Clinical trial NCT03135899
Conditions: Asthma
Sponsor: Boehringer Ingelheim
Start date: 2017-05-18; Completion date: 2018-02-21
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objective of this study is to investigate safety and tolerability of three consecutive administrations, 12 hours apart, at three different dose-levels of BI 443651 administered via oral inhalation in male and female mild asthmatic subjects after a bolus methacholine challenge.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 443651 intervention 2: Placebo
Intervention descriptions: intervention 1: Three doses, each 12 hours apart intervention 2: Three doses, each 12 hours apart

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c11830963-01
EudraCT No.:
EU Trial No:
2016-001506-42  
BI Trial No.:
1363.7
BI Investigational 
Product(s):
BI 443651
Title:
A two part phase I, multiple-dose, single- and double-blind
randomised, double-dummy, placebo-controlled, four-way 
crossover study to assess safety and tolerability of BI 443651 via 
Respimat® versus placebo via Respimat® in subjects with mild 
asthma following methacholine challenge.
Lay Title:
BI 443651 Methacholine challenge
Clinical Phase:
Phase I
Trial Clinical 
Monitor:
Tel: 
                  Fax:  
Coordinating 
Investigator:
Tel: 
       Fax: 
Status:
Final Protocol
Version and Date:
Version: 1.0
Date: 23 February 2017
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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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 443651
Protocol date:
23 February 2017
Trial number:
1363.7
Revision date:
Title of trial:
A two part phase I, multiple-dose, single- and double blind
randomised, double-dummy, placebo-controlled, four-way 
crossover study to assess safety and tolerability of BI 443651 via 
Respimat® versus placebo via Respimat® in subjects with mild 
asthma following methacholine challenge.
Coordinating
Investigator:
Trial site(s):
At least 1
Clinical phase:
I
Objective(s):
The primary objective of the study is to investigate safety and 
tolerability of three consecutive administrations, 12 hours apart, at 
three different dose-levels (100, 400 and 1200 µg) of BI 443651 
administered via oral inhalation in male and female mild asthmatic 
subjects after a methacholine challenge.
Methodology:
Part 1(pilot study):  Multiple dose, single blind, double dummy, 
randomised, 4-way crossover with dose ordered sequences;
Part 2 (main part); Multiple dose, double blind, double-dummy, 
randomised, 4-way crossover.
No. of subjects: 
At least 36


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 443651
Protocol date:
23 February 2017
Trial number:
1363.7
Revision date:
total entered:
At least  36
each treatment:
Part 1:  Minimum 4 completed subjects
Part 2: Minimum 32 completed subjects
Diagnosis :
Mild asthma
Main criteria
for inclusion:
Male and female subjects, age ≥18 and ≤ 60 years, on SABA prn ± 
low dose inhaled corticosteroid only, FEV1 ≥ 70% predicted, PD20
≤ 1 mg, BMI range: ≥18.5 and ≤32.0 kg/m2
Test product:
BI 443651
dose:
100 µg, 400 µg or 1200 µg BI 443651, three consecutives 
administration 12h apart.  
mode of 
administration:
Oral inhalation via the Respimat® 
Comparator products:
Placebo
dose:
N/A
mode of 
administration:
Oral inhalation via the Respimat® 
Duration of treatment:
4 test periods, each separated by a wash-out of at least 14 days
Endpoints
Primary endpoint:
Absolute change from baseline in maximum FEV1 reduction 
following methacholine (MCh) challenge.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 443651
Protocol date:
23 February 2017
Trial number:
1363.7
Revision date:
Secondary endpoints:
Relative change from baseline in FEV1 AUC0-tz following MCh 
challenge; Time to recovery of FEV1 to within 95% of post-diluent 
value.
Safety criteria:
Related AEs (including clinically relevant findings from the physical 
examination), vital signs (BP, PR), 12-lead ECG, safety laboratory 
tests (blood, urine).
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
The primary endpoint absolute change from baseline in maximum 
FEV1 reduction following MCh challenge and the secondary endpoint 
relative change from baseline in FEV1 AUC0-tz following MCh 
challenge will be analysed using mixed effects models on the original 
and logarithmic scale, respectively.
The secondary endpoint time to recovery of FEV1 to within 95% of 
post-diluent value will be analysed using Kaplan-Meier plots and a 
cox proportional hazards model.


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FLOW CHART
1.
Visit structure 
The trial consists of a screening period (Visit 1), pilot and main study periods (Visit 2 to 5) and end of study period (Visit 6). The pilot and main 
study each consist of four separate treatment periods, each separated by at least 14 days wash-out.   For administrative reasons, each of these 
four treatment periods within the pilot and main studies is referred to as a ‘Visit’ and each ‘Visit’ will consist of up to 3 days of procedures (see 
table below). The procedures conducted at each of the treatment period ‘Visits’ (Visit 2 to 5) are the same and are briefly summarized in the 
following chart.  The ‘summary of study procedures’ flow chart provided below provides a more detailed overview.
‘Visit’
‘Days’
Summary of Procedures
Screening Period
1
-14  to  -3
Screening procedures; incremental methacholine (MCh) challenge
Part 1 (Pilot Study)
Treatment Period 1
2
-2 to +2
Day -1 (-2*) – Ambulatory Visit – Baseline bolus MCh challenge
Day 1 – Admission to trial site, baseline safety assessments including measurement of 
electrolytes, randomisation to treatment; dose administration (a.m); dose 
administration (p.m), spirometry
Day 2 - Dose administration (a.m), bolus MCh challenge, 
measurement of electrolytes.
Treatment Period 2
3
-2 to +2
Day -1 (-2*) – Ambulatory Visit – Baseline bolus  MCh challenge
Day 1 – Admission to trial site, baseline safety assessments including measurement of 
electrolytes,; dose administration (a.m); dose administration (p.m), spirometry
Day 2 - Dose administration (a.m), bolus MCh challenge, 
 
measurement of electrolytes.


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FLOW CHART – CONT-D
Treatment Period 3
4
-2 to +2
Day -1 (-2*) – Ambulatory Visit – Baseline bolus MCh challenge
Day 1 – Admission to trial site, baseline safety assessments including measurement of 
electrolytes,; dose administration (a.m); dose administration (p.m), spirometry
Day 2 - Dose administration (a.m), bolus MCh challenge, 
 
measurement of electrolytes.
Treatment Period 4
5
-2 to +2
Day -1 (-2*) – Ambulatory Visit – Baseline bolus MCh challenge
Day 1 – Admission to trial site, baseline safety assessments including measurement of 
electrolytes,; dose administration (a.m); dose administration (p.m), spirometry
Day 2 - Dose administration (a.m), bolus MCh challenge, 
 
measurement of electrolytes.
Part 2 (Main study)
Treatment Period 1
2
-2 to +2
As Part 1 – Treatment Period 1
Treatment Period 2
3
-2 to +2
As Part 1 – Treatment Period 2
Treatment Period 3
4
-2 to +2
As Part 1 – Treatment Period 3
Treatment Period 4
5
-2 to +2
As Part 1 – Treatment Period 4
For both parts
End of Treatment
6
Spirometry, laboratory tests, physical examination, vital signs, ECG
*Assessments may be conducted over a period of 2 days to allow for flexibility in subject scheduling.


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2
Summary of study procedures
Period
Visit
Day
Planned time (relative
to drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]26
Event and comment16
Spiromety 3,25
 
Medical examination
12-lead ECG
Vital signs (BP, PR)
Safety lab 19,20,21,22
Screen1
1
-14 to -36
Screening procedures2 
,
Incremental MCh 
challenge to determine 
PD207
X
X
X
X
X
Period 1-4 -Four identical periods with a 
washout  of at least 14 days and no more 
than 28 days 8
2/3/4/5 
-2 to -16
-48:005
Ambulatory Visit
  X11
X
Morning
Baseline bolus Mch 
challenge 9,
  X23
16
06:00
Admission to trial site12
Device instruction10
Allocation to treatment,13
X
X
X
X
-0:304
07:30
0:00
08.00
Drug administration10, 14
0:10
08:10
X
0:20
08:20
X
0:30
08:30
X
0:45
08:45
X
1:00
09.00
X
X
X
1:30
09:30
X


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2.
Summary of study procedures – cont-d
Period
Visit
Day
Planned time (relative
to drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]26
Event and comment16
Spiromety 3,25
 
Medical examination
12-lead ECG
Vital signs (BP, PR)
Safety lab 19,20,21,22
2:00
10.00
breakfast
X
2:30
10.30
X
3:00
11.00
X
4:00
12.00
lunch
X
6:00
14.00
X
8:00
16:00
snack (voluntary)
10:00
18:00
dinner
11:30
19.30
X
X
X
12:00
20.00
Drug administration14
12:10
20.10
X
12:30
20.30
X
13:00
21.00
snack (voluntary)
X
X
14:00
22.00
X
26
23:00
07:00
X
X
X
23:30
07:30
24:00
08:00
Drug administration14
250mL water intake
24:10
08:10


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2.
Summary of study procedures – cont-d
Period
Visit
Day
Planned time (relative
to drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]26
Event and comment16
Spiromety 3,25
 
 
Medical examination
12-lead ECG
Vital signs (BP, PR)
Safety lab 19,20,21,22
24:45
08:45
X
X
25:00
09:00
Bolus MCh challenge 9
X18
25:30
09:30
26:00
10:00
250mL water intake, 
thereafter breakfast
27:00
11:00
28:00
12:00
250mL water intake, 
thereafter lunch
32:00
16:00
snack (voluntary)
33:00
17:00
Discharge from trial site
X
X
X21
End of Treatment 
6
+146, 27, 15
End of trial (EOT) 
examination15
X
X
X
X
X


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Guidance Notes
1
    All subjects must sign an informed consent consistent with ICH-GCP guidelines
     prior to participation in the trial, which includes medication washout and  
    restrictions.
2
Screening within 14 days before drug administration including review of inclusion
    and exclusion criteria, relevant  medical history, demographics, concomitant 
medication, physical examination and review of vital signs/ECG/laboratory,
    Flexibility in scheduling and repeating screening or baseline procedures according 
to investigator judgement is permitted. Patient’s consent can be obtained prior to 
the screening period.
3
Spirometry is performed at the screening visit (Visit 1) and Treatment period 1 – Day 
1 to determine eligibility for participation in the study. 
Treatment Periods 2 to 4 – Day 1, eligibility to dose based on the predose FEV % of 
predicted will be assessed by clinical judgment of the investigator. 
Prior to methacholine challenge the subject’s FEV1 should be within the range (≥ 
70% of predicted normal*) on Day -2 to Day -1 and at Day 2 at Visits 2-5 (Treatment 
Periods 1 to 4)
*Clinical judgement may be applied in borderline cases.
4
 
5
Timepoint included for technical (database set-up) reasons only
6
  AEs and changes in concomitant therapies will be monitored and recorded 
  throughout the trial
7
Incremental MCh challenge during Visit 1 will use an escalation protocol to 
determine the PD20 in a given volunteer.
8
In exceptional circumstances, the washout between the two treatment periods can be 
extended up to a maximum  of 8 weeks
9
Bolus MCh challenge performed at Day -2 to Day -1 and Day 2 of each treatment 
period (Visits 2-5) will follow a single dose equal to the sum of all doses given 
during the escalation (incremental ) protocol at Visit 1 (i.e: the cumulative dose) . 
The start of the MCh challenge will be scheduled on the time point, and will be 
considered as the time of the first inhalation of methacholine solution.
10
Subjects will be instructed in the use of the Respimat® at Visit 1. Inhalation technique
(using trial medication) will be observed at subsequent clinic visits and instruction in 
correct use will be reinforced as needed.


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Guidance Notes Cont-d
11
  A targeted medical examination (heart, lungs) should be performed at the start of
each treatment period (Visit 2 -5). 
12
The time is approximate; the respective procedures are to be performed and
  completed within 2 hours prior to drug administration.
13
Allocation to treatment only at Visit 2 (i.e: Treatment Period 1- Day 1)
14
Drug inhalation will take place under supervision at the trial site at each of the 
treatment periods (Visits 2 – 5)  
15
The follow up visit should be scheduled at least 14 and no more than 28 days after 
completion of the final treatment period
16
At timepoints where several tasks or procedures are planned pre-dose, the following 
sequence should be followed insuring that 
 take priority with regards to 
timing:
1. Blood for safety assessments 
2. ECG
3  Vital signs
4.  PFTs
NB:  A snack is allowed (if completed) 1 hour prior to the morning dose.
At timepoints where several tasks or procedures are planned post dose, the following 
sequence should be followed ensuring that 
 take priority with regards to 
timing:
1. ECGs
2. Vital signs
3. Blood for safety assessments
5. PFTs   (on the time-point - Day 1)
6. Meals
NB : On Day 2 in the event that there is a timepoint clash with 
 and post 
methacholine spirometry the post methacholine spirometry is to be prioritised on the 
timepoint and the 
 to be taken as close as possible to the planned time (using 
permitted windows).


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Guidance Notes Cont-d
 
18
Spirometry to be performed pre-MCh challenge, post-diluent and post methacholine 
dose.  Post-methacholine spirometry (FEV1 only) timepoints will be relative to the 
last exhalation of methacholine solution and will be scheduled as single 
measurements at 30 seconds and 90 seconds, followed by duplicate measurements
(FEV1 and FVC) at 5,10, 20, 30,45 minutes, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 
3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0 and 8.0 hours
19
Central laboratory: Central laboratory testing (full laboratory screen) will be 
performed at the screening visit (Visit 1) and on completion of the study (EOT visit / 
Visit 6).  Details of the tests required are provided in Section 5.3.3.
20
For female subjects: Blood HCG will be performed at screening to confirm eligibility 
(central laboratory)
21
Electrolytes will be measured prior to start of trial procedures and prior to discharge 
from the clinic on conclusion of trial procedures at each of the treatment periods 
(Visits 2 to 5). Initial assessment will be performed by local laboratory.  In addition 
to local testing, a sample for electrolytes will also be sent to the central laboratory. 
22
If  any significant laboratory test abnormalities are detected, specifically liver 
function tests, the subject should return to the clinic for repeat testing
23
Spirometry to be performed pre-MCh challenge, post-diluent and post-methacholine 
dose. Post-methacholine spirometry (FEV1) timepoints will be relative to the last 
exhalation of final methacholine solution and will be scheduled as single 
measurements at 30 seconds and 90 seconds, followed by duplicate measurements 
(FEV1 and FVC) at 5, 10, 20, 30, 45 minutes, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75 
and 3.0 hours
24
Must be completed within 30 minutes prior to drug administration
25
FEV1 and FVC in triplicate, unless otherwise specified
26
The cumulative times specified in the planned time column are for orientation only.  
Depending on the actual a.m dosing time at the given day, the procedures and 
observations related to that a.m dosing (such as pre a.m dose and post a.m dose 
measurements of the same day) have to be adapted respectively.
27
The end of treatment (EOT) visit should be scheduled no earlier than 14 days after 
the last dose of study medication.  In the event of early discontinuation, an additional 
earlier visit may be scheduled at investigator discretion.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL.......................................................................................... 1
TITLE PAGE........................................................................................................................... 1
CLINICAL TRIAL PROTOCOL SYNOPSIS..................................................................... 2
FLOW CHART ....................................................................................................................... 5
TABLE OF CONTENTS...................................................................................................... 13
ABBREVIATIONS................................................................................................................ 16
1.
INTRODUCTION .............................................................................................. 18
1.1
MEDICAL BACKGROUND............................................................................. 18
1.2
DRUG PROFILE................................................................................................ 20
1.2.1
Nonclinical pharmacology ................................................................................. 20
1.2.2
Safety pharmacology.......................................................................................... 21
1.2.3
Toxicology............................................................................................................ 21
1.2.5
Drug product....................................................................................................... 23
1.2.6
Clinical experience in humans........................................................................... 23
1.2.7
Prediction of human pharmacokinetics........................................................... 27
2.
RATIONALE, OBJECTIVES, AND BENEFIT – RISK ASSESSMENT .... 29
2.1 
RATIONALE FOR PERFORMING THE TRIAL......................................... 29
2.2 
TRIAL OBJECTIVES ....................................................................................... 30
2.3
BENEFIT - RISK ASSESSMENT.................................................................... 30
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION......................... 33
3.1     
OVERALL TRIAL DESIGN AND PLAN....................................................... 33
3.1.1
Administrative structure of the trial................................................................ 35
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)...................................................................................... 36
3.3
SELECTION OF TRIAL POPULATION...................................................... 36
3.3.1
Main diagnosis for trial entry............................................................................ 37
3.3.2 
Inclusion criteria................................................................................................. 37
3.3.3
Exclusion criteria............................................................................................... 37
3.3.4
Removal of subject from therapy or assessments............................................ 40
3.3.4.1
Removal of individual subjects ............................................................................ 40
3.3.4.2 
Discontinuation of the trial by the sponsor........................................................... 41
3.3.5
Replacement of subjects.................................................................................... 42
4
TREATMENTS .................................................................................................. 43
4.1    
INVESTIGATIONAL TREATMENTS........................................................... 43
4.1.1
Identity of the Investigational Medicinal Products ........................................ 43
4.1.2
Selection of doses in the trial ............................................................................. 44


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4.1.3
Method of assigning subjects to treatment groups......................................... 44
4.1.4
Drug assignment and administration of doses for each subject.................... 45
4.1.5
Blinding and procedures for unblinding ......................................................... 46
4.1.5.1
Blinding ............................................................................................................... 46
4.1.5.2
Unblinding and breaking the code........................................................................ 46
4.1.6 
Packaging, labelling, and re-supply.................................................................. 47
4.1. 7 
Storage conditions............................................................................................... 47
4.1.8
Drug accountability........................................................................................... 47
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES.......................... 49
4.2.1
Other treatments and emergency procedures.................................................. 49
4.2.1.1
Rescue medication................................................................................................ 49
4.2.2
Restrictions.......................................................................................................... 50
4.2.2.1
Restrictions regarding concomitant treatment...................................................... 50
4.2.2.2
Medication Restrictions (for Pulmonary Function Testing)................................ 52
4.2.2.3
Restrictions on diet and life style ......................................................................... 52
4.2.2.4
Restrictions regarding women of childbearing potential..................................... 53
4.3
TREATMENT COMPLIANCE....................................................................... 53
5. 
VARIABLES AND THEIR ASSESSMENT.................................................... 53
5. 1
TRIAL ENDPOINTS ........................................................................................ 53
5.1.1
Primary Endpoint(s)........................................................................................... 54
5.1.2
Secondary Endpoint(s)....................................................................................... 54
5.2
ASSESSMENT OF EFFICACY........................................................................ 55
5.3
ASSESSMENT OF SAFETY ............................................................................ 55
5.3.1
Physical examination.......................................................................................... 55
5.3.2
Vital Signs............................................................................................................ 55
5.3.3
Safety laboratory parameters............................................................................ 56
5.3.4
Electrocardiogram.............................................................................................. 58
5.3.5
Other safety parameters .................................................................................... 58
5.3.6
Assessment of adverse events............................................................................ 58
5.3.6.1
Definitions of Aes................................................................................................ 58
5.3.6.2
Adverse event collection and reporting................................................................ 61
 
5.5
ASSESSMENT OF BIOMARKER(S)............................................................. 64
5.6
OTHER ASSESSMENTS................................................................................. 64
5.7
APPROPRIATENESS OF MEASUREMENTS............................................. 64
6.
INVESTIGATIONAL PLAN............................................................................ 66
6.1
VISIT SCHEDULE ............................................................................................ 66
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS................ 66
6.2.1
Treatment period(s)............................................................................................ 67


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6.2.2
End of Trial Period............................................................................................ 68
7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE69
7.1
STATISTICAL DESIGN – MODEL............................................................... 69
7.2
NULL AND ALTERNATIVE HYPOTHESES.............................................. 69
7.3
PLANNED ANALYSES..................................................................................... 69
7.3.1
Primary endpoint analyses ................................................................................ 70
7.3.2
Secondary endpoint analyses............................................................................. 71
7.3.5
Safety analyses .................................................................................................... 75
7.4
INTERIM ANALYSES..................................................................................... 76
7.5
HANDLING OF MISSING DATA................................................................... 76
7.5.1
Safety.................................................................................................................... 76
7.6
RANDOMISATION.......................................................................................... 77
7.7
DETERMINATION OF SAMPLE SIZE......................................................... 77
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY ................................................................................. 78
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT........................................................................................................... 78
8.2
DATA QUALITY ASSURANCE..................................................................... 79
8.3
RECORDS.......................................................................................................... 79
8.3.1
Source documents.............................................................................................. 79
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS.................................. 81
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY ...... 81
8.5.1
Collection, storage and future use of biological samples and corresponding 
data....................................................................................................................... 82
8.6
TRIAL MILESTONES...................................................................................... 82
9.
REFERENCES ................................................................................................... 83
9.1
PUBLISHED REFERENCES ........................................................................... 83
9.2
UNPUBLISHED REFERENCES ..................................................................... 87
10. 
APPENDICES..................................................................................................... 88
10.1   
HANDLING INSTRUCTIONS FOR RESPIMAT® INHALER FOR USE 
IN BI 443651 CLINICAL TRIALS................................................................... 88
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)......................................... 94


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AHR
Airway hyper-responsiveness 
 
 
BI
Boehringer Ingelheim
b.i.d.
bis in die (twice daily dosing)
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
BMI
Body Mass Index
BP
Blood Pressure
CF
Cystic Fibrosis
CfB
Change from baseline
CFTR
Cystic Fibrosis Transmembrane Conductance Regulator
CI
Confidence Interval
CML
Local Clinical Monitor 
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EudraCT
European Clinical Trials Database
EOT
End of Trial
FAS
Full Analysis Set
FC
Flow Chart
FIM
First-into-Man
GCP
Good Clinical Practice
GLI
Global Lung Function Initiative
GMP
Good Manufacturing Practice
HCG
Human chorionic gonadotrophin
HERG
Human Ether-A-Go-Go Related Gene
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IPVs
Important protocol violations
IRB
Institutional Review Board
ISF
Investigator Site File
i.v.
intravenous


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LABA
Long-acting β-adrenergic agonist
LAMA
Long-acting anti-muscarinic
LoEE
List of Essential Element 
LSDD
Last Subject Drug Discontinuation
MCh
Methacholine
MedDRA
Medical Dictionary for Drug Regulatory Activities
MEU
Medicines Evaluation Unit
OPU
Operative Unit
PD
Pharmacodynamics
PD20
Provocative dose causing a 20% decline in FEV1
PK
Pharmacokinetics
p.o.
per os (oral)
q.d.
quaque die (once a day)
RBC
Red Blood Count
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or 17harmacodynamics effects still likely to be present
SABA
Short-acting β-adrenergic agonist
SAE
Serious Adverse Event
s.c.
Subcutaneous
SPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSARS
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
TSH
Thyroid stimulating hormone
WBC
White Blood Cells


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
 
 
CF and COPD are chronic respiratory disorders characterised by airflow obstruction. Cystic 
fibrosis is a lethal, inherited, multi-organ disease due to exocrine gland dysfunction that 
predominantly affects the lower respiratory tract and pancreas leading to chronic respiratory 
failure and pancreatic insufficiency. Despite recent advances, over 90% of patients surviving 
the neonatal period will develop pulmonary involvement and at least 90% will die due to 
pulmonary complications [P96-3855]. The median age of death remains below 40 years old 
[R15-5546].  COPD prevalence is still rising due to increased smoking, particularly among 
women and adolescents. Only smoking cessation has been proven to alter the course of 
disease and 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. By 2030, COPD will be the third leading cause of death worldwide 
[R15-3034]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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BI 443651 has been observed to inhibit acetylcholinesterase with augmented effects in non-
clinical acetylcholine (ACh) / methacholine (MCh) challenge guinea pig models, 
demonstrating an increase in pulmonary resistance compared to the prior challenge 
[c02337864]. This effect is not related to the primary target 
 i.e., it is an 
off target effect for BI 443651. A rapid return to baseline after challenge was observed both 
with, and without administration of BI 443651. No effect of BI 443651 administered in 
isolation (without ACh/MCh challenge) was observed on pulmonary resistance in this guinea 
model. In addition, no adverse respiratory effects were detected in the 4-week toxicology 
studies in rats and dogs or in the safety pharmacology studies at doses of up to 7,750 μg/ kg 
in dogs. 
Airway hyper-responsiveness (AHR) to methacholine challenge is a marker of airway hyper-
reactivity associated with alteration in vagal tone.  Patients with asthma have increased AHR 
to methacholine. The airway hyper reactivity and narrowing is caused by several mechanisms, 
but is primarily driven by the bronchial smooth muscle. Throughout normal ventilation 
bronchoconstriction is thought to be at least partially under the control of the cholinergic 
system [P92-1976]. Asthmatic patients have increased basal airway smooth muscle tone 
[Hashimoto A, 1996] which may result from increased basal activity of pulmonary 
parasympathetic cholinergic nerves i.e. increased cholinergic tone, although the degree to 
which cholinergic tone contributes to airway narrowing in asthmatics is unclear. Proposed 
mechanisms for the increased cholinergic tone include increased release of acetylcholine 
from cholinergic nerve endings P17-01614 and reduced levels of neuromodulators that 
attenuate cholinergic neurotransmission R17-0519, P09-06255. Inhibition of 
acetylcholinesterase could alter cholinergic tone by reducing the degradation of 
acetylcholine, thus leading to bronchoconstriction. The guinea pig ACh/ MCh model 
represents a sensitive model of cholinergic effects, and although the pre-clinical data suggests 
there is no safety concern in patients in an unchallenged state, theoretically 
bronchoconstriction could be observed particularly in patients with heightened cholinergic 
tone. 
Whilst AHR has been observed in patients with CF and COPD [P16-04040, R16-1628, R16-
1652], it is not clear whether this is a direct consequence of the disease or concomitant 
asthma. AHR is not directly correlated with the disease as it is in asthma [R16-1630]. Asthma 
patients represent the most sensitive population of patients with obstructive airways disease
to assess possible adverse effects of acetylcholinesterase inhibition. 
In summary, there is an unmet need for treatments in CF and COPD. BI 443651 is expected 
to improve mucus hydration pulmonary function and reduce exacerbations. An off target 


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effect of BI 443651, aceylcholinesterase inhibition, has been observed in preclinical studies 
under challenge conditions only. The current clinical study is designed to understand 
potential consequences of this effect in a closely monitored sensitive population prior to 
progressing to larger scale studies. 
1.2
DRUG PROFILE
 
 For 
a detailed review see the investigator brochure [c02337864]
1.2.1
Nonclinical pharmacology
 
 
 
 
 
 
 
 
 
In the CEREP screen, BI 443651 revealed an inhibition of acetylcholine esterase with an IC50
value of 1.6 μM. Therefore, BI 443651 was tested in the model of acetylcholine (ACh)-
induced bronchoconstriction in anaesthetized guinea pigs. BI 443651 dose-dependently 
enhanced the magnitude of the ACh-induced bronchoconstriction by 51 and 117% at the 
doses of 80, and 160 μg/kg (reflecting 3.3 and 5 fold ED50) respectively. The potential 
reinforcement effect of BI 443651 on the cholinergic pathway tone was also assessed in the 
model of methacholine (MCh)-induced bronchoconstriction in anaesthetized guinea pigs. As 
with the ACh, BI 443651 at doses of 80 and 160 μg/kg also enhanced the magnitude of the 
MCh-induced bronchoconstriction’s. Inhalation of ipratropium at 60 μg/kg with Respimat® 
led to an instantaneous and full inhibition of MCh-induced bronchoconstriction in those 
studies in which ipratropium was administered


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1.2.2
Safety pharmacology
 
 
 
 
 
Further details of the safety pharmacology studies are provided in the Investigator Brochure 
(c02337864).
1.2.3
Toxicology
BI 443651 did not demonstrate systemic adverse effects in repeat-dose toxicity studies in 
dogs.
 
 
 


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In two in-vitro tests and one in-vivo test, BI 443651 was non-genotoxic. BI 443651 was not a 
locally irritant or and was not phototoxic.
In summary, the non-clinical safety data of BI 443651 support clinical Phase I trials in 
healthy volunteers or patients with inhaled administration for up to 4 weeks.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.5
Drug product
BI 443651 is delivered via the Respimat® as an inhalation solution contained in a drug 
reservoir / cartridge inserted into the inhaler. Several solutions, including a placebo solution, 
with different drug substance concentrations have been developed for use in clinical studies 
(delivered strengths of 10 μg, 100 μg and 300 μg BI 443651 per actuation ex-mouthpiece). A 
spray volume of 11.05 μL per actuation is nebulized by the device. 
1.2.6
Clinical experience in humans
 
 
 
 
 
 
 
The safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of BI 443651 
have been investigated in a randomised, single-blind and placebo-controlled trial in healthy 
male subjects, study 1363.1 [c02861250-03]. The First-into-Man (FIM) study is complete 
with single inhaled doses of 10, 30, 100, 300, 900, 1800, 2700, 3600 μg or their matching 
placebo administered to 63 healthy male volunteers. Details are provided below for both PK
and safety.
Summary of PK data from SRD trial (study 1363.1)
 
 
 
 
 
 
 
 
 


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Table 1.2.6:1
Pharmacokinetic parameters and geometric mean (gCV %) of BI 443651 following a single dose administration of 10 to 
3600 g BI 443651 in healthy male subjects in study 1363.1
 
 
 
 
 


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Summary of clinical safety data from SRD trial (study 1363.1) 
Safety, tolerability and pharmacokinetics of BI 443651 have been investigated in a partially
randomised (within dose groups), single-blind, placebo-controlled trial (study 1363.1). This
First-into-Man study included single inhaled doses of 10, 30, 100, 300, 900, 1800, 2700 and
3600 μg or placebo administered via the Respimat device to 63 healthy male volunteers (47
on BI 443651). 
Adverse events were reported by 16 of 47 subjects (34.0 %) following treatment with BI 
443651 and 4 of 16 subjects (25.0 %) following treatment with placebo.
Ten of 47 subjects (21.3%) experienced AEs that were regarded by the investigator as
possibly related to the administration of study drug, all from the BI 443651 treatment groups.
These include cough (7 subjects), throat irritation (2 subjects), dysphoria (1 subject) and
headache (1 subject).
All AEs were of mild or moderate intensity and recovered or were sufficiently characterized
by follow-up. There were no severe nor serious AEs reported. The most frequently reported
AE was headache, observed in 7 of 47 subjects (14.9%) after BI 443651 treatment without
dose ordering. One subject reported headache in the placebo group (6.3%).
Cough was reported in 7 subjects (14.9%) receiving BI 443651 in a dose ordered fashion: 1 
subject at1800 μg, 3 subjects at 2700 μg and 3 subjects at 3600 μg. No subjects receiving 
placebo reported cough. 
Throat irritation was reported by 3 subjects (6.4%) receiving 1800, 2700 and3600 μg (1 
subject in each dose group) of BI 443651, while none in the placebo group.
With respect to the type, incidence and severity of AEs other than described above, there was
no notable difference between the dose levels. 
In summary, clinical safety data of trial 1363.1 showed that single doses of up 3600 μg
BI 443651 were well tolerated. A bitter taste was noted by all volunteers administered the
highest concentration (300 μg/inhalation), but not in the corresponding placebo group. A
reversible drop in FEV1 and FVC was observed in some volunteers. No clinically relevant
abnormalities were observed in ECG recordings, vital sign or safety laboratories. Adverse
events were broadly balanced across treatment and dose group with the exception of cough
and throat irritation prominently observed after single doses of BI 443651 equal or higher
than 1800 μg.
Further details of this study are provided in the Investigator Brochure (c02337864).


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1.2.7
Prediction of human pharmacokinetics
In order to assess expected exposures in a phase I multiple-dose study (1363.2), the
preliminary BI 443651 concentration-time data for doses up to 900 g available were fitted to 
a single first-order absorption and two-compartment body model for each subject. The 
modeled data were then used to simulate the planned doses. The predicted exposure data 
from the preliminary simulations are given in Table 1.2.7:1 below.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT – RISK 
ASSESSMENT
2.1 
RATIONALE FOR PERFORMING THE TRIAL
This is one of the two first multiple dose administration trials of BI 443651, the other study 
involving multiple dosing in healthy volunteers, COPD and CF patients. The objective of this 
study is to investigate the safety and tolerability of BI 443651 in male and female (of non-
child bearing potential) subjects with asthma using multiple orally inhaled doses to provide 
the basis for a potential ongoing clinical development of BI 443651. The study is designed to 
assess potential drug effects on pulmonary function due to an observed in vitro off target 
effect of acetylcholinesterase inhibition. Nonclinical assessment in in vivo models 
demonstrated dose dependent augmentation of pulmonary resistance following acetyl and 
methacholine challenge (see Section 1.2). 
Patients with asthma have increased airway hyper-responsiveness (AHR) to methacholine,
with chronic inflammation and increased AHR leading to symptoms such as shortness of 
breath by variable expiratory airflow limitation R97-1015. Airway hyper reactivity and 
narrowing is primarily driven by the bronchial smooth muscle, which is at least partially 
under the control of the cholinergic system [P92-1976]. Asthmatic patients have increased 
basal airway smooth muscle tone [Hashimoto A, 1996] which may result from increased 
basal activity of pulmonary parasympathetic cholinergic nerves i.e. increased cholinergic tone, 
although the degree to which cholinergic tone contributes to airway narrowing in asthmatics 
is unclear. Proposed mechanisms for the increased cholinergic tone include increased release 
of acetylcholine from cholinergic nerve endings P17-01614, and reduced levels of 
neuromodulators that attenuate cholinergic neurotransmission [R17-0519, P09-06255]. 
Inhibition of acetylcholinesterase could alter cholinergic tone by reducing the degradation of 
acetylcholine, thus leading to bronchoconstriction. The guinea pig ACh/ MCh model 
represents a sensitive model of cholinergic effects, and although the pre-clinical data suggests 
there is no safety concern in patients in an unchallenged state, theoretically 
bronchoconstriction could be observed particularly in patients with heightened cholinergic 
tone. Patients would asthma should be specifically sensitive to such effects and would 
represent a population in which to closely monitor for such effects.  
This study will derive pulmonary function data following the administration of methacholine 
in mild asthma subjects after 3 multiple administration of BI 443651 and will act as an early 
safety study prior to large scale studies in patients with obstructive airways disease.  By 
performing the study in subjects with asthma, safety information can be obtained in subjects s 
with hyper-reactive airways disease to fully explore possible induction of bronchoconstriction 
that may result due to inhibition of acteylcholinesterase as an off target effect of BI 443651. 
Administration of methacholine to asthmatics is considered to be the most sensitive method 
of assessing bronchoconstriction effects of an acetylcholinesterase inhibition in humans and 
will quantify the effects observed in the non-clinical studies. 
In summary this study aims to assess any potential deleterious effects on pulmonary function 
in man prior to large scale clinical trials.


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2.2 
TRIAL OBJECTIVES
The primary objective of this study is to investigate safety and tolerability of three 
consecutive administrations, 12 hours apart, at three different dose-levels (100, 400 and 1200 
µg) of BI 443651 administered via oral inhalation in male and female mild asthmatic subjects 
after a bolus methacholine challenge.
A description of the endpoints to be determined, and the observations along with specific 
information about how to collect the data, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
BI 443651 is being developed as a therapy for obstructive airways diseases such as cystic 
fibrosis and COPD. Participation in this study is without expected (therapeutic) benefit for 
asthmatic subjects. Their participation in the study is of importance to inform the safety 
profile of BI 443651 specifically with regard potential adverse effects on lung function prior 
to progressing to long term clinical studies. 
Subjects are exposed to risks related to the study procedures and intake of trial medication as 
described below.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venepuncture for blood sampling. 
Sampling times and visits may be adapted based on information obtained during trial conduct 
including addition of samples and visits The total volume of blood to be withdrawn during 
the entire study will not exceed 500mL (roughly equivalent to a normal blood donation). No 
study-related risk to study participants is expected from this blood withdrawal over the course 
of the study.
Methacholine (MCh) challenge is a routine practice in the diagnosis of asthma in the event of 
an unclear history or investigations. The main risk is of bronchoconstriction. Pulmonary 
function will be monitored and adverse findings can be reversed. Adverse effects are 
expected to be reversible with administration of an inhaled anticholinergic agent (ipratropium 
bromide) if necessary.
Drug-related risks and safety measures
The nature of the target and the mechanism of action of BI 443651, 
 are well 
documented. The side effect profile 
 is well 
understood and the adverse events observed in rats following administration of BI 443651 are 
consistent with the mechanism. 
 The animal models are believed to be predictive for the effects in 


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humans.
 
In study 1363.1, 63 
healthy male volunteers have been administered single inhaled doses of BI 443651 up 
to3600μg. In this study, BI 443651 was found to be well tolerated (see Section 
 
 
 
 
he most sensitive species for these effects was the rat with no relevant effects 
observed in the dog, even at high doses, on serum or urinary electrolytes. No other systemic 
safety findings were observed in either the toxicology or safety pharmacology studies.
 
 
 
 
 
 
 
 
 
 This translates to a safety margin of 
approximately 11-fold. The urine cover is regarded as the most relevant exposure for safety 
based mechanism i.e. serum electrolytes.
BI 443651 does not present a genotoxic hazard. BI 443651 is considered to be low risk for
phototoxicity, based on its absorbance pattern and lack of toxicity in 4-week repeat dose
studies.
Fertility has not been assessed in nonclinical species, but no adverse effects have been
observed on reproductive organs in 4-week toxicity studies in rats and dogs, suggesting that
there is a low risk to fertility. At the time this current study is planned to start embryo-fetal 
development studies of BI 443651 will not yet have been conducted.
Off target inhibition of ACh has been observed with augmented effects in non-clinical
ACh/MCh challenge guinea pig models. No adverse effects on pulmonary function were 
observed in the absence of methacholine or acetylcholine challenge. No adverse respiratory 
effects were detected in the 4-week toxicology studies or in the safety pharmacology studies 
at doses of up 7,750 μg/ kg in dog or rat. Exaggerated bronchoconstriction effects may be 
apparent following methacholine challenge however effects on respiratory function will be
monitored and are reversible. Inhaled anticholinergic therapy should reverse these effects if 
required, as is also used if required for MCh testing.
In summary whilst not all safety effects may be predicted, based on mechanism and systemic
toxicological finding the only potential systemic toxicity is changes in serum electrolytes and


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particularly increases in serum potassium. Augmented bronchoconstriction may be induced 
following administration of methacholine. In both cases these changes are easily monitored 
and treatable if observed. The following safety measures will be applied in this study in order 
to minimize the risk for the mild asthmatic subjects:
1
This study (1363.7) will only start once healthy volunteers have been safely 
administered 100 and 400 µg b.i.d. of BI 443651 for 7days in a separate ongoing 
study (1363.2) i.e. no stopping criteria have been triggered in 1363.2.
2
Only mild, controlled, stable asthma subjects with well-maintained lung function 
will be included in the study i.e. subjects on prn SABA or low dose inhaled 
corticosteroid with an FEV1 ≥70% 
 and no recent respiratory tract 
infection or exacerbation.  
3
The study will be split into two parts (see Section 3.1) with an initial pilot (Part 1)
to assess for gross adverse effects of BI 443651 on bronchoconstriction after MCh 
challenge. In Part 1, subjects will receive BI 443651 in a dose ordered fashion with
either placebo or the lowest dose first followed by the higher doses and placebo (if 
not taken first).  Individual subjects will not be dosed further if individual stopping 
criteria (including pulmonary function criteria) are triggered. Stopping criteria are 
described in detail in Section 3.3.4.
The second part of the study (not necessarily dose ordered) will only proceed if no 
subjects triggered the first three discontinuation criteria following administration of 
BI 443651 during Part 1.
4
The subjects will be closely monitored throughout the treatment period with 
frequent evaluation of pulmonary function following MCh challenge. Subjects may 
only be discharged from clinic after medical assessment has been conducted. The 
subject’s FEV1 must have returned to ≥ 90% of the first set of spirometry 
measurements performed that day before the subject can be discharged from the 
clinic. Rescue medication will be provided as required.
5
Safety laboratory testing will be performed during the study with a focus on 
electrolytes (see Flow Chart). The study will be stopped if, during Part 1 (pilot) at 
least 2 subjects in the current cohort or treatment period on active drug showed 
serum potassium levels ≥ 5.5mmol/L in non-haemolysed blood (confirmed by 
repeat). In Part 2 (main study), the study would be stopped if 4 subjects on active 
drug (independent of dose level) showed serum potassium levels ≥ 5.5mmol/L in 
non-haemolysed blood (confirmed by repeat).
Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely 
detection, evaluation, and follow-up of laboratory alterations in selected liver 
laboratory parameters to ensure subjects’ safety (see Section 5.3.6.1). 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1     
OVERALL TRIAL DESIGN AND PLAN
This multiple dose, randomised, placebo controlled, trial will be conducted in two parts. The 
first part (pilot study) will be a single-blind four-way crossover with dose ordered sequences.  
The second part (main study) will be a double-blind four-way crossover, conducted according 
to a William’s design. In both parts of the study, BI 443651 or placebo equivalent will be 
administered three consecutive times, 12 hours apart, per dose level. All subjects will receive 
placebo, 100, 400 and 1200 µg BI 443651 (in Part 1, the dose groups may be altered in case 
evolving data suggests a change in dosage is required (see below)).  Each period will be 
separated by a washout period of at least 14 days (and not more than 28 days). Two 
administrations of BI 443651 will be delivered on Day 1 (morning and evening) and a single 
administration Day 2 (morning). One hour after dosing on Day 2, MCh challenge will be 
performed. A methacholine challenge will be conducted on Day -2 to Day -1 for each
treatment period, (with the Day -2 to Day -1 challenge providing the baseline for each 
treatment period) at the same time of the day. 
The two parts of the study will be conducted as follows:
Part 1:  4 subjects will be included in the first pilot part of the study each being administered 
three active doses of BI 443651 and placebo, with the active doses investigated being in 
ascending order of dose strength. Placebo administered given in a single-blinded manner in 
any order relative to the active treatment as per Table 3.1:1.
Table 3.1:1
Sequences for pilot part of the study 
Treatment Period 1
Treatment Period 2
Treatment Period 3
Treatment Period 4
Placebo  
100 µg
400  µg
1200 µg
100 µg 
Placebo
400  µg
1200 µg
100 µg 
400  µg
Placebo
1200 µg
100 µg 
400 µg
1200  µg
Placebo
Part 2:  32 subjects will participate in the trial with each subject being administered three 
active dose levels of BI 443651 and placebo. This part of the study will be fully randomised, 
double blind. The decision to proceed to Part 2 will be based upon the safety and tolerability 
data of Part 1.  Part 2 will only be conducted if, in the opinion of the investigator, no safety 
concerns arose in Part 1 and if none of the pre-specified trial-specific stopping criteria were 
met (see Section 3.3.4.2).    


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Table 3.1:2
Sequences for main part of the study 
Treatment Period 1
Treatment Period 2
Treatment Period 3
Treatment Period 4
Placebo  
100 µg
400  µg
1200 µg
100 µg 
Placebo
1200  µg
400 µg
400 µg 
1200  µg
Placebo
100 µg
1200 µg 
400 µg
100  µg
Placebo
The first pilot part of the study will not be started until data from an ongoing multiple rising 
dose study (1363.2) in healthy volunteers is available from the first two dose groups (100 and 
400 µg b.i.d. BI 443651). Only if BI 443651 has been safely administered in study 1363.2 
and no stopping criteria have been met, will this study (1363.7) be started. 
In Part 1, dose groups will be investigated consecutively in ascending order of doses with a 
dose escalation review between each treatment period. Data from each treatment level will be 
reviewed prior to progression to the next treatment level. Only if the previous dose of BI 
443651 is safe and well tolerated, without meeting any stopping criteria in subjects 
administered BI 443651 (see Section 3.3.4.1), will the subsequent dose be administered
(Table 3.1:1).
In addition a documented Safety Review by the Coordinating Investigator (or an authorised 
deputy) and appropriate personnel from the Sponsor must take place prior to initiation of Part 
2 of the study. Only if BI 443651 is safe and well tolerated in all subjects in the pilot part 
without the specified number of subjects meeting any individual stopping criteria (see Section 
3.3.4.1), will the transition to Part 2 occur.
An unscheduled safety review meeting can be requested anytime for any reasonable cause by 
the Principal Investigator (or an authorised deputy) or the sponsor of the study, e.g. because 
of any unforeseen adverse events, etc. Dose escalation or transition to Part 2 will only be 
permitted if no safety concerns exist in the opinion of the Principal Investigator (or an 
authorised deputy) and the Trial Clinical Monitor (or an authorised deputy).The minimum 
data set for review consists of the following data:

Results from spirometry in all subjects included in the initial pilot part of the study  

AEs in all subjects including in the initial pilot part of the study,  up to at least 48h 
post dosing (including clinically relevant findings from ancillary safety testing listed 
below) (Note: AEs may be ongoing at the time of Safety Reviews and AE information 
may be subject to change prior to Database Lock)

Check of criteria for stopping subject treatment as per Section 3.3.4.1


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The decision to escalate the dose during the pilot study or transition to Part 2 of the study will 
be made jointly by the Co-ordinating Investigator (or an authorised deputy) and appropriate 
personnel from the Sponsor company after in-depth analysis of all available safety data, 
especially SAEs (if occurred), AEs and out-of-range laboratory results (if considered 
clinically significant). Safety Reviews can be conducted face-to-face or by video/telephone 
conference. The Trial Clinical Monitor is responsible for organization and minutes of the 
reviews. Minutes will be signed off by the Co-ordinating Investigator (or an authorised 
deputy) and filed in the ISF and TMF.
In the pilot study (Part 1), the investigator is allowed to alter the scheduled dose levels (e.g. 
add an intermediate dose level) within the planned and approved dose range on the basis of 
experience gained during the study. In this case, subjects may be required to participate in 
additional treatment periods or additional subjects may be enrolled. The investigator and/or 
the sponsor should stop dose escalation in case the safety evaluation leads to concerns that 
would not allow higher dosing.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI). A Coordinating Investigator has been 
appointed. The tasks and responsibilities of the coordinating investigator are defined in a 
contract. 
Relevant documentation on the participating Investigators and other important participants, 
including their curricula vitae, will be filed in ISF.
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 SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators.
The organisation of the trial will be performed by the respective local BI-organisation 
(Operating Unit, OPU) in accordance with applicable regulations and internal SOPs. 
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
The review of data generated in Part 1 of the study and confirmation of dose escalation 
procedures will be performed in accordance with relevant SOPs.


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Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
Central and local laboratory services will be used in this trial. Details will be provided in ISF.
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
For MCh challenge studies, the crossover design described in Section 3.1 is commonly 
employed to increase sensitivity due to the within subject comparison. An active comparator 
is not appropriate for this assessment and a placebo comparison is required as a negative 
control to quantify the nature of any response observed.
Subjects will be allowed to continue inhaled low dose corticosteroid and SABA use provided 
washout is undertaken prior to MCh challenge. The subjects will be on standard of care 
treatment for the severity of their disease and thus the use of placebo in this setting is 
considered acceptable.
The study will be conducted in two parts: Part 1 in 4 subjects in a dose escalating design and 
Part 2 in which doses may be administered according to a William’s crossover design (i.e. 
highest may be administered first). Three multiple dose levels of BI 443651 are included, to 
assess for a dose-effect relationship as observed in the nonclinical studies and also, in part 
one of the study to allow for effects to be assessed at lower doses prior to subjects being 
exposed to the highest dose as the initial dose (as may be allowed in Part 2 of the study). 
For the pilot part (Part 1), it is planned to include 4 asthma subjects. The planned sample size 
is not based on a power calculation. This sample size is considered sufficient for the initial
evaluation of safety post MCh challenge prior to allowing patients to be administered the 
highest dose of BI 443651 as the first dose level. 
For the main part (Part 2), it is planned to include a total of 32 (8 per sequence) subjects with 
mild asthma, because this sample size is considered sufficient to achieve the aims of this 
exploratory trial. For more details refer to Section 7.7. 
The cumulative bolus dose approach to MCh challenge is used during the treatment phases as 
the primary outcome is based on drop in FEV1 for a given dose rather than dose of MCh 
required to achieve a fall in FEV1.  
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.


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3.3.1
Main diagnosis for trial entry
Please refer to Section 8.3.1 for the documentation requirements pertaining to the inclusion 
and exclusion criteria.
3.3.2 
Inclusion criteria
1. Male or female subjects must have a diagnosis of asthma by a physician at least 3 months 
prior to screening (Visit 1). The diagnosis of asthma must meet the following spirometric 
criteria:
a.
Pre-bronchodilator clinic measured FEV1 ≥70% of predicted normal 
(calculated by the Global Lung Function Initiative equation (GLI)) [R15-
0845] measured ≥ 8 hours after the last use of short acting bronchodilator at 
the screening visit (Visit 1) and on the day of randomisation (Visit 2 i.e: 
Treatment Period 1 – Day 1)).
2.
Age ≥ 18 ≤ 60 years. Subjects must be within the eligible age range on the day of signing 
informed consent.
3.
Diagnosis of asthma must have been made before the subject's age of 40.
or
If the subject is ≥ 40 years and the diagnosis has not yet been recorded in the subject's 
medical files, the investigator should assess whether the subject's medical history (e.g. 
symptoms and prescribed medications) confirms the subject suffered from asthma since 
before the age of 40. If so, this subject may be considered for inclusion after consultation 
with the sponsor. 
4.
ACQ value < 1.5 at the screening visit (Visit 1).
5.
PD20 (Provocative dose causing at least a 20% decline in FEV1) at the screening visit
(Visit 1) of methacholine ≤ 1mg
6.
Body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m2 at the screening visit (Visit 1)
7.
Subjects must be able to perform all study related procedures and assessments, including 
pulmonary function tests, as required by the protocol. 
3.3.3
Exclusion criteria
In order to be eligible for inclusion in the study, the subject must not present with any of the 
following:
1.    Significant pulmonary diseases other than asthma (up to GINA treatment step 2) or 
other medical conditions* ( as determined by medical history, examination** and clinical 
investigations at screening) that may, in the opinion of the investigator result in any of 
the following:
a)
Put the subject at risk because of participation in the study


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b) Influence the results of the study
c) Cause concern regarding the subject’s ability to participate in the study.
*e.g: cardiovascular, gastro-intestinal, hepatic, renal, metabolic, immunological, 
dermatologic, neurological, haematological, oncological, hormonal and psychiatric. A 
malignancy treated by resection, radiation or chemotherapy within the past 5 years. 
Subjects with treated basal cell carcinoma or fully cured squamous cell carcinoma are 
allowed to participate in the study.
** includes clinically relevant abnormal blood pressure, pulse rate or ECG findings.
2.     Respiratory tract infection or asthma exacerbation in the 4 weeks prior to the screening 
visit (Visit 1).  Subjects can be rescreened 4 weeks after resolution of the infection or 
exacerbation.
3.    Hospitalisation for asthma exacerbation within 3 months or intubation for asthma  
within 3 years of the screening visit (Visit 1).
4.    History of relevant orthostatic hypotension, fainting spells, or blackouts.
5.    Major surgery (major according to the investigator's assessment) performed within 12 
weeks prior to randomisation.
6.    Clinically relevant (in the opinion of the investigator) abnormal baseline haematology, 
blood chemistry or urinalysis at the screening visit (Visit 1).
7.    Serum potassium measurement above the ULN at the screening visit (Visit 1).  Any 
value about the ULN excludes the subject irrespective of clinical relevance.
8.    A history of significant alcohol or drug abuse within the last 2 years
9.    Blood donation (more than 100mL within 30 days prior to the administration of trial 
medication or intended during the trial)
10.    Subjects who have been treated with any of the following asthma medications in the 
given interval prior to Visit 1 (see Section 4.2.2) :
o
Non-approved asthma therapies such as methotrexate, 
o
Intravenous, intramuscular or oral corticosteroids
o
Inhaled corticosteroids (iCS) other than low dose iCS (defined as equivalent to equal 
to, or less than 250 µg fluticasone / day) 
o
A long acting beta agonist or anticholinergic bronchodilator (Visit 1), including fixed
dose beta agonist/inhaled corticosteroid combinations and oral bronchodilators.
Note: Withdrawal of bronchodilators or reduction in iCS dose is not acceptable     
        unless for medical reasons.
o
A biological based antagonist therapy including Omalizumab, or immune modulators
o
Asthma controller medications (e.g: leukotriene modifier, methylxanthines, 
nedocromil or cromolyn sodium) 
o
Mucolytics 


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o
Systemically available immunomodulatory treatments for allergic rhinitis or atopic 
dermatitis.
11.     Use of any diuretics (including loop diuretics or potassium sparing diuretics (such as    
    amiloride), renin-angiotensin antihypertensive drugs in the 28 days prior to the  
          screening visit (Visit 1)
12.   Use of drugs that might reasonably influence the results of the trial or that might 
prolong the QT/QTc interval within 10 days prior to the randomisation visit (Visit 2
i.e: Treatment Period 1- Day 1).
13.    A marked baseline prolongation of QT/QTcF interval (such as QTcF intervals that are        
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) 
or any other relevant ECG finding at screening and prior to randomisation 
14.      A history of additional risk factors for Torsades de Pointes (such as heart failure, 
         hypokalemia, or family history of Long QT Syndrome)
15.    Inability to comply with medication or dietary restrictions (see Section 4.2.2).
16.     Intake of drugs with a long half-life (more than 24 hours) within at least 1 month of 
         the screening visit (Visit 1) or less than 10 half-lives of the respective drug prior 
           administration (except asthma or atopic disease modification and permitted
          concomitant medications as described in Table 4.2.2.1:1)
17.     Currently enrolled in another investigational device or drug study, or less than 30 days 
          since receiving another investigational treatment(s)
18.      History of relevant allergies/hypersensitivities (including allergy to the trial 
medication or its excipients)
19.      Pregnant or nursing women or a positive serum pregnancy test at the screening
          visit (Visit 1)
20.     Women of childbearing potential 
       
          All female subjects (and female partners of male subjects) are regarded as being of 
childbearing potential unless they are either post-menopausal or permanently   
sterilised. Post-menopausal is defined as having had, at least 12 months spontaneous 
amenorrhea with an appropriate clinical profile (age, vasomotor symptoms etc).  
Females may have been permanently sterilised by means of hysterectomy, bilateral 
salpingectomy, confirmed tubal occlusion or tubal ligation.
21.      Male subjects who do not agree to minimise the risk of female partners becoming
          pregnant (including sperm donation) from the first dosing day until 3 months after the 
           trial medication treatment has finished.  


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Male subjects with female partners of child bearing potential must use condoms plus 
any one other acceptable method of contraception together with their partners, from 
first dose until 3 months after the last dose of IMP.  Alternatively, true heterosexual 
abstinence is also acceptable (this must be due to subject’s lifestyle choice i.e. the 
subject should not become abstinent just for the purpose of study participation; 
withdrawal or calendar methods are not considered acceptable).
        Acceptable methods of contraception for male subjects with female partners of 
         childbearing potential include:

Condoms

Established hormonal contraception

Intrauterine device (IUD)/intrauterine hormone-releasing system (IUS).
   Male subjects with pregnant partners are excluded.  Male subjects must not donate sperm 
   until 3 months after the last dose of IMP.
22.  Current smokers or ex-smokers who have given up smoking for < 12 months and / or 
       have a smoking pack history of > 5 pack years (1 pack year = 20 cigarettes per day for 1
       year of 5 cigarettes per day for 4 years)
23.   Previous participation in this trial
3.3.4
Removal of subject from therapy or assessments
3.3.4.1
Removal of individual subjects 
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep subjects in the trial as scheduled. This includes 
careful subject selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal. 
An individual subject is to be withdrawn from trial treatment if:
a
FEV1 falls ≥ 45% post methacholine challenge from post diluent value  
If the subject is symptomatic requiring SABA the study physician must be 
informed and the appropriate assessments taken, regardless of time-point.
The PI should be informed of the situation as soon as possible and a decision will 
then be made by the PI as to whether the subject is to continue to receive MCh 
challenges at any further visits or be withdrawn.
b
The subject has a confirmed increase in serum potassium of ≥ 5.5 mmol/L in non-
haemolysed blood.


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c
The subject shows relevant individual QT prolongation, i.e. a QTcF increase of 
greater 60 ms from baseline (pre-dose Day 1 of each Treatment Period)) in 
connection with absolute QT or QTcF greater than 500 ms, which has been 
confirmed by a repeat ECG recording.
d
The subject has an asthma exacerbation.
  
  e
The subject withdraws consent for trial treatment or trial participation, without the
need to justify the decision.
f
The subject needs to take concomitant drugs that interfere with the investigational 
product or other trial medication
g
The subject can no longer be treated with trial medication for other medical reasons
(such as surgery, adverse events, other diseases, or pregnancy)
h
The subject has repeatedly shown to be non-compliant with important trial
procedures and, in the opinion of both, the investigator and sponsor representative,
is not willing or able to comply with the trial requirements in the future. 
If the subject agrees, he/she will undergo the procedures for early treatment discontinuation 
and follow up as outlined in the Flow Chart (FC) and Section 6.2.3.
For all subject the reason for withdrawal (e.g. adverse events) must be recorded in the CRF. 
These data will be included in the trial database and reported.
3.3.4.2 
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1
Failure to meet expected enrolment goals overall or at a particular trial site
2
Emergence of any efficacy/safety information invalidating the earlier positive 
benefit-risk assessment that could significantly affect the continuation of the trial. 
3
Violation of GCP, the CTP or the contract disturbing the appropriate conduct of the 
trial
4
New toxicological findings or serious adverse events invalidate the earlier positive
  benefit-risk assessment. 
More specifically, the trial will be terminated if two subjects have, at least, possibly 
related SAE or in case of the occurrence of three, at least, possibly related severe 
AEs. No further dosing, dose escalation or inclusion of any further 


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subjects (independent of dose level) will occur without approval of 
a substantial amendment.
5
Part 1 (pilot study): At least 2 subjects* in the current cohort or treatment period on
active drug showed serum potassium levels ≥ 5.5mmol/L in non-haemolysed blood
(confirmed by repeat).
Part 2 (main study): At least 4 subjects* on active drug (independent of dose level)
showed serum potassium levels ≥ 5.5mmol/L in non-haemolysed blood (confirmed 
by repeat).
* These are proposed thresholds for potential trial discontinuation however any and 
all individual occurrences of serum potassium levels ≥ 5.5mmol/L in non-
haemolysed blood will be reviewed by the PI and sponsor medical team.
6     At least 2 subjects independent of dose level on active drug showed relevant 
individual QT prolongation, i.e. a QTcF increase of greater 60 ms from baseline 
in connection with absolute QT or QTcF greater than 500 ms, which has been 
confirmed by a repeat ECG recording*
. *These are proposed thresholds for potential trial discontinuation however any and
    all individual occurrences of QT prolongations will be reviewed by the PI and 
sponsor medical team
The Investigator / 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
A ‘completed’ subject is defined as a subject who has completed all treatment periods and 
procedures including MCh challenge. Subjects who do not complete all treatment periods 
must be replaced. A replacement subject will be assigned a unique study subject number. In 
part I of the study, the replacement subject will only undergo the treatment periods not 
completed by the subject he/she replaces. In part II of the study, a replacement subject will be 
assigned to the same treatment sequence as the subject he/she replaces. The method to 
include these replacement patients in the analysis will depend on the time point of inclusion 
of the new patient in the study.  


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4
TREATMENTS
4.1    
INVESTIGATIONAL TREATMENTS
The study medication below will be supplied by Boehringer Ingelheim Pharma GmbH & Co. 
KG
1 mg BI 443651 (MW 571.12 g/mol) equals 1.26 mg BI 443651 salt form (MW 721 g/mol). 
The doses given below refer to the respective free base. 
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1  Test product 1
Substance:
BI 443651
Pharmaceutical formulation:
Solution for inhalation
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100μg/actuation, 300μg/ actuation
Posology:
Depending on dose group
Route of administration:
Oral inhalation
Device:
RESPIMAT A5
Duration of use:
Multiple dose
Table 4.1.1: 2 Test product 2
Substance:
Placebo
Pharmaceutical formulation:
Solution for inhalation
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable
Posology:
Depending on dose group
Route of administration:
Oral inhalation
Device:
RESPIMAT A5
Duration of use:
Multiple dose
For exact amounts and units to be administered per treatment and trial part please refer to 
Section 4.1.4. 


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4.1.2
Selection of doses in the trial
Orally inhaled doses in the range of 100 µg to 1200 µg have been selected in order to assess 
the safety, tolerability and pharmacokinetics of BI 443651 in asthma subjects. The doses 
were selected as follows (C02337864): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the pilot study (Part 1), the investigator can decide at any time to discontinue dosing or to 
decrease the dose escalation by adding intermediate doses in case of intolerability or due to 
safety concerns. The site will follow relevant local SOPs.
4.1.3
Method of assigning subjects to treatment groups
Subjects are randomised to a treatment sequence at Visit 2 (i.e: Treatment Period 1). After 
assessment of all inclusion and exclusion criteria, each eligible subject will be assigned the 
lowest available medication number at the time of randomisation. Note that the medication 
number is different from the subject number (the latter is assigned directly after informed 
consent was obtained). Site personnel will enter the medication number in the eCRF.


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4.1.4
Drug assignment and administration of doses for each subject 
The treatments to be evaluated are administered as outlined in Table 4.1.4:1 below.  
Table 4.1.4: 1
Treatment overview
Treatment
Formulation, dose
regimen
Treatment Administration*
Posology distribution
over the treatment period
Route
Number of 
actuations
Unit strength 
[µg]
Total dose
[µg]
Total no. of 
placebo
1 
(100 µg)
Inhalation solution, three 
administrations 12 hours 
apart
Oral inhalation
1
100
100
3
Day 1: a.m. and p.m.
Day 2: a.m. only
2
(400 µg)
Inhalation solution, three 
administrations 12 hours 
apart
Oral inhalation
4
100
400
0
Day 1: a.m. and p.m. Day 
2:  a.m. only
3
(1200µg)
Inhalation solution, three 
administrations 12 hours 
apart
Oral inhalation
4
300
1200
0
Day 1: a.m. and p.m. 
Day 2: a.m only
Placebo
Inhalation solution, three 
administrations 12 hours 
apart
Oral inhalation
-
-
-
4
Day 1: a.m. and p.m. 
Day 2:  a.m only
*Four separate devices will be used in each treatment administration to maintain blinding.  Placebo devices will be used to make a total of four 
administrations per dosing.


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Each newly assembled RESPIMAT Inhaler has to be primed by qualified, trained, unblinded
study personnel, e.g. pharmacist at the trial site under the responsibility of the investigator,
who is not involved in the conduct of the trial. Except those devices used for training,
priming should NOT take place in the same room where the subject is inhaling trial
medication 
 The inhaler should be primed by actuating it until an
aerosol is visible plus three additional actuations. For detailed priming instructions please 
refer to the RESPIMAT Inhaler handling instructions in Appendix 10.1.
Both the study drug as well as the placebo treatment (depending on randomisation) will be
inhaled with the RESPIMAT in a sitting or standing position under supervision of the
investigating physician or an authorised designee (see section 4.3). Inhalation of study drug
should NOT take place in the same room where the blood samples are taken, to prevent
contamination of samples from airborne drug. If more than one actuation is needed, planned
time 0:00h will always be the first actuation. If more than one actuation will be needed, the
duration from first to last actuation will be recorded. After study drug inhalation, subjects will
drink 250 mL of water.
The so-called four-eye principle (two-person rule) should be applied for administration of
trial medication and – if applicable – its preparation (e.g. assembling of device), if correct
dosage cannot be ensured otherwise.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In the pilot part of the study (Part 1), site staff dosing the subjects will be unblinded.  
Unblinded site staff will not conduct any study assessments.
The main part of the study (Part 2) will be double-blind and subjects, investigators and 
everyone involved in trial conduct or analysis or with any other interest in this trial will 
remain blinded with regard to the randomised treatment assignments until after database lock.
The randomisation code will be kept secret by Clinical Trial Support up to database lock.
The randomisation codes will be provided to bioanalytics prior to the last subject out date to
allow for the appropriate analyses of pharmacokinetic (PK) samples taken from different dose 
strengths. Bioanalytics will not disclose the randomisation code or the results of their 
measurements until the trial is officially unblinded.
The trial will only be unblinded after locking of the database. 
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 


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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.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’s 
Pharmacovigilance group to access the randomisation code for individual subjects during trial 
conduct. The access to the code will only be given to authorised Pharmacovigilance 
representatives and not be shared further. 
4.1.6 
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP). 
For details of packaging and the description of the label, refer to the ISF.
4.1. 7 
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator /pharmacist /investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the principal Investigator 
The investigator /pharmacist /investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each subject, and 
the return to the sponsor or warehouse / drug distribution centre or alternative disposal of 


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unused products. If applicable, the sponsor or warehouse / drug distribution centre will 
maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial subjects. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the subjects were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator / pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial subject and that no remaining supplies are in the Investigator’s possession.


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4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES
The study population is restricted to subjects with mild asthma who do not have other 
significant medical conditions.  They have controlled asthma treated adequately with SABA 
and /or low dose iCS (see Table 4.2.1 for equipotent doses).  It is not foreseen that subjects 
will require other concomitant medications.  
Table 4.2: 1
Estimated Equipotent Daily Doses of (low dose) Inhaled 
Glucocorticosteroids according to GINA 2015 P15-03654.
Drug
Low Dose (μg)
Beclomethasone dipropionate
200-500
Budesonide
200-400
Ciclesonide
80-160
Flunisolide
500-1000
Fluticasone propionate
100-250
Mometasone
200-500
Triamcinolone acetonide
400-1000
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.2.1.1
Rescue medication
Administration of rescue medication can occur at any point during the study. Open label 
salbutamol and /or atrovent MDI will be provided as rescue medication, at screening visit.
If rescue medication is administered during clinic visits (Visits 2– 5), the 24-hour clock time 
of rescue medication, total number of inhalations of rescue medication used, visit number, 
date and the name, route and dosage of any additional rescue medication will be recorded on 
the Rescue Medication eCRF page.
The use of rescue medication during Visits 2 -5 does not necessitate discontinuation of the 
visit. The subject should remain in the clinic in order to complete the remaining other 
procedures (see 4.2.2.2).


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
No concomitant therapy will be allowed except for treatments as specified in Section 4.2.1
above and a low dose of inhaled corticosteroid as defined by GINA guidance [P15-03654], 
paracetamol or medication for atopic conditions. However, in case of adverse events therapy 
according to the judgment of the investigator will be permitted. All concomitant therapies 
and/or rescue therapies will be recorded on the appropriate pages of the case report forms 
(CRFs). Concomitant medications have to be washed out as defined in Section 3.3.2.
Table 4.2.2.1:1 Overview of Permitted and Restricted Medications  
Class
Permission / Restriction and explanation
  Inhaled corticosteroids*
Permitted provided equal to or less than 250 µg     
fluticasone equivalent daily and   
corticosteroids have been stabilized at least 6
weeks prior to randomisation (Visit 2 i.e  
Treatment Period 1 Day 1) and will continue to
be used during the trial at a stable dose
   Paracetamol
  Permitted
   Intravenous, intramuscular or oral
   corticosteroids
  Not permitted 6 weeks prior screening visit
  (Visit 1) and during the trial  
  Oral and patch β-adrenergics
Not permitted 4 weeks prior screening visit
  (Visit 1) and during the trial
  Long acting inhaled β-adrenergics
(including fixed dose beta-agonist/  
  inhaled corticosteroid combinations)1
   Not permitted 6 weeks prior screening visit
   (Visit 1) and during the trial.
  Short acting inhaled β-adrenergics
Not permitted except for supplied 
rescue medication. 
Regarding restrictions for forced
spirometry bronchodilators see
Section 4.2.2.2.
Long acting inhaled anticholinergics   
  (e.g. Tiotropium, Aclidinium)  
  (including fixed dose beta- agonist  
   Not permitted 6 weeks prior screening visit
   (Visit 1) and during the trial


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  /inhaled corticosteroid combinations)1
Short acting inhaled
anticholinergics
(inhalation aerosol, nasal spray)
Not permitted except for supplied 
rescue medication. Regarding
restrictions for forced spirometry
bronchodilators see Section 4.2.2.2
   Antihistamines
Not permitted 4 weeks prior screening visit
(Visit 1) and during the trial
  Cromolyn sodium / nedocromil sodium
  Not permitted 4 weeks prior screening visit
  (Visit 1) and during the trial
   Mucolytics 
   Not permitted 4 weeks prior screening visit
   (Visit 1) and during the trial
  Beta blockers
Permitted provided that beta blockers have   
been stabilized at least 6 weeks prior to
randomisation (Visit 2 i.e: Treatment Period 1
Day 1) and will continue to be used during the
trial in a stable manner
  Investigational drugs
Not permitted, see exclusion criterion number 
17
  Antileukotrienes
Not permitted 4 weeks prior screening visit 
(Visit 1) and during the trial
   Theophylline, Aminophylline
Not permitted 4 weeks prior screening visit 
(Visit 1) and during the trial
     A biological based antagonist therapy 
     including Omalizumab, or immune 
     modulators 
Not permitted within 6 months of the  
  screening visit (Visit 1)
      Non-approved asthma 
     therapies such as methotrexate
  Not permitted within 3 months of the 
  screening visit (Visit 1)
      Systemically available   
      immunomodulatory treatments for 
      allergic rhinitis or atopic dermatitis.
Not permitted
    Medications that may lead to 
    alterations in serum electrolytes 
    (particularly potassium) including but 
    not limited to diuretics**, angiotensin
Not permitted 4 weeks prior screening visit
(Visit 1) and during the trial


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  convertase/ angiotensin receptor 
inhibitors***, 
nonsteroidal anti-inflammatory drugs 
(NSAIDs)****, 
cyclosporine or tacrolimus, Pentamidine, 
Trimethoprim-sulfamethoxazole,  
Heparin, Ketoconazole and Metyrapone
*
Intranasal steroids for atopic condition and topical treatments for eczema are allowed
**
includes spironolactone, amiloride 
***
includes Captopril, Zofenopril, enalapril, 52nalyzin, Quinapril, Perindopril, Lisinopril, 
Benazepril, Imidapril, Trandolapril, Fosinopril, Cilazapril;
****
includes ibuprofen, diclofenac, naproxen, celecoxib, mefenamic acid,etoricoxib, 
indomethacin, aspirin (doses > 600 mg)
1 Withdrawal of bronchodilators or reduction in iCS dose is not acceptable unless for medical
reasons.
4.2.2.2
Medication Restrictions (for Pulmonary Function Testing)
An 8-hour minimum washout period for inhaled short-acting bronchodilators (such as 
salbutamol and ipratropium) must be maintained. The morning dose of inhaled 
corticosteroids should not be taken in the 1-hour period prior to test-day (Day 1 and Day 2) 
pre-dose PFT.
Even if subjects violate these restrictions, as a general rule, scheduled procedures (including 
further dosing and methacholine challenge) should neither be postponed nor skipped. 
Regarding diet and lifestyle restrictions for forced spirometry testing please see Section 
4.2.2.3.
4.2.2.3
Restrictions on diet and life style
Grapefruits, Seville oranges and their juices, dietary supplements (including vitamins and 
garlic supplements) and herbal products are not permitted from 7 days before day 1 and until 
last PK of the study.
Alcoholic beverages are not permitted from 48 hours prior to and during all visits.
Intake of coffee, tea, chocolate, cola, energy drinks and other methylxanthine-containing 
drinks or foods and ice-cold beverages are not allowed for a period of 8 hours prior to clinic 
visits and during in-house confinement at the study site. Decaffeinated beverages are allowed.
Standardised meals will be provided during in-house confinement at the study site. Subjects 
are restricted from consuming any foods or drinks than those provided by the staff.


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Excessive strenuous physical activity should be avoided for 72 hours prior to screening (Visit 
1). Strenuous exercise should be avoided for 48 hours prior to and during all other visits 
(Visits 2-6).
4.2.2.4
Restrictions regarding women of childbearing potential 
Women of childbearing potential are excluded from participation in this study. 
4.3
TREATMENT COMPLIANCE
Each subject will be trained in the correct use of the Respimat® inhaler using the training 
Respimat® inhaler with inserted placebo cartridge.  Please refer to Appendix 10.1
5. 
VARIABLES AND THEIR ASSESSMENT
5. 1
TRIAL ENDPOINTS
Figure 5.1: 1 Illustration of endpoints based on spirometry measurements (FEV1 as example). 
The figure displays measurements during one treatment period that is during the baseline 
bolus challenge prior to drug administration, during drug administration and during the 
treatment challenge on Day 2.  


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In the following baseline refers to the measurement obtained from the baseline bolus MCh 
challenge prior to administration of trial medication within each period.
5.1.1
Primary Endpoint(s)
The primary endpoint for the study to assess safety of BI 443651 is 

Absolute change from baseline in maximum FEV1 reduction following MCh 
challenge. 
The primary endpoint will be compared to placebo for each dose level of BI 443651.
For a visualization of the endpoint refer to Figure 5.1 :1, a detailed description of the primary 
endpoint and the primary statistical analysis is provided in Section 7.
5.1.2
Secondary Endpoint(s)
The following secondary endpoints will be assessed: 

Relative change from baseline in FEV1 AUC0-tz following bolus MCh challenge

Time to recovery of FEV1 to within 95% of post-diluent value
The secondary endpoints will be compared to placebo for each dose level of BI 443651.
For a visualization of the endpoints refer to Figure 5.1:1, a detailed description of the
secondary endpoints including statistical analysis is provided in Section 7.


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5.2
ASSESSMENT OF EFFICACY
There are no efficacy assessments in this study
5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A physical examination will be performed at Screening (Visit 1) and on completion of the 
study.  A targeted physical examination focussing on heart and lungs will be performed at the 
start of each treatment period (Visits 2 – 5).
All clinically significant findings at screening (Visit 1) will be recorded on the Medical 
History/Baseline Conditions in the eCRF.
New clinically significant findings or worsening of screening findings detected at the follow 
up visit (Visit 6) will be recorded as adverse events on the appropriate eCRF page.
An explanation of the aetiology of clinically significant abnormal physical findings must be 
made on the eCRF.  All relevant (in the opinion of the investigator) abnormal physical 
findings have to be followed up until normalised or sufficiently characterised.
5.3.2
Vital Signs
Pulse rate, systolic and diastolic blood pressure will be measured and recorded at the 
screening visit (Visit 1) and at subsequent visits at selected timepoints. Measurements will be 
obtained with the subject supine and rested for at least 5 minutes.


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5.3.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood will be collected by the trial site at the 
time points indicated in the Flow Chart after the subjects have fasted for at least 10h (prior to 
the Screening Visit (Visit 1)) Subjects may drink water during the fasting period.
Subjects do not need to fast prior to laboratory testing at subsequent visits (i.e: after Visit 1)
If safety laboratory measurement is performed at the same time as other blood collection, e.g. 
PK sampling, safety laboratory measurement will always be performed first, preferably 
without any tourniquet.
The parameters that will be determined are listed in Table 5.3.3:.1  Reference ranges will be 
provided in the ISF.
Manual differential white blood cell count or urine sediment examination will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.
Table 5.3.3:1   Routine laboratory tests 
Category
Test name
A
B
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelets
Reticulocytes
x
x
x
x
x
x
x
x
x
x
x
x
Automatic WBC 
differential (relative and 
absolute)
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
x
x
x
x
x
x
x
x
x
x
Manual differential WBC 
(if automatic differential is 
abnormal)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes
Coagulation
Activated partial thromboplastin time (aPTT)
Prothombin Time (Quick and INR)
x
x
x
x
Enzymes
Alanine aminotransferase (ALT/GPT, SGPT)
Alkaline phosphatase
Gamma-glutamyl transferase (GGT)
Lactate dehydrogenase
x
x
x
x
x
x
x
x


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Amylase
Lipase
x
x
x
x
Category
Test name
A
B
Substrates
Glucose (plasma)
Creatinine
eGFR (calculated from serum creatinine using CKD-
EPI formula
Bilirubin, total
Bilirubin direct
Cholesterol, total
Triglycerides
C-reactive protein
Urea
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Electrolytes
Calcium
Sodium
Potassium
Chloride
x
x
x
x
x
x
x
x
Hormones
Thyroid stimulating hormone (TSH)
x
Human chorionic gonadotrophin (HCG)
x
Urinalysis (Stix) [Urin-
Sediment will be
performed, if urinalysis 
abnormal]
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine RBC
Urine WBC
Urine pH
  x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine sediment 
(microscopic examination if 
erythrocytes, leukocytes, 
nitrite or protein are 
abnormal in urine)
Only positive finding will be reported (for instance, 
the presence of sediment bacteria, casts in sediment, 
squamous epithelial cells,
A:   Parameters to be determined at screening examination and during the study (refer to Flow Chart
     for time points)
B:   Parameters to be determined during the follow-up visit
The laboratory tests will be performed by a central laboratory.  


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Instructions for the processing, storage and shipment of samples to the central laboratory will 
be provided to the site.
Where local laboratory results are also used, central laboratory results will take precedence in 
the interpretation of the results.  Local laboratory results will take precedence for dosing 
decisions (e.g: K+). Local laboratory values will not be entered into the database.
Laboratory data will be transmitted electronically from the central laboratory to the trial site.
5.3.4
Electrocardiogram
A standard 12-lead ECG will be performed on all subjects at the screening visit (Visit 1) and 
during treatment period (Visits 2-5).  ECG will be performed with the subject supine and 
rested for at least 5 minutes. At Visit 1, significant findings must be recorded on the Medical 
History/Baseline Condition page.  Any clinically relevant (according to the investigator’s 
opinion) changes in the ECG during the study (after Visit 1) should be documented on the AE 
page of the eCRF.
5.3.5
Other safety parameters
Not applicable
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of Aes
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or 

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

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 jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
Aes considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further Aes, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious Aes” can be found in the RDC system. 
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 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.


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The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These laboratory findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in RDC.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity 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
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).


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•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
5.3.6.2
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all Aes in their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
•
From signing the informed consent onwards through the Residual Effect Period (REP), 
until an individual subject’s end of trial: 
-all Aes (serious and non-serious) and all AESIs.
•
After the individual subject’s end of trial: 
the Investigator does not need to actively monitor the patient for Aes but should only 
report relevant SAEs and relevant AESIs of which the Investigator may become aware of.


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Figure 5.3.6.2: 1 Illustration of Safety Reporting Requirements.
The REP is defined as 
 after the last trial medication application. All Aes which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment (see Section 7.3.4). Events which occurred after the REP and before next drug 
intake or trial termination date (whatever occurs first) will be considered as follow-up 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 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication.
The following should also be recorded as an (S)AE in the CRF and 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.


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All (S)Aes, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the
clinical trial and has taken trial medication, the investigator must report any drug exposure
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male
trial participant becomes pregnant. This requires a written consent of the pregnant partner.
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
 
  
 
 
 
 
 
 
 
 


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5.5
ASSESSMENT OF BIOMARKER(S)
Not applicable
5.6
OTHER ASSESSMENTS
There will be no additional assessments
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed in this trial are standard measurements to monitor safety aspects 
 in an appropriate way.  The primary and 


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secondary endpoints are standard and accepted for evaluation of safety, tolerability, 
 
 and are widely used in this kind of study.
The bolus MCh challenge method (see Section 6.2) has been chosen as this provides a 
consistent degree of muscarinic receptor excitation between treatment levels, allowing 
investigation of the effect of regular dosing with a therapeutic agent on both methacholine 
induced bronchoconstriction and subsequent recovery.
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The trial consists of a screening period (Visit 1), pilot and main study periods (Visit 2 to 5) 
and end of study period (Visit 6). The pilot and main study each consist of four separate 
treatment periods.  For administrative reasons, each of these four treatment periods within the 
pilot and main studies  is referred to as a ‘Visit’ and each ‘Visit’ will consist of up to 3 days 
of procedures. The procedures conducted at each of the treatment period ‘Visits’ (Visit 2 to 5) 
are the same.  A more detailed overview is provided in the Flow Chart.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Methacholine (MCh) challenge
The single methacholine concentration according to Table 6.2.1 (column 4) will be 
administered at both Day -1 or Day -2 and Day 2 of each treatment period. This concentration 
needed to administer this dose considers the cumulative dose administered during the 
incremental challenge at the screening visit (see Table 6.2.1). Single FEV1 measurements
(FEV1 only) are then made at 30 and 90 seconds, followed by duplicate FEV1 and FVC 
measurements at 5, 10, 20, 30, 45 minutes, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75 and 3 hours on 
Day -2 or Day -1, with additional timepoints at 3.5, 4.0, 4.5, 5.0, 6.0, 7.0 and 8.0 hours hours 
on Day 2.
Table 6.2.1: Incremental and bolus MCh challenge dosing schedule.
Dose 
Number
Methacholine 
Concentration during 
Incremental 
Challenge (mg/ml)
Cumulative 
Dose (mg) 
(rounded to 
4 d.p. max)
Methacholine Concentration to be used to 
administer the Bolus Challenge (mg/ml) 
(only highest dose number administered 
at Visit 1)
1
0.03125
0.0014
0.03125
2
0.03125
0.0028
0.0625
3
0.0625
0.0056
0.125
4
0.125
0.0113
0.25
5
0.25
0.0225
0.5
6
0.5
0.045
1.0
7
1.0
0.09
2.0
8
2.0
0.18
4.0
9
4.0
0.36
8.0
10
8.0
0.72
16.0
11
16.0
1.44
32.0


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Spirometry
Spirometry will be performed according to ATS/ERS guidelines for pulmonary function 
testing [P05-12782] in order to characterise the study population, to monitor individuals’
safety in regard to asthma and as an exploratory assessment of drug effect. The subject must 
qualify by demonstrating a pre-bronchodilator clinic measured FEV1 ≥70% of predicted 
normal. FEV1 normal predicted values will be calculated according to GLI [R15-0845] 
measured ≥ 8 hours after the last use of short acting bronchodilator at the screening visit
(Visit 1) and treatment period 1 Day 1. 
Equipment and techniques should conform to American Thoracic Society (ATS) criteria 
[P05-12782].
Spirometry will be conducted with the subject in a seated position. It is preferable that the 
same trained individual performs the PFTs for a given subject. Unless otherwise specified in 
methacholine challenges, the best of three efforts will be defined as the highest FEV1 and the 
highest FVC each obtained on any of three blows meeting the ATS criteria (with a maximum 
of eight attempts). FEV1, FVC, will be measured as indicated in the Flow Chart and recorded 
in the eCRF. The best of the three pre-dose FEV1 measurements will be defined as trough 
FEV1.  The 24-hour clock time of the first  manoeuvre for each PFT time point will be 
recorded.
Screening and run-in period(s)
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.  
6.2.1
Treatment period(s)
Trial medication will be administered by each subject (under the direct supervision of the 
investigator or his designee).  Details on treatments and procedures of administration are 
described are described in Section 4.1.4.
All subjects will attend the trial site (see Flow Chart) after formal assessments and 
confirmation of their fitness by the investigator or designee.  
For details on time points and procedures for collection of plasma samples for PK analysis 
(see Flow Chart).
The safety measures specified during the treatment period are specified in Section 5.2 of the 
protocol and in the Flow Chart.  For details on time points for all other trial procedures, 
refer to the Flow Chart.  Aes and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.


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6.2.2
End of Trial Period
For AE assessment, laboratory tests, recording of ECG and vital signs, physical examination, 
see Sections 5.3.1
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of the trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved.  Adverse events persisting after trial completion must be 
monitored until they have been resolved or have been sufficiently characterised.
The end of the trial as a whole is defined by the ‘last regular visit completed by  last subject’ 
or ‘end date of the last open AE’ or ‘ date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is the latest.


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7. 
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The primary objective of the study is to investigate safety and tolerability of three 
consecutive administrations, 12 h apart, at three different dose-levels (100, 400 and 1200 µg) 
of BI 443651 administered via oral inhalation in male and female mild asthmatic subjects 
after a bolus MCh challenge.
For the main part, the primary endpoint absolute change in maximum reduction of FEV1 and 
the secondary endpoint relative change in AUC0-tz as described in Section 5.1 will be 
analysed using a mixed effects model on the original and logarithmic-scale, respectively, 
taking the crossover design of the trial into account. The models will include treatment and 
period as fixed effects, subject as a random effect and period baseline as well as subject 
baseline as covariates. The subject baseline will be obtained by calculating the mean of 
period baselines for each subject. Active doses will be compared to placebo for both 
endpoints. For investigation of the secondary endpoint time to recovery to within 95% of 
post-diluent value a Cox proportional hazards model will be used to estimate the hazard ratio 
of BI 443651 vs. Placebo.
For the pilot part, the primary and secondary endpoints as described in Section 5.1 will be 
analysed using descriptive statistics. No inferential statistics are planned for this part of the 
trial.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 3 different dose strengths of BI 443651 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Blinded Report Planning 
Meeting and provided in the TSAP.


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The statistical analysis will be based on the following analysis sets based on the actual 
treatment the subject receives.

Enrolled set (ES): This subject set includes subjects that signed informed consent and 
underwent screening procedures.

Randomised set (RS):  This subject set includes all randomised subjects, whether 
treated or not. 

Treated set (TS): The treated set includes all subjects who were randomised and 
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the subjects received.

Methacholine set (MCS): This subject set includes all subjects in the treated set who 
provide at least one pair (baseline and end of treatment) of evaluable measures of 
spirometry parameters that were not excluded due to use of rescue medication within 
3 hours after start of MCh challenge.
 
 
 
 
 
7.3.1
Primary endpoint analyses
The primary endpoint absolute change from baseline in maximum reduction in FEV1 (refer to 
Section 5.1.1) is defined as the difference between the maximum reduction in FEV1 obtained 
during the treatment challenge and during the baseline challenge. 
The primary endpoint will be investigated using descriptive statistics for both trial parts 
separately and combined.
For the main part of the trial (part II), this primary endpoint will be analysed using a mixed 
effects model based on the MCS:
 = 	 +  +  +  + 
 +  + ,
where i = subject 1,…, N, m = period 1,…,4, j = treatment 1,…,4

CfB in maximum FEV1 reduction for the ith subject and the mth
period, receiving randomised treatment j 
	
overall intercept, 

mth period effect,

jth treatment effect,

baseline value for subject i in period m (period baseline), 

associated covariate effect of period baseline, 


the subject baseline value (mean of period baselines) for subject i,

associated covariate effect of subject baseline,

the random effect of subject i,

the random error associated with subject i who received treatment j 
in period m.


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The treatment comparisons will be the contrast between active dose and placebo at the 
endpoint visit. Adjusted means (Least Squares Means) as well as 2-sided 90% Cis will be 
provided.
 
 
 
 
 
 
 
Further details will be provided in the TSAP.
7.3.2
Secondary endpoint analyses
The secondary endpoint relative change from baseline in FEV1 AUC0-tz (see Section 5.1.2) is 
defined as the ratio of FEV1 AUC0-tz obtained during the treatment challenge and during the 
baseline challenge. During each challenge, the area above the curve of the absolute change in 
FEV1 from post-diluent value will be calculated from time 0 to tz using the trapezoidal rule
(refer to 001-MCG-163). The time tz refers to the last time point before recovery of FEV1 to 
within 95% of post-diluent value.
This secondary endpoint will be investigated using descriptive statistics for both trial parts 
separately and combined.
For the main part of the trial (part II), this secondary endpoint will be analysed using a mixed 
effects model on the logarithmic scale based on the MCS:
 = 	 +  +  +  + 
 +  + ,
where i = subject 1,…, N, m = period 1,…,4, j = treatment 1,…,4

Logarithm of CfB in FEV1 AUC0-tz consideration for the ith subject 
and the mth period, receiving randomised treatment j 
	
overall intercept, 

mth period effect, 

jth treatment effect, 

Logarithm of baseline value for subject i in period m (period 
baseline), 

associated covariate effect of period baseline, 


Logarithm of the subject baseline value (mean of period baselines) 
for subject i,

associated covariate effect of subject baseline,


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
the random effect of subject i,

the random error associated with subject i who received treatment j 
in period m.
To this end, the endpoint will be log-transformed (natural logarithm) prior to fitting the 
model given above. The difference between the expected means for log(Active)-log(Placebo) 
will be estimated by the difference in the corresponding adjusted means (Least Squares 
Means), and a two-sided 90% confidence interval based on the t-distribution will be 
computed. These quantities will then be back-transformed to the original scale to provide the 
point estimate and 90% Cis for each endpoint.
 
 
 
 
The secondary endpoint time to recovery of FEV1 within 95% of post-diluent value (see 
Section 5.1.2) is defined as the time from maximum reduction to last time before recovery to
within 95% of pre-MCh challenge during each challenge. The time obtained from the 
treatment challenge represents the endpoint, while the time obtained from the baseline 
challenge will be used for the baseline correction in the analysis.
This secondary endpoint will be investigated using descriptive statistics for both trial parts 
separately and combined, if applicable.
Kaplan-Meier (KM) curves will be plotted for the recovery of FEV1 within 95% of post-
diluent value by treatment irrespective of the period it is administered in, for both trial parts 
separately as well as combined, if applicable. 
For part II of the trial, this endpoint will be analysed using a Cox proportional hazards model 
as given below based on the MCS. The model includes the treatment effect and an effect for 
subject baseline. Thereby, the subject baseline is calculated as median of all period baselines 
per subject. Breslow’s method for handling ties will be used.
The hazard function for the ith subject is assumed to be
λ() = () ⋅exp{  + ! ! + " "},
where i = 1,…, N,
() is the unspecified, non-negative, baseline hazard function

,!," are the unknown regression coefficients

  represents the treatment group

 ! represents the subject baseline (median of period baselines)

 " represents the period


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For treatment comparisons the hazard ratios of BI 443651 vs. Placebo and asymptotic 95% 
Wald confidence intervals will be estimated. A hazard ratio of greater than one means that BI 
443651 is not inferior to placebo.
 
 
 
 
 
 
 
Further details will be provided in the TSAP.


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7.3.5
Safety analyses
Safety will be assessed for the further safety parameters of interest listed in Section 5.1.3 
based on the TS. Safety analyses will be descriptive in nature and will be based on BI 
standards.
Treatments will be compared in a descriptive way. The active treatment groups will be 
compared to the placebo group in a descriptive way. Tabulations of frequencies/proportions 
will be used for the evaluation of categorical (qualitative) data, and tabulations of descriptive 
statistics will be used to analyse continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’.
Measurements (such as ECG, vital signs, or laboratory parameters) or Aes will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent Aes). 
Therefore, measurements planned or Aes recorded prior to first intake of trial medication will 
be assigned to ‘screening’, those between first trial medication intake until next intake or end 
of REP will be assigned to the preceding treatment, and all Aes occurring between the end of 
REP and next treatment intake or trial termination date respectively will be assigned 
to ’follow-up’. In case of two or more treatments, the follow-up will be summarized 
according to the previous treatment. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP. Please note that Aes occurring after the last 
per protocol contact but entered before database lock will be reported to drug safety only and 
will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and follow-up intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, intensity and causal relationship of Aes will be tabulated by 
treatment, primary system organ class and preferred term. SAEs, AESIs (see Section 5.3.6) 
and other significant Aes (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be flagged. Additionally, differences from baseline will be evaluated.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.


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7.4
INTERIM ANALYSES
No inferential statistical interim analysis is planned. However, after part 1 the investigator (or 
his deputy) is allowed to postpone progression to part 2 until a preliminary safety review (see
Section 3.1) of the data already obtained has been performed. For handling of treatment 
blinding refer to Section 4.1.5.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
For evaluation of primary and secondary endpoints a measurement obtained at baseline and 
on-treatment per period is required. Further details will be provided in the TSAP.
Handling of drop-outs is described in Section 3.3.5.
With respect to further safety evaluations (refer to Section 7.3.4), it is not planned to impute 
missing values.
 
 
 


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7.6
RANDOMISATION
For each trial part, subjects will be randomised to one of four treatment sequences (see
Section 3.1) in a 1:1:1:1 ratio. The block size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
For the pilot part, it is planned to include 4 otherwise healthy asthma subjects. The planned 
sample size is not based on a power calculation. This sample size is considered as sufficient 
for the exploratory evaluation of safety after multiple doses in this study population.
For the main part, it is planned to include a total of 32 (8 per sequence) completed otherwise 
healthy asthma subjects (non-completed subjects will be replaced, see Section 3.3.5) to 
achieve the aims of this exploratory trial with the following assumptions:

The primary endpoint is normally distributed

Two-sided significance level α = 10%

Considered  relevant change: -0.2 L

The treatment difference between the means of BI 443651 and placebo is expected  to 
be -0.06 L [data on file]

The within-subject standard deviation (SD) for the difference is expected to be 0.24 L 
[data on file]
Assuming a within-subject SD of 0.24 L for BI 443651 and given the chosen sample size of 
N=32 subjects, the precision of the two-sided 90% confidence interval of the difference will 
be approximately 0.112 (upper confidence limit (UL) – point estimate of the 
difference (Diff)); for a greater within-subject SD of 0.3, the precision would still be 
approximately 0.14. 
Increasing the sample size by 4 (N=36) results in a precision of approximately 0.105 and 
0.131, respectively. Table 7.7: 1 provides an overview of the 90% confidence intervals that 
are expected with 95% tolerance probability, for possible scenarios of the SDs and intra-
subject differences (active drug – placebo).


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Table 7.7: 1 Precision that can be expected with 95% tolerance probability and illustrative
two-sided 90% confidence intervals around the treatment differences 
for different SDs and varying sample sizes in a 4x4x4 crossover
N
SD 
within
Precision
(UL-Diff)
Diff (active – placebo)
-0.1
-0.05
0
0.05
0.1
32
0.24
0.112
(-0.21,0.01)
(-0.16, 0.06)
(-0.11, 0.11)
(-0.06, 0.16)
(-0.01, 0.21)
32
0.3
0.14
(-0.24, 0.04)
(-0.19, 0.09)
(-0.14, 0.14)
(-0.09, 0.19)
(-0.04, 0.24)
36
0.24
0.105
(-0.20, 0.00)
(-0.15, 0.05)
(-0.10, 0.10)
(-0.05, 0.05)
(-0.00, 0.20)
36
0.3
0.131
(-0.23, 0.03)
(-0.18, 0.08)
(-0.13, 0.13)
(-0.08, 0.18)
(-0.03, 0.23)
The calculation was performed as described by Julious [R11-5230] using R Version 3.2.2.
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonised standards for Medical Devices (ISO 14155, current version).
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), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.


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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 patient or the
subject’s legally accepted representative.”
The Investigator must give a full explanation to trial subjects based on the subject
information form. A language understandable to the subject should be chosen, technical terms 
and expressions avoided, if possible. The subject must be 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.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
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) for individual patients will be provided by the sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any


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diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the subject, documented in their 
medical records, would be acceptable.
Before providing any copy of subjects’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. subject’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure subject confidentiality.
If the subject is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Subject identification: gender, date or year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, patient number, date subject 
was informed)

Dates of Subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of Subject’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make
the subject eligible for the clinical trial.
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). The CRA and auditor may review all CRFs and informed consents. The accuracy 
of the data will be verified by direct comparison with the source documents described in 
Section 8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.


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An adaptive approach to clinical trial monitoring will be utilised. The sponsor will perform a 
risk assessment of the trial to determine the extent and nature of monitoring required in order 
to ensure the reliability and robustness of the results. Regular review of risk reports will 
provide sponsor oversight during trial conduct and direct monitoring activities to the areas of 
greatest risk which have the most potential impact to subject safety and data quality.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results. 
The CRA and auditor may review all CRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in Section 8.3.1. 
The sponsor will also monitor compliance with the protocol and ICH GCP.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB/IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results
The CRA and auditor may review all CRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in Section 
8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
the national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Subject privacy will 
be ensured by using subject identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
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 


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need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in ‘Note For Guidance On Good 
Clinical Practice’ (CPMP/ICH/13 5/95)

The BI-internal facilities storing and 82nalyzing biological samples and data from 
clinical trial participants as well as the laboratories’ activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(“Last Subject Out”). The “Last Subject Drug Discontinuation” (LSDD) date is defined as 
the date on which the last subject at an individual trial site ends trial medication (as scheduled 
per protocol or prematurely). Individual Investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LSDD at their site. Early termination of the 
trial is defined as the premature termination of the trial due to any reason before the end of 
the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject
(EU or non-EU).


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, 
Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino 
R, Viegi G, Wanger J Standardisation of spirometry.
Eur Respir J 26 (2), 319 - 338 (2005)
P07-11238
Raissy HH, Harkins M, Esparham A, Kelly HW. Comparison of the dose 
response to levalbuterol with and without pretreatment with S-albuterol 
after methacholine-induced bronchoconstriction. Pharmacotherapy 27 (9), 
1231 – 1236 (2007)
P09- 06255      Park HW, Yang MS, Park CS, Kim TB, Moon HB, Min KU et al. Additive 
role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a 
potential marker to predict response. Allergy 2009; 64: 778–783.
P15-03654
Global Initiative for Asthma (GINA)
Global strategy for asthma management and prevention (updated 2015).
http://www.ginasthma.org/local/uploads/files/GINA_Report_2015.pdf 
(access date: 17 April 2015) ; Global Initiative for Asthma (GINA) (2015)
P16-04040       Nicola Scichilone, Salvatore Battaglia, Alba La Sala, and Vincenzo Bellia. 
Clinical implications of airway hyper-responsiveness in COPD. Int J 
Chron Obstruct Pulmon Dis. 2006 Mar; 1(1): 49–60. 
P17-01614
1992b Barnes PJ. Modulation of neurotransmission in airways. Physiol 
Rev 1992; 72: 699–729
P17-02000
Hashimoto A, Maeda H, Yokoyama M
Augmentation of parasympathetic nerve function in patients with extrinsic 
bronchial asthma – evaluation by coefficiency of variance of R-R interval 
with modified long-term ECG monitoring system.
Kobe J Med Sci 42, 347 – 359 (1996)
P92-1976         Barnes PJ. Neural mechanisms in asthma. Br Med Bull 1992; 48: 149–168.
P96-3855
Ramsey BW, Management of pulmonary disease in patients with cystic 
fibrosis.  N Engl J Med 335 (3), 179-188 (1996)
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group 2010.
R15-0689
Larsen GL, Alexander JA, Stanford W
Thromboembolic phenomena in patients with prosthetic aortic valves who 
did not receive anticoagulants. Ann Thorac Surg 23 (4), 323 – 326 (1977)


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R15-0845
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH et al. 
Multi-ethnic reference values for spirometry for the 3-95 year age range: 
the global lung function 2013 equations: report of the Global Lung 
Function Initiative (GLI) ERS Task Force to establish improved lung 
function reference values. Eur Respir J. 40(6):1324-1343 (2012).
R15-3034
Chronic respiratory diseases:  burden of COPD.  
http://www.who.int/respiratory/copd/burden/en/ (access date:  11 June 
2015) ; World Health Organization (2015)
R15-4945
Donaldson GC, Seemungal TA, Patel IS, Bhowmik A, Wilkinson TM, 
Hurst JR, Maccallum PK, Wedzicha JA
Airway and systemic inflammation and decline in lunch function in 
patients with COPD:  Chest 2005; 128: 1995 – 2004.
Respir Med COPD Update 1 (3), 101 – 102 (2006)
R15-4947
Clunes LA, Bridges A, Alexis N, Tarran R
In vivo versus in vitro airway surface liquid nicotine levels following 
cigarette smoke exposure.
J Anal Toxicol 32 (3), 201 - 207 (2008)
R15-4955
Clunes MT, Boucher RC, Virtual Lung Group
Cystic fibrosis: the mechanisms of pathogenesis of an inherited lung 
disorder.
Drug Discov Today Dis Mech 4 (2), 63-72 (2007)
R15-4575
Clunes LA, Davies CM, Coakley RD, Aleksandrov AA, Henderson AG, 
Zeman KL, Worthington EN, Gentzsch M, Kreda SM, Cholon D, Bennett 
WD, Riordan JR, Boucher RC, Tarran R
Cigarette smoke exposure induces CFTR internalization and insolubility, 
leading to airway surface liquid dehydration.
FASEB J 26 (2), 533 - 545 (2012)
 
 
R15-4985
Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA
Association between airway bacterial load and markers of airway 
inflammation in patients with stable chronic bronchitis.
Am J Med 109 (4), 288 – 295 (2000)
R15-4986
Speizer FE, Fay ME, Dockery DW, Ferris BG
Chronic obstructive pulmonary disease mortality in six U.S cities.
Am Rev Respir Dis 140 (3, Part 2), S49 – S55 (1989)


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R15-4987
Rubin BK, Ramirez O, Zayas JG, Finegan B, King M
Respiratory mucus from asymptomatic smokers is better hydrated and 
more easily cleared by mucociliary action.
Am Rev Respir Dis 145 (3), 545 - 547 (1992)
R15-5349
Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King 
M, Edwards LJ, Helms RW, Boucher RC
A pilot study of aerosolized amiloride for the treatment of lung disease in 
cystic fibrosis. N Engl J Med 322 (17), 1189 - 1194 (1990)
R15-5485
Matthys H, Koehler D. Bronchial clearance in cystic fibrosis.
Eur J Respir Dis Suppl 146, 311 - 318 (1986)
R15-5486
Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC
Defective epithelial chloride transport in a gene-targeted  mouse model of 
cystic fibrosis.  Science 257 (5073), 1125-1128 (1992)
R15-5487
Koehler D, App E, Schmitz-Schumann M, Wuertemberger G, Matthys H
Inhalation of amiloride improves the mucociliary and the cough clearance 
in patients with cystic fibroses.
Eur J Respir Dis Suppl 146, 319 - 326 (1986)
R15-5502
Anderson WH, Coakley RD, Button B, Henderson AG, Zeman KL, Alexis 
NE, Peden DB, Lazarowski ER, Davis CW, Bailey S, Fuller F, Almond M, 
Qauish B, Bordonali E, Rubinstein M, Bennett WD, Kesimer M, Boucher 
RC
Am J Respir Crit Care Med 192 (2), 182-190 (2015)
R15-5505
Pons G, Marchand MC, D'Athis P, Sauvage E, Foucard C, Chaumet-
Riffaud P, Sautegeau A, Navarro J, Lenoir G, Amiloride-AFLM 
Collaborative Study Group
French multicenter randomized double-blind placebo-controlled trial on 
nebulized amiloride in cystic fibrosis patients.
Pediatr Pulmonol 30 (1), 25 - 31 (2000)
R15-5506
Dransfield MT, Wilhelm AM, Flanagan B, Courville C, Tidwell SL, Raju 
SV, Gaggar A, Steele C, Tang LP, Liu B, Rowe SM
Acquired cystic fibrosis transmembrane conductance regulator dysfunction 
in the lower airways in COPD. Chest 144 (2), 498 - 506 (2013)
 
 
R15-5546
Genes and human disease:  monogenic diseases.  
http://www.who.int/genomics/public/geneticdeseases/en/index2.html#CF
(access date:  28 October 2015) ; Geneva:  World Health Organization 


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(WHO) (2015)
R15-5599
Graham A, Hasani A, Alton EWFW, Martin GP, Marriott C, Hodson ME, 
Clarke SW, Geddes DM
No added benefit from nebulized amiloride in patients with cystic fibrosis.
Eur Respir J 6, 1243 - 1248 (1993)
R16-1628   
Eggleston PA1, Rosenstein BJ, Stackhouse CM, Alexander MF. Airway 
hyperreactivity in cystic fibrosis. Clinical correlates and possible effects on 
the course of the disease. Chest. 1988 Aug; 94(2):360-5.
R16-1630   
Sarah McCuaig, James G Martin. How the airway smooth muscle in cystic 
fibrosis reacts in proinflammatory conditions: implications for airway
hyper-responsiveness and asthma in cystic fibrosis. Lancet Respir Med 
2013; 1: 137–47.
R16-1631  
Lanças TI, Kasahara DI, Gross JL, Pires-Neto RC, Deheinzelin D, Mauad 
T, Negri EM, Dolhnikoff M. Cholinergic hyperresponsiveness of 
peripheral lung parenchyma in chronic obstructive pulmonary disease.
Respiration. 2011;82 (2):177-84. 
R16-1649   
Jan Lötvall, Mark Inman, Paul O’Byrne. Measurement of airway 
hyperresponsiveness: new considerations Occasional 
review.Thorax1998;53:419-424 doi:10.1136/thx.53.5.419 
R16-1652
J Vestbo, E F Hansen. Airway hyperresponsiveness and COPD mortality. 
Thorax2001;56:ii11-ii14 
R17-0519
Kanazawa H, Kawaguchi T, Shoji S, Fujii T, Kudoh S, Hirata K et al. 
Synergistic effect of nitric oxide and vasoactive intestinal peptide on 
bronchoprotection against histamine in anesthetized guinea pigs. Am J 
Respir Crit Care Med 1997; 155: 747–750.
P94-2812
Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, 
Conway WA, Enright PL, Kanner RE, O’Hara P, Owens GR, Scanlon PD, 
Tashkin DP, Wise RA
Effects of smoking intervention and the use of an inhaled anticholinergic 
bronchodilator on the rate of decline of FEV1: the Lung Health Study.
JAMA 272 (19), 1497 – 1505 (1994)
R97-1015
Hargreave F.E.,., Dolovich J., O’Byrne P.M., Ramsdale E.H., Daniel E.E. 
The origin of airway hyperresponsiveness. J. Allergy Clin. Immunol. 
1986;78:825–832 gina,2012 or
R99-0658
Vestbo J, Prescott E, Lange P, Copenhagen City Heart Study Group
Association of chronic mucus hypersecretion with FEV1 decline and 
chronic obstructive pulmonary disease morbidity.
Am J Respir Crit Care Med 153, 1530 – 1535 (1996)


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9.2
UNPUBLISHED REFERENCES
C02337864
Investigator’s Brochure
C02861250-03
1363.1 Protocol
001-MCG-163
Statistics and Data Management Respiratory Standards
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamic


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10. 
APPENDICES
10.1   
HANDLING INSTRUCTIONS FOR RESPIMAT® INHALER FOR USE IN 
BI 443651 CLINICAL TRIALS 
These instructions explain generally the use of BI 443651 RESPIMAT inhaler. Depending on 
the clinical study, the product is administered under direct medical supervision or used by 
patients at home. Depending on the situation, the Instructions can be adapted to the specific 
situation as need be.
Read these Instructions for Use before you start demonstrating or using RESPIMAT.
  
How to store BI 443651 RESPIMAT

Keep BI 443651 RESPIMAT out of the sight and reach of children.

Do not freeze BI 443651 RESPIMAT. For further storage conditions, please refer to 
product label.

If BI 443651 RESPIMAT has not been used for more than 1 day, repeat steps 4 to 6 
under ‘Prepare for first Use’ until a cloud is visible. Then repeat steps 4 to 6 three 
more times.

Do not use BI 443651 RESPIMAT after the expiry date
How to care for BI 443651 RESPIMAT
Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or 
tissue only, at least once a week. 
Any minor discoloration in the mouthpiece does not affect BI 443651 RESPIMAT inhaler 
performance.


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When to get a new BI 443651 RESPIMAT
•
BI 443651 RESPIMAT inhaler contains 120 puffs if used as indicated.
•
The dose indicator shows approximately how much medication is left.
•
When the dose indicator enters the red area of the scale, get a new BI 443651 
RESPIMAT from the investigational site; there are approximately 30 puffs left.
•
Once the dose indicator reaches the end of the red scale, BI 443651 RESPIMAT locks
automatically – no more doses can be released. At this point, the clear base cannot be 
turned any further. The inhaler should not be discarded; it should be returned to 
investigational site.
Prepare for first use
1. Remove clear base

Keep the cap closed.

Press the safety catch while firmly 
pulling off the clear base with 
your other hand.
2. Insert cartridge

Insert the narrow end of the 
cartridge into the inhaler.

Place the inhaler on a firm surface 
and push down firmly until it 
snaps into place.


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


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Daily use
TURN

Keep the cap closed.

TURN the clear base in the direction of 
the arrows on the label until it clicks 
(half a turn).
OPEN

OPEN the cap until it snaps fully open.
PRESS

Breathe out slowly and fully.

Close your lips around the mouthpiece 
without covering the air vents.

While taking a slow, deep breath 
through your mouth, PRESS the dose-
release button and continue to breathe 
in.

Hold your breath for 10 seconds or for 
as long as comfortable.

Repeat Turn, Open, Press for a total of 2 
puffs.


Boehringer Ingelheim
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BI Trial No.: 1363.7
c11830963-01                      Trial Protocol
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Answers to Common Questions
It is difficult to insert the cartridge deep enough.
Did you accidentally turn the clear base before inserting the cartridge? Open the cap, 
press the dose-release button, then insert the cartridge.
Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow 
end first.
I cannot press the dose-release button.
Did you turn the clear base? If not, turn the clear base in a continuous movement until it 
clicks (half a turn).
Is the dose indicator on BI 443651 RESPIMAT pointing to zero? BI 443651 RESPIMAT 
inhaler is locked after 120 puffs. Prepare and use a new BI 443651 RESPIMAT inhaler.
I cannot turn the clear base.
Did you turn the clear base already? If the clear base has already been turned, follow steps 
“OPEN” and “PRESS” under “Daily Use” to get your medicine. 
Is the dose indicator on the BI 443651 RESPIMAT pointing to zero? The BI 443651 
RESPIMAT inhaler is locked after 120 puffs. Prepare and use your new RESPIMAT inhaler.
The dose indicator on the BI 443651 RESPIMAT reaches zero too soon. 
Did you turn the clear base before you inserted the cartridge? The dose indicator counts 
each turn of the clear base regardless whether a cartridge has been inserted or not.
Did you spray in the air often to check whether the BI 443651 RESPIMAT is working? 
Once you have prepared BI 443651 RESPIMAT, no test-spraying is required if used daily.
Did you insert the cartridge into a used RESPIMAT? Always insert a new cartridge into a 
NEW RESPIMAT.
BI 443651 RESPIMAT sprays automatically.
Was the cap open when you turned the clear base? Close the cap, then turn the clear base.


Boehringer Ingelheim
23 February 2017
BI Trial No.: 1363.7
c11830963-01                      Trial Protocol
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Did you press the dose-release button when turning the clear base? Close the cap, so the 
dose-release button is covered, then turn the clear base.
Did you stop when turning the clear base before it clicked? Turn the clear base in a 
continuous movement until it clicks (half a turn).
BI 443651 RESPIMAT doesn’t spray.
Did you insert a cartridge? If not, insert a cartridge.
Did you repeat Turn, Open, Press less than three times after inserting the cartridge? 
Repeat Turn, Open, Press three times after inserting the cartridge as shown in the steps 4 to 6 
under “Prepare for first Use”.
Is the dose indicator on BI 443651 RESPIMAT pointing to 0? If the dose indicator points 
to 0, you have used up all your medication and the inhaler is locked.
Once BI 443651 RESPIMAT is assembled, do not remove the clear base or the cartridge. 
Always insert a new cartridge into a NEW RESPIMAT.
Further information
BI 443651 RESPIMAT inhaler must not be disassembled after inserting the cartridge and 
replacing the clear base.
Do not touch the piercing element inside the base.
Boehringer Ingelheim Pharma GmbH & Co. KG
D - 55216 Ingelheim, Germany   


Boehringer Ingelheim
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BI Trial No.: 1363.7
c11830963-01                      Trial Protocol
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
“This is the original protocol.”
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Description of change
Rationale for change

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c17402608-02
BI Trial No.:
1363.7
Title:
A two part phase I, multiple-dose, single- and double-blind
randomised, double-dummy, placebo-controlled, four-way 
crossover study to assess safety and tolerability of BI 443651 via 
Respimat® versus placebo via Respimat® in subjects with mild 
asthma following methacholine challenge. 
Investigational
Product(s):
BI 443651
Responsible trial
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
23-JAN-2018 SIGNED
Version:
Version 2.0 Final
Page 1 of 31
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENT(S)................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINT .....................................................................................17
7.5
SECONDARY ENDPOINTS.............................................................................18
7.7
EXTENT OF EXPOSURE.................................................................................23
7.8
SAFETY ANALYSIS..........................................................................................23
7.8.1
Adverse events.....................................................................................................23
7.8.2
Laboratory data ..................................................................................................25
7.8.3
Vital signs.............................................................................................................25
7.8.4
ECG......................................................................................................................25
7.8.5
Others...................................................................................................................25
8.
REFERENCES....................................................................................................27
9.
ADDITIONAL SECTIONS ...............................................................................28


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9.1
STEPS IN CASE OF CONVERGENCE PROBLEMS FOR REPEATED 
MEASURES MODEL ........................................................................................28
9.2.1
Details for primary analyses ..............................................................................29
10.
HISTORY TABLE..............................................................................................31


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis (for both trial parts)......................11
Table 6.1: 2
Overview of treatments for intra-individual comparison.................................11
Table 6.1: 3
Flow chart of analysis phases for adverse events, laboratory tests, vital signs 
and spirometry..................................................................................................12
Table 6.2: 1
Important protocol violations...........................................................................13
Table 6.3: 1
Subject sets analysed........................................................................................14
Table 10: 1
History table .....................................................................................................31


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
AUC
Area under the curve
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
BP
Blood pressure
BRPM
Blinded report planning meeting
CARE
Clinical data analysis and reporting environment
CfB
Change from baseline
CI
Confidence interval
CML
Clinical Monitor Local
CRA
Clinical Research Assistant
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
EudraCT
European union drug regulating authorities clinical trials
ES
Enrolled Set
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use


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Term
Definition / description
IPV
Important protocol violation
KM
Kaplan-Meier
MCS
Methacholine set
MCh
Methacholine
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
P25
25th precentile
P75
75th precentile
PK
Pharmacokinetic(s)
PKS
PK analysis set
PR
Pulse rate
PV
Protocol violation
RAGe
Report appendix generator
REP
Residual effect period
RS
Randomised set
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SOP
Standard operation procedure
TS
Treated set
TSAP
Trial statistical analysis plan
VC
Variance components
WHO-DD
World Health Organisation – Drug Dictionary


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3.
INTRODUCTION
As per International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (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. In particular, 
the TSAP is based on the planned analysis specification as written in CTP Section 7 
“Statistical Methods and Determination of Sample Size”. Therefore, TSAP readers may 
consult the CTP for more background information on the study, e.g., on study objectives, 
study design and population, treatments, definition of measurements and variables, planning 
of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
The statistical analyses will be performed within the validated working environment CARE 
(Clinical data Analysis and Reporting Environment), including SASTM (current Version 9.4, 
by SAS Institute Inc., Cary, NC, USA), and a number of SASTM-based tools (e.g., macros for 
the analyses of adverse event (AE) data or laboratory data; Report Appendix Generator 
system (RAGe) for compilation/formatting of the clinical trial report (CTR) appendices). 
 


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Descriptive statistics for primary and secondary endpoints will be based on the MCS rather 
than TS to be consistent with the model-based analyses.
 
There are no further changes in the planned analysis of the study.


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5.
ENDPOINTS
Figure 5.1:1 in the CTP displays all spirometry measurements during one treatment period
that is during the baseline bolus challenge prior to drug administration, during drug 
administration and during the treatment challenge on Day 2.
In the following baseline refers to the measurement obtained from the baseline bolus 
Methacholine (MCh) challenge prior to administration of trial medication within each period.
5.1
PRIMARY ENDPOINT
CTP: The primary endpoint for the study to assess safety of BI 443651 is 

Absolute change from baseline in maximum FEV1 reduction following MCh challenge 
The primary endpoint will be compared to placebo for each dose level of BI 443651.
For a visualization of the endpoint refer to Figure 5.1:1, a detailed description of the primary 
endpoint and the primary statistical analysis is provided in Section 7 of the CTP.
5.2
SECONDARY ENDPOINTS
CTP: The following secondary endpoints will be assessed: 

Relative change from baseline in FEV1 AUC0-tz following bolus MCh challenge

Time to recovery of FEV1 to within 95% of post-diluent value
The secondary endpoints will be compared to placebo for each dose level of BI 443651.
For a visualization of the endpoints refer to Figure 5.1:1, a detailed description of the 
secondary endpoints including statistical analysis is provided in Section 7 of the CTP.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatments to be administered please refer to Section 4 of the 
CTP.
The trial is composed of two parts: The first part (pilot study) will be a single-blind four-way 
crossover with dose ordered sequences. The second part (main study) will be a double-blind 
four-way crossover, conducted according to a William’s design. In both parts of the study, BI 
443651 or placebo equivalent will be administered three consecutive times, 12 hours apart, 
per dose level. All subjects will receive placebo, 100, 400 and 1200 µg BI 443651. Each 
period will be separated by a washout period of at least 14 days (and not more than 28 days). 
Two administrations of BI 443651 will be delivered on Day 1 (morning and evening) and a 
single administration on Day 2 (morning).
Table 6.1: 1
Treatments and labels used in the analysis (for both trial parts)
Treatment
Short label
P
Placebo, respimat, bid
Plc
A
BI 443651 Respimat, 1*100 mcg/actuation, ih, bid
BI 100
B
BI 443651 Respimat, 4*100 mcg/actuation, ih, bid
BI 400
C
BI 443651 Respimat, 4*300 mcg/actuation, ih, bid
BI 1200
Table 6.1: 2
Overview of treatments for intra-individual comparison
Test treatment (T)
Reference treatment (R)
BI 100
(A)
Placebo
(P)
BI 400
(B)
Placebo
(P)
BI 1200
(C)
Placebo
(P)
Measurements (such as ECG, vital signs, or laboratory parameters) or adverse events (AE) 
will be assigned to treatments and study periods by applying the following rules:

Screening: measurements planned or AEs recorded prior to first device actuation for
administration of trial medication.

On-treatment: measurements planned or AEs recorded between first device actuation for
administration in one treatment period until first device actuation for administration of 
trial medication in the next treatment period or until the end of the respective residual 
effect period (REP) or until trial completion date (whichever occurs first) will be assigned 
to the preceding treatment. The REP for BI 443651 is defined as 
 after the last 
trial medication application.


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
Follow-up: measurements planned or AEs recorded between the end of REP of one 
treatment period and the first device actuation for treatment administration of the next 
treatment period or trial completion date. In case of more treatments, the follow-up will 
be summarized according to the previous treatment.
Table 6.1: 3
Flow chart of analysis phases for adverse events, laboratory tests, vital signs 
and spirometry
Study analysis 
phase
Start
End
Screening
Date of informed consent 
Date/time of first device actuation for
administration of BI 443651 or placebo
(first period)
On treatment
Date/time of first device actuation for
administration of BI 443651 or placebo
(in the actual treatment period)
0:00 AM on day after end of REP or trial 
completion date or date/time of first 
device actuation for drug administration
in the next treatment period
Follow-up
0:00 AM on day after end of REP
trial completion date or date/time of first
device actuation for drug administration
in the next treatment period
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects in the 
database (i.e. for all randomised subjects). 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 blinded 
report planning and database lock meeting (BRPM/DBLM). At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important protocol 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" (7).
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 (8). The 
following Table 6.2: 1 contains the categories which are considered to be important PVs in 
this trial. The last column describes which iPVs will be used to exclude subjects from the 
different subject analysis sets by default. The final decision about exclusion from analysis 
sets will be made at the BRPM/DBLM. If the data show other important PVs, this table will 
be supplemented accordingly by the time of the BRPM/DBLM.
IPVs will be summarised and listed.


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Table 6.2: 1
Important protocol violations
KEY: * not programmed
Category 
/ Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met
A1
Inclusion criteria violated*
Decision at BRPM/DBLM
None
A2
Exclusion criteria violated*
Decision at BRPM/DBLM
None
B
Informed consent
B1
Informed consent not available*
Informed consent date missing; no 
signature on ICF
All
B2
Informed consent too late*
Date of informed consent was after the 
date of any study-related procedure, or a 
patient signed the correct version of the 
ICF after Visit 1. To be discussed at 
BRPM/DBLM.
None
C
Trial medication and randomisation
C1
Incorrect trial medication taken*
Decision at BRPM/DBLM
None
C2
Randomisation order not followed*
None
C3
Non-compliance*
Decisions at BRPM/DBLM 
None
C4
Medication code broken 
inappropriately*
To be discussed and decided during 
BRPM/DBLM. Only inappropriate code 
breaks at IPVs (e.g., unblinding by 
Global Pharmacovigilance is not).
None
C5
Incorrect intake of trial medication*
Decision at  BRPM/DBLM
None
C6
Improper washout between 
treatments*
Decision at  BRPM/DBLM
None
D
Concomitant medication
D1
Prohibited medication use*
Decision at  BRPM/DBLM
None
D2
Mandatory medication not taken*
Decision at  BRPM/DBLM
None
D3
Improper washout of concomitant 
medication*
Decision at  BRPM/DBLM
None
E
Missing data
E1
Certain violations of procedures used 
to measure primary or secondary data*
Decision at  BRPM/DBLM
None
F
Incorrect timing
F1
Certain violations of time schedule 
used to measure primary or secondary 
data*
Decision at  BRPM/DBLM
None


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6.3
SUBJECT SETS ANALYSED
CTP: The statistical analysis will be based on the following analysis sets based on the actual 
treatment the subject receives.

Enrolled set (ES): This subject set includes subjects that signed informed consent and 
underwent screening procedures.

Randomised set (RS): This subject set includes all randomised subjects, whether 
treated or not. 

Treated set (TS): The treated set includes all subjects who were randomised and 
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the subjects received.

Methacholine set (MCS): This subject set includes all subjects in the treated set who 
provide at least one pair (baseline and end of treatment) of evaluable measures of 
spirometry parameters that were not excluded due to use of rescue medication within 
3 hours after start of MCh challenge.
 
 
 
 
Table 6.3: 1
Subject sets analysed
* An additional MCS presentation of the demographic/baseline endpoints may be provided in the EoT 
section, if subject numbers for MCS and treated set are clearly different.
Subject set
Class of endpoint
ES
RS
TS
MCS
Disposition
X
Exposure
X
Important PVs
X
Demographic data /baseline conditions
X
(X)*
Primary and secondary endpoints

Descriptive statistics
X

Mixed effects model
X
 
Further safety parameters
X


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6.5
POOLING OF CENTRES
Not applicable as this is a single centre trial.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
For evaluation of primary and secondary endpoints a measurement obtained at baseline and 
on-treatment per period is required. If a patient misses a visit, the missing data will not be 
imputed. The random intercept model will handle missing data based on a likelihood method 
under the "missing at random” assumptions.
Generally, it is not planned to impute missing values for further safety 
with 
the exception of missing or incomplete AE dates 
 These will be 
handled according to BI standards (see SOP 001-MCG-156_RD-01 (3) for missing AE dates 
 
 
 
 
 
 
 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline is defined as the last measurement before first study drug administration in each 
treatment period.
For endpoints related to methacholine challenge baseline refers to the measurement obtained 
from the baseline bolus MCh challenge prior to administration of trial medication within each 
treatment period. The post-diluent value refers to the last measurement before methacholine 
administration (i.e. timepoint -0:05 relative to methacholine challenge).
Measurements taken after start of administration of trial medication will be considered on-
treatment values or follow-up values, based on the definition of the study analysis phases in 
Section 6.1.
Adherence to time windows will be checked 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" (9).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number and visit (if visit is applicable in the respective listing). AE listings will be sorted by 
assigned treatment (see Section 7.8.1 below for details). The listings will be contained in 
Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For endpoints related to MCh challenge, the set of summary statistics is: N / Mean / SD / Min 
/ Q1 (1st quartile) / Median / Q3 (3rd quartile) / Max.
 
 
 
 
 
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 only if there are actually missing values. Percentages will be based 
on all subjects in the respective analysis set whether they have non-missing values or not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medication will be coded 
according to the most recent version of the World Health Organisation – Drug Dictionary
(WHO-DD).
Only descriptive statistics are planned for this section of the CTR.
A medication will be considered concomitant to a treatment, if 

it is ongoing at the time of first administration of the respective treatment or

it starts within the on-treatment phase of the respective treatment (see Section 6.1).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the BRPM/DBLM (cf. Section 6.2) and described in the 
CTR.
7.4
PRIMARY ENDPOINT
CTP: The primary endpoint absolute change from baseline in maximum reduction in FEV1 
(refer to Section 5.1.1 of the CTP) is defined as the difference between the maximum 
reduction in FEV1 obtained during the treatment challenge and during the baseline 
challenge.
The primary endpoint will be analyzed based on the MCS.
Descriptive statistics and boxplots of the primary endpoint by treatment (and by trial part) 
will be provided.
As main analysis, the following model will be applied to the main part of the trial (part II). 
Statistical model
CTP: […] this primary endpoint will be analysed using a mixed effects model based on the 
MCS:
 = 	 +  +  +  + 
 +  + ,
where i = subject 1,…, N, m = period 1,…,4, j = treatment 1,…,4


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
CfB in maximum FEV1 reduction for the ith subject and the mth
period, receiving randomised treatment j 
	
overall intercept, 

mth period effect,

jth treatment effect,

baseline value for subject i in period m (period baseline), 

associated covariate effect of period baseline, 


the subject baseline value (mean of period baselines) for subject i,

associated covariate effect of subject baseline,

the random effect of subject i,

the random error associated with subject i who received treatment 
j in period m.
The treatment comparisons will be the contrast (difference) between active dose and placebo 
at the endpoint visit. Adjusted means (Least Squares Means) as well as 2-sided 90% CIs will 
be provided.
For the random ‘subject’ effect in the above model a Variance Components (VC) covariance 
structure will be used; in case of convergence problems refer to Additional Section 9.1. The 
SAS procedure MIXED will be used involving the restricted maximum likelihood estimation 
and the Kenward-Roger approximation for denominator degrees of freedom. This approach is 
described in Kenward and Roger (11).
Programming details are provided in Section 9.2.1.
 
 
 
 
 
 
7.5
SECONDARY ENDPOINTS
The secondary endpoints will be analyzed based on the MCS.
Relative change from baseline in FEV1 AUC0-tz following bolus MCh challenge:
CTP: The secondary endpoint relative change from baseline in FEV1 AUC0-tz (see Section 
5.1.2 of the CTP) is defined as the ratio of FEV1 AUC0-tz obtained during the treatment 
challenge and during the baseline challenge. During each challenge, the area above the 
curve of the absolute change in FEV1 from post-diluent value will be calculated from time 0 


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to tz using the trapezoidal rule (refer to 001-MCG-163). The time tz refers to the last time 
point before recovery of FEV1 to within 95% of post-diluent value.
Note that in case a subject’s FEV1 does not recover to within 95% of post-diluent value the 
time tz refers to the last timepoint at which FEV1 was measured for that subject in that period. 
Furthermore, if a subjects FEV1 does not decrease below 95% of post-diluent value the AUC 
will not be defined and hence not be calculated.
Descriptive statistics and boxplots of the secondary endpoint by treatment (and by trial part) 
will be provided.
As main analysis, the following model will be applied to the main part of the trial (part II). 
The statistical model used for this secondary endpoints is comparable to the one specified for 
the primary endpoint, despite the fact that it is evaluated on the logarithmic scale.
Statistical model
CTP: […] this secondary endpoint will be analysed using a mixed effects model on the 
logarithmic scale based on the MCS:
 = 	 +  +  +  + 
 +  + ,
where i = subject 1,…, N, m = period 1,…,4, j = treatment 1,…,4

Logarithm of CfB in FEV1 AUC0-tz consideration for the ith subject 
and the mth period, receiving randomised treatment j 
	
overall intercept, 

mth period effect, 

jth treatment effect, 

Logarithm of baseline value for subject i in period m (period 
baseline), 

associated covariate effect of period baseline, 


Logarithm of the subject baseline value (mean of period baselines) 
for subject i,

associated covariate effect of subject baseline,

the random effect of subject i,

the random error associated with subject i who received treatment 
j in period m.
To this end, the endpoint will be log-transformed (natural logarithm) prior to fitting the 
model given above. The difference between the expected means for log(Active)-log(Placebo) 
will be estimated by the difference in the corresponding adjusted means (Least Squares 
Means), and a two-sided 90% confidence interval based on the t-distribution will be 
computed. These quantities will then be back-transformed to the original scale to provide the 
point estimate and 90% CIs for each endpoint.


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For the random ‘subject’ effect in the above model a Variance Components (VC) covariance 
structure will be used; in case of convergence problems refer to Additional Section 9.1. 
The SAS procedure MIXED will be used involving the restricted maximum likelihood 
estimation and the Kenward-Roger approximation for denominator degrees of freedom. This 
approach is described in Kenward and Roger (11).
Programming details are provided in Section 9.2.1.
 
 
 
 
Time to recovery of FEV1 to within 95% of post-diluent value
CTP: The secondary endpoint time to recovery of FEV1 within 95% of post-diluent value 
(see Section 5.1.2 of the CTP) is defined as the time from maximum reduction to last time 
before recovery to within 95% of pre-MCh challenge during each challenge. The time 
obtained from the treatment challenge represents the endpoint, while the time obtained from 
the baseline challenge will be used for the baseline correction in the analysis.
Descriptive statistics of the secondary endpoint by treatment (and by trial part) will be 
provided.
Kaplan-Meier (KM) curves will be plotted for the recovery of FEV1 within 95% of post-
diluent value by treatment irrespective of the period it is administered in, for both trial parts 
separately as well as combined, if applicable. 
As a main analysis the following model will be applied to the main part of the trial (part II). 
Statistical model
CTP: […] this endpoint will be analysed using a Cox proportional hazards model as given 
below based on the MCS. The model includes the treatment effect and an effect for subject 
baseline. Thereby, the subject baseline is calculated as median of all period baselines per 
subject. Breslow’s method for handling ties will be used.
The hazard function for the ith subject is assumed to be 
() = () ⋅{ +  +   },
where i = 1,…, N,


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() is the unspecified, non-negative, baseline hazard function

,, are the unknown regression coefficients

 represents the treatment group

 represents the subject baseline (median of period baselines)

  represents the period
For treatment comparisons the hazard ratios of BI 443651 vs. Placebo and asymptotic 95% 
Wald confidence intervals will be estimated. A hazard ratio of greater than one means that BI 
443651 is not inferior to placebo. 
Programming details are provided in Section 9.2.1.
 
 
 
 
 
 
 


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7.7
EXTENT OF EXPOSURE
Treatment exposure will be listed by means of the date and time of drug administration.
7.8
SAFETY ANALYSIS
All safety analyses of further safety parameters of interest will be performed on the treated 
set (and will be presented for both trial parts combined).
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 electronic case report form (eCRF) will be 
collapsed into one event provided that all of the following applies:


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
All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest (AESI))

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
For further details on summarization of AE data, please refer to 'Handling and summarization 
of adverse event data for clinical trial reports and integrated summaries' (4) and "Handling of 
missing and incomplete AE dates" (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs, i.e. all AEs will 
be assigned to the treatment phase, screening phase or follow-up phase 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 
adverse events of special interest (AESI). For the definition of AESI please refer to Section 
5.3.6.1 of the CTP.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 
will be summarised separately. Separate tables will also be provided for subjects with serious 
AEs (SAEs), related SAEs, subjects with AESIs and subjects with other significant AEs 
(according to ICH E3 (5)). AEs will also be summarized by maximum intensity.
The system organ classes will be sorted according to the standard sort order specified by the 
European Medicines Agency (EMA), preferred terms will be sorted by total frequency 
(within system organ class).
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary system organ class and preferred term. The frequency of subjects with 
SAEs will also be summarised.
For disclosure of AE data in the European union drug regulating authorities clinical trials
(EudraCT) register, the frequency of AEs, the frequency of non-serious AEs with an 
incidence of greater than 5 % (in preferred terms) and the frequency of SAEs will be 
summarised.


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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 (6). If possible, analyses will be based on normalized values. If multiple reference 
ranges apply for one parameter (e.g. due to different age groups), analyses will be based on 
normalised values, which means transforming to a standard unit and a standard reference 
range.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done by comparing laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Treatment groups will be compared based on descriptive statistics of laboratory values over 
time and by analysing differences from baseline. Additionally, frequency tables of changes 
between baseline and last values on treatment with respect to the reference ranges as well as 
frequencies and percentages of subjects with abnormal values or clinically relevant abnormal 
values will be presented.
Clinically relevant findings in laboratory data will be reported as AEs and will be analysed as 
part of AE analysis.
7.8.3
Vital signs
The analyses of vital signs will be descriptive in nature. Descriptive statistics of vital signs 
over time and for the changes from baseline (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
Abnormal findings in the 12-lead ECG will be reported as baseline conditions (at screening) 
or as AEs (during the trial) if judged clinically relevant by the investigator.
7.8.5
Others
7.8.5.1
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.
7.8.5.2
Pulmonary function tests
Clinically relevant findings in spirometry data (FEV1 and FVC) will be reported as AEs and 
will be analysed as part of AE analysis.


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Descriptive statistics will be provided for FEV1 and FVC obtained at the screening visit 
based on the TS.
Analyses of further endpoints and parameters of interest related to PFT are described in 
Section 7.6.1.
7.8.5.3
Methacholine challenge
Descriptive statistics will be provided for the methacholine concentration (PD20) obtained 
from the incremental challenge during screening visit based on the TS.


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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 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
3.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON.
4.
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
5.
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
6.
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
7.
001-MCS-50-413_RD-01: "Protocol Violation Handling Definitions", current version, 
IDEA for CON
8.
001-MCS-50-413_RD-02: "Important Manual Protocol Violations Spreadsheet", current 
version, IDEA for CON
9.
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current version; 
IDEA for CON.
10. 001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON
11. Kenward, M.G. and Roger, J.H. (2010) The use of baseline covariates in cross-over 
studies. Biostatistics, 11:1-17 [R10-4391]


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9.
ADDITIONAL SECTIONS
9.1
STEPS IN CASE OF CONVERGENCE PROBLEMS FOR REPEATED 
MEASURES MODEL 
In case of convergence problems one may try one (or more) of the following steps:
1) Set SINGULAR=1E-10 as option (for PROC MIXED: in the model statement) – This 
raises the threshold at which columns are declared linearly dependent (from typically 1e-
12).
2) Set MAXITER=100 (or even higher for PROC GLIMMIX) and/or MAXFUNC=200
(for PROC GLIMMIX, these options are available within the NLOPTIONS 
statement) – This increases the number of convergence iterations used from a default of 
50.
3) Use option SCORING=4 in the final run to request a Fisher scoring algorithm to be 
used for the first 4 iterations.
4) Include the additional statement in the PROC MIXED call:
PERFORMANCE NOTHREAD;
– this removes multi-threading from the calculations.
5) Provide starting values for covariance parameters using a ‘parms’ statement.
Perform an initial run including the statement
ODS OUTPUT COVPARMS=covstart;
followed by a final run using
PARMS / PARMSDATA=covstart;
In the special case with the note “Convergence criteria met but final hessian is not 
positive definite” try instead/in addition
PARMS / OLS;
to request ordinary least squares starting values.
One may also use estimates from a simpler model (e.g. using AR(1)) as starting 
values for the run with TYPE=UN or UNR
In case the VC covariance matrix does not work, also in conjunction with all steps from 1)-6) 
mentioned above, the following covariance structures will be chosen, in the pre-defined 
order:
-
Unstructured covariance matrix (type = UN)
-
Toeplitz structure with heterogeneous variances (type = TOEPH) 
-
Standard Toeplitz matrix (type = TOEP)
-
first-order autoregressive structure (type = AR(1))


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9.2.1
Details for primary analyses
The following SAS code can be used to fit the model for the primary endpoint:
PROC MIXED data=indata METHOD=reml ORDER=formatted;
    CLASS SUBJID ATRTSL APERIOD;
    MODEL CHG = ATRTSL APERIOD BASE baseavg / SOLUTION DDFM = KR 
OUTP=pred;
    RANDOM INTERCEPT / SUBJECT = SUBJID TYPE=VC;
    LSMEANS ATRTSL / PDIFF=control('Placebo') CL ALPHA=0.1;
RUN ;
The following SAS code can be used to fit the model for the secondary endpoint ‘FEV1
AUC0-tz’:
PROC MIXED data= indata METHOD=reml ORDER=formatted ;
    CLASS SUBJID ATRTSL APERIOD;
    MODEL LNRATIO = ATRTSL APERIOD  lnbase lnbaseavg / SOLUTION DDFM 
= KR OUTP=pred;
    RANDOM INTERCEPT / SUBJECT = SUBJID TYPE=VC;
    LSMEANS ATRTSL / PDIFF=control('Placebo') CL ALPHA=0.1;
RUN ;
The following SAS code can be used to fit the model for the secondary endpoint ‘Time to 
recovery’:
PROC PHREG DATA= adtte;
    CLASS ATRTSL (REF='Placebo') APERIOD;
    MODEL aval*cnsr(1) = ATRTSL APERIOD BASEAVG  / TIES=BRESLOW;
    HAZARDRATIO ATRTSL / DIFF=REF CL=WALD ALPHA=0.05;
    ODS OUTPUT HAZARDRATIOS=hazard;
RUN;
 


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
17-MAY-17
None
This is the initial TSAP with necessary 
information for trial conduct
Final
23-JAN-18
All
This is the final TSAP.