Clinical trial NCT03907280
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2019-04-23; Completion date: 2019-12-06
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of this trial is to investigate the absolute bioavailability of BI 1265162 following administration of oral solution and inhaled (with and without charcoal) via Respimat.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: BI 1265162 (T1) intervention 2: BI 1265162 (T2) intervention 3: BI 1265162 (R) intervention 4: BI 1265162 (T3)
Intervention descriptions: intervention 1: oral solution intervention 2: Solution for inhalation intervention 3: concentrate for i.v. solution intervention 4: Solution for inhalation

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 08 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c25000855-04
EudraCT No.
2018-002689-38
BI Trial No.
1399-0014
BI Investigational
Medicinal Product
BI 1265162
Title
Absolute bioavailability of BI 1265162 following oral and inhaled
administration in healthy male volunteers (an open-label, 
randomised, single-dose, three-period, three-sequence crossover 
study followed by a fixed treatment)
Lay Title
A study in healthy men that tests if taking BI 1265162 by mouth, 
intravenously, or inhaled influences the amount of BI 1265162 in 
the blood
Clinical Phase
I
Trial Clinical Leader
Phone: 
Fax:
Principal 
Investigator
Phone: 
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 3))
Version and Date
Version: 4.0
Date: 20 August 2019
Page 1 of 81
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
30 Jan 2019
Revision date
20 Aug 2019
BI trial number
1399-0014
Title of trial
Absolute bioavailability of BI 1265162 following oral and inhaled administration in 
healthy male volunteers (an open-label, randomised, single-dose, three-period, 
three-sequence crossover study followed by a fixed treatment)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
This study will generate pharmacokinetic information on the absolute 
bioavailability following inhaled (with and without charcoal) and oral dosing versus 
intravenous infusion to support the planned human ADME trial and future 
development of BI 1265162 in patients.
Trial objective
To investigate the absolute bioavailability of BI 1265162 following oral and inhaled 
(with and without charcoal) administration
Trial design
Randomised, open-label, three-way crossover followed by a fixed treatment design 
Trial endpoints:
Primary endpoints: AUC0-of BI 1265162
Number of subjects 
total entered
12
each treatment
12
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product 1
Drug formulation BI 1265162 oral solution
dose
*Doses are tentative and may be adapted after first period (cf. 7.4)
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 8 h (T1)


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Test product 2
Drug formulation BI 1265162 solution for inhalation
dose
mode of admin.
Inhaled by Respimat after an overnight fast of at least 8 h in combination with 
activated charcoal (T2) and without activated charcoal (T3).
Reference product
Drug formulation (R) BI 1265162 concentrate for infusion
dose
* Doses are tentative and may be adapted after first period (cf. 7.4)
mode of admin.
Intravenous over 1h after an overnight fast of at least 8 h 
Duration of treatment
One day (single dose) for each treatment with a wash out period of at least 6 days 
between each treatment period
Statistical methods
Absolute bioavailability (F) will be estimated by the ratios of the geometric means 
(Ti/R, i=1,2, 3) for the dose-normalized primary endpoint following oral and
inhaled administrations. Additionally, their two-sided 90% confidence intervals 
(CIs) will be provided. This method corresponds to the two one-sided t-test 
procedure, each at a 5% significance level. Since the main focus is on estimation 
and not testing, a formal hypothesis test and associated acceptance range is not 
specified. The statistical model will be an analysis of variance (ANOVA) on the 
logarithmic scale including effects for sequence, subjects nested within sequences, 
period and treatment. CIs will be calculated based on the residual error from the 
ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART – ORAL ADMINISTRATION (T1)
Period
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
PK/Metabolites blood
Safety laboratory
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
x
1/2/3/4 (four periods separated by a wash-out of 
at least 6 days)
2/3
/4
-1
-12:00
20:00
Admission to trial site (Device training
if needed)
x5
x
1
-1:00
07:00
Allocation to treatment2 (visit 2 only)
(Device training if needed)
x2
x2
x2
x2
x2
0:00
08:00
BI 1265162 administration + 240 mL 
fluid intake
0:30
08:30
x
0:45
08:45
x
1:00
09:00
x
2:00
10:00
240 mL fluid intake
x
x7
x
x
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
11:00
19:00
Dinner
12:00
20:00
x
x 
2
24:00
08:00
Breakfast (voluntary)3,
discharge from trial site
x
x
x
x
x
FU
6
3 to 7
End of trial (EOS) examination4
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the End of trial (EoTrial) examination includes physical examination, vital signs, ECG, safety 
laboratory, recording of AEs and concomitant therapies. 
5.
Only urine drug screening and alcohol breath test will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Serum electrolytes only 


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FLOW CHART – INHALED ADMINISTRATION (T2 AND T3)
Period
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
PK/Metabolites blood
Safety laboratory
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
x
1/2/3/4 (four periods separated by a wash-out of at least 6 days)
2/3
/4/
5*
-1
-12:00
20:00
Admission to trial site (Device training 
if needed)
x5
x
1
-1:00
07:00
Allocation to treatment2 (visit 2 only)
(Device training if needed)
x2
x2
x2
x2
x2
-0:15
07:45
Active charcoal administration (T2 
only)
0:00
08:00
BI 1265162 administration
0:02
08:02
x
0:03
08:03
Active charcoal administration (T2 
only)
0:05
08:05
x
0:10
08:10
x
0:15
08:15
x
0:40
08:40
x
1:00
09:00
x
1:05
09:05
Active charcoal administration (T2 
only)
2:00
10:00
240 mL fluid intake
x
x7
x
x
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
8:00
16:00
Snack (voluntary) 3
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x 
2
24:00
08:00
Breakfast (voluntary)3,
discharge from trial site
x
x
x
x
x
FU
6
3 to 7
End of trial (EOS) examination4
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. 
5.
Only urine drug screening and alcohol breath test will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Serum electrolytes only
*
At Visit 5/period 4 all subjects receive treatment T3


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FLOW CHART – INTRAVENOUS ADMINISTRATION (R)
Period
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Intravenous admin.
PK/Metabolites blood
Safety laboratory
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
x
1/2/3/4 (four periods separated by a wash-out of at least 6 days)
2/3
/4
-1
-12:00
20:00
Admission to trial site (Device training 
if needed)
x5
x
1
-1:00
07:00
Allocation to treatment2 (visit 2 only) 
(Device training if needed)
x2
x2
x2
x2
x2
0:00
08:00
Start of BI 1265162 administration  + 
240 mL fluid intake
▲
0:05
08:05
│
x
0:30
08:30
│
x
0:59
08:59
│
x
1:00
09:00
▼
x
x
1:05
09:05
x
1:10
09:10
x
1:20
09:20
x
1:40
09:40
x
2:00
10:00
240 mL fluid intake
x
x7
x
x
x8
2:30
10:30
x
3:00
11:00
x
3:30
11:30
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
5:00
13:00
x
7:00
15:00
x
8:00
16:00
Snack (voluntary)
9:00
17:00
x
11:00
19:00
Dinner3
x
13:00
21:00
x
x
2
24:00
08:00
Breakfast (voluntary)3,
discharge from trial site
x
x
x
x
x8
FU
6
3 to 7
End of trial (EOS) examination4
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. 
5.
Only urine drug screening and alcohol breath test will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Serum electrolytes only
8. 
Includes assessment of local tolerability


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART – ORAL ADMINISTRATION (T1) .....................................4
FLOW CHART – INHALED ADMINISTRATION (T2 AND T3)...............5
FLOW CHART – INTRAVENOUS ADMINISTRATION (R).....................6
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 28
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......28
2.1.1
Main objectives......................................................................................28
2.1.2
Primary endpoint..................................................................................28
2.1.3
Secondary endpoint ..............................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 30
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................30
3.3.1
Main diagnosis for trial entry..............................................................31
3.3.2
Inclusion criteria...................................................................................31


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3.3.3
Exclusion criteria ..................................................................................31
3.3.4
Withdrawal of subjects from treatment or assessments ...................32
3.3.4.1
Discontinuation of trial treatment............................................33
3.3.4.2
Withdrawal of consent to trial participation ............................33
3.3.4.3
Discontinuation of the trial by the sponsor..............................33
3.3.5
Replacement of subjects .......................................................................34
4.
TREATMENTS........................................................................................ 35
4.1
INVESTIGATIONAL TREATMENTS ..........................................................35
4.1.1
Identity of the Investigational Medicinal Products ...........................35
4.1.2
Method of assigning subjects to treatment groups ............................36
4.1.3
Drug assignment and administration of doses for each subject .......36
4.1.4
Blinding and procedures for unblinding ............................................37
4.1.5
Packaging, labelling, and re-supply ....................................................38
4.1.6
Storage conditions.................................................................................38
4.1.7
Drug accountability ..............................................................................38
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................39
4.2.1
Other treatments and emergency procedures....................................39
4.2.2
Restrictions............................................................................................39
4.2.2.1
Restrictions regarding concomitant treatment .........................39
4.2.2.2
Restrictions on diet and life style.............................................39
4.3
TREATMENT COMPLIANCE.......................................................................40
5.
ASSESSMENTS....................................................................................... 41
5.1
ASSESSMENT OF EFFICACY.......................................................................41
5.2
ASSESSMENT OF SAFETY............................................................................41
5.2.1
Physical examination ............................................................................41
5.2.2
Vital signs...............................................................................................41
5.2.3
Safety laboratory parameters..............................................................41
5.2.4
Electrocardiogram................................................................................43
5.2.5
Other safety parameters.......................................................................44
5.2.5.1
Local tolerability......................................................................44
5.2.6
Assessment of adverse events...............................................................44
5.2.6.1
Definitions of adverse events...................................................44
Adverse event ............................................................44
5.2.6.1.1
Serious adverse event ................................................45
5.2.6.1.2
AEs considered ‘Always Serious’.............................45
5.2.6.1.3
Adverse events of special interest .............................45
5.2.6.1.4
Intensity (severity) of AEs.........................................46
5.2.6.1.5
Causal relationship of AEs ........................................46
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................47


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AE collection.............................................................47
5.2.6.2.1
AE reporting to the sponsor and timelines ................48
5.2.6.2.2
Information required..................................................48
5.2.6.2.3
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................48
5.3.1
Assessment of pharmacokinetics .........................................................48
5.3.2
Methods of sample collection...............................................................48
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................48
5.3.2.2
Plasma sampling for metabolism analysis ...............................49
5.3.3
Analytical determinations ....................................................................50
5.3.3.1
Analytical determination of analyte plasma concentration......50
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................50
5.4
ASSESSMENT OF BIOMARKER(S) .............................................................50
5.5
BIOBANKING ...................................................................................................50
5.6
OTHER ASSESSMENTS .................................................................................50
5.6.1
Pharmacogenomic evaluation..............................................................50
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................50
6.
INVESTIGATIONAL PLAN.................................................................. 52
6.1
VISIT SCHEDULE............................................................................................52
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................52
6.2.1
Screening period....................................................................................52
6.2.2
Treatment period ..................................................................................52
6.2.3
Follow-up period and trial completion ...............................................53
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 54
7.1
STATISTICAL DESIGN – MODEL ...............................................................54
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................54
7.3
PLANNED ANALYSES....................................................................................55
7.3.1
Primary endpoint analyses...................................................................56
7.3.2
Secondary endpoint analyses ...............................................................58
7.3.4
Safety analyses.......................................................................................58
7.4
EXPLORATORY PK ANALYSES..................................................................59
7.5
HANDLING OF MISSING DATA ..................................................................60
7.5.1
Safety......................................................................................................60
7.5.2
Pharmacokinetics..................................................................................60
7.6
RANDOMISATION ..........................................................................................60
7.7
DETERMINATION OF SAMPLE SIZE ........................................................60


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 62
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................62
8.2
DATA QUALITY ASSURANCE .....................................................................63
8.3
RECORDS..........................................................................................................63
8.3.1
Source documents .................................................................................63
8.3.2
Direct access to source data and documents.......................................64
8.3.3
Storage period of records.....................................................................64
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................65
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......65
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................65
8.6
TRIAL MILESTONES .....................................................................................65
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................66
9.
REFERENCES......................................................................................... 67
9.1
PUBLISHED REFERENCES...........................................................................67
9.2
UNPUBLISHED REFERENCES.....................................................................68
10. APPENDICES .......................................................................................... 70
10.1
HANDLING INSTRUCTIONS BI 1265162 ORAL SOLUTION .................70
10.1.1 Overview................................................................................................70
10.1.2 List of Consumables..............................................................................70
10.1.3 Preparation for administration of the BI 1265162 oral solution 
(0.25 mg/mL) .........................................................................................70
10.1.4 In-use stability.......................................................................................71
10.1.5 Mode of application ..............................................................................71
10.2
HANDLING INSTRUCTIONS FOR BI 1265162 CONCENTRATE FOR 
SOLUTION FOR INFUSION ..........................................................................71
10.2.1 Overview................................................................................................71
10.2.2 List of Consumables..............................................................................71
10.2.3 Preparation of the BI 1265162 solution for infusion (5 µg/mL) .......72
10.2.4 In-use stability.......................................................................................73
10.2.5 Mode of application ..............................................................................73
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 79
11.1
GLOBAL AMENDMENT 1 .............................................................................79
11.2
GLOBAL AMENDMENT 2 .............................................................................80
11.3
GLOBAL AMENDMENT 3 .............................................................................81


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BID
Three times daily
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CML
Clinical Monitor Local
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial (EOS)
End of trial
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FU
Follow-up


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GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HPC
Human Pharmacology Centre
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
IV
Intravenous
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRT,in(ex)
Mean residence time of the analyte in the body after intravascular
(extravascular) administration
PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QD
Twice daily 
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)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or treatment
tz,start(end)
Lower (upper) limit on time for values to be included in the calculation of 
z


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t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
XTC
Ecstasy 


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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 
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-


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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 due 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.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the absolute bioavailability of BI 1265162
following administration of oral solution and inhaled (with and without charcoal) via
Respimat.
2.1.2
Primary endpoint
The following pharmacokinetic parameter will be determined for BI 1265162:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
2.1.3
Secondary endpoint
Not applicable.


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Safety and tolerability of BI 1265162 will be assessed based on:  

Adverse events (including clinically relevant findings from the physical examination)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, three-way crossover trial followed 
by a fixed treatment in healthy male subjects in order to compare BI 1265162 given as oral 
solution (T1) and inhaled via Respimat with activated charcoal(T2) and without activated 
charcoal (T3) compared to BI 1265162 given intravenous (Reference, R). The subjects will 
be randomly allocated to one of the treatment sequences (T1-T2-R-T3 or R-T1-T2-T3 or T2-
R-T1-T3). For details, refer to Section 4.1.
For logistical reasons, subjects may receive the treatments on Day 1 e.g. first all subjects with 
oral, followed by all subjects with inhaled and last all subjects with intravenous 
administration. All 12 subjects will be dosed on Day 1 in a staggered fashion, e.g. 10 min in 
between intravenous administration. From a safety perspective it is acceptable to treat all 
subjects on the same calendar day: Low doses BI 1265162 have been selected to ensure that, 
even in case of a higher bioavailability of the planned oral dose, the expected plasma 
concentrations of BI 1265162 are in the range of plasma concentrations observed in First-in-
Man trial 1399-0001. In that previous trial, all single doses of BI 1265162, up to 1200µg 
inhaled, were safe and well tolerated. No safety concerns were identified.
The doses for intravenous and/or oral administration might be adapted for PK purposes after 
the first treatment period (see Section 7.4). In case this is needed, this will be implemented 
via a non-substantial amendment.
There will be a washout period of at least 6 days between the treatments, i.e. the dose in the 
previous treatment period and the dose in the current treatment period are separated by at 
least 6 days.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For this absolute bioavailability trial, the crossover design is required as the assessment is 
within a subject.
The open-label treatment is not expected to bias results, since the primary endpoint is derived 
from measurement of plasma concentrations of the analyte which are provided by a 
bioanalytical laboratory.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 12 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
Only male subjects will be included in the study because no data on reproductive toxicology 
are available at this time.


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A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory 
2. Age of 18 to 50 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. 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) deviating from 
normal and assessed 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 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or 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


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10. History of relevant allergy or hypersensitivity (including allergy to the trial 
medication or its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc 
interval prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation 
in another clinical trial in which investigational drug is administered
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 than 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance,
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
23. The subject has a diagnosis history of pulmonary hyperreactivity
24. A history of chronic kidney disease
25. Cannot use Respimat® appropriately 
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 


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withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF 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 CRF. If the discontinuation occurs before the end of the 
REP, the discontinued subject should if possible be questioned for AEs and concomitant 
therapies at or after the end of the REP in order to ensure collection of AEs and concomitant 
therapies throughout the REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1 Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
The subject wants to discontinue trial treatment, without the need to justify the decision
The subject has repeatedly shown to be non-compliant with important trial procedures and, in 
the opinion of both, the investigator and sponsor representative, is not willing or able to 
adhere to the trial requirements in the future.
The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed up 
according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2 Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3 Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
Failure to meet expected enrolment goals overall or at a particular trial site
New toxicological findings, serious adverse events, or any safety information invalidating the 
earlier positive benefit-risk-assessment. More specifically, the trial will be terminated if more 
than 50% of the subjects have drug-related and clinically relevant adverse events of moderate 
or severe intensity, or if at least 1 drug-related serious adverse event is reported


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Violation of GCP, or the CTP impairing the appropriate conduct of the trial-
The sponsor decides to discontinue the further development of the investigational product
3.3.5
Replacement of subjects
In case subjects do not complete the trial the Trial Clinical Leader 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 trial subject number, and will be 
assigned to the same treatment sequence as the subject he replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products have been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products


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4.1.2
Method of assigning subjects to treatment groups
The randomisation list will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
list will be allocated to the subjects by drawing lots. Subjects are then assigned to a treatment 
sequence according to the randomisation list.
Once a randomisation number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.6.
4.1.3
Drug assignment and administration of doses for each subject
This trial is a 3-way crossover study. All subjects will receive the 3 treatments in randomised 
order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule


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*At the time points given in the flow chart, 10 g activated charcoal will be taken by the respective subjects to 
avoid possible gastrointestinal absorption of BI 1265162
** Doses are tentative and may be adapted after first period (cf. 7.4)
Administration of all trial medications will be performed after subjects have fasted overnight; 
fasting is to start no later than 8 h before the scheduled dosing / start of infusion. 
The oral medication will be administered as a single dose together with about 240 mL of 
water to a subject in the sitting or standing position under supervision of the investigating 
physician or an authorised designee. 
During the first 4 h after oral drug administration, they are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture).
The intravenous medication will be administered as a continuous intravenous infusion over 
60 minutes under supervision of the investigating physician or an authorised designee. Start 
and end time of the infusion will be recorded. Subjects will receive 240 mL of water upon 
start of infusion.
The inhaled medication will be administered with the RESPIMAT in a sitting or standing 
position under supervision of the investigating physician or an authorised designee. Planned 
time 0:00h will always be the first actuation. 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. Subjects will receive some water after the 2nd
actuation to rinse the mouth.
For all drug administrations, the so-called four-eye principle (two-person rule) should be 
applied. For this, one authorised employee of the trial site should witness the administration 
of trial medication, and – if applicable – its preparation (e.g. reconstitution – not applicable 
for assembling of RESPIMAT), if correct dosage cannot be ensured otherwise.
Subjects will be kept under close medical surveillance until 24 h after drug administration. 
The treatments will be separated by a wash-out phase of at least 6 days.
4.1.4
Blinding and procedures for unblinding
This open-label Phase I trial will be handled in an open fashion throughout (that is, during the 
conduct, including data cleaning and preparation of the analysis).
Emergency envelopes will not be provided, because the dose and administration method of 
trial medication is known to investigators and subjects.


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4.1.5
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the 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. 
No re-supply is planned.
4.1.6
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.7
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority,  e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each 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 medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.


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4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1 Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. 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
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake / start of 
infusion.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug (for intravenous treatment after start of infusion), and an additional 240 mL of 
water at 2 h and 4 h post-dose / start of infusion. From lunch until 24 h post-dose, subjects 
should be instructed not to exceed a total fluid intake of 3000 mL.
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 each study drug administration and until 24 h after 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 allowed from 10 h before until 24 h after administration of trial 
medication.
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.


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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 
of trial medication will provide additional confirmation of compliance.
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.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported),
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG, laboratory tests, 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.
5.2.2
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 
(Dinamap Pro 100, 
) 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.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
If safety laboratory measurement is performed with other blood collection, e.g. PK sampling,
safety laboratory measurement will always be performed first, preferably without any
tourniquet.
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
Functional lab group
BI test name [comment/abbreviation]
A
B
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes 
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils Bands;  
Neutrophils Bands, absol.; Eosinophils/Leukocytes; Eosinophils, 
absol.; Basophils/ Leukocytes; Basophils, absol.; Monocytes/ 
Leukocytes; Monocytes, absol.; Lymphocytes/Leukocytes; 
Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time - INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI3
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Electrolytes2
Sodium
Potassium
Chloride
Calcium
X
X
X
X
X
X
X
X
Urinalysis1 (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment1
(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)
X
X
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2,3,4,5 and Visit 6 (end of trial examination) (for time points refer to 
Flow Chart)
1 if erythrocytes, leukocytes nitrite or protein are abnormal in urinalysis


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2 Sample tubes will be centrifuged for about 8 minutes at about 4000 g and stored at room temperature until 
shipment to the clinical lab.
3 Estimated glomerular filtration rate according to CKD-EPI formula (R12-1392)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. It is planned to perform these tests during screening only. Drug screening will be 
performed at screening and prior to each treatment period on Day -1.
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 (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410, 
) will be performed prior to each treatment, and may be 
repeated at any time during the study at the discretion of an investigator or designee. The 
results will not be included in the CTR
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of 
drug screening tests. These tests will be performed at the trial site using Drogenschnelltest 
Multidrogen-Pipettiertest M-10/14-PDT, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 
) at the times provided in the Flow Chart.
To achieve a stable 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.


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All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
 Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for 
assessment. Additional (unscheduled) ECGs may be collected by the investigator for safety 
reasons. 
5.2.5
Other safety parameters
5.2.5.1 Local tolerability
After iv administration, local tolerability will be assessed by the investigator on the basis of 
swelling, induration, heat, redness, pain, and other findings at the times provided in the Flow 
Chart.
5.2.6
Assessment of adverse events
5.2.6.1 Definitions of adverse events
Adverse event
5.2.6.1.1
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 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.


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Serious adverse event
5.2.6.1.2
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 subject 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 subject 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’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
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
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury


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A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥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 (severity) of AEs
5.2.6.1.5
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
5.2.6.1.6
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)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:


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
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2 Adverse event collection and reporting
AE collection
5.2.6.2.1
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
time, 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.

After the individual subject’s end of trial: 


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o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and 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 the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
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.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. PK sampling times may be adapted during the 
trial based on information obtained during trial conduct (e.g. exploratory PK analysis) 
including addition of samples as long as the total blood volume taken per subject does not 
exceed 500 mL. Such changes would be implemented via non-substantial CTP Amendment.
5.3.2
Methods of sample collection
5.3.2.1 Blood sampling for pharmacokinetic analysis
For quantification of analyte concentrations in plasma, 2.7 mL of blood will be drawn from 
an antecubital or forearm vein into an K2-EDTA (dipotassium ethylenediaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venepuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 


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stored in polypropylene tubes. The first aliquot should contain at least 0.7 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 90 min. The time each aliquot was placed in the freezer will be 
documented. Until transfer on dry ice to the analytical laboratory, the aliquots will be stored 
upright at approximately -20°C or below at the trial site. The second aliquot will be 
transferred to the analytical laboratory after the bioanalyst has acknowledged safe arrival of 
the first aliquot. At the analytical laboratory, the plasma samples will be stored at 
approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
5.3.2.2 Plasma sampling for metabolism analysis
Additional K3-EDTA plasma samples for the identification of drug metabolites will be 
investigated. 
The blood samples will be drawn in parallel to PK samples (see Flow Chart). At each of these 
time points specified in Flow Chart, 4.9 mL blood will be needed for metabolite analysis. The 
blood samples will be processed in the same way as the PK samples described in Section 
5.3.2.1 However, obtained plasma (approximately 2 mL) will be transferred into a single 
polypropylene tube. Samples should be stored from blood collection until transfer of plasma 
aliquots in ice water or on ice. Samples will be stored at about -20°C or below until transfer 
to the metabolism laboratory.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, e.g. “metabolic samples” and planned sampling time. Further 
information such as matrix and analyte may also be provided. 
Plasma samples dedicated to metabolism investigation can be transferred together with the 
PK samples to (but packed separately): 
These plasma samples may be used for further methodological investigations (e.g. for 
stability testing or assessment of metabolites. However, only data related to the analyte 
and/or its metabolite(s) will be generated by these additional investigations. The investigation 
results will not be reported as part of this study. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the CTR is 
archived.


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5.3.3
Analytical determinations
5.3.3.1 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 
 
 
 All details of the analytical method will be available prior to the 
start of sample analysis.
5.3.4
Pharmacokinetic - pharmacodynamic relationship
Not applicable.
5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
5.6.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
obtained at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the CTR. However, the data may be part of the CTR, if necessary.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally, IV or inhaled administered drug, and are 


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widely used in clinical trials. The pharmacokinetic parameters and measurements outlined in 
Section 5.3 are generally used assessments of drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 min for the first 4 hours after 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 venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of 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 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 provide 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.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.3).
6.2.2
Treatment period
Each subject is expected to participate in 4 treatment periods (Days -1, 1 and 2 in each 
period). At least 6 days will separate drug administrations in the first, second, third and fourth 
treatment periods.
On Day -1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration/start of 
infusion. The subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. 


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For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate absolute bioavailability (F) of BI 1265162 
following oral administration (T1) and inhalation with activated charcoal (T2) and without 
charcoal (T3) on the basis of the primary pharmacokinetic endpoint, as listed in Section 2.1.2.
Therefore the primary endpoint obtained after T1,T2 and T3 will be compared to the primary 
endpoint obtained after intravenous administration of BI 1265162 (R). For details regarding 
treatments R, T1, T2 and T3 see Section 4.1.1. The trial is designed to allow intra-subject 
comparisons and will be evaluated statistically by use of a linear model for logarithmically 
transformed PK endpoint.
Further objectives include the evaluation of the proportion of the absolute bioavailability of 
BI 1265162 that is absorbed from the GI tract following inhalation without charcoal by 
comparison to the absolute bioavailability following inhalation with charcoal and to evaluate 
and compare further pharmacokinetic parameters, as listed in Section 2.2.2.1 between all
treatments. These pharmacokinetic parameters will be assessed by descriptive statistics.
Furthermore, the assessment of safety and tolerability is a further objective of this trial, and 
will be evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2 and 
Section 2.2.2.3.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The absolute bioavailability (F) of BI 1265162 following oral (T1), inhaled with activated 
charcoal (T2) and without charcoal (T3) administration will be estimated by the ratios of the 
geometric means (Ti/R, i=1,2, 3) of the primary endpoint, and their corresponding 2-sided 
90% confidence intervals (CIs) will be provided. This method corresponds to the two one-
sided t-test procedure, each at the 5% significance level. Since the main focus is on 
estimation and not testing, a formal hypothesis test and associated acceptance range is not 
specified.
To evaluate the proportion of the absolute bioavailability of BI 1265162 after inhalation that 
is absorbed by the GI tract, the intra-individual difference between the absolute 
bioavailability of BI 1265162 inhaled with activated charcoal (T2) and without charcoal (T3) 
will be estimated using an analysis of variance model and a 2-sided 90% CI will be provided.
Since the main focus is on estimation and not testing, a formal hypothesis test is not 
specified.


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7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for 
disposition and safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
further and was not excluded due to a protocol deviation relevant to the evaluation of 
PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment.
Descriptive and model based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(IPD) categories will be suggested in the IQRM Plan. Important protocol deviations will be 
identified no later than in the Report Planning Meeting, and the IPD categories will be 
updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1.2 and 2.2.2.1 for drug BI 1265162 will 
be calculated according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations 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 concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

After oral administration, the subject experienced emesis that occurred at or before 
two times median tmax of the respective treatment (Median tmax is to be determined 
excluding the subjects experiencing emesis), 

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve


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Plasma concentration data and parameters of a subject, which is flagged for exclusion, will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
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). 
7.3.1
Primary endpoint analyses
The primary and further pharmacokinetic endpoints (refer to Section 2.1.2 and 2.2.2.1) will 
be calculated according to the BI SOP ‘Standards and processes for analyses performed 
within Clinical Pharmacokinetics/ Pharmacodynamics’ (001-MCS-36-472). The non-
compartmental analysis will be performed using a validated software program such as 
Phoenix WinNonlinTM software (version 6.3 or higher, Certara USA Inc., Princeton, NJ, 
USA) or SAS® Version 9.4 (or later version). 
Primary analyses
The absolute bioavailability (F) will be estimated based on different administration methods 
of BI 1265162. As different doses are investigated among the administration methods, the 
primary endpoint (see Section 2.1.2) will be dose normalized for the statistical analysis. The 
statistical model used for the analysis of the primary endpoint will be an analysis of variance 
(ANOVA) model on the logarithmic scale. That is, the dose normalized PK endpoint will be 
log-transformed (natural logarithm) prior to fitting the ANOVA model. This model will 
include effects accounting for the following sources of variation: ‘sequence’, ‘subjects within 
sequences’, ‘period’ and ‘treatment’. The effect 'subjects within sequences' will be considered 
as random, whereas the other effects will be considered as fixed. The model is described by 
the following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of dose normalized AUC0-∞measured on subject m in sequence i 
                       receiving treatment k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2, 3
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, 3, 4
j = the jth period effect, j = 1, 2, 3
k = the kth treatment effect, k = 1, 2, 3
eijkm = the random error associated with the mth subject in sequence i who received
           treatment k in period j.


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where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (Ti/R, i=1, 2), i.e. for the absolute 
bioavailability F, and their two-sided 90% confidence intervals (CIs) will be provided.
The difference between the expected means for log(Ti)-log(R), i=1, 2, will be estimated by 
the difference in the corresponding adjusted means (Least Squares Means). Additionally their 
two-sided 90% confidence intervals will be calculated based on the residual error from the 
ANOVA and quantiles from the t-distribution. These quantities will then be back-transformed 
to the original scale to provide the point estimate and 90% CIs for each comparison of 
interest.


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7.3.2
Secondary endpoint analyses
Not applicable.
7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.3) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as 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 the screening period, those between first trial medication intake and end of 
REP (see Section 1.2.6) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
These assignments including the corresponding time intervals will be defined in detail in the 
TSAP. Note that AEs occurring after the last per protocol contact but entered before final 
database lock will be reported to Pharmacovigilance only and will not be captured in the trial 
database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
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 
intervals).


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Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
For safety assessments such as ECG, vital signs, or laboratory parameters, the baseline value 
is defined as the last measurement prior to drug administration on Day 1 of the respective 
treatment period.
Laboratory data will be compared to their reference ranges. A normalisation of lab values
will not be performed as this is a single site with one local laboratory. Values outside the 
reference range as well as values defined as possibly clinically significant will be highlighted 
in the listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
EXPLORATORY PK ANALYSES


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7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Subjects will be randomised to one of the 3 treatment sequences (T1-T2-R-T3 or R-T1-T2-T3
or T2-R-T1-T3) in a 1:1:1 ratio. The block size will be documented in the CTR.
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 that uses 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 Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 12 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (Ti/R, i=1, 2, 3), i.e. the respective 
absolute bioavailability F, can be expected with 95% probability. Precision is defined as the 


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ratio of upper CI limit to the absolute BA estimate. Note that the precision is independent of 
the actual ratio of geometric means.
Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (Ti/R, i=1,2,3) for different gCVs in a 3x3 crossover trial 
(N=12)
gCV [%]
Precision upper 
CL / absolute BA 
estimate
Ratio [%]*
Lower CI limit
[%]
Upper CI limit
[%]
15.0
1.14
  5
4.38
  5.70
15.0
1.14
50
43.83
57.03
15.0
1.14
75
65.75
85.55
15.0
1.14
100
87.67
114.07
20.0
1.19
  5
4.20
  5.95
20.0
1.19
50
41.98
59.55
20.0
1.19
75
62.97
89.32
20.0
1.19
100
83.97
119.10
25.0
1.24
  5
  4.02
  6.21
25.0
1.24
50
40.24
62.13
25.0
1.24
75
60.35
93.20
25.0
1.24
100
80.47
124.27
*Ratio of geometric means (Ti/R, i=1,2,3) for a PK endpoint is defined by exp(Ti)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit,  = exp(ln(θ) ± ω),
with θ being the ratio (Ti/R, i=1, 2, 3) on original scale and ω the distance from the estimate θ 
to either confidence interval limit on the log-scale, which was obtained from the achievable 
precision on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a 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 retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.7.
ClinBaseTM
In the 
 Phase I unit – the 
validated ClinBase
system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.


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For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.


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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 AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) 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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Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 
 under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
).
Analyses of BI 1265162 concentrations in plasma will be performed at the 
 
.
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 according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P96-3855
Ramsey BW. Management of pulmonary disease in patients with cystic 
fibrosis. N Engl J Med 1996;335(3):179-188.
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.
R01-1277
Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care 
Med 1996;154:1229-1256.
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI). A new equation to 
estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-612
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


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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 
(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.
R17-1997
Rowe SM, Verkman AS. Cystic fibrosis transmembrane regulator 
correctors and potentiators. Cold Spring Harb Perspect Med 
2013;3:a009761.
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:1-
9.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R18-3859
Kohle-Pulvis (Koehler Pharma) (Fachinformation, Stand der Information: 
November 2011).
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version


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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.
c22991563-01
 Safety, tolerability and 
pharmacokinetics of single rising inhaled doses of BI 1265162 in healthy 
male volunteers in a partially randomised, single blind, placebo-controlled 
trial.
c16304878
  Investigator`s Brochure BI-1265162 Cystic fibrosis and COPD.
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.
n00257013-02
Prediction of BI 1265162 Pharmacokinetics and Exposure at Anticipated 
Therapeutic Dose in Human


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10.
APPENDICES
10.1
HANDLING INSTRUCTIONS BI 1265162 ORAL SOLUTION 
10.1.1
Overview
The BI 1265162 oral solution 20 mL (0.25 mg/mL) is ready to use. Prior to oral drug
administration, the needed volume of the oral solution is withdrawn from the vials into a 
syringe. The oral solution can be stored for up to 24 hours at room temperature in the syringe.
Finally, the oral solution is administered directly into the mouth of the person.
The following description provides a list of required consumables and a step by step 
instruction.
10.1.2
List of Consumables
Table 10.1.2: 1
Material for withdrawal and administration of the BI 1265162 oral 
solution (0.25 mg/mL)
Material
Manufacturer
Process Step
Vial Adapter, 
20 mm diameter
Withdrawal of solution from 
glass vial
Injekt® syringe, 
5/10/20 mL / Luer Solo
Withdrawal of solution from 
glass vial, storage, 
administration
Combi Stopper
Capping of syringe
10.1.3
Preparation for administration of the BI 1265162 oral solution (0.25 mg/mL) 
Step 1: Remove the flip-off seal from the glass vial containing BI 1265162 oral 
solution 20 mL (0.25 mg/mL)
Step 2: Attach a new Vial Adapter on the vial and mount the Injekt® syringe 
Step 3: Withdraw the required volume (adding a little surplus) from the vial 
Step 4: Disconnect the syringe from the Vial Adapter
Step 5: Holding the syringe upright, push the plunger to the exact volume needed, 
thereby removing any air bubbles from the syringe
Step 6: Put a Combi Stopper to the Injekt® syringe for safe storage of the system 
until administration 
Step 7: Before administration, remove the Combi Stopper from the Injekt® syringe 


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10.1.4
In-use stability
After withdrawal of the BI 1265162 oral solution (0.25 mg/mL) from the vial into the 
syringe, storage of the solution in the capped syringe is allowed for up to 24 hours at room 
temperature. Vial and syringe shall be protected from direct sun exposure. No additional light 
protection measures are required. 
10.1.5
Mode of application
The vials are for single use only. 
10.2
HANDLING INSTRUCTIONS FOR BI 1265162 CONCENTRATE FOR 
SOLUTION FOR INFUSION 
10.2.1
Overview
Prior to intravenous drug administration, the needed volume of the concentrate for solution 
for infusion is withdrawn from the vials into a syringe. This is diluted by a factor of five with 
0.9 % saline. Subsequently, the application system is flushed with the solution for infusion.
Finally, the needed volume of solution for infusion is administered over 60 minutes. Residual 
solution for infusion is discarded. 
The following description provides a list of required consumables and a step by step 
instruction.
10.2.2
List of Consumables
Table 10.2.2: 1
Material for withdrawal of solutions and preparation and 
administration of the BI 1265162 solution for infusion (5 µg/mL)
Material
Manufacturer
Process Step
Mini-Spike®
Withdrawal of solution from 
glass vial
Omnifix® syringe, 
20 mL / Luer Lock Solo
Withdrawal of solutions 
from glass vial, mixing, 
infusion
Original Perfusor® Syringe 
50 mL, Luer Lock
Withdrawal of solutions 
from glass vial, mixing, 
infusion
Original Perfusor® Line
IV-Standard – PE, Luer Lock
Infusion
Combi Stopper
Capping of infusion line 
after priming
Introcan Safety® iv catheter 
Infusion
Octeniderm®
Desinfection


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10.2.4
In-use stability
After mixing the BI 1265162 concentrate for solution for infusion and the 0.9 % saline to 
obtain the BI 1265162 solution for infusion (5 μg/mL) and priming of the Original Perfusor® 
Line, storage of the solution before start of infusion is allowed for 2 hours at room 
temperature. Vial and syringe shall be protected from direct sun exposure. No additional light 
protection measures are required. 
10.2.5
Mode of application
The vials are for single use only.
10.3
HANDLING INSTRUCTIONS FOR RESPIMAT INHALER 
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.


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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.
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.


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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.
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.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)


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APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25000855
4.0
clinical-trial-protocol-revision-3
Absolute bioavailability of BI 1265162 following oral and inhaled administration in
healthy male volunteers (an open-label, randomised, single-dose, three-period,
three-sequence crossover study followed by a fixed treatment)
Approval-Therapeutic Area 
20 Aug 2019 14:03 CEST
Author-Clinical Trial Leader
20 Aug 2019 14:07 CEST
Approval-Team Member Medicine
20 Aug 2019 14:09 CEST
Author-Trial Clinical
Pharmacokineticist
20 Aug 2019 21:16 CEST
Verification-Paper Signature
Completion
21 Aug 2019 12:08 CEST
Author-Trial Statistician
22 Aug 2019 08:16 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25000855
4.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c30364560-01
BI Trial No.:
1399-0014
Title:
Absolute bioavailability of BI 1265162 following oral and inhaled
administration in healthy male volunteers (an open-label,
randomised, single-dose, three-period, three-sequence crossover
study followed by a fixed treatment)
Including Protocol Amendment 3 [c25000855-04]
Investigational
Product:
BI 1265162
Responsible trial 
statistician:
Phone: 
Fax: 
Phone:
Fax:
Date of statistical 
analysis plan:
13 DEC 2019 SIGNED
Version:
Final
Page 1 of 23
Proprietary confidential information
2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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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 endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................13
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........15
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................16
7.3
TREATMENT COMPLIANCE........................................................................16
7.4
PRIMARY ENDPOINT .....................................................................................16
7.4.1
Primary analysis of the primary endpoint........................................................16
7.5
SECONDARY ENDPOINTS.............................................................................17
7.5.1
Key secondary endpoints....................................................................................17
7.5.2
Secondary endpoints...........................................................................................17
7.7
EXTENT OF EXPOSURE.................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................18


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7.8.1
Adverse Events ....................................................................................................18
7.8.2
Laboratory data ..................................................................................................19
7.8.3
Vital signs.............................................................................................................20
7.8.4
ECG......................................................................................................................20
7.8.5
Others...................................................................................................................20
8.
REFERENCES....................................................................................................21
10.
HISTORY TABLE..............................................................................................23


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs, vital signs and safety 
laboratory data ..................................................................................................12
Table 6.2: 1
Handling of iPDs ..............................................................................................13
Table 6.3: 1
Subject sets analyzed........................................................................................14
Table 10: 1
History table .....................................................................................................23


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity
BI 
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BP
Blood pressure
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
eCRF
Electronic case report form
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
iPD
Important protocol deviations
IQRMP
Integrated quality and risk management plan
MedDRA
Medical Dictionary For Regulatory Activities
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter set
PR
Pulse rate
RAGe
Report appendix generator
RPM
Report Planning Meeting
SAE
Serious adverse event
SD
Standard Deviation


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Term
Definition / description
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 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 Medidata Rave 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
Deviating from Section 7.3.4 in the CTP laboratory data will be analysed on normalised 
values.
If for some reason AUC0-∞can not be calculated, AUC0-tz will be used instead as the primary 
endpoint.
The PK analysis of absolute bioavailability will also be performed for the comparison T3/R. 
This will be done in the same way as the comparisons of T1 and T2 with R, which is 
described in Section 7.3.1 of the CTP.
All other analyses described in this TSAP are in accordance with the statistical methods 
described in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is a PK endpoint of BI 1265162, as defined in Section 2.1.2 of the CTP:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)
If for some reason AUC0-∞can not be calculated, AUC0-tz will be used instead as the primary 
endpoint.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Not applicable.

Adverse events (including clinically relevant findings from the physical examination)


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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 4.1.1 of the CTP.
Each subject is planned to be treated in four subsequent treatment periods, with one single 
dose in each treatment period:

Test treatment 1 (T1):
 BI 1265162 as oral solution

Test treatment 2 (T2):
 BI 1265162 for inhalation with activated charcoal

Test treatment 3 (T3):
 BI 1265162 for inhalation without activated charcoal

Reference treatment (R):
BI 1265162 as infusion
Each subject is planned to be randomly allocated to one of three treatment sequences (T1-T2-
R-T3 or R-T1-T2-T3 or T2-R-T1-T3), with T3 as fixed sequence. Each treatment period is 
separated by a washout period of at least 6 days.
For statistical analyses of AEs, vital signs and safety laboratory data the following separate 
analysis phases will be defined for each subject:


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Table 6.1: 1
Analysis phases for statistical analysis of AEs, vital signs and safety laboratory
data
Study analysis 
phase
Label
Start
End
Screening
Screening
Date of informed consent
Date/time of first administration 
of BI 1265162
On treatment 
BI oral,
BI inh cha,
BI inh or
BI iv,
respectively
Date/time of first administration 
of the respective formulation of 
BI 1265162
Date/time of administration of the 
respective formulation of 
BI 1265162 + residual effect 
period (2 days * 24 h/day)
or
Date/time of administration of 
study drug in the next treatment 
period
or
12:00 a.m. on day after subject's 
end of study participation date
whatever comes first
Follow-up
F/U
End of the respective on-
treatment period (see line 
above)
Date/time of administration of 
BI 1265162 in the next treatment 
period, if applicable,
otherwise
12:00 a.m. on day after subject's 
end of study participation date
AE displays in CTR Section 15.3, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 will 
present results for the on-treatment phase only.
In AE tables in CTR Section 15.3 (but not in Appendix 16.1.13.1.8.2 and Appendix 
16.1.13.1.8.3 AE tables), the following total will be provided in addition: 

"Total BI", defined as the total over all on-treatment phases involving BI
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
CTP Section 7.3: Important protocol deviation (iPD) categories will be suggested in the 
IQRM Plan. Important protocol deviations will be identified no later than in the Report 
Planning Meeting, and the IPD categories will be updated as needed.
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 Meeting (RPM). At this meeting, it will be 
decided whether a discrepant data value can be used in the analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an iPD. For the process of identification and managing iPDs refer to the BI 
reference document "Identify and Manage Important Protocol Deviations (iPD)" (2). For a 


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detailed specification of PDs and iPDs of this trial refer to the Integrated Quality and Risk 
Management Plan (IQRMP) Section 4.1.
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. Categories which are considered to be iPDs in this trial are defined in the 
integrated quality and risk management plan (IQRMP). If the data show other iPDs, the 
definition in the IQRMP and the table below will be supplemented accordingly by the time of 
the RPM.
iPDs will be summarized and listed. Table 6.2: 1 below specifies which kind of iPDs could 
potentially lead to exclusion from which analysis set. The decision on exclusion of subjects 
from analysis sets will be made at the latest at the RPM, after discussion of exceptional cases 
and implications for analyses.
Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Excluded from which analysis set
A1
Inclusion Criteria Not Met
PKS
A2
Exclusion Criteria Met
PKS
B1
Informed consent not available/not 
done
TS, PKS
B2
Informed consent too late
None
C2
Randomisation not followed
PKS
C3
Non-compliance
PKS
C5
Incorrect intake of trial medication
PKS
C6
Improper washout between treatments
PKS
D1
Prohibited medication use
PKS
E1
Certain violations of procedures used to 
measure primary or secondary data
PKS
F1
Certain violations of time schedule used 
to measure primary or secondary data
PKS
6.3
SUBJECT SETS ANALYSED
Subject sets will be used as defined in the CTP, Section 7.3.


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Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PKS
Disposition
X
iPDs
X
Primary PK endpoint 
X
Further PK endpoints 
X
Safety parameters & 
treatment exposure
X
Demographic/baseline 
characteristics
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.
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 reported in the CTR.
CTP Section 7.5.1: It is not planned to impute missing values for safety parameters.
One exception 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) and (5). 
CTP Section 7.5.2: PK parameters that cannot be reasonably calculated based on the 
available drug concentration-time data will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
A separate baseline is defined for each study treatment: Baseline is the last available value 
before administration of the respective formulation of BI 1265162.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM.


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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" (6).
The individual values of all subjects will be listed. Listings will be sorted by sequence 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 with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
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.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.


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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 most recent version of the World 
Health Organisation – Drug Dictionary. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
A medication will be considered concomitant, if it

is ongoing at the time of first study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a definition 
of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
Only descriptive statistics are planned for this section of the CTR.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analyzed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
Primary analysis of the primary endpoint will be performed as defined in Section 7.3.1 of the 
CTP.
To assess the absolute bioavailability of the treatments, the statistical model for the primary 
analysis defined in the CTP is an analysis of variance (ANOVA) model on the logarithmic 
scale including "sequence", "period" and "treatment" as fixed effects and "subject within 
sequence" as random effect. Absolute bioavailability of the study treatments will be estimated 
by the ratios of the geometric means of (T1/R), (T2/R) and (T3/R) of the primary endpoint.
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.


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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".
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (5).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoints
This section is not applicable as no secondary endpoint has been specified in the protocol.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report.
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 screening, on-treatment or follow-up phases 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 Section 5.2.6.2.2: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
○
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥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.


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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
(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 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)). AEs will also 
be summarized by maximum intensity.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of 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 summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Display and Analysis of Laboratory Data" (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. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Unscheduled measurements of laboratory 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. Descriptive statistics 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).
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM at the latest. It is the Investigator's responsibility to 
decide whether a lab value is clinically significant abnormal or not. Standard or project-


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specific rules for flagging clinically significant values in an automated manner will not be 
applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
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.
Unscheduled measurements of vital signs will be assigned to planned time points in the same 
way as described above for laboratory data. However, for vital signs, 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).
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment)
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.4
ECG
Relevant ECG findings will be reported as relevant medical history/baseline condition (if a 
condition already exists before first administration of study treatment) or as AE (if condition 
emerges after first administration of study treatment) and will be summarized as such. No 
separate listing or analysis of ECG findings will be prepared.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.
Local tolerability
Local tolerability (absence or presence of "swelling", "induration", "heat", "redness", "pain", 
or "other findings") will be summarized with counts and percentages overall (i.e. over all on-
treatment time points, cf. Section 6.1) as well as by time point.


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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-40-413_1.0: "Identify and Manage Important Protocol Deviations 
(iPD)", current version; IDEA for CON
3
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE 
dates", current version; KMED
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON
5
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", current version; IDEA for CON
6
KM Asset BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED
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
KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED


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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
13-DEC-19
None
This is the final TSAP