Clinical trial NCT02657408
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2016-03-11; Completion date: 2017-03-13
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary and secondary objectives of the current study are the assessments of anti-inflammatory pharmacodynamic effects on segmental endotoxin induced inflammatory response after 4 weeks treatment with BI 1026706.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 1026706 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03143538-05
EudraCT No.:
2015-001789-25
BI Trial No.:
1320.17
BI Investigational 
Product(s):
BI 1026706
Title:
A randomized, double-blind, placebo-controlled, parallel group, 
Phase I trial in healthy current smoker subjects to assess 
pharmacodynamic effects on segmental endotoxin induced 
inflammatory response and safety of 4 weeks oral administration 
of BI 1026706
Brief Title:
Clinical trial to assess pharmacodynamic effects on segmental 
endotoxin induced inflammatory response of BI 1026706 versus 
placebo
Clinical Phase:
Phase I
Trial Clinical 
Monitor:
Phone.: 
Fax: 
Principal 
Investigator:
 MD.
Tel: 
Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment 4)
Version and Date:
Version:
Date:
5.0
19 Dec 2016
Page 1 of 77
Proprietary confidential information.
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
N/A
Name of active ingredient:
BI 1026706
Protocol date:
06 Aug 2015
Trial number:
1320.17
Revision date:
19 Dec 2016
Title of trial:
A randomized, double-blind, placebo-controlled, parallel group, 
Phase I trial in healthy current smoker subjects to assess 
pharmacodynamic effects on segmental endotoxin induced 
inflammatory response and safety of 4 weeks oral administration of 
BI 1026706
Principal Investigator:
, MD.
Tel: 
Fax: 
Trial site(s):
single center trial 
Clinical phase:
I
Objective(s):
The primary and secondary objectives of the current study are the 
assessments of anti-inflammatory pharmacodynamic effects on 
segmental endotoxin induced inflammatory response after 4 weeks 
treatment with BI 1026706.
Further objectives are to evaluate the pharmacokinetics and safety of 
BI 1026706
Methodology:
Randomized, double-blind, placebo-controlled, parallel group, 4 
weeks treatment of 100 mg BI 1026706 or placebo b.i.d. prior to 
segmental bronchial LPS challenge, single center
No. of subjects: 
total entered:
50
each treatment:
25 subjects per arm
Diagnosis :
Healthy volunteers
Main criteria
for inclusion:
Volunteers of both sex with females being of non-childbearing 
potential, age 18 and 65 years, current smokers with at least 1 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
N/A
Name of active ingredient:
BI 1026706
Protocol date:
06 Aug 2015
Trial number:
1320.17
Revision date:
19 Dec 2016
cigarette per day over the last 12 months and a smoking history of at 
least 1 pack year, healthy as assessed by the investigator on a 
screening examination, FEV1 > 80% and FEV1/FVC > 70%
predicted, BMI range: ≥18.5 and 29.9 kg/m2, negative drug screen, 
positive cotinine test
Test product:
BI 1026706 film-coated tablet for oral administration (formulation 
A1)
dose:
100 mg b.i.d.
mode of 
administration:
Oral administration 
Comparator products:
Placebo film-coated tablet for oral administration (formulation A1)
dose:
Not applicable
mode of 
administration:
Oral administration
Duration of treatment:
28 days
Endpoints
The primary endpoint will be total cell count of neutrophils in 
Bronchoalveolar Lavage (BAL) after 24 hours of the segmental 
endotoxin challenge.
As secondary endpoints total and differential cell counts of 
neutrophils (only differential cell count), eosinophils, monocytes, 
macrophages and lymphocytes will be determined in BAL, 24 hours 
following segmental endotoxin challenge
Safety criteria:
Physical examination, vital signs (blood pressure, pulse rate), 12-lead 
ECG, body weight, lung function, adverse events and clinical 
laboratory tests
Statistical methods:
Treatment differences of primary and secondary endpoints between 
both treatment groups will be analyzed with an analysis of variance 
(ANOVA) model. In the primary analysis, the dependent variable is 
the respective endpoint at 24 hours post endotoxin challenge on the 
logarithmic scale, while treatment will be used as independent 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
N/A
Name of active ingredient:
BI 1026706
Protocol date:
06 Aug 2015
Trial number:
1320.17
Revision date:
19 Dec 2016
variable. 
 
Descriptive statistics will be calculated for all endpoints


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FLOW CHART
1All subjects must sign an informed consent form consistent with ICH-GCP guidelines prior to participation in the trial. Re-
consenting may become necessary when new relevant information becomes available and should be conducted according to 
the sponsor’s instructions
 
Trial Periods
Screening 
Period
Randomized Treatment Period
Follow-up
Period
End of 
trial
Visit
1
2
3
4
5
6 
7
88
Day
-28 to -3
1
8
15
22
2811
29
32 to 34
Weeks after randomization
1
2
3
4
Time window (±days) for visits
±2
±2
±2
±2
none
Informed consent 1
X
Review of in-/exclusion criteria
X
X
Demographics
X
Smoking status
X
X
X
X
Medical history / baseline 
conditions
X
Skin prick test
X
Drug screening10
X
Cotinine test10
X
X
Alcohol screening10
X
X
X
Physical examination
X
X
X
X
X
X
Body weight and height6
X
X
X
Vital signs
X
X
X
X
X
X
X
X
12-lead resting ECG
X
X
X
X
X
X
Pulmonary function test
X
X
X
X
X
X
Pulse oximetry
X
X
Safety dipstick urine test
X
X14
X
X14
X14
X14
Safety laboratory blood tests
X12, 13
X
X12
X
X
X
Randomization
X
 
Bronchoscopy with BAL5
X
X7
LPS challenge
X
Administration of trial drugs in 
clinic9
X
X
X
X
X
Dispense trial drug for home 
administration
X
X
X
X
Dispense drug diary
X
Check subject’s drug diary
X
X
X
X
Collection of trial drug used at 
home
X
X
X
X
X
Treatment compliance check
X
X
X
X
X
Assessment of adverse events
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
Trial Completion8
X


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5Biopsies will be taken during bronchoscopy. Bronchoscopies and medical checks (including spirometry) prior to discharge 
of subject will be performed according to the SOP of the investigational trial site (provided in the ISF), which is based on 
guidelines for investigative bronchoscopies
6Height will only be captured at screening
7The bronchoscopy at Visit 7 has to be performed 24±1 hours after LPS-challenge. The bronchoscopy will occur following 
an overnight fast of at least 8 hours.
8End of trial visit also needs to be completed if the subject withdraws from or is removed from the trial following 
randomization
9On Day 1 (Visit 2) and Day 28 (Visit 6), the morning administration of trial medication (i.e. the first drug administration of 
the day) will occur following an overnight fast of at least 8 hours and will be administered with about 240 mL of water. On 
Days 1 and 28, fasting will continue up to 2 hours following morning administration of trial medication and no liquid intake 
will be allowed within the 2 hours before and 2 hours after the morning administration of trial medication
11The maximum treatment period of 28 days should not exceed the given time window
 
13Safety laboratory to include serum pregnancy testing for female subjects.
14Urine dipstick test to include pregnancy testing for female subjects. Testing at Visit 2 is only needed if the time period 
between Visit 1 and Visit 2 exceeds 7 days.


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FLOW CHART – STUDY DRUG ADMINISTRATION, 
Day
Time windows 
(days)
Clinic visit Number
(applicable for PK
only)
Planned Time 
[h:min]
time (actual day) 
[h:min]
Event1 and
comment
1
2
-0:10
07:50
Prior to first IMP administration
0:00
08:00
First drug administration in clinic with about 
240 mL of water
(following an overnight fast of at least 8 hours)
0:30
08:30
2:30
10:30
8:00
16:00
12:00
20:00
drug administration at home2
2 to 
7
0:00
08:00
drug administration at home2
12:00
20:00
drug administration at home2
8
±2
3
-0:10
07:50
0:00
08:00
drug administration in clinic
12:00
20:00
drug administration at home2
9 to 
14 
0:00
08:00
drug administration at home2
12:00
20:00
drug administration at home2
15
±2
4
-0:10
07:50
0:00
08:00
drug administration in clinic
12:00
20:00
drug administration at home2
16 
to 
21
0:00
08:00
drug administration at home2
12:00
20:00
drug administration at home2
22
±2
5
-0:10
07:50
0:00
08:00
drug administration in clinic
12:00
20:00
drug administration at home2
23 
to 
27
0:00
08:00
drug administration at home2
12:00
20:00
drug administration at home2
28
-2
6
-0:10
07:50
Prior to IMP administration
0:00
08:00
drug administration in clinic with about 
240 mL of water
(following an overnight fast of at least 8 hours)
1:00
09:00
2:30
10:30
8:00
16:00
12:00
22:00
drug administration at home
1Actual time of drug intake will be documented by the subject in a subject drug diary 


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2 subjects are asked to take their medication at home between 7-10 a.m. in the morning and between 7-10 p.m. in the 
evening. 
3The time between tablet intake in the evening on Day 28 (Visit 6) and the bronchoscopy on Day 29 (Visit 7) should 
preferable not exceed 14 hours. Subjects are asked to take medication on Day 28 (Visit 6) as late as possible and ideally 
close to 10 p.m. in the evening


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
FLOW CHART – STUDY DRUG ADMINISTRATION, PK SAMPLING......................7
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................15
.......................................................................16
1.2
DRUG PROFILE................................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....17
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................17
....................................................................................17
2.3
BENEFIT - RISK ASSESSMENT.....................................................................17
2.3.1
The risks of the study procedures......................................................................18
.............................................................................................19
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................21
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................21
3.1.1
Administrative structure of the trial .................................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................23
3.3
SELECTION OF TRIAL POPULATION .......................................................24
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................24
3.3.3
Exclusion criteria ................................................................................................25
3.3.4
Removal of subjects from therapy or assessments...........................................26
3.3.4.1
Removal of individual subjects.............................................................................26
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................27
3.3.5
Replacement of subjects .....................................................................................27
4.
TREATMENTS...................................................................................................28
4.1
TREATMENTS TO BE ADMINISTERED.....................................................28
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........29
4.1.2
Method of assigning subjects to treatment groups ..........................................29
4.1.3
Selection of doses in the trial..............................................................................29
4.1.4
Drug assignment and administration of doses for each subject .....................30
4.1.4.1
Reserve trial medication........................................................................................31
4.1.4.2
Trial medication administration at investigational sites (in clinic).......................31
4.1.4.3
Trial medication administration at home ..............................................................31


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4.1.4.4
Returning of trial medication after home administration:.....................................31
4.1.4.5
Time of administration of any trial medication: ...................................................31
4.1.4.6
Skipping of trial medication:.................................................................................32
4.1.4.7
Missed administration of trial medication: ...........................................................32
4.1.5
Blinding and procedures for unblinding...........................................................32
4.1.5.1
Blinding.................................................................................................................32
4.1.5.2
Unblinding and breaking the code ........................................................................32
4.1.6
Packaging, labelling, and re-supply...................................................................33
4.1.7
Storage conditions...............................................................................................33
...........................................................................................33
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
TREATMENT.....................................................................................................34
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....34
4.2.2
Restrictions ..........................................................................................................34
4.2.2.1
Restrictions regarding concomitant treatment ......................................................34
4.2.2.2
Restrictions on diet and life style..........................................................................34
4.3
TREATMENT COMPLIANCE........................................................................35
5.
VARIABLES AND THEIR ASSESSMENT ....................................................36
5.1
TRIAL ENDPOINTS..........................................................................................36
5.1.1
Primary Endpoint(s)...........................................................................................36
5.1.2
Secondary Endpoint(s) .......................................................................................36
...........................................................................................36
5.2
ASSESSMENT OF EFFICACY........................................................................37
5.3
ASSESSMENT OF SAFETY.............................................................................37
5.3.1
Physical examination ..........................................................................................37
.........................................................................................................37
5.3.3
Safety laboratory parameters ............................................................................37
5.3.3.1
Safety laboratory parameters obtained from blood...............................................37
5.3.3.2
Safety laboratory parameters obtained from urine................................................39
5.3.4
Electrocardiogram ..............................................................................................39
5.3.5
Other safety parameters.....................................................................................40
5.3.5.1
Pulmonary Function Testing.................................................................................40
............................................................................................40
5.3.6
Assessment of adverse events.............................................................................41
5.3.6.1
Definitions of AEs ................................................................................................41
5.3.7
Adverse event collection and reporting.............................................................42
...............44
...............44
...............45
...............45
...............45
...............45
...............45
...............46
...............46


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7
 
7
7
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................48
6.
INVESTIGATIONAL PLAN.............................................................................50
6.1
VISIT SCHEDULE.............................................................................................50
6.1.1
Adherence to the protocol visits and procedures.............................................50
6.1.2
Visit scheduling ...................................................................................................50
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................50
6.2.1
Screening period..................................................................................................50
6.2.2
Treatment period(s)............................................................................................51
6.2.3
Follow-up Period and End of Trial ...................................................................52
6.2.4
Timing for selected observations and procedures............................................53
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................54
7.1
STATISTICAL DESIGN - MODEL.................................................................54
7.1.1
Objectives.............................................................................................................54
7.1.2
Endpoints.............................................................................................................54
7.1.3
Model....................................................................................................................54
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................54
7.3
PLANNED ANALYSES.....................................................................................55
7.3.1
Primary endpoint analyses.................................................................................56
7.3.2
Secondary endpoint analyses .............................................................................56
...............................................................................56
7.3.4
Safety analyses.....................................................................................................57
..............................................................................58
...............................................................................58
7.5
HANDLING OF MISSING DATA ...................................................................59
7.6
RANDOMIZATION...........................................................................................59
7.7
DETERMINATION OF SAMPLE SIZE .........................................................59
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........61
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ...........................................................................................................61
8.2
DATA QUALITY ASSURANCE ......................................................................62
8.3
RECORDS...........................................................................................................62
8.3.1
Source documents ...............................................................................................62
8.3.2
Direct access to source data and documents.....................................................62
8.3.3
Storage period of records ...................................................................................62
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS63
8.4.1
Listedness.............................................................................................................63
8.4.2
Expedited reporting to health authorities and IEC/IRB.................................63
8.5
STATEMENT OF CONFIDENTIALITY........................................................63
8.6
END OF TRIAL..................................................................................................63


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8.7
PROTOCOL VIOLATIONS .............................................................................63
8.8
COMPENSATION AVAILABLE TO THE SUBJECT IN THE EVENT 
OF TRIAL RELATED INJURY.......................................................................64
9.
REFERENCES....................................................................................................65
9.1
PUBLISHED REFERENCES............................................................................65
9.2
UNPUBLISHED REFERENCES......................................................................67
10.
APPENDICES.....................................................................................................68
10.1
CALCULATION OF NUMBER OF PACK YEARS......................................68
10.2
CONTRACEPTION...........................................................................................68
.........................................................68
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................69


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ABBREVIATIONS
AE
Adverse Event
AESI
ALT
ANOVA
AST
Adverse Event of Special Interest
Alanine Aminotransferase
Analysis of Variance
Aspartate Aminotransferase
ATS
American Thoracic Society
BAL
BI
Bronchoalveolar Lavage
Boehringer Ingelheim
b.i.d.
bis in die (twice daily dosing)
BIRDS
BMI
BP
Boehringer Ingelheim Regulatory Documents for Submission
Body Mass Index
Blood Pressure 
CA
Competent Authority
CC-RE
Clinical Center Reference Endotoxin
CI
Confidence Interval
CML
Local Clinical Monitor 
COPD
CRA
Chronic Obstructive Pulmonary Disease
Clinical Research Associate
CRF
CRO
Case Report Form
Contract Research Organization
CTP
Clinical Trial Protocol
CTR
CV
DDI
DILI
Clinical Trial Report
Coefficient of Variation
Drug-Drug Interaction
Drug-Induced Liver Injury
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
ERS
Electronic Data Capture
European Respiratory Society
EudraCT
European Clinical Trials Database
FEV
Forced Expiratory Volume
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GLI
Global Lung Function Initiative
IB
ICS
Investigator’s Brochure
Inhaled Corticosteroids 
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File


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i.v.
Intravenous
HCG
Human Chorionic Gonadotropin
HV
LABA
LAMA
LPS
Healthy Volunteer
Long Acting Beta Agonist
Long Acting Muscarinic Agonist
Lipopolysaccharide
mL
Milliliter
MedDRA
MRD
Medical Dictionary for Drug Regulatory Activities
Multiple Rising Dose
ST
OCS
Medical Sub team
Oral corticosteroids
OPU
Operative Unit
PD
PDS
Pharmacodynamics
Pharmacodynamics Set
p.o.
per os (oral)
q.d.
RDC
quaque die (once a day)
Remote Data Capture 
REP
RS
SABA
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
Randomized Set
Short Acting Beta Agonist
SAE
SAMA
Serious Adverse Event
Short Acting Muscarinic Agonist
s.c.
Subcutaneous
SmPC
SRD
SOP
Summary of Product Characteristics
Single Rising Dose 
Standard Operating Procedure 
TCM
Trial Clinical Monitor
TDMAP
TEAE
Trial Data Management and Analysis Plan
Treatment Emergent Adverse Events
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TMW
TS
Trial Medical Writer
Treated Set
TSAP
Trial Statistical Analysis Plan
WHO
World Health Organization


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1.
INTRODUCTION
COPD is characterized by progressive airflow limitation that is not fully reversible. The 
airflow limitation is associated with an atypical chronic inflammatory reaction to particulate 
matter of the airways, in which many cell types play a role, in particular macrophages, 
neutrophils and CD8 T lymphocytes.
Smoking is responsible for 90% of all cases of COPD, in the developed world, although only 
about 20% of all cigarette smokers develop relevant airways obstruction. Other risk factors 
for COPD, such as environmental exposure to dust or fumes and 1antitrypsin deficiency, 
have less impact on the prevalence of COPD [P15-01740].
COPD prevalence is still rising due to increased smoking, particularly among women and 
adolescents. According to the 2015 estimates of the World Health Organization (WHO), 
65 million people suffer from moderate to severe COPD. By 2030, COPD will be the third 
leading cause of death worldwide [R15-3034].
Despite the available treatment options, COPD remains associated with significant morbidity 
and mortality signifying the need for developing new drugs for the treatment of COPD. 
Medical intervention should improve the disease-related quality of life by relieving 
symptoms and reduce COPD exacerbations.
Smoking cessation is the cornerstone of COPD management. Bronchodilator medications, 
short- and long-acting ß2 agonists (SABA and LABA) as well as short- and long-acting 
muscarinic antagonists (SAMA and LAMA) and their combinations are the foundation of 
pharmacologic treatment with LABA and LAMA central to the symptomatic management of 
COPD [P14-01052].
The principles of anti-inflammatory treatment of COPD have been derived from the treatment 
of asthma, leading to the use of inhaled corticosteroids (ICS). In contrast to asthma, ICS has 
little effect on the neutrophilic inflammation characteristic to COPD. ICS is used in 
combination with LABA or LAMA in patients with more severe COPD and history of 
exacerbations [P14-01052]. Oral corticosteroids (OCS) are mainly used for the acute 
treatment of exacerbations, usually co-administered with antibiotics.
The only non-steroidal anti-inflammatory medication available on the market is roflumilast, a 
PDE4 inhibitor (Daxas® or Daliresp®), indicated for severe COPD with chronic bronchitis 
and a history of exacerbations. In the EU, roflumilast is indicated as maintenance treatment 
and in the USA to reduce risk of exacerbation [R11-4791] in COPD. The efficacy of this 
compound may be limited by dose-limiting side effects such as diarrhea, nausea, and
headache [R11-4442, P09-11235].


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1.2
DRUG PROFILE
For a more detailed description of the drug profile BI 1026706, refer to the current 
Investigator’s Brochure (IB) For LPS as IMP, refer to the IB
 
 The documents are included 
in the Investigator Site File (ISF).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This study is primarily conducted as a proof of mechanism trial to investigate the anti-
inflammatory properties of BI 1026706 administered for 4 weeks at the dosage of 100 mg 
b.i.d. followed by segmental endotoxin challenge in smoking healthy subjects being current 
smokers at time of inclusion. The study may provide an initial indication of whether 
treatment may have an effect on pharmacodynamics (PD) biomarkers in particular the 
number of neutrophils in bronchoalveolar lavage (BAL) will be assessed - and could be used 
as a potential indicator of anti-inflammatory action in the airways.
 
Safety and tolerability of BI 1026706 will also be monitored. 
 
 
 
 
 
 
2.3
BENEFIT - RISK ASSESSMENT
A possible direct individual benefit for the healthy subjects participating in this trial is 
unlikely during the 28 days of treatment with BI 1026706. However, their participation in the 
study is of major importance to the clinical development of BI 1026706 for the improvement 
of symptoms in patients with COPD.


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Subjects on BI 1026706 may have an improved, faster resolution of the inflammatory lung 
condition induced by the LPS challenge. Subjects will have a 50% chance to receive placebo.  
Beyond close monitoring of safety, clinical laboratories, and clinical evaluations there is no 
specific benefit for these subjects, apart from encouragement to discontinue smoking. The
decision to include a placebo group is essential for the evaluation of PD effects as well as for 
the assessment of safety and tolerability of BI 1026706 in healthy current smokers.
As per ICH M3 guidance, women not of childbearing potential can be included in this study 
as repeated dose toxicity studies (including an evaluation of the female reproductive organs) 
have been conducted with no cause of concern. Close monitoring of pregnancy status during 
the concerned trial will be implemented to further safeguard this decision. 
Overall, the risk to the subjects participating in this study is considered low compared with 
the potential benefit that a successful clinical development of 
 
could provide to patients with COPD.
The risk for subjects is acceptable based on the data and trial results mentioned in Section
2.3.2 below. The subjects participating in this study will be exposed to:

the risks of the study procedures

the known risks related to exposure to the investigational product

unknown risks that might be related to exposure to the investigational product
2.3.1
The risks of the study procedures
The use of an indwelling cannula for the purpose of blood sampling may be accompanied by 
mild bruising and also, in rare cases, by transient inflammation of the vein wall. After initial 
irritation, the presence of an indwelling cannula is usually painless and hardly noticeable. The 
same applies to vein puncturing for further blood sampling. In rare cases, a nerve might be 
injured while inserting the cannula. This could be followed by paresthesia, reduced sensibility 
or pain for a long-term period.
The total amount of blood to be withdrawn during the trial as scheduled will not exceed 
 
No safety-related risk to the subjects is 
expected from this blood withdrawal.
Bronchoscopy will be performed twice in each subject as part of the LPS challenge protocol
to obtain BAL. Potential risks related to the bronchoscopy procedure are lidocaine 
intoxication, lidocaine overdose (seizures or heart rhythm problems), vocal cord spasm, lung 
infections or pneumonia, sore throat, and fever. The instillation of LPS to the lung at the 
selected dose is in general a well-tolerated procedure with only limited systemic effects. 
Possible side effects include fever, headache, nausea, bradycardia, and bronchoconstriction.
Bronchial biopsies are a standardized and safe procedure. They may lead to mucosal bleeding 
which can be treated with topical application of adrenalin.


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The bronchoscopy and biopsies procedures with LPS instillation in this study will only be 
performed by physicians with extensive training and experience with this procedure, with the 
intent to mitigate the above risks.
Bronchoscopies, BAL and LPS challenge will not be conducted or will be stopped if a subject 
experiences any adverse event regarded by the investigator as contraindication to the 
procedure. 
The investigational site is appropriately trained and experienced in the conduct of these 
procedures in human beings, is aware of expected side effects of the procedures and 
knowledgeable of the required therapeutic actions. 
Other study procedures such as spirometry, electrocardiogram (ECG) recording and blood 
pressure measurements are standard procedures in general medical care and unlikely to cause 
any side effects.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
An overview of the trial design is shown in Figure 3.1.1.
Figure 3.1:1 Study Design
This is a randomized, double-blind, placebo-controlled, parallel-group, single center study to 
assess the proof of mechanism and safety of BI 1026706 
 
compared to placebo. The respective treatment will be administered orally as tablet twice 
daily during the 4 week treatment period. The random allocation to active or placebo 
treatment will have a ratio of 1:1.
A total of 50 subjects will participate in the trial consisting of 2 treatment groups of 25
subjects, each treated for 28 ±2 days.
This trial consists of 8 Visits. Visit 1 is the screening visit. Between Visits 2-6 subjects will 
receive either BI 1026706 or placebo for 28 ±2 days, depending on the treatment group they 
have been randomized to. In addition, at Visit 6 baseline BAL will be conducted following 
LPS and saline challenge. At Visit 7 the BAL will be examined for the 24 hours post LPS and 
saline challenge. Visit 8 is the end-of-trial examination.
The screening period lasts from the signature of informed consent at Visit 1 until 
randomization (directly followed by first administration of trial medication) on Day 1 
(Visit 2).
The screening visit (Visit 1) will take place 3 to 28 days prior to randomization. 


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The treatment period lasts from the first administration of trial medication on Day 1 (Visit 2) 
until Day 28 ± 2 days (Visit 6).
The follow-up period lasts from Day 29 (Visit 7) until the End of trial (Day 32 to 34, Visit 8).
Please refer to Section 8.6 for the definition of the end of trial.
Subjects are included in the study once they have signed the informed consent and their 
participation concludes when they have undergone the last planned visit. The end of trial visit 
(Visit 8) also needs to be completed if the subject withdraws from or is removed from the 
trial following randomization (see Section 3.3.3)
All trial relevant documentation will be stored by Boehringer Ingelheim in the Trial Master 
File (TMF). Trial relevant documentation for the study sites will be filed in the Investigator 
Site File (ISF).
An overview of all relevant trial activities is provided in the Flow Chart. For details on the 
administered treatments, refer to Section 4.1. For visit schedule 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
Boehringer Ingelheim 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 standard operating procedures (SOPs), direct the clinical trial team in the preparation, 
conduct, and reporting of the trial, order the materials as needed for the trial, and ensure 
appropriate training and information of local clinical monitors (CML), Clinical Research 
Associates (CRAs), and investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organize, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information 
can be found in the ISF.
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in ISF.
The study will be conducted at a clinical research center
 specialized on 
pulmonary diseases, and experienced in the management of healthy volunteers and patients 
with respiratory diseases. The Principal Investigator is an expert in the respiratory therapy 
area. 


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A local laboratory facility will handle all laboratory analyses of the trial. Lung function 
assessment (spirometry) will be performed with site’s own equipment according to 
international accepted guidelines.
Safety status will be assessed by clinical laboratory tests, vital signs, physical examination, 
electrocardiogram (ECG), and monitoring of adverse events. As a further safety measure, the 
pulmonary function will be examined by spirometry according to Flowchart.
Bronchoscopies and medical checks (including spirometry) prior to discharge of subject will 
be performed according to the Fraunhofer Institute study site standard operating procedure
(provided in the ISF), which is based on guidelines for investigative bronchoscopies.
On the last day of treatment (Visit 6), subjects undergo bronchoscopy with BAL and 
segmental instillation of endotoxin and saline (control), each in different segments of contra-
lateral lungs. Twenty-four hours later (Visit 7), subjects undergo a second bronchoscopy for 
the collection of BAL fluid from both challenged segments. BAL fluid from both days will be 
processed and total and differential cell counts will be determined.
During bronchoscopies at Visits 6 and 7 biopsies will be taken and further processed for 
biomarker analyses. Instructions on the procedures are provided in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A randomized, double-blind, placebo-controlled, parallel-group design is chosen for this trial 
in order to assess anti-inflammatory PD effects, safety, tolerability 
 in 
subjects treated with BI 1026706 compared with placebo.
To avoid extensive trial duration and minimize the risks related with the planned trial 
procedures, this trial has a parallel group design. All subjects are smoking healthy volunteers 
who will not have clinically significant diseases and related treatment. Therefore, treating the 
control group with placebo does not raise ethical concerns and allows to assess the effect of 
BI 1026706 on inflammation after LPS challenge as well as to reliably evaluate safety and 
tolerability of BI 1026706. 
The reliability of safety and tolerability observations is further ensured by the double-blind 
design of the trial.
A balanced random allocation with a ratio of 1:1 to receive BI 1026706 or placebo is chosen 
to create treatment groups comparable with respect to known as well as unknown risk factors 
and to maximize the power of analyzing any effects.


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The sample size of 50 entered (randomized) subjects should result in a sufficient precision to 
estimate relevant differences between treatments in this exploratory trial.
The treatment period of 4 weeks for BI 1026706 or placebo to be administered orally as 
tablets twice daily to subjects is deemed adequate to evaluate safety, tolerability, 
, pharmacodynamics, and effect on inflammation after LPS challenge.
3.3
SELECTION OF TRIAL POPULATION
A log of all subjects enrolled into the trial (i.e. who have signed 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 trial entry
Healthy smoking volunteers with FEV1 of >80% and FEV1/FVC of >70% of the predicted 
normal value at screening visit are eligible for inclusion if they fulfil all the inclusion criteria 
(Section 3.3.2) and none of the exclusion criteria (Section 3.3.3).
Please refer to Section 8.3.1 (source documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1) Signed informed consent consistent with ICH-GCP guidelines and local legislation 
prior to participation in the trial.
2) Healthy volunteers of both sex between 18 and 65 years (inclusive) of age, on the day 
of subject’s signature of informed consent. 
3) Healthy subjects as assessed by the investigator, based on a screening examination 
including medical history, physical examination, vital signs (Blood pressure, pulse 
rate, body temperature 12-lead ECG, lung function and clinical laboratory results.
4) FEV1 of >80% and FEV1/FVC of >70% of the predicted normal value at screening 
visit will be calculated according to the Global Lung Function Initiative (GLI) 
Equations as described in [R15-0845].
5) Current smokers with a smoking history of at least 1 pack year (see Appendix 10.1 for 
calculation) and with at least 1 cigarette per day in the previous year confirmed by a 
positive cotinine test. 
6) BMI range: >18.5 and < 29.9kg/m2 at screening visit (Visit 1)
7) Hemoglobin levels within normal ranges or assessed as clinically non-significant 
deviation by the investigator at screening visit (Visit 1).
8) Subjects must show a negative urine drug screening.
9) Negative breath alcohol test.
10) Negative skin prick test or positive skin prick test; without clinical equivalent of an 
allergy, performed within the 12 months prior to study start or at Visit 1. . Subjects 
with a positive skin prick test are considered to be sensitized and are allowed to 
participate if there is no expected exposure during the planned trial participation 
period of the subject as assessed and documented by investigator. Positive skin prick 


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test should be documented as baseline condition (e.g. ´ allergen skin test positive´). 
The specific allergen and the off-season character should be entered as additional 
information in the eCRF.
11) GFR must be ≥30 mL/min at Visit 1.
12) Females NOT of childbearing potential are defined as: Women who are 
postmenopausal (12 months with no menses without an alternative medical cause; in 
questionable cases a blood sample with simultaneous levels of FSH above 40 U/L and 
estradiol below 30 ng/L is confirmatory) or who are permanently sterilized (defined as 
hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
3.3.3
Exclusion criteria
1) History of any relevant lung disease (i.e. COPD, asthma, chronic bronchitis, 
pulmonary fibrosis, pulmonary alveolar proteinosis (PAP), pneumocystis infection, 
active tuberculosis, silicosis or any other lung surfactant overproduction syndromes).
2) Lower respiratory tract infection not resolved 4 weeks prior to Screening.
3) Subjects with clinically relevant abnormal hematology, blood chemistry, or urinalysis 
at the screening visit (Visit 1).
4) Any finding of the medical examination (including blood pressure, pulse rate, body 
temperature and ECG) deviating from normal and of clinical relevance.
5) Subjects with a history of any clinically significant cardiovascular, metabolic, renal 
(including renal stones), hepatic, gastrointestinal, hematological, dermatological, 
venereal, neurological, psychiatric or other major disorders.
6) Subjects with a malignancy for which the subject has undergone resection, radiation 
therapy or chemotherapy within the last five years. Subjects with treated basal cell 
carcinoma or fully cured squamous cell carcinoma are allowed to participate.
7) Subjects with previous surgery of the gastro-intestinal tract likely to affect drug 
absorption.
8) History of relevant orthostatic hypotension, fainting spells or blackouts.
9) Subjects with clinically relevant infection or known ongoing clinically relevant 
inflammatory process.
10) History of relevant allergy/hypersensitivity including allergy to drug or its excipients 
or medications in line with bronchoscopy (bronchodilators, sedatives and local 
anesthetics).
11) Subjects with a marked baseline prolongation of QT/QTcB interval (such as repeated 
demonstration of a QTcB interval >450 ms), or any other relevant ECG finding at 
screening visit (Visit 1) according to the investigator.
12) Subjects with a history of additional risk factors for Torsades de Pointes (such as heart 
failure, hypokalemia, or family history of Long QT Syndrome).
13) Subjects with previous surgeries that may have left ferromagnetic material in the 
body, ferromagnetic implants or pacemakers.
14) Any HIV infection (1+2) or active, infectious hepatitis B or C at screening visit (Visit 
1)
15) Neutrophil blood count indicative of immunosuppression according to the investigator
at screening visit (Visit 1).


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16) Participation in another study with any investigational product within 2 months prior 
to screening or if screening occurs within 6 half-lives of intake of another 
investigational drug (whichever is greater). 
17) Subjects who are being treated with non-permitted concomitant medication (please 
refer to Section 4.2.2.1 “Restrictions regarding concomitant treatment”).
18) Subjects with a history of and/or active significant alcohol or drug abuse as assessed 
by the investigator.
19) Subjects who donated more than 100 mL blood in the 4 weeks prior to screening or 
subjects who have the intention to donate blood between screening and 4 weeks after 
the end of trial visit.
20) Male subjects who do not agree to minimize the risk of female partners becoming 
pregnant from the first dosing day until 3 months after the trial medication treatment 
has finished. For details, please see Appendix 10.2.
21) Subjects who are committed to an institution by way of official or juridical order will 
not be enrolled in the trial.
22) Receipt of live (attenuated) vaccine within the 4 weeks prior to screening or during 
the trial.
23) Excessive physical activities within 1 week prior to first administration of study 
medication or during the trial.
24) Subjects who are unable to comply with the dietary regimen.
25) Subjects who have been previously randomized in this study.
26) Subject is assessed as unsuitable for inclusion by the investigator; for instance, 
because he is not considered able to understand and comply with study requirements 
or has a condition that would not allow safe participation in the study
27) For female subjects:

Positive pregnancy test at screening Visit 1, pregnancy or plans to become 
pregnant within 30 days after study completion

Lactation
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be withdrawn from trial treatment if:

The subject withdraws consent for study treatment or study participation, without the 
need to justify the decision.

The subject needs to take concomitant drugs that interfere with the trial medication (see 
Section 4.2.2)

The subject can no longer be treated with trial medication for any medical reason (e.g. 
surgery, adverse events, other diseases or pregnancy) or experiences a respiratory tract 
infection during the treatment period which might interfere with safe conduct of 
bronchoscopies or its analyses.

Decision by Boehringer Ingelheim to discontinue a specific subject (for instance, in case 
of the occurrence of an SAE that would be incompatible with trial continuation).

Administrative reasons (protocol violations, persistent non-compliance).


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A subject can be removed from the trial after discussion between sponsor and investigator if 
eligibility criteria are being violated or if the subject fails to comply with the protocol (e.g. 
non-adherence to dietary rules, non-attendance at study assessments). 
For subjects who discontinue participation in the trial, with the subject’s agreement, the 
subject will undergo the procedures for the end of trial visit as outlined in the flow chart and 
Section 6.2.3.
Data of subjects who discontinue trial participation prior to randomization will be entered in 
the trial database and will be listed. Data of subjects who discontinue or withdraw after
randomization must be documented. For all subjects the reason for withdrawal (e.g. adverse 
events) must be recorded in the eCRF. These data will be included in the trial database and 
reported.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for 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 1 drug-related serious adverse event is reported that is 
considered to be unacceptable.

The expected enrolment goals are not met.

The trial site or investigator violates GCP or the CTP, disturbing the appropriate conduct 
of the trial.

The sponsor decides to discontinue the further development of the investigational 
product.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case more than 6 subjects do not or are not expected to complete the trial (e.g. due to drop-
out rate in the ongoing trial), the trial clinical monitor 
 
 and the trial statistician are to decide if and how many subjects will be 
replaced to ensure a sufficient number of evaluable subjects (as defined in 7.7). A 
replacement subject will be assigned a unique study subject number, and will be assigned to 
the same treatment as the subject to be replaced.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The study medication will be supplied by Boehringer Ingelheim Pharma GmbH & Co. KG, 
Biberach, Germany.
Treatment administration period:
Treatments (BI 1026706 or placebo) will be administered twice daily starting after
randomization at Day 1 in the clinic (Visit 2) and lasts until Day 28. The last study drug 
administration will be performed in the evening of Day 28 at home.
LPS challenge:
The subjects will also be administered LPS as part of the LPS challenge which will be 
prepared by the reconstitution of E. coli type O113, Clinical Center Reference Endotoxin 
(CC-RE).
The dose that will be administered to the individual subject is 40 EU (endotoxin units) 
endotoxin / kilogram body weight (kg b.w).  According to the drug fact sheet, this is equal to 
4ng endotoxin / kg b.w. 


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4.1.1
Identity of BI investigational product(s) and comparator product(s)
Table 4.1.1: 1
Test product 1:
Substance:
BI 1026706
Pharmaceutical formulation:
Film-coated tablets (formulation A1)
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG,
Birkendorfer Str. 65, 88397 Biberach,
Germany
Unit strength:
100 mg
Posology
Twice daily
Route of administration:
Oral
Table 4.1.1: 2
Test product 2 (placebo):
Substance:
Placebo to match BI 1026706 
Pharmaceutical formulation:
Film-coated tablets (formulation A1)
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG,
Birkendorfer Str. 65, 88397 Biberach,
Germany
Unit strength:
Placebo to match 100 mg
Posology
Twice daily
Route of administration:
Oral
4.1.2
Method of assigning subjects to treatment groups
At Visit 2 subjects are randomized to treatment group BI 1026706 or placebo in a 1:1 ratio. 
After assessment of all in- and exclusion criteria, each eligible subject will be assigned the 
lowest available medication number at the time of randomization in a blinded manner. Note 
that the medication number is different from the subject number (the latter is assigned at trial 
entry). Site personnel will enter the medication number in the eCRF.
4.1.3
Selection of doses in the trial
Based on animal pharmacology data and pharmacokinetic characteristics determined in 
humans, a dose of 100 mg b.i.d. of BI1026706 has been selected for the present trial and is 


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expected to meet the anticipated therapeutic exposure (please refer to IB). 
 
 
 
 
4.1.4
Drug assignment and administration of doses for each subject
At Visit 2 (Day 1) eligible subjects will be randomized to one of 2 double-blinded treatment 
arms (100 mg BI 1026706, Placebo in a 1:1 ratio).
BI 1026706 or placebo will be administered orally twice a day (in the morning and evening), 
beginning on Day 1 (Visit 2) until Day 28.
BI 1026706 or placebo will be administered according to the time given in Flowchart.
Each medication bottle contains 20 tablets of BI 1026706 or Placebo. 
At Visit 2 the trial-medication-bottles used for the first administration of trial medication will 
be dispensed to the subject for home administration. At Visits 3, 4, and 5 new trial-
medication bottles will be dispensed for home administration. For details please refer to 
Section 4.1.4.3 “Trial medication administration at home”.
At Visits 3, 4, 5, 6 and 7 the investigator or qualified site staff will take back the remaining 
medication from the subject. For details please refer to Section 4.1.4.4 “Returning of trial 
medication after home administration”.
Site personnel will enter all medication numbers dispensed to each subject in the Medication 
Record page of the eCRF.
Any repacking, transferring of tablets from one bottle to another is strictly prohibited. 
Tablets may only be removed from a bottle directly before the dose administration. 


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4.1.4.3
Trial medication administration at home
At home, trial medication (BI 1026706 or placebo) will be self-administered by the subject as 
an oral dose (tablets) with water. Regarding restriction diet and life style please refer to 
Section 4.2.2.2 “Restrictions on diet and life style”.
The subject will complete a subject-diary confirming whether the trial medication at home 
has been taken correctly by documenting date and time of each intake.
Dispensing trial medication for home administration prior to release from investigational site:
At the end of the on-site study visits preceding home administration, the subject will be 
provided with sufficient trial medication for self-administration at home until the next clinic 
visit. 
The correct use of trial medication will be explained in detail to the subject by the 
investigator or qualified site staff at every visit preceding administration of trial medication at 
home. The subject will be instructed to bring all trial medication bottles (regardless of 
whether empty or not) back to the investigational site. 
4.1.4.4
Returning of trial medication after home administration:
During on-site study Visits 3, 4, 5 and 6, the returned trial medication has to be collected and 
checked for correctness together with the subject’s diary. Any discrepancy has to be 
documented by the investigator.
4.1.4.5
Time of administration of any trial medication:
The morning dose will be administered between 07:00 a.m. and 10:00 a.m.
The evening dose will be administered between 07:00 p.m. and 10:00 p.m.


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4.1.4.6
Skipping of trial medication:
In the event that the a.m. trial medication is not administered before 12:00 noon, this a.m. 
trial medication will be skipped and the next p.m. trial medication will be administered as 
scheduled. In the event that the p.m. trial medication is not administered before 12:00 
midnight, this p.m. trial medication will be skipped and the next a.m. trial medication will be 
administered as scheduled. This information is included in the written subject information.
4.1.4.7
Missed administration of trial medication:
If a subject missed one or more doses of trial medication, he should take the following doses 
according to the CTP. This information is included in the written subject information.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Subjects, investigators and anyone else involved in trial conduct or analysis or with any other 
interest in this double-blind trial will remain blinded with regard to the randomized treatment 
assignments until after database lock.
 
 
 
The randomization code will be kept secret by Clinical Trial Support until database lock.
4.1.5.2
Unblinding and breaking the code
An emergency code break (envelope) will be available to the Investigator / Pharmacist / 
investigational drug storage manager. This code break may only be opened in an emergency 
situation when the identity of the trial drug must be known to the Investigator in order to 
provide appropriate medical treatment or otherwise assure safety of trial participants. If the 
code break for a subject is opened, the Sponsor must be informed immediately. The reason 
for opening the code break must be documented on the envelope and/or appropriate CRF 
page along with the date and the initials of the person who broke the code. At the end of the 
trial all emergency envelopes have to be sent back to the sponsor.


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4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to 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 storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
No concomitant therapy will be allowed. An exemption is the use of a bronchodilator as well 
as lidocaine for the conduct of bronchoscopies.
However, in case of adverse events requiring treatment, symptomatic therapy, according to 
the judgment of the investigator will be permitted. In case of adverse events, the subjects will 
be treated as necessary and kept under constant supervision at the investigational site or 
transferred to hospital until such time that all the results of the evaluations have returned to a 
medical acceptable level.
A concomitant therapy can be authorized by the investigator, as long as this is not in conflict 
with the criteria for eligibility (please refer to Section 3.3.3) and with restrictions regarding 
concomitant treatments (see Section 4.2.2.1). In case of doubt, a case-by-case decision will be 
made after consultation with the sponsor.
All concomitant medications and/or rescue therapies will be recorded on the source 
documents and recorded in the eCRF.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Please see Section 4.2.1. 
4.2.2.2
Restrictions on diet and life style
Diet and lifestyle restrictions before and after administration of trial medication:
Alcohol, coffee, tea, cola energy drinks and chocolate are not permitted 24 hours preceding 
the administration of study medication (V2) and until the end of 
 
 bronchoscopy at Visit 7.
Citrus fruits, in particular grapefruits and Seville oranges (sour or bitter oranges), and their 
juices as well as products containing St. John's Wort (Hypericum perforatum) are not 
permitted 5 days prior to the first trial drug administration (Day 1, Visit 2) 
 
While admitted to the trial site the subjects are restricted from consuming any foods or drinks 
other than those provided by the site staff. Standard clinic meals will be served when subjects 
are at the clinic. 
Excessive physical activity should be avoided starting 1 week prior to the first trial drug 
administration and during the course of the study (competitive sport etc.).


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On Day 1 (Visit 2) and Day 28 (Visit 6), the morning administration of trial medication will 
occur following an overnight fast of at least 8 hours. In addition, on these two days, before 
administration of the morning trial medication (BI 1026706 or placebo), no liquid intake is 
allowed 2 hours before and 2 hours after administration of trial medication. On all other days 
there are no restrictions before and after administration concerning food and liquid intake.
On Day 29 (Visit 7), the second bronchoscopy will occur following an overnight fast of at 
least 8 hours.
As a general rule, scheduled procedures (after randomization) should neither be postponed 
nor skipped due to violation against these restrictions.
4.3
TREATMENT COMPLIANCE
Subjects are requested to bring all remaining trial medication including empty package 
material with them when attending visits.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint(s)
Total cell count of neutrophils in Bronchoalveolar Lavage (BAL) after 24 hours of the 
segmental endotoxin challenge.
5.1.2
Secondary Endpoint(s)
Total and differential cell count of neutrophils (only differential cell count), eosinophils, 
monocytes, macrophages and lymphocytes in BAL after 24 hours of the segmental endotoxin 
challenge.
Further endpoints related to safety assessment:
Number (%) of subjects with treatment emergent adverse events (TEAE).
Number (%) of subjects with drug related AEs 


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5.2
ASSESSMENT OF EFFICACY
Please refer to Section 5.1 “Trial Endpoints”
5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A physical examination will be carried out according to the Flow Chart and will be 
performed as complete physical examination. In addition further physical examination should 
be performed if clarification of AEs is necessary.
After randomization, new clinically significant findings or worsening of screening conditions 
that are, in the opinion of the investigator, clinically significant or meet other AE criteria 
defined in Section 5.3.7 will be reported as adverse events.
5.3.3
Safety laboratory parameters
5.3.3.1
Safety laboratory parameters obtained from blood
For the assessment of laboratory parameters, blood samples will be collected by the trial site 
at the time points indicated in the Flow Chart.


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The local laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the Investigator will be reported as adverse events (please refer to Section 5.3.6).


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5.3.3.2
Safety laboratory parameters obtained from urine
For the assessment of laboratory parameters, urine samples will be collected by the trial site 
at the time points indicated in the Flow Chart.
 
 
 by the investigator will be reported as 
adverse events (please refer to Section 5.3.6).
5.3.4
Electrocardiogram
12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using the ECG machine 
of the investigator site. For time points refer to the Flow Chart. 
 


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The ECG records will be checked for pathological results by the investigator or a designee. 
Clinically relevant abnormal findings as judged by the Investigator will be reported as 
adverse events (please refer to Section 5.3.6).
For the inclusion or exclusion of a subject and for the assessment of cardiac safety during the 
study, the QT and QTcB values generated by the ECG machines or their manual corrections 
by the investigators will be used.
Any ECG abnormalities will be carefully monitored and, if necessary, the subject will be 
removed from the trial and medically treated. Baseline measurements will be defined as the 
measurements taken prior to the first administration of trial medication. 
5.3.5
Other safety parameters 
5.3.5.1
Pulmonary Function Testing
Spirometry measurements will be performed on the device of the investigational sites. The 
spirometer and its use must meet American Thoracic Society (ATS) / European Respiratory 
Society (ERS) criteria [P05-12782] (this includes daily calibration, daily calibration checks 
and weekly linearity checks before performance of the measurements). In addition peak flow 
must be reached earlier than 120 ms after the extrapolated start of the maneuver in order to 
fulfil the acceptable criteria for a forced spirometry maneuver.


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5.3.6
Assessment of adverse events
5.3.6.1
Definitions of AEs
Adverse event
AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medical product and which does not necessarily have to have a causal 
relationship with this treatment.
An AE can therefore be any unfavorable 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:

results in death,

is life-threatening,

requires in subject hospitalization or prolongation of existing hospitalization,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Life-threatening in this context refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
Every new occurrence of cancer must be reported as a serious event regardless of the duration 
between discontinuation of the drug and the occurrence of the cancer.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the Remote Data Capture (RDC) 
system. These events should always be reported as SAEs as described in Section 5.3.7.
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. AESI 


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need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT > 3 fold upper limit normal (ULN) combined with an 
elevation of total bilirubin > 2 fold ULN measured in the same blood draw sample, and/or

marked peak aminotransferase (ALT and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed according to the “DILI checklist” provided via the RDC
system.
In case clinical symptoms of hepatic injury (for example, icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain) without 
available lab results (ALT, AST, total bilirubin), the investigator should make sure these 
parameters are analyzed, if necessary in an unscheduled blood test. Should the results meet 
the criteria of hepatic injury, the procedures described in the DILI checklist should be 
followed.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough 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 between an AE and trial 
medication, 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.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
The reason for the decision on causal relationship for unlisted AEs could be provided in the 
(e)CRF as deemed necessary by the investigator.
5.3.7
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the 
Investigator:


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•
From signing the informed consent onwards through the Residual Effect Period (REP), 
until individual subject’s end of trial:
o
All AEs (serious and non-serious), and all AESIs.
•
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 relevant SAEs and relevant AESIs of which the investigator may 
become aware of.
 All AEs which 
onsidered as on 
treatment please see Section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.
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 
eCRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication and any possible interactions 
between the investigational drug and a Non-Investigational Medicinal Product 
(NIMP)/Auxiliary Medicinal Product (AMP) as comment.


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The following should also be recorded as an (S)AE in the eCRF and 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 trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual subject´s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Screening failures:
SAEs occurring in patients after having discontinued in the trial due to screening failures, i.e. 
after the screening period and who did not receive any trial medication, are to be reported if 
the investigator considered the SAE related to the screening procedure. SAEs which occurred 
during the screening period are to be reported according to standard procedures.
Pregnancy:
In rare cases pregnancy may occur in a clinical trial. Once a subject has been enrolled into 
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used. The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up and 
reported to the sponsor’s unique entry point on the Pregnancy Monitoring Form for Clinical 
Trials (Part B). The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part 
A and B). As pregnancy itself is not to be reported as an AE, in the absence of an 
accompanying SAE and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials 
and not the SAE form is to be completed. If there is an SAE and/or AESI associated with the 
pregnancy an SAE form must be completed in addition.
Exemptions to SAE Reporting
Not applicable.


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BAL sample will be taken at time points indicated in the Flow Chart. Instruction describing 
the BAL procedure is provided in the ISF.
The provided BAL samples will be processed in order to the procedure for BAL and 
processing provided in the ISF. BAL samples need to be processed directly (within 2 hours 
maximum) after the sample has been taken.
Cellular fraction will be used for total and differential cell count (see section 5.1). If 
sufficient material is available, transcriptome analysis may be performed.


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5.7
APPROPRIATENESS OF MEASUREMENTS
Measurements performed during this trial are standard measurements and will be performed 
 to monitor safety aspects in an appropriate 
way.
The PK parameters and measurements outlined in Section 7.3.5 are generally used as 
measurements to assess drug exposure.


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The scheduled measurements are appropriate to see drug induced changes in vital signs, lung 
function, standard laboratory values and ECG. 
These primary and secondary endpoints are standard and accepted for evaluation of 
pharmacodynamic parameters of an oral drug, and they are widely used in this kind of 
studies.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
6.1.1
Adherence to the protocol visits and procedures
Subjects should make all efforts to complete the study which includes the follow-up period 
and end of trial visit. Investigators should encourage treatment compliance and adherence to 
the protocol procedures. All subjects are to adhere to the visit schedule as specified in the 
Flow Chart. All deviations from the planned visit schedule should be documented.
Regarding randomization please refer to Section 7.6.
Regarding removal of subjects please refer to Section 3.3.4.
6.1.2
Visit scheduling
All observations and procedures as mentioned in the Flow Chart for an individual visit should 
be performed on the same day. Clinical and safety laboratory evaluation of Visit 1 can be 
repeated maximum twice within the screening period for clinical and/or technical reasons 
(e.g. the blood sample is clotted) based on investigator’s judgment. If more than 2 repeated 
evaluations are necessary the subject will be discontinued from the study and will be marked 
as screening failure. 
At clinic visits, the administration is under the supervision of the investigator or qualified site 
staff.
All subjects are to adhere to the visit schedule as specified in the Flow Chart. Some flexibility 
is allowed in scheduling the visits according to visit time windows as specified in the Flow 
Charts (+2 days during the treatment period for Visits 3, 4, 5 and 6). Visit 7 must be 
performed on the day following Visit 6. 
If any visit has to be rescheduled, subsequent visits should follow the original visit date 
schedule (calculated from Visit 2). The total treatment period of 28 ±2 days must not be 
exceeded, i.e. Visit 6 must be performed between Day 26 and 30 following randomization 
(Visit 2).
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Informed Consent prior to trial participation:
All subjects must sign and date an Informed Consent consistent with ICH-GCP guidelines 
prior to trial participation. Please refer to Section 8.1 for details. 
Re-screening
Subjects who do not fulfil the eligibility criteria (i.e. subjects who do not fulfil all of the 
inclusion criteria or fulfil at least one of the exclusion criteria) are to be entered as screening 


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failure. Subjects are allowed to be re-screened twice based on investigator´s judgment. Re-
screening requires a new informed consent and unique study subject number
Details on particular observations and procedures at Visit 1 (screening visit):
Visit 1 will take place 3 to 28 days prior to randomization. 
Observations and procedures will be performed as mentioned in Flow Chart.

Review of in-/exclusion criteria

Demographics will be recorded 

Smoking status / calculation of pack-years

Relevant medical history and baseline conditions

Alcohol and drug screening

Cotinine and skin prick test

Complete physical examination will be conducted

Body weight and height 

Vital signs measurement 

ECG recording 

Pulmonary function test

Safety dipstick urine test 

Safety blood sampling and processing,
. For 
female subjects, pregnancy will be tested in serum. 

AE assessment

Concomitant therapy documentation and recording, diet and lifestyle restrictions
6.2.2
Treatment period(s)
Details on particular observations and procedures at Visits 2, 3, 4, 5, and 6:
Observations and procedures will be performed as mentioned in the Flow Chart.

Review of in-/exclusion criteria at Visit 2

Smoking status to be checked at Visit 2, 4, and 6

Alcohol screening and cotinine test at Visit 6

Complete physical examination will be conducted at Visit 2, 4, and 6

Body weight at Visit 2 and 6

Vital signs measurement 

ECG recording at Visit 2, 4, and 6

Pulmonary function test at Visit 2, 4, and 6

Safety dipstick urine test at Visit 2, 4, and 6

For female subjects, urine pregnancy testing will be conducted at Visit 2 (only if the 
time period between Visit 1 and Visit 2 exceeds 7 days), Visit 5 and Visit 6 prior to 
 bronchoscopy, respectively. 


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
Safety blood sampling and processing at Visit 2, 4, and 6. 
 

Randomization will be conducted at Visit 2 after all safety measurements are 
completed (see Section 4.1.2)

Regarding administration of trial medication, dispense trial drug for home 
administration, collection of trial drug used at home, and use of diary please see 
Sections 4.1.4 and 6.2.4)

Treatment compliance check will be performed at Visit 3, 4, 5, and 6

Subjects drug diary will be dispensed at Visit 2 and checked at Visits 3, 4, 5, and 6

AE assessment

Concomitant therapy documentation and recording, diet and lifestyle restrictions

Bronchoscopy with LPS challenge and retrieval of BAL and biopsies will be 
performed at Visit 6. Pulse oximetry will be done during bronchoscopy. In case of 
female subjects, a negative urine pregnancy testing is required at Visit 6.
As this is a trial in healthy volunteers, no special care after the end of trial is needed.
6.2.3
Follow-up Period and End of Trial
Details on particular observations and procedures at Visit 7 and 8
Observations and procedures will be performed as mentioned in the Flow Chart. Timing of 
Visit 7 in relation to Visit 6 is described in section 6.2.4.

Complete physical examination will be conducted

Alcohol screening at Visit 7

Vital signs measurement 

ECG recording

Safety dipstick urine test at Visit 8 including a pregnancy testing for female subjects

Safety blood sampling and processing

Treatment compliance check will be performed at Visit 7

Subjects drug diary will be checked at Visits 7

AE assessment


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
Concomitant therapy documentation and recording, diet and lifestyle restrictions


Bronchoscopy with retrieval of BAL and biopsies will be performed at Visit 7, 
24 hours (±1 h) after LPS challenge at Visit 6. In case of female subjects, a negative 
urine pregnancy testing is required at Visit 6. Pulse oximetry will be done during 
bronchoscopy. Trial is completed at Visit 8. 
Subjects who took the trial medication and discontinue prematurely should undergo the EOT 
examination (Visit 8) as soon as possible after the last dose of trial drug.
6.2.4
Timing for selected observations and procedures
On Day 1 (Visit 2), study participants will be admitted to the trial site and kept under close 
medical surveillance following drug administration. The subjects will then be allowed to 
leave the trial site after formal assessment and confirmation of their fitness. 
On all other study days during treatment period, the study will be performed in an ambulatory 
fashion.
On Day 28 (Visit 6), subjects will stay at the investigational site for approximately 9 hours 
for PK sampling and bronchoscopy with LPS challenge and BAL as well as biopsy sampling.
Prior to bronchoscopy, all relevant procedures according to Flow Chart will be performed.
On Day 29 (Visit 7), 24 hours after Visit 6, the second bronchoscopy with sampling of BAL 
and biopsies will be performed. Prior to bronchoscopy, all relevant procedures according to 
Flow Chart
 will be performed. Subjects have to stay at the investigational 
site for approximately 8 hours and kept under close medical surveillance.
The time between tablet intake in the evening on Day 28 (Visit 6) and the bronchoscopy on 
Day 29 (Visit 7) should preferable not exceed 14 hours. Subjects are asked to take medication 
on Day 28 (Visit 6) as late as possible and ideally close to 10 p.m. The second bronchoscopy 
should be performed in the morning of Day 29 (Visit 7).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
7.1.1
Objectives
The trial objectives are stated in Section 2.2.
7.1.2
Endpoints
The primary endpoint is the total neutrophil count in BAL 24 hours following endotoxin 
challenge, see Section 5.1.1.
Secondary endpoints regarding BAL in the segment with endotoxin challenge are stated in 
Section 5.1.2.
7.1.3
Model
The statistical model used for the primary analysis of primary and secondary endpoints will 
be an analysis of variance (ANOVA) model on the logarithmic scale. This model will include 
the effect ‘treatment’ and is described by the following equation:
yik= + k + eik, where
yjk
logarithm of response (primary or secondary endpoint) measured on subject i 
receiving treatment k, i = 1, …, 50,  k = 1, 2,

the overall mean,
k
the kth treatment effect, 
eik
the random error associated with subject i receiving treatment k.
where eik~ N(0, -.
/) i.i.d.
7.2
NULL AND ALTERNATIVE HYPOTHESES
This trial will be conducted to detect statistically significant differences between 
BI 1026706 and placebo in BAL neutrophil counts 24 hours following endotoxin challenge
at the end of treatment.
The null and alternative hypotheses are
H0: geometric mean ratio of neutrophil counts at the end of the treatment is 1. 
Ha: geometric mean ratio of neutrophil counts at the end of the treatment is not equal to 1. 


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Safety and tolerability of BI 1026706 is to be determined on the basis of the safety 
assessments 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.
7.3
PLANNED ANALYSES
Measurements regarding BAL of a subject will be included in the analysis, if they are not 
flagged for exclusion, e.g. due to PD non-evaluability or a protocol violation relevant to the 
evaluation of these PD endpoints, which will be decided no later than in the Blinded Report 
Planning Meeting.
A PD endpoint regarding BAL may be considered as non-evaluable, if for example

the amount of BAL was not sufficient, 

the LPS administration was not conducted as planned.
Detailed list of protocol violations will be provided in the TSAP. 
The statistical analysis will be based on the following analysis sets.

Randomized set (RS): 
This subject set includes all randomized subjects, whether treated or not.

Treated set (TS):
The treated set includes all subjects who were randomized and treated with at least 
one dose of study drug. This is the full analysis set population in the sense of ICH-E9.

Pharmacodynamic set (PDS):
The pharmacodynamic set includes all treated subjects that have evaluable cell counts 
for the cell types defined in the primary or secondary endpoints following 24 hours of 
LPS administration.


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7.3.1
Primary endpoint analyses
The primary objective of this study will be assessed using the primary endpoint, see Section 
7.1.2. The primary endpoint will be logarithmically transformed, and analyzed using the 
ANOVA as described in Section 7.1.3. The least square means (LS means) of treatment 
difference and its 90% confidence interval (CI) on the log scale will be obtained from this 
model and will be exponentiated to obtain the geometric mean ratio and 90% CI in total 
neutrophil count between BI 1026706 and placebo on the original scale 24 hours post 
endotoxin challenge. 
The primary analysis will be based on the PDS.
7.3.2
Secondary endpoint analyses
Secondary endpoints regarding BAL, see Section 5.1.2, will be statistically assessed using the 
same methods as described for the primary analysis of the primary endpoint. The analysis 
will be based on the PDS.


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7.3.4
Safety analyses
Safety will be assessed for the further endpoints listed in Section 5.1.3 as well as the further 
safety assessments described in Section 5.3. All treated subjects (that is, all subjects who 
received at least one dose of study drug), will be included in the safety evaluation. Safety 
analyses will be descriptive in nature and will be based on BI guideline ‘Analysis and 
presentation of adverse event data from clinical trials’ (001-MCG-156).
The analyses will be done by ‘treatment at onset’.
Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyze continuous 
(quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the end of the REP 
will be assigned to ‘on-treatment’, and those between end of REP and end-of-trial 
examination will be assigned to ‘post-treatment’ and those after the end of trial examination 
will be assigned to ‘post-study’. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and post-study intervals).
Adverse events will be coded using the MedDRA. Frequency, intensity and causal 
relationship of AEs will be tabulated by treatment, primary system organ class and preferred 
term. SAEs and other significant AEs (according to ICH E3), and AESIs will be listed 
separately (see Section 5.3.7). 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
and drug-related adverse events. To this end, all adverse events occurring between start of 
treatment and end of the residual effect period will be considered ‘treatment-emergent’. 
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).


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Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.


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7.5
HANDLING OF MISSING DATA
Missing safety and pharmacodynamic data will not be imputed.
7.6
RANDOMIZATION
Subjects will be randomized in blocks to double-blind treatment in a 1:1 ratio, receiving 
either placebo or 100 mg BI 10276706 b.i.d. The block size will be documented in the CTR.
The sponsor will arrange for the randomization as well as packaging and labelling of trial 
medication. The randomization list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
treatment is both reproducible and non-predictable. Access to the codes will be controlled and 
documented.
7.7
DETERMINATION OF SAMPLE SIZE
This is the first clinical trial conducted in healthy smoking subjects with 28-day exposure, 
and the sample size of 25 subjects per treatment group is considered sufficient to achieve the 
aims of this exploratory trial.
Hohlfeld et al. [R13-0305] investigated the effect of Roflumilast compared to placebo on the 
cell count of different cell types in BAL. Based on their results it is assumed that the mean 
neutrophil count 24 hours post endotoxin challenge in the placebo group is 1256 *103/ml with 
a standard deviation (SD) of 870 *103 /ml. The mean number of neutrophils in the 
Roflumilast treatment group was 836 *103/ml with SD of 314*103 /ml and thus it was only 
67% of that for the placebo group 24 hours post endotoxin challenge. This corresponds to a 
fold-change of 1.50 (placebo vs. roflumilast). 
The sample size calculation is based on the following assumptions: 
•
The primary endpoint is log-normally distributed
•
1-sided significance level α = 5%
•
BI 1026706 will have a similar effect like Roflumilast. Hence a fold-change of 1.50 or 
in case of number of neutrophils is only 60% under BI 1026706 compared to placebo 
a fold-change of 1.67.
•
The expected coefficient of variation (CV) is similar to the observed CVs in Hohlfeld 
et al. 
•
Based on Hohlfeld et al. the expected rate of neutrophil counts being unavailable due 
to reasons such as dropout, unqualified samples, discontinuation of procedure etc., is 
10% to 20%.
Table 7.7:1 below shows the expected power under the assumptions stated above and for 
various coefficient of variations (CV), evaluable subjects and fold-changes. 


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Table 7.7: 1 
Expected power to detect differences in the treatments based on the 
primary endpoint for various coefficients of variation, evaluable 
subjects per group and expected fold-changes.
CV
N per group
Fold-change 
1.50
1.67
0.38
20
96 %
99 %
22
97 %
99 %
0.53
20
81 %
93 %
22
84 %
95 %
0.69
20
64 %
81 %
22
68 %
84 %
From the Table above, a sample size of 22 evaluable subjects per group will have at least 
84% power to detect a significant difference in case the total cell count of neutrophils under 
BI 1026706 is at most 67% (corresponds to a 1.5 fold-change) of the respective number for 
placebo on original scale and the CV is not greater than 53%. To account for the potential 
10% subjects without evaluable neutrophil counts, a total sample size of 2 * 25 = 50 subjects 
will be entered in the study.
The calculation was performed using the MTT0cv routine from the commercial software 
nQuery Advisor® Version 7.0 (Statistical Solutions Ltd., Cork, Ireland).


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the subject.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial 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 the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the subjects, and 
is stored in the ISF (Investigator Site File).
8.1
TRIAL 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 subject participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH / GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The Investigator must give a full explanation to trial subjects including the items listed below 
in association with the use of the subject information form, which is prepared avoiding the 
use of technical terms and expressions. The subject is given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the subject’s own free 
will with the informed consent form after confirming that the subject understands the 
contents. The Investigator must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB/IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRF) / eCRF for individual subjects will be provided by the Sponsor.
See Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF 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; current medical records must also be available.
For eCRFs all data must be derived from source documents.
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. 
CRF/eCRF and all source documents, including progress notes 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 (CRA) / on site monitor and auditor may review all CRF/eCRF, 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 documents and essential documents for a period defined 
by the GCP regulation and trial site’s contract with the sponsor.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
When it is no longer necessary for the trial site to retain the source documents and essential 
documents, the Sponsor must notify the head of trial site.


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8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For BI 1026706, this is the current version of the Investigator’s Brochure provided in the ISF.
For LPS, the reference document for assessing international listedness is the current version 
of the IBprovided in the ISF. The reference document for the contrast medium as auxiliary 
medicinal product is the UK SmPC of DOTAREM provided in the ISF. 
No AEs are classified as listed for matching placebo or invasive procedures.
8.4.2
Expedited reporting to health authorities and IEC/IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC/IRB, will be done according to local 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be given 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.
8.6
END OF TRIAL
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.
The IEC / competent authority in Germany needs to be notified about the end of the trial or 
early termination of the trial.
8.7
PROTOCOL VIOLATIONS
The investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.


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8.8
COMPENSATION AVAILABLE TO THE SUBJECT IN THE EVENT OF 
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the Sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P03-05533
Crapo RO, Jensen RL, Hargreave FE, Airway inflammation in COPD: 
physiological outcome measures and induced sputum. Symp 'Measurement 
and Evaluation of Outcomes in COPD', Paris, 29 Apr - 1 May 2001. EurRespir 
J 21 (Suppl 41), 19S - 28S (2003)
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. EurRespir J 26 (2), 319 - 338 (2005)
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Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, Bundschuh DS, Brose M, 
Martinez FJ, Rabe KF, M2-127 Study Group, M2-128 Study Group. 
Roflumilast in moderate-to-severe chronic obstructive pulmonary disease 
treated with longacting bronchodilators: two randomised clinical trials.
Lancet 374:9691, 695-703 (2009)
P14-01052
Global Initiative for Chronic Obstructive Lung Disease (GOLD): Global 
strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease (updated 2014)
P15-01740
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
strategy for the diagnosis, management and prevention of chronic obstructive 
pulmonary disease (updated 2015). 
http://www.goldcopd.org/uploads/users/files/GOLD_Report_2015.pdf (access 
date: 16 February 2015); 2015
R13-0305
Hohlfeld JM, Schoenfeld K, Lavae-Mokhatri M, Schaumann F, Mueller M, 
Bredenbroeker D, Krug N, Hermann R, Roflumilast attenuates pulmonary 
inflammation upon segmental endotoxin challenge in healthy subjects: a 
randomized placebo-controlled trial. PulmPharmacolTher 21, 616 - 623 (2008)
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Miravitlles M, Guerrero T, Mayordomo C, Sanchez-Agudo L, Nicolau F, Segu 
JL, EOLO Study Group Factors associated with increased risk of exacerbation 
and hospital admission in a cohort of ambulatory COPD patients: a multiple 
logistic regression analysis. Respiration 67, 495 - 501 (2000)
R08-1495
Mannino DM COPD: epidemiology, prevalence, morbidity and mortality, and 
disease heterogeneity. Chest 121 (5) (Suppl), 121S - 126S (2002)


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R10-1412
Daxas 500 micrograms film-coated tablets (Nycomed) (summary of product
characteristics).
http://www.daxas.com/~/media/Nycomed%20Daxas/SmPC/Daxas%20EU%2
0SmPC.ashx (access date: 4 October 2010) (2010)
R11-4442
Calverley PMA, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez 
FJ, M2-124 Study Group, M2-125 Study Group. Roflumilast in symptomatic 
chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 
374, 685 - 694 (2009)
R11-4791
Daliresp (roflumilast) tablets (Nycomed), Rx only (prescribing information, 
revised February 2011).
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(2011)
R12-5301
Pizzichini E, Pizzichini MMM, Leigh R, Djukanovic R, Sterk PJ Safety of 
sputum induction.EurRespir J 20 (Suppl 37), 9S - 18S (2002)
R15-03546
Lacy P, Lee JL, Vethanayagam D. Sputum analysis in diagnosis and 
management of obstructive airway diseases.TherClin Risk Manag 2005; 
1:169-79
R15-0709
Singh D, Edwards L, Tal-Singer R, Rennard S. Sputum neutrophils as a 
biomarker in COPD: findings from the ECLIPSE study. Respir Res (Lond) 
2010; 11:77
R15-0845
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, 
Hankinson JL, Ip MSM, Zheng J, Stocks J, and the ERS Global Lung 
Function Initiative. Multi-ethnic reference values for spirometry for the 3-95-
yr age range: the global lung function 2012 equations. EurRespir J 2012;40 
1324-1343
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Robinson PD, et al Consensus statement for inert gas washout measurement 
using multiple- and single-breath tests. Eur Respir J 41 (3), 507 - 522 (2013)


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R15-1774
Paggiaro PL, Chanez P, Holz O, Ind PW, Djukanović R, Maestrelli P, Sterk 
PJ. Sputum induction.EurRespir J 2002; 20 (Suppl. 37): 3s-8s
R15-1775
Makris D, Tzanakis N, Moschandreas J, Siafakas NM.Dyspnea assessment 
and adverse events during sputum induction in COPD.BMC Pulm Med 2006; 
6: 17.doi:10.1186/1471-2466-6-17.
R15-3034
Chronic respiratory diseases: burden of COPD.
http://www.who.int/respiratory/copd/burden/en/ (access date: 11 June 2015); 
World Health Organization (2015)
9.2
UNPUBLISHED REFERENCES
c03035551
Investigator’s Brochure. BI 1026706


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10.
APPENDICES
10.1
CALCULATION OF NUMBER OF PACK YEARS
Pack years = Number of cigarettes per day
20
× years of smoking
10.2
CONTRACEPTION
Male subjects will only be included in this trial when they agree to minimize the risk of 
female partners becoming pregnant from the first dosing day until 3 months after the trial 
medication treatment has finished (see Section 3.3.3).
Hence, male subjects who have sexual intercourse with women of childbearing potential (i.e. 
fertile, following menarche until becoming post-menopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy) will be instructed and must agree to use at least one of the acceptable forms 
of effective contraception listed below.
Acceptable forms of effective contraception include:
Established use of oral, injected or implanted hormonal methods of contraception or 
tubal ligation by the female partner of the male subject
Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female 
partner of the male subject
Use of barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
Sterilization of the male subject (with the appropriate post-vasectomy documentation 
of the absence of sperm in the ejaculate)


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
16-DEC-2015
EudraCT number
2015-001789-25
BI Trial number
1320.17
BI Investigational Product(s)
BI 1026706
Title of protocol
A randomized, double-blind, placebo-controlled, 
parallel group, Phase I trial in healthy male current 
smoker subjects to assess pharmacodynamic effects 
on segmental endotoxin induced inflammatory 
response and safety of 4 weeks oral administration
of BI 1026706
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
YES
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
NO
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
NO
Section to be changed
5.6 and related changes in sections Flowchart 
footnote 4, 3.3.2, 4.2.1, 5.1.3, 5.3.3.1, 5.6, 6.2.1, 
6.2.2, 6.2.3, 7.3.3, 8.4.1
 
 
 
Section to be changed
4.2.1, 8.4.1


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Section to be changed
Title page
Section to be changed
Flowchart –footnote 5, 3.1.1 
Description of change
Medical checks (including spirometry) will be 
performed prior to discharge of subject according 
to the SOP of the investigational trial site
Rationale for change
To reflect the SOP of the investigational trial site
Section to be changed
3.3.5
Description of change
Female subjects will not be used for replacement
Rationale for change
Only male subjects are allowed in the trial
Section to be changed
4.1, 8.4.1
Description of change
Deletion of batch specific information and addition 
of IMPD as document for assessment of listedness
Rationale for change
To allow use of LPS as IMP as approved
Section to be changed
4.2.2.2, 5.3.2
Description of change
To clarify that standard clinic meals (and not 
standardized meals) and a certified blood pressure 
instrument without need for the identical 
instrument being used are sufficient
Rationale for change
To specify operative requirements at the trial site
Section to be changed
5.3.3.1
Description of change
The date and blood collection times must be 
recorded in the eCRF or transferred electronically 
to the sponsor (if possible).


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Rationale for change
To allow electronic transfer if possible
Section to be changed
5.3.6.1
Description of change
Need to provide the reason for decision on causal 
relationship for unlisted AE was clarified 
Rationale for change
Investigator could comment in the CRF AE-page 
as needed, but is not compulsory
Number of global amendment
2
Date of CTP revision
14-JUL-2016
EudraCT number
2015-001789-25
BI Trial number
1320.17
BI Investigational Product(s)
BI 1026706
Title of protocol
A randomized, double-blind, placebo-controlled, 
parallel group, Phase I trial in healthy male current 
smoker subjects to assess pharmacodynamic effects 
on segmental endotoxin induced inflammatory 
response and safety of 4 weeks oral administration 
of BI 1026706
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
YES
To be implemented immediately 
in order to eliminate hazard –
NO


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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
NO
Section to be changed
2.1
Description of change
The study population was specified as healthy male 
subjects being current smokers at Visit 1. The LPS-
endotoxin challenge was added to the rationale. 
Rationale for change
To describe precisely rationale and population 
Section to be changed
2.3.2


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Section to be changed
3.3.2 (Inclusion Criterion number 10)
Description of change
Positive responses to skin prick tests are allowed if 
the subject is without clinical equivalent of 
allergies and if an exposure during trial 
participation is not expected
Rationale for change
To allow inclusion of non-allergic, sensitized 
subjects without expected exposure during  the trial 
Section to be changed
3.3.2, 3.3.3
Description of change
Inclusion criteria number 6 and 7, exclusion 
criterion number 14 and 15 will be assessed based 
on data collected at Visit 1
Rationale for change
To harmonize time points of assessments of these 
eligibility criteria
Section to be changed
3.3.3
Description of change
Clarification of the exclusion criterion 23
Rationale for change
To clarify exclusion criterion 23
Section to be changed
3.3.3 (Exclusion Criterion number 25); 6.2.1
Description of change
Re-screening will be allowed twice based on 
investigator´s judgment.
Rationale for change
To allow re-screening of subjects 
Section to be changed
3.3.4.1
Description of change
To add withdrawals if the subject experiences a 
respiratory tract infection during the treatment 
period which might interfere with safe conduct of 
bronchoscopies or its analyses.
Rationale for change
To specify handling of premature discontinuations 
in case of respiratory tract infections during the 
treatment period which might interfere with safe 
conduct of bronchoscopies or its analyses.
Section to be changed
4.1
Description of change
Clarification of the reconstitution process in the 
protocol that serves as example for the nominal 
dose of 10,000 endotoxin units. This process will 
be adapted to the actual endotoxin content given in 
the Certificate of Analysis to ensure an appropriate 
application dose of LPS.  
Rationale for change
To update the reconstitution of LPS.


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Section to be changed
4.2.2.2
Description of change
Restrictions on diet and life style were harmonized 
with site´s procedures and harmonized with the 
revised informed consent form.
Rationale for change
To add alcohol restrictions during the trial 
Section to be changed
5.3.3
Description of change
The header of the table 5.3.3.1:1 was aligned with 
the chapter, i.e. local laboratory to include safety 
laboratory parameters only 
Rationale for change
To ensure consistency within the protocol
Section to be changed
5.3.7
Description of change
Possible interactions between IMP and AMP 
should be part of AE-reporting
Rationale for change
To receive information on possible interactions
Section to be changed
6.1.2
Description of change
Repeat-testing of clinical and safety laboratory 
parameters will be allowed maximum twice based 
on investigator´s judgement 
Rationale for change
To allow re-testing of clinical and safety 
parameters 
Description of change
The reference document for assessing listedness for 
LPS will be the Investigator´s Brochure 
Rationale for change
To harmonize the reference documents
Number of global amendment
3
Date of CTP revision
02 Nov 2016
EudraCT number
2015-001789-25
BI Trial number
1320.17
BI Investigational Product(s)
BI 1026706
Title of protocol
A randomized, double-
 
 in healthy male current 
smoker subjects to assess pharmacodynamic effects 
on segmental endotoxin induced inflammatory 
response and safety of 4 weeks oral administration 


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of BI 1026706
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
YES
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
NO
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
NO
Section to be changed
Title, Synopsis, Benefit-Risk-Assessment (2.3), 
Drug-related Risks (2.3.2), Inclusion and Exclusion 
Criteria (3.3.2; 3.3.3)
Description of change
Women NOT of childbearing potential are added to 
the study population. Pregnant, lactating and/or 
females of childbearing potential are still excluded.
Rationale for change
Trial procedures do not include an increased risk to 
females as compared to male healthy volunteers. 
Inclusion of females not of childbearing potential is 
in line with ICH M3.
Section to be changed
Flow Chart, Safety Laboratory Parameters (5.3.3), 
Details of Trial Procedures at Selected Visits (6.2) 
Description of change
Serum pregnancy testing will be added at Visit 1. 
Urine pregnancy testing will be implemented at 
Visit 2 (only if time period between Visit 1 and 
Visit 2 exceeds 7 days), Visits 5, 6 and 8.
Rationale for change
Addition of pregnancy testing for females not of 
childbearing potential to safeguard their inclusion.
Section to be changed
Removal of Subjects from Therapy or Assessments 
(3.3.4), Adverse Event Collection and Reporting 
(5.3.7)
Description of change
Instructions to the investigator are added in case of 
pregnancy in females not of childbearing potential.
Rationale for change
Addition of instructions regarding removal of 
pregnant subjects and its reporting within the trial 
are added to safeguard the inclusion of women not 
of childbearing potential.


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Section to be changed
Inclusion Criteria (3.3.2), Exclusion Criteria (3.3.3)
Description of change
Several in- and exclusion criteria were revised to 
allow investigator´s medical judgement. 
Rationale for change
Strict eligibility criteria are revised to allow more 
medical judgement by the investigator
Section to be changed
Synopsis, Inclusion Criteria (3.3.2)
Description of change
Upper age limit was moved from 50 to 65 years
Rationale for change
Higher age group has an equal risk for the trial.
Section to be changed
Flowchart, Overall Trial design and Plan (3.1)
Description of change
The time window for Visit 6 was revised to allow 
plus/minus 2 days
Rationale for change
To give more flexibility regarding Visit 6
Section to be changed
Appendix 10.2 - Contraception
Description of change
Instructions for male study subjects regarding 
female partners and their definition of childbearing 
potential and effective contraception were updated, 
e.g. tubal ligation is considered as effective 
contraception only
Rationale for change
To follow the “Recommendations related to 
contraception and pregnancy testing in clinical 
trials” of the Clinical Trial Facilitation Group
Number of global amendment
4
Date of CTP revision
19 Dec 2016
EudraCT number
2015-001789-25
BI Trial number
1320.17
Title of protocol
A randomized, double-blind, placebo-controlled, 
parallel group, Phase I trial in healthy male current 
smoker subjects to assess pharmacodynamic effects 
on segmental endotoxin induced inflammatory 
response and safety of 4 weeks oral administration 
of BI 1026706
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
NO
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
NO
Can be implemented without 
IRB / IEC / Competent 
YES


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Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
3.3.5, 4.1.4.1
Description of change
Replacement strategy and handling of medication 
dispense to replacement subjects is specified to 
allow adaptation to actual drop-out rate
Rationale for change
The drop-out rate in the trial after approximately 
50% of subjects recruited into the trial is close to 
the cut-off point for replacement. To allow a 
seamless recruitment in the trial, replacement of 
subjects will need to start already prior to reaching 
the cut-off of maximum numbers of drop-outs.
Spare reserve medication at the site will be used for 
this purpose which will require implementation of 
a trial-independent site-staff member with 
restricted access to randomization codes. This 
dedicated function will instruct the site´s trial staff
in a blinded manner which medication is to be 
dispensed to the replacement subjects. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03143538
5.0
clinical-trial-protocol
A randomized, double-blind, placebo-controlled, parallel group, Phase I trial in
healthy current smoker subjects to assess pharmacodynamic effects on segmental
endotoxin induced inflammatory response and safety of 4 weeks oral administration
of BI 1026706.
Approval-Team Member Medicine
19 Dec 2016 15:17 CET
Approval-Trial Clinical Monitor
19 Dec 2016 16:39 CET
Author-Trial Clinical
Pharmacokineticist
19 Dec 2016 16:51 CET
Author-Trial Statistician
20 Dec 2016 10:47 CET
Approval-Therapeutic Area
21 Dec 2016 09:54 CET
Verification-Paper Signature
Completion
21 Dec 2016 10:08 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03143538
5.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c09084743-01
BI Trial No.:
1320.17
Title:
A randomized, double-blind, placebo-controlled, parallel group, 
Phase I trial in healthy current smoker subjects to assess 
pharmacodynamic effects on segmental endotoxin induced 
inflammatory response and safety of 4 weeks oral administration of 
BI 1026706
Final Protocol (including protocol revisions 1,2, 3 and 4
(c03143538-05 ))
Investigational
Products:
BI 1026706
Responsible trial 
statisticians:
 
Phone:
Fax:
Phone: 
Fax: 
Date of statistical 
analysis plan:
23 MAR 2017        SIGNED
Version:
Final
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2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT .....................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoints....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
...................................10
...................................13
...................................13
...................................13
...................................14
...................................14
5.4.5
Other safety parameters.....................................................................................14
5.4.5.1
Physical examination findings ..............................................................................14
5.4.5.2
Vital signs .............................................................................................................14
5.4.5.3
Safety laboratory parameters ................................................................................14
5.4.5.4
Electrocardiogram.................................................................................................14
5.4.5.5
Pulmonary function testing...................................................................................15
5.4.5.6
Oxygen saturation .................................................................................................15
5.4.5.7
Adverse events ......................................................................................................15
...........................15
...........................15
...........................15
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................16
6.1
TREATMENTS...................................................................................................16
6.2
IMPORTANT PROTOCOL VIOLATION......................................................18
6.3
SUBJECT SETS ANALYSED...........................................................................20
.....................................................................................................22
6.5
POOLING OF CENTRES .................................................................................22
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................22
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................23
7.
PLANNED ANALYSIS......................................................................................24
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........24
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................25
7.4
PRIMARY ENDPOINT .....................................................................................25
7.5
SECONDARY ENDPOINTS.............................................................................26
7.5.1
Key secondary endpoints....................................................................................26


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7.5.2
Secondary endpoints...........................................................................................26
..................................26
..................................26
..................................27
7.6.3
Endpoints related to safety assessments............................................................27
...............................................27
...............................................28
................................................29
7.8
SAFETY ANALYSIS..........................................................................................29
7.8.1
Adverse events.....................................................................................................29
7.8.2
Laboratory data ..................................................................................................31
7.8.3
Vital signs.............................................................................................................31
7.8.4
ECG......................................................................................................................31
7.8.5
Others...................................................................................................................31
7.8.5.1
Physical examination findings ..............................................................................31
7.8.5.2
Pulmonary function testing...................................................................................31
7.9.1
Smoking status.....................................................................................................32
............................................................................32
8.
REFERENCES....................................................................................................33
........34
.......34
10.
HISTORY TABLE..............................................................................................35


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LIST OF TABLES
Table 6.1: 1
Flow chart of study analysis phases for adverse events, laboratory tests, vital 
signs and body weight ......................................................................................17
Table 6.2: 1
Important protocol violations ...........................................................................19
Table 6.3: 1
Subject sets analysed ........................................................................................22
Table 10: 1
History table .....................................................................................................35


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis data set
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
AST
Aspartate transaminase
ANOVA
Analysis of variance
BAL
Bronchoalveolar lavage
BI
Boehringer Ingelheim
BMI
Body mass index
BP
Blood pressure
BRPM
Blinded report planning meeting
CD14-positive 
monocytes
cell count of monocytes, determined by flow cytometry
 
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
differentialany, microsc
differential cell count of neutrophils, eosinophils or lymphocytes, 
determined by cytospin microscopy
differentialmacro, microsc
differential cell count of macrophages, determined by cytospin 
microscopy
differentialmacro+mono, 
derived
differential cell count of macrophages plus monocytes, derived
differentialmono, microsc
differential cell count of monocytes, determined by cytospin 
microscopy
differentialmono, flow
differential cell count of monocytes, determined by flow cytometry
ECG
Electrocardiogram 
eCRF
electronic case report form


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Term
Definition / description
EMA
European Medicines Agency
EOT
End-of-trial
ES
Enrolled set
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FEV1
Forced expiratory volume in one second
FVC
Forced vital capacity
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference on Harmonisation
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
number of non-missing observations
O*C
Oracle Clinical
PD
Pharmacodynamic(s)
PDS
Pharmacodynamic set
PR
Pulse rate
PV
Protocol violation
REP
Residual effect period
RS
Randomised set
SAE
Serious adverse event
SAS®
Statistical Analysis System


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Term
Definition / description
SD
Standard deviation
T
Test treatment
TEAE
Treatment emergent adverse event
totalany, derived
total cell count of neutrophils, eosinophils or lymphocytes, derived
totalany, derived,standardised
total cell count of neutrophils, eosinophils or lymphocytes, derived and 
standardised to the retrieved BAL volume
total cells, standardised
total cell count of all cells together standardised to the retrieved BAL 
volume
totalmacro+mono, derived, 
standardised
total cell count of macrophages plus monocytes, derived and 
standardised to the retrieved BAL volume
totalmono, derived, 
standardised
total cell count of monocytes determined by flow cytometry, derived
and standardised to the retrieved BAL volume
totalnon-squamous cells, 
microsc
total cell count of non-squamous cells, determined by cytospin
microscopy
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per International Conference on Harmonisation (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 clinical trial protocol (CTP), and to include detailed procedures 
for executing the statistical analysis of the primary and secondary variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the CTP, including 
protocol amendments. In particular, the TSAP is based on the planned analysis specification 
as written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. 
Therefore, TSAP readers may consult the CTP for more background information on the study,
e.g., on study objectives, study design and population, treatments, definition of measurements 
and variables, planning of sample size, randomization.
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system.
SAS® Version 9.4 will be used for all analyses
.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in the TSAP are outlined in the CTP and its amendments.
In addition to what has already been outlined in the CTP, the following changes in the 
analyses are introduced in this TSAP: 

Differential (i.e. relative) cell count of neutrophils, eosinophils, monocytes, macrophages 
and lymphocytes, as well as the total cell count of non-squamous cells in BAL will be 
determined using the method of cytospin microscopy. Since it is not possible with this 
method to clearly differentiate between macrophages and monocytes, the secondary and 
further endpoints regarding the cell type macrophages will actually present the total and 
differential cell count of macrophages and monocytes together and will be named as such 
in the analyses.
Note, the secondary
 endpoints regarding the cell type monocytes used in the 
analyses are based on the differential cell count determined using flow cytometry which is 
more accurate due to immunostaining (CD14).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
CTP: Total cell count of neutrophils in Bronchoalveolar Lavage (BAL) after 24 hours of the 
segmental endotoxin challenge.
For detailed information regarding the determination of this primary endpoint please refer to 
Section 5.3 of this TSAP.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
CTP: Total and differential cell count of neutrophils (only differential cell count), 
eosinophils, monocytes, macrophages and lymphocytes in BAL after 24 hours of the 
segmental endotoxin challenge.
For detailed information regarding the determination of these secondary endpoints please 
refer to Section 5.3 of this TSAP.
Differential (i.e. relative) cell count of neutrophils, eosinophils, monocytes, macrophages and
lymphocytes will be determined using the method of cytospin microscopy. The total cell 
count of non-squamous cells, which will be determined in a microscopic counting chamber, is 
the denominator of the differential cell counts. Multiplication of the differential cell counts 
determined by cytospin microscopy (differentialany, microsc) with the total cell count of non-
squamous cells (totalnon-squamous cells, microsc) will result in the total cell count for the various cell 
types (totalany, derived). Furthermore the total cell count for the various cell types will be 
standardised to the retrieved BAL volume (totalany, derived, standardised). These differential and total 
cell counts for the various cell types will be analysed as primary, secondary and further 
endpoints:
For neutrophils, eosinophils and lymphocytes (primary, secondary and further endpoints):
totalany, derived, standardised = differentialany, microsc * totalnon-squamous cells, microsc / BAL volume


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The differential cell count of macrophages plus monocytes (differentialmacro+mono, derived) will be 
derived as the sum of differential cell counts of monocytes (differentialmono, microsc) plus 
macrophages (differentialmacro, microsc) from cytospin microscopy. The total cell count of 
macrophages plus monocytes (totalmacro+mono, derived, standardised) will then be derived by 
multiplying the derived differential cell count with the total cell count of non-squamous cells 
standardised to the retrieved BAL volume. The derived differential and total cell counts of 
macrophages plus monocytes will be analysed as secondary 
 endpoints:
For macrophages plus monocytes (secondary 
 endpoints):
differentialmacro+mono, derived
= differentialmono, microsc + differentialmacro, microsc
totalmacro+mono, derived, standardised = differentialmacro+mono, derived * totalnon-squamous cells, microsc / 
BAL volume
The differential cell count of monocytes will in addition be determined using flow cytometry
which is more accurate due to immunostaining (CD14). Thus, the differential cell counts of 
CD14-positive monocytes will be analysed as secondary 
 endpoints and will be 
used for derivation of the total cell counts of the monocytes (totalmono, derived), which will also 
be analysed as secondary 
 endpoints. This total monocyte cell count will be derived 
by multiplying the differential cell count of CD14-positive monocytes (differentialmono, flow) 
with the total cell count of non-squamous cells:
For monocytes (secondary 
 endpoints):
totalmono, derived, standardised = differentialmono, flow * totalnon-squamous cells, microsc / BAL volume
In addition the total cells in BAL before segmental challenge, 24 hours after segmental 
endotoxin challenge and 24 hours after segmental saline challenge will be analysed. They are 
derived according to:
total cells, standardised = totalnon-squamous cells, microsc / BAL volume
The unit of the reported total cell counts for each cell type and for total cells will be 10^3/mL.
For the inferential statistical analysis of the primary and secondary endpoints, log transformed 
data will be used and subjects with zero values will not be considered in the inferential 
analysis of the respective cell type. To overcome a reduced sample size for this situation, for 
all cell types that have a zero cell count at Visit 7 in the LPS challenged segment, this value 
will be “imputed” with a small value for the ease of log transformation. To minimize the 
impact of such “imputation”, we will use 1/10th of the roundup value of the minimal non-zero 
value of the total cell count observed in the data for each cell type. For the differential cell 
count of all cell types 0.01 will be added onto the zero values. This imputation strategy will 
only be applied to the data which will be inferentially analysed. The descriptive analysis will 
be based on the actual data.


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Further endpoints related to safety assessment:

Number (%) of subjects with treatment emergent adverse events (TEAE).

Number (%) of subjects with drug related AEs


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5.4.5
Other safety parameters
5.4.5.1
Physical examination findings
Results of physical examination will not be analysed as a specific endpoint. Clinically 
significant findings will be reported as baseline conditions or adverse events (AEs), cf.
Section 5.3.1 of the CTP, and will be analysed as such.
5.4.5.2
Vital signs
CTP: Systolic and diastolic blood pressure (BP) and pulse rate (PR) will be measured after 
the subject has rested for at least 5 minutes in a supine position.
5.4.5.3
Safety laboratory parameters
Cf. CTP Section 5.3.3 for a definition of safety laboratory parameters assessed in this trial.
Urine dipstick data will not be included in the database.
5.4.5.4
Electrocardiogram
Results from electrocardiogram (ECG) will not be analysed as a specific endpoint. Relevant 
ECG findings will be reported as AEs and will be analysed as such.


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5.4.5.5
Pulmonary function testing
The highest FEV1 and FVC from 3 blows as well as the time point of the first pulmonary 
function testing maneuver will be recorded in the eCRF.
5.4.5.6
Oxygen saturation
CTP: Oxygen saturation will be measured by single finger pulse oximetry while conducting
bronchoscopies. However, oxygen saturation data will not be included in the database. 
5.4.5.7
Adverse events

Number (%) of subjects with serious AEs (SAEs)

Number (%) of subjects with AEs of special interest (AESIs).

Number (%) of subjects with other significant AEs (according to ICH E3)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of dose groups, and 
selection of doses, cf. Section 4 of the CTP.
Subjects will be treated with either

100 mg BI 1026706 (test treatment, T) or

placebo (reference treatment, R),
twice daily for 28 +/- 2 days.
The following separate study analysis phases will be defined for the analyses of AEs, 
laboratory tests, vital signs and body weight:

Screening (ranging from 0:00 h on day of informed consent until first administration 
of study drug)

On treatment (separately for each treatment, ranging from the time of first study drug 
administration 
4 days after the last administration of study drug; note that 4 days 
after the last trial medication application are defined in CTP Section 5.3.7 as the 
residual effect period [REP])

Post-treatment (separately for each treatment, ranging 
 days after the last 
administration of study drug, i.e. the end of the REP, to start of post-study phase)

Post-study (
 after the last administration of study drug or at 0:00 h on 
the day after the EOT visit, whichever is later)
Note that the post-treatment phase might not exist for individual subjects, e.g. if the EOT visit 
is 
 of the last administration of study drug.


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Table 6.1: 1
Flow chart of study analysis phases for adverse events, laboratory tests, vital 
signs and body weight
Study analysis 
phase
Start
End
Screening
Date of informed consent 
Date/time of first administration of study 
drug
On treatment
Date/time of first administration of study 
drug
Date/time of last administration of study 
drug + REP, 
 * 24 h
Post-treatment1
Date/time of last administration of study 
drug + REP (
 * 24 h)
12:00 AM on day after trial completion 
date
Post study
Date/time of last administration of study 
drug + REP (
 * 24 h)
or
12:00 AM on day after trial completion 
date
(whichever is later)
Not defined – a placeholder date is used, 
e.g. a date after database lock
1 does not necessarily exist
Displays of AEs, laboratory tests, vital signs and body weight will be presented separately for 
the treatments, labelled "BI 1026706" and "Placebo". 
CTR Section 15, Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 AE displays will present 
results for these study treatments during on-treatment phases only, labelled as indicated 
above. Screening, post-treatment and post-study periods will not be included in this analysis.
CTR Appendix 16.1.9.2.8.1 displays will present results for the following study analysis 
phases:

Screening

On-treatment (separately per study treatment listed above, labelled with the name of 
the respective study treatment)

Post-treatment (separately per study treatment listed above, labelled "Post-BI" and 
"Post-Placebo")

Post-study
In CTR Section 15 AE tables and CTR Appendix 16.1.9.2.8.1 displays, a total over both on-
treatment phases (i.e., BI 1026706 plus placebo, labelled "Total on-trt") will be provided in 
addition.
In CTR Appendix 16.1.9.2.8.1 displays, a total over all study phases (labelled "Total") will be 
provided in addition.
No total columns will be provided in CTR Appendices 16.1.9.2.8.2 and 16.1.9.2.8.3.


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Displays of laboratory tests, vital signs and body weight will present results by study 
treatment.
More details on the technical implementation of these analyses are provided in the analysis 
data set (ADS) Plan of this TSAP.
6.2
IMPORTANT PROTOCOL VIOLATION
Data discrepancies and deviations from the CTP will be identified for all subjects in the 
database (i.e., treated subjects and subjects with SAEs which the investigator considered 
related to the screening procedure). 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 combined blinded report 
planning meeting (BRPM) and database lock meeting (DBLM). At this meeting, it will be 
decided whether the discrepant data value can be used in analysis or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important protocol violation (PV). For definition of important PVs, and for 
the process of identification of these, refer to the Boehringer Ingelheim (BI) reference 
document "Protocol Violation Handling Definitions" (3).
If any important PVs are identified, they are to be summarised into categories and will be 
captured in the BRPM/DBLM minutes via an accompanying Excel spreadsheet (2). The 
following table contains the categories which are considered to be important PVs in this trial. 
If the data show other important PVs, this table will be supplemented accordingly by the time 
of the BRPM/DBLM.


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Table 6.2: 1
Important protocol violations
Category
/Code
Description
Identification
A
Entrance criteria not met
A1
Inclusion criteria violated
programmed
A2
Exclusion criteria violated
programmed
B
Informed consent
B1
Informed consent not available
programmed
B2
Informed consent too late
programmed
C
Trial medication and randomization
C1
Incorrect trial medication taken
manual
C2
Randomisation not followed
manual
C3
Non-compliance, which may risk the attainment of steady 
state reached at Visit 6 or 
the planned time of 14 hours between last drug 
administration and start of the bronchoscopy at Visit 7 is 
exceeded by more than 2 hours.
manual (see 
CTP Section 
4.3) and BRPM
C4
Medication code broken inappropriately
manual
C5
Incorrect route of intake of trial medication
manual
D
Concomitant medication
D1
Concomitant medication with potential influence on 
 
 primary/secondary endpoints, see CTP 
Section 4.2.1. 
BRPM
E
Missing data (for primary and secondary endpoints)
E1
Certain violations of procedures used to measure primary 
and secondary data
BRPM
F
Incorrect timing1
F1
Time difference between start of bronchoscopy at Visit 6 
and 7 deviates by more than 2 hours from 24 hours.
BRPM
G
Other trial specific important violations
G1
No or improper instillation of LPS challenge at Visit 6
manual
G2
AE in respiratory tract ongoing during bronchoscopy at Visit 
6 or 7.
manual
G3
BAL sampling at Visit 7 is not conducted in the segment 
with the respective challenge at Visit 6.
BRPM
G4
 
manual


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Category
/Code
Description
Identification
1 Time deviations will only be flagged as important PV, when leading to exclusion of the entire subject from an analysis set
Source: ‘Protocol Violation Handling Definitions’ [001-MCS-50-413_RD-01] (3)
6.3
SUBJECT SETS ANALYSED
All subjects who received study medication will be included in the safety analysis and in the 
analysis of pharmacodynamic (PD) and PK endpoints depending on the availability of 
measurement values, and on their adherence to the CTP.
The following analysis sets will be defined for this trial:

Enrolled set (ES)
This subject set includes all subjects who were screened for inclusion into the study, 
i.e., who were assigned a subject number.
It will be used for analyses of subject disposition.

Randomised set (RS):
This subject set includes all randomised subjects, i.e., who were assigned a 
randomisation umber, whether treated or not.
It will be used for analyses of subject disposition.

Treated set (TS):
This subject set includes all subjects in the RS 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.


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
Pharmacodynamic set (PDS):
This subject set includes all subjects in the TS who have evaluable cell counts 
measured after 24 hours of the segmental challenge in primary, secondary or further 
endpoints related to BAL assessment. Whether a subject has evaluable cell counts will 
be decided no later than in the BRPM (cf. CTP Section 7.3).
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to populations will be made at latest at the BRPM/DBLM.


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Table 6.3: 1
Subject sets analysed
Analysis set
Class of endpoint
ES
RS
TS
PDS
Primary and secondary endpoints and
further endpoints related to BAL 
assessment which were measured after 
24 hours of the segmental challenge
X
Safety endpoints 
X
Demographic/baseline endpoints
X
Important PVs
X
Disposition
X
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
The endpoints will be used as defined in the CTP, Section 7.4.
CTP: Missing safety and pharmacodynamic data will not be imputed.


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Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
In general, baseline is defined as the last measurement before first trial mediation intake at 
Visit 2. This applies e.g. to laboratory data, vital signs, body weight, and pulmonary function 
testing, exceptions are BAL assessments 
For endpoints related to BAL assessments, baseline is defined as the measurement at Visit 6.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked via the consistency check listings at the BRPM/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" (001-MCG-159) (6).
The individual values of all subjects will be listed, sorted by treatment group, subject number
and visit (if visit is applicable in the respective listing). AE listings will be sorted by assigned 
treatment (see Section 7.8.1 below for details). The listings will be contained in Appendix 
16.2 (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
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 are actually missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR, based on the TS.
The data will be summarised for each treatment group and in total.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the CTR, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of 
 PD will be decided no 
later than at the BRPM/DBLM.  
7.4
PRIMARY ENDPOINT
As described in CTP Section 7.3.1, the primary analysis of the primary endpoint will be an 
analysis of variance (ANOVA) on the log-transformed scale, based on the PDS. The ANOVA 
model is described in CTP Section 7.1.3.
As described in CTP Section 7.2, the primary endpoint is subject of a confirmatory statistical 
hypothesis test, based on the primary analysis:
H0: geometric mean ratio, i.e. T/R, of the primary endpoint is 1.
Ha: geometric mean ratio, i.e. T/R, of the primary endpoint is not equal to 1.
H0 will be rejected if its p-value is ≤ 0.1.
Ha is a two-sided alternative hypothesis; testing this hypothesis at the 10% significance level 
is equivalent to using two one-sided tests, each at the 5% significance level.
No other confirmatory statistical hypothesis tests will be conducted in this trial.


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Descriptive statistics and boxplots of the primary endpoint by treatment will also be provided.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the CTP.
7.5.2
Secondary endpoints
As described in CTP Section 7.3.2, secondary endpoints will be statistically assessed using 
the same methods as described for the primary analysis of the primary endpoint, based on the 
PDS.
No confirmatory statistical hypothesis tests will be conducted based on the secondary 
endpoints.
Descriptive statistics and boxplots of the secondary endpoints by treatment will also be 
provided.


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7.6.3
Endpoints related to safety assessments
These endpoints will be analysed based on the TS.
For analysis related to AEs, refer to Section 7.8.1.
CTP: For weight the measurements per time point and the difference from baseline for the 
on-treatment measurements will be analyzed descriptively.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by actual treatment.
Data of screened subjects, who withdrew after screening examination but prior to treatment, 
will not be included in the CTR. Exceptions are screen-failed subjects who had an SAE after 
the screening period, which was considered by the investigator to be related to the screening 
procedure. The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs. 
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy 
required, seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the later occurrence started at most 1 hour after the first 
occurrence ended).
For further details on summarization of AE data, please refer to 'Handling and summarization 
of AE data for clinical trial reports and integrated summaries' (8) [001-MCG-156] and 
"Handling of missing and incomplete AE dates" (4) [001-MCG-156_RD-01].
The analysis of AEs will be based on the concept of TEAEs. That means that all AEs will be 
assigned to the treatment, post-treatment, screening or post-study phases as defined in Section 
6.1.
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 and for the class of 
AESIs.


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CTP: The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST and/or ALT > 3 fold upper limit normal (ULN) combined with an 
elevation of total bilirubin > 2 fold ULN measured in the same blood draw sample, 
and/or

marked peak aminotransferase (ALT and/or AST) elevations ≥10 fold ULN
The investigator had to classify in 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 with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or AEs which lead to significant 
concomitant therapy as identified by the Clinical Monitor/Investigator at the BRPM. 
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class and preferred term. This summary table will be shown based on all reported AEs. 
Furthermore separate tables will be presented for the frequency of subjects with procedural 
on-treatment AEs, the frequency of subjects with LPS related on−treatment AEs, and the 
frequency of subjects with non-procedural and non-LPS-related on-treatment AEs. AEs which 
were considered by the investigator to be related to the investigational study drug will be 
summarised separately. Separate tables will be provided for subjects with SAEs, subjects with 
AESIs and subjects with other significant AEs (according to ICH E3 (9)). AEs will also be 
summarised by maximum intensity.
The system organ classes will be sorted according to the standard sort order specified by the 
European Medicines Agency (EMA), preferred terms will be sorted by total frequency (within 
system organ class). The MedDRA version number will be displayed as a footnote in the 
respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% (in 
preferred terms) for at least one treatment will be summarised by treatment, primary system 
organ class and preferred term.
For disclosure of AE data in the European Union Drug Regulating Authorities Clinical Trials
(EudraCT) register, additional information not included in a standard AE analysis will be 
performed. The following three entries will be created:

AEs per arm for disclosure on EudraCT

Non-serious AEs for disclosure on EudraCT

Serious AEs for disclosure on EudraCT


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(10). If possible, analyses will be based on original values. If multiple reference ranges apply 
for a parameter (e.g. due to different age groups), analyses will be based on normalised 
values, which means transforming to a standard unit and a standard reference range.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7, for on-treatment measurements) will be provided. Frequency tables of changes 
between baseline and last value on treatment with respect to the reference range will be 
presented.
CTP: Values outside the reference range as well as values defined as clinically relevant will 
be highlighted in the listings.
Urine dipstick data will neither be listed nor analysed.
Clinically relevant abnormal findings in laboratory data as judged by investigator will be 
reported as AEs (CTP Section 5.3.3) and will be analysed as part of AE analysis. Standard or 
project-specific rules for flagging clinically significant values will not be applied in this study.
7.8.3
Vital signs
The analyses of vital signs will be descriptive in nature. Descriptive statistics of vital signs 
over time and for the difference from baseline (see Section 6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as AEs and will be analysed as 
part of AE analysis.
7.8.4
ECG
Clinically relevant findings in ECG data will be reported as AEs and will be analysed as part 
of AE analysis.
7.8.5
Others
7.8.5.1
Physical examination findings
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of first study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.
7.8.5.2
Pulmonary function testing
CTP: For the measurements obtained from the pulmonary function testing, descriptive 
statistics over time and for the differences from baseline will be evaluated.


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7.9.1
Smoking status
Smoking status at Visit 2, Visit 4 and Visit 6 will be listed, together with the stop date, if 
applicable, and the date and time of the last cigarette smoked prior to bronchoscopies at Visit 
6 and 7 and the start date and time of the respective bronchoscopies.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCS-50-413_RD-02: “Important Manual Protocol Violations Spreadsheet”, current 
version, IDEA for CON.
3
001-MCS-50-413_RD-01: “Protocol Violation Handling Definitions”, current version, 
IDEA for CON.
4
001-MCG-156_RD-01: “Handling of missing and incomplete AE dates”, current 
version; IDEA for CON.
6
001-MCG-159: “Reporting of clinical trials and project summaries”, current version; 
8
001-MCG-156: “Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries”, Version 5; 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.


Boehringer Ingelheim
TSAP for BI Trial No: 1320.17
Page 34 of 35
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No: 1320.17
Page 35 of 35
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
23-MAR-2017
,
None
This is the final TSAP without any 
modification