Clinical trial NCT03349723
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-11-23; Completion date: 2018-03-05
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Secondary objective is the exploration of the pharmacokinetics (PK) of BI 1265162 after single dosing.

Detailed description:
To investigate safety, tolerability and pharmacokinetics of BI 1265162 in man.

Arms: arm 1: BI 1265162 arm 2: Placebo
Interventions: intervention 1: BI 1265162 intervention 2: Placebo
Intervention descriptions: intervention 1: Single rising dose groups intervention 2: Single rising dose groups

Protocol documents:
Prot_000.pdf: 
1
1
1
2
87
16. APPENDICES..................................................................................................
16.1 TRIAL INFORMATION..........................................................................
16.1.1 Protocol and amendments..................................................................
16.1.1.1 Protocol..........................................................................................
16.1.1.2 Revised protocol and protocol amendments..................................
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Clinical Trial Protocol
TITLE PAGE
Document Number:
c15848245-01
EudraCT No.:
BI Trial No.:
2017-001106-15
1399-0001
BI Investigational
Product:
BI 1265162
Title:
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
Lay Title
This study tests the safety, tolerability and how different doses of 
BI 1265162 are taken up in the body of healthy men.
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax: 
Principal Investigator:
Phone:
Fax:
Status:
Final Protocol
Version and Date:
Version: 1.0
Date: 19 September 2017
Page 1 of 80
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable 
Name of active ingredient:
BI 1265162
Protocol date:
Trial number:
Revision date:
Not applicable
19 September 2017
1399-0001
Title of trial:
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
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability and pharmacokinetics, following single doses of 
BI 1265162
Methodology:
Single-blind, partially randomised within dose groups, placebo-controlled, parallel-
group design
No. of subjects: 
total entered:
56*
each treatment:
8 per dose group (6 on active drug and 2 on placebo)
* Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned and 
approved highest dose will not be exceeded. Thus, the actual number of subjects entered may 
exceed 56, but will not exceed 72 subjects entered.
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 50 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Test product:
BI 1265162
dose:
mode of admin.:
Inhalation by RESPIMAT
Comparator product:
Placebo
dose:
Not applicable
mode of admin.:
Inhalation by RESPIMAT 
Duration of treatment: Single dose
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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable 
Name of active ingredient:
BI 1265162
Protocol date:
Trial number:
Revision date:
Not applicable
19 September 2017
1399-0001
Criteria for 
pharmacokinetics:
Secondary endpoints: AUCt1-t2 and Cmax
 
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 1265162 is the number [N 
(%)] of subjects with drug-related adverse events.
Further criteria of interest:
AEs including clinically relevant findings from the physical examination, safety 
laboratory tests, 12-lead electrocardiogram (ECG), continuous ECG monitoring, vital 
signs (blood pressure [BP], pulse rate [PR])
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
 
2.2
TRIAL OBJECTIVES.......................................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 28
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................28
3.1.1
Administrative structure of the trial...................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for study entry............................................................31
3.3.2
Inclusion criteria...................................................................................31
3.3.3
Exclusion criteria ..................................................................................31
3.3.4
Removal of subjects from therapy or assessments.............................33
3.3.4.1
Removal of individual subjects................................................33
3.3.4.2
Discontinuation of the trial by the sponsor..............................33
3.3.5
Replacement of subjects .......................................................................34
4.
TREATMENTS........................................................................................ 35
4.1.2
Method of assigning subjects to treatment groups ............................35
4.1.3
Selection of doses in the trial................................................................36
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4.1.4
Drug assignment and administration of doses for each subject .......36
4.1.5
Blinding and procedures for unblinding ............................................38
4.1.5.1
Blinding....................................................................................38
4.1.5.2
Procedures for emergency unblinding .....................................38
4.1.6
Packaging, labelling, and re-supply ....................................................38
4.1.7
Storage conditions.................................................................................39
4.1.8
Drug accountability ..............................................................................39
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................40
4.2.1
Other treatments and emergency procedures....................................40
4.2.2
Restrictions............................................................................................40
4.2.2.1
Restrictions regarding concomitant treatment .........................40
4.2.2.2
Restrictions on diet and life style.............................................40
4.3
TREATMENT COMPLIANCE.......................................................................41
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 42
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................42
5.1.1
Endpoints of efficacy.............................................................................42
5.1.2
Assessment of efficacy...........................................................................42
5.2
SAFETY..............................................................................................................42
5.2.1
Endpoints of safety................................................................................42
5.2.2
Assessment of adverse events...............................................................42
5.2.2.1
Definitions of adverse events...................................................42
5.2.2.2
Adverse event collection and reporting ...................................45
5.2.3
Assessment of safety laboratory parameters......................................47
5.2.4
Electrocardiogram................................................................................49
5.2.4.1
12-lead resting ECG.................................................................49
5.2.4.2
Continuous ECG monitoring ...................................................51
5.2.5
Assessment of other safety parameters...............................................51
5.2.5.1
Vital signs ................................................................................51
5.2.5.2
Medical examinations..............................................................52
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................52
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................52
5.5.1
Pharmacokinetic endpoints..................................................................53
5.5.1.1
Secondary endpoints................................................................53
5.5.2
Methods of sample collection...............................................................54
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................54
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5.5.3
Analytical determinations ....................................................................57
5.5.3.1
Analytical determination of analyte plasma concentration......57
5.6
BIOMARKER....................................................................................................57
5.7
PHARMACODYNAMICS................................................................................57
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....57
6.
INVESTIGATIONAL PLAN.................................................................. 58
6.1
VISIT SCHEDULE............................................................................................58
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................58
6.2.1
Screening period....................................................................................58
6.2.2
Treatment period ..................................................................................58
6.2.3
End of trial period.................................................................................59
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 60
7.1
STATISTICAL DESIGN – MODEL ...............................................................60
7.1.1
Objectives...............................................................................................60
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................60
7.3
PLANNED ANALYSES....................................................................................60
7.3.1
Primary analyses...................................................................................60
7.3.2
Secondary analyses ...............................................................................60
7.3.3
Safety analyses.......................................................................................62
7.3.5
Pharmacokinetic analyses ....................................................................64
7.4
HANDLING OF MISSING DATA ..................................................................64
7.4.1
Safety......................................................................................................64
7.4.2
Plasma/urine drug concentration - time profiles ...............................64
7.4.3
Pharmacokinetic parameters...............................................................64
7.5
RANDOMISATION ..........................................................................................65
7.6
DETERMINATION OF SAMPLE SIZE ........................................................65
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 66
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................66
8.2
DATA QUALITY ASSURANCE .....................................................................66
8.3
RECORDS..........................................................................................................67
8.3.1
Source documents .................................................................................67
8.3.2
Direct access to source data and documents.......................................67
8.3.3
Storage period of records.....................................................................67
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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................67
8.5
STATEMENT OF CONFIDENTIALITY.......................................................68
8.6
COMPLETION OF TRIAL..............................................................................68
9.
REFERENCES......................................................................................... 69
9.1
PUBLISHED REFERENCES...........................................................................69
9.2
UNPUBLISHED REFERENCES.....................................................................71
10. APPENDICES .......................................................................................... 72
10.1
HANDLING INSTRUCTIONS FOR RESPIMAT INHALER FOR USE 
IN CLINICAL TRIALS ....................................................................................72
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 80
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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
AMG
Arzneimittelgesetz (German drug law)
ANCOVA
Analysis of covariance
 
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
 
 
BI
Boehringer Ingelheim
b.i.d.
Bis in die, twice daily
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CF
Cystic fibrosis
CI
Confidence interval
 
Cmax
Maximum measured concentration of the analyte in plasma
 
COPD
Chronic obstructive pulmonary disease
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
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EOT
End of trial
 
gCV
Geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
 
NC
Not calculated
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
NOTEL
No toxic effect level
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
q.d.
Quaque die, once 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)
 
RDC
Remote data capture
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SRD
Single-rising dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
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TMF
Trial master file
 
TDMAP
Trial Data Management and Analysis Plan
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
 
 
 
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2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 1265162 in 
healthy male subjects following inhalative administration of single rising doses.
Secondary objective is the exploration of the pharmacokinetics (PK) of BI 1265162 after 
single dosing.
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A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single-rising dose trial is designed as single-blind, partially randomised, and placebo-
controlled within parallel dose groups.
Partially randomised means that the subjects will be treated in two equally sized cohorts per 
dose group, with the first cohort being treated in a fixed sequence and the second cohort 
being treated in a randomised order.
A total of 56 healthy male subjects is planned to participate in the trial, according to 7
sequential groups comprising 8 subjects per group. However, additional subjects may be 
entered to allow testing of intermediate doses within the planned and approved dose range on 
the basis of experience gained during trial conduct (e.g. preliminary PK data), i.e. the actual 
number of subjects entered may exceed 56. Such changes may be implemented via non-
substantial CTP Amendments.
Within each dose group, 6 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
On the first study day of each dose level, the first cohort will be treated in the following 
order: first subject (active) followed at least 1 h later by the second subject (placebo) 
followed at least 1 h later by the third subject (active) followed at least 10 min later by the 
fourth subject (active). If BI 1265162 treatment is safe and showed acceptable tolerability in 
the first cohort, the subjects in the second cohort will be treated not earlier than 2 days later 
than the first treated volunteer in the first cohort. In the second cohort, a time interval of at 
least 10 min will be maintained between dosing of individual subjects in a random order. The 
dose groups will be investigated consecutively in ascending order of doses. A time interval of 
at least 6 days will be maintained between the administration of the study drug to the first 
cohort in a dose group and the first cohort in the next dose group. The decision to proceed to 
the next dose group will be based upon the safety, tolerability data of the preceding dose 
groups and explorative PK data in some dose groups (see Section 7.3.4).
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The next dose will only be given if, in the opinion of the investigator, no safety concerns 
arose in the preceding dose group (i.e. no dose-limiting events occurred) and if none of the 
pre-specified trial-specific stopping criteria were met (refer to Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by the 
Principal Investigator (or an authorised deputy) or the sponsor of the study, e.g. because of 
any unforeseen adverse events, etc. Dose escalation will only be permitted if no safety 
concerns exist in the opinion of the Principal Investigator (or an authorised deputy) and the 
Trial Clinical Monitor (or an authorised deputy). 
The minimum data set for review consists of the following data:

AEs in the current and preceding dose groups up to at least 48h post dosing (including 
clinically relevant findings from ancillary safety testing listed below) (Note: AEs may 
be ongoing at the time of Safety Reviews and AE information may be subject to 
change prior to Database Lock)

Results from 12-lead ECG and continuous ECG monitoring in the current and 
preceding dose groups.

Vital signs in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Preliminary PK data as per Section 7.3.4

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the Trial Clinical Monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 
face-to-face or by video/telephone conference. The Trial Clinical Monitor is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (or an authorised deputy) and filed in the ISF and TMF.
The investigator (after consultation with the sponsor) is allowed to alter the scheduled dose 
levels (e.g. add low and/or intermediate dose levels) on the basis of experience gained during 
the study, provided the planned and approved highest dose is not exceeded. In this case, the 
total number of subjects in this trial might increase. The investigator and/or the sponsor 
should stop dose escalation in case the safety evaluation leads to concerns that would not 
allow higher dosing.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
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BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany.
The trial will be conducted at
 
under the supervision of the Principal 
Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
(Medizinisches Versorgungszentrum Dr. Klein, Dr. Schmitt & Partner, Kaiserslautern, 
Germany).
The analyses of BI 1265162 concentrations in plasma and urine will be performed at the 
Department of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation 
for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single -rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 1265162.
With the rising dose design, single-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to the dose-depending effects as well as time effects, but it has the 
virtue of minimizing subject risk by sequentially studying ascending doses. As time-effects 
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are expected to be small relative to the differences between the doses in the broad range 
investigated, unbiased comparisons between treatments can still be expected.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety and tolerability. Each dose group consists of 8 subjects with 6 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. 6 subjects per active treatment group are in general considered 
as sufficient for the exploratory evaluation of pharmacokinetics.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 56 healthy male will enter the study. The actual number of subjects entered 
may exceed the total of 56 if additional intermediate doses will be tested (see Section 3.1). 
Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 50 years (incl.) 
3. BMI of 18.5 to 29.9 kg/m2 (incl.) 
4. FEV1 and FVC of equal or greater than 80% of predicted normal, at screening and prior 
to randomisation
5. Signed and dated written informed consent prior to admission to the study in accordance
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
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2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational 
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more 30 g per day for males)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
22. A history of chronic kidney disease (EGFR <59 mls/min including corrections as per 
ethnicity)
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
24. The subject has a diagnosis history of pulmonary hyperreactivity
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25. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from the first administration of trial medication until 
14 days after last administration of trial medication (BI 1265162 or placebo)
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:

The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision

The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication

The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:

New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported.
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
The expected enrolment goals overall or at a particular trial site are not met

Violation of GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial

The sponsor decides to discontinue the further development of the investigational 
product.

Dose escalation will be stopped as soon as at least 2 subjects at one dose level on active 
drug showed relevant individual QT prolongation, i.e. a QTc increase of greater 60 ms 
from baseline in connection with absolute QT or QTc greater than 500 ms, which has 
been confirmed by a repeat ECG recording (e.g. follow-up ECG).
 
 
 
 
 
 
 trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case that more than 2 subjects on active per dose group do not complete the trial, the trial 
clinical monitor together with the trial pharmacokineticist and the trial statistician are to 
decide if and how many subjects will be replaced. A replacement subject will be assigned a 
unique study subject number, and will be assigned to the same treatment as the subject he 
replaces.
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4.
TREATMENTS
 
 
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects have been allocated to 1 
of the 14 dose cohorts (2 cohorts per dose group), the following subjects will be allocated to 
one of the other dose cohorts. Therefore, the allocation of subjects to dose cohorts is not 
influenced by trial personnel, but only by the subjects’ temporal availability. As the study 
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includes healthy subjects from a homogenous population, relevant imbalances between the 
dose groups are not expected.
The randomization list with study subject numbers and allocated treatments will be provided 
to the trial site and the sponsor (TCM) in advance. The allocation of subjects to study subject 
numbers will be performed prior to the first administration of trial medication. For this 
purpose, the subjects will be allocated to a study subject number by the method 'first come 
first served'. Once a subject number has been assigned, it cannot be reassigned to any other 
subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
The doses selected for this trial cover the subtherapeutic as well as the estimated therapeutic 
range and include a safety margin (see Section 1.2).
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of actuations 
for placebo corresponds to the number of actuations of the respective dose level.
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Each newly assembled RESPIMAT Inhaler (has to be done on the day of application) has to 
be primed by qualified medical/pharmaceutical study personnel at the trial site under the 
responsibility of the investigator. To avoid contamination, except those devices used for 
training, priming should NOT take place in the same room where the subject is inhaling trial 
medication or the trial will be performed or samples will be processed. The inhaler should be 
primed under e.g. hood/outside by actuating it until an aerosol is visible plus three additional 
actuations. All priming actuations should be directed to the ground. For detailed priming 
instructions please refer to the RESPIMAT Inhaler handling instructions in Appendix 10.1.
Both the study drug as well as the placebo treatment (depending on randomisation) will be 
inhaled with the RESPIMAT in a sitting or standing position under supervision of the 
investigating physician or an authorised designee. If more than one actuation is needed,
planned time 0:00h will always be the first actuation. If more than one actuation will be 
needed, the duration from first to last actuation will be recorded. To avoid any contamination 
(e.g PK tubes), administration of trial medication should be performed in a separate room; 
subject and staff should wear e.g. gloves and protective wear. After study drug inhalation, 
subjects will drink 240 mL of water.
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The so-called four-eye principle (two-person rule) should be applied for administration of 
trial medication and – if applicable – its preparation (e.g. assembling of device), otherwise
correct dosage cannot be ensured.
Subjects will be kept under close medical surveillance until 24 h following drug 
administration. During the first 4 h after 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 except for 
medical examination), or to sleep. For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The treatments administered (active or placebo) will be single-blind (blinded to subjects 
only). However, the current dose level will be known to the subjects. 
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded with respect to the treatment and also with regard to the recording date and 
time as well as the time points of the ECGs. The interval measurements for a given subject 
will be performed in a random and blinded sequence by a single technician. No more than 
two different blinded readers will evaluate the ECGs of the study.
In addition, the trial pharmacokineticist, trial pharmacometrician and bioanalyst may receive 
the randomisation codes prior to official unblinding to perform the interim / preliminary PK 
analysis. He or she will confirm in writing that the codes will be treated confidentially.
In addition, the drug metabolism scientist may receive the randomisation codes prior to 
official unblinding to perform metabolites in safety testing analysis (MIST). He or she will 
confirm in writing that the codes will be treated confidentially.
The database of this trial will be handled open-label, because no bias with regard to data 
cleaning of safety measures is expected. 
4.1.5.2
Procedures for emergency unblinding
As this trial will be conducted single-blinded, the treatment information will be known. 
Therefore, no emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
The clinical trial supply consists of containers holding the trial medication which are labelled  
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Smaller boxes within the 
clinical trial supply containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 
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
Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Subject or medication number

Batch Number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
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investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the sponsor.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
No special emergency procedures are to be followed. No additional treatment is planned.
However, in case of adverse events in need of treatment (e.g. treatment of hyperkalaemia), 
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 medical evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is 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 are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to 240 mL of water served at 
2 h and 4 h post-dose (mandatory for all subjects). From lunch onwards, liquid intake is 
restricted to an additional 3000 mL. Subjects will be asked to drink the additional amount till 
one hour prior to the stop of urine collection on day 2. The total amount of liquid intake will 
be documented.
Standardised meals (identical for each dose group) will be served at the time points described 
in the study Flow Chart. Use of table salt is not allowed during in-house confinement at the 
trial site.
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 after the last PK sample is 
collected.
Alcoholic beverages, consumption of seafood and dried fruits are not permitted from 48 
hours before the study drug administration and until last blood sampling.
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 24 h before until 24 h after each administration of trial 
medication.
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Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 
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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 1265162 is the number [N (%)] of 
subjects with drug-related adverse events.
Further criteria of interest:  

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring 

Vital signs (blood pressure, pulse rate)
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 
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
is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, 
or 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.2.2 subsections ‘AE collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term 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 above.
The following are considered as AESIs in this trial:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
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These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
RDC. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure these parameters are analysed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described in 
the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
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
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful 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, and intensity of the event as 
well as 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: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report related SAEs and related AESIs of which the investigator 
may become aware of by any means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.
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The REP for BI 1265162, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known for this first-in-human trial. Therefore, all 
AEs reported until the end of trial examination (last per protocol contact) will be considered 
on treatment; please see Section 7.3.3.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (if applicable). The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)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 CRF only.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.
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5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 8 h (excluding sample at 06:00h post administration). 
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.
Table 5.2.3: 1
Routine laboratory tests
Category
Test name
A1
B2
C3
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelets
Reticulocyte count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential 
(relative and absolute)
Neutrophiles 
Eosinophils 
Basophils 
Monocytes 
Lymphocytes 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal and clinically
relevant in the opinion of 
the investigator)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin Time (Quick and INR)
X
X
X
X
X
X
Enzymes
Aspartate aminotransferase (AST/GOT, SGOT) 
Alanine aminotransferase (ALT/GPT, SGPT) 
Alkaline phosphatase
Gammaglutamyl transferase (GGT)  
Lactate dehydrogenase
Amylase
Lipase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 5.2.3: 1
Routine laboratory tests (cont’d)
Category
Test name
A1
B2
C3
Substrates
Glucose (plasma)
Creatinine
eGFR, calculated from serum creatinine using
CKD-EPI formula
Bilirubin, total
Bilirubin, direct
Cholesterol, total
Triglycerides
C-reactive protein
Urea
X
X
X
X
X
X
X
X
X
-
X
X
X
X
X
X
X
X
-
X
X
X
X
X
X
X
X
Electrolytes
Calcium
Sodium
Potassium
Chloride
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid stimulating hormone (TSH)
*Aldosterone
X
-
-
X
-
-
24h collection Urine**
Urine potassium
Urine sodium
Urine chloride
Urine creatinine
-
-
-
-
X
X
X
X
-
-
-
-
Urinalysis (Stix)
[Urin-Sediment will be 
performed , if urinalysis 
abnormal]
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine RBC
Urine WBC
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, leukocytes
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (for 
instance, the presence of sediment bacteria, 
casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1A: parameters to be determined at screening examination 
2B: parameters to be determined during the study (for time points refer to Flow Chart)
3C: parameters to be determined during the Follow-up-examination
* Aldosterone (after a 15-minute resting period in supine position) samples may be stored at 
about -20C in case shipment/analytics on the same day is not possible
** For baseline from blank urine sample and all Urine collected from 0-24h. These will be 
stored intermittent in a refrigerator. After processing the 12-24h PK urine fraction (cf.
Section 5.5.2.3), all collected fractions (0-24h) will be mixed for the 24h urine electrolyte 
measurement. Mixing should be done by transferring the entire content of all collection 
containers into a single PE/PP or glass container, and stirring the mixed fractions for about 1 
min (manually or using a stir bar or other stirring device out of PE, PP, Teflon or glass).
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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. It is planned to perform these tests during screening only. Drug screening will be 
performed at screening and on Day 1.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody/p24-antigen (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed as indicated in the Flow Chart and may be 
repeated at any time during the study at the discretion of an investigator or designee. The 
results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at Medizinisches 
Versorgungszentrum Dr. Klein, Dr. Schmitt & Partner, Kaiserslautern, Germany with the 
exception of the urinalysis stix and drug screening tests. These tests will be performed at the 
trial site using Combur 9 Test (Roche Diagnostics, GmbH, Mannheim, Germany) and 
AccuSign® DOA 10 test (Diagnostik Nord GmbH, Schwerin, Germany).
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart. Electrode placement will be performed 
according to the method of Wilson, Goldberger and Einthoven modified by Mason and Likar 
(hips and shoulders instead of ankles and wrists). Precise electrode placement will be marked 
with an indelible mark on the skin to allow reproducible placement throughout the study.
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To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart. Three triple ECGs will be recorded at baseline 
as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point. For the repeats due to quality reasons, only the repeated ECG recordings will be 
sent to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Additional (unscheduled) ECGs may be collected by the Investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths. 
Data transfer
ECGs will be transferred electronically to the central ECG lab 
 
 for evaluation.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab
Central ECG lab evaluation (of visit 2 ECGs only) will be performed for the first of 
three replicate ECGs per time point given in the Flowchart. For baseline, where 3 
triplicate ECGs are recorded, only the first triplicate ECG (i.e. 3 single ECGs) will be 
evaluated. 
RR and QT intervals will be determined semi-automatically, whereas PR, QRS 
intervals and QRS-axis are measured automatically by a validated GE 12-SL-
algorithm or equivalent. 
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will 
be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
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same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements no lead will be provided
For blinding arrangements see Section 4.1.5.1. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. Evaluation of ECGs will comply with the ICH E14 guidance 
document and supplements [R07-4722, R16-0366] as well as the FDA requirements 
for annotated digital ECGs [R09-4830].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 
computerised ECG system or their manual corrections by the investigators will be 
used. 
In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data transfer) for
cardiologic assessment by the central lab. In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment. 
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 3-lead ECG
recording for at least 15 min before (for baseline assessment) until 4 h following drug 
administration using patient monitors (e.g. ApexPro Telemetry System, GE Medical Systems, 
Freiburg, Germany).
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor (e.g. 
Dash 3000, GE Medical Systems, Freiburg, Germany) at the times indicated in the Flow 
Chart, after subjects have rested for at least 5 min in a supine position. All recordings should 
be made using the same type of blood pressure recording instrument on the same arm if 
possible.
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5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination.
 
 
 
 
 
 
 
 
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an inhalative administered drug, and are widely used 
in clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5
are generally used assessments of drug exposure.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs. Planned sampling times should be adhered to as close as possible. However, these 
sampling times only represent guidance; thus, deviations which may occur especially shortly 
after inhalation are not regarded as protocol violations.
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PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints

AUCt1-t2 (area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2)

Cmax (maximum measured concentration of the analyte in plasma)
 
 
 
 
 
 
 
 
 
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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 1265162 plasma concentrations, 4.9 mL of blood will be taken from 
an antecubital or forearm vein into an K3-EDTA (tripotassium 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 venipuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene tubes. The first aliquot should contain at least 1.0 mL plasma. The process 
from blood collection until transfer of plasma aliquots into the freezer should be completed 
within 60 min, with interim storage of blood samples and aliquots in ice water or on ice. For 
each aliquot the time when the sample was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
about -20°C or below at the trial site. The second aliquot will be transferred to the analytical 
laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At the 
analytical laboratory the plasma samples will be stored at about -20°C or below until 
analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as matrix and 
analyte may also be provided. 
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.
 
 
 
 
 
 
 
 
 
 
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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
BI 1265162 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. The analysis will be performed at Drug 
Metabolism and Pharmacokinetics Germany, Boehringer Ingelheim Pharma GmbH & Co 
KG, Biberach, Germany. All details of the analytical method will be available prior to the 
start of sample analysis.
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.
 
 
 
5.6
BIOMARKER 
Not applicable.
5.7
PHARMACODYNAMICS
Not applicable.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
Not applicable.
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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK).
The acceptable deviation from the scheduled time for vital signs, spirometry, ECG and 
laboratory tests will be ± 30 min for the first 4 h after trial drug administration and ± 45 min 
thereafter.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements (if at the same time point as spirometry, spirometry should be last 
measurement) due to its inconvenience to the subject and possible influence on physiological 
parameters.
For planned individual plasma concentration sampling times and 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study. 
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.  
6.2.2
Treatment period
Each subject will receive one dose of the respective trial medication (BI 1265162 or placebo) 
at Visit 2.
Trial medication will be administered by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
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Study participants will be admitted to the trial site in the morning of Day 1 and kept under 
close medical surveillance for at least 24 h following drug administration. The subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their fitness 
by the investigator or 
 designee. On all other study days, the study will be performed in an 
ambulatory fashion.
For details on time points and procedures for collection of plasma 
 samples for PK 
analysis, refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. Adverse events persisting after trial completion must be 
monitored until they have normalised or have been sufficiently characterised. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.
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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 1265162
by using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in Section 5.2.1. Inferential statistics is not planned (as explained 
in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) of BI 1265162 after 
single dosing. Endpoints as specified in Section 5.5.1 will be analysed by descriptive 
statistics. Secondary endpoints (AUCt1-t2 and Cmax) as defined in Section 5.5.1.1 will be 
subjected to 
 The main analysis is 
based on the descriptive statistics and the 
 is regarded as 
further analysis.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of the different dose groups of BI 1265162 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.
7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
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Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). Analyses will be 
performed for parent drug.
Plasma and urine 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 violation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma and urine concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

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),

missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one PK parameter that was not excluded according to the description above.
Descriptive statistics will be calculated for PK endpoints.
 
 
 
 
 
 
 


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7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is, 
all subjects who received at least one dose of study drug), will be included in the safety 
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the trial 
termination date will be assigned to the treatment period. These assignments including the 
corresponding time intervals will be defined in detail in the TSAP.
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Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be flagged in the listings. Additionally, differences from baseline will be 
evaluated.
For vital signs and 
 the differences from baseline will be evaluated. Additionally, 
plots over the time will be provided for spirometry data.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the derivation of further ECG parameters based on the ECG variables QT, HR, QTcF, 
QTcB, PR, QRS, and RR. The baseline value of an ECG variable is defined as the mean of 
the triple ECG measurements prior to drug administration. The derivation of the quantitative 
and qualitative ECG endpoints and their analyses will be described in the TSAP.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1265162 will be 
calculated according to the BI SOP ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma / urine concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma / urine concentrations, 
pharmacokinetic parameters or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
 
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma/urine drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification) will be displayed as such 
and not replaced by zero at any time point (this rule also applies also to the lag phase, 
including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
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Drug concentration data identified with NOS, NOR or NOA will generally not be considered. 
Concentration values in the lag phase identified as BLQ will be set to zero. All other BLQ
values of the profile will be ignored. The lag phase is defined as the period between time zero 
and the first time point with a concentration above the quantification limit. 
7.5
RANDOMISATION
The subjects of the first cohort per dose level will not be randomised to maintain a treatment
sequence of active-placebo-active-active due to safety reasons. In the second cohort subjects 
will be randomised within each dose group in a 3:1 ratio, which reflects the ratio of subjects 
receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 56 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics [R95-0013].
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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs 
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
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auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained. 
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
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8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.
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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P87-3333
Beasley CRW, Rafferty P, Holgate ST. The role of preservatives in
Atrovent-induced bronchoconstriction. Thorax. 1987. 42: 230-231.
P88-1291
Rafferty P, Beasley R, Holgate ST. Comparison of the efficacy of
preservative free ipratropium bromide and ATROVENT® nebulizer
solution. Thorax. 1988. 43: 446-450.
P96-3855
Ramsey B W. Management of Pulmonary Disease in patients with Cystic 
Fibrosis. NEJM 1996; 335 (3): 179-188. July 18.
P05-08465
Hodder R; Pavia D; Dewberry H; Alexander K; Iacono P; Ponitz H; et al.
Low incidence of paradoxical bronchoconstriction in asthma and COPD
patients during chronic use of Respimat Soft Mist inhaler. Respir Med.
2005. 99: 1087-1095.
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson 
DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi
G, Wanger J Standardisation of spirometry. Eur Respir J 26 (2), 319 - 338 
(2005).
P11-05794
Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic
obstructive pulmonary disease. Cochrane Database Syst Rev. 2010 Feb
17;(2):CD001287.
P13-14084
Mogayzel PJ Jr, 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 Apr 1;187(7):680-9.
R95-0013
Broom C. Design of first-administration studies in healthy man. Early 
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R01-1277
Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care 
Med. 1996;154(5):1229-56.
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial
clinical trials for therapeutics in adult healthy volunteers. U.S.Department
of Health and Human Services, Food and Drug Administration, Center for
Drug Evaluation and Research (CDER) 2005.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER); 2005.
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R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R15-3034
Chronic respiratory diseases: burden of COPD. 
www.who.int/respiratory/copd/burden/en/ (access date: 11 June 2015) ; 
World Health Organization (2015).
R15-4955
Clunes MT, Boucher RC. Drug Discov Today Dis Mech. Cystic Fibrosis: 
The Mechanisms of Pathogenesis of an Inherited Lung Disorder. 
2007;4(2):63-72.
R15-4984
Elborn JS, Shale DJ. Lung injury in cystic fibrosis. Thorax 1990; 45:970-
973.
R15-5349
Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King 
M, Edwards LJ, Helms RW, Boucher RC. A pilot study of aerosolized 
amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med. 
1990 Apr 26;322(17):1189-94.
R15-5485
App EM, King M, Helfesrieder R, Köhler D, Matthys H. Acute and 
longterm amiloride inhalation in cystic fibrosis lung disease. A rational 
approach to cystic fibrosis therapy. Am Rev Respir Dis. 1990 
Mar;141(3):605-12.
R15-5486
Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC. 
Defective epithelial chloride transport in a gene-targeted mouse model of 
cystic fibrosis. Science. 1992 Aug 21;257(5073):1125-8.
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 146, 319 – 326 
(1986).
R15-5503
Walters S, Mehta A. Epidemiology of cystic fi brosis. In: Hodson M, 
Geddes DM, Bush A, eds. Cystic fibrosis, 3rd edn. London: Edward Arnold 
Ltd, 2007: 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, M. A., Button, B., Johannesson, B., Zhou, Z., Livraghi, A., Caldwell, 
R. A, and Boucher, R. C. Airway surface liquid volume regulation 
determines different airway phenotypes in liddle compared with 
βENaCoverexpressing mice. J. Biol. Chem., 285(35), 26945-26955 2010.
R15-5546
Genes and human disease: monogenic diseases. 
who.int/genomics/publicdiseases/en/index2.html#CF (access date: 28 
October 2015); Geneva: World Heath Organization (WHO) (2015).
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R15-5599
Graham, A., Hasani, A., Alton, E. W. F. W., Martin, G. P., Marriott, C., 
Hodson, M. E., and Geddes, D. M. (1993). No added benefit from 
nebulized amiloride in patients with cystic fibrosis. Eur. Respir. J., 6(9), 
1243-1248.
R16-0366
E14 Implementation Working Group. ICH E14 guideline: the clinical 
evaluation of QT/QTc interval prolongation and proarrhythmic potential for 
non-antiarrhythmic drugs: questions & answers (R3) (current version dated 
10 December 2015). 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2015) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use; 2015.
R17-1997
Rowe S.M., Verkman A.S. Cystic Fibrosis Transmembrane Regulator 
Correctors and Potentiators. Cold Spring Harb Perspect Med 
2013;3:a00976.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c10884768
 Safety, tolerability and 
pharmacokinetics of single rising inhaled doses of BI 443651 in healthy 
male volunteers in a partially randomised, single blind, placebo-controlled 
trial.
c16304878
Investigator`s Brochure BI 1265162 Cystic fibrosis and COPD
05 September 2017.
U97-0056
 A three-way crossover study in healthy volunteers of
lung deposition of fenoterol hydrobromide (100 μg via one puff) delivered
from either a BINEB® (ARIANE) nebuliser, or a conventional MDI, or
conventional MDI with a spacer. (260.2706) 20 June 1996.
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10.
APPENDICES
10.1
HANDLING INSTRUCTIONS FOR RESPIMAT INHALER FOR USE IN 
CLINICAL TRIALS 
These instructions explain generally the use of BI 1265162 RESPIMAT inhaler. Depending 
on the clinical study, the product is administered under direct medical supervision or used by 
patients at home. Depending on the situation, the Instructions can be adapted to the specific 
situation as need may be.
Read these Instructions for Use before you start demonstrating or using RESPIMAT.
How to store BI 1265162 RESPIMAT
Keep BI 1265162 RESPIMAT out of the sight and reach of children.
Do not freeze BI 1265162 RESPIMAT. For further storage conditions, please refer to product 
label.
If BI 1265162 RESPIMAT has not been used for more than 7 days, repeat steps 4 to 6 (turn, 
open, press) under ‘Prepare for first Use’ until a cloud is visible. Then repeat steps 4 to 6 
three more times.
Do not use BI 1265162 RESPIMAT after the expiry date.
How to care for BI 1265162 RESPIMAT
Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or 
tissue, at least once a week. Cleaning on a daily basis or daily disinfection with an alcoholic 
tissue is also possible.
Any minor discoloration in the mouthpiece does not affect BI 1265162 RESPIMAT inhaler 
performance.
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When to get a new BI 1265162 RESPIMAT
•
BI 1265162 RESPIMAT inhaler contains 120 puffs if used as indicated.
•
The dose indicator shows approximately how much medication is left.
•
When the dose indicator enters the red area of the scale, get a new 
BI 1265162 RESPIMAT from the investigational site; there are approximately 30 puffs 
left.
•
Once the dose indicator reaches the end of the red scale, BI 1265162 RESPIMAT locks 
automatically – no more doses can be released. At this point, the clear base cannot be 
turned any further. The inhaler should not be discarded; it should be returned to 
investigational site.
Prepare for first use
Remove clear base
Keep the cap closed.
Press the safety catch while firmly pulling 
off the clear base with your other hand.
Insert cartridge
Insert the narrow end of the cartridge into 
the inhaler.
Place the inhaler on a firm surface and 
push down firmly until it snaps into place.
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Replace clear base
Put the clear base back into place until it 
clicks. 
Turn
Keep the cap closed.
Turn the clear base in the direction of the 
arrows on the label until it clicks (half a 
turn).
Open
Open the cap until it snaps fully open.
Press
Point the inhaler toward the ground
Press the dose-release button.
Close the cap.
Repeat steps 4-6 until a cloud is visible.
After a cloud is visible, repeat steps 4-6 
three more times.
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Daily use
TURN
Keep the cap closed.
TURN the clear base in the direction of the 
arrows on the label until it clicks (half a turn).
OPEN
OPEN the cap until it snaps fully open.
PRESS
Breathe out slowly and fully.
Close your lips around the mouthpiece without 
covering the air vents.
While taking a slow, deep breath through your 
mouth, PRESS the dose-release button and 
continue to breathe in.
Hold your breath for 10 seconds or for as long as 
comfortable.
Repeat Turn, Open, Press for a total of puffs
required by the clinical trial protocol.
Close the cap until you use your BI 1265162 
RESPIMAT inhaler again.
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Answers to Common Questions
It is difficult to insert the cartridge deep enough.
Did you accidentally turn the clear base before inserting the cartridge? Open the cap, 
press the dose-release button, then insert the cartridge.
Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow 
end first.
I cannot press the dose-release button.
Did you turn the clear base? If not, turn the clear base in a continuous movement until it 
clicks (half a turn).
Is the dose indicator on BI 1265162 RESPIMAT pointing to zero? 
BI 1265162 RESPIMAT inhaler is locked after 120 puffs. Prepare and use a new 
BI 1265162 RESPIMAT inhaler.
I cannot turn the clear base.
Did you turn the clear base already? If the clear base has already been turned, follow steps 
“OPEN” and “PRESS” under “Daily Use” to get your medicine. 
Is the dose indicator on the BI 1265162 RESPIMAT pointing to zero? The 
BI 1265162 RESPIMAT inhaler is locked after 120 puffs. Prepare and use your new 
RESPIMAT inhaler.
The dose indicator on the BI 1265162 RESPIMAT reaches zero too soon. 
Did you turn the clear base before you inserted the cartridge? The dose indicator counts 
each turn of the clear base regardless whether a cartridge has been inserted or not.
Did you spray in the air often to check whether the BI 1265162 RESPIMAT is working? 
Once you have prepared BI 1265162 RESPIMAT, no test-spraying is required if used daily.
Did you insert the cartridge into a used RESPIMAT? Always insert a new cartridge into a 
NEW RESPIMAT.
BI 1265162 RESPIMAT sprays automatically.
Was the cap open when you turned the clear base? Close the cap, then turn the clear base.
Did you press the dose-release button when turning the clear base? Close the cap, so the 
dose-release button is covered, then turn the clear base.
Did you stop when turning the clear base before it clicked? Turn the clear base in a 
continuous movement until it clicks (half a turn).
BI 1265162 RESPIMAT doesn’t spray.
Did you insert a cartridge? If not, insert a cartridge.
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Did you repeat Turn, Open, Press less than three times after inserting the cartridge? 
Repeat Turn, Open, Press three times after inserting the cartridge as shown in the steps 4 to 6 
under “Prepare for first Use”.
Is the dose indicator on BI 1265162 RESPIMAT pointing to 0? If the dose indicator 
points to 0, you have used up all your medication and the inhaler is locked.
Once BI 1265162 RESPIMAT is assembled, do not remove the clear base or the cartridge. 
Always insert a new cartridge into a NEW RESPIMAT.
Further information
BI 1265162 RESPIMAT inhaler must not be disassembled after inserting the cartridge and 
replacing the clear base.
Do not touch the piercing element inside the base.
Boehringer Ingelheim Pharma GmbH & Co. KG
D - 55216 Ingelheim, Germany  
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Description of change
Rationale for change
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15848245
1.0
clinical-trial-protocol
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
Author-Clinical Monitor
19 Sep 2017 14:30 CEST
Approval-Team Member Medicine
19 Sep 2017 14:41 CEST
Author-Trial Statistician
19 Sep 2017 15:42 CEST
Approval-Therapeutic Area
19 Sep 2017 16:17 CEST
Author-Trial Clinical
Pharmacokineticist
20 Sep 2017 09:05 CEST
Verification-Paper Signature
Completion
20 Sep 2017 13:19 CEST
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Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15848245
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Clinical Tiial Protocol 
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LOCAL SIGNATURE 
(Local Clinical Monitor) 
Trial Title: 
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 
Trial Number: 
1399-0001 
Clinical Trial Protocol Version: 1.0 
I herewith certify that I agree to adhere to the Clinical Trial Protocol and to all 
documents referenced in the Clinical Trial Protocol. 
Local Clinical Monitor (Print full name) 
1001-MCS-40-106 RD-09 (5.0) / Saved on: 15 Mar 2016 
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87
88
172
173
174
175
16.1.1.2 Revised protocol and protocol amendments..............................................
clinical-trial-protocol-revision-02........................................................................
clinical-trial-protocol-revision-01-signature-pi-
clinical-trial-protocol-revision-01-signature-cml-
clinical-trial-protocol-revision-02-signature-pi-
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Clinical Trial Protocol
TITLE PAGE
Document Number:
c15848245-03
EudraCT No.:
BI Trial No.:
2017-001106-15
1399-0001
BI Investigational
Product:
BI 1265162
Title:
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
Lay Title
This study tests the safety, tolerability and how different doses of 
BI 1265162 are taken up in the body of healthy men.
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax: 
Principal Investigator:
Phone:
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 19 February 2018
Page 1 of 82
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable 
Name of active ingredient:
BI 1265162
Protocol date:
Trial number:
Revision date:
19 February 2018
19 September 2017
1399-0001
Title of trial:
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
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability and pharmacokinetics, following single doses of 
BI 1265162
Methodology:
Single-blind, partially randomised within dose groups, placebo-controlled, parallel-
group design
No. of subjects: 
total entered:
56*
each treatment:
8 per dose group (6 on active drug and 2 on placebo)
* Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned and 
approved highest dose will not be exceeded. Thus, the actual number of subjects entered may 
exceed 56, but will not exceed 72 subjects entered.
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 50 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Test product:
BI 1265162
dose:
mode of admin.:
Inhalation by RESPIMAT
Comparator product:
Placebo
dose:
Not applicable
mode of admin.:
Inhalation by RESPIMAT 
Duration of treatment: Single dose
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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable 
Name of active ingredient:
BI 1265162
Protocol date:
Trial number:
Revision date:
19 February 2018
19 September 2017
1399-0001
Criteria for 
pharmacokinetics:
Secondary endpoints: AUCt1-t2 and Cmax
 
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 1265162 is the number [N 
(%)] of subjects with drug-related adverse events.
Further criteria of interest:
AEs including clinically relevant findings from the physical examination, safety 
laboratory tests, 12-lead electrocardiogram (ECG), continuous ECG monitoring, vital 
signs (blood pressure [BP], pulse rate [PR])
.
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
 
2.2
TRIAL OBJECTIVES.......................................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 28
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................28
3.1.1
Administrative structure of the trial...................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for study entry............................................................31
3.3.2
Inclusion criteria...................................................................................31
3.3.3
Exclusion criteria ..................................................................................31
3.3.4
Removal of subjects from therapy or assessments.............................33
3.3.4.1
Removal of individual subjects................................................33
3.3.4.2
Discontinuation of the trial by the sponsor..............................33
3.3.5
Replacement of subjects .......................................................................34
4.
TREATMENTS........................................................................................ 35
4.1.2
Method of assigning subjects to treatment groups ............................35
4.1.3
Selection of doses in the trial................................................................36
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4.1.4
Drug assignment and administration of doses for each subject .......36
4.1.5
Blinding and procedures for unblinding ............................................38
4.1.5.1
Blinding....................................................................................38
4.1.5.2
Procedures for emergency unblinding .....................................38
4.1.6
Packaging, labelling, and re-supply ....................................................38
4.1.7
Storage conditions.................................................................................39
4.1.8
Drug accountability ..............................................................................39
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................40
4.2.1
Other treatments and emergency procedures....................................40
4.2.2
Restrictions............................................................................................40
4.2.2.1
Restrictions regarding concomitant treatment .........................40
4.2.2.2
Restrictions on diet and life style.............................................40
4.3
TREATMENT COMPLIANCE.......................................................................41
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 42
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................42
5.1.1
Endpoints of efficacy.............................................................................42
5.1.2
Assessment of efficacy...........................................................................42
5.2
SAFETY..............................................................................................................42
5.2.1
Endpoints of safety................................................................................42
5.2.2
Assessment of adverse events...............................................................42
5.2.2.1
Definitions of adverse events...................................................42
5.2.2.2
Adverse event collection and reporting ...................................45
5.2.3
Assessment of safety laboratory parameters......................................47
5.2.4
Electrocardiogram................................................................................49
5.2.4.1
12-lead resting ECG.................................................................49
5.2.4.2
Continuous ECG monitoring ...................................................51
5.2.5
Assessment of other safety parameters...............................................51
5.2.5.1
Vital signs ................................................................................51
5.2.5.2
Medical examinations..............................................................52
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................52
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................52
5.5.1
Pharmacokinetic endpoints..................................................................53
5.5.1.1
Secondary endpoints................................................................53
5.5.2
Methods of sample collection...............................................................54
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................54
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5.5.3
Analytical determinations ....................................................................57
5.5.3.1
Analytical determination of analyte plasma concentration......57
5.6
BIOMARKER....................................................................................................57
5.7
PHARMACODYNAMICS................................................................................57
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....57
6.
INVESTIGATIONAL PLAN.................................................................. 58
6.1
VISIT SCHEDULE............................................................................................58
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................58
6.2.1
Screening period....................................................................................58
6.2.2
Treatment period ..................................................................................58
6.2.3
End of trial period.................................................................................59
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 60
7.1
STATISTICAL DESIGN – MODEL ...............................................................60
7.1.1
Objectives...............................................................................................60
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................60
7.3
PLANNED ANALYSES....................................................................................60
7.3.1
Primary analyses...................................................................................60
7.3.2
Secondary analyses ...............................................................................60
7.3.3
Safety analyses.......................................................................................62
7.3.5
Pharmacokinetic analyses ....................................................................64
7.4
HANDLING OF MISSING DATA ..................................................................64
7.4.1
Safety......................................................................................................64
7.4.2
Plasma/urine drug concentration - time profiles ...............................64
7.4.3
Pharmacokinetic parameters...............................................................64
7.5
RANDOMISATION ..........................................................................................65
7.6
DETERMINATION OF SAMPLE SIZE ........................................................65
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 66
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................66
8.2
DATA QUALITY ASSURANCE .....................................................................66
8.3
RECORDS..........................................................................................................67
8.3.1
Source documents .................................................................................67
8.3.2
Direct access to source data and documents.......................................67
8.3.3
Storage period of records.....................................................................67
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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................67
8.5
STATEMENT OF CONFIDENTIALITY.......................................................68
8.6
COMPLETION OF TRIAL..............................................................................68
9.
REFERENCES......................................................................................... 69
9.1
PUBLISHED REFERENCES...........................................................................69
9.2
UNPUBLISHED REFERENCES.....................................................................71
10. APPENDICES .......................................................................................... 72
10.1
HANDLING INSTRUCTIONS FOR RESPIMAT INHALER FOR USE 
IN CLINICAL TRIALS ....................................................................................72
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 80
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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
AMG
Arzneimittelgesetz (German drug law)
ANCOVA
Analysis of covariance
 
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
 
 
BI
Boehringer Ingelheim
b.i.d.
Bis in die, twice daily
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CF
Cystic fibrosis
CI
Confidence interval
 
Cmax
Maximum measured concentration of the analyte in plasma
 
COPD
Chronic obstructive pulmonary disease
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
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EOT
End of trial
 
gCV
Geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
 
NC
Not calculated
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
NOTEL
No toxic effect level
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
q.d.
Quaque die, once 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)
 
RDC
Remote data capture
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SRD
Single-rising dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
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TMF
Trial master file
 
TDMAP
Trial Data Management and Analysis Plan
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
 
 
 
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2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 1265162 in 
healthy male subjects following inhalative administration of single rising doses.
Secondary objective is the exploration of the pharmacokinetics (PK) of BI 1265162 after 
single dosing.
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A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single-rising dose trial is designed as single-blind, partially randomised, and placebo-
controlled within parallel dose groups.
Partially randomised means that the subjects will be treated in two equally sized cohorts per 
dose group, with the first cohort being treated in a fixed sequence and the second cohort 
being treated in a randomised order.
A total of 56 healthy male subjects is planned to participate in the trial, according to 7
sequential groups comprising 8 subjects per group. However, additional subjects may be 
entered to allow testing of intermediate doses within the planned and approved dose range on 
the basis of experience gained during trial conduct (e.g. preliminary PK data), i.e. the actual 
number of subjects entered may exceed 56. Such changes may be implemented via non-
substantial CTP Amendments.
Within each dose group, 6 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
On the first study day of each dose level, the first cohort will be treated in the following 
order: first subject (active) followed at least 1 h later by the second subject (placebo) 
followed at least 1 h later by the third subject (active) followed at least 10 min later by the 
fourth subject (active). If BI 1265162 treatment is safe and showed acceptable tolerability in 
the first cohort, the subjects in the second cohort will be treated not earlier than 2 days later 
than the first treated volunteer in the first cohort. In the second cohort, a time interval of at 
least 10 min will be maintained between dosing of individual subjects in a random order. The 
dose groups will be investigated consecutively in ascending order of doses. A time interval of 
at least 6 days will be maintained between the administration of the study drug to the first 
cohort in a dose group and the first cohort in the next dose group. The decision to proceed to 
the next dose group will be based upon the safety, tolerability data of the preceding dose 
groups and explorative PK data in some dose groups (see Section 7.3.4).
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The next dose will only be given if, in the opinion of the investigator, no safety concerns 
arose in the preceding dose group (i.e. no dose-limiting events occurred) and if none of the 
pre-specified trial-specific stopping criteria were met (refer to Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by the 
Principal Investigator (or an authorised deputy) or the sponsor of the study, e.g. because of 
any unforeseen adverse events, etc. Dose escalation will only be permitted if no safety 
concerns exist in the opinion of the Principal Investigator (or an authorised deputy) and the 
Trial Clinical Monitor (or an authorised deputy). 
The minimum data set for review consists of the following data:

AEs in the current and preceding dose groups up to at least 48h post dosing (including 
clinically relevant findings from ancillary safety testing listed below) (Note: AEs may 
be ongoing at the time of Safety Reviews and AE information may be subject to 
change prior to Database Lock)

Results from 12-lead ECG and continuous ECG monitoring in the current and 
preceding dose groups.

Vital signs in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Preliminary PK data as per Section 7.3.4

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the Trial Clinical Monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 
face-to-face or by video/telephone conference. The Trial Clinical Monitor is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (or an authorised deputy) and filed in the ISF and TMF.
The investigator (after consultation with the sponsor) is allowed to alter the scheduled dose 
levels (e.g. add low and/or intermediate dose levels) on the basis of experience gained during 
the study, provided the planned and approved highest dose is not exceeded. In this case, the 
total number of subjects in this trial might increase. The investigator and/or the sponsor 
should stop dose escalation in case the safety evaluation leads to concerns that would not 
allow higher dosing.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
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BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany.
The trial will be conducted at
 
under the supervision of the Principal 
Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
(Medizinisches Versorgungszentrum Dr. Klein, Dr. Schmitt & Partner, Kaiserslautern, 
Germany).
The analyses of BI 1265162 concentrations in plasma and urine will be performed at the 
Department of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single -rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 1265162.
With the rising dose design, single-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to the dose-depending effects as well as time effects, but it has the 
virtue of minimizing subject risk by sequentially studying ascending doses. As time-effects 
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are expected to be small relative to the differences between the doses in the broad range 
investigated, unbiased comparisons between treatments can still be expected.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety and tolerability. Each dose group consists of 8 subjects with 6 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. 6 subjects per active treatment group are in general considered 
as sufficient for the exploratory evaluation of pharmacokinetics.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 56 healthy male will enter the study. The actual number of subjects entered 
may exceed the total of 56 if additional intermediate doses will be tested (see Section 3.1). 
Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 50 years (incl.) 
3. BMI of 18.5 to 29.9 kg/m2 (incl.) 
4. FEV1 and FVC of equal or greater than 80% of predicted normal, at screening and prior 
to randomisation
5. Signed and dated written informed consent prior to admission to the study in accordance
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
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2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational 
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more 30 g per day for males)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
22. A history of chronic kidney disease (EGFR <59 mls/min including corrections as per 
ethnicity)
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
24. The subject has a diagnosis history of pulmonary hyperreactivity
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25. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from the first administration of trial medication until 
14 days after last administration of trial medication (BI 1265162 or placebo)
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:

The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision

The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication

The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:

New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported.
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
The expected enrolment goals overall or at a particular trial site are not met

Violation of GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial

The sponsor decides to discontinue the further development of the investigational 
product.

Dose escalation will be stopped as soon as at least 2 subjects at one dose level on active 
drug showed relevant individual QT prolongation, i.e. a QTc increase of greater 60 ms 
from baseline in connection with absolute QT or QTc greater than 500 ms, which has 
been confirmed by a repeat ECG recording (e.g. follow-up ECG).
 
 
 
 
 
 
 trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case that more than 2 subjects on active per dose group do not complete the trial, the trial 
clinical monitor together with the trial pharmacokineticist and the trial statistician are to 
decide if and how many subjects will be replaced. A replacement subject will be assigned a 
unique study subject number, and will be assigned to the same treatment as the subject he 
replaces.
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4.
TREATMENTS
 
 
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects have been allocated to 1 
of the 14 dose cohorts (2 cohorts per dose group), the following subjects will be allocated to 
one of the other dose cohorts. Therefore, the allocation of subjects to dose cohorts is not 
influenced by trial personnel, but only by the subjects’ temporal availability. As the study 
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includes healthy subjects from a homogenous population, relevant imbalances between the 
dose groups are not expected.
The randomization list with study subject numbers and allocated treatments will be provided 
to the trial site and the sponsor (TCM) in advance. The allocation of subjects to study subject 
numbers will be performed prior to the first administration of trial medication. For this 
purpose, the subjects will be allocated to a study subject number by the method 'first come 
first served'. Once a subject number has been assigned, it cannot be reassigned to any other 
subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
The doses selected for this trial cover the subtherapeutic as well as the estimated therapeutic 
range and include a safety margin (see Section 1.2).
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of actuations 
for placebo corresponds to the number of actuations of the respective dose level.
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Each newly assembled RESPIMAT Inhaler (has to be done on the day of application) has to 
be primed by qualified medical/pharmaceutical study personnel at the trial site under the 
responsibility of the investigator. To avoid contamination, except those devices used for 
training, priming should NOT take place in the same room where the subject is inhaling trial 
medication or the trial will be performed or samples will be processed. The inhaler should be 
primed under e.g. hood/outside by actuating it until an aerosol is visible plus three additional 
actuations. All priming actuations should be directed to the ground. For detailed priming 
instructions please refer to the RESPIMAT Inhaler handling instructions in Appendix 10.1.
Both the study drug as well as the placebo treatment (depending on randomisation) will be 
inhaled with the RESPIMAT in a sitting or standing position under supervision of the 
investigating physician or an authorised designee. If more than one actuation is needed,
planned time 0:00h will always be the first actuation. If more than one actuation will be 
needed, the duration from first to last actuation will be recorded. To avoid any contamination 
(e.g PK tubes), administration of trial medication should be performed in a separate room; 
subject and staff should wear e.g. gloves and protective wear.
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The so-called four-eye principle (two-person rule) should be applied for administration of 
trial medication and – if applicable – its preparation (e.g. assembling of device), otherwise
correct dosage cannot be ensured.
Subjects will be kept under close medical surveillance until 24 h following drug 
administration. During the first 4 h after 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 except for 
medical examination), or to sleep. For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The treatments administered (active or placebo) will be single-blind (blinded to subjects 
only). However, the current dose level will be known to the subjects. 
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded with respect to the treatment and also with regard to the recording date and 
time as well as the time points of the ECGs. The interval measurements for a given subject 
will be performed in a random and blinded sequence by a single technician. No more than 
two different blinded readers will evaluate the ECGs of the study.
In addition, the trial pharmacokineticist, trial pharmacometrician and bioanalyst may receive 
the randomisation codes prior to official unblinding to perform the interim / preliminary PK 
analysis. He or she will confirm in writing that the codes will be treated confidentially.
In addition, the drug metabolism scientist may receive the randomisation codes prior to 
official unblinding to perform metabolites in safety testing analysis (MIST). He or she will 
confirm in writing that the codes will be treated confidentially.
The database of this trial will be handled open-label, because no bias with regard to data 
cleaning of safety measures is expected. 
4.1.5.2
Procedures for emergency unblinding
As this trial will be conducted single-blinded, the treatment information will be known. 
Therefore, no emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
The clinical trial supply consists of containers holding the trial medication which are labelled  
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Smaller boxes within the 
clinical trial supply containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 
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
Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Subject or medication number

Batch Number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
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investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the sponsor.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
No special emergency procedures are to be followed. No additional treatment is planned.
However, in case of adverse events in need of treatment (e.g. treatment of hyperkalaemia), 
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 medical evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is 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 are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to 240 mL of water served at 
2 h and 4 h post-dose (mandatory for all subjects). From lunch onwards, liquid intake is 
restricted to an additional 3000 mL. Subjects will be asked to drink the additional amount till 
one hour prior to the stop of urine collection on day 2. The total amount of liquid intake will 
be documented.
Standardised meals (identical for each dose group) will be served at the time points described 
in the study Flow Chart. Use of table salt is not allowed during in-house confinement at the 
trial site.
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 after the last PK sample is 
collected.
Alcoholic beverages, consumption of seafood and dried fruits are not permitted from 48 
hours before the study drug administration and until last blood sampling.
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 24 h before until 24 h after each administration of trial 
medication.
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Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 
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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 1265162 is the number [N (%)] of 
subjects with drug-related adverse events.
Further criteria of interest:  

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring 

Vital signs (blood pressure, pulse rate)
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 
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
is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, 
or 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.2.2 subsections ‘AE collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term 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 above.
The following are considered as AESIs in this trial:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
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These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
RDC. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure these parameters are analysed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described in 
the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
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
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful 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, and intensity of the event as 
well as 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: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report related SAEs and related AESIs of which the investigator 
may become aware of by any means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.
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The REP for BI 1265162, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known for this first-in-human trial. Therefore, all 
AEs reported until the end of trial examination (last per protocol contact) will be considered 
on treatment; please see Section 7.3.3.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (if applicable). The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)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 CRF only.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.
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5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 8 h (excluding sample at 06:00h post administration). 
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.
Table 5.2.3: 1
Routine laboratory tests
Category
Test name
A1
B2
C3
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelets
Reticulocyte count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential 
(relative and absolute)
Neutrophiles 
Eosinophils 
Basophils 
Monocytes 
Lymphocytes 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal and clinically
relevant in the opinion of 
the investigator)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin Time (Quick and INR)
X
X
X
X
X
X
Enzymes
Aspartate aminotransferase (AST/GOT, SGOT) 
Alanine aminotransferase (ALT/GPT, SGPT) 
Alkaline phosphatase
Gammaglutamyl transferase (GGT)  
Lactate dehydrogenase
Amylase
Lipase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 5.2.3: 1
Routine laboratory tests (cont’d)
Category
Test name
A1
B2
C3
Substrates
Glucose (plasma)
Creatinine
eGFR, calculated from serum creatinine using
CKD-EPI formula
Bilirubin, total
Bilirubin, direct
Cholesterol, total
Triglycerides
C-reactive protein
Urea
X
X
X
X
X
X
X
X
X
-
X
X
X
X
X
X
X
X
-
X
X
X
X
X
X
X
X
Electrolytes
Calcium
Sodium
Potassium
Chloride
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid stimulating hormone (TSH)
*Aldosterone
X
-
-
X
-
-
0-4h and 0-24h 
collection Urine**
Urine potassium
Urine sodium
Urine chloride
Urine creatinine
Potassium-creatinine-quotient
Sodium-creatinine-quotient
-
-
-
-
-
-
X
X
X
X
X
X
-
-
-
-
-
-
Urinalysis (Stix)
[Urin-Sediment will be 
performed , if urinalysis 
abnormal]
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine RBC
Urine WBC
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (for 
instance, the presence of sediment bacteria, 
casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1A: parameters to be determined at screening examination 
2B: parameters to be determined during the study (for time points refer to Flow Chart)
3C: parameters to be determined during the Follow-up-examination
* Aldosterone (after a 15-minute resting period in supine position) samples may be stored at 
about -20C in case shipment/analytics on the same day is not possible
** For baseline from blank urine sample (planned time -1:30), urine collected 0-4h and all 
Urine collected from 0-24h. These will be stored intermittent in a refrigerator. After 
processing the 12-24h PK urine fraction (cf. Section 5.5.2.3), all collected fractions (0-24h) 
will be mixed for the 24h urine electrolyte measurement. Mixing should be done by 
transferring the entire content of all collection containers into a single PE/PP or glass 
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container, and stirring the mixed fractions for about 1 min (manually or using a stir bar or 
other stirring device out of PE, PP, Teflon or glass).
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. It is planned to perform these tests during screening only. Drug screening will be 
performed at screening and on Day 1.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody/p24-antigen (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed as indicated in the Flow Chart and may be 
repeated at any time during the study at the discretion of an investigator or designee. The 
results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at Medizinisches 
Versorgungszentrum Dr. Klein, Dr. Schmitt & Partner, Kaiserslautern, Germany with the 
exception of the urinalysis stix and drug screening tests. These tests will be performed at the 
trial site using Combur 9 Test (Roche Diagnostics, GmbH, Mannheim, Germany) and 
AccuSign® DOA 10 test (Diagnostik Nord GmbH, Schwerin, Germany).
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart. Electrode placement will be performed 
according to the method of Wilson, Goldberger and Einthoven modified by Mason and Likar
(hips and shoulders instead of ankles and wrists). Precise electrode placement will be marked 
with an indelible mark on the skin to allow reproducible placement throughout the study.
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To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart. Three triple ECGs will be recorded at baseline 
as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point. For the repeats due to quality reasons, only the repeated ECG recordings will be 
sent to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Additional (unscheduled) ECGs may be collected by the Investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths. 
Data transfer
ECGs will be transferred electronically to the central ECG lab 
 
 for evaluation.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab
Central ECG lab evaluation (of visit 2 ECGs only) will be performed for the first of 
three replicate ECGs per time point given in the Flowchart. For baseline, where 3 
triplicate ECGs are recorded, only the first triplicate ECG (i.e. 3 single ECGs) will be 
evaluated. 
RR and QT intervals will be determined semi-automatically, whereas PR, QRS 
intervals and QRS-axis are measured automatically by a validated GE 12-SL-
algorithm or equivalent. 
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will 
be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
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same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements no lead will be provided
For blinding arrangements see Section 4.1.5.1. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. Evaluation of ECGs will comply with the ICH E14 guidance 
document and supplements [R07-4722, R16-0366] as well as the FDA requirements 
for annotated digital ECGs [R09-4830].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 
computerised ECG system or their manual corrections by the investigators will be 
used. 
In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data transfer) for
cardiologic assessment by the central lab. In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment. 
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 3-lead ECG
recording for at least 15 min before (for baseline assessment) until 4 h following drug 
administration using patient monitors (e.g. ApexPro Telemetry System, GE Medical Systems, 
Freiburg, Germany).
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor (e.g. 
Dash 3000, GE Medical Systems, Freiburg, Germany) at the times indicated in the Flow 
Chart, after subjects have rested for at least 5 min in a supine position. All recordings should 
be made using the same type of blood pressure recording instrument on the same arm if 
possible.
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5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination.
 
 
 
 
 
 
 
 
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an inhalative administered drug, and are widely used 
in clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5
are generally used assessments of drug exposure.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs. Planned sampling times should be adhered to as close as possible. However, these 
sampling times only represent guidance; thus, deviations which may occur especially shortly 
after inhalation are not regarded as protocol violations.
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PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints

AUCt1-t2 (area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2)

Cmax (maximum measured concentration of the analyte in plasma)
 
 
 
 
 
 
 
 
 
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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 1265162 plasma concentrations, 4.9 mL of blood will be taken from 
an antecubital or forearm vein into an K3-EDTA (tripotassium 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 venipuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene tubes. The first aliquot should contain at least 1.0 mL plasma. The process 
from blood collection until transfer of plasma aliquots into the freezer should be completed 
within 60 min, with interim storage of blood samples and aliquots in ice water or on ice. For 
each aliquot the time when the sample was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
about -20°C or below at the trial site. The second aliquot will be transferred to the analytical 
laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At the 
analytical laboratory the plasma samples will be stored at about -20°C or below until 
analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as matrix and 
analyte may also be provided. 
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.
 
 
 
 
 
 
 
 
 
 
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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
BI 1265162 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. The analysis will be performed at Drug 
Metabolism and Pharmacokinetics Germany, Boehringer Ingelheim Pharma GmbH & Co 
KG, Biberach, Germany. All details of the analytical method will be available prior to the 
start of sample analysis.
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.
 
 
 
5.6
BIOMARKER 
Not applicable.
5.7
PHARMACODYNAMICS
Not applicable.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
Not applicable.
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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK).
The acceptable deviation from the scheduled time for vital signs, spirometry, ECG and 
laboratory tests will be ± 30 min for the first 4 h after trial drug administration and ± 45 min 
thereafter.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements (if at the same time point as spirometry, spirometry should be last 
measurement) due to its inconvenience to the subject and possible influence on physiological 
parameters.
For planned individual plasma concentration sampling times and 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study. 
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.  
6.2.2
Treatment period
Each subject will receive one dose of the respective trial medication (BI 1265162 or placebo) 
at Visit 2.
Trial medication will be administered by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
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Study participants will be admitted to the trial site in the morning of Day 1 and kept under 
close medical surveillance for at least 24 h following drug administration. The subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their fitness 
by the investigator or 
 designee. On all other study days, the study will be performed in an 
ambulatory fashion.
For details on time points and procedures for collection of plasma 
 samples for PK 
analysis, refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. Adverse events persisting after trial completion must be 
monitored until they have normalised or have been sufficiently characterised. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.
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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 1265162
by using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in Section 5.2.1. Inferential statistics is not planned (as explained 
in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) of BI 1265162 after 
single dosing. Endpoints as specified in Section 5.5.1 will be analysed by descriptive 
statistics. Secondary endpoints (AUCt1-t2 and Cmax) as defined in Section 5.5.1.1 will be 
subjected to 
 The main analysis is 
based on the descriptive statistics and the 
 is regarded as 
further analysis.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of the different dose groups of BI 1265162 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.
7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
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Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). Analyses will be 
performed for parent drug.
Plasma and urine 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 violation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma and urine concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

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),

missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one PK parameter that was not excluded according to the description above.
Descriptive statistics will be calculated for PK endpoints.
 
 
 
 
 
 
 


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7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is, 
all subjects who received at least one dose of study drug), will be included in the safety 
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the trial 
termination date will be assigned to the treatment period. These assignments including the 
corresponding time intervals will be defined in detail in the TSAP.
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Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be flagged in the listings. Additionally, differences from baseline will be 
evaluated.
For vital signs and 
 the differences from baseline will be evaluated. Additionally, 
plots over the time will be provided for spirometry data.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the derivation of further ECG parameters based on the ECG variables QT, HR, QTcF, 
QTcB, PR, QRS, and RR. The baseline value of an ECG variable is defined as the mean of 
the triple ECG measurements prior to drug administration. The derivation of the quantitative 
and qualitative ECG endpoints and their analyses will be described in the TSAP.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1265162 will be 
calculated according to the BI SOP ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma / urine concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma / urine concentrations, 
pharmacokinetic parameters or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
 
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma/urine drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification) will be displayed as such 
and not replaced by zero at any time point (this rule also applies also to the lag phase, 
including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
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Drug concentration data identified with NOS, NOR or NOA will generally not be considered. 
Concentration values in the lag phase identified as BLQ will be set to zero. All other BLQ
values of the profile will be ignored. The lag phase is defined as the period between time zero 
and the first time point with a concentration above the quantification limit. 
7.5
RANDOMISATION
The subjects of the first cohort per dose level will not be randomised to maintain a treatment
sequence of active-placebo-active-active due to safety reasons. In the second cohort subjects 
will be randomised within each dose group in a 3:1 ratio, which reflects the ratio of subjects 
receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 56 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics [R95-0013].
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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs 
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
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auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained. 
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
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8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.
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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P87-3333
Beasley CRW, Rafferty P, Holgate ST. The role of preservatives in
Atrovent-induced bronchoconstriction. Thorax. 1987. 42: 230-231.
P88-1291
Rafferty P, Beasley R, Holgate ST. Comparison of the efficacy of
preservative free ipratropium bromide and ATROVENT® nebulizer
solution. Thorax. 1988. 43: 446-450.
P96-3855
Ramsey B W. Management of Pulmonary Disease in patients with Cystic 
Fibrosis. NEJM 1996; 335 (3): 179-188. July 18.
P05-08465
Hodder R; Pavia D; Dewberry H; Alexander K; Iacono P; Ponitz H; et al.
Low incidence of paradoxical bronchoconstriction in asthma and COPD
patients during chronic use of Respimat Soft Mist inhaler. Respir Med.
2005. 99: 1087-1095.
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson 
DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi 
G, Wanger J Standardisation of spirometry. Eur Respir J 26 (2), 319 - 338 
(2005).
P11-05794
Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic
obstructive pulmonary disease. Cochrane Database Syst Rev. 2010 Feb
17;(2):CD001287.
P13-14084
Mogayzel PJ Jr, 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 Apr 1;187(7):680-9.
R95-0013
Broom C. Design of first-administration studies in healthy man. Early 
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R01-1277
Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care 
Med. 1996;154(5):1229-56.
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial
clinical trials for therapeutics in adult healthy volunteers. U.S.Department
of Health and Human Services, Food and Drug Administration, Center for
Drug Evaluation and Research (CDER) 2005.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER); 2005.
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R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R15-3034
Chronic respiratory diseases: burden of COPD. 
www.who.int/respiratory/copd/burden/en/ (access date: 11 June 2015) ; 
World Health Organization (2015).
R15-4955
Clunes MT, Boucher RC. Drug Discov Today Dis Mech. Cystic Fibrosis: 
The Mechanisms of Pathogenesis of an Inherited Lung Disorder. 
2007;4(2):63-72.
R15-4984
Elborn JS, Shale DJ. Lung injury in cystic fibrosis. Thorax 1990; 45:970-
973.
R15-5349
Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King 
M, Edwards LJ, Helms RW, Boucher RC. A pilot study of aerosolized 
amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med. 
1990 Apr 26;322(17):1189-94.
R15-5485
App EM, King M, Helfesrieder R, Köhler D, Matthys H. Acute and 
longterm amiloride inhalation in cystic fibrosis lung disease. A rational 
approach to cystic fibrosis therapy. Am Rev Respir Dis. 1990 
Mar;141(3):605-12.
R15-5486
Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC. 
Defective epithelial chloride transport in a gene-targeted mouse model of 
cystic fibrosis. Science. 1992 Aug 21;257(5073):1125-8.
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 146, 319 – 326 
(1986).
R15-5503
Walters S, Mehta A. Epidemiology of cystic fi brosis. In: Hodson M, 
Geddes DM, Bush A, eds. Cystic fibrosis, 3rd edn. London: Edward Arnold 
Ltd, 2007: 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, M. A., Button, B., Johannesson, B., Zhou, Z., Livraghi, A., Caldwell, 
R. A, and Boucher, R. C. Airway surface liquid volume regulation 
determines different airway phenotypes in liddle compared with 
βENaCoverexpressing mice. J. Biol. Chem., 285(35), 26945-26955 2010.
R15-5546
Genes and human disease: monogenic diseases. 
who.int/genomics/publicdiseases/en/index2.html#CF (access date: 28 
October 2015); Geneva: World Heath Organization (WHO) (2015).
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R15-5599
Graham, A., Hasani, A., Alton, E. W. F. W., Martin, G. P., Marriott, C., 
Hodson, M. E., and Geddes, D. M. (1993). No added benefit from 
nebulized amiloride in patients with cystic fibrosis. Eur. Respir. J., 6(9), 
1243-1248.
R16-0366
E14 Implementation Working Group. ICH E14 guideline: the clinical 
evaluation of QT/QTc interval prolongation and proarrhythmic potential for 
non-antiarrhythmic drugs: questions & answers (R3) (current version dated 
10 December 2015). 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2015) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use; 2015.
R17-1997
Rowe S.M., Verkman A.S. Cystic Fibrosis Transmembrane Regulator 
Correctors and Potentiators. Cold Spring Harb Perspect Med 
2013;3:a00976.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c10884768
 Safety, tolerability and 
pharmacokinetics of single rising inhaled doses of BI 443651 in healthy 
male volunteers in a partially randomised, single blind, placebo-controlled 
trial.
c16304878
Investigator`s Brochure BI 1265162 Cystic fibrosis and COPD
05 September 2017.
U97-0056
A three-way crossover study in healthy volunteers of
lung deposition of fenoterol hydrobromide (100 μg via one puff) delivered
from either a BINEB® (ARIANE) nebuliser, or a conventional MDI, or
conventional MDI with a spacer. (260.2706) 20 June 1996.
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10.
APPENDICES
10.1
HANDLING INSTRUCTIONS FOR RESPIMAT INHALER FOR USE IN 
CLINICAL TRIALS 
These instructions explain generally the use of BI 1265162 RESPIMAT inhaler. Depending 
on the clinical study, the product is administered under direct medical supervision or used by 
patients at home. Depending on the situation, the Instructions can be adapted to the specific 
situation as need may be.
Read these Instructions for Use before you start demonstrating or using RESPIMAT.
How to store BI 1265162 RESPIMAT
Keep BI 1265162 RESPIMAT out of the sight and reach of children.
Do not freeze BI 1265162 RESPIMAT. For further storage conditions, please refer to product 
label.
If BI 1265162 RESPIMAT has not been used for more than 7 days, repeat steps 4 to 6 (turn, 
open, press) under ‘Prepare for first Use’ until a cloud is visible. Then repeat steps 4 to 6 
three more times.
Do not use BI 1265162 RESPIMAT after the expiry date.
How to care for BI 1265162 RESPIMAT
Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or 
tissue, at least once a week. Cleaning on a daily basis or daily disinfection with an alcoholic 
tissue is also possible.
Any minor discoloration in the mouthpiece does not affect BI 1265162 RESPIMAT inhaler 
performance.
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When to get a new BI 1265162 RESPIMAT
•
BI 1265162 RESPIMAT inhaler contains 120 puffs if used as indicated.
•
The dose indicator shows approximately how much medication is left.
•
When the dose indicator enters the red area of the scale, get a new 
BI 1265162 RESPIMAT from the investigational site; there are approximately 30 puffs 
left.
•
Once the dose indicator reaches the end of the red scale, BI 1265162 RESPIMAT locks 
automatically – no more doses can be released. At this point, the clear base cannot be 
turned any further. The inhaler should not be discarded; it should be returned to 
investigational site.
Prepare for first use
Remove clear base
Keep the cap closed.
Press the safety catch while firmly pulling 
off the clear base with your other hand.
Insert cartridge
Insert the narrow end of the cartridge into 
the inhaler.
Place the inhaler on a firm surface and 
push down firmly until it snaps into place.
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Replace clear base
Put the clear base back into place until it 
clicks. 
Turn
Keep the cap closed.
Turn the clear base in the direction of the 
arrows on the label until it clicks (half a 
turn).
Open
Open the cap until it snaps fully open.
Press
Point the inhaler toward the ground
Press the dose-release button.
Close the cap.
Repeat steps 4-6 until a cloud is visible.
After a cloud is visible, repeat steps 4-6 
three more times.
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Daily use
TURN
Keep the cap closed.
TURN the clear base in the direction of the 
arrows on the label until it clicks (half a turn).
OPEN
OPEN the cap until it snaps fully open.
PRESS
Breathe out slowly and fully.
Close your lips around the mouthpiece without 
covering the air vents.
While taking a slow, deep breath through your 
mouth, PRESS the dose-release button and 
continue to breathe in.
Hold your breath for 10 seconds or for as long as 
comfortable.
Repeat Turn, Open, Press for a total of puffs
required by the clinical trial protocol.
Close the cap until you use your BI 1265162 
RESPIMAT inhaler again.
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Answers to Common Questions
It is difficult to insert the cartridge deep enough.
Did you accidentally turn the clear base before inserting the cartridge? Open the cap, 
press the dose-release button, then insert the cartridge.
Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow 
end first.
I cannot press the dose-release button.
Did you turn the clear base? If not, turn the clear base in a continuous movement until it 
clicks (half a turn).
Is the dose indicator on BI 1265162 RESPIMAT pointing to zero? 
BI 1265162 RESPIMAT inhaler is locked after 120 puffs. Prepare and use a new 
BI 1265162 RESPIMAT inhaler.
I cannot turn the clear base.
Did you turn the clear base already? If the clear base has already been turned, follow steps 
“OPEN” and “PRESS” under “Daily Use” to get your medicine. 
Is the dose indicator on the BI 1265162 RESPIMAT pointing to zero? The 
BI 1265162 RESPIMAT inhaler is locked after 120 puffs. Prepare and use your new 
RESPIMAT inhaler.
The dose indicator on the BI 1265162 RESPIMAT reaches zero too soon. 
Did you turn the clear base before you inserted the cartridge? The dose indicator counts 
each turn of the clear base regardless whether a cartridge has been inserted or not.
Did you spray in the air often to check whether the BI 1265162 RESPIMAT is working? 
Once you have prepared BI 1265162 RESPIMAT, no test-spraying is required if used daily.
Did you insert the cartridge into a used RESPIMAT? Always insert a new cartridge into a 
NEW RESPIMAT.
BI 1265162 RESPIMAT sprays automatically.
Was the cap open when you turned the clear base? Close the cap, then turn the clear base.
Did you press the dose-release button when turning the clear base? Close the cap, so the 
dose-release button is covered, then turn the clear base.
Did you stop when turning the clear base before it clicked? Turn the clear base in a 
continuous movement until it clicks (half a turn).
BI 1265162 RESPIMAT doesn’t spray.
Did you insert a cartridge? If not, insert a cartridge.
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Did you repeat Turn, Open, Press less than three times after inserting the cartridge? 
Repeat Turn, Open, Press three times after inserting the cartridge as shown in the steps 4 to 6 
under “Prepare for first Use”.
Is the dose indicator on BI 1265162 RESPIMAT pointing to 0? If the dose indicator 
points to 0, you have used up all your medication and the inhaler is locked.
Once BI 1265162 RESPIMAT is assembled, do not remove the clear base or the cartridge. 
Always insert a new cartridge into a NEW RESPIMAT.
Further information
BI 1265162 RESPIMAT inhaler must not be disassembled after inserting the cartridge and 
replacing the clear base.
Do not touch the piercing element inside the base.
Boehringer Ingelheim Pharma GmbH & Co. KG
D - 55216 Ingelheim, Germany  
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
15 November 2017
EudraCT number
2017-001106-15
BI Trial number
1399-0001
BI Investigational Product(s)
BI 1265162
Title of protocol
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
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
A: 
Flow-Chart
5.2.3 Assessment of safety laboratory parameters
B:
4.1.4 Drug assignment and administration of 
doses for each subject
Description of change
A:
Measurement of urine electrolytes out of the 0-4h 
PK urine fraction was added 
B:
Wrong entry
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Number of global amendment
1
Rationale for change
A:
To assess possible early changes in urine 
electrolytes 
B:
Correction
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Trial Protocol
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Number of global amendment
2
Date of CTP revision
19 February 2018
EudraCT number
2017-001106-15
BI Trial number
1399-0001
BI Investigational Product(s)
BI 1265162
Title of protocol
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
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flow Chart
Description of change
Additional PK sampling time point at 72:00h
Rationale for change
Preliminary PK results revealed that for better 
characterization of BI 1265162 an additional 
sampling time point (72:00h) is needed in dose 
group 7. 
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15848245
3.0
clinical-trial-protocol-revision-02
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
Approval-Team Member Medicine
19 Feb 2018 12:36 CET
Author-Trial Clinical Monitor
19 Feb 2018 12:46 CET
Author-Trial Clinical
Pharmacokineticist
19 Feb 2018 12:58 CET
Author-Trial Statistician
19 Feb 2018 13:06 CET
Approval-Therapeutic Area 
19 Feb 2018 15:21 CET
Verification-Paper Signature
Completion
19 Feb 2018 16:57 CET
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15848245
3.0
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Clinical Trial Protocol 
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LOCAL SIGNATURE 
(Local Clinical Monitor) 
Trial Title: 
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 
Trial Number: 
1399-0001 
Clinical Trial Protocol Version: 2.0 
I herewith certify that I agree to adhere to the Clinical Trial Protocol and to all 
documents referenced in the Clinical Trial Protocol. 
Local Clinical Monitor (Print full name) 
2,01cki Cnr 
Date (dd Mmm yyyy) 
Signature 
001-MCS-40-106_RD-09 (5.0) / Saved on: 15 Mar 20161 
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LOCAL SIGNATURE 
(Local Clinical Monitor) 
Trial Title: 
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 
Trial Number: 
1399-0001 
Clinical Trial Protocol Version: 
3.0 
I herewith certify that I agree to adhere to the Clinical Trial Protocol and to all 
documents referenced in the Clinical Trial Protocol. 
Local Clinical Monitor (Print full name) 
Date (dd Mmm yyyy) 
!()Oi-MCS-40-106 RD-09 (5.0) I Saved on: 15 Mar 
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c22093092-01
BI Trial No.:
1399-0001
Title:
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
Final Protocol (including protocol revision 1 (c15848245-02))
Investigational
Product(s):
BI 1265162
Responsible trial 
statistician(s):
Phone: 
Fax:
 
Phone: 
Fax:
Date of statistical 
analysis plan:
10 APR 2018 SIGNED 
Version:
“Final”
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
...............................................9
...............................................9
...............................................9
.............................................10
.............................................10
.............................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
.........................................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY ENDPOINT .....................................................................................18
7.5
SECONDARY ENDPOINTS.............................................................................18
7.5.1
Key secondary endpoint .....................................................................................18
7.5.2
Secondary endpoints...........................................................................................18
.......................................................................19
.......................................................................19
.......................................................................19
7.7
EXTENT OF EXPOSURE.................................................................................19
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse events.....................................................................................................19
7.8.2
Laboratory data ..................................................................................................21
7.8.3
Vital signs.............................................................................................................21


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7.8.4
ECG......................................................................................................................22
7.8.7
Others...................................................................................................................23
8.
REFERENCES....................................................................................................24
...25
...25
 
...25
10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data, vital signs, 
 and ECG.............................................12
Table 6.2: 1
Important protocol violations ...........................................................................13
Table 6.3: 1
Subject sets analysed ........................................................................................14
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation ..........16
Table 10: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
 
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
BI 
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
gCV
geometric coefficient of variation
HR
Heart rate
ICH
International Conference On Harmonisation
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter set
PR
Pulse rate
PV
Protocol Violation
QRS complex
Combination of the Q, R, and S waves


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Term
Definition / description
QT interval
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTcB
QT interval, heart rate corrected according to Bazetts formula
QTcF
QT interval, heart rate corrected according to Fridericias formula
RAGe
Report appendix generator
RPM
Report Planning Meeting
RR interval
ECG interval from the peak of the R wave to the peak of the subsequent R 
wave
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its amendments. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 "Statistical Methods 
and Determination of Sample Size". Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
Certara USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint is the number of subjects with drug-related AEs, as defined in Section 5.2.1 
of the CTP.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints of this trial are AUCt1-t2 and Cmax of BI 1265162 in plasma, as defined in 
Section 5.5.1.1 of the CTP.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, cf. Section 4 of the CTP.
Subjects were planned to be treated either with 

a single dose of 3, 10, 30, 100, 300, 600, or 1200 μg of BI 1265162 (test treatments)
or

a single dose of placebo (reference treatment)
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).
Analysis phases for statistical analysis of AEs, safety laboratory data, vital signs, 
and ECG are defined for each subject as described in the table below.
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data, vital signs, 
and ECG
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
Pbo,
3 ug BI,
10 ug BI,
30 ug BI,
100 ug BI,
300 ug BI,
600 ug BI,
or 1200 ug BI,
respectively
Date/time of 
administration of study 
drug
12:00 a.m. on day after 
subject's trial termination date
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only.
In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 
AE tables), the following totals will be provided in addition:

"Total BI", defined as the total over all on-treatment phases involving BI

"Total on-trt", defined as the total over all on-treatment phases, including placebo
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening and on-treatment
phases.


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Additionally to the totals defined above, the following total will be provided in CTR Section 
16.1.13.1.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment)
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Consistency check listings (for identification of violations of 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 RPM/DBLM. At this meeting, it will be decided whether a 
discrepant data value can be used in analyses or whether it must be corrected in the clinical 
database. Each protocol deviation must be assessed to determine whether it is an IPV. For 
definition of IPVs, and for the process of identification of these, refer to the BI reference 
document "Protocol Violation Handling Definitions" (2).
Table 6.2: 1
Important protocol violations
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C3
Non-compliance
C4
Incorrect intake of trial medication
D
Concomitant medication
D1
Prohibited medication use
E
Missing data
None1
G
Other trial specific important violations
G1
Certain violations of procedures used to measure secondary PK data
Violations C1, C2 and G1 can only be detected at the trial site.
1 Missing visits, evaluations, and tests will be considered missing data, not PVs
Source: BI reference document "Protocol Violation Handling Definitions" (2).
If any IPVs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet (3) The table above


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contains the categories which are considered to be IPVs in this trial. If the data show other 
IPVs, this table will be supplemented accordingly by the time of the RPM/DBLM.
IPVs will be summarised and listed.
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH-E9. It will be used for 
analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one PK parameter 
that was not excluded because of PVs relevant to the statistical evaluation of PK 
endpoints as defined in Section 7.3 of the CTP.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
IPVs
X
Demographic/baseline endpoints
X
Primary endpoint
X
Other safety parameters
X
Secondary PK endpoints
X


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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 recorded in the CTR.
CTP: With respect to safety evaluations, it is not planned to impute missing values.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (4).
No imputation will be done for ECG endpoints. If replicate ECG recordings are missing, the 
arithmetic means per time point will be computed with the reduced (1 or 2) number of 
recordings. If single cardiac cycles (also denoted as beats or waveforms) are missing, the 
arithmetic mean per single ECG will be computed with the reduced (1, 2 or 3) number of 
cardiac cycles.
Missing data and outliers of PK data are handled according to BI standards (5).
Plasma / Urine concentration-time tables
CTP: Drug concentration data identified with NOS (no sample available), NOR (no valid 
result), NOA (not analysed), BLQ (below the lower limit of quantification) will be displayed 
as such and not replaced by zero at any time point (this rule also applies also to the lag 
phase, including the predose values).
Pharmacokinetic parameters 
CTP: Drug concentration data identified with NOS, NOR or NOA will generally not be 
considered. Concentration values in the lag phase identified as BLQ will be set to zero. All 
other BLQ values of the profile will be ignored. The lag phase is defined as the period 
between time zero and the first time point with a concentration above the quantification limit.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
There will be a centralised evaluation of 12-lead ECG recordings at the time points specified 
in Table 6.7: 1.
Triple ECGs (3 single ECGs recorded within 180 sec) will be recorded on all on-treatment
time points with centralised ECG evaluation.
At predose, 3 triplicate ECGs (9 single ECGs) will be recorded within 10 minutes (planned 
time -1:30 on Day 1). The baseline value of an ECG variable is defined as the mean of the 


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first triple ECG measurements prior to first drug administration. For all on-treatment 
assessments, only the first of the three replicate ECG at a single assessment time will be 
evaluated.
In all other analyses (except for analyses of ECG variables), the last non-missing value 
determined prior to the first dosing of BI 1265162 will be defined as baseline. 
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation
Visit
Day
Planned time [hh:mm]
(relative to respective drug 
administration)
Study phase
2
1
-01:30
Baseline 
00:05
On-treatment
00:15
01:00
00:30
01:00
02:00
04:00
06:00
12:00
2
24:00
3
48:00
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.


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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 generally be sorted by dose 
group, subject number and visit (if visit is applicable in the respective listing). AE listings will 
be sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical 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.


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


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Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (5) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (7).
7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.


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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" (8) and "Handling of missing and incomplete AE 
dates" (4). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to the screening or on-treatment phase as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (9) and for the class of 
AESIs.
CTP: The following are considered as AESIs in this trial:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
○
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or
○
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (9), 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 (primary 
endpoint) will be summarised separately. Separate tables will also be provided for subjects 
with SAEs, subjects with AESIs and subjects with other significant AEs (according to ICH E3
(9)). The frequency of subjects with AEs and the frequency of subjects with AEs considered 
by the investigator to be drug related will also be summarised by maximum intensity, primary 
SOC and preferred term.
The system organ classes and preferred terms within system organ classes will be sorted by 
descending frequency overall treatment groups.


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For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Display and Analysis of Laboratory Data" (10).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. In addition, median urine and plasma electrolytes over time will 
be presented graphically. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM/DBLM at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. Standard 
or project-specific rules for flagging clinically significant values in an automated manner will 
not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.


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7.8.4
ECG
12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator. 
All evaluation of ECG data will be based on the TS. 
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. 
Occurrences of notable findings will be flagged.
For all subjects with any notable finding in quantitative ECG recordings, a separate listing 
will be created as end-of-text display (based on the same display template as in 
Appendix 16.2), and the corresponding time profiles will be shown.
Comments regarding the ECGs will be listed.
Analysis of central tendency
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time in all ECG variables.
For QTcF, QT and HR, a repeated measurements analysis of the changes from baseline with 
baseline as a covariate will be performed. The model will include the fixed effects "baseline", 
"treatment", "time", "baseline*time" interaction, and "treatment*time" interaction. The 
covariance model for the repeated effect "time" will be unstructured (i.e. TYPE=UN or UNR); 
in case of convergence problems refer to Additional Section 9.2. For each dose group and 
each time point, the contrast of the means for "treatment-placebo" will be estimated by the 
difference in the corresponding adjusted means (Least Squares Means); two-sided 90% CIs 
based on the t-distribution will also be computed. For each of the above ECG variables, the 
time profiles of the mean differences to placebo in the changes from baseline and the 
corresponding 90% CIs will be presented in a figure.
The following SAS code can be used to fit the model:
PROC MIXED DATA=indata CL METHOD=REML;
CLASS subject treat time;
MODEL ECGep = treat time base treat*time base*time / DDFM=KR CL ALPHA=0.1;
REPEATED time / TYPE=UN SUBJECT=subject;
LSMEANS treat*time / DIFF CL ALPHA=0.1;
SLICE treat*time / SLICEBY=time DIFF CL ALPHA=0.1 NOF PLOT=none;
RUN;
For PR, QRS, RR as well as QTcB, the time profiles of mean and SD for the changes from 
baseline on treatment will be displayed graphically by treatment.


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Categorical Endpoints
For the categorical endpoints, frequency tables will be provided.
For subjects with notable findings, the individual time courses of QTcF, QT, HR, PR and 
QRS of these subjects will be presented in figures.
 
 
 
7.8.7
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of 
Clinical Trialss, current version
2
001-MCS-50-413_RD-01: "Protocol Violation Handling Definitions", current 
version; IDEA for CON
3
001-MCS-50-413_RD-02: "Important Manual Protocol Violations Spreadsheet", 
current version; IDEA for CON
4
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON
5
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON
6
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON
7
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", current version; IDEA for CON
8
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical 
Trials", current version; IDEA for CON
9
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
10
001-MCG-157: "Display and Analysis of Laboratory Data", current version; IDEA 
for CON


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