Clinical trial NCT03576144
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2018-07-11; Completion date: 2018-12-06
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the safety and tolerability of BI 1265162 in healthy male subjects following inhalative administration of multiple rising doses.

Secondary objectives is the exploration of the pharmacokinetics (PK) including dose proportionality and time dependency of BI 1265162 after multiple dosing

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 1265162 intervention 2: Placebo
Intervention descriptions: intervention 1: Multiple rising inhaled doses intervention 2: Multiple rising inhaled doses

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c15848749-03
EudraCT No.:
BI Trial No.:
2017-001107-71
1399-0002
BI Investigational
Product
BI 1265162
Title:
Safety, tolerability and pharmacokinetics of multiple rising inhaled
doses of BI 1265162 in healthy male subjects in a randomised, double 
blind, placebo-controlled trial
Lay Title:
This study in healthy men tests how different doses of BI 1265162 are 
taken up in the body and how well they are tolerated. 
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:
Principal Investigator:
Phone:
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 04 July 2018
Page 1 of 84
Proprietary confidential information
© 2018 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
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1265162
Protocol date:
Trial number:
Revision date:
04 July 2018
23 May 2018
1399-0002
Title of trial:
Safety, tolerability and pharmacokinetics of multiple rising inhaled doses of 
BI 1265162 in healthy male subjects in a randomised, double blind, placebo-
controlled trial
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability and pharmacokinetics, following multiple doses of 
BI 1265162
Methodology:
Double-blind, randomised within dose groups, placebo-controlled, parallel-group 
No. of subjects: 
total entered:
50*
each treatment:
10 per dose group (8 on active drug and 2 on placebo) 
* Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct, provided the planned and approved highest dose will 
not be exceeded. Thus, the actual number of subjects entered may exceed 50, but will not 
exceed 70 subject entered.
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 45 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Test product:
BI 1265162
dose:
10, 30, 100, 300, 600 µg bid
mode of admin.:
Inhalation by RESPIMAT
Comparator product:
Placebo
dose:
Not applicable
mode of admin.:
Inhalation by RESPIMAT 
Duration of treatment: 8 days (single dose administration on day 1 and 8, bid dosing on days 2-7 )


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1265162
Protocol date:
Trial number:
Revision date:
04 July 2018
23 May 2018
1399-0002
Criteria for
pharmacokinetics:
Secondary endpoints:
After the first dose:
AUCτ,1 and Cmax
After the last dose:
AUCτ,ss and Cmax,ss
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 1265162 is the number 
[N (%)] of subjects with drug-related adverse events.
Statistical methods:
Descriptive statistics will be calculated for all endpoints


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FLOW CHART
Visit
Day
Planned time (relative to drug 
administration [h:min]
Approximate clock time of
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
11
12-lead ECG10
Vital signs (BP, PR)
Spirometry
Questioning for AEs and 
concomitant therapy 6
1
-21 to -2
Screening (SCR)1
x
x
x
x
2
-3 to -1
Ambulatory visit (Device 
training)
x7
x
-1
-25:00
07:00
Admission to trial site (Device 
training, if needed)
x5
x
-24:00
08:00
-22:00
10:00
240 mL fluid intake
-20:00
12:00
240 mL fluid intake, thereafter 
lunch3
-16:00
16:00
Snack (voluntary)3
-11:00
19:00
Dinner
-12:00
20:00
1
-1:30
06:30
Allocation to treatment2 (Device 
training, if needed)
x2,18
x2
x2,9
x2
x2
x2
0:00
08:00
Drug administration
0:02
08:02
x
0:05
08:05
x
0:10
08:10
x
x
x
x
0:15
08:15
x
0:20
08:20
x
x
0:40
08:40
x
1:00
09:00
x
x
x
x
2:00
10:00
240 mL fluid intake
x13
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
x
8:00
16:00
Snack (voluntary)3
x
11:00
19:00
Dinner3
12:00
20:00
x
x
x
x 
2
23:55
07:55
x
x
x
24:00
08:00
Drug administration
24:10
08:10
x
x
24:30
08:30
Breakfast
28:00
12:00
Lunch
32:00
16:00
Snack (voluntary)
35:00
19:00
Dinner
36:00
20:00
Drug administration
x
3
47:55
07:55
x
x
48:00
08:00
Drug administration


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Visit
Day
Planned time (relative to drug 
administration [h:min]
Approximate clock time of
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
11
12-lead ECG10
Vital signs (BP, PR)
Spirometry
Questioning for AEs and 
concomitant therapy 6
48:10
08:10
x
x
48:30
08:30
Breakfast
50:00
10:00
x13
52:00
12:00
Lunch
56:00
16:00
Snack (voluntary)
59:00
19:00
Dinner
60:00
20:00
Drug administration
x
4
71:55
07:55
x
72:00
08:00
Drug administration
72:30
08:30
Breakfast 
74:00
10:00
x13
76:00
12:00
Lunch
80:00
16:00
Snack (voluntary)
83:00
19:00
Dinner
84:00
20:00
Drug administration
x
5
95:55
07:55
x
x
96:00
08:00
Drug administration
96:10
08:10
x
x
x
96:15
08:15
98:00
10:00
240 mL fluid intake
x
100:00
12:00
240 mL fluid intake, thereafter 
lunch3
104:00
16:00
Snack (voluntary)
107:00
19:00
Dinner3
108:00
20:00
Drug administration
x
6
119:55
07:55
x
120:00
08:00
Drug administration
120:10
08:10
x
x
120:30
08:30
Breakfast 
122:00
10:00
x13
124:00
12:00
Lunch
128:00
16:00
Snack (voluntary)
131:00
19:00
Dinner
132:00
20:00
Drug administration
x
7
143:55
07:55
x
x
144:00
08:00
Drug administration
144:10
08:10
x
144:30
08:30
Breakfast 
148:00
12:00
Lunch
152:00
16:00
Snack (voluntary)
155:00
19:00
Dinner
156:00
20:00
Drug administration
x


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Visit
Day
Planned time (relative to drug 
administration [h:min]
Approximate clock time of
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
11
12-lead ECG10
Vital signs (BP, PR)
Spirometry
Questioning for AEs and 
concomitant therapy 6
8
164:30
06:30
x
x
x
167:55
07:55
x13
x8
168:00
08:00
Drug administration
168:02
08:02
x8
168:05
08:05
x8
168:10
08:10
x8
x
x
168:15
08:15
x8
168:20
08:20
x8
x
168:40
08:40
x8
169:00
09:00
x8
x
x
170:00
10:00
240 mL fluid intake
x13
x8
x
172:00
12:00
240 mL fluid intake, thereafter 
lunch3
x8
x
x
x
176:00
16:00
Snack (voluntary)3
x8
179:00
19:00
Dinner3
180:00
20:00
x8
x
x
x 
9
191:30
07:30
x
x
x
192:00
08:00
x13
x19
192:30
08:30
Breakfast 
196:00
12:00
Lunch
200:00
16:00
Snack (voluntary)
203:00
19:00
Dinner
x
10
216:00
08:30
Breakfast (voluntary) -
discharge
x20
3
10 to 15
End of trial (EOS) examination4
x
x
x
x
1.
Screening includes subject information, informed consent, physical examination, check of vital signs, 12-lead ECG), 
safety laboratory (including alcohol breath test, drug screening), demographics (including determination of body height 
and weight, smoking status and alcohol history), medical history, concomitant therapy and review of 
inclusion/exclusion criteria.
2.
The time is approximate; the respective procedure is to be performed and completed within 3 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to (first) drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs and 
concomitant therapies (if on the same day as Day 10 of visit 2, breakfast and discharge from site will be done after last 
EOS procedures).
5.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
safety laboratory can be omitted, if the screening examination is performed on Days -3, or -2. 
 
9.
At baseline (i.e. Day 1, prior to drug administration) 3 triplicate ECGs are recorded within approximately one hour. The 
recordings should be separated by at least 15 minutes.


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10. The ECG recording has to be performed as triple at this time points (Visit 1 and 3, ECGs as single only)
11. Sampling times and periods may be adapted based on information obtained during the trial including addition of 
samples and visits as long as the total blood volume taken does not exceed 500 mL per subject
13. Serum electrolytes only
20. Must not be performed when day 10 of visit 2 is on the same day as EOT


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................16
1.2.5
Clinical experience in humans.............................................................20
1.2.6
Residual Effect Period..........................................................................23
1.2.7
Drug product.........................................................................................23
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 25
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................25
2.2
TRIAL OBJECTIVES.......................................................................................28
2.3
BENEFIT - RISK ASSESSMENT ...................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 31
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................31
3.1.1
Administrative structure of the trial...................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................33
3.3
SELECTION OF TRIAL POPULATION ......................................................34
3.3.1
Main diagnosis for study entry............................................................34
3.3.2
Inclusion criteria...................................................................................34
3.3.3
Exclusion criteria ..................................................................................34
3.3.4
Removal of subjects from therapy or assessments.............................36
3.3.4.1
Removal of individual subjects................................................36
3.3.4.2
Discontinuation of the trial by the sponsor..............................36
3.3.5
Replacement of subjects .......................................................................37
4.
TREATMENTS........................................................................................ 38
4.1
TREATMENTS TO BE ADMINISTERED....................................................38
4.1.1
Identity of BI investigational product and comparator product......38
4.1.2
Method of assigning subjects to treatment groups ............................38


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4.1.3
Selection of doses in the trial................................................................39
4.1.4
Drug assignment and administration of doses for each subject .......39
4.1.5
Blinding and procedures for unblinding ............................................40
4.1.5.1
Blinding....................................................................................40
4.1.5.2
Procedures for emergency unblinding .....................................41
4.1.6
Packaging, labelling, and re-supply ....................................................41
4.1.7
Storage conditions.................................................................................42
4.1.8
Drug accountability ..............................................................................42
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................42
4.2.1
Other treatments and emergency procedures....................................42
4.2.2
Restrictions............................................................................................43
4.2.2.1
Restrictions regarding concomitant treatment .........................43
4.2.2.2
Restrictions on diet and life style.............................................43
4.3
TREATMENT COMPLIANCE.......................................................................43
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 45
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................45
5.1.1
Endpoints of efficacy.............................................................................45
5.1.2
Assessment of efficacy...........................................................................45
5.2
SAFETY..............................................................................................................45
5.2.1
Endpoints of safety................................................................................45
5.2.2
Assessment of adverse events...............................................................45
5.2.2.1
Definitions of adverse events...................................................45
5.2.2.2
Adverse event collection and reporting ...................................48
5.2.3
Assessment of safety laboratory parameters......................................49
5.2.4
Electrocardiogram................................................................................52
5.2.4.1
12-lead resting ECG.................................................................52
5.2.5
Assessment of other safety parameters...............................................54
5.2.5.1
Vital signs ................................................................................54
5.2.5.2
Medical examinations..............................................................54
5.2.5.3
Spirometry................................................................................54
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................55
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................56
5.5.1
Pharmacokinetic endpoints..................................................................56
5.5.1.1
Secondary endpoints................................................................56
5.5.2
Methods of sample collection...............................................................58


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5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................58
5.5.3
Analytical determinations ....................................................................60
5.5.3.1
Analytical determination of analyte plasma concentration......60
5.6
BIOMARKER....................................................................................................60
5.7
PHARMACODYNAMICS................................................................................61
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....61
6.
INVESTIGATIONAL PLAN.................................................................. 62
6.1
VISIT SCHEDULE............................................................................................62
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................62
6.2.1
Screening period....................................................................................62
6.2.2
Treatment period ..................................................................................62
6.2.3
End of trial period.................................................................................63
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 64
7.1
STATISTICAL DESIGN – MODEL ...............................................................64
7.1.1
Objectives...............................................................................................64
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................64
7.3
PLANNED ANALYSES....................................................................................64
7.3.1
Primary analyses...................................................................................64
7.3.2
Secondary analyses ...............................................................................65
7.3.3
Safety analyses.......................................................................................68
7.3.4
Interim analyses ....................................................................................69
7.3.5
Pharmacokinetic analyses ....................................................................69
7.4
HANDLING OF MISSING DATA ..................................................................69
7.4.1
Safety......................................................................................................69
7.4.2
Plasma drug concentration - time profiles..........................................69
7.4.3
Pharmacokinetic parameters...............................................................69
7.5
RANDOMISATION ..........................................................................................70
7.6
DETERMINATION OF SAMPLE SIZE ........................................................70
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 71
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................71
8.2
DATA QUALITY ASSURANCE .....................................................................71
8.3
RECORDS..........................................................................................................72
8.3.1
Source documents .................................................................................72
8.3.2
Direct access to source data and documents.......................................72
8.3.3
Storage period of records.....................................................................72


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................72
8.5
STATEMENT OF CONFIDENTIALITY.......................................................72
8.6
COMPLETION OF TRIAL..............................................................................73
9.
REFERENCES......................................................................................... 74
9.1
PUBLISHED REFERENCES...........................................................................74
9.2
UNPUBLISHED REFERENCES.....................................................................76
10. APPENDICES .......................................................................................... 77
10.1
HANDLING INSTRUCTIONS FOR RESPIMAT INHALER FOR USE 
IN CLINICAL TRIALS ....................................................................................77
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 83


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
AMG
Arzneimittelgesetz (German drug law)
AUCτ,1
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose
BI
Boehringer Ingelheim
bid
Bis in die, twice daily
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CF
Cystic fibrosis
CFTR
Cystic fibrosis transmembrane conductance regulator
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
COPD
Chronic obstructive pulmonary disease
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report


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CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
ENaC
Epithelial sodium channel
EOS
End of study
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
gCV
Geometric coefficient of variation
gMean
Geometric mean
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NC
Not calculated
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
qd
Quaque die, once daily


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QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected Unexpected Serious Adverse Reaction
TDMAP
Trial Data Management and Analysis Plan
TMF
Trial master file
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
BI 1265162, an epithelial sodium channel (ENaC) inhibitor, is to be developed in cystic 
fibrosis (CF) and chronic obstructive pulmonary disease (COPD). CF and COPD are chronic 
respiratory disorders characterized by airflow obstruction. ENaC is expressed on airway 
epithelial cells and functions as an ion channel for sodium. It mediates sodium reabsorption 
and regulates the water content and volume of the luminal fluid thereby maintaining airway 
surface liquid (ASL) and in turn regulating mucociliary clearance.
Cystic fibrosis is a lethal, inherited, multi-organ disease due to exocrine gland dysfunction 
that predominantly affects the lower respiratory tract and pancreas leading to chronic 
respiratory failure and pancreatic insufficiency. It is the most common lethal inherited disease 
in Caucasians [R01-1277] occurring in approximately 1 in 3000 births [R15-5503]. 
Pulmonary treatments include supportive care e.g. airway clearance techniques, antibacterial 
(including inhaled tobramycin and aztreonam), muco-active (e.g. dornase alpha and 
hypertonic saline) therapies are the cornerstone of pharmacotherapy [P13-14084], and more 
recently therapies targeting the CFTR [R17-1997]. Lung transplantation is also used. Despite 
recent advances, over 90% of patients surviving the neonatal period will develop pulmonary 
involvement and at least 90% will die due to pulmonary complications [P96-3855]. The 
median age of death is below 40 years old [R15-5546].
In CF, the cystic fibrosis transmembrane conductance regulator (CFTR) gene is dysfunctional 
resulting in impaired epithelial chloride (Cl-) transport [R15-5486] leading, in turn, to 
reduced water secretion into the airway surface layer (ASL). The functional defect of the 
CFTR is also associated with an increase of ENaC activation, increased sodium [R15-5507] 
and water absorption from the airway epithelial lining fluid. These effects lead to mucus 
dehydration and reduction in the height of the periciliary layer, which is normally tightly 
controlled to maintain optimal mucocillary clearance. The mucus becomes thickened, 
tenacious and adherent leading to collapsed cilia and poor mucus clearance [R15-4955]. The 
static mucus can, in itself, trigger an inflammatory response, but also provides an ideal 
environment for bacterial colonisation with bacterial infection that is often acquired in 
childhood and that persists throughout the patient’s life [R15-4984, R15- 4955]. Lung 
destruction is caused by a cycle of infection, inflammation, and injury, with obstruction of the 
airways. The dehydrated, thickened secretions, resultant endobronchial infection, and 
exaggerated inflammatory response lead to mucus plugging, bronchiectasis and progressive 
obstructive airways disease.
COPD prevalence is still rising due to increased smoking, particularly among women and 
adolescents. According to the 2015 estimates of the World Health Organization (WHO), 
65 million people suffer from moderate to severe COPD. By 2030, COPD will be the third 
leading cause of death worldwide [R15-3034].
COPD is associated with significant morbidity and mortality. Smoking cessation is the only 
therapy known to alter the natural history of COPD. The management of stable COPD is 


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directed towards reducing symptoms and future risk (prevention and treatment of 
exacerbations and disease progression). Pharmacotherapy is based primarily on 
bronchodilator drugs including long acting beta agonists (LABA) and long anti-muscarinic 
antagonists (LAMA) and inhaled or oral corticosteroids. Other treatments include the anti-
inflammatory roflumilast, influenza and pneumococcal vaccinations, and treatment of 
exacerbations. The mucolytic therapy N-acetylcysteine may have a small effect on 
exacerbations [P11-05794]. An ENaC inhibitor would be expected to have additional effect 
compared to mucolytic therapies given the direct effects on mucus hydration.
ENaC is expressed widely on the apical side of epithelial cells in the lung and there is 
increasing evidence for the role the ENaC in the pathogenesis of both CF and COPD. Despite 
the differences in the underlying pathology between the two diseases, changes in the 
biophysical characteristics of the mucus are apparent with impaired transport of mucus 
(reduced mucus clearance) leading to mucus plugging, airflow obstruction and a milieu 
conductive to bacterial colonisation which in turn leads to worsening symptoms, lung 
function, and an increase in exacerbations. In both CF and COPD inhibition of ENaC is 
anticipated to reduce sodium uptake and water absorption in the airways which should 
translate to improvement of mucociliary clearance, pulmonary function, symptoms and 
quality of life whilst reducing bacterial colonization of the lower airways, and exacerbations 
and hospitalizations. Administration of an inhaled formulation of the potassium sparing 
diuretic amiloride, an ENaC inhibitor, resulted in increased mucus clearance in cystic fibrosis 
patients [R15-5487, R15-5485, R15-5349], but not clinical efficacy, possibly die to poor 
pharmacokinetic properties of administering this normally oral drug by the inhalation route 
[R15-5349, R15-5599, R15-5505]. The more favourable potency and kinetics demonstrated 
by BI 1265162 are expected to translate into clinical efficacy.
ENaC is also located on the apical side of the epithelial layer in the kidney and the colon as 
well as being expressed in the brain, eye, vascular endothelial, and smooth muscle cells and 
in the tongue. Inhibition of ENaC in the kidney leads to reduced absorption of sodium with a 
concomitant reduction in potassium excretion from/ into the urine. As demonstrated by the 
reference oral compound amiloride, increases in serum potassium or reduction in serum 
sodium/ chloride may be expected based on mechanism in case of excessive systemic 
exposure. This is not expected with therapeutic inhalational administration of BI 1265162. 
Based on preclinical in vitro and in vivo models, BI 1265162 administered by the inhalational 
route may be beneficial.
1.2
DRUG PROFILE
BI 1265162, an epithelial sodium channel (ENaC) inhibitor, is entering phase I of clinical 
development in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).


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1.2.5
Clinical experience in humans


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Systemic ENaC inhibitors such as amiloride have been used for years as potassium sparing 
diuretics in the treatment of hypertension, congestive heart failure and cirrhotic ascites. The 
side effect profile is well documented. Amiloride is normally well tolerated and, except for 
hyperkalaemia, significant side effects are infrequent. Nausea, anorexia, abdominal pain, 
flatulence and mild skin rashes are considered potentially related to amiloride but other side 
effects are generally associated with diuresis. 
In addition there are clinical data of inhaled ENaC inhibitors administered to healthy 
volunteers and patients with cystic fibrosis for up to 6 months [R15-5485, R15-5349, 
R15- 5599, R15-5505]. Phase II studies with competitor ENaC inhibitors are ongoing. The 
compounds appear to have been well tolerated, with effects limited to serum potassium 
increases after multiple dosing, particularly in a compound with an active metabolite 
[R15-0689].
1.2.6
Residual Effect Period
The Residual Effect Period (REP) of BI 1265162 is
. This is the period after the last 
dose with measurable drug levels still likely to be present.
1.2.7
Drug product
Administration of BI 1265162 RESPIMAT Inhalation Solution is achieved with the 
RESPIMAT inhaler in combination with a drug reservoir / cartridge. At the present time, 
several solutions for inhalation with different drug substance concentrations have been 


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developed for use in clinical studies, representing dose strengths of 
 
BI 1265162, as well as a placebo solution for inhalation. A spray volume of 
 per 
actuation is nebulized by the RESPIMAT inhaler.
BI 1265162 RESPIMAT Inhalation Solution is formulated as an aqueous solution of 
BI 1265162. The pH is adjusted with hydrochloric acid to 3.8 +/- 0.2. This pH value assures 
physico-chemical stability and physiological tolerability.
BI 1265162 RESPIMAT Inhalation Solution contains the stabilizer disodium edetate (EDTA) 
and the preservative benzalkonium chloride. EDTA and benzalkonium chloride have been 
reported to induce administration related bronchospasm in some patients inhaling such 
solutions from a nebulizer [P87-3333, P88-1291]. However, the concentration of each of 
these substances amounts to approximately 1 μg per actuation, which is well below the 
amounts at which bronchospasm has been reported [P87-3333, P88-1291]. A deposition / 
scintigraphic study in healthy volunteers using an aqueous formulation similar to the one 
used here in the RESPIMAT Inhaler indicated that approximately 40% of the dose deposited 
in the lungs [U97-0056]. Thus, the approximate actual pulmonary exposure per actuation to 
the patient will be 0.4 μg of EDTA and 0.4 μg of benzalkonium chloride. In addition, the 
occurrence of paradoxical bronchoconstriction in clinical trials using the RESPIMAT Inhaler 
conducted with a variety of substances was uncommon and limited to asymptomatic declines 
in FEV1 in COPD patients, primarily recorded in placebo treatment groups and comparable 
among RESPIMAT Inhaler and metered dose inhaler (MDI) formulations. The use of the 
RESPIMAT inhaler in Phase III trials has been shown to be safe with regards to paradoxical 
bronchoconstriction during chronic use in patients with asthma and COPD [P05-08465]. The 
administration of BI 1265162 RESPIMAT Inhalation Solution / Inhalation Spray is therefore 
not expected to cause EDTA- or BAC-related bronchospasm.
For the first clinical trials, a placebo matching the RESPIMAT platform Inhalation Solutions 
will be used. It uses the same excipients as the verum. The pH of this placebo has been 
adjusted by hydrochloric acid to a more acidic pH.
For a more detailed description of the BI 1265162 profile please refer to the current 
‘Investigator’s Brochure’, c16304878.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This is the second trial with BI 1265162 and the first with multiple dose administration. 
The objective of this trial is to investigate the safety, tolerability and pharmacokinetics of 
BI 1265162 in healthy male subjects. The chosen population of healthy volunteers using 
multiple rising inhalative doses is adequate to provide the basis for the phase 2 clinical 
development program of BI 1265162 in CF and COPD. This trial will provide 
pharmacokinetic information in healthy volunteers at steady state exposure.
The inclusion of male healthy volunteers as a trial population in phase I studies is ideal as 
they provide relatively stable physiological, biochemical and hormonal conditions (steady 
state) for studying drug effects. Healthy volunteers can be tested under standardised 
conditions in an environment which allows repeated testing.
In this multiple rising dose (MRD) study, within each dose group, all actively treated 
individuals will receive the same BI 1265162 dose. The next higher dose will only be 
administered (to the next group) if the treatment in the preceding dose groups was safe and 
showed acceptable tolerability.
Dose Selection
It is intended to investigate the following dose levels of BI 1265162 in the MRD part of this 
trial: 10, 30, 100, 300 and 600µg twice daily (bid) for Days 2-7 and single dose on Day 1 and 
8. The background for this dose selection is described in the following.
Starting dose
Considering the favourable preclinical and clinical safety profile of BI 1265162, and taking 
into consideration other systemic and inhaled ENaC inhibitors which have been well 
tolerated, with known, easily monitorable and reversible side effects (changes in electrolytes), 
a sub-therapeutic dose of 10 µg bid has been selected as the starting dose in this MRD trial. 
This dose is within the range of ED50 (cf. Table 2.1: 1). 
Maximum dose and dose escalation
As stated above, a minimum daily dose of approximately 
 
 may be required to achieve therapeutic exposure to BI 1265162. 


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However, higher doses might still be well tolerated while providing a larger magnitude of 
therapeutic effects.
Further, even if the therapeutic dose turned out to be as low as 
 higher than therapeutic 
doses are typically explored in MRD studies to provide a safety margin for following studies 
e.g. drug-drug-interaction studies, or patients with impaired excretion function, etc., where 
substantial increases in exposure may be observed. Studies in patients may demonstrate that 
an ED70 is insufficient to show a clinical effect and even higher doses of BI 1265162 are 
required e.g. in case an 
 
(cf. Table 2.1: 1). To adequately address all these aspects a dose of 600 µg bid 
has been selected as the maximum dose. This dose will not exceed the highest (and well 
tolerated) tested dose in the SRD 1399.0001 of 
The relevant findings in the toxicology studies in the rat were changes in serum and urine 
electrolytes due to the mode of action of an ENaC antagonist which will be fully reversible 
and will be monitored thoroughly in this clinical trial. In addition, effects on blood 
electrolytes should be demonstrable with increasing dosing, so an acute increase would not be 
expected. No such findings were seen in the SRD trial 1399.0001.


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Table 2.1: 2
1399.0001 preliminary results Geometric Mean PK Parameter 
(gCV%) [* Median (Min-Max)]
A noncompartmental prediction of BI 1265162 plasma concentrations based on the 
preliminary PK results of study 1399.0001 revealed that BI 1265162 systemic exposure 
increases approximately dose-proportional over the studied dose range. Bid dosing results
predicted in only relatively little accumulation. Steady-state is predicted to reach with respect 
to average, peak and trough concentrations by 4-5 days.
Preliminary results from the SRD 1399.0001 show that urinary excretion of BI 1265162 was 
around 1% of the administered dose within 48 hours after inhalation. Thus the risk of effects 
on the kidney regarding exchange of urine electrolytes is seen to be low.
Based on the above considerations a stepwise and careful dose increase up to a maximum 
dose of 600 µg bid has been selected for this trial. This selection is supported by the overall 
favourable preclinical and clinical safety profile of BI 1265162 in addition to the well 


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documented effects of ENaC inhibition in man. Dose escalation will be in the range of factor 
3 and the escalation factor will be lower than 2 for the higher dose range. This dose escalation 
scheme is considered to be adequate and safe, particularly when the good safety profile of 
BI 1265162 seen in the SRD 1399.0001 is taken into consideration.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 1265162 in 
healthy male subjects following inhalative administration of multiple rising doses.
Secondary objectives is the exploration of the pharmacokinetics (PK) including dose 
proportionality and time dependency of BI 1265162 after multiple dosing
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of 
BI 1265162. The subjects are exposed to the risks of the study procedures and the risks 
related to the exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall 
of the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
As the nature of the target and the mechanism of action of BI 1265162 are well understood,
comparable compounds have been tested internally and by other companies before, and the 
animal models are believed to be predictive for the effects in humans, BI 1265162 is not seen 
as a high risk compound. The specific mechanism of action is also well recognized for when 
administered systemically (orally) as a diuretic with a well-established safety profile and 
known side effects (effects on serum and urine electrolytes at exposures much higher than 
expected to be achieved with the current inhaled compound). Healthy subjects will not be 
exposed to undue risks and AEs in relation to the information expected from this trial.
The pharmacological effects of BI 1265162 are dose dependent and no evidence for 
prolonged or irreversible effects has been observed.


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The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers:

Careful dose selection as described in Section 2.1. 

For safety reasons, each dose group of 10 subjects (8 on active drug, 2 on placebo) 
will be divided into 2 cohorts of 5 subjects each (4 on active drug, 1 on placebo). Both 
cohorts will be dosed in a randomized fashion and each drug administration will be 
separated by at least 10 minutes. For inhalative administered drugs, this is usually a 
sufficient time frame to observe acute effects. 

For each dose group, the 2 cohorts will be separated by at least 5 days (first dosing of 
the first cohort and first dosing of the second) to assess steady state conditions of the 
first cohort. A continuous safety evaluation, including results of safety laboratories, 
ECG readings, spirometry, recordings of vital signs and adverse events will be 
performed before the individual subject and the subsequent cohort is dosed.

Based on the preclinical toxicology findings and taking the mode of action into 
consideration, dose escalation will be stopped as soon as at least 2 subjects at one 
dose level on active drug showed serum potassium levels > 5.5 mmol/L in non-
hemolyzed blood. 

An extensive safety laboratory will be performed with special focus on serum
electrolytes (see Flow Chart). 

Lung function assessments will be performed via spirometry.

Only subjects with a normal kidney function (using the eGFR, calculated from serum 
creatinine using CKD-EPI formula) will be included in the study

The subjects will stay at the trial site from 1 day prior first dosing till at least 48h after 
last study drug administration at each dose level. 

During in house-confinement the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events.

Only if the respective dose of BI 1265162 is safe and showed acceptable tolerability 
and if the stopping criteria are not met (refer to Section 3.3.4.2), the next higher dose 
will be given at least 5 days later (referring to the last dosing of the 1st subject of each 
dose group).
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.2.1, adverse events of special interest.
In summary, BI 1265162 is in early clinical development. Single doses up to 
 were 
well tolerated in the first in man trial 1399.0001. Based upon preclinical and early clinical 
data for BI 1265162 and clinical information from systemically and inhaled administered 
ENaC inhibitors and competitor inhaled compounds as well as the implemented safety 
measures described above, healthy subjects will not be exposed to undue risks. Healthy 


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volunteers are not expected to have any direct medical benefit from participation in this
clinical trial with BI 1265162, as is the usual case in such phase I trials. Subjects will be 
closely monitored. BI 1265162 has the potential to be an inhalative treatment for CF, a 
disease of high unmet medical need. The expected potential benefits for patients and the 
important information expected from this trial as a basis for further clinical development of 
this compound are felt to outweigh the potential risks and justify exposure of healthy human 
volunteers in the clinical development of BI 1265162.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This multiple-rising dose trial is designed as double-blind, randomised, and placebo-
controlled within parallel dose groups.
A total of 50 healthy male subjects is planned to participate in the trial, according to 5
sequential groups comprising 10 subjects per group. However, additional subjects may be 
entered to allow testing of additional doses on the basis of experience gained during the trial 
conduct, provided the planned and approved highest dose will not be exceeded. Thus, the 
actual number of subjects entered may exceed 50, but will not exceed 70 subjects entered. 
Such changes may be implemented via non-substantial CTP Amendments.
Within each dose group, 8 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group. Each dose group will consist of 2 cohorts 
(5 subjects each, 4 on active drug and 1 on placebo) which will be treated subsequently for 
safety reasons. The time interval between these cohorts will be at least 70 hours from first 
subject dosed.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
5
Dose (µg) bid
10
30
100
300
600
Number of subjects
10
10
10
10
10
Subjects receiving placebo
2
2
2
2
2
Subjects receiving active drug
8
8
8
8
8
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 5 days between the last drug administration in the previous dose 
group and the first drug administration of the subsequent dose group. The decision to proceed 
to the next dose group will be based upon the safety and tolerability of the preceding dose 
groups. The next dose will only be given if, in the opinion of the investigator, no safety 
concerns arose in the preceding dose group (i.e. no dose-limiting events occurred) and if none 
of the pre-specified trial-specific stopping criteria were met (refer to Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by the 
Principal Investigator (or an authorised deputy) or the sponsor of the study, e.g. because of 
any unforeseen adverse events, etc. Dose escalation will only be permitted if no safety 
concerns exist in the opinion of the Principal Investigator (or an authorised deputy) and the 
trial clinical monitor (or an authorised deputy). 
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 


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absence of any safety concern (i.e. no dose-limiting events occurred) and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4.2).
The minimum data set for review consists of the following data:

AEs in the current and preceding dose groups (including clinically relevant findings 
from ancillary safety testing listed below) (Note: AEs may be ongoing at the time of 
Safety Reviews and AE information may be subject to change prior to Database Lock)

Results from 12-lead EGG in the current and preceding dose groups.

Vital signs in the current and preceding dose groups

Spirometry data

Clinical laboratory tests in the current and preceding dose groups

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the trial clinical monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 
face-to-face or by video/telephone conference. The trial clinical monitor is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (or an authorised deputy) and filed in the ISF and TMF. 
The investigator (after consultation with the sponsor) is allowed to alter the scheduled dose 
levels (e.g. add low and/or intermediate dose levels) on the basis of experience gained during 
the study, provided the planned and approved highest dose is not exceeded. In this case, the 
total number of subjects in this trial might increase. The investigator and/or the sponsor 
should stop dose escalation in case the safety evaluation leads to concerns that would not 
allow higher dosing.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany.


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The trial will be conducted at
 
 under the supervision of the Principal 
Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
The analyses of BI 1265162 concentrations in plasma and urine will be performed at the 
Department of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For multiple-rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 1265162.
With the rising dose design, double-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to the dose-depending effects as well as time effects, but it has the 
virtue of minimizing subject risk by sequentially studying ascending doses. As time-effects 
are expected to be small relative to the differences between the doses in the broad range 
investigated, unbiased comparisons between treatments can still be expected.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety and tolerability. Each dose group consists of 10 subjects with 8 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. 8 subjects per active treatment group are in general considered 
as sufficient for the exploratory evaluation of pharmacokinetics. 


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After the first dose (single dose segment), a sufficient wash-out period will be included 
before the second dose (first dose of the multiple dose segment) is administered. This will 
allow for appropriate calculation of the pharmacokinetic parameters after a single dose 
administration and for comparison with pharmacokinetic parameters at steady state.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 50 healthy males will enter the study. The actual number of subjects entered 
may exceed the total of 50 if additional intermediate doses will be tested (see Section 3.1). 
Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 
12-lead ECG, and clinical laboratory tests 
2. Age of 18 to 45 years (incl.) 
3. BMI of 18.5 to 29.9 kg/m2 (incl.) 
4. FEV1 and FVC of equal or greater than 80% of predicted normal, at screening and 
prior to randomisation
5. Signed and dated written informed consent prior to admission to the study in 
accordance with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 
140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse 
rate outside the range of 50 to 90 bpm


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3. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the 
investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy and simple hernia 
repair)
7. Diseases of the central nervous system (including but not limited to any kind of 
seizures or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial 
medication or its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered 
within 60 days prior to planned administration of trial medication, or current 
participation in another trial involving administration of investigational drug
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more 30 g per day for males)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to 
administration of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at 
screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
22. A history of chronic kidney disease (EGFR <59 mls/min including corrections as per 
ethnicity)
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, 
because considered not able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
24. The subject has a diagnosis history of pulmonary hyperreactivity
25. Cannot use Respimat® appropriately 


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26. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from the first administration of trial medication until 
14 days after last administration of trial medication (BI 1265162 or placebo)
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:

The subject withdraws consent for trial treatment or trial participation, without the 
need to justify the decision

The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication

The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)

The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
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 any of the following reasons:


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
New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. Dose escalation will be terminated if more than 50% of the 
subjects at one dose level show drug-related and clinically relevant adverse events of 
moderate or severe intensity, or if at least one drug-related serious adverse event is 
reported.

The expected enrolment goals overall or at a particular trial site are not met

Violation of GCP, or the CTP or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial

The sponsor decides to discontinue the further development of the investigational 
product.

Dose escalation will be stopped as soon as at least 2 subjects at one dose level on 
active drug showed relevant individual QT prolongation, i.e. a QTc increase of greater 
60 ms from baseline in connection with absolute QT or QTc greater than 500 ms, 
which has been confirmed by a repeat ECG recording.

Dose escalation will be stopped as soon as at least 2 subjects at one dose level on 
active drug showed serum potassium levels > 5.5 mmol/L in non-hemolyzed blood
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case that more than 2 subjects on active per dose group do not complete the trial, the trial 
clinical monitor together with the trial pharmacokineticist and the trial statistician are to 
decide if and how many subjects will be replaced. A replacement subject will be assigned a 
unique study subject number, and will be assigned to the same treatment as the subject he 
replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator product
Substance:
BI 1265162
Pharmaceutical formulation: Solution for inhalation
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 µg/actuation, 100 µg/actuation
Route of administration:
Oral inhalation
Device:
RESPIMAT A5
Duration of use:
Single and multiple doses
Posology:
1-0-0 on trial days 1 and 8; 1-0-1 on days 2-7
Substance:
Placebo
Pharmaceutical formulation: Solution for inhalation
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable
Route of administration:
Oral inhalation
Device:
RESPIMAT A5
Duration of use:
Single and multiple doses
Posology:
1-0-0 on trial days 1 and 8; 1-0-1 on days 2-7
A placebo matching the Respimat® platform Inhalation Solutions will be used. It uses the 
same excipients as the verum.
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects have been allocated to 
1 of the 10 dose cohorts (2 cohorts per dose group), the following subjects will be allocated to 
one of the other dose cohorts. Therefore, the allocation of subjects to dose cohorts is not 
influenced by trial personnel, but only by the subjects’ temporal availability. As the study 


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includes healthy subjects from a homogenous population, relevant imbalances between the 
dose groups are not expected.
A list of medication numbers will be provided to the trial site in advance. The allocation of 
subjects to study subject numbers will be performed prior to the first administration of trial 
medication. For this purpose, the subjects will be allocated to a study subject number by the 
method first come first served. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
The doses selected for this trial cover the subtherapeutic as well as the estimated therapeutic 
range and include a safety margin (see Section 1.2).
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of actuations 
for placebo corresponds to the number of actuations of the respective dose level.
Table 4.1.4: 1
BI 1265162 and placebo treatments, inhalative administration 
Dose Substance
Pharmaceutical 
form
Dose per actuation 
(BI 1265162, 
administered dose)
Number of device 
actuations per single 
dose
Total daily 
dose (Day 1 
and 8)
Total daily 
dose (Day 
2-7)
1
BI 1265162
inhalation 
solution, 
RESPIMAT
10 µg
1
10 µg
20 µg
2
BI 1265162
inhalation 
solution, 
RESPIMAT
10 µg
3
30 µg
60 µg
3
BI 1265162
inhalation 
solution, 
RESPIMAT
100 µg
1
100 µg
200 µg
4
BI 1265162
inhalation 
solution, 
RESPIMAT
100 µg
3
300 µg
600 µg
5
BI 1265162
inhalation 
solution, 
RESPIMAT
100 µg
6
600 µg
1200 µg
1-5
Placebo*
inhalation 
solution, 
RESPIMAT
--
identical to active 
treatment for that 
dose level
--
--
* Subjects receiving placebo are equally distributed across dose groups 
On Day 1 and 8 subjects will receive a single (qd) dose in the morning only. On all other trial 
days (2-7) BI 1265162 will administered bid. 


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Each newly assembled RESPIMAT Inhaler has to be primed by an unblinded (not involved in 
the conduct of the trial) qualified medical/pharmaceutical staff at the trial site under the 
responsibility of the investigator. To avoid contamination, except those devices used for 
training, priming should NOT take place in the same room where the subject is inhaling trial 
medication or the trial will be performed or samples will be processed. The inhaler should be 
primed under e.g. hood/outside by actuating it until an aerosol is visible plus three additional 
actuations. All priming actuations should be directed to the ground. For detailed priming 
instructions please refer to the RESPIMAT Inhaler handling instructions in Appendix 10.1.
Both the study drug as well as the placebo treatment (depending on randomisation) will be 
inhaled with the RESPIMAT in a sitting or standing position under supervision of the 
investigating physician or an authorised designee. If more than one actuation is needed,
planned time 0:00h will always be the first actuation. If more than one actuation will be 
needed, the duration from first to last actuation will be recorded. To avoid any contamination 
(e.g PK tubes), administration of trial medication should be performed in a separate room; 
subject and staff should wear e.g. gloves and protective wear.
The so-called four-eye principle (two-person rule) should be applied for administration of 
trial medication, otherwise correct dosage cannot be ensured.
To ensure a dosing interval of 12 h, the administration of trial medication should take place at 
the same time every day.
Subjects will be kept under close medical surveillance until 24 h following the last drug 
administration. For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The trial is designed double-blind with regard to the subjects and the investigators (as well as 
the research staff at the trial site) in order to eliminate observer or performance bias. This 
means avoiding systematic differences in assessments regarding the subject’s treatment 
(active or placebo). 
At the trial site, access to the randomisation schedule is restricted to unblinded pharmacists, 
pharmacy staff members or staff who will prepare the trial medication. Access to the codes 
will be controlled and documented by a signed confidentiality statement, which will be stored 
in the TMF. Persons directly involved in the clinical conduct of the trial will not have access 
to the treatment allocation prior to database lock.
In addition, the trial pharmacokineticist, trial pharmacometrician and bioanalyst may receive
the randomisation codes prior to official unblinding to perform preliminary PK analysis. He 
or she will confirm in writing that the codes will be treated confidentially.
In addition, the drug metabolism scientist may receive the randomisation codes prior to
official unblinding to perform metabolites in safety testing analysis (MIST). He or she will
confirm in writing that the codes will be treated confidentially.


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Within the central ECG lab, the staff involved with interval measurements and morphological 
analyses will be blinded with respect to the treatment and also with regard to the recording 
date and time as well as planned time points of the ECGs. The interval measurements for a 
given subject will be performed in a random and blinded sequence by a single technician. No 
more than two different blinded readers will evaluate the ECGs of the study.
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical monitor, data manager, 
statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug metabolism scientist as 
well as dedicated CRO personnel). The objective of the trial is not expected to be affected.
4.1.5.2
Procedures for emergency unblinding
For blinded trials, the investigator will be supplied with a set of sealed envelopes containing 
the medication codes for each subject according to the randomisation scheme. The envelopes 
will be kept unopened at the trial site until the end of data collection. An envelope may only 
be opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or to assure safety of trial 
participants. If the envelope for a subject is opened, the sponsor must be informed 
immediately. The reason for opening the code break must be documented on the envelope or 
appropriate CRF page along with the date and the initials of the person who broke the code. 
At the close-out visit all envelopes are collected.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
The clinical trial supply consists of containers holding the trial medication which are labelled
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. The clinical trial supply 
containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Subject or medication number

Batch number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.


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No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator / pharmacist must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator / pharmacist will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP, and that reconcile all investigational products 
received from the sponsor. At the time of disposal, the investigator / pharmacist must verify 
that all unused or partially used drug supplies have been returned by the clinical trial subject 
and that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 


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required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is. All concomitant or rescue therapies will be recorded 
(including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
Prior to Day -1, Day 1, Day 5 and Day 8 the subjects have fasted for at least 8 h.
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardized meals will be served at the time points 
described in the Flow Chart. Composition of food on Day -1, Day 1, Day 5 and Day 8 should 
be identical. Use of table salt is not allowed during in-house confinement at the trial site.
On Day -1, Day 1, Day 5 and Day 8, from 1 h before drug intake until lunch, fluid intake is 
restricted to 240 mL of water served at 2 h and 4 h post-dose (mandatory for all subjects). 
From lunch onwards, liquid intake is restricted to an additional 3000 mL. Subjects will be 
asked to drink the additional amount till one hour prior to the stop of urine collection on the 
following day. The total amount of liquid intake will be documented.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products including St. John's wort (Hypericum perforatum) are not permitted starting 7 
days before the first administration of trial medication until 24 h after last administration of 
trial medication.
Alcoholic beverages, consumption of seafood and dried fruits are not permitted from 48 
hours before the study drug administration and until 24 h after last administration of trial 
medication.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not during in-house phase.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of study examination. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion will provide additional confirmation of compliance.


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Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 1265162 is the number [N (%)] of 
subjects with drug-related adverse events.
Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Spirometry (FEV1, FVC, FEF25-75)
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable): 

Worsening of the underlying disease or of other pre-existing conditions <adjust if 
these are trial endpoints and/or if they are exempted events, e.g. in oncology trials> 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator. 


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If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
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 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse.
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 5.2.2, 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, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
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 5.2.2.2.


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The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
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 sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
eCD. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
Intensity 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
Causal relationship of AEs
Medical judgment should be used to determine the relationship, 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. 
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.


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
After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report related SAEs and related AESIs of which the investigator 
may become aware of by any means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timelines apply as for initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 8 h. Overnight fasting is not required at the discretion of the investigator or designee for 
retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis,
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Category
Test name
A1
B2
C3
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelets
Reticulocyte count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential 
(relative and absolute)
Neutrophiles 
Eosinophils 
Basophils 
Monocytes 
Lymphocytes 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal and clinically 
relevant in the opinion of 
the investigator)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin Time (Quick and INR)
X
X
X
X
X
X
Enzymes
Aspartate aminotransferase (AST/GOT, SGOT) 
Alanine aminotransferase (ALT/GPT, SGPT) 
Alkaline phosphatase
Gammaglutamyl transferase (GGT)  
Lactate dehydrogenase
Amylase
Lipase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Substrates
Glucose (plasma)
Creatinine
eGFR, calculated from serum creatinine using
CKD-EPI formula
Bilirubin, total
Bilirubin, direct
Cholesterol, total
Triglycerides
C-reactive protein
Urea
X
X
X
X
X
X
X
X
X
-
X
X
X
X
X
X
X
X
-
X
X
X
X
X
X
X
X
Electrolytes
Calcium
Sodium
Potassium
Chloride
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid stimulating hormone (TSH)
X
--
--
* From urine collection 
cf. Flow Chart
Urine potassium
Urine sodium
Urine chloride
Urine creatinine
Potassium-creatinine-quotient
Sodium-creatinine-quotient
-
-
-
-
-
-
X
X
X
X
X
X
-
-
-
-
-
-


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Table 5.2.3: 1
Routine laboratory tests (cont’d)
Category
Test name
A1
B2
C3
24h collection Urine
Urine potassium
Urine sodium
Urine chloride
Urine creatinine
Urine-aldosterone
-
-
-
-
-
X
X
X
X
X
-
-
-
-
-
Urinalysis (Stix)
[Urin-Sediment will be 
performed , if urinalysis 
abnormal]
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine RBC
Urine WBC
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (for 
instance, the presence of sediment bacteria, 
casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1A: parameters to be determined at screening examination 
2B: parameters to be determined during the study (for time points refer to Flow Chart)
3C: parameters to be determined during the Follow-up-examination
* Urine collection fractions will be stored intermittent in a refrigerator. All collected fractions 
(0-24h) will be mixed for the 24h urine electrolyte measurement (intervals from 12:00-24:00, 
108:00-120:00,180:00-192:00h will only be used for urine electrolytes not PK). Mixing 
should be done by transferring the entire content of all collection containers into a single 
PE/PP or glass container, and stirring the mixed fractions for about 1 min (manually or using 
a stir bar or other stirring device out of PE, PP, Teflon or glass). 
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. It is planned to perform these tests during screening only. Drug screening will be 
performed at screening and on Day 1.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody/p24-antigen (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed as indicated in the Flow Chart and may be 
repeated at any time during the study at the discretion of an investigator or designee. The 
results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at Medizinisches 
Versorgungszentrum Dr. Klein, Dr. Schmitt & Partner, Kaiserslautern, Germany with the 
exception of drug screening tests. These tests will be performed at the trial site using 
Multidrogen Pipettiertest (Urin) (Diagnostik Nord GmbH, Schwerin, Germany).
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart. Electrode placement will be performed 
according to the method of Wilson, Goldberger and Einthoven modified by Mason and Likar 
(hips and shoulders instead of ankles and wrists). Precise electrode placement will be marked 
with an indelible mark on the skin to allow reproducible placement throughout the study.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.


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ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart. Three triple ECGs will be recorded at baseline 
as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point. All ECG recordings including the repeat ECGs will be sent to the ECG core lab. 
The central ECG lab will select the ECGs with the best quality at each time point. 


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Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment.
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor (e.g. 
Dash 3000, GE Medical Systems, Freiburg, Germany) at the times indicated in the Flow 
Chart, after subjects have rested for at least 5 min in a supine position. All recordings should 
be made using the same type of blood pressure recording instrument on the same arm if 
possible.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination.
5.2.5.3
Spirometry
Functional FEV1 (Forced expiratory volume in 1 second), FEF25-75 (Forced expiratory
flow) and FVC (Forced vital capacity) will be measured with a diagnostic system (e.g 
FlowScreen® or MasterScope). Measurements will be taken with the subject in seated
position and carried out by an observer (It is preferable that the same trained individual 
performs the measurements for a given subject). The best of three efforts will be defined as 
the highest FEV1 and the highest FVC each obtained on any of three blows meeting the ATS 
criteria (with a maximum of eight attempts). The highest FEV1, FVC and best FEF25-75 


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(taken from the blow with the largest sum of FEV1 and FEV) will be selected regardless of 
whether they come from different spirometric manoeuvres or from the same manoeuvre
(Refer to Flow Chart for time points). Equipment and techniques should conform to 
American Thoracic Society (ATS) criteria [P05-12782].
Abnormal findings will be recorded as AEs if judged clinically relevant by the investigator.
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 


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in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an inhalative administered drug, and are widely used 
in clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5
are generally used for assessments of drug exposure.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct including addition of samples and visits as long as the total 
blood volume taken per subject does not exceed 500 mL. Such changes would be 
implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints
After the first dose:

AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose)

Cmax (maximum measured concentration of the analyte inplasma)
After the last dose:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of analyte plasma concentrations, 3 mL of blood will be taken from an 
antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube (e.g. K2-EDTA BD Vacutainer®, Item no. 368856) at the 
times indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling 
venous catheter or by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8°C. Two plasma aliquots will be obtained and stored in 
polypropylene tubes. The first aliquot should contain at least 0.7 mL plasma. The process 
from blood collection until transfer of plasma aliquots into the freezer should be completed 
within 90 min. For each aliquot the time when the sample was placed in the freezer will be 
documented. Until transfer on dry ice to the analytical laboratory, the aliquots will be stored 
upright at about -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory the plasma samples will be stored at about -20°C or below until 
analysis.


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At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as matrix and 
analyte may also be provided. 
After completion of the trial the plasma samples may be used for further methodological 
investigations,
 
 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.


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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
BI 1265162 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. The analysis will be performed at Drug 
Metabolism and Pharmacokinetics Germany, Boehringer Ingelheim Pharma GmbH & Co 
KG, Biberach, Germany. All details of the analytical method will be available prior to the 
start of sample analysis.
As described in Section 4.1.5, the bioanalyst may be unblinded during sample analysis.
5.6
BIOMARKER
Not applicable.


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5.7
PHARMACODYNAMICS
Not applicable.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
Not applicable.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Days 1 and 8 are to be performed and completed within a 3 h-period prior 
to the trial drug administration (including blank values for PK).
The acceptable deviation from the scheduled time for vital signs, spirometry, ECG and 
laboratory tests will be ± 30 min for the first 4 h after trial drug administration and ± 45 min 
thereafter.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements (if at the same time point as spirometry, spirometry should be last 
measurement) due to its inconvenience to the subject and possible influence on physiological 
parameters.
For planned individual plasma concentration sampling times and 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
6.2.2
Treatment period
Each subject will receive one dose of the respective trial medication (BI 1265162 or placebo) 
at Visit 2.


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Each subject will receive a single dose of BI 1265162 or placebo on Day 1 and Day 8 and 
then daily multiple doses (bid) of BI 1265162 of the respective dose strength or placebo for 
from Day 2 onwards.
Trial medication will be administered by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
Study participants will be admitted to the trial site in the morning of Day -1 for base line 
assessment and kept under close medical surveillance for at least 48 h following the last drug 
administration. The subjects will then be allowed to leave the trial site after formal 
assessment and confirmation of their fitness by the investigator or 
 designee.
For details on time points and procedures for collection of plasma and 
 samples for PK 
analysis, refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 1265162
by using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in Section 5.2.1. Inferential statistics is not planned (as explained 
in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) of BI 1265162. 
Endpoints as specified in Section 5.5.1 will be analysed by descriptive statistics. Secondary 
endpoints as defined in Section 5.5.1.1 will be subjected to analysis of dose proportionality 
by use of the power model.
 
 
 
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 5 different dose groups of BI 1265162 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
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 violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
All treated subjects (that is, all subjects who received at least one dose of study drug), will be
included in the treated set.
The primary endpoint will be analysed only descriptively on the treated set. For more details
see Section 7.3.3.


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7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). Analyses will be 
performed for parent drug.
Plasma and 
concentration data and parameters of a subject will be included in the
statistical pharmacokinetic analysis if they are not flagged for exclusion due to a protocol 
violation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications 
Plasma and 
 concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

the subject experiences emesis at or before two times median tmax of the respective 
treatment. Median tmax is to be determined for the test product excluding the subjects 
experiencing emesis,

missing samples/concentration data at important phases of PK disposition curve.
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 above.
All statistical evaluations of PK parameters will be based on the PKS.
The main analysis of PK parameters will be based on descriptive statistics.
e 
ε
)
X
exp(
)
exp(Y








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7.3.3
Safety analyses
Safety will be assessed for the endpoints and parameters of interest listed in Section 5.2.1. All 
treated subjects (that is, all subjects who received at least one dose of study drug), will be 
included in the safety analysis. Safety analyses will be descriptive in nature and will be based 
on BI standards.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’. 
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until end of the residual 
effect period (see Section 5.2.2.2) will be assigned to the treatment period. Events after the 
residual effect period but prior trial termination date will be summarized as ‘follow-up’.
These assignments including the corresponding time intervals will be defined in detail in the 
TSAP. Please note that AEs occurring after the last per protocol contact but entered before 
database lock will be reported to drug safety only and will not be captured in the trial 
database.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and follow-up).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
For vital signs and spirometry, the differences from baseline will be evaluated.


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7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1265162 will be 
calculated according to the BI SOP ‘Standards and processes for analyses performed within
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma concentrations and individual pharmacokinetic parameters; however, they 
will not be included in descriptive statistics for plasma concentrations, pharmacokinetic 
parameters or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), or BLQ (below the lower limit of quantification) will be displayed as 
such and not replaced by zero at any time point (this rule also applies also to the lag phase,
including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For tabulation and graphical displays, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ will 
be set to zero. All other BLQ values of the profile will be ignored. The lag phase is defined as 
the period between time zero and the first time point with a concentration above the 
quantification limit.


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7.5
RANDOMISATION
Subjects will be randomised within each dose group in a 4:1 ratio, which reflects the ratio of 
subjects receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 50 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 10 subjects per dose group (8 on active treatment, and 2
on placebo) is commonly used in multiple-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics [R95-0013].
Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct provided the planned and approved highest dose 
will not be exceeded. Thus, the actual number of subjects entered may exceed 50, but will not 
exceed 70 subjects entered.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs 
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
As a general rule, no trial results should be published prior to finalisation of the CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’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 subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, 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.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.


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8.3
RECORDS
CRFs for individual subjects 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
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 


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need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P87-3333
Beasley CRW, Rafferty P, Holgate ST. The role of preservatives in 
Atrovent - induced bronchoconstriction. Thorax 1987;42:230-231.
P88-1291
Rafferty P, Beasley R, Holgate ST. Comparison of the efficacy of 
preservative free ipratropium bromide and Atrovent nebulizer solution. 
Thorax 1988;43:446-450.
P96-3855
Ramsey BW. Management of pulmonary disease in patients with cystic
fibrosis. N Engl J Med 1996;335(3):179-188.
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 
2005;99:1087-1095.
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).
P11-05794
Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic 
obstructive pulmonary disease (review). Cochrane Database Syst Rev 
2010(2).
P13-14084
Mogayzel PJ, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, 
Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B, Pulmonary Clinical 
Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines: 
chronic medications for maintenance of lung health. Am J Respir Crit Care 
Med 2013;187(7):680-689.
R95-0013
Broom C. Design of first-administration studies in healthy man. Early 
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R01-1277
Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care 
Med 1996;154:1229-1256.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005).
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).


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R15-0689
O'Riordan TG, Donn KH, Hodsman P, Ansede JH, Newcomb T, Lewis SA, 
Flitter WD, White VS, Johnson MR, Montgomery AB, Warnock DG, 
Boucher RC. Acute hyperkalemia associated with inhalation of a potent 
ENaC antagonist: phase 1 trial of GS-9411. J Aerosol Med Pulm Drug 
Deliv 2014;27(3):200-208.
R15-3034
Chronic respiratory diseases: burden of COPD. 
http://www.who.int/respiratory/copd/burden/en/ (access date: 
11 June 2015); World Health Organization; 2015.
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 2007;4(2):63-72.
R15-4984
Elborn JS, Shale DJ. Lung injury in cystic fibrosis. Thorax 1990;45:970-
973.
R15-5349
Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King 
M, Edwards LJ, Helms RW, Boucher RC. A pilot study of aerosolized 
amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med. 
1990 Apr 26;322(17):1189-94
R15-5485
App EM, King M, Helfesrieder R, Köhler D, Matthys H. Acute and 
longterm amiloride inhalation in cystic fibrosis lung disease. A rational 
approach to cystic fibrosis therapy. Am Rev Respir Dis. 1990 
Mar;141(3):605-12
R15-5486
Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC. 
Defective epithelial chloride transport in a gene-targeted mouse model of 
cystic fibrosis. Science 1992;257(5073):1125-1128.
R15-5487
Koehler D, App E, Schmitz-Schumann M, Wuertemberger G, Matthys H. 
Inhalation of amiloride improves the mucociliary and the cough clearance 
in patients with cystic fibroses. Eur J Respir Dis Suppl 1986;146:319-326.
R15-5503
Walters S, Mehta A. Epidemiology of cystic fibrosis. In: Hodson M, 
Geddes D, Bush A, editors. Cystic fibrosis. 3rd ed. London: Hodder 
Arnold; 2007. p. 21-45.
R15-5505
Pons, G., Marchand, M. C., D'Athis, P., Sauvage, E., Foucard, C., 
Chaumet-Riffaud, and Lenoir, G. (2000). French multicenter randomized 
double-blind placebo-controlled trial on nebulized amiloride in cystic 
fibrosis patients. Pediatr. Pulmonol., 30(1), 25-31
R15-5507
Mall MA, Button B, Johannesson B, Zhou Z, Livraghi A, Caldwell RA, 
Schubert SC, Schultz C, O'Neal WK, Pradervand S, Hummler E, Rossier 
BC, Grubb BR, Boucher RC. Airway surface liquid volume regulation 
determines different airway phenotypes in Liddle compared with 
betaENaC-overexpressing mice. J Biol Chem 2010;285(35):26945-26955.
R15-5546
Genes and human disease: monogenic diseases. 
http://www.who.int/genomics/public/geneticdiseases/en/index2.html#CF 


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(access date: 28 October 2015) ; Geneva: World Health Organization 
(WHO); 2015.
R15-5599
Graham, A., Hasani, A., Alton, E. W. F. W., Martin, G. P., Marriott, C., 
Hodson, M. E., and Geddes, D. M. (1993). No added benefit from 
nebulized amiloride in patients with cystic fibrosis. Eur. Respir. J., 6(9), 
1243-1248.
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015).
R17-1997
Rowe SM, Verkman AS. Cystic fibrosis transmembrane regulator 
correctors and potentiators. Cold Spring Harb Perspect Med 
2013;3:a009761.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c10884768
. Safety, tolerability and 
pharmacokinetics of single rising inhaled doses of BI 443651 in healthy 
male volunteers in a partially randomised, single blind, placebo-controlled 
trial.
c16304878
  Investigator`s Brochure BI-1265162 Cystic fibrosis and COPD  
05 Sep 2017.
U97-0056
  A three way crossover study in healthy 
volunteers of lung deposition of fenoterol hydrobromide (100 mcg via one 
puff) delivered from either a BINEB (Ariane) nebuliser, or a conventional 
MDI, or a conventional MDI with a spacer.  260.2706  20 Jun 1996.


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10.
APPENDICES
10.1
HANDLING INSTRUCTIONS FOR RESPIMAT INHALER FOR USE IN 
CLINICAL TRIALS 
These instructions explain generally the use of BI 1265162 RESPIMAT inhaler. Depending 
on the clinical study, the product is administered under direct medical supervision or used by 
patients at home. Depending on the situation, the Instructions can be adapted to the specific 
situation as need may be.
Read these Instructions for Use before you start demonstrating or using RESPIMAT.
How to store BI 1265162 RESPIMAT
Keep BI 1265162 RESPIMAT out of the sight and reach of children.
Do not freeze BI 1265162 RESPIMAT. For further storage conditions, please refer to product 
label.
If BI 1265162 RESPIMAT has not been used for more than 7 days, repeat steps 4 to 6 (turn, 
open, press) under ‘Prepare for first Use’ until a cloud is visible. Then repeat steps 4 to 6 
three more times.
Do not use BI 1265162 RESPIMAT after the expiry date.
How to care for BI 1265162 RESPIMAT
Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or 
tissue, at least once a week. Cleaning on a daily basis or daily disinfection with an alcoholic 
tissue is also possible.
Any minor discoloration in the mouthpiece does not affect BI 1265162 RESPIMAT inhaler 
performance.


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BI Trial No.: 1399-0002
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When to get a new BI 1265162 RESPIMAT
•
BI 1265162 RESPIMAT inhaler contains 120 puffs if used as indicated.
•
The dose indicator shows approximately how much medication is left.
•
When the dose indicator enters the red area of the scale, get a new 
BI 1265162 RESPIMAT from the investigational site; there are approximately 30 puffs 
left.
•
Once the dose indicator reaches the end of the red scale, BI 1265162 RESPIMAT locks 
automatically – no more doses can be released. At this point, the clear base cannot be 
turned any further. The inhaler should not be discarded; it should be returned to 
investigational site.
Prepare for first use
Remove clear base
Keep the cap closed.
Press the safety catch while firmly pulling 
off the clear base with your other hand.
Insert cartridge
Insert the narrow end of the cartridge into 
the inhaler.
Place the inhaler on a firm surface and 
push down firmly until it snaps into place.


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Replace clear base
Put the clear base back into place until it 
clicks. 
Turn
Keep the cap closed.
Turn the clear base in the direction of the 
arrows on the label until it clicks (half a 
turn).
Open
Open the cap until it snaps fully open.
Press
Point the inhaler toward the ground
Press the dose-release button.
Close the cap.
Repeat steps 4-6 until a cloud is visible.
After a cloud is visible, repeat steps 4-6 
three more times.


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Daily use
TURN
Keep the cap closed.
TURN the clear base in the direction of the 
arrows on the label until it clicks (half a turn).
OPEN
OPEN the cap until it snaps fully open.
PRESS
Breathe out slowly and fully.
Close your lips around the mouthpiece without 
covering the air vents.
While taking a slow, deep breath through your 
mouth, PRESS the dose-release button and 
continue to breathe in.
Hold your breath for 10 seconds or for as long as 
comfortable.
Repeat Turn, Open, Press for a total of puffs
required by the clinical trial protocol.
Close the cap until you use your BI 1265162 
RESPIMAT inhaler again.


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Answers to Common Questions
It is difficult to insert the cartridge deep enough.
Did you accidentally turn the clear base before inserting the cartridge? Open the cap, 
press the dose-release button, then insert the cartridge.
Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow 
end first.
I cannot press the dose-release button.
Did you turn the clear base? If not, turn the clear base in a continuous movement until it 
clicks (half a turn).
Is the dose indicator on BI 1265162 RESPIMAT pointing to zero? 
BI 1265162 RESPIMAT inhaler is locked after 120 puffs. Prepare and use a new 
BI 1265162 RESPIMAT inhaler.
I cannot turn the clear base.
Did you turn the clear base already? If the clear base has already been turned, follow steps 
“OPEN” and “PRESS” under “Daily Use” to get your medicine. 
Is the dose indicator on the BI 1265162 RESPIMAT pointing to zero? The 
BI 1265162 RESPIMAT inhaler is locked after 120 puffs. Prepare and use your new 
RESPIMAT inhaler.
The dose indicator on the BI 1265162 RESPIMAT reaches zero too soon. 
Did you turn the clear base before you inserted the cartridge? The dose indicator counts 
each turn of the clear base regardless whether a cartridge has been inserted or not.
Did you spray in the air often to check whether the BI 1265162 RESPIMAT is working? 
Once you have prepared BI 1265162 RESPIMAT, no test-spraying is required if used daily.
Did you insert the cartridge into a used RESPIMAT? Always insert a new cartridge into a 
NEW RESPIMAT.
BI 1265162 RESPIMAT sprays automatically.
Was the cap open when you turned the clear base? Close the cap, then turn the clear base.
Did you press the dose-release button when turning the clear base? Close the cap, so the 
dose-release button is covered, then turn the clear base.
Did you stop when turning the clear base before it clicked? Turn the clear base in a 
continuous movement until it clicks (half a turn).
BI 1265162 RESPIMAT doesn’t spray.
Did you insert a cartridge? If not, insert a cartridge.


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Did you repeat Turn, Open, Press less than three times after inserting the cartridge? 
Repeat Turn, Open, Press three times after inserting the cartridge as shown in the steps 4 to 6 
under “Prepare for first Use”.
Is the dose indicator on BI 1265162 RESPIMAT pointing to 0? If the dose indicator 
points to 0, you have used up all your medication and the inhaler is locked.
Once BI 1265162 RESPIMAT is assembled, do not remove the clear base or the cartridge. 
Always insert a new cartridge into a NEW RESPIMAT.
Further information
BI 1265162 RESPIMAT inhaler must not be disassembled after inserting the cartridge and 
replacing the clear base.
Do not touch the piercing element inside the base.
Boehringer Ingelheim Pharma GmbH & Co. KG
D - 55216 Ingelheim, Germany  


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
25 June 2018
EudraCT number
2017-001107-71
BI Trial number
1399-0002
BI Investigational Product(s)
BI 1265162
Title of protocol
Safety, tolerability and pharmacokinetics of 
multiple rising inhaled doses of BI 1265162 in 
healthy male subjects in a randomised, double 
blind, placebo-controlled trial
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis and 3.3.2 Inclusion Criteria No 2
Description of change
Upper age was changed from 50 to 45 years
Rationale for change
Request by CA


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Number of global amendment
2
Date of CTP revision
04 July 2018
EudraCT number
2017-001107-71
BI Trial number
1399-0002
BI Investigational Product(s)
BI 1265162
Title of protocol
Safety, tolerability and pharmacokinetics of 
multiple rising inhaled doses of BI 1265162 in 
healthy male subjects in a randomised, double 
blind, placebo-controlled trial
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flowchart
Description of change
Planned time corrected on day 3 (47:00 to 47:55)
Rationale for change
Initial wrong planned time on day 3


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15848749
3.0
clinical-trial-protocol-revision-02
Safety, tolerability and pharmacokinetics of multiple rising inhaled doses of BI
1265162 in healthy male subjects in a randomised, double blind, placebo-controlled
trial
Author-Trial Clinical
Pharmacokineticist
04 Jul 2018 20:58 CEST
Approval-Biostatistics
05 Jul 2018 07:58 CEST
Author-Trial Clinical Monitor
05 Jul 2018 08:30 CEST
Approval-Therapeutic Area 
05 Jul 2018 12:02 CEST
Approval-Team Member Medicine
05 Jul 2018 14:17 CEST
Verification-Paper Signature
Completion
09 Jul 2018 10:26 CEST
Author-Trial Statistician
09 Jul 2018 12:17 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15848749
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26340025-01
BI Trial No.:
1399-0002
Title:
Safety, tolerability and pharmacokinetics of multiple rising inhaled 
doses of BI 1265162 in healthy male subjects in a randomised, 
double blind, placebo-controlled trial
Final protocol (including protocol revision 1 (c15848749-02) and 2 
(c15848749-03))
Investigational
Product(s):
BI 1265162
Responsible trial 
statistician(s):
Phone: 
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
11 JAN 2019 SIGNED 
Version:
“Final”
Page 1 of 31
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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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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 .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........20
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINT .....................................................................................20
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoint .....................................................................................20
7.5.2
Secondary endpoints...........................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse events.....................................................................................................22
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................24


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7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................26
8.
REFERENCES....................................................................................................27
10.
HISTORY TABLE..............................................................................................31


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data, vital signs, spirometry and ECG.............................................12
Table 6.2: 1
Important protocol deviations...........................................................................14
Table 6.3: 1
Subject sets analysed ........................................................................................15
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation ..........17
Table 6.7: 2
Time schedule of urine electrolyte measurements ...........................................18
Table 10: 1
History table .....................................................................................................31


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
 
 
AUCτ,1
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a dosing interval τ
BI 
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
FEF25-75
Forced expiratory flow
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
gCV
geometric coefficient of variation
ICH
International Conference On Harmonisation
IPD
Important Protocol Deviation
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed
NOR
No valid result
NOS
No sample available


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Term
Definition / description
PD
Protocol Deviation
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter set
PR
Pulse rate
RAGe
Report appendix generator
RPM
Report Planning Meeting
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its 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, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
Certara USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the revised CTP.
The secondary endpoint AUCτ,1 (as defined in the CTP) is described as AUC0-12 in this TSAP.
This is not a change in the planned analysis. Only a more precise parameter name is used.
The definition of baseline ECG is not described properly in the CTP (Section 5.2.4.1). In this 
TSAP, the derivation of baseline ECG values is described in more detail to clarify how data 
are analysed. Prior to first study drug administration, 3 triplicate ECGs (9 single ECGs) will 
be recorded. The mean of the first ECG measurement of each triple ECG will be analysed.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint is the number of subjects with drug-related AEs, as defined in Section 5.2.1 
of the CTP.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints of this trial are AUC0-12 and Cmax of BI 1265162 in plasma after the first 
dose, AUCτ,ss and Cmax,ss of BI 1265162 in plasma after the last dose, as defined in 
Section 5.5.1.1 of the CTP.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, cf. Section 4 of the CTP.
Subjects were planned to be treated either with

multiple doses of 10, 30, 100, 300, or 600 μg of BI 1265162 (test treatments)
or

multiple doses of placebo (reference treatment)
The subjects will receive a single dose of BI or placebo in the morning on Day 1 and Day 8. 
On days 2-7 the subjects will receive the dose of BI or placebo twice daily. For the analysis, 
the on-treatment period will include all treatment days independent of the number of the total 
number of doses per day.
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).
Analysis phases for statistical analysis of AEs, safety laboratory data, vital signs, spirometry
and ECG are defined for each subject as described in the table below.
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data, vital signs, spirometry and ECG
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
Pbo,
10 ug BI,
30 ug BI,
100 ug BI,
300 ug BI,
or 600 ug BI,
respectively
Date/time of first 
administration of study 
drug
Date/time of last 
administration of BI 1265162
+ REP 
 or 12:00 
a.m. on day after subject's trial 
termination date, whichever 
occurs earlier
Follow-up1
F/U Pbo,
F/U 10 ug BI,
F/U 30 ug BI,
F/U 100 ug BI,
F/U 300 ug BI,
or F/U 600 ug BI,
respectively
Date/time of last 
administration of 
BI 1265162 + REP 
 
12:00 a.m. on day after 
subject's trial termination date
1 Follow-up phases might not exist, e.g. if the subject's trial termination date is within 2 days after last administration of
BI 1265162.
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only.


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In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 
AE tables), the following totals will be provided in addition:

"Total BI", defined as the total over all on-treatment phases involving BI

"Total on-trt", defined as the total over all on-treatment phases, including placebo
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening, on-treatment and 
follow-up phases.
Additionally to the totals defined above, the following total will be provided in CTR Section 
16.1.13.1.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment + follow-up)
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients entered and 
randomised who did not fail during screening.
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the report planning and database lock meeting (RPM/DBLM). 
At this meeting, it will be decided whether a discrepant data value can be used in analyses or 
whether it must be corrected in the clinical database. Each protocol deviation must be 
assessed to determine whether it is an important protocol deviation (iPD). For definition of 
iPDs, and for the process of identification of these, refer to the Boehringer Ingelheim (BI) 
SOP "Integrated Quality and Risk Management Process" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying excel spreadsheet. The table below contains 
the categories which are considered to be iPDs in this trial. If the data show other important 
PDs, this table will be supplemented accordingly by the time of the RPM/DBLM.
iPDs will be summarised and listed.


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Table 6.2: 1
Important protocol deviations
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C3
Non-compliance
C4
Incorrect intake of trial medication
C5
Incorrect dose of trial medication taken
D
Concomitant medication
D1
Prohibited medication use
E
Missing data
None1
G
Other trial specific important deviation
G1
Certain deviations of procedures used to measure secondary PK data
Deviations C1, C2, C5 and G1 can only be detected at the trial site.
1 Missing visits, evaluations, and tests will be considered missing data, not protocol deviations
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH-E9. It will be used for 
analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one PK parameter 
that was not excluded because of PDs relevant to the statistical evaluation of PK 
endpoints as defined in Section 7.3 of the CTP.


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The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
IPDs
X
Demographic/baseline endpoints
X
Primary endpoint
X
Other safety parameters
X
Secondary PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.


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Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) will 
be reported in the CTR as far as their data are available. All withdrawals will be documented 
and the reason for withdrawal recorded in the CTR.
CTP: With respect to safety evaluations, it is not planned to impute missing values.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
Missing data and outliers of PK data are handled according to BI standards (4).
Plasma 
 concentration-time tables
CTP: Drug concentration data identified with NOS (no sample available), NOR (no valid 
result), NOA (not analysed) or BLQ (below the lower limit of quantification) will be displayed 
as such and not replaced by zero at any time point (this rule also applies to the lag phase, 
including the predose values).
Pharmacokinetic parameters 
CTP: For tabulation and graphical displays, concentration data identified with NOS, NOR or 
NOA will generally not be considered. Concentration values in the lag phase identified as 
BLQ will be set to zero. All other BLQ values of the profile will be ignored. The lag phase is 
defined as the period between time zero and the first time point with a concentration above 
the quantification limit.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
There will be a centralised evaluation of 12-lead ECG recordings at the time points specified 
in Table 6.7: 1.
Triple ECGs will be recorded at Visit 2 assessments and will be evaluated by a central lab. At 
Visit 1 and 3 only single ECGs will be recorded. This data will not be evaluated centrally. At 
predose (Visit 2, Day 1, planned time point -01:30, notation for data transfer -01:30, -01:25, 
and -01:20), three triplicate ECGs (9 single ECGs) will be recorded.


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For all on-treatment assessments as well as for the 3 predose triplicates, only the first of the 3 
replicate ECGs at a single assessment time will be evaluated centrally.
The baseline value of an ECG variable is defined as the mean of the first single ECG 
measurement of each triple ECG prior to first drug administration.
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation
Visit
Day
Planned time [hh:mm]
- relative to respective drug 
administration
Study phase
2
1
-01:30
Baseline 
00:10
On-treatment
01:00
04:00
12:00
2
24:10
3
48:10
5
96:10
6
120:10
8
164:30
168:10
169:00
172:00
180:00
9
191:30
For urine electrolytes there is a whole baseline day to have time matched baseline 
measurements (see Table 6.7: 2 for details).
In all other analyses 
 the last non-missing value 
determined prior to the first dosing of BI 1265162 will be defined as baseline. 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.
Unscheduled measurements of laboratory data, vital signs or spirometry data will be assumed 
to be repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement.


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Table 6.7: 2
Time schedule of urine electrolyte measurements
Visit
Day
Planned time interval [hh:mm]
- relative to respective drug administration
(planned time at the day)
Study phase
2
-1
-24:00 to -20:00 (08:00 to 12:00)
Baseline 
-20:00 to -16:00 (12:00 to 16:00)
-16:00 to -12:00 (16:00 to 20:00)
-12:00 to 00:00 (20:00 to 08:00 on Day 1)
5
96:00 to 100:00 (08:00 to 12:00)
On-treatment
100:00 to 104:00 (12:00 to 16:00)
104:00 to 108:00 (16:00 to 20:00)
108:00 to 120:00 (20:00 to 08:00 on Day 6)
8
168:00 to 172:00 (08:00 to 12:00)
172:00 to 176:00 (12:00 to 16:00)
176:00 to 180:00 (16:00 to 20:00)
180:00 to 192:00 (20:00 to 08:00 on Day 9)
Descriptive statistics of laboratory data will be calculated by planned time point based on the 
worst value of the subject at that planned time point (or assigned to that planned time point).
For vital signs and spirometry, descriptive statistics will be calculated by planned time point 
based on the last value of the subject at that planned time point (or assigned to that planned 
time point).


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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" (5).
The individual values of all subjects will be listed. Listings will generally be sorted by dose 
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 (SDL) 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 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
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical to 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 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the World Health Organisation – Drug 
Dictionary, version March 2018.
Only descriptive statistics are planned for this section of the CTR based on the TS.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of first administration of the respective treatment or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM/DBLM (cf. Section 6.2) and described in the 
CTR.
7.4
PRIMARY ENDPOINT
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis of 
the number of subjects with drug related AEs, which is the primary endpoint of this trial.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.
Dose proportionality will be evaluated as defined in the CTP, Section 7.3.2, by use of the 
power model for the secondary endpoints AUC0-12, Cmax, AUCτ,ss and Cmax,ss of BI 1265162 in 
plasma. 


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Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (6).


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7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
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.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to the screening or on-treatment phase as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1: 1.
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 (8) and for the class of 
AESIs.
CTP: The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
○
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 sample, or
○
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or


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(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related (primary 
endpoint) will be summarised separately. Separate tables will also be provided for subjects 
with SAEs, subjects with AESIs and subjects with other significant AEs (according to ICH E3 
(8)). The frequency of subjects with AEs and the frequency of subjects with AEs considered 
by the investigator to be drug related will also be summarised by maximum intensity, primary 
SOC and preferred term.
The system organ classes and preferred terms within system organ classes will be sorted by 
descending frequency overall treatment groups.
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 SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. For urine electrolytes (including potassium-creatinine quotient 
and sodium-creatinine quotient), the time matched change from baseline is analysed. In 
addition, median urine and serum electrolytes over time will be presented graphically. The 
graphics will also be prepared for the ratio of sodium / potassium in urine. Frequency tables 
of changes between baseline and last value on treatment with respect to the reference range 
will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM/DBLM at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. Standard 
or project-specific rules for flagging clinically significant values in an automated manner will 
not be applied in this study.


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Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
Exposure-response analysis
The relationship between BI 1265162 plasma concentrations and serum potassium and 
sodium difference from baseline (see Section 6.7) will be analysed descriptively. Scatterplots 
of plasma concentration versus lab parameter will be prepared by dose groups. All time points 
with available lab data and valid time-matched plasma drug concentrations will be included. 
The following time points are matched time points for serum electrolytes and drug 
concentration: Day 1 2:00, Day 2 23:55, Day 8 07:55 and Day 8 10:00.  
For the handling of missing values, see Section 6.6. The placebo subjects will not be included 
in this analysis.
The relationship between the amount of BI 1265162 that is eliminated in urine during a 12h 
interval and urine potassium and sodium change from baseline will be analysed similarly. The 
following time points are matched time points for urine electrolytes and amount of eliminated 
BI 1265162: Day 1 08:00 to 20:00, Day 5 08:00 to 20:00, and Day 8 08:00 to 20:00.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
12-lead ECG
ECG data will be analysed based on dose groups.
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator. 


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7.8.5
Others
Spirometry
CTP: For […] spirometry, the differences from baseline will be evaluated.
Descriptive statistics of spirometry endpoints (FEV1, FVC and FEF25-75) over time and their 
change from baseline will be presented. Additionally, plots over the time will be provided for 
spirometry data. Individual subject data and the mean per dose group will be presented.
Clinically relevant findings in spirometry data will be reported as AEs and will be analysed as 
part of AE analysis.
Physical examinations
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
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9; 
Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical Trialss, 
current version
2
001-MCS-40-135: “Integrated Quality and Risk Management Process”, current version; 
IDEA for CON
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON
5
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current version; 
IDEA for CON
6
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD Data 
Files", current version; IDEA for CON
7
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical Trials", 
current version; IDEA for CON
8
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version
9
001-MCG-157: "Display and Analysis of Laboratory Data", current version; IDEA for 
CON


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
11-JAN-18
None
This is the final TSAP without any 
modification