirement of vaccination against 
Streptococcus pneumoniae should be in 
accordance with national vaccination 
recommendations. 
Added that BI 1323495 is not expected to affect 
the benefit/risk ratio of a COVID-19 vaccine
Rationale for change
Add information to Streptococcus p. and Covid-19 


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vaccination
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Specify that vaccination against Streptococcus 
pneumoniae is required in accordance with 
national vaccination recommendations
Rationale for change
Correction of wording for Streptococcus p. 
vaccination
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Exclusion Criterion #11 specified, and Exclusion
Criterion #25 added
Rationale for change
Specify the patient population in more detail with 
respect to suspected malignancy or history of 
malignancy and history of allergy/hypersensitivity
to trial medication
Section to be changed
4.15, 7.2.7
Description of change
Addition of unblinding possibility after an 
individual patient has been allocated to a treatment
instead after completion of a trial part
Rationale for change
Specify blinding procedure
Section to be changed
5.2.3 Safety laboratory
Description of change
Manual differentials removed and Urinalysis 
specified
Rationale for change
Manual differential White Blood Counts are not 
required to be tested in this trial setting.
Some parameters for urinalysis described in more 
detail
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c31693972
2.0
clinical-trial-protocol-version-02
Safety, tolerability, pharmacokinetics, and pharmacodynamics of different oral doses
of BI 1323495 versus placebo in patients with non-cystic fibrosis bronchiectasis
(randomised, double-blind, placebo-controlled, parallel group trial)
Approval-Therapeutic Area 
26 Apr 2021 10:09 CEST
Approval-Team Member Medicine
26 Apr 2021 11:18 CEST
Author-Trial Clinical
Pharmacokineticist
26 Apr 2021 11:47 CEST
Author-Trial Statistician
26 Apr 2021 12:14 CEST
Approval-Clinical Trial Leader
27 Apr 2021 09:07 CEST
Approval-Clinical Trial Leader
27 Apr 2021 12:37 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c31693972
2.0

SAP_001.pdf: 
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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c40185913-01
BI Trial No.:
1405-0008
Title:
Safety, tolerability, pharmacokinetics, and pharmacodynamics of
different oral doses of BI 1323495 bid versus placebo in patients
with non-cystic fibrosis bronchiectasis (randomised, double-blind,
placebo-controlled, parallel group trial)
Revised protocol #02
Investigational
Product(s):
BI 1323495
Responsible trial 
statistician(s):
Phone.
Email:
Date of statistical 
analysis plan:
15 SEP 2022 SIGNED
Version:
Final
Page 1 of 25
Proprietary confidential information
2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS..........................................................................................................8
5.1
PRIMARY ENDPOINT........................................................................................8
5.2
SECONDARY ENDPOINTS ...............................................................................8
5.2.1
Key secondary endpoint........................................................................................8
5.2.2
Secondary endpoints .............................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED ...........................................................................12
6.5
POOLING OF CENTRES..................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................13
6.6.1
Safety parameters................................................................................................13
6.6.2
Pharmacodynamic biomarkers..........................................................................13
6.6.3
Spirometry ...........................................................................................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................15
7.
PLANNED ANALYSIS ......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........17
7.2
CONCOMITANT DISEASES AND MEDICATION......................................17
7.3
TREATMENT COMPLIANCE ........................................................................18
7.4
PRIMARY ENDPOINT......................................................................................18
7.4.1
Primary analysis of the primary endpoint........................................................18
7.5
SECONDARY ENDPOINTS .............................................................................18
7.5.1
Secondary endpoints ...........................................................................................18
7.7
EXTENT OF EXPOSURE .................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................20


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7.8.1
Adverse Events ....................................................................................................20
7.8.2
Laboratory data...................................................................................................21
7.8.3
Vital signs.............................................................................................................21
7.8.4
ECG ......................................................................................................................22
7.8.5
Others ...................................................................................................................22
8. 
REFERENCES ....................................................................................................23
10.
HISTORY TABLE..............................................................................................25


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data and vital signs........................................................11
Table 6.3: 1
Subject sets for planned analyses .....................................................................13
Table 6.7: 1
Definition of baseline values for planned multiple measurements of 
biomarkers ........................................................................................................15
Table 6.7: 2
Time windows for assignment of safety assessment – laboratory....................16
Table 6.7: 3
Time windows for assignment of lung function assessment (spirometry) .......16
Table 10: 1
History table .....................................................................................................25


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2.
LIST OF ABBREVIATIONS
Abbreviations not in Medicine Glossary are described below.
Term
Definition / description
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BID 
Bis in die (twice daily)
BM
Biomarker
BMI
Body Mass Index
CASA-Q
Cough And Sputum Assessment Questionnaire
Cfu
Colony forming units
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CQM
Clinical Quality Monitoring
CV
Arithmetic Coefficient of Variation
DBLM
Database Lock Meeting
DILI
Drug induced liver injury
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
LLT
Lower Level Term
Max
Maximum
Min
Minimum
N
Number non-missing observations
NE
Neutrophil elastase
P10
10th percentile
P90
90th percentile


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Term
Definition / description
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
PK parameter analysis set
PRO
Patient Reported Outcome
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
QOL-B
Quality of Life Questionnaire-Bronchiectasis
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
SD
Standard Deviation
SGRQ
St. George's Respiratory Questionnaire
SOC
System Organ Class
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TMF
Trial Master File
TS
Treated Set
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomization.
Study data will be stored in a trial database within Medidata Rave system.
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (current Version 9.4, by 
), and a number of 
SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
 
 Due to a limited number of patients 
randomized in Part A, the planned analyses described in the CTP will be limited in descriptive 
analyses only. 
 
 
 
 
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint to assess safety and tolerability of BI 1323495 is the occurrence of drug-
related adverse events after 12 weeks of treatment. The timeframe for the primary endpoint is
from the first drug administration until end of the REP after the last drug administration.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Pharmacodynamic biomarkers of target engagement:

Change from baseline to week 12 in absolute activity of neutrophil elastase (NE) [RFU] in 
sputum 

Change from baseline to week 12 in NE activity in whole blood after stimulation with 
zymosan, normalized to neutrophil counts
Pharmacodynamic biomarkers of physiological response:


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
Change from baseline to week 12 in absolute number of neutrophils [counts] in sputum
For details regarding the derivation see Section 5.3.2.
Early signs of clinical efficacy:

Change from baseline to week 12 in absolute post-bronchodilator forced expiratory 
volume in one second, FEV1 [mL]


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered in each trial part, assignment of 
treatment groups, and selection of doses, cf. Section 4 of the CTP.
Placebo patients will be analysed according to their respective study part, i.e. posology. If 
deemed appropriate the assessment of a pooled placebo group will be added.
Analysis phases for statistical analysis of AEs, safety laboratory data, vital signs and 
biomarkers are defined for each patient as described in Table 6.1: 1.
Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data and vital signs
Study analysis 
phase
Label
Start (included)
End (excluded)
Screening
Screening
Date of informed 
consent at 12 a.m.
Date/time of first 
administration of study drug
On-treatment
Placebo bid
Placebo qd  
BI 30mg bid 
BI 150mg qd
respectively 
Date/time of first 
administration of
study drug 
12:00 a.m. on day after last 
administration of study drug
+ REP (7 days)
or
12:00 a.m. on day after last
contact date
(whichever occurs first)
Follow-up1
Follow-up
12:00 a.m. on day 
after last 
administration of 
study drug + REP (7 
days)
12:00 a.m. on day after last
contact date
1This phase exists only in those patients who have last contact 7 or more days after last trial drug administration. 
AE displays in CTR Section 15.3, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 will 
present results for the on-treatment phase only.
Safety laboratory data, vital signs and clinical assessment data will be analysed based on dose 
groups (not on analysis phases defined above), with clear differentiation between baseline 
(refer to Section 6.7) and on-treatment measurements. Measurements will be considered on-
treatment, if they were taken within the on-treatment phases as defined in Table 6.1: 1. 


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6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation (PD) is considered “important” if it can be expected that the deviation 
had a distorting influence on the biomarker or clinical assessments or could affect the rights or 
safety of the study patients. Potentially important protocol deviations will be handled 
according to Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol 
Deviations (iPD)" (2).
A list of potentially iPDs as well as the handling of iPDs in analysis is included in the DV 
domain specifications and stored within the TMF in EDMS. Note, that this is a working list 
and may not be finalised until database lock. During the study conduct, protocol deviations
will be monitored and identified iPDs will be summarised into categories and captured in the 
DV domain specification. Guidance for improving / teaching the respective sites with iPD 
occurrences should be discussed during the study Clinical Quality Monitoring (CQM) 
meetings.
iPDs will be summarized and listed. Non-important Covid-19 related PDs will only be listed. 
6.3
SUBJECT SETS ANALYSED
The subject sets as defined in detail in the CTP, Section 7.2 will be used. These include the 
Screened set (SCS), Randomized Set (RS), Treated set (TS), 
 
 
Table 6.3: 1 shows which analysis set is used for each class of assessment.


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Table 6.3: 1
Subject sets for planned analyses
      Subject set
Class of endpoint
TS
PKS
RS
SCS
Primary endpoint
X
Secondary endpoints
            biomarker endpoints
X
              clinical assessment
X
Safety parameters
X
iPDs
X
Compliance/exposure
X
Demographic/baseline characteristics
X
Analysis sets
X
Disposition
X
The decision on exclusion of patients from respective analysis set will be made prior to 
database lock at the latest and documented in the decision log. 
6.5
POOLING OF CENTRES
No pooling of centres will be performed.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Safety parameters
With regard to the safety analysis, no imputation of safety data is foreseen except for missing 
or incomplete AE dates. Missing or incomplete AE dates are imputed according to BI 
standards (5).
6.6.2
Pharmacodynamic biomarkers
No imputation will be applied to pharmacodynamic biomarkers for missing data. 


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Values of biomarkers will be excluded from analysis according to the following rules:

For NE activity data from sputum samples generated from sputum processing starting ≥
1.15 hours after completion of sputum collection

All BM data (refer to Section 5.2.2
) collected from the first use of 
restricted medications (such cases will be identified during the CQM meetings and 
documented as iPDs on the DV domain specifications)
 
 
 
 
 
6.6.3
Spirometry
No imputation method will be implemented for missing data. 
Values of spirometry test will be excluded from analysis according to the following rules:

All spirometry data (refer to Section 5.2.2
) collected from the first use 
of restricted medications (such cases will be identified during the CQM meetings and 
documented as iPDs on the DV domain specifications)
 
 
 


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For all parameters, except for biomarkers, baseline is defined as the last non-missing value 
prior to first administration of the trial treatment. In case of planned multiple measurements of 
biomarkers within the run-in period prior to first drug administration (e.g. at Visit 2a, 2b or 3), 
the following will apply:
Measurements taken after first administration of trial treatment will be considered either on-
or off-treatment values based on the definition in Table 6.1: 1, and will be assigned to visits 
for statistical analysis, if applicable, as defined below.
Analysis of AE data (including findings in 12-lead ECG assessments or physical 
examinations), potentially clinically significant abnormal laboratory values, concomitant 
medication or non-drug therapies will not be based on visits. Frequency tables for AE data 
will be using on-treatment data and categorized based on their occurring/starting dates. 
Therefore, no assignment to time windows will be necessary for such data.
Analysis day is calculated as follows:
If assessment date and time is prior to the date and time of first study drug intake: 
Date of assessment – date of first study drug intake 
If assessment date and time is greater or equal to the date and time of first study drug 
intake: Date of assessment – date of first study drug intake +1 day
Analysis visit windows for other assessments during the study are given in the following 
tables. The date of the first drug intake will be used as study day 1 for the time windowing 
(including planned first drug administration visit V3 and repeated V3). If more than one value 
is available within one time window the one which is closest to the planned time/day is used 
for analysis. In case two values are equidistant from the planned time/day, then the last one 
will be picked.


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Table 6.7: 2
Time windows for assignment of safety assessment – laboratory
Time window [days]
Visit 
number 
(CTP)
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(analysis)
End
(analysis)
V1
Screening
-27
± 14
All pre-baseline measurements
V3
Baseline 
1
± 0
NA
Date/time of first 
administration of 
study drug
V5
Week 2
15
± 3
Start of on-
treatment phase 
as defined in 
table 6.1.1
22
V6
Week 4
29
± 3
23
36
V7
Week 6
43
± 3
37
50
V8
Week 8
57
± 3
51
70
V10
Week 12/EoT
84
+3
71
End of on-
treatment phase 
as defined in 
table 6.1.1
V11
Follow-up
98
± 4
All post-treatment measurements
Table 6.7: 3
Time windows for assignment of lung function assessment (spirometry)
Visit 
number 
(CTP)
Visit label 
(analysis)
Planned 
Day
Time window [days]
Window 
per CTP
Start 
(analysis)
End
(analysis)
V1
Screening
-27
± 14
All pre-baseline measurements
V2b
Baseline 
-2
+ 1
NA
Date/time of first 
administration of 
study drug
V5
Week 2
15
± 3
Start of on-treatment 
phase
35
V8
Week 8
57
± 3
36
70
V10
Week 12/EoT
84
+3
71
End of on-
treatment phase
V11
Follow-up
98
± 4
All post-treatment measurements


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI standards (6).  The individual values of 
all patients will be listed. Listings will be sorted by treatment group, patient number and visit 
(if visit is applicable in the respective listing). The listings will be contained in Appendix 16.2 
(SDL) of the CTR. If not stated otherwise, patients will be grouped by actual treatment 
received.
The following standard descriptive statistical parameters will be displayed in summary tables
of continuous variables that are non-PK parameters:
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment group. Percentages will be rounded to one decimal place and will be based on all 
patients in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR, based on the TS.
The data will be summarized by treatment group and in total.
Demographics: 
Sex, ethnicity, race, age [years], age (categories), height [cm], weight [kg] and BMI [kg/m2], 
history of substance use (tobacco, nicotine, vaping products, alcohol, cannabis), UGT2B17 
genotype.
BMI will be calculated as weight [kg] / (0.01 * height [cm])2.
Baseline characteristics:
Pharmacogenetic results of UGT2B17 genotype will be reported as: *1/*1 or *1/*2. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive analysis by treatment group is planned for this section of the CTR.


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Baseline conditions / concomitant diagnoses will be summarized by Medical Dictionary for
Regulatory Activities (MedDRA) system organ class (SOC) and preferred term (PT).
Concomitant medication taken at baseline or during the treatment period will be summarized 
by World Health Organization-Drug Dictionary (WHO-DD) ATC3 class and PT. Previous 
concomitant medication, i.e. those taken and stopped prior to entering the treatment period, 
will be listed only. 
All data will be coded using the most recent versions of WHO-DD and MedDRA dictionaries.
The relevance of the concomitant therapies to the evaluation of PD and PK will be decided no 
later than at the RPM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will be listed and descriptive statistics for each assessment day will be 
displayed by treatment group. Deviations from planned intake will be addressed in the RPM 
(refer to Section 6.2) and relevant deviations will be described in the CTR.
Treatment compliance (yes/no) will be based on the adherence to the expected range of 80-
120% for number of tablets actually taken vs. number of tablets which should have been taken
as directed by the investigator, see CTP Section 4.3.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
The primary endpoint (cf. Section 5.1) will be derived according to BI standards (7) and (8). 
The proportion of patients with at least one treatment emergent drug-related AE per treatment 
group will be calculated. The analysis will be based on the TS and will be descriptive in 
nature.
7.5
SECONDARY ENDPOINTS
7.5.1
Secondary endpoints
The primary analysis of the secondary endpoints listed in Section 5.2.2. will be descriptive in 
nature and will be based on the TS. 
For biomarkers determined on sputum the mean of all available valid samples which are 
within the analysis time window, will be used as Week 12/EoT value in the analyses. Actual 
observed values at these visits will only be listed. 
Descriptive statistics of absolute values as well as changes from baseline (refer to Section 6.7) 
and percent changes from baseline (if applicable) will be presented by planned time point for 
the secondary endpoints. 
For NE activity in zymosan stimulated blood, neutrophil counts measured from safety lab will 
be used for normalisation of NE activity when collection time points match. Otherwise, the


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neutrophil count from the time point closest to sampling for NE activity assessment will be 
used for normalisation. The derivation detail of NE activity in whole blood is in Section 9.1
The assessment of NE activity in sputum and blood will further comprise the analysis of the 
% inhibition of NE activity. For each time point including baseline, % inhibition will be 
calculated as:
 ％ℎ	
 =  

 − 


 


× 100
Descriptive statistics of maximum NE % inhibition (on patient level) will be presented by 
dose group. Individual line plots over time by dose group will be presented.
 
 
Individual NE activity data will be listed including % inhibition in sputum, % inhibition in 
blood, neutrophil count normalised and UGT2B17 genotype.


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7.7
EXTENT OF EXPOSURE
Not all drug administrations are captured in the data base. Thus, no analysis of comprehensive 
exposure data is planned for the CTR. The date and time of drug administration captured in 
the eCRF will be listed for each patient.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
The safety data for treated patients who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and not on the number of AEs.
For further details on summarization of AE data, please refer to "Analysis and presentation of 
adverse event data from Clinical Trials" (8) and "Handling of missing and incomplete AE 
dates" (7). 
The analysis of AEs will be based on the concept of treatment emergent AEs.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of AESIs. 
CTP: The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold
ULN measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.


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According to ICH E3 (9), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the CTR. These will be any non-serious adverse event 
that led to an action taken with study drug (e.g. discontinuation).
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). AEs which were considered by the investigator to be 
drug related will be summarised separately. A listing will be provided for patients with AEs, 
where SAEs, drug-related AEs, AEs leading to drug withdrawal and AESIs will be presented 
in the listing.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups. 
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of patients with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of patients with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Display and Analysis of Laboratory Data" (10).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Listings of laboratory values over time and for the difference from baseline (refer to Section 
6.7) will be provided. Values outside the reference range as well as possibly clinically 
significant values will be flagged in the listings.
Individual line plots over time by dose group will be presented.
Clinically relevant findings in laboratory data will be reported as baseline conditions (when 
they occurred prior to first administration of study treatment) or as AEs (when they occurred 
after first administration of study treatment) if judged clinically relevant by the investigator,
and will be analysed as such.
7.8.3
Vital signs
Vital signs will be analysed based on treatment groups, as defined in Table 6.1: 1. Listings of 
each parameter over time and for the difference from baseline (refer to Section 6.7) will be 
provided. 


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7.8.4
ECG
12-lead ECG recordings will be checked by the investigator for pathological results.
Clinically relevant abnormal findings for ECG will be reported either as baseline condition
(when they occurred before intake of first study treatment) or will be reported as AEs (when 
they occurred after first administration of study treatment) and will be summarized as such.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of first study treatment) or as AE (after first 
administration of study treatment) and will be summarized as such.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCS-40-413: Identify and Manage Important Protocol Deviations (iPD)”, current 
version, Group “Clinical Operations”; IDEA for CON.
3
Jones PW. St George’s Respiratory Questionnaire Manual, version 2.3 (June 2009) [R12-
2870].
4
Manual Scoring Instructions for QOL-B Version 3.1 (2020), [c34996255], BIRDS
5
CASA-Q User Manual. Boehringer Ingelheim (v4.0 2015), [R18-2689]
6
KM Asset BI-KMED-BDS-HTG-0045: " Standards for Reporting of Clinical Trials and 
Project Summaries", current version, group “Clinical Trial Data Analysis”; KMED
7
KM asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version, group “Clinical Trial Data Analysis”; KMED
8
KM Asset BI-KMED-BDS-HTG-0066: " Analysis and Presentation of Adverse Event 
Data from Clinical Trials", current version, group “Clinical Trial Data Analysis”; KMED 
9
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, current 
version
10
KM Asset BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory 
Data", current version, group “Clinical Trial Data Analysis”; KMED
11
KM Asset BI-KMED-TMCP-MAN-0014: "Noncompartmental PK/PD Analyses of 
Clinical Studies", current version; KMED
12
KM Asset BI-KMED-TMCP-MAN-0010: "Description of Analytical Transfer Files,
PK/PD Data files and ADA files", current version; KMED


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
Author
Sections 
changed
Brief description of change
Final
15 SEP 2022
None
This is the final TSAP