Clinical trial NCT04059094
Conditions: Cystic Fibrosis
Sponsor: Boehringer Ingelheim
Start date: 2019-09-16; Completion date: 2020-04-24
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to assess the efficacy, safety and pharmacokinetics of twice daily inhaled doses of BI 1265162 delivered by Respimat® inhaler versus placebo in adolescents and adult patients with cystic fibrosis.

Detailed description:

Arms: arm 1: 2 puffs ofmatching placebowere inhaledorally via theRespimat®inhaler twice dailyfor a treatmentperiod of 4 weeksin patients withcystic fibrosis. arm 2: 2 puffs of 25micrograms (μg)BI 1265162(Total: 50μg)were inhaledorally via theRespimat®inhaler twice daily(b.i.d., daily dose:100μg) for atreatment periodof 4 weeks inpatients withcystic fibrosis. arm 3: 2 puffs of 50micrograms (μg)BI 1265162(Total: 100μg)were inhaledorally via theRespimat®inhaler twice daily(b.i.d., daily dose:200μg) for atreatment periodof 4 weeks inpatients withcystic fibrosis. arm 4: 2 puffs of 100micrograms (μg)BI 1265162(Total: 200μg)were inhaledorally via theRespimat®inhaler twice daily(b.i.d., daily dose:400μg) for atreatment periodof 4 weeks inpatients withcystic fibrosis. arm 5: 2 puffs of 10micrograms (μg)BI 1265162(Total: 20μg)were inhaledorally via theRespimat®inhaler twice daily(b.i.d., daily dose:40μg) for atreatment periodof 4 weeks inpatients withcystic fibrosis.
Interventions: intervention 1: BI 1265162 intervention 2: Placebo
Intervention descriptions: intervention 1: Inhalation solution intervention 2: Inhalation solution

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (15.0) / Saved on: 30 Nov 2017
Clinical Trial Protocol
TITLE PAGE
Document Number:
c23936559-02
EudraCT No.
EU Trial No.
2019-000261-21
BI Trial No.
1399-0003
BI Investigational
Medicinal Product(s)
BI 1265162
Title
A randomised, double-blind, placebo-controlled and parallel group 
trial to evaluate efficacy and safety of twice daily inhaled doses of 
BI 1265162 delivered by Respimat® inhaler as add-on therapy to 
standard of care over 4 weeks in patients with cystic fibrosis –
BALANCE – CFTM 1
Lay Title
A 4-week study to test different doses of BI 1265162 in 
adolescents and adults with cystic fibrosis using the Respimat®
inhaler – BALANCE – CFTM1
Clinical Phase
Phase II
Trial Clinical 
Monitor
Tel: 
Fax:
Coordinating 
Investigator
Status
Final Protocol (Revised Protocol based on global amendment 1)
Version and Date
Version: 2.0
Date: 18 Nov 2019
Page 1 of 79
Proprietary confidential information.
2019 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
08 March 2019
Revision date
18 November 2019
BI trial number
1399-0003
Title of trial
A randomised, double-blind, placebo-controlled and parallel group 
trial to evaluate efficacy and safety of twice daily inhaled doses of BI 
1265162 delivered by Respimat® inhaler as add-on therapy to 
standard of care over 4 weeks in patients with cystic fibrosis –
BALANCE – CFTM1
Coordinating 
Investigator
Trial site(s)
Multi-centre trial conducted in approximately 10 countries
Clinical phase
II
Trial rationale
Dose ranging to determine the optimal dose to be evaluated in the 
phase III program.
Trial objective(s)
The primary objective of this trial is to assess the efficacy, safety and 
pharmacokinetics of twice daily inhaled doses of 20 µg, 50 µg, 100µg 
and 200 µg of BI 1265162 delivered by Respimat® inhaler versus 
placebo in adult and adolescent patients with cystic fibrosis.
Trial endpoints
Primary endpoint:

Change from baseline in percent predicted trough FEV1 after 4 
weeks of treatment
Secondary endpoints:

Change from baseline in Lung Clearance Index (LCI) assessed
by N2MBW procedure after 4 weeks of treatment

Change from baseline in CFQ-R total score after 4 weeks of 
treatment

Change from baseline in CASA-Q (4 separate sub-scores)
after 4 weeks of treatment

Percentage of patients with treatment-emergent Adverse 
Events (AE) up to Day 36

Ct,N (concentration of the analyte in plasma at time t following 
dose N)

Cpre,N (predose concentration measured for dose N) AUC0-t,N 
(area under the concentration-time curve of the analyte in 
plasma until t hours after dose N)
Trial design
Randomised, double-blind, placebo-controlled and parallel group 
design over 4 weeks.
Total number of patients
randomised
98 patients including 21 adolescent patients
Number of patients

28 patients on placebo including 6 adolescent patients


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entered on each 
treatment

14 patients on BI 1265162 20µg bid including 3 adolescent 
patients

14 patients on BI 1265162 50µg bid including 3 adolescent 
patients

14 patients on BI 1265162 100µg bid including 3 adolescent 
patients

28 patients on BI 1265162 200µg bid including 6 adolescent 
patients
Diagnosis
Cystic Fibrosis
Main in- and exclusion 
criteria
Inclusion criteria
1.
Male or female patients / 12 years of age or older at screening;
2.
Documented diagnosis of cystic fibrosis including:
• positive sweat chloride ≥ 60 mEq/L, by pilocarpine 
iontophoresis or 
• a genotype with 2 identifiable mutations consistent with cystic 
fibrosis accompanied by one or more clinical features with 
cystic fibrosis phenotype;
3.
FEV1 ≥ 40% and ≤ 90% of predicted values at screening and 
predose at Visit 2.
4.
Women of childbearing potential must be willing and able to use 
highly effective methods of birth control
Exclusion criteria
1.
Evidence of acute upper or lower respiratory tract infection 
within 4 weeks prior to randomisation based on investigator’s 
judgement;
2.
Pulmonary exacerbation requiring use of i.v./oral/inhaled 
antibiotics or oral corticosteroids within 4 weeks prior to 
randomisation.
Test product(s)
BI 1265162
dose
20, 50, 100 and 200 µg bid
method and route of 
administration
Inhalation via the Respimat®
Comparator product(s)
Placebo
dose
Not applicable
method and route of
administration
Inhalation via the Respimat®
Duration of treatment
4 weeks
Statistical methods
The primary objective is to demonstrate proof of concept with respect 
to a non-flat dose response curve and define a suitable dose range for 
BI 1265162 regarding efficacy and safety for further pivotal testing in 
Phase III. For this purpose, a multiple comparison procedure with 
modelling techniques (MCPMod) approach is considered.
An efficacy interim analysis will be conducted on the first 28 patients 
included in the placebo and BI 1265162 200µg bid arms once they 
will have completed the 4-week treatment period.


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FLOW CHART
During trial visit, the sequence in which specific assessments are performed is important. The  
sequence of procedures at each visit (where applicable) should be as defined in Section 6.2.
Trial Periods
Screening 
Randomised Treatment 
Follow-up 
Visit
1
2
3
Ambulatory 
Visit6
4
EoT** 
5
FUP 
Days calculated from Day 1
-14
1*
8
15
29
EoT plus 7
days
Time window for visits
±3 days
none
±3 days
±3 days
±3days
+3days
Informed consent
X
Demographics
X
Medical history
X
Physical examination
X
X
X
Chest examination
X
X
X
X
Height
X
Body weight
X
X
Vital signs
X
X
X
X
X
Laboratory tests
X
X
X
X
Serum electrolytes tests
X
X2
X2
X2
X
Serum K+ test
X3
Pregnancy test5 
X
X
X
X
X
12 lead-ECG
X
X
X
X
Review of in-/exclusion criteria
X
X
Randomisation
X
Dispense trial drugs
X
Administer trial drugs
X
X
X
Collect trial drugs
X
Optional biobanking (sputum, 
blood)****
X
X
X
PK Sampling1
X
X
X
X
Pulmonary Function Tests (PFTs)
X
X
X
X
X
Dispense patient diary
X
Patient diary review
X
X
CASA-Q
X
X
X
CFQ-R
X
X
N2 Multiple Breath Washout 
(N2MBW)4
X
X
Respimat® inhaler training
X
X
X
Phone contact
X
All Aes/SAEs/AESIs***
X
X
X
X
X
X
Compliance check 
X
X
Concomitant therapy
X
X
X
X
X
X
Completion of patient 
participation 
X
(*)
Day of Randomisation / Day of first intake of randomised medication
(**)
Patients who discontinue trial treatment prematurely should come to the clinic as soon as possible for 
an early End of Treatment Visit. Study procedures will be the same as for V4/EoT except for PK blood 
sampling, serum electrolytes and PFTs. Those assessments will be performed once at anytime during 
the EoT visit. Follow-up (FUP) visit should take place one week after the early End of Treatment Visit


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(***)
After the individual patient’s end of the trial the investigator should report only any occurrence of 
cancer, related SAEs and related AESIs of which the investigator may become aware of and only via the SAE 
form, please see section.5.2.6.2.1.
(****) Only for patients who can legally consent. Requires separate informed consent for sputum and DNA 
Biobanking. Whole blood for DNA biobanking sample will be collected on Day 1 only (Visit 2), and if not 
possible on day 1, this sample may also be collected at a later visit.
Spontaneous sputum will be collected on Day 1, Day 29 and Follow-up Visit.
1 Site staff should contact the patients by phone/text/email to remind them to inhale the drug at the appropriate 
times on the day before the clinic visit.
2 Blood sampling for serum electrolytes to be performed before and 5 min (+5 min) after study drug inhalation. 
In case of early treatment discontinuation, blood sampling for serum electrolytes will be performed once at 
anytime during the early EoT visit.
3 A laboratory kit to conduct blood sampling by local laboratory/doctor/health care provider for serum 
potassium by central laboratory will be used. This kit will be provided to the patient at Visit 3. Blood 
sampling can be performed anytime.
4 Patients will qualify for N2MBW test if demonstrating a FEV1 > 60% of predicted values at screening and are 
able to complete the N2MBW test at Visit 2. When a patient fails N2MBW test at visit 2 for quality 
reasons, the patient should not complete the N2MBW test at visit 4
5 Pregnancy testing will be performed locally to all women of childbearing potential and to female adolescents 
who have reached menarche, even irregular, using the urine pregnancy test kits supplied by the central 
laboratory. Serum pregnancy test is required in case of positive urine test.
6 It is also possible to perform this visit at site if more appropriate for patient.


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FLOW CHART FOR PK BLOOD SAMPLING
Visits
Timepoints
[hrs post dose]
2
Day 1
Pre-dose
5 min (+5 min)
3
Day 8
Pre-dose
5 min (+5 min)
30 min (+/- 15 min)
1 h(+/- 15 min)
4 h (+/- 30 min)
4 EoT
Day 29
Pre-dose
Post-dose (anytime with a preference 
around 5-15 minutes post-dose)
In case of 
early EoT
Anytime
5 FUP
Day 36
Anytime


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FLOW CHART FOR N2MBW TEST
Visits
Timepoints
1
NA
2
Day 1
Predose 
3
Day 8
NA
4 EoT
Day 29
Predose
In case of 
early EoT
Anytime
5 FUP
Day 36
NA
Only for patient with FEV1 > 60% of predicted values at screening and who are able to complete the N2MBW 
test at V2
FLOW CHART FOR PULMONARY FUNCTION TEST
Visits
Timepoints
[min post dose]
1
No bronchodilator washout required
2
Day 1
Predose 
5-20
60-120
3
Day 8
Predose 
5-20
60-120
4 EoT
Day 29
Predose 
5-20
60-120
In case of 
early EoT
Anytime
5 FUP
Day 36
Anytime


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
FLOW CHART FOR PK BLOOD SAMPLING..................................................................6
FLOW CHART FOR N2MBW TEST....................................................................................7
FLOW CHART FOR PULMONARY FUNCTION TEST .................................................7
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
................................................................................................15
1.2.1
The Respimat® Inhaler......................................................................................15
1.2.2
BI 1265162 ...........................................................................................................16
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................18
1.4
BENEFIT - RISK ASSESSMENT.....................................................................19
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint(s)............................................................................................22
2.1.3
Secondary endpoint(s) ........................................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................26
3.3.1
Main diagnosis for trial entry ............................................................................27
3.3.2
Inclusion criteria .................................................................................................27
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Withdrawal of patients from treatment or assessments..................................28
3.3.4.1
Discontinuation of trial treatment .........................................................................29
3.3.4.2
Withdrawal of consent to trial participation .........................................................29
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................30
4.
TREATMENTS...................................................................................................31
4.1
INVESTIGATIONAL TREATMENTS ...........................................................31
4.1.1
Identity of the Investigational Medicinal Products..........................................31


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4.1.2
Selection of doses in the trial and dose modifications......................................33
4.1.3
Method of assigning patients to treatment groups...........................................33
4.1.4
Drug assignment and administration of doses for each patient......................33
4.1.4.1
Drug assignment and Dispensing of medication...................................................33
4.1.4.2
Training and Priming of the Respimat® inhaler....................................................34
4.1.4.3
Study medication administration ..........................................................................34
4.1.4.4
Respimat® malfunctioning....................................................................................35
4.1.5
Blinding and procedures for unblinding...........................................................35
4.1.5.1
Blinding.................................................................................................................35
4.1.5.2
Unblinding and breaking the code ........................................................................36
4.1.6
Packaging, labelling, and re-supply...................................................................36
4.1.7
Storage conditions...............................................................................................36
4.1.8
Drug accountability.............................................................................................36
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................37
4.2.1
Other treatments and emergency procedures..................................................37
4.2.2
Restrictions ..........................................................................................................37
4.2.2.1
Restrictions regarding concomitant treatment ......................................................37
4.2.2.2
Restrictions on diet and life style..........................................................................38
4.2.2.3
Contraception requirements..................................................................................38
4.3
TREATMENT COMPLIANCE........................................................................39
5.
ASSESSMENTS..................................................................................................40
5.1
ASSESSMENT OF EFFICACY........................................................................40
5.1.1
Pulmonary Function Testing (FEV1
................................................40
5.1.2
Cystic Fibrosis Questionnaire-Revised (CFQ-R).............................................40
5.1.3
Cough and Sputum Assessment Questionnaire (CASA-Q©)...........................41
5.1.4
N2 Multiple Breath Washout test (LCI)............................................................41
5.2
ASSESSMENT OF SAFETY.............................................................................41
5.2.1
Physical examination and chest examination...................................................41
5.2.2
Vital signs.............................................................................................................41
5.2.3
Safety laboratory parameters ............................................................................42
5.2.4
Electrocardiogram ..............................................................................................44
5.2.5
Other safety parameters.....................................................................................44
5.2.6
Assessment of adverse events.............................................................................44
5.2.6.1
Definitions of AEs ................................................................................................44
5.2.6.2
Adverse event collection and reporting ................................................................47
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................48
5.3.1
Assessment of pharmacokinetics .......................................................................48
5.3.2
Methods of sample collection .............................................................................48
5.3.2.1
Plasma sampling for pharmacokinetic analysis ....................................................49
5.3.3
Analytical determinations ..................................................................................49
5.3.4
Pharmacokinetic and Pharmacokinetic – pharmacodynamic relationship...49
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................50
5.5
BIOBANKING ....................................................................................................50
5.5.1
Methods and timing of sample collection..........................................................50


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5.6
OTHER ASSESSMENTS...................................................................................50
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................50
6.
INVESTIGATIONAL PLAN.............................................................................52
6.1
VISIT SCHEDULE.............................................................................................52
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................52
6.2.1
Screening period..................................................................................................53
6.2.2
Treatment period(s)............................................................................................54
6.2.3
Follow up period and trial completion..............................................................54
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................56
7.1
STATISTICAL DESIGN - MODEL.................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................56
7.3
PLANNED ANALYSES.....................................................................................56
7.3.1
Primary endpoint analyses.................................................................................57
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.4
Safety analyses.....................................................................................................60
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................60
7.4
INTERIM ANALYSES ......................................................................................61
7.5
HANDLING OF MISSING DATA ...................................................................61
7.6
RANDOMISATION ...........................................................................................61
7.7
DETERMINATION OF SAMPLE SIZE .........................................................62
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........65
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................65
8.2
DATA QUALITY ASSURANCE ......................................................................66
8.3
RECORDS...........................................................................................................66
8.3.1
Source documents ...............................................................................................66
8.3.2
Direct access to source data and documents.....................................................67
8.3.3
Storage period of records ...................................................................................67
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................68
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........68
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................68
8.6
TRIAL MILESTONES.......................................................................................68
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................69
9.
REFERENCES....................................................................................................71
9.1
PUBLISHED REFERENCES............................................................................71
9.2
UNPUBLISHED REFERENCES......................................................................72
10.
APPENDICES.....................................................................................................73
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................74


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11.1
GLOBAL AMENDMENT 1 ..............................................................................74
11.2
GLOBAL AMENDMENT 2 ..............................................................................78


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ASL
Airway Surface Layer
AST
Aspartate Transaminase 
AUC
Area under the Curve
b.i.d.
bis in die (twice daily dosing)
β-HCG
Beta-Human Chorionic Gonadotropin 
BI
Boehringer Ingelheim
BMI
Body Mass Index
CA
Competent Authority
CASA-Q
Cough and Sputum Assessment Questionnaire
CF
Cystic Fibrosis
CFQ-R
Cystic Fibrosis Questionnaire Revised
CFTR
Cystic Fibrosis Transmembrane conductance Regulator
CI
Confidence Interval
Cl
Chlorure
Cmax
Maximum Concentration
Cmin
Minimum Plasma Concentration
CML
Clinical Monitor Local
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
DeoxyriboNucleic Acid
ECG
Electrocardiogram


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eCRF
Electronic Case Report Form
ED
Effective Dose
eDC
Electronic Data Capture
ENaC
Epithelial Sodium Channel
EoT
End of Treatment
ES
Enrolled Set
EudraCT
European Clinical Trials Database
FC
Flow Chart
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 Second
FUP
Follow Up
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GMP
Good Manufacturing Practice
HA
Health Authority
i.v.
intravenous
IB
Investigator’s Brochure
ICH
International Council on Harmonization
IEC
Independent Ethics Committee
IPD
Important Protocol Deviation
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
K
Potassium
LCI
Lung Clearance Index
LPLT
Last Patient Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
Na
Sodium
NCA
Non-Compartmental Analysis
N2MBW
N2 Multiple Breath Washout
N2MBWS
N2 Multiple Breath Washout Set


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NOAEL
No Observable Adverse Effect Level
OPU
Operative Unit
PFT
Pulmonary Function Test
PD
Pharmacodynamics
PK
Pharmacokinetics
PKS
Pharmacokinetic Set
RA
Regulatory Authority
REP
Residual Effect Period
RS
Randomised Set
SAE
Serious Adverse Event
SRD
Single Rising Dose
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Half Life Time
TCM
Trial Clinical Monitor
TS
Treated Set
tmax
Timepoint of Maximum Plasma Concentration
ULN
Upper Level of Normal
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Cystic Fibrosis (CF) is an inherited disease of the exocrine glands, primarily affecting the 
gastrointestinal and respiratory systems and characterized by exocrine pancreatic 
insufficiency and abnormally high sweat electrolytes. CF is a life-threatening disease 
affecting approximately 30,000 children and adults in the United States and more than 70,000 
worldwide. CF is an inherited autosomal recessive trait (i.e., an individual must inherit two 
defective CF genes – one from each parent – to have CF). The gene responsible for the 
disease encodes a membrane-associated protein called the cystic fibrosis transmembrane 
conductance regulator (CFTR) and is located on the long arm of chromosome 7 [R15-5856]. 
The gene defect causes the body to produce abnormally thick, sticky mucus that clogs the 
lungs and leads to life-threatening lung infections. 
In addition, evidence suggests a role for the epithelial sodium channel (ENaC) in the 
pathogenesis of CF that exacerbates the dehydration of mucus, which becomes thickened, 
tenacious and adherent, and leads to collapsed cilia and poor mucus clearance [R15-4955].
Standard therapy for CF patients, adult and paediatric, includes various CFTR modulators
alone or in combination, antibiotics, airway clearance techniques and devices, pancreatic 
enzymes and nutritional supplements, and drugs such as dornase alfa (Pulmozyme®), 
ibuprofen and, most often, inhaled bronchodilators. 
In CF, inhibition of ENaC is anticipated to modify the abnormal electrolytic exchange across 
the cell membrane, by specifically reducing sodium uptake and water absorption in the 
airways, thus counteracting dehydration of the mucus. This should translate to improved 
mucociliary clearance and pulmonary function (especially FEV1). A decrease in static mucus 
would be expected to reduce bacterial colonisation of the lower airways, which could cause 
fewer exacerbations and hospitalisations. As a result, the patient would experience a relief of 
clinical symptoms and a better quality of life.
1.2
DRUG PROFILE
1.2.1
The Respimat® Inhaler
BI 1265162 is administered with the Respimat® inhaler from an aqueous solution in a 
cartridge, which is inserted into the inhaler prior to first use. Several solutions with different 
drug substance concentrations have been developed for use in clinical studies, including a 
placebo solution.
The Respimat® Inhaler generates a soft mist (without the use of propellants) which is released 
over a period of approximately 1.5 seconds. The drug formulation contains disodium edetate
as a stabilizer and as a multi-dose inhaler and solution; it contains the antimicrobial 
preservative benzalkonium chloride. Both excipients have been reported to induce 
bronchospasms in some patients. However, the concentrations of disodium edetate and 
benzalkonium chloride in the BI 1265162 Respimat® formulation are well below the amounts 


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for which bronchospasm has been reported with nebulised solutions [P05-08465] and are 
already widely used in Spiriva Respimat® for the treatment of asthma and COPD, Spiolto and 
Combivent Respimat® for the treatment of COPD.
1.2.2
BI 1265162
Mode of action/pharmacology
BI 1265162 is a potent inhibitor of the epithelial sodium channel (ENaC)
 
Key pharmacokinetic characteristics
Drug interactions


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Based on the plasma BI 1265162 concentrations observed in the single rising dose study in 
man, no drug interaction is predicted in man.
Residual Effect Period
Data from toxicology studies
Data from clinical studies


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For a more detailed description of BI 1265162 profile, please refer to the current 
Investigator’s Brochure (IB).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Because CF is an inherited disease, there is no preventative treatment. Even though new 
disease modifying therapies have been approved, there is still a need for symptomatic 
treatment that works in conjunction with existing medications to reduce the risk of CF-related 
exacerbations, improve the quality of life and prolong patient survival.
One particular unmet medical need in CF is for a safe and effective muco-active medication. 
In comparison to marketed mucolytic therapies, an ENaC inhibitor would be expected to have 
additional effects as a result of its direct influence on mucus hydration. 
Indeed, an ENaC inhibitor does not act directly on mucus but by inhibiting the ENaC which 
is highly upregulated in CF, it modifies the abnormal electrolytic exchange across the cell 


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membrane. ENaC represents a new target in CF and is part of a physiological pathway that 
complements CFTR in the regulation of the fluid volume and composition of the airway 
surface layer (ASL), a key factor in determining the potential of mucociliary clearance. This 
could result in potential synergy between CF treatments targeting the two mechanisms.
Historically, CF has been considered a paediatric disease, becoming symptomatic at a young 
age. However, newer treatments and improved disease management allow patients to live into 
adulthood. The underlying aetiology, a genetic defect in the CFTR gene, remains the same 
irrespective of the age. The clinical manifestations of the disease are similar in children and 
adults, while the main cause of death in both populations is pulmonary insufficiency. 
This trial will evaluate the efficacy and safety of several doses of BI 1265162 in adolescents 
(12-17 years of age) and adults with CF. This trial aims to determine the optimal dose to be 
evaluated in the phase III program.
Rationale for the N2 Multiple Breath Washout (N2MBW) test
Lung Clearance Index (LCI) based on N2MBW test is a valuable endpoint to explore the 
small airway function and the distribution of ventilation among lung regions, aspects of lung 
function which are not captured by spirometry. N2MBW test is a very sensitive test which 
requires experienced site staff and can only be performed in patients with less impaired lung 
function. 
1.4
BENEFIT - RISK ASSESSMENT
The nature of the target and the mechanism of action of BI 1265162 are well understood and
ENaC inhibition is a well-established target for systemic potassium sparing diuretics such as 
amiloride. The mechanism has been studied in multiple animal species as well as in clinical 
trials of up to 6 months duration via the inhaled route. The mechanism is not pleiotropic, does 
not have any amplification properties and will not bypass normal physiological control 
mechanisms. The tissue distribution of the target is well characterized and the adverse effect 
profile of the on target effect of inhibition is well known. 
The established functions of ENaC fit to its involvement in the pathogenesis of Cystic 
Fibrosis and effects demonstrated in rats and sheep are expected to translate into effects in 
man. 


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Patients who will be randomised in the placebo group may have a higher probability of 
treatment failure, i.e. no improvement of the lung function. However, BI 1265162 will be 
assessed on top of standard CF therapies. Therefore, the patients randomised in the placebo 
group will still be treated as per the standard clinical practice. The severity of CF is 
determined by a combination of factors including the CFTR mutation, so the underlying 
cause of disease does not alter with age. In addition, the expression and function of ENaC is 
not considered to differ between the age groups. Therefore, the mechanism of action and the 
dose of BI 1265162 are anticipated to be the same in adults and paediatrics. It is expected that 
BI 1265162 will have a similar effect on mucociliary clearance and pulmonary function in all 
age groups, this is why adolescent patients aged 12 or older will be included in this phase II 
trial. However, patient recruitment will start with adult patients only. The enrolment of 
adolescents will be allowed by an independent Data and Monitoring Committee (DMC), 
based on periodic safety adult data reviews (please refer to the DMC charter for further 
details). 
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators for all investigational products. Therefore, this trial will define 
procedures for the timely detection, evaluation, and follow-up of laboratory alterations in 


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selected liver laboratory parameters to ensure patients´ safety, see also Section 5.2.6, adverse 
events of special interest.
Some improvements are expected in CF patients after a 4-week exposure, especially on lung 
function and symptoms. The risks of the study procedures themselves are, in general, similar 
to what the patient population in question routinely experiences with the 
treatment/management of their disease. 
Overall, the expected potential benefits for CF patients outweigh potential risks and justify 
exposure to BI 1265162 in this trial, at the selected doses twice daily over 4 weeks.


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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 assess the efficacy, safety and pharmacokinetics of 
twice daily inhaled doses of 20 µg, 50 µg, 100µg and 200 µg of BI 1265162 delivered by 
Respimat® inhaler versus placebo in adolescents and adult patients with cystic fibrosis.
2.1.2
Primary endpoint(s)
The primary endpoint to assess efficacy of BI 1265162 is the change from baseline in percent 
predicted trough Forced Expiratory Volume in 1 Second (FEV1) after 4 weeks of treatment.
Trough FEV1 is defined as measurement performed within 30 minutes prior to dosing.
2.1.3
Secondary endpoint(s)
The secondary endpoints of this trial are:

Change from baseline in Lung Clearance Index (LCI) assessed by N2 Multiple Breath 
Washout (N2MBW) procedure after 4 weeks of treatment

Change from baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) total score 
after 4 weeks of treatment

Change from baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) (4 
separate sub-scores) after 4 weeks of treatment

Percentage of patients with treatment-emergent Adverse Events (AE) up to Day 36

Ct,N (concentration of the analyte in plasma at time t following dose N)

Cpre,N (predose concentration measured for dose N)

AUC0-t,N (area under the concentration-time curve of the analyte in plasma until t 
hours after dose N)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-center, multinational, randomised, double-blind, placebo-controlled, parallel 
group dose-ranging trial of BI 1265162 inhaled from the Respimat® inhaler in patients with 
CF.
The study consists of a 2-week screening period, a 4-week, randomised treatment period, and
a 7-day follow-up period.
Patients will be enrolled (screened) in the trial once the appropriate informed consent and 
assent (if applicable) have been given. Patients who successfully complete the screening visit 
and still meet the inclusion/exclusion criteria at Visit 2 will be randomised. After the 
completion of the treatment period or in case of early discontinuation, patients will be 
evaluated for an additional 7 days.
Overall, each patient’s participation in the trial is estimated to last a total of approximately 7 
weeks.
The patient’s participation is concluded when they have undergone the last planned visit (i.e. 
Follow-up Visit). 
As described in the Figure 3.1.1 below, patient randomisation in the trial will start to either 
200µg bid of BI 1265162 or placebo. Once 28 patients are allocated to these two arms (14 
patients in each arm), the remaining patients will be randomised to the additional doses of BI 
1265162 (20, 50 and 100µg bid) as well as 200µg bid and placebo with 14 patients per 
treatment arm.
As a result, patients will be distributed in a 2:1:1:1:2 ratio to receive twice daily via the 
Respimat® inhaler either:
-
Placebo, or
-
2x10µg (i.e. 20µg bid) of BI 1265162, or
-
2x25µg (i.e. 50µg bid) of BI 1265162, or
-
2x50µg (i.e. 100µg bid) of BI 1265162, or
-
2x100µg (i.e. 200µg bid) of BI 1265162.
Furthermore, patient recruitment in the trial will start with adult patients only. Enrolment of 
adolescent patients will be based on periodic reviews of adult patient safety data. Those 
safety data reviews allowing the recruitment of adolescent patients will be performed by an 
independent Data Monitoring Committee (DMC). The independent DMC will decide when 
adolescent patients can be enrolled and inform the Sponsor accordingly.
Randomisation will be stratified by age (<18 years old and ≥ 18 years old at day of 
randomisation) in order to ensure that approximately 20% of adolescent patients are 
randomised per treatment group (i.e., at least 3 adolescents in the 20µg, 50µg and 100µg bid 
of BI 1265162 groups and at least 6 adolescents in the 200µg bid of BI 1265162 and placebo 
groups).


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For a graphical presentation of the trial, see Figure 3.1:1 below.
Figure 3.1.1 Trial Design
In addition, in order to prevent the exposure of further patients in case of insufficient 
efficacy, an efficacy interim analysis will be conducted on the first 28 patients exposed to
placebo or BI 1265162 200µg bid. Please refer to Section 7.4 for further details.
Patient recruitment will not be stopped during the conduct of the interim analysis and this
efficacy interim analysis is not correlated with the periodic safety data reviews that will be 
performed by the independent DMC. 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Since the initial pulmonary defect in CF is airway obstruction, FEV1 is the recommended 
primary endpoint for assessing the efficacy of a new drug in patients with CF [R12-2800]. 
Due to its mechanism of action, a 4-week treatment period is considered sufficient to evaluate 
the indirect effects of BI 1265162 on trough FEV1.
A parallel group, randomized, double-blind and placebo controlled trial is considered the 
most appropriate design to assess efficacy and safety of four doses of BI 1265162.
The rationale for the BI 1265162 dose selection is described in Section 4.1.2.
In order to prevent the exposure of further patients in case of insufficient efficacy, patients 
will be first randomised to either the highest dose of BI 1265162 or placebo. An interim 
efficacy analysis will be conducted on the first 28 patients exposed to either placebo or the 
highest dose of BI 1265162. As described in Section 3.1 and 7.4, depending on the results of 
the interim analysis, the trial may be stopped.


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The 1-week follow-up period is considered to be sufficient, as previous studies with BI 
1265162 have shown that the majority of the drug, measured in the systemic circulation, is 
excreted from the body within 1 week. 
As described in Section 8.7, a data monitoring committee (DMC), which is independent of 
the sponsor, will be established to assess the progress of the clinical trial, including safety
reviews at specified intervals, and to recommend to the sponsor whether to continue, modify, 
or stop the trial. The DMC will also be in charge of allowing enrolment of adolescent patients
in the trial. Further details are provided in the DMC charter.
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 cystic fibrosis will be screened from approximately 40
trial sites to ensure the randomisation of 98 patients including 21 adolescents (12 to 17 years 
of age).
It is expected that 2 to 3 patients will be randomised at each trial site. If enrolment is delayed, 
additional sites may be recruited. The number of adolescent patients to be included in each 
treatment arm should be as follows:
-
Placebo: at least 6 adolescents
-
2x10µg (i.e. 20µg bid) of BI 1265162: at least 3 adolescents
-
2x25µg (i.e. 50µg bid) of BI 1265162: at least 3 adolescents
-
2x50µg (i.e. 100µg bid) of BI 1265162: at least 3 adolescents
-
2x100µg (i.e. 200µg bid) of BI 1265162: at least 6 adolescents
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 
becomes eligible. 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. The current approved version of the information sheet and 
consent form should be signed again. 
In case of pulmonary exacerbation requiring use of i.v./oral/inhaled antibiotics or oral 
corticosteroids 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.
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 based on 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.


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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 is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Adult and adolescent (12 to 17 years of age) patients diagnosed with CF and who comply 
with eligibility requirements may qualify for participation in this trial.
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
1. Male or female patients, 12 years of age or older at screening;
2. Documented diagnosis of cystic fibrosis including:

positive sweat chloride ≥ 60 mEq/L, by pilocarpine iontophoresis OR

genotype with 2 identifiable mutations consistent with cystic fibrosis accompanied 
by one or more clinical features with cystic fibrosis phenotype;
3. Patients able to perform acceptable spirometric manoeuvres according to American 
Thoracic Society (ATS) standards;
4. FEV1 ≥ 40% and ≤ 90% of predicted* values at screening and predose at Visit 2;
5. Women of childbearing potential (WOCBP) 1 must be willing and able to use highly 
effective methods of birth control per ICH M3 (R2) that result in a failure rate of less than 
1% per year when used consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the patient (or patient’s legal guardian) information;
6. Signed and dated written informed consent and assent in accordance with ICH
Harmonized Guideline for Good Clinical Practice (GCP) and local legislation prior to 
admission in the trial.
*Global Lung Initiative (GLI) lung function reference equations [R15-0845]. 
3.3.3
Exclusion criteria
1. Evidence of acute upper or lower respiratory tract infection within 4 weeks prior to 
randomisation based on investigator’s judgement;
2. Pulmonary exacerbation requiring use of i.v./oral/inhaled antibiotics or oral 
corticosteroids within 4 weeks prior to randomisation;
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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3. Patients with history of Acute Tubular Necrosis (ATN);
4. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ
carcinoma of uterine cervix;
5. Patients unable to inhale trial drug in an appropriate manner from the Respimat® inhaler 
based on investigator’s judgement;
6. Patients who have started a new chronic medication for CF within 4 weeks of 
randomisation;
7. Patients who have previously received a lung transplant or patients who are currently on a 
waiting list to receive a lung transplant;
8. Patients with a significant history of allergy/hypersensitivity (including medication 
allergy) which is deemed relevant to the trial as judged by the investigator or with a 
known hypersensitivity to trial drug or its components. “Significance” in this context 
refers to any increased risk of hypersensitivity reaction to trial medication;
9. Any clinically significant laboratory abnormalities at screening as judged by the 
investigator, or any of the following:

Potassium > upper limit of normal (ULN) in non-haemolysed blood

Abnormal renal function defined as estimated Glomerular Filtration Rate (eGFR) < 
60ml/min/1.73m²

Abnormal liver function, defined by serum level of either alanine transaminase 
(ALT), aspartate transaminase (AST) or total bilirubin ≥3 x upper limit of normal 
(ULN)
10. Clinically significant disease or medical condition other than CF or CF-related conditions 
that, in the opinion of the investigator, would compromise the safety of the patient or the 
data quality. This includes significant haematological, hepatic, renal, cardiovascular and 
neurologic disease. Patients with diabetes may participate if their disease is under good 
control prior to screening;
11. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled;
12. Previous randomisation in this trial;
13. Currently enrolled in another investigational device or drug trial, or less than 30 days or 
six half-lives (whichever is greater) since ending another investigational device or drug 
trial(s), or receiving other investigational treatment(s);
14. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable trial patient or unlikely to complete the trial; 
15. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
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”); 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. 


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The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If the reason for discontinuation is
death, this should be reported on the SAE form as well, regardless of causal relationship.
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).
If a patient becomes pregnant during the trial, the trial medications will need to be 
stopped and patient will be followed up until birth or otherwise termination of pregnancy. 
The data of the patient will be collected and reported in the clinical trial report until 
patient last visit and that any events thereafter will be reported in the BI 
Pharmacovigilance database. Please refer to Section 5.2.6.2.3 for detailed information on 
event reporting in case of pregnancy.

The patient has a confirmed level of serum potassium of > ULN in non-haemolysed 
blood.
Each result of elevated serum potassium level > ULN should be confirmed, either by a 
second measurement or by presence of clinical symptoms. At least one measurement 
should be performed by central laboratory. If second measurement is required and if 
blood sampling for central laboratory cannot be done in a reasonable timeframe according 
to investigator´s judgement, confirmation of serum potassium level can be evaluated by 
local laboratory.
An individual patient may be considered to be withdrawn from trial treatment if: 

The patient is not consistently taking a concomitant chronic CF medication. Changes in 
concomitant treatment required due to medically valid reasons will be permitted as judged 
by the investigator. 

The patient experiences more than one acute upper or lower respiratory tract infection or 
pulmonary exacerbation. In this case, a documented discussion should take place between 
investigator and sponsor to determine how to proceed.

The patient has repeatedly shown to be non-compliant with trial medication intake (below 
80% or above 120%).
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and Section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the CRF. These data will be included in the trial database and reported.
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.


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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.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of
the trial.
Furthermore, based on the interim analysis to be conducted on the first 28 patients included, 
the trial may be stopped as defined in Section 3.1 and Section 7.4.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The trial medication will be provided by BI.
Chronic CF medications are not considered as part of the clinical trial supplies and therefore 
will not be provided by BI.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test products are as shown below.
Table 4.1.1:1 Test product 1
Substance:
BI 1265162
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10µg per actuation
Posology:
2 inhalations twice a day
Method and route of administration:
Oral inhalation via Respimat® inhaler
Table 4.1.1:2 Test product 2
Substance:
BI 1265162
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength:
25µg per actuation
Posology:
2 inhalations twice a day
Method and route of administration:
Oral inhalation via Respimat® inhaler


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Table 4.1.1:3 Test product 3
Substance:
BI 1265162
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength:
50µg per actuation
Posology:
2 inhalations twice a day
Method and route of administration:
Oral inhalation via Respimat® inhaler
Table 4.1.1:4 Test product 4
Substance:
BI 1265162
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength:
100µg per actuation
Posology:
2 inhalations twice a day
Method and route of administration:
Oral inhalation via Respimat® inhaler
Table 4.1.1:5 Test product 5
Substance:
Placebo
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength:
Not applicable
Posology:
2 inhalations twice a day
Method and route of administration:
Oral inhalation via Respimat® inhaler


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4.1.2
Selection of doses in the trial and dose modifications
In this trial, the doses of 20 µg, 50 µg, 100 µg and 200 µg bid of BI 1265162 will be 
compared to placebo. The medication will be inhaled twice daily during four weeks, using the 
Respimat® inhaler. Each dose will consist of two inhalations; therefore the 20 µg dose will 
consist of two inhalations of 10 µg, the 50 µg dose will consist of two inhalations of 25 µg, 
the 100 µg dose will consist of two inhalations of 50 µg and the 200 µg dose will consist of 
two inhalations of 100µg. 
The doses selected were based on the previous SRD and MRDstudies in healthy volunteers 
(please refer to the Investigator Brochure for further details). The doses were selected in 
order to cover the expected therapeutic range (50 µg to 200 µg) and a sub-therapeutic dose 
(20 µg) which is required for a proper modeling of the dose response shape. With these
selected doses, sufficient information should be gathered to select a safe and effective dose to 
be assessed in Phase III pivotal studies.
4.1.3
Method of assigning patients to treatment groups
As described in Section 3.1, patient randomisation will start with only adult patients to either 
200 µg bid of BI 1265162 or placebo in a 1:1 ratio. As soon as 28 patients are allocated to 
these two treatment arms, the remaining patients will be allocated to the other doses of BI 
1265162 as well as the highest dose and placebo in a 1:1:1:1:1 ratio (14 patients per treatment 
arm).
The assignment will occur in a blinded fashion via Interactive Response Technology (IRT).
The IRT will assign the appropriate medication number based on the treatment sequence. The 
randomisation code will be controlled and documented. All instructions for use of the IRT 
system will be described in a user guide/manual which will be available in the ISF.
4.1.4
Drug assignment and administration of doses for each patient
4.1.4.1
Drug assignment and Dispensing of medication
Patients who qualify for randomisation will be randomly assigned by the IRT to one of the 
treatment groups listed below. 
Table 4.1.4: 1
Dosage and treatment schedule for the treatment period
Total Daily Dose 
(µg)
Visit 2 
4 weeks
40 (20 µg bid)
2x10 µg twice a day
100 (50 µg bid)
2x25µg twice a day
200 (100 µg bid)
2x50µg twice a day
400 (200µg bid)
2x100µg twice a day
Placebo
2 puffs twice a day


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Dispensation of the appropriate medication kits will occur at Visit 2. The patient will receive 
one Respimat® medication kits and one reserve Respimat® inhaler. Medications will be
dispensed by the investigator, study coordinator or pharmacist, depending on the site 
structure. The reserve kit allows the patient the flexibility of not having to return to the clinic 
immediately to replace a lost or malfunctioning Respimat® inhaler. In the event that the 
patient may need additional extra Respimat® inhalers and cartridges due to rescheduled visits, 
inhaler loss or malfunction, these will be supplied on an ‘on demand’ basis. Dispensing of 
these extra Respimat® inhalers will also be managed via the IRT.
4.1.4.2
Training and Priming of the Respimat® inhaler
Patients will receive training on the use of the Respimat® inhaler at Visit 1 to familiarize 
themselves with assembling, priming and using the inhaler. Training will be repeated at Visit 
2 and 3 where observance of the inhalation procedure will occur.
Each newly assembled Respimat® inhaler needs to be primed prior to first time use. The 
inhaler should be primed by actuating it until an aerosol is visible, plus three additional 
actuations. All priming actuations should be directed to the ground and priming should NOT 
take place in the same room where the patient is inhaling trial medication or in the room 
where PK blood samples are taken or being processed. On the PK sampling days, should 
priming of a new Respimat® inhaler be required, it should be performed by site personnel, 
and not by the patient. Gloves must be worn and discarded immediately after the priming to 
avoid contamination of the PK samples to be taken and processed subsequently (see also 
Section 5.3.2).
4.1.4.3
Study medication administration
At Visit 2, the first dose of study medication will be self-administered in the clinic. The clock 
time of the end of second inhalation will be captured on the source documents and in the 
eCRF. At all subsequent visits, medication will also be self-administered in the clinic and the 
clock time of the end of inhalation will be captured. 
The utmost care should be taken to ensure that during the treatment period, the study 
medication is not taken prior to coming to the site for a visit. In case the patient would take 
the study medication in the morning of the clinic visit, the trial visit should be re-scheduled 
the day after.
Study Medication administration at home:
Twice a day, each morning (other than clinic visit days) and each evening, medication will be 
self-administered by the patient. The patient will inhale two puffs of study medication from 
the assigned Respimat® inhaler. Patients should be encouraged to take their study medication 
at approximately the same time each morning and each evening after all other (inhaled) CF 
treatments. If a dose is missed for more than 4 hours, the next dose should be taken as 
planned. If the evening dose is missed on the day prior to a clinic visit, the visit should be 
rescheduled the day after. A glass of water can be taken after the trial drug inhalation, if 
needed.


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The patients will be given a patient specific paper diary in which they will record the date and 
time he/she took the doses of trial medication for the 3 days preceding the clinic visits. Time 
of administration means the end of the second inhalation.
If the current used Respimat® inhaler is locked, lost or malfunctions, the patient must 
assemble and prime the reserve Respimat® inhaler at home. 
4.1.4.4
Respimat® malfunctioning
Any Respimat® inhaler that has been reported as malfunctioning by a patient or a patient’s 
legal representative or investigator will be returned to BI for investigation. See the ISF for 
specific instructions. 
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments until after database lock.
The randomisation code will be kept secret by Clinical Trial Support up to database lock.
The randomisation codes will be provided to Bioanalytics prior or during the study to allow 
for the exclusion from the analyses of pharmacokinetic (PK) samples taken from placebo 
patients and to analyse the PK data on an ongoing basis. The project pharmacometrician and 
trial pharmacokineticist will also be given access to the randomisation code, along with 
preliminary BI 1265162 concentration data during the study to allow the PK, PK/PD
modelling to be started from at least 53 evaluable patients. This will also allow minimizing 
the time from database lock to obtaining the final PK modelling results. If required, and draft 
PK data is available, this can be supplied to the DMC upon request. This data, including the 
randomisation codes, will be kept separate and securely in a manner not to unblind any 
members of the medical team or team personnel interacting with the study sites or 
investigators.
The interim analysis to be performed on the primary efficacy endpoint once 28 patients have 
completed 4 weeks of treatment will be conducted by a Sponsor team independent from the 
trial team. The randomisation codes will be provided to this team who will keep those 
separate and securely in a manner not to unblind any members of the medical team or team 
personnel interacting with the study sites or investigators. 
The randomisation codes will also be provided to the independent DMC in case unblinded
data review is required by any of the DMC members. This data including the outputs of the 
unblinded analysis will not be communicated to the Sponsor. Please refer to Section 8.7 for 
further details.


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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 CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual 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. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the sponsor must be 
contacted immediately. Please refer to the ISF for further details.
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,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.


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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
Four doses of BI 1265162 will be assessed on top of CF standard therapies.
There are no specific emergency procedures defined in this trial.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
BI 1265162 will be assessed as add-on therapy to standard of care and thus, patients will 
remain on their current treatment(s). It is recommended that patients remain on a stable CF 
medication regimen from 4 weeks prior to randomisation through Week 4 or, if applicable, 
through the Follow-up Visit, with the exception of bronchodilators (see below).
Stable medication regimen is defined as the current medication regimen for CF that the 
patient has been following for at least 4 weeks before Day 1 (randomisation).
In terms of physiotherapy, there are no restrictions in the morning of study visits. If 
physiotherapy is scheduled in the morning of study visits, it has to be performed in the same 
fashion as on Day 1.
Patients who are using a bronchodilator must have their spirometry (except the one at 
screening) and N2 Multiple Breath Washout measurements performed according to the 
guidelines provided below:
-
Withhold short–acting β2-agonist (e.g. albuterol) or anticholinergic bronchodilators 
(e.g., Atrovent) for more than 4 hours before the assessments,
-
Withhold twice-daily long–acting bronchodilators (e.g. salmeterol) for more than 12 
hours before the assessments,
-
Withhold once-daily long–acting bronchodilators (e.g. tiotropium) for more than 24 
hours before the assessments.
Patients who require bronchodilation prior to inhaling hypertonic saline solution (according 
to investigator´s judgement) should withheld the use of hypertonic saline solution in line with 


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the instructions for bronchodilators. Consistency of any withholding decisions across visits is 
required. 
In case a patient forgets to withhold bronchodilator(s) intake (and hypertonic saline solution 
intake if applicable) in the morning of clinic visits, the study visit has to be re-scheduled the 
day after.
For patients who are on a stable regimen of inhaled cycling antibiotics, the Day 1 visit (Visit 
2) should occur on the Day 1 of an “On-cycle” (+/- 1 or 2 days); whatever the antibiotic is. 
For patients cycling different antibiotics, the Day 1 visit (Visit 2) should occur on the Day 1 
of a new antibiotic cycle.
Acute exacerbations should be treated according to best standard practice, and decision to 
interrupt BI 1265162 left to investigator’s judgment.
All concomitant medications will be recorded on the appropriate pages of the eCRF.
4.2.2.2
Restrictions on diet and life style
Patients should only follow the CF dietary recommendations provided by the investigational 
site staff.
Lifestyle restrictions for PFT and N2MBW test:
The patient must refrain from strenuous activity and smoking for at least 2 hours prior to 
pulmonary function testing (forced spirometry) and N2MBW measurement (if applicable). 
4.2.2.3
Contraception requirements
Women of childbearing potential must maintain a highly effective method of contraception
throughout the course of trial and for a period of at least 2 weeks after the last trial drug 
intake.
Contraception methods meeting these criteria are defined as: 

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal). 

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable). 

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). 

Bilateral tubal occlusion 

Vasectomized sexual partner (with appropriate post-vasectomy documentation of that 
absence of sperm in the ejaculate and provided that partner is the sole sexual partner of 
the WOCBP CT participant) 

Sexual abstinence: Patients must abstain from male-female sex. This is defined as being 
in line with the preferred and usual lifestyle of the patient. Periodic abstinence e.g. 
calendar, ovulation, symptothermal, post-ovulation methods; declaration of abstinence for 
the duration of exposure to study drug; and withdrawal are not acceptable.
Contraception of male trial participants and female partners of male trial participants is not 
required.


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4.3
TREATMENT COMPLIANCE
Patients are requested to bring all used and unused trial medication including partially used or 
empty Respimat® inhalers, packages and reserve kit with them when attending visits.
Based on the Respimat® dose counter indicating the remaining number of available 
actuations, 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 actuations actually taken 100
     Number of actuations which should have been taken
Note: 2 actuations (inhalation) per dose, twice a day (after priming)
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
Pulmonary Function Testing (FEV1
FEV1
 will be assessed using standardised spirometry equipment which will be 
supplied to all participating sites at trial initiation. Only these spirometers are to be used for 
this trial. Spirometry performance will be centrally reviewed. Spirometry equipment will be 
provided centrally with supplies of pre-calibrated disposable flow sensors.  These sensors 
demonstrate variability within the required standards of +/-3% determined by the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) [P05-12782].As such there is 
no need to conduct daily calibration prior to use.
For each patient, pulmonary function testing will always start at approximately the same time 
of day. Spirometry will be conducted while the patient is in a seated position. It is preferable 
that the same trained individual performs the PFTs for a given patient. The best of three 
efforts will be defined as the highest FEV1
 each obtained on any of three 
blows meeting the ATS/ERS criteria (with a maximum of eight attempts). FEV1
will be measured at the timepoints indicated in Flow Chart. Spirometry results captured by 
spirometers provided by the sponsor will be electronically transmitted and confirmed by 
central reading. 
Spirometry predicted values will be based on the Global Lung Initiative (GLI) 2012 lung 
function reference equations [R15-0845].
5.1.2
Cystic Fibrosis Questionnaire-Revised (CFQ-R)
The CFQ-R is a disease specific instrument that measures health related quality of life. 
For adolescents and adults (patients 14 years old and older), the questionnaire consists of 50
items in four sections. 
For children ages 12 and 13 there is a self-report format consisting of 35 items as well as a 
version for parents/caregivers consisting of 44 items. In case a patient would turn 14 years 
old during the trial participation, the same version of the questionnaire should be used at Visit 
2 and for the subsequent visits to ensure an appropriate comparison of the results.
The CFQ-R will be completed at the time points indicated in the Flow Chart. 
The CFQ-R should be administered at the start of the clinic visit, prior to any other tests or 
procedures. The CFQ-R will be paper-based and available in the local language (provided in 
the ISF). 


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5.1.3
Cough and Sputum Assessment Questionnaire (CASA-Q©)
The Cough and Sputum Assessment Questionnaire (CASA-Q©) will be completed at the time 
points indicated in the Flow Chart. The CASA-Q should be administered at the start of the 
clinic visit, after the CFQ-R, prior to any other tests or procedures. The questionnaire will be 
paper-based and available in the local language (provided in the ISF).
5.1.4
N2 Multiple Breath Washout test (LCI) 
N2 Multiple Breath Washout (N2MBW) measurements will be carried out at the timepoints 
indicated in the Flow Chart, and only in qualified patients. Patients will qualify for N2MBW 
test if demonstrating a FEV1 > 60% of predicted values at screening and are able to complete 
the N2MBW test at Visit 2.
LCI will be assessed using a standardised washout recording system with 100% medical 
grade oxygen as to washout the tracer gas, nitrogen. N2MBW measurements 
 
 will be centrally reviewed. 
N2MBW tests will be conducted with the patient in a seated position. A suitable nose clip 
must be used and the subject has to maintain a tight mouthpiece seal. Three technically 
acceptable N2MBW runs according to the ERS/ATS consensus statement for acceptability 
criteria have to be performed during relaxed tidal breathing of the subject [R15-1327]. The 
 lung clearance index (LCI), 
of these 
N2MBW runs will be recorded. LCI, 
are measures of ventilation homogeneity. 
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination and chest examination
A complete physical examination will be performed at the time points specified in the 
flowchart. It includes at a minimum general appearance, neck, cardiovascular system, 
abdomen, extremities, and skin. 
Chest examination will be performed at the time points specified in the flowchart.
Measurement of height and body weight will be performed at the time points specified in the 
flowchart. In order to get comparable body weight values, it should ideally be performed in 
the following way:

after bladder voiding

shoes and coat/jackets should be taken off

pockets should be emptied of heavy objects (i.e. keys, coins etc.)
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 Flowchart, prior to blood 
sampling and prior to the pre-dose PFT measurement.  This includes systolic and diastolic 


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blood pressure and pulse rate (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. For the sampling time 
points please see the flowchart.
Overall, approximately 80 mL of blood will be collected throughout the trial, to evaluate
patient safety, PK and for optional biobanking. For PK, each sample will require 
approximately 4 ml.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in Laboratory Manual in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Pregnancy testing will be performed locally to all women of childbearing potential and to 
female adolescents who have reached menarche, even irregular, using the urine pregnancy 
test kits supplied by the central laboratory. Immediately after the result of a pregnancy test is 
known, the pregnancy test kit will be discarded at the site. In case of positive result, a serum 
pregnancy test will be performed by the central laboratory. The results of the test must 
therefore be documented in the source documents available at the site for future verification 
by the CRA. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
Laboratory reports will be provided through the central laboratory web-based system. 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 eDC system.
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.


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Table 5.2.3:1 Safety laboratory tests
Panel
Parameters to be tested
Hematology
Hematocrit
Hemoglobin
Erythrocyte count
Total and differential leucocyte count
Platelet count
Serum Chemistry
Albumin
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Gamma-glutamyltranspeptidase (GGT)
Alkaline phosphatase (AP)
Lactic dehydrogenase (LDH)
Total bilirubin
Direct bilirubin
Indirect bilirubin
Protein (total)
Creatinine (IDMS standardised Jaffe Method)
Urea
Uric acid
Glucose
Serum electrolytes
Potassium
Sodium
Chloride
Inorganic phosphorus
Calcium
Serum pregnancy test
β-HCG (only for female patients in case of positive urine 
pregnancy test)
The estimated glomerular filtration rate (eGFR) will be calculated according to:

Bedside/interim Schwartz formula for patients below 18 years of age
eGFR (mL/min/1.73 m2) = 0.413 x height / Serum creatinine (mg/dL)

CKD/EPI formula for adult patients
eGFR (mL/min/1.73 m2) = 141 x min(SCr /κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x
1.018 [if female] x 1.159 [if Black]
SCr = standardized serum creatinine (mg/dL)
κ = 0.7 (females) or 0.9 (males)


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α = -0.329 (females) or -0.411 (males)
min = indicates the minimum of SCr/κ or 1
max = indicates the maximum of SCr/κ or 1
age = years
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flowchart. 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.
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.


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5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation,
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
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”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. These events should 
always be reported as SAEs as described above.
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:
1. A confirmed elevation of serum potassium > upper limit of normal (ULN) in non-
haemolysed blood (see definition in Section 3.3.4)


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2. Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST (aspartate transaminase) and/or ALT (alanine 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 eDC 
system.
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. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
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 CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
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 in the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the sponsor’s 
unique entry point (country specific reporting process 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 send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
All (S)AEs, including those persisting after 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.


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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.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and 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 Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Blood samples for pharmacokinetic analysis will be collected at the time points indicated in 
the Flow Chart for PK blood sampling.
The date and exact clock time of drug administration and of sampling times have to be 
recorded and documented in the eCRF by the investigator or designated site-personnel. The 
actual sampling times will be used for determination of pharmacokinetic parameters. These 
samples may also be used for metabolite determination or for further methodological 
investigation if required. The study samples will be discarded after completion of the 
additional investigations but not later than 5 years upon the final study report has been signed.
5.3.2
Methods of sample collection
The planned PK analyses will require blood sampling at the time points indicated in the 
Flowchart. 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 and planned sampling time
or planned sampling time interval.
All samples will be stored at about -20°C or below and be shipped on dry ice. Further details
to the information provided in the following chapters on sample collection, preparation of
plasma aliquots, sample handling, and shipping are provided in the laboratory manual.


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5.3.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of analyte plasma concentrations, blood will be taken from an antecubital
or forearm vein into a blood drawing tube that contains potassium EDTA–anticoagulant at 
the times indicated in the flow chart.
During the whole trial, a maximum of 40 mL of blood per person will be drawn for PK 
purposes.Plasma samples will be obtained by centrifugation. Sample aliquots will be stored at 
the trial site and at the logistics CRO until shipment and at the analytical laboratory until 
analysis.
First and second sample aliquots are to be shipped separately.
For further details please refer to laboratory manual.
5.3.3
Analytical determinations
BI 1265162 concentrations in plasma will be determined by validated a LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assays. All details of the analytical methods will 
be available prior to the start of sample analysis.
5.3.4
Pharmacokinetic and Pharmacokinetic – pharmacodynamic relationship
The following PK parameters will be determined if feasible through a population PK 
approach:

Ct,N (concentration of the analyte in plasma at time t following dose N)

Cpre,N (predose concentration measured for dose N) 

AUC0-t,N (area under the concentration-time curve of the analyte in plasma until t hours 
after dose N)
A non-compartmental (NCA) PK analysis may be undertaken on Day 8 if the data allows. 
The following parameters may be calculated;

Ct,N (concentration of the analyte in plasma at time t following dose N)

Cpre,N (predose concentration measured for dose N) 

AUC0-t,N (area under the concentration-time curve of the analyte in plasma until t hours 
after dose N)
For both methods of PK analysis, additional PK parameters may be generated if warranted by 
the data.  
Using appropriate population methodology, the relationship between BI 1265162 dose, 
systemic exposures and outcome (e.g. clinical outcomes such as FEV1, LCI, AEs and/or
safety labs) will be investigated using a population PK/PD approach. The details will be
documented in the population PK, PK/PD SAP, and the resulting data will be reported 
separately outside of the Clinical Study Report for this study. The results from a NCA 
analysis, if undertaken, along with listings of the plasma concentration-time data will be 
included in the study report.


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5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable. 
5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Both adults and adolescents will be included in this trial. However, sputum and DNA 
biobanking will be performed only in patients who can legally consent.
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements. Banked samples may be analysed 
in the future to further understand, for example, the mechanistic of drug effects and/or to 
identify genetic or other factors associated with response to therapy or the risk of adverse 
drug reactions.
5.5.1
Methods and timing of sample collection
Sampling will be performed at the time points specified in the Flow Chart.
Whole blood (DNA) banking:
Approximately 8.5mL blood will be drawn into a PAXgene Blood DNA tube.
DNA extracted from the original whole blood sample will be stored at the Sponsors’ site. All 
other sample types will be stored at an external biobanking facility contracted by the Sponsor.
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual
Spontaneous sputum
For all biospecimens collected, detailed instructions on sampling, preparation, processing, 
shipment and storage are provided in the laboratory manual. 
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
The primary and secondary endpoints related to pulmonary function tests are standard 
assessments for the efficacy evaluation of an inhaled drug in cystic fibrosis.
The secondary PK endpoints outlined in Section 2.1.3 are standards PK parameters to assess 
drug exposure. 
Assessments performed to assess the safety of the trial drug (ECG, physical examination, 
vital signs and safety laboratory tests) are also standard assessments for such kind of clinical 
trial.
Efficacy measurements based on N2MBW test have proven to be valuable assessments of the 
small airway function and the distribution of ventilation among lung regions in patients with 
cystic fibrosis.


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Therefore, all measurements performed in this trial are considered by the sponsor to be 
appropriate.


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6.
INVESTIGATIONAL PLAN
For investigational sites where patients below 18 years of age will be enrolled, trial visits 
should take place at a location within the clinical site that has a child-friendly infrastructure 
(e.g. an environment that is familiar to the patients, the setting is physically appropriate, if 
desired by the patient, parent(s)/legal guardian are allowed to stay with them during the trial 
procedures). Furthermore, site-personnel should be knowledgeable and skilled in dealing with 
the paediatric population and its age-appropriate needs.
6.1
VISIT SCHEDULE
Patients should make every attempt to complete the visits as specified in the Flow Chart (FC)
and within the applicable visit windows. Investigators should encourage patient treatment 
compliance and adherence to protocol specific activities. 
Patients who discontinue study medication prematurely will undergo the procedures for an 
early treatment discontinuation and a follow up visit as outlined in the FC.
Rescheduling visits:
A visit may be rescheduled within the acceptable visit window, due to:

lack of bronchodilator(s) washout compliance, or 

no intake of study medication on the evening preceding the visit, or

intake of study medication at home in the morning of the visit.
All deviations from the planned visit schedule will be documented. If any visit has to be re-
scheduled, subsequent visits should follow the original visit schedule (calculated from Visit 
2).
If bronchodilator(s) washout restrictions are not adhered to, the visit will be rescheduled once. 
The importance of adherence to washout requirements should be discussed and documented. 
If a dose of study medication is missed on the day prior to a clinic visit with PK, the patient 
should contact the site for instructions and to determine if the visit should be rescheduled. 
If a patient mistakenly takes trial medication in the morning of a visit where blood samples 
are drawn for PK assessment, the visit should be re-scheduled to the next day reminding the 
patient about the expected conditions. 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart.
During trial visit, the sequence in which specific assessments are performed is important. 
The sequence of procedures at each visit (where applicable) should be as follows:
1. CFQ-R questionnaire
2. CASA-Q questionnaire


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3. AE and concomitant therapy collection
4. Physical examination / vital signs/body weight
5. ECG
6. N2MBW test
7. Pulmonary Function Tests prior to dosing
8. Training on Respimat® inhaler
9. Laboratory tests including serum electrolytes
10. PK pre-dose
11. Trial medication intake
12. Serum electrolytes tests 5 min post inhalation
13. PK blood sampling 5 min post inhalation
14.
15. PK blood samplings 
Laboratory testing including serum electrolytes can be conducted also prior to N2MBW 
testing according to site´s preference. 
PK pre-dose sample should be taken within 60 minutes prior to dosing. 
With regards to the optional biobanking, blood drawing can be performed with other blood 
drawings for safety laboratory tests. Sputum collection can be performed at anytime but after 
the questionnaire administration.
Additional details regarding visit procedures are provided below. 
6.2.1
Screening period
Screening Period
No trial procedure is allowed unless the appropriate consent and assent are in place. Consent 
and assent must be obtained prior to the screening visit procedures.
Visit 1 is the beginning of the screening period. The patient should be recorded on the 
enrolment log and be registered in the IRT as a screened patient when Visit 1 is performed.
Once Visit 1 procedures are complete and laboratory results are received, inclusion/exclusion 
criteria must be reviewed. If the patient meets inclusion/exclusion criteria, he/she should be 
contacted to schedule Visit 2.
If the patient does not meet inclusion/exclusion criteria, the patient must be recorded in eCRF 
as a screen failure. Patient must be registered as a screen failure in IRT.
Baseline Conditions
Any pre-existing medical conditions considered as relevant by the investigator, excluding the 
indication of the trial, are recorded into the eCRF in the appropriate page. This concern all 
active pathology, chronic disease or recurrent event.
Medical History:
All relevant medical histories according to the investigator judgement have to be captured in 
the eCRF.


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At the end of Visit 1, patients who remain eligible for randomisation, should be reminded of 
bronchodilator(s) washouts and restrictions pertinent to Visit 2.
6.2.2
Treatment period(s)
For patients eligible to be randomised, assessments should be performed as mentioned in the 
Flow Chart and the respective protocol sections.
Randomisation Visit (Visit 2)
Eligible patients will be randomised by using the IRT system; all visit assessments should 
have been completed prior to this, and before the first intake of study medication. Patients 
will be trained on correct use of the Respimat® inhaler. First dose of trial drugs will be 
administered in the clinic (Day 1).
For patients who are on a stable regimen of inhaled cycling antibiotics, the Visit 2 should 
occur on the Day 1 of an “On-cycle” (+/- 1 or 2 days); whatever the antibiotic is. For patients 
cycling different antibiotics, the Visit 2 should occur on the Day 1 of a new antibiotic cycle.
A patient diary will be dispensed at Visit 2. Patients should be instructed to use the diary to 
record the date and time of administration of study medication for the 3 days preceding the 
clinic visits. Time of administration means the end of the second inhalation.
Next clinic visits will be scheduled after 1 and 4 weeks of treatment (Visit 3 and 4). For 
detailed description of the trial procedures at each visit and dispensing schedule, please refer 
to the Flow Chart.
In between clinic visits, serum potassium will be measured for safety monitoring. A 
laboratory kit to perform blood sampling by local laboratory/doctor/heatlh care provider will 
be provided to the patient at Visit 3 for measurement by central laboratory. The patient 
should be instructed to use the patient diary to record the date and time of the blood drawing. 
A phone contact with the patient will be required to check any adverse event and any 
concomitant medications. It is also possible to perform this serum potassium sampling at site 
if more appropriate for patient. 
To ensure consistent and correct dosing, at each visit patients will be re-trained on use of the 
Respimat® inhaler. 
6.2.3
Follow up period and trial completion
A follow-up (FUP) Visit should be planned 1 week after last trial drug administration. For 
detailed description of the trial procedures at the FUP Visit, please refer to the Flow Chart.
The FUP visit will be required for all patients, even those who discontinue treatment early. If 
laboratory tests were not completed at the end of treatment visit, they should be done at 
follow up. 


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Trial completion
The trial completion eCRF page has to be filled-in when the patient has terminated the trial.
The end of the trial is:
•
At the end of the FUP visit for patients who have completed the trial on treatment as 
planned;
•
After the early end of treatment (EOT) and follow-up Visits, if a patient prematurely 
withdrawn from treatment.
Patients who prematurely discontinued trial medication
Patients who prematurely discontinue study drug (refer to Section 3.3.4) before the planned 
end of treatment at Visit 4, should come to the clinic as soon as possible after last drug intake 
for an early EOT Visit. The reason for premature trial drug discontinuation must be 
documented in the eCRF. For detailed description of the trial procedures at this visit, please 
refer to the Flow Chart. Then a Follow-up Visit should take place 7 days after the early EOT 
Visit.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a Phase II, randomised, double-blind, placebo-controlled and parallel group trial to 
evaluate efficacy and safety of twice daily inhaled doses of BI 1265162 delivered by 
Respimat® inhaler as add-on therapy to standard of care over 4 weeks in patients with cystic 
fibrosis.
The primary objectives of this trial is to assess the efficacy, safety and pharmacokinetics of 
twice daily inhaled doses of 20 µg, 50 µg, 100µg and 200 µg of BI 1265162 delivered by 
Respimat® inhaler versus placebo in adolescents and adult patients with cystic fibrosis. 
The primary trial objective includes demonstration of proof of concept (PoC) with respect to 
a non-flat dose response curve based on percent predicted trough FEV1, characterization of 
the dose-response relationship within the therapeutic range, and selection of the optimal dose 
for phase III development. For this purpose, the primary analysis uses methodology for dose 
finding employing both multiple comparison procedures and modelling techniques 
(MCPMod).
7.2
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis is that there is a flat dose response curve comparing change from 
baseline in trough FEV1 percent predicted at 4 weeks in the placebo and the BI 1265162 dose 
groups. The alternative hypothesis is that there is a non-flat dose response curve indicating a 
benefit of BI 1265162 over placebo.
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of Type I error (one sided α of 
5%). The pre-specified models and their parameters used for this test are outlined in Section 
7.3.1.
7.3
PLANNED ANALYSES
The statistical analysis will be based on the following analysis sets.

Enrolled set (ES): This subject set includes subjects that signed informed consent and 
underwent screening procedures.

Randomized set (RS): This subject set includes all randomised subjects, whether treated 
or not.

Treated set (TS): The treated set includes all subjects who were randomized and treated 
with at least one dose of study drug. The treatment assignment will be determined based 
on the first treatment the subjects received. 


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
N2 multiple breath washout set (N2MBWS): The N2MBWS includes all subjects in the 
treated set, who provided at least one pair (baseline and end of treatment) of evaluable 
measures of the N2MBW parameter.

Pharmacokinetic set (PKS): The PK parameter analysis set (PKS) includes all subjects in 
the Treated Set (TS) who provide at least one PK parameter that was not excluded
according to the description in Section 7.3.5 of the CTP. Excluded subjects will be listed 
with their individual plasma concentrations and individual pharmacokinetic parameters, 
however, will not be included in descriptive statistics for plasma concentrations, 
pharmacokinetic parameters or other statistical assessment.
All individual data will be listed. Adherence to the protocol (such as inclusion/exclusion 
criteria, times of measurement, compliance with intake of trial medication, treatment 
dispensing errors, prohibited concomitant medication, completeness and consistency of data) 
will be checked. Important protocol deviations (IPDs) will be identified no later than in the 
Blinded Report Planning Meeting (BRPM) and pre-defined in the TSAP.
7.3.1
Primary endpoint analyses
The analyses for PoC and dose-finding will be performed using multiple comparison and 
modelling techniques (MCPMod) [R10-1424] whereby several possible dose response 
models (patterns) will be evaluated, while keeping full control of the type I error at 5%, one-
sided) to identify the best-fitting model or subset of models. 
To account for the repeated nature of the data and the covariates in the nature, a restricted 
maximum likelihood (REML) based approach using a mixed model with repeated 
measurements (MMRM) will be carried out comparing the change from baseline in trough 
FEV1 percent predicted at 4 weeks of treatment. 
The primary analysis will be performed on the Treated Set. The analysis will include the 
fixed, categorical effects of treatment at each visit, age (adolescents vs. adults) and the fixed 
continuous effects of baseline at each visit. Visit will be treated as the repeated measure with 
an unstructured covariance structure used to model the within-patient measurements.
The statistical model will be as follows: 
ijkm=	j
i+k+ m+ij
                                                                ij ~ NZ(0, ∑)
yijkm = response variable for subject i in age stratum m at visit j receiving treatment k
	j = coefficient of baseline effect at visit j

I= the baseline measurement of subject i, i=1,2,…
jk= the effect of treatment k at visit j, j=1,2 and k=1,2,…,5
k= the effect of age stratum (adolescents vs. adults), k=1, 2 
eij = the random error associated with the jth visit of the ith subject. Errors are independent between 
subjects.
∑= unstructured covariance matrix
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. 


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The MMRM analysis will be carried out in SAS and covariate-adjusted fixed effect estimates 
of average response for each dose group and the covariance matrix will be extracted from the 
fit and used for MCPMod analysis.
For PoC testing and for the sample size calculation, the basic shape of each of the models to 
be tested must be pre-defined. The following models will be considered for this analysis: 
linear, exponential, Emax, SigEmax and quadratic.
The model assumptions and resulting graphs were selected to cover both plausible and a 
diverse range of dose response patterns. These are shown in Figure 7.3.1:1. The parameters 
for each model shape are listed in Table 7.3.1:1.
Figure 7.3.1:1 Shape of the considered dose response patterns for the MCPMod Analysis


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Table 7.3.1:1 Parameter(s) in each Model depicted above
Model
Pre-specified parameters
Emax
ED50 = 25.555556 (90% of the maximum effect is achieved at 100 µg 
b.i.d.)
Sigmoidal Emax
ED50 = 50, h=3 (50% of the maximum effect is achieved at 45 µg 
b.i.d. and 90% of the maximum effect is achieved at 100 µg b.i.d.)
Linear
No assumption needed
Exponential
δ=300 (20% of the maximum effect is achieved at 60 µg b.i.d.
Quadratic
δ= -.003333 (50% of the maximum effect is achieved at 40 µg b.i.d. 
and 90% of the maximum effect is achieved at 100 µg b.i.d.)
PoC is established if at least one model is statistically significant, rejecting the null 
hypothesis of a flat dose response relationship over trough FEV1 percent predicted at 4 weeks 
for each of the candidate dose response models with a contrast test controlled for the family–
wise type I error rate at one sided α = 5%.
If PoC is established, the statistically significant (best fitting) model(s) from the above 
candidate set are refitted to the data to generate new estimates for all model parameters from 
the data. The average model will be determined and will be used to refit the data and generate 
the new estimates.
The target dose(s) can be estimated from the average model by incorporating information on 
the minimum clinically relevant effect and accounting for safety.
Pairwise comparisons of BI 1265162 doses to placebo (90% confidence intervals (CI) and p-
values) based on the mixed effects model will be reported. These are further, descriptive 
analyses of the primary endpoint to supplement the MCPMod analysis, which is the primary 
analysis.
To assess the homogeneity of the treatment effect on the primary endpoint across the levels 
of age (< 18 years old and ≥ 18 years old), the same MMRM model will be fitted but 
replacing the treatment-by-visit term by a treatment-by-age-by-visit term. A descriptive p-
value of treatment effect homogeneity at Week 4 will be calculated. No overall treatment 
effect will be estimated from this model as it is not interpretable.
7.3.2
Secondary endpoint analyses
The linear mixed effects model described above will be used to analyse the secondary 
endpoints including LCI, CFQ-R and CASA-Q scores. 90% confidence intervals and p-
values will be provided for the comparison of each dose of BI 1265162 to placebo. Since type 


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I error will not be protected for these comparisons the resulting confidence intervals and p -
values will be considered as nominal or descriptive statistics.
7.3.4
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.
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. 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.
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.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Using a sparse population PK approach that jointly analyses the combined data from this 
study along with that from the previous studies in healthy volunteers, the following 
pharmacokinetic parameters will be determined if feasible for each subject.


Ct,N (concentration of the analyte in plasma at time t following dose N)

Cpre,N (predose concentration measured for dose N) 

AUC0-t,N (area under the concentration-time curve of the analyte in plasma until t hours 
after dose N)


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Depending on the resulting data, additional pharmacokinetic parameters might be calculated 
as appropriate. Parameters such as age, weight, BMI may be used as covariates to investigate 
the pharmacokinetics fully in the current adult and patient population.
The results from the population analysis will be reported separately outside of the current 
Clinical Trial Report (CTR).
A non-compartmental (NCA) PK analysis may be undertaken on Day 8 if the data allows. 
The following parameters may be calculated;

Ct,N (concentration of the analyte in plasma at time t following dose N)

Cpre,N (predose concentration measured for dose N) 

AUC0-t,N (area under the concentration-time curve of the analyte in plasma until t hours 
after dose N)
The results from a NCA analysis, if undertaken, along with listings of the plasma 
concentration-time data will be included in the study report.
7.4
INTERIM ANALYSES
An interim futility analysis will be conducted on the primary efficacy endpoint once 28 
patients in the placebo and BI 1265162 200µg bid arms have completed the 4-week treatment 
period. Additional details of the interim analysis will be specified in the TSAP.
7.5
HANDLING OF MISSING DATA
No imputation will be applied while the MMRM will use all available data. The mixed effect 
model will handle missing data based on a likelihood method under the "missing at random” 
assumption.
7.6
RANDOMISATION
Patient randomisation will start with only adult patients to either 200 µg bid of BI 1265162 or 
placebo in a 1:1 ratio. As soon as 28 patients are allocated to these two treatment arms, the 
remaining patients will be allocated to the other doses of BI 1265162 as well as the highest 
dose and placebo in a 1:1:1:1:1 ratio (14 patients per treatment arm).
As a result, patients will be distributed to one of the five treatment groups in a 2:1:1:1:2 ratio. 
Randomisation will be stratified by age (< 18 years old and ≥ 18 years old).
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.


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7.7
DETERMINATION OF SAMPLE SIZE
The sample size calculation is based on the following assumptions:

the primary endpoint “change from baseline in trough FEV1 % predicted at Week 4” 
is normally distributed

one-sided significance level α = 5% (for MCP-Mod analysis)

mean treatment difference (the highest dose of BI 1265162 vs placebo) is 6%  (for 
interim analysis only)

true maximum treatment effect size of BI 1265162 versus placebo is 6% (for MCP-
Mod analysis)

standard deviation is 8% [R16-1992]

pre-specified candidate models listed in Section 7.3.1 (for MCP-Mod analysis).
Table 7.7.1 shows the probability of Continue the trial after interim analysis in case of no 
treatment effect and overall type I error rate (probability of Continue after interim analysis
and Succeed at final analysis in case of no treatment effect) for different cut-offs. Probability 
of Continue is 32.3% at cut-off 1.5% in case of no treatment effect, and overall Type I error
rate is controlled under 5% for all cut-offs. 
Table 7.7.2 shows probability of Continue the trial after interim analysis in case of true 
treatment effect and overall power (probability of Continue and Succeed in case of true 
treatment effect) for different cut-offs and assumed true models. Probability of Continue is > 
91% and overall power is ≥80% for cut-off ≤ 1.5% for all true candidate monotone shapes.
With a cut-off value ranging from 1% to 2% to continue the trial after the interim analysis, a 
sample size of 12 evaluable patients in each of the placebo arm and the highest dose arm at 
interim analysis, and additional 12 evaluable patients in each of five arms for final analysis 
will guarantee overall power >79.8% for all true candidate monotone shapes; and overall type 
I error is also controlled below 5%.


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Table 7.7:1 Overall Type I error based on 12 evaluable patients per treatment arm (Placebo 
and the highest dose of BI 1265162)
Cut-off
Probability of 
continue
Probability of 
continue and succeed
at final analysis
0
50.0%
4.8%
1%
38.0%
4.5%
1.5%
32.3%
4.3%
2%
27.0%
4.1%
3%
17.9%
3.5%
Table 7.7:2 Probability of Continue in case of true treatment effect and overall power based 
on 12 evaluable patients per treatment arm (5 treatment arms)
Cut-off
Probability of continue
Linear
Exponential
Emax
SigEmax
Quadratic
0
96.7%
96.7%
96.7%
96.7%
93.6%
1%
93.7%
93.7%
93.7%
93.7%
88.7%
1.5%
91.6%
91.6%
91.6%
91.6%
85.5%
2%
89.0%
89.0%
89.0%
89.0%
81.8%
3%
82.1%
82.1%
82.1%
82.1%
72.6%
Cut-off
Probability of continue and succeed
Linear
Exponential
Emax
SigEmax
Quadratic
0
84.0%
84.0%
84.7%
88.0%
76.22%
1%
82.5%
82.6%
83.2%
86.3%
74.1%
1.5%
81.3%
81.5%
82.0%
84.9%
72.4%
2%
79.8%
79.9%
80.4%
83.0%
70.22%
3%
75.2%
75.3%
75.7%
77.8%
64.3%
In order to ensure 12 evaluable patients per arm with primary endpoint data for interim 
analysis, at least 14 patients per arm will be randomised (total 28).


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In order to ensure additional 12 patients per group are evaluable for final analysis, at least 14
patients will be randomised per treatment group (total 70). Overall, 98 patients will be 
randomised in the trial.
This calculation has been performed using R software, version 3.2.2.


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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 / the EU regulation 536/2014 and other relevant regulations. Investigators and 
site staff must adhere to these principles. Deviation from the protocol, the principles of ICH 
GCP or applicable regulations 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 finalization 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/parent(s)/legal guardian-information form retained by the investigator as part of the 
trial records. A signed copy of the informed consent and any additional patient/parent(s)/legal 
guardian information must be given to each patient or the patient’s legally accepted 
representative.
For adolescents, the patient will be provided with an age-adapted information sheet where 
his/her assent will be collected according to the regulatory and legal requirements of the 
participating country. The refusal of an adolescent to participate must be accepted
independently of the consent of his/her parent(s)/legal guardian.


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For patients who may legally consent during the trial participation (turning to the age of legal 
consent in the participating country), written informed consent must be obtained to confirm 
the patient’s willingness to pursue trial participation.
The patient (or patient’s parent(s)/legal guardian) must be given sufficient time to consider 
participation in the trial. The investigator or delegate obtains written consent of the patient’s 
(or patient’s parent(s)/legal guardian) own free will with the informed consent form after 
confirming that the patient (or patient’s parent(s)/legal guardian) understands the contents. 
The investigator or 
 delegate must sign (or place a seal on) and date the informed consent 
form. If a trial collaborator has given a supplementary explanation, the trial collaborator also 
signs (or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
must be conducted according to the sponsor’s instructions.
The consent and re-consenting process must be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual 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 must be traceable (audit trail).


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Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
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 CRF, data must be derived from source documents, for example:

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 CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(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.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the 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”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last patient 
in the whole trial is administered the last dose of trial treatment (as scheduled per protocol or 
prematurely). Individual investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPLT at their site.


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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.
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 DMC will be established. Members of the DMC are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician. 
The DMC will periodically evaluate safety data.
While DMC members may be unblinded, measures are in place to ensure the blinding for 
everyone else involved in the trial. Regular DMC meetings will be held at specified intervals. 
The DMC will recommend continuation, modification or termination of the trial as detailed in 
the DMC charter. The DMC recommendations as well as the final BI decision will be 
reported to the appropriate Regulatory Authorities (RAs)/Health Authorities (HAs), 
IRBs/ECs, and to investigators as required by local law. The tasks and responsibilities of the 
DMC are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Trial Clinical Monitor (TCM), 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,


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-
ensure appropriate training and information of Local Clinical Monitors (CML), 
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 PFT central reading services, a N2MBW test central reading 
services and an IRT vendor will be used in this trial. Details will be provided in the dedicated 
Manuals, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P05-08465
Hodder R, Pavia D, Dewberry H, Alexander K, Iacono P, Ponitz H, Beck E. 
Low incidence of paradoxical bronchoconstriction in asthma and COPD
patients during chronic use of Respimat Soft Mist inhaler. Respir Med 99, 
1087 - 1095 (2005)
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson 
DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi 
G, Wanger J. Standardisation of spirometry. Eur Respir J 26 (2), 319 - 338 
(2005)
R05-1456
Konstan MW, Butler SM, Schidlow DV, Morgan WJ, Julius JR, Johnson 
CA, Investigators and Coordinators of the Epidemiologic Study of Cystic 
Fibrosis. Patterns of medical practice in cystic fibrosis: part II. Use of 
therapies. Pediatr Pulmonol 28, 248 - 254 (1999)
R10-1424
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding 
studies combining multiple comparisons and modeling procedures. J 
Biopharm Stat 16 (5), 639 - 656 (2006)
R12-2800
European Medicines Agency (EMEA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on the clinical development of 
medicinal products for the treatment of cystic fibrosis (London, 22 October 
2009, doc. ref. EMEA/CHMP/EWP/9147/2008-corr).
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidel
ine/2009/1 2/WC500017055.pdf (access date: 22 June 2012) ; London: 
European Medicines Agency (EMEA) (2009)
R15-0845
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright 
PL, Hankinson JL, Ip MSM, Zheng J, Janet Stocks on behalf of the ERS 
Global Lung Function Initiative. Multi-ethnic reference values for 
spirometry for the 3 - 95 year age range: the global lung function 2012 
equations: report of the Global Lung Function Initiative (GLI), ERS task 
force to establish improved lung function reference values. Eur Respir J 40 
(6), 1324 - 1343 (2012)
R15-1327
Robinson PD, et al. Consensus statement for inert gas washout 
measurement using multiple- and single-breath tests. Eur Respir J 41 (3), 
507 - 522 (2013)


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R15-4955
Clunes MT, Boucher RC, Virtual Lung Group. Cystic fibrosis: the 
mechanisms of pathogenesis of an inherited lung disorder. Drug Discov 
Today Dis Mech 4 (2), 63 - 72 (2007)
R15-5856
Riordan JR et al. Identification of the cystic fibrosis gene: cloning and 
characterization of complementary DNA. Science 245 (4922), 1066 - 1073 
(1989)
R16-1992
Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli 
M, Colombo C, Davies JC, Boeck K de, Flume PA, Konstan MW, 
McColley SA, McCoy K, McKone EF, Munck A, ratjen F, Rowe SM, 
Waltz D, Boyle MP, TRAFFIC Study Group, TRANSPORT Study Group
Lumacaftor-ivacaftor in patients with cysticfibrosis homozygous for 
Phe508del CFTR. N Engl J Med 373 (3), 220 - 231 (2015)
9.2
UNPUBLISHED REFERENCES
Not applicable.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
18 NOVEMBER 2019
EudraCT number
EU number
2019-0001261-21
BI Trial number
1399-0003
BI Investigational Medicinal 
Product(s)
BI 1265162
Title of protocol
A randomised, double-blind, placebo-controlled 
and parallel group trial to evaluate efficacy and 
safety of twice daily inhaled doses of BI 1265162 
delivered by Respimat® inhaler as add-on therapy 
to standard of care over 4 weeks in patients with 
cystic fibrosis
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Title page
Synopsis
Description of change
Administrative change
Rationale for change
To add trial name ‘BALANCE-CFTM1’
Section to be changed
Title page
Description of change
Trial Clinical Monitor
Rationale for change
Personal change
Section to be changed
Synopsis
Section 2.1.3 Secondary endpoints
Description of change
Change (Cmax replaced by Ct ) and clarification in 
PK parameters to be measured as secondary 
endpoint 
Rationale for change
Updated PK parameter list is more in line with the 
sparse sampling that is planned at various visits 
Section to be changed
Synopsis
Description of change
Inclusion criteria 3 corrected to : FEV1 ≥ 40% and 
≤ 90% of predicted values at screening and 
predose at Visit 2.
Rationale for change
To align with inclusion criterion in section 3.3.2
Section to be changed
Synopsis
Section 3.3.2 Inclusion Criteria and 3.3.3 Exclusion 
criteria
Description of change
Adaptation of inclusion criterion 5 and exclusion 
criteria 15 to allow recruitment of WOCBP using 


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adequate contraception
Rationale for change
Inclusion of WOCBP using adequate contraception
allowed in all countries following availability of 
EFD study data in new IB
Section to be changed
Synopsis
Section 3.3.3 Exclusion criteria
Description of change
Addition of new exclusion criteria 15: Women who 
are pregnant, nursing, or who plan to become 
pregnant while in the trial.
Section to be changed
Section 3.3.3 Exclusion criteria
Section to be changed
Flowchart
Description of change
Removal of trial drug collection at V3
Rationale for change
To align with section 4.1.4.1.
Section to be changed
Flowchart & Footnote 5
Section 5.2.3 Safety laboratory parameters
Description of change
Addition of pregnancy tests 
Rationale for change
Addition of Pregnancy Testing for female patients 
who have reached menarche, even irregular,
required due to allowed recruitment of Women of 
Childbearing Potential
Section to be changed
Synopsis
Section 3.3.3 Exclusion criteria
Description of change
Removal of exclusion criteria 15 to allow 
recruitment of WOCBP
Rationale for change
Inclusion of WOCBP allowed in all countries 
following availability of EFD study data in new IB
Section to be changed
Flowchart for PK blood sampling
Flowchart for Pulmonary Function Test
Description of change
Timing of flowchart for PK updated with unit of 
timepoints
Flowchart for N2MBW test added
Rationale for change
Clarification on procedures to be performed in the 
study
Section to be changed
Flowchart –footnote (**)
Flowchart –footnote 2
Flowchart for PK blood sampling
Flowchart for Pulmonary Function Test
Description of change
Details of procedures to be performed in case of 
early treatment discontinuation were added. Study 
procedures will be the same as for V4/EOT except 
for PK blood sampling, serum electrolytes and 
PFTs. Those assessments will be performed once at 
anytime during the EOT visit. Follow up (FUP)
visit should take place one week after the early End 
of Treatment Visit
Rationale for change
Clarification on procedures to be performed in case 


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of early treatment discontinuation
Section to be changed
Flowchart –footnote (****)
Section 5.5 BIOBANKING
Description of change
Restriction of sputum and DNA biobanking to 
patients who can legally consent only.
Rationale for change
Clarification
Section to be changed
Flowchart & footnote 2
Section 5.2.3 Safety laboratory parameters
Description of change
Addition of monitoring of 3 new electrolytes 
Rationale for change
To implement  more standard electrolyte analysis
Section to be changed
Flowchart - footnote 2
Description of change
Addition of time window for serum electrolyte test 
Rationale for change
To allow flexibility
Section to be changed
Flowchart footnote 6
Section 6.2.2 Treatment period(s)
Description of change
Possibility to perform ambulatory visit at site if 
more appropriate for patient
Rationale for change
To add flexibility
Section to be changed
Section 1.3 RATIONALE FOR PERFORMING 
THE TRIAL
Section to be changed
Section 1.4 BENEFIT - RISK ASSESSMENT
Description of change
Addition of data related to embryo-fetal 
development toxicity studies and update on 
contraception requirement for this trial
Rationale for change
Change due to update of recent IB
Section to be changed
Section 3.1 OVERALL TRIAL DESIGN AND 
PLAN
Description of change
Specification that age to be used for stratification 
of randomisation is age at day of randomisation 
Rationale for change
Clarification
Section to be changed
Section 3.3.2 Inclusion criteria 5
Description of change
update to include contraception of WOCBP and to 
remove contraception of male participant 
Rationale for change
To update contraception requirements according to 
IB update
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
Addition of new exclusion criteria 15: Women who 
are pregnant, nursing, or who plan to become 
pregnant while in the trial.
Rationale for change
To follow update of recent IB
Section to be changed
Section 3.3.4.1 discontinuation of trial treatment 
Description of change
Addition of pregnancy as case of trial 
discontinuation


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Rationale for change
Inclusion of WOCBP allowed in all countries
Section to be changed
Section 3.3.4.1 discontinuation of trial treatment 
Description of change
Addition of requirements for confirmation of elevated 
value of potassium:Each result of elevated serum 
potassium level > ULN should be confirmed, 
meaning either by a second measurement either by 
presence of clinical symptoms.
Rationale for change
Clarification
Section to be changed
Section 4.1.4.2 Training and priming of the 
respimat® inhaler 
Description of change
Addition of restriction for priming of the 
Respimat® inhaler 
Rationale for change
To avoid any contamination of PK samples
Section to be changed
Section 4.1.4.3. study medication administration
Description of change
Clarification on timing of study medication intake 
in relation to other CF treatments 
Addition of recommendation in case of missed 
dose: If a dose is missed for more than 4 hours, the 
next one should be taken as planned.
Rationale for change
Clarification
Section to be changed
Section 4.1.4.3. study medication administration
Section 6.1 Visit schedule
Description of change
No need to reschedule visit if only morning dose is 
missed on the day preceding the visit 
Rationale for change
Clarification
Section to be changed
Section 4.2.2.2 Restrictions regarding concomitant 
treatment
Description of change
Patients who are using hypertonic saline solution 
just after using bronchodilator on regular basis 
should also follow the same washout period than 
period required for the bronchondilator. In case of 
the washout of hypertonic saline solution cannot be 
followed by the patient according to investigator’s 
judgement, then the patient should inhale in the 
hypertonic saline solution in the same manner at 
each visit during the study
Rationale for change
To take in consideration hypertonic saline solution 
as possible CF concomitant treatment
Section to be changed
Section 5.1.1 Pulmonary Function Testing (FEV1 
Description of change
Removal of calibration of spirosphere
Rationale for change
Daily Calibration prior to use not needed with this 
type of material
Section to be changed
Section 5.2.3 Safety laboratory parameter
Description of change
Specification of total blood volume collected 
Rationale for change
Clarification


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Section to be changed
Section 5.2.6.1.4 Adverse events of special interest
Description of change
Elevation of serum potassium > upper limit of 
normal (ULN) in non-haemolysed blood should be 
confirmed to be considered as AESI
Rationale for change
Clarification
Section to be changed
Section 5.3.1 Assessment of pharmacokinetics
Description of change
Maximum storage time for PK samples for 
additional evaluations added
Rationale for change
Clarification
Section to be changed
Section 5.3.2.1 Plasma sampling for 
pharmacokinetic analysis
Description of change
Maximum blood volume for PK samples corrected
Rationale for change
Correction
Section to be changed
Section 5.3.4 pharmacocinetic –
pharmacodynamics relationship
Section 7.3.5. pharmacokinetic and 
pharmacodynamics analyses
Description of change
More detail added regarding data analysis using 
population PK and noncompartmental PK analysis
Rationale for change
Clarification
Section to be changed
Section 6.2 details of trial procedures at selected 
visits
Description of change
Section updated with only mandatory requirements 
on sequence of procedures 
Rationale for change
To allow flexibility
Section to be changed
Section 6.2.2 treatment period(s)
Description of change
Ambulatory visit can be performed at site if more 
appropriate for the patient 
Rationale for change
Clarification
Section to be changed
Section 7.3
Description of change
Add data analysis set
Rationale for change
Clarification
Section to be changed
Section 7.3.1
Description of change
Modify the layout of statistical model and point out 
the analysis set for primary endpoint
Rationale for change
Update the typo in the statistical model and add the 
analysis set used for primary analysis
Section to be changed
Section 5.5.6.2.2
Description of change
SAE reporting update
Rationale for change
SAEs may be submitted to BI by means other than 
Fax
11.2
GLOBAL AMENDMENT 2
Date of amendment


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EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
Global Amendment due to urgent safety reasons
Global Amendment
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23936559
2.0
clinical-trial-protocol-version-02
A randomised, double-blind, placebo-controlled and parallel group trial to evaluate
efficacy and safety of twice daily inhaled doses of BI 1265162 delivered by Respimat
inhaler as add-on therapy to standard of care over 4 weeks in patients with cystic
fibrosis
Author-Clinical Trial Leader
18 Nov 2019 15:29 CET
Approval-Team Member Medicine
18 Nov 2019 17:42 CET
Approval-Biostatistics
19 Nov 2019 15:35 CET
Author-Trial Clinical
Pharmacokineticist
19 Nov 2019 17:25 CET
Approval-Therapeutic Area 
20 Nov 2019 08:45 CET
Verification-Paper Signature
Completion
20 Nov 2019 10:30 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23936559
2.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c32169102-01
BI Trial No.:
1399-0003 
Title:
A randomised, double-blind, placebo-controlled and parallel group 
trial to evaluate efficacy and safety of twice daily inhaled doses of 
BI 1265162 delivered by Respimat inhaler as add-on therapy to 
standard of care over 4 weeks in patients with cystic fibrosis –
BALANCE – CF 1
Including Protocol Amendment 1 [c23936559-02]
Investigational
Product(s):
BI 1265162 
Responsible trial 
statistician(s):
Tel.: 
Fax: 
Date of statistical 
analysis plan:
  18 May 2020 SIGNED 
Version:
1.0
Page 1 of 27
Proprietary confidential information
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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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(S) ....................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENT(S)................................................................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.4
PRIMARY ENDPOINT(S) ................................................................................19
7.4.1
Primary analysis of the primary endpoint(s) ...................................................19
7.5
SECONDARY ENDPOINT(S) ..........................................................................20
7.5.1
Key secondary endpoint(s).................................................................................20
7.5.2
Secondary endpoint(s) ........................................................................................20
7.5.2.1
Analysis of LCI.....................................................................................................20
7.5.2.2
Safety endpoints....................................................................................................20
7.5.2.3
Pharmacokinetic endpoints ...................................................................................20
7.5.2.4
Analysis of Questionnaires (CASA-Q© and CFQ-R) ...........................................21


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7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse Events ....................................................................................................22
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24
7.8.5.1
Physical examination ............................................................................................24
8.
REFERENCES....................................................................................................25
10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.2: 1
Handling of iPDs..............................................................................................13
Table 6.3: 1
Analysis Sets ....................................................................................................15
Table 10: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
BI
Boehringer Ingelheim
BMI
Body mass index
CASA-Q
Cough and sputum assessment questionnaire
BRPM
Blinded report planning meeting
CF
Cystic fibrosis
CFQ-R
Cystic Fibrosis Questionnaire-Revised
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
EudraCT
European union drug regulating authorities clinical trials
FEV1
Forced expiratory volume in 1 second
FEV1 % 
predicted
FEV1 percent predicted
gCV
Geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IPD
Important protocol deviation
LCI
Lung clearance index
MBW
Multiple breath washout


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Term
Definition / description
MedDRA
Medical Dictionary for Regulatory Activities
NOP
No peak detectable
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
PK analysis set
RS
Randomised set
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
TEAE
Treatment emergent adverse event
TS
Treated set
TSAP
Trial statistical analysis plan


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3.
INTRODUCTION
As per ICH E9 (10), 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 excluding interim analysis. Another TSAP document for the interim 
analysis is provided separately.
This 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.
SAS® Version 9.4 will be used for all analyses. PK parameters will be calculated using 
Phoenix WinNonlinTM software (version Phoenix 6.3 or higher, Certara USA Inc., Princeton, 
NK, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The testing on the hypothesis of flat dose response curve that described in CTP will not be 
performed
 
 In addition, model-based analysis of primary endpoint (trough FEV1 % 
predicted) and secondary endpoint (LCI),
 
 
For secondary endpoint (LCI), 
an analysis of covariance (ANCOVA) will be used to compare the change from baseline of 
LCI after 4 weeks of treatment. Other endpoints including patient reported outcomes (CASA-
Q and CFQ-R) will be summarized descriptively for all dose levels.
 age effect (adult versus adolescent) will 
be removed from the statistical model.
 


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint to assess efficacy of BI 1265162 200 µg bid over placebo is the 
absolute change from baseline in percent predicted trough Forced Expiratory Volume in 1 
Second (FEV1) after 4 weeks of treatment. 
Trough FEV1 is defined as measurement performed within 30 minutes prior to dosing.
Analysis is conducted using a restricted maximum likelihood (REML) based approach using 
a mixed model with repeated measurements (MMRM). Please refer to Section 7.4.1 for 
details on the MMRM model.
Tables and/or spaghetti plots will display individual trough FEV1 % predicted values over 
time and the change from baseline values overtime. In addition, a waterfall plot for change 
from baseline at Week 4 will be presented.
Baseline trough FEV1 % predicted is defined as the last measurement taken on day 1 before 
first study drug administration.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)
The secondary endpoints of this trial are:

Change from baseline in Lung Clearance Index (LCI) assessed by N2 Multiple Breath 
Washout (N2MBW) procedure after 4 weeks of treatment

Change from baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) total score 
after 4 weeks of treatment

Change from baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) (4 
separate sub-scores) after 4 weeks of treatment

Percentage of patients with treatment-emergent Adverse Events (AE) up to Day 36

Ct,N (concentration of the analyte in plasma at time t following dose N) 

Cpre,N (predose concentration measured for dose N) 


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
AUC0-t,N (area under the concentration-time curve of the analyte in plasma until t 
hours after dose N) 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatments to be administered please refer to Section 4 of the 
CTP.
Patient randomisation will start with only adult patients to either 200 µg bid of BI 1265162 or 
placebo in a 1:1 ratio. Enrolment of adolescent patients will be based on periodic reviews of 
adult patient safety data. The analysis plan for periodic safety reviews of adult patients will 
be described separately.
As soon as 28 patients are allocated to these two treatment arms, the remaining patients will 
be allocated to the other doses of BI 1265162 as well as the highest dose and placebo in a 
1:1:1:1:1 ratio (14 patients per treatment arm). As a result, it was planned to have patients 
distributed in a 2:1:1:1:2 ratio (2 for either placebo or 200 µg bid of BI 1265162 and 1 for 
other doses of BI 1265162 ) with around 20% of adolescents per group.
Patients will be analysed according to Table 6.3: 1. All planned analysis will be presented by 
this treatment group, unless specified otherwise. Handling of patients where treatment
assignment has not been followed will be handled on a case-by-case basis, to be agreed at 
report planning meetings or DBL meeting (but prior to database lock).


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6.3
SUBJECT SETS ANALYSED
The statistical analysis will be based on the following analysis sets.

Enrolled set (ES): This subject set includes subjects that signed informed consent and
underwent screening procedures.

Randomized set (RS): This subject set includes all randomised subjects, whether
treated or not.


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
Treated set (TS): The treated set includes all subjects who were randomized and
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the subjects received. 

N2 multiple breath washout set (N2MBWS): The N2MBWS includes all subjects in 
the treated set, who provided at least one pair (baseline and end of treatment) of 
evaluable measures of the N2MBW parameter.

Pharmacokinetic set (PKS): The PK parameter analysis set (PKS) includes all 
subjects in the Treated Set (TS) who provide at least one PK parameter that was not 
excluded according to the description in Section 7.3.5 of the CTP. Excluded subjects 
will be listed with their individual plasma concentrations and individual 
pharmacokinetic parameters, however, will not be included in descriptive statistics 
for plasma concentrations, pharmacokinetic parameters or other statistical 
assessment.
Table 6.3: 1
Analysis Sets
Analysis Set
Class of endpoint
ES
RS
TS
PKS
N2MBWS
Disposition
X
Exposure
X
iPDs
X
Demographic/baseline endpoints
X
Safety endpoints 
X
Secondary PK endpoints
X
Efficacy endpoints based on 
N2MBW measurements (LCI, 
 
X
Efficacy endpoints from pulmonary 
function tests
X
CASA-Q, CFQ-R
X


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Generally, it is not planned to impute missing values for safety or efficacy evaluations with 
the exception of missing or incomplete AE dates and missing data of PK data. These will be 
handled according to BI standards (see SOP 001-MCG-156_RD-01 for missing AE dates (3) 
and SOP 001-MCS-36-472 for missing PK data (4)).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For endpoints regarding pulmonary function testing (e.g. FEV1) in-clinic, baseline is defined 
as the last measurement taken on day 1 before first study drug administration.
For all other endpoints, baseline is defined as the last measurement before first study drug 
administration. I.e., in case the pre-dose measurement on Day 1 is missing, the measurement 
between Day -17 and Day -11 will be used as baseline (note. Not possible for pulmonary 
function testing due to different bronchodilator washout requirements).
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the MQRM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (7).
The individual values of all subjects will be listed, sorted by treatment group, subject number 
and visit (if visit is applicable in the respective listing). AE listings will be sorted by assigned 
treatment (see Section 7.8.1 below for details). The listings will be contained in Appendix 
16.2 subject data listings (SDL) of the CTR.
Inferential statistical analyses of PK NCA endpoints will be presented in Section 15.5 of the 
CTR and in Appendix 16.1.9.3.
Descriptive data analysis of PK NCA endpoints will be presented in Section 15.6 of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For scores derived from questionnaire data, the following descriptive statistics will be 
calculated:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
For plasma concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 


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missing will be displayed only if there are actually missing values. Percentages will be based 
on all subjects in the respective analysis set whether they have non-missing values or not.


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7.4
PRIMARY ENDPOINT(S)
The primary endpoint to assess efficacy of BI 1265162 is the change from baseline in percent 
predicted trough Forced Expiratory Volume in 1 Second (FEV1) after 4 weeks of treatment.
Trough FEV1 is defined as measurement performed within 30 minutes prior to dosing.
7.4.1
Primary analysis of the primary endpoint(s)
To account for the repeated nature of the data and the covariates in the nature, a restricted 
maximum likelihood (REML) based approach using a mixed model with repeated 
measurements (MMRM) will be carried out comparing the change from baseline in percent 
predicted trough FEV1 percent predicted at 4 weeks of treatment. 
The analysis will include the fixed, categorical effects of treatment at each visit and the fixed 
continuous effects of baseline at each visit. Visit will be treated as the repeated measure with 
an unstructured covariance structure used to model the within-patient measurements. The 
model will only include data from highest dose level and placebo because of limited sample 
size from other dose levels.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. 
The MMRM analysis will be carried out in SAS and covariate-adjusted fixed effect estimates 
of average response for each dose group and the covariance matrix will be extracted from the 
fit. 
The following SAS® code for MMRM will be used:
PROC MIXED DATA=alldata cl method=reml ocovtest;
CLASS usubjid trtpso avisitn;
MODEL ept = trtpso*avistin base*avisitn /ddfm=kr solution;
REPEATED avisitn /subject=usubjid type UN r rcorr;
LSMEANS trtpso*avistin / pdiff=all om cl alpha=0.05;
RUN;
If the model failed to converge, the following covariance structures will be tested in order:
UN AR(1).
For subgroup analysis, same MMRM model will be carried out within each subgroup.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
Not applicable.
7.5.2
Secondary endpoint(s)
7.5.2.1
Analysis of LCI
An analysis of covariance (ANCOVA) will be used to compare the change from baseline of 
LCI after 4 weeks of treatment with adjustment for categorical effects of treatment and the 
fixed continuous effect of baseline. The model will include data from highest dose level and 
placebo. Descriptive analysis will be performed for other dose levels.
Tables and/or spaghetti plots will display individual LCI values over time. In addition, a 
waterfall plot for change from baseline at Week 4 will be presented.
7.5.2.2
Safety endpoints
For analysis for AE, refer Section 7.8.1.
7.5.2.3
Pharmacokinetic endpoints
The PK analysis of secondary endpoints will be based on the PKS. For each of dose 
proportionality of secondary endpoints (Cmax,N, Cpre,N and AUC0-t,N), displaying geometric 
means of pairwise ratios together with 95% confidence intervals will be provided by dose 
group. Additional PK, PKPD modelling will be defined in a separate analysis plan.


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7.5.2.4
Analysis of Questionnaires (CASA-Q© and CFQ-R) 
CASA-Q
The derivation of the CASA-Q domain scores will be performed according to the CASA-Q©
user manual (11). All reported answers will be listed together with the derived domain scores. 
Descriptive analysis will be done by treatment and domain score for baseline, Day 8, Day 29 
and change from baseline.
CFQ-R
As no adolescent randomized, CFQ-R Teen/Adult version will be used. 
The derivation of the CFQ-R scores will be performed according to the CFQ-R scoring 
instructions (12). The CFQ-R total score is the sum of each domain score. All reported 
answers will be listed together with the derived scores. 
Descriptive analysis will be done by treatment and score for baseline, Day 29 and change 
from baseline and will be presented separately for total score and each domain score.
To explore the relationship between primary endpoint and CFQ-R respiratory domain score, a 
scatter plot of baseline CFQ-R respiratory domain score against change from baseline in 
FEV1 % predicted after 4 weeks of treatment.


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7.7
EXTENT OF EXPOSURE
Extent of exposure to trial medication within the study will be displayed by treatment for the 
TS. Treatment exposure will be calculated as drug stop date - drug start date + 1 day. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs occurring between first drug intake till 7 days after last drug intake will be 
assigned to the randomised treatment. All AEs occurring before first drug intake will be 
assigned to ‘screening’ and all AEs occurring after last drug intake + 7 days will be assigned 
to ‘follow-up’ (for listings only).
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 and for the class of 
adverse events of special interest (AESI). For the definition of AESI please refer to Section 
5.2.6.1.4 of the CTP.
The frequency of subjects with AEs will be summarised by treatment (dose), primary system 
organ class and preferred term. AEs which were considered by the investigator to be drug 
related will be summarised separately. Separate tables will also be provided for subjects with 
serious AEs (SAEs), subjects with AESIs and subjects with other significant AEs (according 
to ICH E3). AEs will also be summarized by maximum intensity.
The system organ classes will be sorted according to the standard sort order specified by the 
European Medicines Agency (EMA), preferred terms will be sorted by total frequency 
(within system organ class).
A further table will present AEs by preferred term, dose group and intensity, sorted by 
descending relative frequency in any dose group.


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Adverse events ongoing at Visits 2 (baseline), 3 (week 1) and 4 (week 4) will be provided to
help explaining outliers regarding efficacy. 
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary system organ class and preferred term. The frequency of subjects with 
SAEs will also be summarised.
For disclosure of AE data in the European union drug regulating authorities clinical trials
(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 
summarised.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (6). If multiple reference ranges apply for one parameter (e.g. due to different age 
groups), analyses will be based on normalised values, which means transforming to a 
standard unit and a standard reference range. If references ranges are not available, analyses 
will be based on original values.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done over comparing laboratory data to their reference ranges. Values outside the 
reference range will be highlighted in the listings. 
Dose groups will be compared with descriptive statistics of laboratory values over time and 
by analysing differences from baseline. Additionally, frequency tables of changes between 
baseline and last values on treatment with respect to the reference ranges will be presented.
Furthermore graphical representations over time will be generated for serum electrolytes.
Clinically relevant findings in laboratory data will be reported as AEs and will be analysed as 
part of AE analysis.
Spaghetti plots will display individual potassium over time.
7.8.3
Vital signs
The analyses of vital signs will be descriptive in nature. Descriptive statistics of vital signs 
over time and for the changes from baseline will be provided.
Clinically relevant findings in vital signs data will be reported as AEs and will be analysed as 
part of AE analysis.


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7.8.4
ECG
Abnormal findings will be reported either as baseline condition (if identified at the screening 
visit) or otherwise as AEs if judged clinically relevant by the investigator. 
7.8.5
Others
7.8.5.1
Physical examination
Descriptive statistics of body weight and its changes from baseline will be provided.
Other physical examination findings will be reported as relevant medical history/baseline 
condition (i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", 
current version, KMED
2
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED
3
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", current 
version; KMED
4
001-MCS-36-472_1: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; KMED
5
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; IDEA for CON.
6
BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", current 
version, KMED
7
BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project Summaries", 
current version; KMED
8
BI position paper: “Statistical Methods for PK”, current version
9
TDMAP: “8-07-other-analyses-logistics-plan”
10
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical 
Trials, current version
11
CASA-Q User Manual. Boehringer Ingelheim (v4.0 2015), [R18-2689]
12
CFQ-R – General Scoring Instructions, [R18-2688]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1.0
18-MAY-20
None
This is the final TSAP