Conditions: Cystic Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 64
Healthy volunteers: yes

Brief summary:
The objective of this study is to investigate the safety, tolerability, and pharmacokinetics of BI 443651 in male and female healthy volunteers and subjects with Cystic Fibrosis (CF).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 443651 intervention 2: Placebo
Intervention descriptions: intervention 1: twice daily intervention 2: twice daily

Protocol document:
Prot_001.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c09013915-08
EudraCT No.:
2016-001504-31
BI Trial No.:
1363.2
BI Investigational 
Product(s):
BI 443651
Title:
A Phase Ib, multicentre, double blind, randomized, two-part 
study, first part multiple rising dose and second part two-way 
cross-over, to assess safety, tolerability, efficacy and 
pharmacokinetics of BI 443651 compared to placebo via 
Respimat® in healthy volunteers and CF subjects.
Lay Title:
BI 443651 multiple rising dose in Healthy Volunteers followed 
by a cross-over in CF subjects
Clinical Phase:
Phase Ib
Trial Clinical 
Monitor:
Tel: 
Fax: 
Email:
Coordinating 
Investigators:
Tel: 
Fax: 
Email: 
Status:
Final Protocol (Revised Protocol (based on Amendment 7))
Version and Date:
Final Version: 8.0
Date: 09 November 2017
Page 1 of 125
Proprietary confidential information.
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:
NA
Name of active ingredient:
BI 443651
Protocol date:
01 August 2016
Trial number:
1363.2
Revision date:
09 November 2017
Title of trial:
A Phase Ib, multicentre, double blind, randomized, two-part study, first part 
multiple rising dose and second part two-way cross-over, to assess safety, 
tolerability, efficacy and pharmacokinetics of BI 443651 compared to placebo via 
Respimat® in healthy volunteers and CF subjects.
Coordinating
Investigators:
Tel: 
Fax: 
Email: 
Clinical phase:
Ib
Objective(s):
The primary objectives of this trial are to:
(Part 1 MRD part) Investigate the safety and tolerability of inhaled BI 443651 in 
comparison to placebo in healthy volunteers.
(Part 2 Cross-over part) Investigate the safety and tolerability of inhaled BI 443651 
in a cross-over design, in comparison to placebo in Cystic Fibrosis (CF) subjects.
The secondary objective is to investigate pharmacokinetics of BI 443651.
All doses of BI 443651 and placebo will be given via the Respimat®.
Methodology:
Part 1: Multiple rising dose in healthy volunteers, double blind within dose groups, 
randomised; 
Part 2: Two period cross-over part in CF subjects, double blind, randomized with at 
least 30 day washout.
No. of subjects: 
total entered:
64 (Additional subjects may be entered to allow testing of additional (e.g. 
intermediate) doses within the planned dose range on the basis of experience gained 
during trial conduct, i.e. the actual number of subjects entered may differ from 64)
each treatment:
Part 1: Healthy volunteers in all four dose groups: 10 per dose group (8 on active 
drug and 2 on placebo) = 40 total
Part 2: CF subjects in a two period, two treatment design: 24 subjects (12 per 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 443651
Protocol date:
01 August 2016
Trial number:
1363.2
Revision date:
09 November 2017
sequence)
Diagnosis :
Part 1: Healthy male or female volunteers
Part 2: Stable male or female Cystic Fibrosis subjects
Main criteria
for inclusion:
Healthy volunteers: age 18 and 55 years; BMI range: 18.5 and 32 kg/m2; male 
or female (complying with highly effective methods of contraception)
CF: Subjects with confirmed diagnosis of CF; FEV1 ≥ 70% predicted; age 18 and 
55; male or female (complying with highly effective methods of contraception)
Test product(s):
BI 443651 via the Respimat®
dose:
All doses are ex-mouthpiece b.i.d for six and a half day for Healthy Volunteers and 
thirteen and a half days for CF subjects.
Healthy volunteers: 100 µg, 400 µg, 1200 µg and 1800 µg BI 443651 b.i.d. CF: 600
µg BI 443651 b.i.d
Doses may change based on data obtained during the study (will not exceed 1800 
µg BI 443651 b.i.d, ex mouthpiece)
mode of 
administration:
Inhalation via the Respimat®
Comparator products:
Placebo via the Respimat®
dose:
N/A
mode of 
administration:
Inhalation via the Respimat®
Duration of treatment:
Part 1: 6.5 days treatment for healthy volunteers
Part 2: two 13.5 days treatment periods separated by a wash-out of at least 30 days 
for CF subjects.
Endpoints
Primary endpoint:
Safety and tolerability of BI 443651, as assessed by frequency (in percent) of 
Healthy volunteers and CF subjects respectively with treatment-emergent adverse 
events (TEAE) over the treatment period (results for each of the subject populations 
will be reported separately)
Secondary endpoints:
For Part 1, after the first dose: AUC0-12 and Cmax 
After the last dose at steady state: AUCτ, ss and Cmax, ss
 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 443651
Protocol date:
01 August 2016
Trial number:
1363.2
Revision date:
09 November 2017
Criteria for safety:
Safety and tolerability of BI 443651, as assessed by frequency (in percent) of 
Healthy volunteers and CF subjects with treatment-emergent adverse events 
(TEAE) over the treatment period (results will be reported separately for each
group).
Statistical methods:
The two trial parts will be evaluated separately.
Descriptive statistics will be calculated for all endpoints.
If feasible, in Part 1 only, dose proportionality of BI 443651 will be explored using 
a regression model. A 95% confidence interval (CI) for the slope will be computed.
 
 
 


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FLOW CHART I – HEALTHY VOLUNTEERS
Visit
Day
Planned Time relative to 
first drug administration 
[h:min]
Approximate clock time 
(actual day) [h:min]
Event and comment
Safety Laboratory3
PK blood
 
12-lead ECG6
Pulmonary function 
testing 17
Body plethysmography
Vital signs (BP, PR)12
Adverse events / 
Concomitant Meds11
1
-21 to -3
screening1
X3,15,19
x
x
x
x
x
2
-7 to -3
in-clinic visit
X3,4
x
1
-02.00
06:00
admission, device train14
x8,15,19
x
-01:30
06:30
allocation to treatment14
x
x
x
x
-01:00
07:00
x16
x
-00:15
07:45
x2
x
00:00
08:00
drug administration7, 250 
mL water intake
x
00:05
08:05
x
x
00:15
08:15
x
x
00:30
08:30
x
x
x
x
x
00:45
08:45
x
x16
x
01:00
09:00
x
x
x
x
02:00
10:00
250 mL water intake, 
thereafter breakfast13
x
x16
x
x
x
x
04:00
12:00
250 mL water intake, 
thereafter lunch13
x
x16
x
x
x
06:00
14:00
x
x
08:00
16:00
snack (voluntary)13
x
x
x
10:00
18:00
dinner
x
11:00
19:00
x16
x
x
x
11:45
19:45
x2
x
12:00
20:00
drug administration7
x
12:05
20:05
x
x
12:30
20:30
x
x
x
13:00
21:00
x
x
x
2
23:00
07:00
x16
x
x
x
23:45
07:45
x8
x2
x
24:00
08:00
drug administration7
x
24:05
08:05
x
x
24:30
08:30
x
x
x
25:00
09:00
x
x
26:00
10:00
breakfast13
x
x
x
28:00
12:00
lunch
x
32:00
16:00
snack (voluntary)
x
34:00
18:00
dinner
x
35:00
19:00
x
x
x
36:00
20:00
drug administration7
x
3
47:00
07:00
x
x
x
47:45
07:45
x8
x2
x
48:00
08:00
drug administration7
x
48:30
08:30
x
x
x
49:00
09:00
x
x
50:00
10:00
breakfast13
x
x
52:00
12:00
lunch
x
56:00
16:00
snack (voluntary)
x
58:00
18:00
dinner
x
59:00
19:00
x
x
x
60:00
20:00
drug administration7
x


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FLOW CHART I – HEALTHY VOLUNTEERS (cont.)
Visit
Day
Planned Time relative to 
first drug administration 
[h:min]
Approximate clock time 
(actual day) [h:min]
Event and comment
Safety Laboratory3
PK blood
 
12-lead ECG6
Pulmonary function 
testing17
Body plethysmography
Vital signs (BP, PR)12
Adverse events / 
Concomitant Meds11
2
4
71:00
07:00
x
x
x
x
71:45
07:45
x8
x2
x
72:00
08:00
drug administration7
x
73:00
09:00
x
x
74:00
10:00
breakfast13, discharge
x
x
83:00
19:00
x
x
84:00
20:00
in-clinic drug admin7
x
5
96:00
08:00
in-clinic drug admin7
x8
x
108:00
20:00
in-clinic drug admin7
x
6
119:45
07:45
in-clinic
x8
x2
x
120:00
08:00
in-clinic drug admin7
x
121:00
09:00
allow home
x
x
132:00
20:00
in-clinic drug admin7
x
7
143:00
07:00
admission
x16
x
x
x
x
143:45
07:45
x3,8,15
x2
x
144:00
08:00
drug administration7, 250 
mL water intake
x
144:05
08:05
x
x
144:15
08:15
x18
x
144:30
08:30
x18
x
x
x
x
144:45
08:45
x18
x16
x
145:00
09:00
x18
x
x
x
146:00
10:00
250 mL water intake, 
thereafter breakfast13
x18
x16
x
x
x
x
148:00
12:00
250 mL water intake, 
thereafter lunch13
x18
x16
x
x
x
150:00
14:00
x18
x
152:00
16:00
snack (voluntary)13
x18
x
x
154:00
18:00
dinner
x
155:00
19:00
x16
x
x
x
x
155:45
19:45
x18, 2
x
156:00
20:00
x
8
167:00
07:00
x16
x
x
x
168:00
08:00
breakfast (voluntary),
discharge
x8
x
x
12
264:00
08:00
follow-up in-clinic visit
x
x
16
360:00
08:00
follow-up in-clinic visit
x8
x
x
x
x
x
23
528:00
08:00
follow-up in-clinic visit
x8
x
x
x
x
x
30
696:00
08:00
follow-up in-clinic visit
x8
x
x
x
x
x
4
37-44
9999:00
08:00
e.o.s.9 
X3,15
x
x
x
x
x
x
Note:
- 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: 
○
Pre-dose procedures will be performed in the following order, ensuring that PK bloods take priority with 
regards to timing:
1.
ECGs


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2.
Vital signs
3.
PFTs 
4.
Body Plethysmography
5.
PK blood (on the time-point)
6.
Meals
○
Post-dose procedures will be performed in the following order, ensuring that PK bloods take priority with 
regards to timing:
1.
ECGs
2.
Vital signs
3.
PK blood (on the time-point)
4.
PFTs
5.
Body Plethysmography
6.
Meals
1)
Screening including subject information, informed consent, physical examination and review of vital signs/ECG/
safety laboratory tests, drug screening (urine at site), alcohol breath test; additionally, demographics including 
determination of the body weight/height, smoking and alcohol history, relevant medical history, concomitant 
medication, pregnancy test for female subjects of childbearing potential and review of inclusion/exclusion criteria.
2)
 Pre-dose blood samples for PK will be taken from approximately 15 minutes prior to dosing. 
All remaining PK samples will be taken as close as possible to the planned times, as mentioned in section 6.1.
3)
Full Clinical Safety Labs as per section 5.3.7, unless otherwise specified. Safety labs for electrolytes should be 
centrifuged and stored as per requirements in section 5.3.7.
4)
Safety laboratory to be taken and to be medically evaluated within 7 days prior to administration of study drug; this 
safety laboratory can be omitted, if the screening examination is performed on Days -7,-6, -5, -4 or -3.. Female 
subjects of childbearing potential will have progesterone levels measured (between Day 7 and Day 10 of their pill 
packet) during the screening period and Day-5 to -3.
6)
ECGs will be recorded for a 10-sec duration after the subjects have rested for at least 5 min in a supine position. 
Screening ECG can be performed with site ECG equipment but transferred to 
7)
All pre-dose measurements to be completed prior to dosing. Drug inhalation will take place at the same clock time, 
for morning and evening dosing, throughout the investigational period. Dosing will be under supervision at the trial 
site for all days. 
8)
Serum electrolyte samples only to be collected on Day 1, 2, 3, 4, 5, 6, 7, 8, 16, 23, 30 using local laboratory values 
in addition to central laboratory values.
9)
End-of-study visit ; Including physical examination, weight, pregnancy test, review of vital signs/ECG/laboratory, 
serum pregnancy test (WOCBP only) at the end-of-study examination.
11)
AEs and concomitant therapies will be recorded throughout the trial but will be specifically asked for at the time 
points indicated in the Flow Chart above
12)
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a blood pressure monitor 
at the times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine position
13)
If several actions are indicated at the same time point, the intake of fluid/meals will be the last action.
14)
The time is approximate; the respective procedure is to be performed and completed within 3 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed 
prior to first drug administration.
15)
Urine pregnancy test for females (WOCBP only) on Day 1 and Day 7. Serum pregnancy test at screening, Day-5 to 
-3, and e.o.s. visit.
16)
All ECGs on Day 1, Day 2, Day 7 & Day 8 will be in triplicate. All other ECGs to be single.
17)
Body Plethysmography / Pulmonary function to be performed using Investigative site spirometry equipment.
18)
On Day 7 for dose group 400µg and 1200µg only, for each PK timepoint, both a PK sample and a metabolite 
identification (MIST) sample will be taken (refer to Section 5.4.2.2).
19)
Urine drug screen and alcohol breath test to be performed at screening and Pre-dose Day 1.


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FLOW CHART II – CF SUBJECTS
Period
Visit
Day
Planned Time relative to 
first drug administration 
[h:min]
Planned Time relative to 
a.m. drug administration 
at corresponding day ) 
[h:min]
Approximate clock time 
(actual day) [h:min]
Event and comment
Safety Laboratory3
PK blood
12-lead ECG6
CASA-Q & CFQ-R
Pulmonary function 
testing 5
Vital signs (BP, PR)18
Adverse events / 
Concomitant Meds16
SCR
1
-21 to 
-3
screening1,
X19,22
x
x
x
x
Period 1 / 2 – Two identical periods with a wash-
out of at least 30 days
2 / 3
-7 to -
325
08:00
in-clinic visit, device 
training17, allow 
home
x4,19
x
x13
x
x
1
-01:00
-01:00
07:00
in-clinic visit
x,19,22,24
x21
x
-00:30
-00:30
07:30
x
x
x
-00:15
-00:15
07:45
randomisation15
x2
x
00:00
00:00
08:00
drug administration7, 
250 mL water intake
x
00:05
00:05
08:05
x
x
00:15
00:15
08:15
00:30
00:30
08:30
x
x
x
x
x
00:45
00:45
08:45
device instruction17
x
x
01:00
01:00
09:00
x
x
x
02:00
02:00
10:00
250 mL water intake, 
thereafter, breakfast12
allow home
x
x
x
12:00
12:00
20:00
drug administration
x20
x
2
to 
6
00:00
08:00
drug administration
x20
x14
12:00
20:00
drug administration
x20
x14


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FLOW CHART II – CF SUBJECTS (cont.)
Period
Visit
Day
Planned Time relative to 
first drug administration 
[h:min]
Planned Time relative to 
first drug administration 
[h:min]
Approximate clock time 
(actual day) [h:min]
Event and comment
Safety Laboratory3
PK blood
12-lead ECG6
CASA-Q & CFQ-R
Pulmonary function 
testing5
Vital signs (BP, PR)18
Adverse events / 
Concomitant Meds16
Period 1 / 2 – Two identical periods with a wash-out of at least 
30 days between drug administration
7 (+/- 2 
days)
143:00
-01:00
07:00
in-clinic visit
x
x
143:30
-00:30
07:30
x
x
x
143:45
-00:15
07:45
X19, 24
x2
x
144:00
00:00
08:00
device instruction17, 
drug administration7,
x
144:30
00:30
08:30
allow home
x
x
x
x
156:00
12:00
20:00
drug administration
x20
x14
2 / 3
8 to 13
00:00
08:00
drug administration
x20
x14
12:00
20:00
drug administration
x20
x14
14 (-1/+3 
days)
311:00
-01:00
07:00
in-clinic visit
x
x
x
x
311:30
-00:30
07:30
x
x
x
311:45
-00:15
07:45
x19,24
x
x
312:00
00:00
08:00
drug administration7,
250 mL water intake
x
312:05
00:05
08:05
x
x
312.15
00:15
08.15
x
312:30
00:30
08:30
x
x
x
x
312:45
00:45
08:45
x
x
313:00
01:00
09:00
x
x
x
314:00
02:00
10:00
250 mL water intake, 
thereafter, breakfast12
allow home
x
x
x
23 (+/-2 
days)
528:00
00:00
08:00
telephone call
x
30 (+/- 5 
days)
696:00
00:00
08:00
in-clinic visit
x19
x
x
x
x
After Day 14 of Visit 2 (Period 1), subjects will washout for at least 30 days prior to crossing-over and commencing
Day 1 of Visit 3 (Period 2). A second baseline (Day-7 to -3) will be conducted within the washout period.
At the end of Visit 3 (Period 2), subjects will continue to the end of study visit (Visit 4).
Period
Visit
Day
Planned Time relative to 
first drug administration 
[h:min]
Planned Time relative to 
first drug administration 
[h:min]
Approximate clock time 
(actual day) [h:min]
Event and comment
Safety Laboratory3
PK blood
12-lead ECG6
CASA-Q & CFQ-R
Pulmonary function 
testing5
Vital signs (BP, PR)18
Adverse events / 
Concomitant Meds16
EOS
4
–44-51
9999:00
00:00
08:00
e.o.s.9, in-clinic visit
X19
x
x
x
x
x
Note:
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:


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o
Pre-dose procedures will be performed in the following order, ensuring that PK bloods take priority with 
regards to timing:
1.
ECGs
2.
Vital signs
4.
PFTs 
5.
Safety labs/ PK blood (on the time-point)
6.
Meals
o
Post-dose procedures will be performed in the following order, ensuring that PK bloods take priority with 
regards to timing:
1.
ECGs
2.
Vital signs
4.
Safety labs/ PK blood (on the time-point)
5.
PFTs 
6.
Meals
- If mentioned at the same time point meals will be served after completion of the planned procedure (i.e. PK, 
pulmonary function).
- Urinalysis and urine samples can be performed any time pre-dose.
1)
Screening including subject information, informed consent, physical examination and review of vital 
signs/ECG/safety laboratory tests, drug screening; additionally, demographics including determination of the body 
weight/height, smoking and alcohol history, relevant medical history, concomitant medication, pregnancy test for 
female subjects and review of inclusion/exclusion criteria. 
2)
Pre-dose blood samples for PK will be taken from approximately 15 minutes prior to dosing. All remaining PK 
samples will be taken as close as possible to the planned times, as mentioned in section 6.1.
3)
Full Clinical Safety Labs as per section 5.3.7, unless otherwise specified. Safety labs for electrolytes should be 
centrifuged and stored as per requirements in section 5.3.7.
4)
Must be completed and medically evaluated within 7 days prior to administration of study drug; this safety 
laboratory can be omitted, if the screening examination is performed on Days-7, -6, -5, -4 or -3. Female subjects of 
childbearing potential will have progesterone levels measured (between Day 7 and Day 10 of their pill packet) 
during the screening period and Day -5 to -3 then prior to the second treatment period. 
5)
Should be completed 
at relevant visits. Pulmonary function to be performed using Investigative site 
spirometry equipment (FEV1, FVC, FEF25-75) at in-house visits except Day -7 to -3 of each treatment period. 
 (FEV1,) to be used at home (ex-clinic).
6)
ECGs will be recorded for a 10-sec duration after the subjects have rested for at least 5 min in a supine position
7)
All pre-dose measurements should be completed prior dosing. Dosing will be under supervision at the trial site 
during all in-house test-days (Period 1 & 2 - Days 1, 7, and 14).
9)
End-of-study visit; including physical examination, review of vital signs/ECG/laboratory at the end-of-study 
examination 
12)
If several actions are indicated at the same time point, the intake of fluids/meals will be the last action.
13)
Unsupervised Pulmonary Function (FEV1, PEF) with AM3® device
14) 
Phone call to be made twice a day, ideally at the time of study drug administration (see section 5.3.6). During the
afternoon or evening calls, AEs should be collected in line with a morning call
15) 
Allocation to treatment may be performed at any time following enrolment but must be completed prior to first
drug administration. Randomisation not required for CF subjects undergoing second treatment period
16)
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time 
points indicated in the Flow Chart II above including during phone calls when patients are ex clinic.
17)
Respimat device and AM3® device training initially, then instruction (if required).
18)
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a blood pressure monitor 
at the times indicated in the Flow Chart II, after subjects have rested for at least 5 min in a supine position.
19)
Includes, urine pregnancy test for females at Screening, Day 1, Day 7, Day 14 and Day 30. Serum pregnancy test 
at Day-5 to -3, and e.o.s. visit.
20)
To be measured on home based spirometer (AM3®), prior to drug administration.
21)
Baseline ECG (Day 1) must be in triplicate. All other ECGs to be single.
22)
Urine drug screen and alcohol breath test to be performed at both screening and Pre-dose Day 1,.
 
24) 
Serum electrolytes to be collected using local laboratory values in addition to central laboratory values.
25)
Planned time is required for technical reasons and the actual dates and times could be between Day -7 to -3.


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TABLE OF CONTENTS  
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART I
– HEALTHY VOLUNTEERS.............................................................5
FLOW CHART II – CF SUBJECTS.....................................................................................8
TABLE OF CONTENTS ......................................................................................................11
ABBREVIATIONS................................................................................................................15
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................18
1.2.1
Nonclinical pharmacology..................................................................................18
1.2.2
Safety pharmacology...........................................................................................19
1.2.3 
Toxicology............................................................................................................19
 
1.2.5
Drug product .......................................................................................................20
1.2.6
Clinical studies and experience in humans.......................................................20
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....22
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................22
2.2
TRIAL OBJECTIVES........................................................................................22
2.3
BENEFIT - RISK ASSESSMENT.....................................................................22
2.3.1 
Procedure-related risks ......................................................................................23
2.3.2
Drug-related risks and safety measures............................................................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................27
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................27
3.1.1
Start of CF dose groups:.....................................................................................28
3.1.2
Dose escalation: ...................................................................................................28
3.1.3
Administrative structure of the trial .................................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................30
3.3
SELECTION OF TRIAL POPULATION .......................................................31
3.3.1
Main diagnosis for trial entry ............................................................................31
3.3.2
Inclusion criteria .................................................................................................31
3.3.3
Exclusion criteria (all Parts) ..............................................................................33
3.3.4
Removal of subjects from therapy or assessments...........................................35
3.3.4.1
Discontinuation of the trial ...................................................................................36
3.3.5
Subject replacement............................................................................................37
4.
TREATMENTS...................................................................................................38
4.1
INVESTIGATIONAL TREATMENTS ...........................................................38
4.1.1
Identity of the Investigational Medicinal Products..........................................38


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4.1.2
Selection of doses in the trial..............................................................................39
4.1.3
Method of assigning subjects to treatment groups ..........................................40
4.1.4
Drug assignment and administration of doses for each subject .....................40
4.1.5
Blinding and procedures for unblinding...........................................................42
4.1.5.1
Blinding.................................................................................................................42
4.1.5.2
Unblinding and breaking the code ........................................................................43
4.1.6
Packaging, labelling, and re-supply...................................................................43
4.1.7
Storage conditions...............................................................................................43
4.1.8
Drug accountability.............................................................................................44
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................44
4.2.1
Other treatments and emergency procedures..................................................44
4.2.1.1 
Rescue medication ................................................................................................44
4.2.2
Restrictions ..........................................................................................................45
4.2.2.1
Restrictions regarding concomitant treatment ......................................................45
4.2.2.2
Medication restrictions for all lung function testing 
47
4.2.2.3
Restrictions on diet and life style..........................................................................47
4.2.2.4
Restrictions regarding women of childbearing potential ......................................49
4.3
TREATMENT COMPLIANCE........................................................................49
5.
VARIABLES AND THEIR ASSESSMENT ....................................................50
5.1
TRIAL ENDPOINTS..........................................................................................50
5.1.1
Primary Endpoint(s)...........................................................................................50
5.1.2
Secondary Endpoint(s) .......................................................................................50
5.1.3
Further Endpoint(s)............................................................................................50
5.3
ASSESSMENT OF SAFETY.............................................................................52
5.3.1
Physical examination ..........................................................................................52
5.3.2
Vital Signs............................................................................................................53
5.3.3
Medical examinations .........................................................................................53
5.3.4
Spirometry...........................................................................................................53
5.3.5
Body Plethysmography.......................................................................................54
5.3.6
CF control during the trial.................................................................................54
5.3.7
Safety laboratory parameters ............................................................................55
5.3.8
Electrocardiogram ..............................................................................................58
5.3.10
Assessment of adverse events.............................................................................60
5.3.10.1
Definitions of Adverse Events (AEs )...................................................................60
5.3.10.2
Adverse event collection and reporting ................................................................63
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................65
5.4.1
Assessment of Pharmacokinetics.......................................................................65
5.4.2
Methods of sample collection .............................................................................65
5.4.2.1
Plasma sampling for pharmacokinetic analysis ....................................................65
5.4.3
Analytical determinations ..................................................................................67
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................68


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5.5
ASSESSMENT OF BIOMARKER(S) ..............................................................68
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................68
6.
INVESTIGATIONAL PLAN.............................................................................70
6.1
VISIT SCHEDULE.............................................................................................70
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................71
6.2.1
Screening and run-in period(s)..........................................................................71
6.2.2
Treatment period(s)............................................................................................71
6.2.3
End of Trial Period .............................................................................................71
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................72
7.1
STATISTICAL DESIGN - MODEL.................................................................72
7.1.1
Objectives.............................................................................................................72
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................72
7.3
PLANNED ANALYSES.....................................................................................73
7.3.1
Primary endpoint analyses.................................................................................73
7.3.2
Secondary endpoint analyses .............................................................................73
................................................................................75
7.3.4
Safety analyses.....................................................................................................76
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................78
7.4
INTERIM ANALYSES ......................................................................................78
7.4.1
Analysis of Part 1 (HV).......................................................................................78
7.4.2
Analysis of Part 2 (CF) .......................................................................................79
7.5
HANDLING OF MISSING DATA ...................................................................79
7.5.1
Safety and efficacy ..............................................................................................79
7.5.2
Plasma
 drug concentration - time profiles .............................................79
7.5.3
Pharmacokinetic parameters.............................................................................79
7.6
RANDOMISATION ...........................................................................................79
7.7
DETERMINATION OF SAMPLE SIZE .........................................................80
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................81
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................81
8.2
DATA QUALITY ASSURANCE ......................................................................82
8.3
RECORDS...........................................................................................................82
8.3.1
Source documents ...............................................................................................82
8.3.2
Direct access to source data and documents.....................................................83
8.3.3
Storage period of records ...................................................................................84
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................84
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY........84
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................85
8.6
TRIAL MILESTONES.......................................................................................85


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9.
REFERENCES....................................................................................................86
9.1
PUBLISHED REFERENCES............................................................................86
9.2
UNPUBLISHED REFERENCES......................................................................90
10.
APPENDICES.....................................................................................................91
10.1
HANDLING INSTRUCTIONS FOR RESPIMAT INHALER FOR USE IN 
CLINICAL TRIALS...........................................................................................91
10.4
PHARMACOKINETIC ANALYSES.............................................................108
10.5
HANDLING PROCEDURE OF BLOOD SAMPLES FOR PLASMA 
CONCENTRATION-TIME MEASUREMENTS .........................................108
10.6
CF EXACERBATION......................................................................................108
10.7
CONTRACEPTION SECTION......................................................................108
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................112


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ASL
Airway Surface Liquid/Airway Surface Layer
ATS
American Thoracic Society
AUC
Area under the concentration-time curve of the analyte in plasma
AUC0-12
Area under the concentration-time curve of the analyte in plasma until 12 h 
after the first dose
AUCτ, 13
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ on day 7
AUCτ, ss
Area under the concentration-time curve of the analyte in plasma at steady 
state, over a uniform dosing interval τ
b.i.d.
bis in die (twice daily dosing)
BLQ
Below the Lower Limit of  Quantification
BMI
Body Mass Index
BP
Blood Pressure
CF
CFTR
Cystic Fibrosis
Cystic Fibrosis Transmembrane conductance Regulator
CI
Confidence Interval
CML
Local Clinical Monitor 
COPD
Chronic Obstructive Pulmonary Disease
C1,N
Concentration of the analyte in plasma 1 hour after administration of the 
Nth dose
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
Cmax,13
Maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ on day 7
Cpre,N
Predose concentration of the analyte in plasma immediately before 
administration of the next dose
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
ENaC
Epithelial Sodium Channel
EDC
Electronic Data Capture
ePRO
Electronic Patient Reported Outcome
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
FEF
Forced Expiratory Flow
FEV
Forced Expiratory Volume


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FIM
FRC
First-into-Man
Functional Residual Capacity
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
hERG
Human Ether-A-go-Go Related Gene
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous
MedDRA
Medical Dictionary for Drug Regulatory Activities
NOA
Not Analysed
NOP
No Peak Detectable
NOR
No Valid Result
NOS
No Sample Available
OPU
Operative Unit
PD
Pharmacodynamics
PEF
Peak expiratory flow
PK
Pharmacokinetics
PR
Pulse Rate
RA,AUC,13
Accumulation ratio of the analyte in plasma at steady state after multiple 
oral administration over a uniform dosing interval τ, expressed as ratio of
AUC on Day 7 at steady state and after single dose
RA,Cmax,13
Accumulation ratio of the analyte in plasma at steady state after multiple 
oral administration over a uniform dosing interval τ, expressed as ratio of
Cmax,13 on Day7 at steady state and Day 1
Raw
Airway resistance
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SOP
Standard Operating Precedure 
SPC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
t1/2
Half life of the analyte in plasma
tmax
Time from dosing to maximum concentration of the analyte in plasma
TEAE
Treatment-Emergent Adverse Events
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
WOCBP
Women of Child-Bearing Potential
λz, N
Terminal rate constant in plasma


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
BI 443651 is an oral inhaled ENaC inhibitor in phase I of clinical development for the 
indications of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).   
CF chronic respiratory disorders characterised by airflow obstruction. ENaC is expressed on 
airway epithelial cells and functions as an ion channel for sodium. It mediates sodium 
reabsorption and regulates the water content and volume of the luminal fluid thereby 
maintaining airway surface liquid (ASL) and in turn regulating mucociliary clearance.
Cystic fibrosis is a lethal, inherited, multi-organ disease. Exocrine gland dysfunction 
predominantly affects the lower respiratory tract and pancreas leading to chronic respiratory 
failure and pancreatic insufficiency. It is the most common lethal inherited disease in 
Caucasians [R01-1277]. Pulmonary treatments include supportive care (airway clearance 
techniques), pharmacotherapy and lung transplantation. 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].
In CF, the cystic fibrosis transmembrane conductance regulator (CFTR) gene is dysfunctional
resulting in impaired epithelial chloride (Cl-) transport [R15-5486] leading, in turn, to 
reduced water secretion into the airway surface layer (ASL). This is aggravated by the fact 
that the functional defect of the CFTR is associated with increase of ENaC activation and
increased sodium [R15-5507] and water absorption from the airway epithelial lining fluid. 
These effects lead to changes in the biophysical properties of the mucus resulting in poor 
mucus clearance [R15-4955]. The static mucus can trigger an inflammatory response, and 
lead to bacterial colonisation and infection. Lung destruction is caused by a cycle of 
infection, inflammation, and injury, with obstruction of the airways. 
COPD results from an inflammatory process driven by exogenous stimuli such as cigarette 
smoke and air pollution. Mucus hyper secretion is an important manifestation of COPD and 
is associated with adverse outcomes including mortality and forced expiratory volume in 1 
second (FEV1) decline [R15-4986, R99-0658]. Recent data suggests that increased mucus 
concentration is associated with reduced mucus clearance, which in turn is associated with 
reduced FEV1 in chronic bronchitis patients [R15-5502]. The airways of COPD patients are 
often colonized by bacteria, and higher airway bacterial loads are associated with increased 
airway inflammation [R15-4985], more frequent exacerbation [R02-2234] and faster lung 
function decline [R15-4945] in smokers [P94-2812]. The airway surface layer (ASL) is 
dehydrated in COPD patients attributable to a tobacco smoke-induced decrease in CFTR-
mediated anion secretion, which may be worsened by ENaC channel activation [R15-4947]. 
Together with a concomitant increase in mucus secretion, these effects may lead to mucus 
plugging, bacterial infection, and chronic neutrophilia [R15-5506, R15-4975, R15-4987]. 
Furthermore, preclinical data in smoke models suggests improvements in ASL hydration and 
mucus clearance following ENaC inhibition [R15-4976], supporting the hypothesis that 
ENaC is involved in the pathogenesis of COPD.


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ENaC is expressed on the apical side of lung epithelial cells and evidence is available to 
suggest a role in the pathogenesis of both CF and COPD. Despite the differences in the 
underlying pathology between the two diseases, changes in the biophysical characteristics of 
the mucus are apparent with impaired transport of mucus (reduced mucus clearance) leading 
to mucus plugging, airflow obstruction and a milieu conducive to bacterial colonisation 
which in turn leads to worsening symptoms and lung function, and an increase in 
exacerbations. In both CF and COPD, inhibition of ENaC is anticipated to reduce epithelial 
sodium uptake and water absorption in the airways which should translate to improvement of 
mucociliary clearance, pulmonary function, symptoms and quality of life, while reducing 
bacterial colonization of the lower airways exacerbations and hospitalizations. Administration 
of an inhaled formulation of the potassium sparing diuretic amiloride, an ENaC inhibitor, 
resulted in increased mucus clearance in cystic fibrosis patients [R15-5487, R15-5485, R15-
5349] although poor pharmacokinetics , poor pharmacokinetic properties with inhalation are 
likely responsible for a lack of efficacy observed in some clinical trials. [R15-5349, R15-
5599, R15-5505]. The more favourable potency and kinetics demonstrated by BI 443651 are 
expected to translate into clinical efficacy.  
1.2
DRUG PROFILE
BI 443651, an epithelial sodium channel (ENaC) inhibitor, is in phase I clinical development 
in cystic fibrosis (CF).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® 


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led to an instantaneous and full inhibition of MCh-induced bronchoconstriction in those 
studies in which ipratropium was administered.
1.2.2
Safety pharmacology
Cardiovascular
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.3 
Toxicology
BI 443651 did not demonstrate systemic adverse effects in repeat-dose toxicity studies in 
dogs.
 
 
 
 
 
 
 
In two in vitro and one in vivo tests, BI 443651 was non-genotoxic. BI 443651 was not a
locally irritant or and was not phototoxic.


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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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 studies and experience in humans
 
 
 


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Systemic ENaC inhibitors such as amiloride have been used for years as potassium sparing 
diuretics in the treatment of hypertension, congestive heart failure and cirrhotic ascites. The 
side effect profile is well documented. Amiloride is normally well tolerated and, except for
hyperkalaemia, significant side effects are infrequent. Nausea, anorexia, abdominal pain, 
flatulence and mild skin rashes are considered potentially related to amiloride but other side 
effects are generally associated with diuresis. 
In addition there are clinical data of inhaled ENaC inhibitors administered to healthy 
volunteers and patients with cystic fibrosis for up to 6 months [R15-5485, R15-5349, R15-
5599, R15-5505]. Phase II studies with competitor ENaC inhibitors are ongoing. The 
compounds appear to have been well tolerated, with effects limited to serum potassium 
increases after multiple dosing, particularly in a compound with an active metabolite [R15-
0689].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This is the first of two multiple dose administration trials for BI 443651 the other being a 
multiple dose study in asthma subjects. The objective of this study is to investigate the safety, 
tolerability, and pharmacokinetics of BI 443651 in male and female healthy volunteers. A 
sparse PK investigation will be undertaken in subjects with cystic fibrosis (CF), along with 
exploratory efficacy.. The study will use multiple rising orally inhaled doses, to provide the 
basis for development of BI 443651 in cystic fibrosis. The safety, pharmacokinetic and 
exploratory efficacy data obtained in this study will help to assess an appropriate dosing 
range for further studies with this compound. 
The study will be conducted in two parts. The first part is a multiple rising dose design in 
healthy volunteers. In the second part, cystic fibrosis subjects will participate in a cross-over 
design to placebo or active treatment, after safety has been demonstrated at the twice higher 
dose level in healthy volunteers.
By including subjects with CF, this allows initial safety 
 to be 
obtained in the target population as well as completely healthy volunteers. The 
pharmacokinetic information at steady state exposure from healthy volunteers will act as a 
bridging safety study for later studies of longer duration. The exploratory efficacy outcome 
measures include spirometry and body plethysmography (healthy volunteers only),
 
 in CF subjects may help guide decision making and dose 
selection for phase II studies.
2.2
TRIAL OBJECTIVES
The primary objectives of part one of the study is to investigate safety, and tolerability 
of inhaled administration of:
BI 443651 100 µg b.i.d., 400 µg b.i.d., 1200 µg b.i.d. and 1800 b.i.d. µg BI 443651 in 
healthy male and female volunteers over 6.5 days.
The primary objective of part two of the study is to investigate the safety and 
tolerability of orally inhaled administration of BI 443651 in stable male and female CF 
subjects following administration of repeated doses of 600 µg b.i.d. BI 443651 over 13.5
days.
A secondary objective is the exploration of the pharmacokinetics of BI 443651 after multiple 
dosing in healthy volunteers.
 
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 any (therapeutic) benefit for healthy 


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volunteers. Their participation in the study is of importance as a safety bridge to investigate 
effective treatment in COPD and CF. CF subjects may have a short term benefit during the 
present trial. 
The subjects are exposed to the risks of the study procedures and the risks related to the 
exposure to the trial medication as outlined below.
During the whole course of the trial, sites will provide open-label salbutamol/albuterol or 
atrovent HFA MDI to be used as rescue medication for all CF subjects from screening, after 
they have signed their informed Consent. For the CF patients, safety information from the 
healthy volunteer portion of the study will be available and fully analysed.
2.3.1 
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.
The total volume of blood to be withdrawn during the entire study will be below 300 mL per 
subject and thereby a little bit more than the half of a normal blood donation (450-500 mL). 
No safety-related risk to study participants is expected from this blood withdrawal over a 
minimum 3 week period. Sampling times and visits may be adapted based on emerging 
information during the trial conduct.
2.3.2
Drug-related risks and safety measures
The nature of the target and the mechanism of action of BI 443651, ENaC inhibition, are well 
documented. The side effect profile of systemic ENaC inhibitors (amiloride) is well 
understood and the adverse events observed in rats following administration of BI 443651 are 
consistent with the mechanism. Inhaled amiloride has been administered to patients [R15-
5349; R15-5505]. The animal models are believed to be predictive for the effects in humans. 
ENaC inhibition is not expected to be involved in cascading of any pharmacologic pathways, 
exaggerated pharmacodynamic effects, pleiotropy of mechanism, or amplification and bypass 
properties of normal physiological control mechanisms. 
Based on clinical safety data exposed in section 1.2.6 above, BI 443651 was well tolerated in 
male healthy volunteers either after single dose up to 3600 µg or after chronic dosing up to 
1800 µg bid over 6.5 days. There were no relevant adverse effects on lung function, serum 
and urine electrolytes, vital signs or ECG. 
Side effects were restricted to dose-dependent administration-related events such as cough, 
throat irritation and taste complaints. These adverse events, frequently seen with inhaled 
products, were all mild in intensity and mostly of short duration.


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Safety margins (dose multiples) are  calculated from the predicted quantity of  drug deposited 
in the preclinical species lung compared to the human lung, assuming 100% of the human 
dose is deposited in the lung i.e. worst case scenario. The current dose multiples are: 

5 for the NOAEL dose in the 4-week rat study versus the maximum planned human 
daily dose ( 1800 g b.i.d or 3600 g/day) based on mg BI 443651 deposited per g 
lung weight

3.7 for the NOAEL dose  in the 4-week dog study versus the maximum planned 
human daily dose based (1800 g b.i.d or 3600 g/day) on mg BI 443651 deposited 
per g lung weight
Non-clinical studies support repeat-dose clinical trials of up to 4 weeks duration. The relevant 
systemic findings in the toxicology studies in the rat were changes in serum and urine 
electrolytes, at delivered doses of 4200 μg/kg/day (4-times higher than the NOAEL dose of 
1080 μg/kg) and were consistent with the mode of action of an ENaC antagonist in the 
kidney. The 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. The effects on 
electrolytes are consistent with the urinary exposure to drug. No other systemic safety 
findings were observed in either the toxicology or safety pharmacology studies. 
Exposure in the present study, for the highest dose of 1800 g b.i.d (3600 µg/day) is 
predicted to be approximately 2-fold lower for Cmax and similar exposures for AUC0-24 0-as
to the NOAEL values observed in the 4 week rat study. For the highest single dose of 
3600ug, less than 1% of parent drug was measured in urine over the first 48 h post dose 
period (gmean 0.27%, CV 45%).
Off target inhibition of ACh has been observed pre-clinically with augmented effects in non-
clinical ACh/MCh challenge guinea pig models. 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. The off target effect is not considered relevant in unchallenged healthy 
volunteers, and otherwise CF patients. An additional study is planned to assess possible 
effects in those exposed to acetylcholine or methacholine. Effects on respiratory function will 
be monitored and are reversible with standard inhaled anticholinergic therapy. 
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 have been conducted. Therefore only female 
subjects of child bearing potential willing to accept highly effective methods of contraception 
[See exclusion criteria section 3.3.3 for definition of highly effective methods of 
contraception] through the duration of this study and for 30 days after will be included, 
otherwise only males, and females of non-child bearing potential and non-lactating women 
will be included in this study.
The nonclinical safety studies (safety pharmacology and pivotal toxicity studies) to support 
the clinical study 1363.2 are described and referred to in the Investigator’s Brochure for BI 
443651 in Cystic Fibrosis and COPD.  These studies have been conducted in compliance 
with Good Laboratory Practice and have been carried out in an OECD country.


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The only exception is the study on the effects of BI 443651 on the hERG (human ether-a-go-
go related gene)-mediated potassium current [n00248843].  This study was performed in an 
OECD country but without formal adherence to the principles of GLP (non-GLP).  Data 
quality and integrity of the study however are given as study reconstruction is ensured 
through adequate documentation of the study conduct and archiving of data.  Therefore the 
validity of the study is considered not compromised by its non-GLP status and as such there 
is no impact on the evaluation of the respective endpoints of this safety pharmacology study.
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 
particularly increases in serum potassium. 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 healthy volunteers and CF subjects:

Frequent safety laboratory testing will be performed with a focus on electrolytes (see
Flow Chart I & Flow Chart II. Dose escalation will be stopped as soon as at least 2 
subjects at one dose level within one population type on active drug showed serum 
potassium levels ≥5.5 mmol/L in non-haemolysed blood

Selection of a starting dose for healthy volunteers (100 µg b.i.d.) that is at least 107 and 
63 fold below the plasma Cmax and AUC0-24 respectively (at the NOAEL in the most 
sensitive species (see memo for details [c09837286] and section 4.1.2 for justification of 
dose selection. 

Treatment of patient populations will occur in a staggered fashion to healthy volunteers.
For CF subjects, an exposure of 600 µg b.i.d. will only occur after 1200 µg b.i.d. is safely 
administered to healthy volunteers (see section 3.1).

Dose escalation for healthy volunteers is based on adequate safety in a preceding lower 
dose cohort. For each dose level the starting of subsequent dose groups will be separated 
by at least 9 days, implying 7 days of blinded safety and tolerability data (see section 
3.1.2). Specific stopping criteria are specified in section 3.3.4.1 with the potential to 
either not dose or delay dosing the next cohort is also based on physician judgment. 

Dose escalation factor is limited to less than 2 at the highest dose step in healthy 
volunteers (1200 to 1800 µg b.i.d.). 

The maximum total daily dose in healthy volunteers (1800 µg b.i.d.) is limited to the 
same maximum single dose (3600 µg) administered in the FIM study 1363.1. The total 
daily dose for CF is lower than the maximum dose delivered in the 1363.1 (See section 
4.1.2 for dose justification).

All subjects will be monitored throughout the study via in-clinic visits to site or interim 
telephone calls at home. Healthy volunteers will remain at the study site for at least four 
days following first study drug administration at each dose level, with medication 
administered under supervision of the site staff. Thereafter, dependent on medical 
assessment, subjects will be allowed to leave the site. Once discharged from site and 
whilst continuing treatment, volunteers will undertake twice daily in-clinic visits to site 
for supervision of medication administration. CF subjects are allowed to leave the site at 
an earlier time point as safety information will already have been collected for healthy 
volunteers. Nevertheless CF subjects will be required to attend the clinic for in-clinic 


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visits and medical examination including safety laboratories. An ambulatory spirometer, 
Asthma Monitoring Device (AM3®), will be used to monitor lung function at home.

All randomised CF subjects must have stable disease (see section 3.3.2) and will continue 
their regular medication (e.g. pulmozyme and antibiotics ). Worsening of disease is not 
expected. No therapy is being withdrawn from patients and the addition of placebo 
treatment on top of usual care in this study is considered acceptable. Nevertheless, 
subjects will be closely monitored for worsening of CF by monitoring of symptoms and 
pulmonary function in the clinic. In the event of deterioration subjects will be 
immediately invited back to the site. It is not expected that these co-medications interact 
with BI 443651. 

Although based on pre-clinical data no signal for QT prolongation has been observed, 
dosing will be stopped as soon as at least 2 subjects, on active drug at one dose level 
showed relevant and confirmed individual QTc prolongation (see section 3.3.4.1 and
4.1.5).

Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters 
to ensure subjects´ safety, see also section 5.3.10.1.
In summary, BI 443651 is in early clinical development. Single doses up to 3600 μg have 
been safely administered in study (1363.1). Multiple doses of up to 1800 μg b.i.d. are 
supported by preclinical safety data results from study 1363.1. Based on preclinical data for 
BI 443651 and clinical information from systemically administered ENaC inhibitors and 
other inhaled compounds previously tested in the clinic, which have been well tolerated, 
along with the implemented safety measures described above, healthy subjects and subjects 
with CF will not be exposed to undue risks. Healthy volunteers are not expected to have any 
direct medical benefit from participation in this clinical trial with BI 443651, as is the usual 
case in such phase I trials. CF subjects may receive transient benefit from participating in this 
trial. BI 443651 has the potential to be an inhalative treatment for CF, a disease of high 
unmet medical need. The expected potential benefits for patients and the important 
information expected from this trial as a basis for further clinical development of this 
compound are felt to outweigh the potential risks and justify exposure of healthy human 
subjects and CF subjects in the clinical development of BI 443651.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial will be composed of two parts – a multiple rising-dose (MRD) part and a cross-over 
part. Both parts will be randomised, placebo-controlled and double-blind. 
Part 1 (MRD): MRD part will be double-blind within dose groups and includes healthy 
volunteers. 
A total of 40 healthy volunteers are planned to participate in the trial according to 4
sequential dose groups compromising 10 subjects per group. Within each dose group 8 
volunteers will receive the active drug and 2 will receive placebo.
For healthy volunteers, one dose will be tested within each dose group. The groups will be 
treated consecutively in ascending order of dose. The dose groups to be evaluated are as 
outlined in Table 3.1: 1 below.
Additional subjects may be entered to allow testing of additional (e.g. intermediate) doses 
within the planned dose range on the basis of experience gained during trial conduct, i.e. the 
actual number of subjects entered in Part 1 may exceed 40 subjects. Such a change would be 
implemented as a non-substantial CTP amendment provided that the additional dose levels to 
be tested were within the approved dose range. 
Table 3.1: 1 Dose groups for Part 1 (MRD) and Part 2 (cross-over)
Dose group
1
2
3
5
7
Subjects
HV
HV
HV
HV
CF
Dose
100 µg 
b.i.d.
400 µg 
b.i.d.
1200 µg 
b.i.d.
1800 µg 
b.i.d.
600 µg 
b.i.d.
Daily dose 
(µg)
200
800
2400
3600
1200
No. of
subjects
10
10
10
10
24
Subjects on
placebo
2
2
2
2
24
Subjects on 
active drug
8
8
8
8
24
For healthy volunteers four different dose groups (100, 400, 1200 and 1800 µg b.i.d.) will be 
investigated consecutively in ascending order of daily doses (see section 3.1.2 for information 
on dose escalation).
Part 2 (cross-over): 24 CF subjects will be included in the second part of the study (cross-
over design). Each CF subject will receive both placebo and the active drug at one dose-level 
in a randomised sequence with 12 subjects on each of the following sequences: 
Active/Placebo, Placebo/Active (See section 3.1.1 for starting rules).


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3.1.1
Start of CF dose groups:
The second part of the study including CF subjects will only start once the 1200 µg b.i.d dose 
been shown to be well tolerated in healthy volunteers (see table 3.1.2: 1). 
The decision to administer BI 443651 to CF subjects will be taken in a documented safety 
review meeting (see section 3.1.2). 
3.1.2
Dose escalation:
The dose groups will be investigated consecutively in ascending order of doses with a dose 
escalation review between each dose group.
Healthy volunteers: The healthy volunteer dose groups will be investigated first. Each cohort 
of healthy volunteers, 10 subjects (8 on active, 2 on placebo) will be dosed up to 7 days in an 
incremental order with a dose escalation meeting in between each dose step. Only if the 
previous dose of BI 443651 is safe and well tolerated in the prior dose group, without 
meeting any stopping criteria (see Section 3.3.4.1), will the subsequent dose be administered
(see table 3.1.2: 1). 
For each dose level in healthy volunteers, the dosing of the first subject in subsequent dose 
groups will be separated by at least 9 days, implying at least 7 days of blinded safety and 
tolerability data from the preceding dose group, which is expected to cover the period to 
predicted steady state.
Table 3.1.2: 1 
Dose escalation schedule (b.i.d.)
Time
Healthy volunteer
CF
DG1 (100 µg)
-
DG2 (400 µg)
-
DG3 (1200 µg)
-
DG5 (1800 µg)
DG7 (600 µg)
-
-
A documented dose escalation safety review meeting must take place prior to each dose 
escalation. Furthermore, an unscheduled safety review meeting can be requested anytime for 
any reasonable cause by the Principal Investigator (or an authorised deputy) or the sponsor of 
the study, e.g. because of any unforeseen adverse events, etc. Dose escalation will only be 
permitted if no safety concerns exist in the opinion of the safety review committee, with 
appropriate representation from Sponsor company and the Principal Investigator (or an 
authorised deputy).
The minimum data set for review consists of the following data on 8 Healthy Volunteers (see 
section 3.3.5 for subject replacement): 


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
AEs in the current and preceding dose groups up to at least end of treatment (including 
clinically relevant findings from ancillary safety testing listed below) (Note: AEs may be 
ongoing at the time of Safety Reviews)

Clinical laboratory tests in the current and preceding dose groups

Results from 12-lead EGG in the current and preceding dose groups.

Vital signs in the current and preceding dose groups

Pulmonary function (in clinic) tests in the current and preceding dose groups

Check of criteria for stopping subject treatment as per Section 3.3.4.1.
The decision to escalate the dose will be made jointly by the safety review committee, with 
appropriate representation from Sponsor company and the Coordinating Investigator (or an 
authorised deputy) after in-depth analysis of all available safety data, especially SAEs (if 
occurred), AEs and out-of-range laboratory results (if considered clinically significant). 
Safety Reviews can be conducted face-to-face or by video/telephone conference. The Trial 
Clinical Monitor is responsible for organization and minutes of the reviews. Minutes will be 
signed off by the Principal Investigator (or an authorised deputy) and filed in the ISF and 
TMF.
The investigator is allowed to alter the scheduled dose levels (e.g. add an intermediate dose 
level, decrease the planned dose, give the same dose again) within the planned and approved 
dose range on the basis of experience gained during the study. In this case, the total number 
of subjects in this trial might increase. The investigator and/or the sponsor should stop dose 
escalation in case the safety evaluation leads to concerns that would not allow higher dosing.
An overview of all relevant trial activities is provided in the relevant Flow Chart I & Flow 
Chart II. For visit schedules and details of trial procedures at selected visits, refer to Sections 
6.1 and 6.2, respectively.
3.1.3
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim Pharma GmbH (BI).
The Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre trial. Tasks and responsibilities are defined in a contract. 
Healthy subjects will only be recruited at one site, thus the dose escalation meeting will 
comprise of appropriate personnel, with appropriate representation from Sponsor company 
and the Coordinating Investigator (or an authorised deputy). Minutes of the dose escalation 
meetings will be documented and filed in the TMF.
The composition of the dose escalation committee will be documented in the Trial Master 
File (TMF).
Relevant documentation on the participating (Principal) Investigators and other relevant site 
study team members, 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,


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-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and internal SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
The two trial parts will be evaluated separately depending on their completion, for details 
refer to Section 7.4.
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.     
A central laboratory service, ECG and an IRT vendor will be used in this trial. Details will be 
provided in IRT Manual, ECG and Central Laboratory Manual, available in ISF.  
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Part 1 (MRD part): For multiple rising dose trials, the design described in Section 3.1 is 
viewed favourably under the provision not to expose the subjects involved to undue risks 
since the main study objective is to investigate safety and tolerability as well as 
pharmacokinetics of BI 443651.
With the rising dose design, double -blind conditions regarding the subjects' treatment (active 
or placebo) are maintained within each dose group, however the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to the dose dependent effects as well as time effects but it has the 
virtue of minimising subject risk by sequentially studying ascending doses. As time-effects 
are expected to be small relative to the difference between the doses in the broad range 
investigated, unbiased comparisons between treatments can still be expected. It is standard in 
trials in early development involving healthy volunteers and subjects, to use placebo as a 
control group in order to evaluate safety, tolerability and pharmacokinetics.
Healthy volunteers: Each dose group of healthy volunteers consists of 10 volunteers with 8 
on active treatment, and 2 on placebo. The placebo control group includes all subjects on 
placebo of all dose groups. 8 subjects per active treatment group are in general considered as 
sufficient for the exploratory evaluation of pharmacokinetics and safety.
Part 2 (cross-over part of the study): A total of 24 CF subjects are included which is 
considered sufficient to assess the safety, tolerability, sparse pharmacokinetics and 
exploratory efficacy (see section 7.7).The cross over design and the within patient 


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comparisons is implemented to limit the number of subjects required for the assessment of 
exploratory efficacy in this early phase I study. A washout of at least 30 days and a maximum 
of 6 weeks is regarded as a sufficient time period between treatment periods. Depending on 
emerging data, the washout period if required may be extended to prevent carryover of drug 
from Active to Placebo.
All CF subjects included in the study will have stable disease and be of mild or moderate 
severity. The subjects will be on standard of care treatment and thus the use of placebo in this 
setting is considered acceptable.
3.3
SELECTION OF TRIAL POPULATION
This trial will be conducted in at least 6 sites in at least 2 European countries (UK & 
Germany – 1 site for healthy subjects and at least 6 sites for CF). The selected sites 
participating in the study will have expertise in conducting studies for respiratory and 
pharmacokinetic assessments. All sites participating in the assessments of lung clearance 
index will have expertise in the conduct of this type of study. 
Part 1 (MRD part): The inclusion and exclusion criteria are designed to include healthy 
volunteers.
It is planned that 40 healthy volunteers will be randomised in the study. Volunteers will be 
recruited from the volunteer’s pool and EC approved advertisement from the 
. 
Part 2 (cross-over part of the study): The inclusion / exclusion criteria are designed to 
include mild stable CF subjects. To ensure the safety of the CF subjects in this trial, subjects 
must be stable without recent exacerbation or acute respiratory tract infection and have a pre-
bronchodilator FEV1 ≥70% at Visit 1 (screening) and prior to randomisation. A sufficient 
number of volunteers will be randomised (at least 24) to ensure a minimum of 20 CF subjects
complete treatment. 
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.  
3.3.2
Inclusion criteria
Part 1: (MRD part) 
Healthy volunteers: 
1. Signed informed consent consistent with ICH-GCP guidelines and local legislation prior 
to participation in the trial.


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2. Healthy male or female subjects (see exclusion criteria regarding contraceptive measures) 
according to the investigators assessment, based on a complete medical history including 
a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests.
3. Women of childbearing potential (WOCBP) should only be dosed after a confirmed 
menstrual period and/or with a progesterone level at Day -5 to Day -3 that demonstrates a 
dip from baseline, indicating a menstrual bleed prior to dosing.
4. Age of 18 to 55 years (incl.) on the day of subject´s signature of informed consent. 
5. BMI of 18.5 to 32.0 kg/m2 (incl.)
6. FEV1 and FVC of equal or greater than 80% of predicted normal, at screening and prior 
to randomisation.
Part 2: (Cross over part) 
Cystic Fibrosis
1. Signed informed consent consistent with ICH-GCP guidelines and local legislation prior 
to participation in the trial. Medication washout and medication restrictions are allowed 
only after signed informed consent is obtained.
2. Males or females (see exclusion criteria regarding contraceptive measures) with a 
documented diagnosis of cystic fibrosis (confirmed by a positive sweat chloride of 60 
mEq/L or more, measured by pilocarpine iontophoresis) or a genotype with 2 identifiable 
mutations consistent with cystic fibrosis accompanied by 1 or more clinical features with 
the cystic fibrosis phenotype.
3. Women of childbearing potential (WOCBP) should only be dosed after a confirmed 
menstrual period and/or with a progesterone level at Day -5 to Day -3, that demonstrates 
a dip from baseline, indicating a menstrual bleed prior to dosing. For CF subjects of child 
bearing potential this must confirmed prior to second treatment period.  
4. Age of between 18 and 55 years (each inclusive) of age, on the day of subject´s signature 
of informed consent. 
5. BMI of 18 to 32.0 kg/m2 (incl.).
6. Pre-bronchodilator FEV1 greater than or equal to 70% of predicted normal at screening 
and prior to randomisation.
7. Clinical stability as defined by: 
a.
No evidence of acute upper or lower respiratory tract infection within 4 
weeks of screening.
b. No pulmonary exacerbation requiring use of i.v./oral/inhaled antibiotics, or 
oral corticosteroids within 4 weeks of screening or prior to randomisation.
c.
No change in pulmonary disease therapy within 4 weeks of study day 1. If 
on cycling antibiotics, these must be initiated 2 weeks prior to 
randomisation.


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d. No acute (serious or non-serious) illness not related to cystic fibrosis 
within 4 weeks of Day 1.
e.
No infection with an organism associated with more rapid decline in 
pulmonary function (eg, Burkholderia cenocepacia, B dolosa, or 
Mycobacterium abscessus).
8. Subjects must be able to perform technically acceptable pulmonary function tests (forced 
spirometry). 
3.3.3
Exclusion criteria (all Parts)
1. Any evidence of a concomitant disease judged as clinically relevant by the investigator 
including gastrointestinal, hepatic, renal, respiratory*, cardiovascular, metabolic**, 
immunological, dermatologic, hematologic, neurological and psychiatric, oncological, 
coagulation or hormonal disorders 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.
b. Influence the results of the study.
c.
Cast doubt on the subject’s ability to participate in the study.
* except cystic fibrosis subjects who may be included with concomitant asthma provided on 
stable medications for 6 weeks prior to inclusion into the study. Patients with acute 
bronchopulmonary aspergillosis may not be included.
** CF subjects with diabetes are allowed to participate if their disease is under good control 
prior to screening as assessed by the principal investigator.
2. Chronic or relevant acute infections.
3. History of relevant orthostatic hypotension, fainting spells, or blackouts.
4. History of myocardial infarction; history of acute coronary syndrome within 6 months of 
the screening visit (Visit 1) or between the screening visit (Visit 1) and randomization.
5. History of and/or active life-threatening cardiac arrhythmia, as assessed by the 
investigator.
6. Major surgery (major according to the investigator's assessment) performed within 12 
weeks prior to randomization or planned within 12 months after screening, e.g. hip 
replacement.
7. A history of chronic kidney disease (EGFR <59 mls/min including corrections as per 
ethnicity)
8. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients).
9. Unsuitable veins for venipuncture (for instance, veins which are difficult to locate, access 
or puncture, veins with a tendency to rupture during or after puncture) as assessed by the 
investigator.
10. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator.


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11. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance, specifically volunteers with serum potassium > upper limit of normal 
should be excluded; Safety laboratory screening and Day -7 to Day -3, evaluation can be 
repeated twice during screening.
12. For healthy volunteers, repeated measurement (i.e. > 2 measurements) of systolic blood 
pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range 
of 50 to 90 mmHg. Volunteers will be excluded with a pulse rate outside the range of 45 
to 90 bpm.
13. A marked baseline prolongation of mean 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 or prior to randomisation (see section 
5.3.8).
14. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome).
15. Within 10 days prior to administration of trial medication, use of drugs that might 
reasonably influence the results of the trial or that might prolong the QT/QTcF interval 
16. Intake of drugs with a long half-life (more than 24hrs) within 30 days or less than 10 half-
lives of the respective drug prior to administration of trial medication unless this is 
allowed medications as indicated in Table 4.2.2.1:1.
17. CF subjects treated with non-permitted concomitant medication. Specifically medications 
causing changes in serum potassium are restricted (please refer to Table 4.2.2.1:1)
18. Current or previous participation in another interventional trial, including where an 
investigational drug has been or will be administered within 60 days or 5 half-lives 
(whichever is longer) prior to screening.
19. For healthy volunteers and CF subjects: current smokers or ex-smokers of less than 12 
months and/or with a pack year history of more than 5 years.
20. Positive test for alcohol or drugs, at screening or pre-dose on Day 1 prior to 
randomization. (Unless this can be explained by the subject’s medication).
21. Drug or alcohol abuse or any condition that, in the investigator's opinion, makes them an 
unreliable study subject or unlikely to complete the trial. Consumption of 20 g/day (2 
units of alcohol) in females, or 30 g/day (3 units of alcohol) in males.
22. Subjects who have donated more than 100 mL blood in the 4 weeks prior to Visit 1 and 
between Visit 1 and Visit 3 or subjects who have the intention to donate blood between 
Visit 3 and four weeks after the end of trial visit.
23. Intention to perform excessive physical activities within 72 hours prior to administration 
of trial medication or during the trial.
24. Inability to comply with dietary regimen of the trial site.
25. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
26. Women of childbearing potential (WOBCP) not willing to use highly effective methods 
of birth control per ICH M3 [R09-1400] during the study and for 30 days after. 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. 


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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, bilateral 
oophorectomy, confirmed tubal occlusion or tubal ligation (see Section 10.7).
27. Male subjects who do not agree to minimize 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. Male subjects with pregnant partners are 
excluded. 
28. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
he/ she is considered not able to understand and comply with study requirements, or has a 
condition that would not allow safe participation in the study.
29. Previous randomisation in this trial.
3.3.4
Removal of subjects from therapy or assessments
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:

The subject has a confirmed increase in serum potassium of ≥ 5.5 mmol/L in non-
haemolysed blood.

The subject shows relevant individual QT prolongation, i.e. a QTcF increase of greater 60 
ms (mean where triplicate is performed) from baseline (pre-dose Day 1) in connection 
with absolute QT or QTcF greater than 500 ms, which has been confirmed by a repeat 
ECG recording.

CF: A CF exacerbation occurs during treatment (for definition see Appendix 10.6). 
Patients may continue in the study if an exacerbation occurs during the washout period 
between treatment period 1 and 2, provided that patients have been off antibiotics (IV or 
oral, prescribed for the exacerbation) for at least 4 weeks and FEV1 has returned to within 
10% of the baseline values. Treatment washout between the two treatment periods can be 
extended up to a maximum of 6 weeks.

The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision.
The investigator should ask the subject who withdraws consent whether the withdrawal is 
related to the further administration of trial medication or to all trial-related observations 
and procedures. The investigator should explain the importance of the further measures 
for the assessment of the subject´s safety. The observations and procedures to be followed 
for subjects who terminate the administration of trial medication prematurely (please see 
details below) will be performed accordingly.

The subject needs to take concomitant drugs that interfere with the investigational product 
or other trial medication (see Section 4.2.2)


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
The subject experiences a serious adverse event or any AE, that in the opinion of the 
investigator, may jeopardise the safety of the trial participant.

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 stick to the trial requirements in the future.

The subject can no longer be treated with trial medication for any medical reason (e.g. 
surgery, adverse events, other diseases, or pregnancy)

Decision by Boehringer Ingelheim to discontinue treatment of a specific subject (for 
instance, in case of the occurrence of an SAE that would be incompatible with trial 
continuation)
Given the subject’s agreement, the subject will undergo the procedures for early treatment 
discontinuation and follow up as outlined in Flow Chart I & Flow Chart II and section 6.2.3.
For all subjects 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. In case of patient’s 
discontinuation, the investigator/site staff will inform the sponsor in a timely manner. This 
communication should always include the reason for withdrawal.
3.3.4.1
Discontinuation of the trial 
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1.
At least 2 subjects at one dose level within one population type, on active drug 
showed serum potassium levels > 5.5 mmol/L in non-haemolysed blood 
2.
At least 2 subjects at one dose level within one population type, on active drug 
showed relevant individual QT prolongation, i.e. a QTcF increase of greater 60 ms 
from baseline (mean where applicable) in connection with absolute QT or QTcF
greater than 500 ms, which has been confirmed by a repeat ECG recording. For CF 
subjects, the baseline for Treatment Period 2 will be calculated again at Visit 3 Day 1.
3.
Failure to meet expected enrolment goals overall or at a particular trial site.
4.
Emergence of any efficacy/safety information invalidating the earlier positive benefit 
risk- assessment that could significantly affect the continuation of the trial.
5.
Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the 
trial. 
6.
New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment.
7.
For healthy volunteers, in the event of any subject having an, at least, possibly related 
SAE or in case of the occurrence of two, at least, possibly related severe AEs the 
study group will be halted. No further dosing, dose escalation or inclusion of any 
further subjects at the same dose will occur without approval of a substantial 
amendment
8.
For CF subjects, in the event of 2 subjects having an, at least, possibly related SAE or 
in case of the occurrence of three, at least, possibly related severe AEs the study group 


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will be halted. No further dosing, dose escalation or inclusion of any further subjects 
at the same dose will occur without approval of a substantial amendment
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the fifth reason).
3.3.5
Subject replacement
If more than 2 healthy volunteers per dose group do not complete up to the end of the dosing 
periods, the trial clinical monitor together with the trial pharmacokineticist and the trial 
statistician are to decide if and how many subjects will be replaced.
A sufficient number of CF subjects (planned 24) should be recruited to ensure at least 20 
completed both dosing periods. If less than 20 subjects complete both dosing periods, the trial 
clinical monitor together with the trial statistician are to decide if and how many subjects will 
be replaced. 
To be considered as completing the dosing period, volunteers or subjects are required to be 
80 - 120% compliant with treatment (section 4.3).
A replacement subject will be assigned a unique study subject number, and will be assigned 
to the same sequence as the subject he/she replaces.


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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. 
BI 443651 inhalation solution is administered via the Respimat® inhaler (Version 5).  
4.1.1
Identity of the Investigational Medicinal Products     
Table 4.1.1: 1
Test product:
Substance:
BI 443651
Pharmaceutical formulation:
inhalation solution 
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 μg/actuation, 300 μg/actuation
Posology
b.i.d.
Route of administration:
Inhalation
Device:
RESPIMAT A5
Duration of use:
6.5 days, 13.5 days 
Table 4.1.1: 2
Placebo:
Substance:
Placebo to BI 443651
Pharmaceutical formulation:
inhalation solution 
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable
Posology
b.i.d.


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Table 4.1.1: 2    
Placebo (cont.):
Route of administration:
Inhalation
Device:
RESPIMAT A5
Duration of use:
6.5 days, 13.5 days
A placebo matching the Respimat® platform Inhalation Solution will be used. It uses the 
same excipients as the verum. All Respimat® treatments will be double-blind.
4.1.2
Selection of doses in the trial
The dose levels to be studied in this trial are 100 μg, 400 μg, 1200 μg and 1800 µg b.i.d. in 
healthy volunteers and 600 µg b.i.d. in CF subjects. The background for this dose selection is 
described as follows:
 
 
 
 
 
 
 
 
 
 
 
Starting and maximum dose 
Whilst 100 µg may be an efficacious dose, the selection of 100 µg as the starting dose is 
supported by the benign safety profile of BI 443651 observed in study 1363.1 at single doses 
of up to 3600 µg, including a lack of effect on serum electrolytes 
 
 
 To adequately address all these aspects 1800 μg 
b.i.d. has been selected as the maximum dose to be delivered in healthy volunteers. The 
highest doses for CF subjects will be 600 μg b.i.d, administered once the 1200 µg b.i.d. dose 
level is confirmed as safe and well tolerated in healthy volunteers. 
The investigator can decide at any time to discontinue dosing, to decrease the dose escalation 
by adding intermediate doses in case of intolerability or decrease the dose based on safety 
concerns.


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4.1.3
Method of assigning subjects to treatment groups
Part 1 (MRD part):
At Visit 2 (Day 1) eligible subjects will be randomized to treatment groups active or placebo 
for the current dose level under investigation in a 4:1 ratio. The assignment will occur in a 
blinded fashion via Interactive Response Technology (IRT). To facilitate the use of the IRT, 
the investigator will receive all necessary instructions.
Part 2 (cross-over part):
At Visit 2 (Day 1) of the first period eligible CF subjects will be randomized to treatment 
sequences active-placebo/placebo-active in a 1:1 ratio. The assignment will occur in a 
blinded fashion via Interactive Response Technology (IRT). To facilitate the use of the IRT, 
the investigator will receive all necessary instructions.
4.1.4
Drug assignment and administration of doses for each subject
The trial will be divided into two parts:
1. multiple rising dose (Healthy volunteers)
2. multiple single dose (CF subjects)
For both parts of the study the treatment phase includes a multiple-dose phase starting on Day 
1 in the morning and subjects will receive medication twice daily for:

6 days (Day 1-6) in healthy volunteers, with a single dose administration on Day 7

13 days (Day 1-13) in CF subjects in a cross-over design, with a single dose 
administration on Day 14
For CF subjects, a second treatment phase will follow a washout period of at least 30 days.
(cf. Table 4.1.4: 1 and Table 4.1.4: 2 for treatments and posology overview)
Generally medication intake will be at the same time every day during the entire study to 
ensure a dose interval of 12 hours, respectively. The same study medication will be used
during in-house confinement and outpatient periods.
Table 4.1.4: 1
Treatment overview healthy volunteers
Treatment
Formulation, 
dose regimen
Route of
adminis
tration
Number of
actuations 
per single 
administra 
tion
Unit strength
[µg]
Total dose per
administration
[µg]
Posology
distribution 
over the 
treatment 
period
1
Inhalation
solution,
13 administrations
12 hours apart
Inhal
ation
1
100
100
Day 1 to Day 6 
a.m./ p.m.
and Day 7 
a.m.


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Table 4.1.4: 1
Treatment overview healthy volunteers (cont.)
Treatment
Formulation, 
dose regimen
Route of
adminis
tration
Number of
actuations per
single administra
tion
Unit strength
[µg]
Total dose per
administration[µg]
Posology
distribution over the
treatment period
2
Inhalation solution,
13 administrations
12 hours apart
Inhalation
4
100
400
Day 1 to Day 6 a.m./ 
p.m. and Day 7 a.m.
3
Inhalation solution,
13 administrations
12 hours apart
Inhalation
4
300
1200
Day 1 to Day 6 a.m./ 
p.m. and Day 7 a.m.
4
Inhalation solution,
13 administrations
12 hours apart
Inhalation
6
300
1800
Day 1 to Day 6 a.m./ 
p.m. and Day 7 a.m.
Placebo*
Inhalation solution,
13 administrations
12 hours apart
Inhalation
Matching active 
treatment
-
-
Day 1 to Day 6 a.m./ 
p.m. and Day 7 a.m.
* Subjects receiving placebo are equally distributed across dose groups
Table 4.1.4: 2
Treatment overview CF
Treatment
Formulation, 
dose regimen
Route of
adminis
tration
Number of
actuations per
single administra
tion
Unit strength
[µg]
Total dose per
Administration  
[µg]
Posology
distribution over
the treatment
period
1
Inhalation solution,
27 administrations**
12 hours apart
Inhalation
2
300
600
Day 1 to Day 13 
a.m./ p.m. and Day 
14 a.m.
Placebo*
Inhalation solution,
27 administrations
12 hours apart
Inhalation
Matching active 
treatment
-
-
Day 1 to Day 13 
a.m./ p.m. and Day 
14 a.m
* Each subject will receive active and placebo
** Theoretical number of administrations when no time windows applied
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 or PK sample preparation. 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.


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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.
For restrictions with regard to diet see section 4.2.2.3.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, Investigators and everyone involved in trial conduct or analysis or with any other 
interest in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments until after database lock. According to the rising dose design, the current dose 
level will be known to subjects and investigators. At the trial site, access to the randomisation 
schedule is restricted to unblinded pharmacists.
The randomization code will be kept secret by Clinical Trial Support up to database lock. 
Access to the codes will be controlled and documented by a signed confidentiality statement, 
which will be stored in the TMF.
The randomization codes will be provided to bioanalytics prior to last patient out to allow 
them to exclude PK samples taken from placebo subjects from the bioanalytical analyses.
The Trial Bioanalyst will sign a confirmation that the codes will be treated confidentially and 
that all unblinding information is restricted to the laboratory staff involved in sample 
analysis.
In addition, the trial pharmacometrician may receive the randomisation codes of part 1 of the 
trial prior to official unblinding to carry out analyses to guide further internal decision 
making. He or she will confirm in writing that the codes will be treated confidentially. The 
unblinded results are not to be presented prior to official unblinding of the trial.
In addition, the trial pharmacokineticist may receive the randomisation codes of part 1 of the 
trial prior to official unblinding to perform preliminary PK analysis. He or she will confirm in 
writing that the codes will be treated confidentially. The unblinded results are not to be 
presented prior to official unblinding of the trial.
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded with respect to the treatment and also with regard to the recording date and 
time as well as time the points of the ECGs. The interval measurements for a given subject 


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will be performed in a random and blinded sequence by a single technician. No more than 
two different blinded readers will evaluate the ECGs of the study.
If an interim safety analysis of ECG data is required, a part of the staff of the ECG laboratory 
may be unblinded. This part of the staff is strictly separated from those parts of the staff, 
which is involved with interval measurements and assessments of single ECGs (blinded).
After completion of part 1 with HV an interim database lock will be made. After this the data 
of HV will be unblinded. The objective of the trial especially part 2 is not expected to be 
affected by this as part 1 with HV will be completed and the analysis will have no impact on 
the conduct (in the sense of randomisation, blinding and analyses of primary endpoint) of the 
second part.
After completion of part 2 the final database lock of the trial will occur and the trial will be 
fully unblinded.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the Investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used 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 subjects or in order to make decisions on dose 
escalation in case of stopping criteria being triggered. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page along with the date of 
when the code was broken.
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). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
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.


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4.1.8
Drug accountability
The Investigator, Pharmacist and/or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the 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 and/or 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 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 and/or 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, the Investigator, Pharmacist and/or 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.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
For healthy subjects, no special emergency procedures are to be followed. However, in case 
of adverse events in need of treatment (e.g. treatment of hyperkalaemia), the investigator can 
authorise any required therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level, same holds true for patients.
4.2.1.1 
Rescue medication
Administration of PRN (Pro re nata (as occasion requires)) inhaled short acting β-
adrenergics, inhaled short acting anticholinergics or combinations of both can occur at any 
time during the trial as deemed necessary by the subject or the investigator. However, the 
medication restrictions prior to lung function testing
(please refer to section 
4.2.2.2) must be observed as long as this is compatible with the safety of the subject. 
Otherwise there are no special emergency procedures to be followed.
During the whole course of the trial the site will be responsible for providing open-label


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salbutamol/albuterol and / or atrovent HFA MDI to be used as rescue medication for all CF 
subjects at screening after they have signed their informed Consent.
Regarding the use of salbutamol for post-bronchodilator spirometry measurement please refer 
to Section 5.3.6.
If rescue medication is administered during clinic visits, the 24-hour clock time of rescue 
medication, total number of inhalations of salbutamol 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 all visits with laboratory sampling does not necessitate 
discontinuation of the visit. The subject should remain in the clinic in order to complete the 
blood 
 sampling. 
 
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Medications causing alterations in serum electrolytes should not be administered during the 
study (a list of common medications effecting serum electrolyte balance is included in Table 
4.2.2.1: 1). All concomitant medications must be assessed by the investigator for potential
effects on serum electrolytes based on the summary of product characteristics (SPC), if 
applicable. Specific questions of eligibility based on this criterion should be clarified by the 
clinical monitor prior to inclusion. Medications not included in Table 4.2.2.1:1 may be 
administered at the discretion of the investigator e.g. paracetamol.
In case of adverse events in need of treatment, symptomatic therapy will be permitted as 
considered appropriate by the investigator. All concomitant and/or rescue therapies will be 
recorded (including time of intake on study days, except for salbutamol or atrovent rescue 
medication) on the appropriate pages of the CRF.
In addition, please note Section 4.2.2.2 regarding restrictions prior to forced spirometry and 
Section 4.2.2.3 regarding restrictions on diet and life style.
Part 1 (MRD part)
Healthy volunteers
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Hormonal contraception must be used in WOCBP (section 10.7).
Part 2 (cross-over part)
Cystic Fibrosis 
Table 4.2.2.1:1 provides an overview of permitted and restricted medications.


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Table 4.2.2.1:1 Permitted and restricted medications
Class
Permission / Restriction and explanation
Hormonal contraceptives
Permitted prior screening visit (Visit 1) and during the trial.
Pulmozyme®
Permitted provided that Pulmozyme has been stabilized at 
least 6 weeks prior to randomisation (Day 1) and will
continue to be used during the trial in a stable manner.
Intravenous / oral antibiotics 
Not permitted within 4 weeks of screening and during 
each treatment period when prescribed for exacerbation or 
acute infection. Continued stable therapy is permitted if 
given at that dose for at least 2 months prior to the 
screening visit (Visit 1) and will continue to be used during 
the trial in a stable manner.
Inhaled antibiotics 
Permitted provided that antibiotics are started within 2
weeks prior to randomisation (Day 1) and will continue to
be used during both treatment periods (including washout 
period), 
or are started within 2 weeks prior to randomisation and 
re-started  within 2 weeks prior to treatment period 2 (Visit 
3).
Ivacaftor
Not permitted 6 weeks prior screening visit (Visit 1) and
during the trial.
Lumacaftor
Not permitted 6 weeks prior screening visit (Visit 1) and
during the trial.
Mucolytics including inhaled 
hypertonic saline, Inhaled or 
oral N-acetylcysteine, or 
inhaled glutathione
Not permitted 2 weeks prior randomization (Day 1) and
during the trial.
Inhaled corticosteroids
Permitted provided that inhaled corticosteroids have been
stabilized at least 6 weeks prior to randomization (Day 1) 
and will continue to be used during the trial in a stable
manner (including combinations containing β-adrenergics).
Systemic corticosteroids
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 β-adrenergics
(mono-product or combined)
Permitted provided that inhaled long-acting
anticholinergics have been stabilized at least 6 weeks prior
to randomization (Visit 2) and will continue to be used
during the trial in a stable manner. Regarding restrictions
for forced spirometry bronchodilators see Section 4.2.2.2.
Antihistamines
Permitted if prescribed for non-asthma condition


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Table 4.2.2.1:1 Permitted and restricted medications (cont.)
Class
Permission / Restriction and explanation
Investigational drugs
Not permitted, see exclusion criterion number 17
Medications that may lead to 
alterations in serum 
electrolytes (particularly 
potassium) including but not 
limited diuretics* 
angiotensin convertase/ 
angiotensin receptor 
inhibitors**, nonsteroidal 
anti-inflammatory drugs 
(NSAIDs)***, cyclosporine 
or tacrolimus, Pentamidine, 
Trimethoprim-
sulfamethoxazole, Heparin, 
Ketoconazole and 
Metyrapone
Not permitted 4 weeks prior screening visit (Visit 1) and
during the trial
*includes frusemide, spironolactone, amiloride
** includes Captopril, Zofenopril, enalapril, ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril Trandolapril, 
Fosinopril, Cilazapril; 
*** includes ibuprofen, diclofenac, naproxen, celecoxib, mefenamic acid,etoricoxib, indomethacin, aspirin (doses > 600 mg)
4.2.2.2
Medication restrictions for all lung function testing
CF subjects
Throughout the study and post treatment period including end of study visit usual background 
medications and trial medication should not be taken before the morning pre-dose pulmonary 
function testing (forced spirometry) 
 (Flow Chart II). An 8-hour minimum washout 
period for inhaled short-acting bronchodilators (such as salbutamol and ipratropium) must be 
maintained. 
On visits with several spirometry (Day 1 and Day 14), background therapy may be given 
after the 30 min spirometry post BI 443651 administration.
 
For all subjects, even if subjects violated restrictions, as a general rule, scheduled procedures 
(after randomization) should neither be postponed nor skipped. Regarding diet and lifestyle 
restrictions for forced spirometry testing please refer to Section 4.2.2.3.
4.2.2.3
Restrictions on diet and life style
Diet and lifestyle restrictions before and after administration of trial medication:
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in Flow Chart I & Flow Chart II.


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Day 1, Day 7 and Day 14
While admitted to site on Day 1, Day 7 and Day 14, from 1 hour before drug intake until 
lunch, water intake and meals are restricted as per Flow Chart I & Flow Chart II. From lunch 
onwards (on Day 1, Day 7and Day 14), for healthy volunteers only, water intake must be up 
to an additional 750 mL (maximum 1,500 mL) until 1 hour prior to the evening drug 
administration.
The total 
amount of liquid intake will be documented.
For all subjects while in the unit, standardised meals will be served at the time points 
described in respective flowcharts. A snack is allowed (if completed) 1 hour prior to the 
morning dose, or started 30 minutes after the evening dose, post-body plethysmography
(healthy volunteers only), if required. Use of additional table salt is not allowed during in-
house confinement at the trial site.
On all other days (excl. Day 1, Day 7 and Day 14), no time restrictions will occur to meals 
outside of 07:00 to 20:00.
Grapefruits, Seville oranges and their juices should be avoided 7 days before and until the last 
PK timepoint. Excess of dried fruits (defined at > 1 standard adult portion per day) and
dietary supplements containing high level of sodium and potassium should also be avoided 
during the trial. All non-prescribed supplements should be avoided.
For HV subject alcoholic beverages are not permitted from 48 hours prior to:

screening

study drug administration at Day 1, until after safety laboratory tests at Day 12.

end of study visit
For CF subjects excess of alcoholic beverages are not permitted 48 hours prior to:

screening

each treatment period (Visit 2 & 3) at Day 1, until after safety laboratory tests at Day 
14.

end of study visit
Intake of methylxanthine-containing drinks or foods (coffee*, tea, cola*, energy drinks*, 
chocolate, etc.) are not allowed during in-house confinement and 8 hours prior to the morning 
of in-clinic appointments with pulmonary function tests.
*Decaffeinated beverages are allowed.
Subjects will have to adhere to restrictions resulting from ATS/ERS guidelines (P05-12782)
for conduct of correct pulmonary function testing.
Excessive strenuous physical activities should be avoided starting from 72 hours prior to 
study drug administration and until the end-of-study examination.
Diet and lifestyle restrictions for lung function testing
The subject must refrain from strenuous activity for at least 24 hours prior to lung function
testing (forced spirometry, body plethysmography
). Subjects should 


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also avoid cold temperatures, environmental smoke, dust or areas with strong odours (e.g. 
perfumes). Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, 
and ice-cold beverages are not allowed at least 8 hours prior to and during the pulmonary 
function testing period at site visits. Decaffeinated beverages are acceptable.
4.2.2.4
Restrictions regarding women of childbearing potential 
WOCBP must use the highly effective methods of contraception as described in the subject
information.
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 section 10.1.
Patients will be asked to return inhalation aerosols and devices (used and unused) to the study
site. The trial medication adherence should be reviewed by the investigator and recorded on 
the appropriate drug accountability forms.
Compliance whilst in clinic will be assured by administration of all study medication under 
supervision of the investigating physician or a designee. 
CF subjects will be reminded to administer drug during a phone call from site (morning and 
evening). The AM3® device will alarm to remind the patient to take drug. Drug 
administration (morning and evening) will be captured by site staff directly (whilst in clinic) 
or via telephone (whilst ex-clinic). 
The measured plasma concentrations will provide additional information about compliance.
Estimating Compliance to trial medication
Compliance for Healthy Volunteers will be observed and recorded by site staff at the trial 
site. Compliance for CF subjects will be estimated using the records by site staff at the trial 
site (dosing in-clinic) and telephone calls to subjects (dosing at home). The acceptable 
medication compliance should have an overall value in the range from 80% to 120%. If the 
compliance is less than 80% or greater than 120%, the patient needs to be retrained.
Randomised patients should not be discontinued for a lack of compliance without prior
discussion with the clinical monitor.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
All endpoints listed below apply for both parts of the trial. 
5.1.1
Primary Endpoint(s)
The primary endpoint to assess safety and tolerability of BI 443651, is the frequency (in 
percent) of subjects with treatment-emergent adverse events (TEAE) over the treatment 
period. The primary endpoint will be reported separately for Healthy volunteers and CF 
subjects.
5.1.2
Secondary Endpoint(s)
The following pharmacokinetic parameters will be determined if feasible forhealthy 
volunteers in Part 1
.
After the first dose on Day 1:

Cmax (maximum measured concentration of the analyte in plasma)

AUC0-12 (area under the concentration-time curve of the analyte in plasma until 12 h after 
the first dose)
After the last dose on Day 7 (:

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over a 
uniform dosing interval τ)

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady state 
over a uniform dosing interval τ)
5.1.3
Further Endpoint(s)
Further safety criteria of interest:

Related AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Pulmonary function tests (FEV1, FVC, FEF25-75)
 
 


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5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A physical examination will be carried out according to the Flows Chart I & Flow Chart II
and will be performed as complete physical examination; at screening and end of study 
(e.o.s.) visits. In addition further physical examination should be performed if clarification of 
an AE is necessary. 
All clinically significant findings at screening will be documented on the source documents 
and recorded in the eCRF as baseline conditions.
After randomization, new clinically significant findings or worsening of screening conditions 
that are, in the opinion of the investigator, clinically significant or meet other adverse event 
criteria defined in Section 5.3.9 will be reported as adverse events.


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Body weight and height will be determined at the screening visit (Visit 1) as per Flow Chart I
& Flow Chart II. In addition body weight will be determined at end of study (e.o.s.) visit.
Body weight and height will be documented on the source documents and recorded. Body 
height will be recorded in the spirometry measurement device and the body weight of the 
screening Visit 1 (relevant for body plethysmography
 
assessment in CF subjects) will be recorded in the body plethysmography 
 
 device and used for subsequent measurements.
5.3.2
Vital Signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor at the times indicated in Flow Chart I & Flow Chart II after subjects 
have rested for at least 5 min in a supine position (if blood sampling for PK/safety purposes 
will be drawn from a cannula, this procedure will not affect the resting time). Where possible, 
all recordings should be made using the same blood pressure recording instrument on the 
same arm.
5.3.3
Medical examinations
At the screening visit, the medical examination will include documentation of subject 
information, informed consent, demographics including height and body weight, smoking 
and alcohol history, relevant medical history and concomitant therapy, review of inclusion 
and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination.
5.3.4
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 CF and as an exploratory assessment of drug effect. The CF subjects must 
qualify by demonstrating a pre-bronchodilator clinic measured FEV1 ≥70% of predicted 
normal (calculated according to GLI [R15-0845]) measured ≥ 8 hours after the last use of 
short acting bronchodilator at Visit 1 and prior to randomisation.
PFTs will be performed in triplicate using spirometry equipment provided by the site and 
calibrated by study staff on all test days. Equipment and techniques should conform to 
American Thoracic Society (ATS) criteria [P05-12782]. An ambulatory spirometer, Asthma 
Monitoring Device (AM3®), will be used to perform PFTs while the subject is at home (ex-
clinic).
Spirometry in-clinic will be conducted with the subject in a seated position. Spirometry using 
the AM3® device will be conducted in a standing position. It is preferable that the same 
trained individual performs the PFTs for a given subject. The best of three efforts will be 
defined as the highest FEV1 and the highest FVC each obtained on any of three blows 
meeting the ATS criteria (with a maximum of eight attempts). FEV1, FVC, FEF25-75 and PEF 
will be measured as indicated in Flow Chart I & Flow Chart II and recorded in the eCRF. Ex-
clinic measured values of PEF will not need to be collected in the database. The best of the 


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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.
5.3.5
Body Plethysmography
Airway resistance (Raw) will be measured with a constant volume whole-body 
plethysmograph as supplied and calibrated by the trial site. Measurements will be taken with 
the subject in the sitting position and carried out by an observer. The mean of at least three 
values recorded, will be taken as airway resistance. Refer to Flow Chart I for time points.
Practice sessions can be performed with volunteers from consent and screening onwards for 
those volunteers that would like to experience the body plethysmography prior to collecting 
data. This data will not be captured or collected.
5.3.6
CF control during the trial
The safety of the subjects regarding CF during the trial will be assured by monitoring of
FEV1 and assessment of rescue and controller medication use and CF signs and symptoms. 
Subjects should be discontinued from the trial if, in the opinion of the Principle investigator, 
the subject is developing unstable CF, based on assessment of safety parameters described 
above.
The subjects will be instructed to make themselves available for the regular telephone 
monitoring for drug administration and their general well-being. Site staff will assess drug 
compliance, a subject’s general well-being, rescue medication use and FEV1 measurements
via in-clinic visits, documented telephone monitoring and the AM3® device.
At home (ex-clinic) FEV1 measurements:
At Day 1 for CF subjects, eligible subjects will receive hand-held electronic spirometers, 
[AM3®, eResearch Technology, Inc] from the site for their regular use during the entire 
study to monitor their FEV1 whilst at home (Flow Chart II). In addition, CF subjects will 
perform an unsupervised manoeuvre on their AM3® device at screening (Day -7 to -3).
The subject should perform three FEV1 manoeuvres consistently, in a standing position with 
the AM3®. Instructions for use of the AM3® device will be provided to the subject.
All acceptable FEV1 values are stored in the AM3® device with date and time of recording.
CF subjects: 
Whilst the subject is at home (ex-clinic) morning and evening FEV1 measurements will be 
performed on the AM3® prior to administration of study medication and background 
respiratory medication. In the morning, whilst the subject is at home (ex-clinic), the 
manoeuvre will be performed prior to or as part of the telephone visit under the supervision 
of the study site staff. If a relevant drop in FEV1 compared to baseline (Day -7 to Day -3,
morning, unsupervised AM3® manoeuvre) is observed the site staff will evaluate whether the 
subject needs to return to clinic prior to the morning visit. 
During in clinic visits the AM3® data will be downloaded to a computer, the corresponding 
report printed and the data reviewed by the site in the morning on each visit day. The 
investigator will review/discuss the data with the subject and assesses the subject in regard to 
the data observed.
FEV1 should also be measured at any time whenever the subject feels breathless or otherwise 
uncomfortable. The AM3® is primed to alarm following a 20% relative drop vs. baseline in 


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FEV1. Subjects must not take their trial medication dose, and must call the site if the device 
alarms.
FEV1 data will be downloaded to a computer at each visit and printed out for review, 
signature and date by the investigator. Equipment will be withdrawn at end of study. Print-
outs will be filed in the ISF.
Telephone visits:
During the treatment period when subjects are at home (ex-clinic), regular appointments for 
telephone calls between subject and investigator will be made. Calls will be made in the 
morning and evening for CF subjects. The following issues will be covered at each telephone 
visits in a sequential way:
1. Subjects will be reminded to take their correct trial medication dose.
2. Subjects will be questioned regarding general wellbeing.
3. Whether the subjects have performed a FEV1 measurement with the AM3® that evening 
or that morning, if not subjects will need to perform the measurements during the course 
of the telephone calls. Site staff will ask whether the AM3 device has alarmed.
4. Subjects will be asked whether any AEs have occurred
5. Subjects will be reminded to conduct a FEV1 reading and subsequently administer drug in 
the following evening or morning.  
In any case of emergency during the trial the investigator must be available by phone for 
immediate assistance, therefore the subjects will be provided with 24-hour contact details.
Note: Documentation of AE if any (also if related due to i.e. a worsening of AE), change of 
any medication and intake of study medication have to be captured in the medical records and 
eCRF.
Details of any telephone visits as mentioned above, will be documented as source data in the 
subjects medical records.
5.3.7
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in Flow Chart I & Flow Chart II. 
If safety laboratory measurement is performed with other blood collection, e.g. PK sampling, 
safety laboratory measurement will always be performed first, preferably without any 
tourniquet.
The parameters that will be determined are listed in Tables 5.3.7: 1 and 5.3.7: 2. Reference 
ranges will be provided in the ISF
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.3.7: 1
Routine laboratory tests
Category
Test name
A1
B2
C3
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelets
Reticulocyte count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential (relative 
and absolute)
Neutrophiles
Eosinophils
Basophils
Monocytes
Lymphocytes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Manual differential 
WBC (if automatic 
differential WBC is 
abnormal)
Polymorphnuclear neutrophils (segs), band (only for HV)
neutrophils (stabs), eosinophils, basophils,
monocytes, lymphocytes
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin Time (Quick and INR)
X
X
X
X
X
X
Enzymes
Aspartate aminotransferase (AST/GOT, SGOT)
Alanine aminotransferase (ALT/GPT, SGPT)
Alkaline phosphatase
Gammaglutamyl transferase (GGT)
Lactate dehydrogenase
Amylase
Lipase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 5.3.7: 1
Routine laboratory tests (cont.)
Category
Test name
A1
B2
C3
Substrates
Glucose (plasma)
Creatinine
eGFR, calculated from serum creatinine using
CKD-EPI formula
Bilirubin, total
Bilirubin, direct
Cholesterol, total
Triglycerides
C-reactive protein
Urea
X
X
X
-
X
X
X
X
X
X
-
X
X
-
X
X
X
X
X
X
-
X
X
-
X
X
X
X
X
X
Electrolytes
Calcium
Sodium
Potassium
Chloride
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid stimulating hormone (TSH)
Progesterone
X
X
-
**
-
-
Urinalysis (Stix) 
[Urin-Sediment will 
be performed, if 
urinalysis abnormal]
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine RBC
Urine WBC
Urine pH
X
X
X
X
X
X
X
     X
X
-
-
-
-
-
-
-
-
-
X
X
X
X
X
X
X
     X
X
* From urine 
collection at 0-4, 4-8 
and 8-12 hr
Urine potassium
Urine sodium
Urine chloride
Urine creatinine
Potassium-creatinine-quotient
Sodium-creatinine-quotient
-
-
-
-
-
-
X
X
X
X
X
X
-
-
-
-
-
-
Urine sediment 
(microscopic 
examination if
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1A: parameters to be determined at screening examination
2B: parameters to be determined during the study (for time points refer to Flow Chart I & Flow Chart II)
3C: parameters to be determined during the Follow-up-examination
* Urine collected and samples taken from 0-12h will be stored at room temperature. Only to be 
collected on PK profile days for HV.
** Progesterone will need to be taken prior to second treatment period, for WOCBP.
The tests listed in Table 5.3.7: 2 are exclusionary laboratory tests which may be repeated as
required. The results will not be entered in the CRF/database and will not be reported in the
CTR. It is planned to perform these tests during screening only. Drug screening will be
performed at screening and on Day 1.


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Table 5.3.7: 2
Exclusionary laboratory tests
Functional lab group
Test name
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine
Methadone
Methamphetamines/MDMA/XTC
Opiates
Phencyclidine
Tricyclic antidepressants
Infectious serology 
(blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
The laboratory tests listed in Table 5.3.7: 1 and 5.3.7: 2 will be performed by the central 
laboratory, with the exception of the urine pregnancy tests (administered using a urine 
dipstick), urine drug abuse and alcohol breath tests.   
With regards to serum electrolytes samples, where local laboratory results are also used, 
central laboratory results will take precedence in the interpretation of the results. Local 
laboratory results will be stored as source data at the trial site and will take precedence for 
initial and continued 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.
5.3.8
Electrocardiogram
Standard 10 second twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be 
recorded using a computerised electrocardiograph (MAC 2000, GE Medical Systems, 
Freiburg, Germany) at the time points given in Flow Chart I & Flow Chart II. Electrode 
placement will be performed according to the method of Wilson, Goldberger and Einthoven 
modified by Mason and Likar (hips and shoulders instead of ankles and wrists). Precise 
electrode placement will be marked with an indelible mark on the skin to allow reproducible 
placement throughout the study.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for a 10-sec duration after the subjects 
have rested for at least 5 min in a supine position (if blood sampling for PK/safety purposes 
will be drawn from a cannula, this procedure will not affect the resting time). The site 
personnel will be instructed to assure a relaxed and quiet environment so that all subjects are 
at complete rest during the recordings. ECG assessment will always precede all other study 
procedures of the same time point to avoid impact of sampling on the ECG quality.
Triple ECGs (three ECGs recorded within 180 sec) will be recorded as the baseline on Day 1, 
before the first drug administration for all volunteer and subject groups. A second baseline 


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will be performed on Day 1 of Treatment Period 2 for CF subjects. For the healthy volunteers 
group all ECGs on Day 1, 2, 7 and 8, will be recorded in triplicate. For all other subject 
groups, single ECGs will be recorded, except for baseline (Day 1).
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation).
All ECGs that are locally printed will be evaluated by the investigator or a designee. For 
triplicate ECG QTcF values, the mean value will be calculated and interpreted by the 
investigator or designee. Additional (unscheduled) ECGs may be collected by the investigator 
for safety reasons. These ECGs are assigned to the prior scheduled time point. Unscheduled 
ECGs will not be included into the statistical analysis of interval lengths and not evaluated 
centrally.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of cardiac 
safety during the study, the QT and QTcF values generated by the ECG machines or their 
manual corrections by the investigators will be used. In doubtful cases, ECGs may be sent 
upfront for centralised evaluation (see below). In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. For all volunteers and subjects, for determination 
of safety and continued inclusion in the study the mean ECG of triplicates will be used for the 
evaluation.
All ECGs will be stored electronically and transmitted to an ECG core lab 
 
). At minimum, electrocardiograms recorded at the following time points 
will be evaluated centralized at the core lab:

Healthy volunteers: Days 1 and 2, and Days 7 and 8 (triplicate ECGs, only)

CF subjects: All ECGs
The analysis will include the determination of the intervals RR, PR, QRS and QT measured 
semi-automatically. Other parameters (e.g. cardiac axis) are determined by a validated GE 
12-SL-algorithm or equivalent but do not undergo semi-automatic evaluation. All interval 
measurements in one subject will be performed on the same lead. The intervals will be 
measured from four cardiac cycles (beats) in lead II. If lead II shows a flat T wave or is not 
measurable for any reason, lead V5 will be used, or if that lead is not measurable, then lead I 
will be used. The lead actually used will be reported in the CTR. HR and QTc (QT interval 
corrected for HR, e.g. QTcF and QTcB) will be determined in-house (see TSAP for details).
For CF subjects, morphological analyses of the centrally evaluated ECGs (see above) will be 
performed by a board-certified cardiologist or equivalent. In case of triplicate ECGs recorded 
at a time point one ECG will be selected randomly for this evaluation. In case additional 
(unscheduled) ECGs due to safety reasons are recorded at the study site, these ECGs are 
assigned to the previous scheduled time point, and all ECGs of this time point including the 
additional ECGs will undergo interpretation. The ECG interpretation will include an overall 
assessment and a classification of each finding (normal, abnormal clinically relevant, 
abnormal clinically not relevant, not assessable), in regard to rhythm, conduction and 
morphological abnormalities, presence of myocardial infarction, ST segment deviations, T-
wave morphology (normal, flat, inverted or biphasic) and presence of U-wave (normal and 


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abnormal). Abnormalities detected during centralised ECG evaluation will not necessarily 
qualify as AE.
For blinding arrangements see section 4.1.5.
For quality assurance and control of the measurements, all ECGs of a subject will be 
subsequently reviewed by the ECG technician supervisor or his/her designee with respect to 
the overall variance of the measured intervals, in order to detect accidentally switching of 
leads and/or false subject assignments of the ECGs. After the quality control the fiducial 
point markings will be reviewed by the cardiologist assigned to the study.
Assessed ECGs will comply with the ICH E14 guidance document and supplements
[R05-2311, R13-0801, R13-4095] as well as the FDA requirements for annotated digital
ECGs [R09-4830].
 
5.3.10
Assessment of adverse events
5.3.10.1
Definitions of Adverse Events (AEs )
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a subject 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.
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 subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or 

prolongation of existing hospitalisation,


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
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 subject 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 
subject 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”
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. 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.
The latest list of “Always Serious AEs” can be found in the Remote Data Capture (RDC)
system. These events should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs in this trial:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

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 lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the RDC 
system
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 


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(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).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.


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•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
5.3.10.2
Adverse event collection and reporting
AE Collection
Upon enrolment into the trial, a subject’s baseline conditions will be assessed (by 
documentation of medical history, concomitant diagnoses etc) at screening, and relevant 
changes from baseline will be subsequently noted.
Subjects will be required to report any AEs as well as the time of onset, end, and intensity of 
these events. In addition, each subject will be regularly assessed for AEs by the medical staff 
throughout the clinical trial and whenever the investigator deems necessary. As a minimum, 
subjects will be questioned for AEs (and concomitant therapies) at the time points indicated 
in Flow Chart I & Flow Chart II. Where no AEs are observed at these time points, the 
Investigator, or other members of site staff should document, ‘No AEs Observed’. 
Assessment will be made using non-specific questions such as ‘How do you feel?’. Specific 
questions will be asked wherever necessary in order to more precisely describe an AE.
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
A careful written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
•
From signing the informed consent onwards through the Residual Effect Period (REP), 
until individual subject’s end of trial: 
○
all AEs (serious and non-serious) and all AESIs.
○
The only exception to this rule are AEs (serious and non-serious) and AESIs in 
Phase I trials, when subjects discontinue from the trial due to screening failures 
prior to administration of any trial medication. In these cases, the subjects’ data 
must be collected at trial site but will not be entered into the CRF or trial database 
and will not be reported in the CTR.
○
However, if an individual subject discontinues trial medication prematurely but 
stays in the trial (i.e. if further visits at home incl. telephone visits are planned)
from then on and until the individual subject’s end of the trial the Investigator
must report related SAEs and related AESIs.
•
After the individual subject’s end of trial: 
the Investigator does not need to actively monitor the subject for AEs but should only 
report relevant SAEs and relevant AESIs of which the Investigator may become aware of.


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The REP for BI 433651 is defined as 30 days after the last trial medication application. All 
AEs which occurred through the treatment phase and throughout the REP will be considered 
as on treatment, please see Section 7.3.4. Events which occurred after the REP and before 
trial termination date 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 and any possible interactions between the investigational drug and a 
Non-Investigational Medicinal Product (NIMP).
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.
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.


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Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a subject has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) any potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used. This includes if the 
subject is female and becomes pregnant, or the subject is male and his female partner 
becomes pregnant.
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.
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Exact time points of plasma sampling will be documented in the CRFs by the medical 
personnel or sent as electronic files to the trial data manager. The actual sampling times will 
be used for determination of pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and
visits as long as the total blood volume taken per subject does not exceed 500 mL. Such
changes would be implemented via non-substantial CTP Amendments.
5.4.1
Assessment of Pharmacokinetics
Pharmacokinetic endpoints are listed in section 5.1. Further details will be given in the TSAP.
5.4.2
Methods of sample collection
5.4.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 443651 plasma concentrations, 4.0 mL of blood will be taken from
an antecubital or forearm vein into a K-EDTA (potassium ethylenediaminetetraacetic acid) 
anticoagulant blood drawing tube at the times indicated in Flow Chart I & Flow Chart II. 
Blood will be withdrawn by means of either an indwelling venous catheter or by 
venipuncture with a metal needle.
The K-EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in


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polypropylene (PP) tubes. The first aliquot should contain at least 1.0 mL plasma, the second 
aliquot will contain the remaining plasma. The process from blood collection until transfer of 
plasma aliquots into the freezer should be completed within 90 min. Immediately after 
centrifugation the samples should be pipetted and put into the freezer. For each aliquot the 
time when the sample was placed in the freezer will be documented.
The plasma samples have to be stored at about -20°C or below at the clinical site until 
shipment on dry ice to the logistic CRO. They will also be stored at about -20°C or below at 
the logistic CRO and the analytical laboratory until analysis. Further details on sample 
collection, preparation of plasma aliquots, sample handling, and shipping are provided in the 
lab manual.
At a minimum, the sample tube labels should list the following information: BI trial number,
subject number, visit, and planned sampling time. Further information such as matrix and
analyte may also be provided.
After completion of the trial the plasma samples may be used for further methodological
investigations, e.g. for stability testing, assessment of metabolites. However, only data related
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be
generated by these additional investigations. The study samples will be discarded after
completion of the additional investigations but not later than 5 years upon the final study
report has been signed.
 
 
 
 
 
 
 
 


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5.4.3
Analytical determinations
BI 443651 concentrations in plasma 
 will be determined by validated LC-MS/MS


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(liquid chromatography tandem mass spectrometry) assays. All details of the analytical
methods will be available prior to the start of sample analysis. Analyses will be performed at
Drug Metabolism & Pharmacokinetics Germany, Boehringer Ingelheim Pharma GmbH & Co. 
KG, Biberach, Germany.
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis..
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
If applicable, an exploratory PK-PD analysis may be undertaken.
5.5
ASSESSMENT OF BIOMARKER(S)
This section is not applicable.
 
 
 
 
 
 
  
5.7
APPROPRIATENESS OF MEASUREMENTS
The primary and secondary endpoints are standard and accepted for evaluation of safety, 
tolerability, and PK of an inhaled drug, and are widely used in this kind of studies.
The PK parameters and measurements outlined in Section 7.3.5 are generally used as 
measurements to assess drug exposure.
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects and to determine PK parameters in an 
appropriate way. 


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Therefore, overall, all measurements applied in this trial are considered by the sponsor to be 
appropriate.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows are given in Flow Chart I & Flow Chart II.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration on the main PK sampling days - Day 1, Day 7 and Day 14 - are to be 
performed and completed within 180 mins prior to drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, lung function testing
and laboratory tests will be ±15 min during the 2 hours after the first drug administration on 
the main PK sampling days (Day 1, Day 7 and Day 14) and ±45 min for vital signs, ECG, 
lung function testing and laboratory tests at all other time points.
Pre-dose blood samples for PK will be taken from 15 minutes prior to dosing. The acceptable 
deviation from the scheduled time for PK sampling on the main PK sampling days (Day 1, 
Day 7 & Day 14) will be ±5 min during the 4 hours after the first drug administration, ±10
min from 4h to 8h and ±15 min from 8h to 12h. On all other days, the acceptable deviation 
from the scheduled time for PK sampling will be ±15 min.
 
The tolerance for drug administration will be the following:

± 30 min on Days 1 and 7

± 30 min on Day 14 for CF subjects

± 45 min on all other treatment days. 
If scheduled in Flow Chart I & Flow Chart II at the same time as a meal, blood sampling and
vital signs, the 12- lead ECG recordings have to be done first. In general, if several 
measurements including venepuncture are scheduled for the same time, venepuncture should 
be on the time-point of the measurements, and lung function will be the last procedure due to 
its inconvenience to the patient and possible influence on physiologic parameters (see section 
5.3.4).
For planned individual plasma concentration sampling times 
refer to Flow Chart I & Flow Chart II. While these nominal times should be adhered to as 
closely as possible, the actual sampling times will be recorded and used for determination of
pharmacokinetic parameters.
If a volunteer/subject misses an appointment, it will be rescheduled if possible. Relevant time 
violations will be identified and their handling discussed no later than at the Report Planning 
Meeting.


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
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.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, and physical examination, refer to Sections 5.3.1 to 5.3.8.
6.2.2
Treatment period(s)
Each subject will receive the respective trial medication (BI 443651 or placebo b.i.d.) at Day 
1 until Day 6 for healthy volunteers, and Day 13 for CF subjects, and then one dose of the 
respective trial medication (BI 443651 or placebo) in the morning of the final day. CF 
subjects will undergo subsequent washout period of at least 30 days prior to an additional two 
weeks of respective trial medication i.e. the alternative medication administered during the 
first treatment period. 
Trial medication will be administered by each subject (under direct supervision, whilst in-
clinic of the investigator or his designee). Details on treatments and procedures of 
administration are described in Section 4.1.4.
All healthy volunteers and CF subjects will attend the trial site, as per Flow Chart I & Flow 
Chart II, after formal assessment and confirmation of their fitness by the investigator or 
designee. On all other study days, the study will be performed in an ambulatory fashion (at 
home / ex-clinic).
For details on time points and procedures for collection of plasma 
 samples for PK
analysis, refer to Flow Chart I & Flow Chart II.
The safety measurements performed during the treatment period are specified in Section 5.2.
of this protocol and in Flow Chart I & Flow Chart II. For details on time points for all other 
trial procedures, refer to Flow Chart I & Flow Chart II. AEs and concomitant therapy will be 
assessed continuously from screening until the end of trial examination.
6.2.3
End of Trial Period
For AE assessment, laboratory tests, recording of ECG and vital signs, physical examination, 
weight and pregnancy test for female subjects of child bearing potential, during the end of 
trial period, see Sections 5.3.1 to 5.3.7.
Subjects who discontinue treatment before the end of the planned treatment period should
undergo the follow-up and end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by
the investigator will be monitored using the appropriate tests until a return to a medically
acceptable level is achieved. Adverse events persisting after trial completion must be 
monitored until they have normalised or have been sufficiently characterised.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
7.1.1
Objectives
Part 1 (MRD): The primary objective is to investigate safety, and tolerability of orally inhaled 
administration of BI 443651 for 6.5 days b.i.d, in healthy male and female volunteers 
following administration of 100 µg b.i.d., 400 µg b.i.d., 1200 µg b.i.d. and 1800 b.i.d. µg.
Part 2 (cross-over): The primary objective is to investigate the safety and tolerability of orally 
inhaled administration of BI 443651 in stable male and female CF subjects following 
administration of repeated doses of 600 µg b.i.d. BI 443651 over 13.5 days.
For both parts, the primary safety endpoint is defined in Section 5.1.1. Inferential statistics 
are not planned (as explained in Section 7.2).
The secondary objective for part 1 is the exploration of the pharmacokinetics of BI 443651 
after multiple dosing.
PK endpoints as specified in Section 5.1 will be analysed by descriptive statistics. 
Secondary PK endpoints as defined in Section 5.1.2 will be subjected to analysis of dose 
proportionality by use of the power model for part 1 of this trial. 
 
 
 
 
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 5 groups of 5 different dose levels 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.
For both trial parts, 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.


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7.3
PLANNED ANALYSES
The statistical analysis will be based on the following analysis sets.

Enrolled set (ES): This subject set includes subjects that signed informed consent and 
underwent screening procedures.

Randomized set (RS): This subject set includes all randomised subjects, whether 
treated or not. 

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the subjects received.
 

Pharmacokinetic set (PKS): The PK parameter analysis set (PKS) includes all subjects 
in the Treated Set (TS) who provide at least one PK parameter that was not excluded 
according to the description in Section 7.3.2. Excluded subjects will be listed with 
their individual plasma concentrations and individual pharmacokinetic parameters, 
however, will not be included in descriptive statistics for plasma concentrations, 
pharmacokinetic parameters or other statistical assessment.
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 pre-defined in the TSAP.
7.3.1
Primary endpoint analyses
Analysis of safety and tolerability is described in Section 7.3.4.
7.3.2
Secondary endpoint analyses
The secondary PK parameters (refer to Section 5.1.2) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472, current version).
Analyses will be performed for parent drug.
Plasma 
 concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol violation relevant to the evaluation of PK (to be decided no later than in the Blinded 
Report Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, 
based on the criteria specified below). Exclusion of a subject’s data will be documented in the 
CTR.
Relevant protocol violations may be


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
Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma 
 concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example missing samples/concentration data occur at important phases of the 
PK disposition curve.
Assessment of dose proportionality (Part 1 only)
Dose proportionality will be assessed using the secondary pharmacokinetic endpoints after 
the first dose AUC0-12, Cmax and after the last dose AUCτ,ss , Cmax,ss as specified in Section 
5.1.2 for HV. 
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints.
The model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate. 
Together with 
and 
, taking natural logarithms converts this model 
to a linear form as follows:
where
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, …, 4, j = 1, …, 8 for HV

intercept parameter;
slope parameter;
logarithm of dose i;
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model.
Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
For further details refer to the TSAP (such as selection of covariance structure and 
comparison of time points).
ij
i
ij
ε
)
X
exp(
)
exp(Y







)
exp(


)
exp(
ε
ij
ij



ij
i
ij
ε
X
β
α
Y




ij
Y
β
i
X
ij
ε


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7.3.4
Safety analyses
Safety will be assessed for the endpoints and parameters of interest listed in Section 5.1.1 and 
5.1.3 based on the treated set. Safety analyses (except of ECG data) will be descriptive in 
nature and will be based on BI standards.


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Treatments will be compared in a descriptive way. The control group for HV in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. For CF, each subject will appear in the active treatment group and the 
placebo group, due to the cross-over structure. The active treatment groups will be compared 
to the respective 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 ‘randomised treatment’. 
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 the 
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.
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment emergent’.
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 
5.3.10.1) and other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of 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 descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of subjects with abnormal 
values or clinically relevant abnormal values. 
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial, follow-up period and at the end of trial evaluation will 
be assessed with regard to possible changes compared to findings before start of treatment. 
Baseline refers to the last measurement before drug administration.


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The ECG variables QT, HR, QTcF, QTcB, PR, QRS, and RR obtained from the centralised 
evaluation of 12-lead ECG recordings will be the basis for the derivation of quantitative and 
categorical ECG endpoints. These endpoints and their analyses will be described in the 
TSAP.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
The pharmacokinetic parameters listed in Section 5.1 for BI 443651 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3) will be reported with their 
individual plasma / urine concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma 
 concentrations, 
pharmacokinetic parameters or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
If applicable, PK/PD analyses will be conducted.
7.4
INTERIM ANALYSES
No formal inferential statistical interim analysis is planned. However, after each dose group 
the investigator (or 
 deputy) is allowed to postpone further dose progression until a 
preliminary safety review (refer to Section 3.1.2) of the data already obtained has been 
performed. For details of handling of treatment blinding refer to Section 4.1.5.
As this trial is conducted in two separate parts, these two parts will be evaluated separately 
after each completion. 
7.4.1
Analysis of Part 1 (HV)
After completion of part 1 with HV the final unblinded analysis of this data will be performed 
to enhance further project planning. As this will only occur after all HV have completed the 
trial the potential for bias seems to be low and does not outweigh practical considerations.
To support this analysis the data obtained from part 1 will be cleaned and an interim database 
lock will be made before unblinding and finalization of the outputs. For details of handling of 
treatment blinding refer to Section 4.1.5. Logistical details will be documented in a separate 
logistics plan stored in TDMAP. The unblinded results will be summarized in a draft CTR. It 
is not planned to repeat the final analyses of part 1 data after completion of both trial parts. 
However, the analyses could be repeated in case of changes of the underlying data (e.g. 
update of MedDRA version) are necessary.


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7.4.2
Analysis of Part 2 (CF)
After completion of part 2 with CF subjects the final analyses of this study will be performed. 
The draft CTR containing the results from part 1 will be updated with the final analysis.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety and efficacy
With respect to safety evaluations, it is not planned to impute missing values.
For the assessment of lung function, missing data will not be imputed. The mixed effect model 
will handle missing data based on a likelihood method under the "missing at random” 
assumption.
7.5.2
Plasma
 drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP (001-MCS-36-
472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the pre-dose values).   
7.5.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP (001-MCS-36-
472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit. 
7.6
RANDOMISATION
For Part 1, healthy volunteers will be randomised within each dose group in a 4:1 ratio, which 
reflects the ratio of subjects receiving active drug to placebo.   
For Part 2, otherwise healthy CF subjects will be randomised to one of the two treatment 
sequences in a 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).


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Access to the codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
For Part 1, it is planned to include a total of 40 healthy volunteers. The planned sample size is 
not based on a power calculation. The size of 10 healthy volunteers per dose group (8 on 
active treatment, and 2 on placebo) is commonly used in multiple-rising dose studies of the 
present type and is in general considered as sufficient for the exploratory evaluation of 
multiple dose safety and pharmacokinetics [R95-0013].
Additional healthy volunteers may be entered to allow testing of additional intermediate 
doses within the planned dose range on the basis of experience gained during trial conduct 
(e.g. preliminary PK data), i.e. the actual number of subjects entered may exceed 40.
For Part 2, it is planned to include a total of 24 (12 per sequence) otherwise healthy CF 
subjects 
 
 
 
 
 
 
 
 


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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.
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 subjects, and 
is stored in the ISF (Investigator Site File).
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to 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 patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each subject or the 
subject’s legally accepted representative.”
The Investigator must give a full explanation to trial subjects based on the patient 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.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, 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 subjects will be provided by the sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
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 
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 subject identifiers (e.g. subject’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure subject confidentiality.


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If the subject is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the subject 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, subject number, date subject
was informed)

Dates of Subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

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 subject 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.
8.3.2
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.
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 


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(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.
An adaptive approach to clinical trial monitoring will be utilised. This is initiated by an 
assessment of the risk associated with the trial combined with identification of critical data 
and processes. An Integrated Quality and Risk Management Plan documents the strategies 
involved with the implementation of onsite, offsite and central monitoring activities in order 
to direct focus to the areas of greatest risk which have the most potential impact to subject
safety and data quality. Trial oversight is achieved by regular review of a report of risk which 
then influences any monitoring adaptations. 
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.
8.3.3
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
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY 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 subjects 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 analysing biological samples and data from 
clinical trial subjects 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 Patient Out”) or end date of the last open AE or date of the last follow-up test or date 
of an AE has been decided as sufficiently followed-up, whichever is latest. The “Last Patient
Drug Discontinuation” (LPDD) 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 LPDD 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)
P16-00121
Global Strategy for the Diagnosis, Management and Prevention of COPD, 
Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. 
Available from: http://goldcopd.org/
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 1994;272(19):1497-1505.
P96-3855
Ramsey BW. Management of pulmonary disease in patients with cystic 
fibrosis. N Engl J Med 1996;335(3):179-188.
R01-1277
Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care 
Med 1996;154:1229-1256.
R02-2234
Patel IS, Seemungal TAR, Wilks M, Lloyd-Owen SJ, Donaldson GC, 
Wedzicha JA. Relationship between bacterial colonisation and the 
frequency, character, and severity of COPD exacerbations. Thorax 
2002;57:759-764.
R05-2311
ICH E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonised 
tripartite guideline, recommended for adoption at step 4 of the ICH process 
on 12 May 2005 by the ICH Steering Committee). www.emea.eu.int, 1 - 14 
(2005)
R09-1400
ICH topic M3 (R2) non-clinical safety studies for the conduct of human 
clinical trials and marketing authorization for pharmaceuticals: step 4: note 
for guidance on non-clinical safety studies for the conduct of human clinical 
trials and marketing authorization for pharmaceuticals (June 2009, 
CPMP/ICH/286/95). http://www.emea.europa.eu (2009)
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).


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R13-0801
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs: 
questions and answers (R1) (ICH, October 2012).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo
rmation/Guida nces/ucm073161.pdf (access date: 22 February 2013) ; U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Center for Biologics 
Evaluation and Research (CBER) (2012)
R13-4095
European Medicines Agency (EMA) Committee for Medicinal Products for 
Human Use (CHMP): ICH guideline E14 - questions and answers: step 5 
(May 2012, EMA/CHMP/ICH/310133/2008).
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidel
ine/2009/0 9/WC500002878.pdf (access date: 13 September 2013) ; 
London: European Medicines Agency (EMA) (2012)
R15-0689
O'Riordan TG, Donn KH, Hodsman P, Ansede JH, Newcomb T, Lewis SA, 
et al. Acute hyperkalemia associated with inhalation of a potent ENaC 
antagonist: phase 1 trial of GS-9411. J Aerosol Med Pulm Drug Deliv 2014. 
27(3):200-208.
R15-0845 
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)
R15-1325
Boulet LP, Coeytaux RR, McCrory DC, French CT, Chang AB, Birring SS, 
Smith J, Diekemper RL, Rubin B, Irwin RS, CHEST Expert Cough Panel
Tools for assessing outcomes in studies of chronic cough: CHEST guideline 
and expert panel report. Chest 147 (3), 804 - 814 (2015)
R15-1327
Robinson PD, et al Consensus statement for inert gas washout measurement 
using multiple- and single-breath tests. Eur Respir J 41 (3), 507 - 522 
(2013)
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 lung function in patients with COPD: Chest 2005; 128: 1995 
- 2004. Respir Med COPD Update 2006;1(3):101-102.
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 2008;32(3):201-207.
R15-4955
Clunes MT, Boucher RC, Virtual Lung Group. Cystic fibrosis: the 
mechanisms of pathogenesis of an inherited lung disorder. Drug Discov 
Today Dis Mech 2007;4 (2):63-72.


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R15-4975
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 2012; 26(2):533-545.
R15-4976
Astrand ABM, Hemmerling M, Root J, Wingren C, Pesic J, Johansson E, 
Garland AL, Ghosh A, Tarran R. Linking increased airway hydration, 
ciliary beating, and mucociliary clearance through ENaC inhibition. Am J 
Physiol 2015;308(1, Part 1):L22-L32.
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 2000;109(4):288-295.
R15-4986
Speizer FE, Fay ME, Dockery DW, Ferris BG. Chronic obstructive 
pulmonary disease mortality in six U.S. cities. Am Rev Respir Dis 
1989;140(3, Part 2): S49-S55.
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 1992;145(3):545-547.
R15-5349
Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King M, 
Edwards LJ, Helms RW, Boucher RC. A pilot study of aerosolized 
amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med. 
1990 Apr 26;322(17):1189-94
R15-5485
App EM, King M, Helfesrieder R, Köhler D, Matthys H. Acute and 
longterm amiloride inhalation in cystic fibrosis lung disease. A rational 
approach to cystic fibrosis therapy. Am Rev Respir Dis. 1990 
Mar;141(3):605-12.
R15-5486
Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC. 
Defective epithelial chloride transport in a gene-targeted mouse model of 
cystic fibrosis. Science 1992;257(5073):1125-1128.
R15-5487
Koehler D, App E, Schmitz-Schumann M, Wuertemberger G, Matthys H. 
Inhalation of amiloride improves the mucociliary and the cough clearance 
in patients with cystic fibroses. Eur J Respir Dis Suppl 1986;146:319-326.
R15-5502
Anderson WH, Coakley RD, Button B, Henderson AG, Zeman KL, Alexis 
NE, Peden DB, Lazarowski ER, Davis CW, Bailey S, Fuller F, Almond M, 
Qaqish B, Bordonali E, Rubinstein M, Bennett WD, Kesimer M, Boucher 
RC. The relationship of mucus concentration (hydration) to mucus osmotic 
pressure and transport in chronic bronchitis. Am J Respir Crit Care Med 
2015;192(2):182-190.


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R15-5505
Pons, G., Marchand, M. C., D'Athis, P., Sauvage, E., Foucard, C., 
Chaumet-Riffaud, and Lenoir, G. (2000). French multicenter randomized 
double-blind placebo-controlled trial on nebulized amiloride in cystic 
fibrosis patients. Pediatr. Pulmonol., 30(1), 25-31.
R15-5506
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 2013;144(2):498-506.
R15-5507
Mall MA, Button B, Johannesson B, Zhou Z, Livraghi A, Caldwell RA, 
Schubert SC, Schultz C, O'Neal WK, Pradervand S, Hummler E, Rossier 
BC, Grubb BR, Boucher RC. Airway surface liquid volume regulation 
determines different airway phenotypes in Liddle compared with 
betaENaC-overexpressing mice. J Biol Chem 2010;285(35):26945-26955.
R15-5546
Genes and human disease: monogenic diseases. 
http://www.who.int/genomics/public/geneticdiseases/en/index2.html#CF 
(access date: 28 October 2015) ; Geneva: World Health Organization 
(WHO); 2015.
R15-5599
Graham, A., Hasani, A., Alton, E. W. F. W., Martin, G. P., Marriott, C., 
Hodson, M. E., and Geddes, D. M. (1993). No added benefit from 
nebulized amiloride in patients with cystic fibrosis. Eur. Respir. J., 6(9), 
1243-1248.
R16-2498
Jane Davies, Helen Sheridan, Nicholas Bell, Steve Cunningham, Stephanie 
D Davis, J Stuart Elborn, Carlos E Milla, Timothy D Starner, Daniel J 
Weiner, Po-Shun Lee, Felix Ratjen, Assessment of clinical response to 
ivacaftor with lung clearance index in cystic fibrosis subjects with a 
G551D-CFTR mutation and preserved spirometry: a randomised controlled 
trial, The Lancet Respiratory Medicine, Volume 1, Issue 8, October 2013, 
Pages 630-638
R95-0013
Broom C, Design of first-administration studies in healthy man. In: 
O'Grady J, Linet OI, editors. Early Phase Drug Evaluation in Man. London: 
Macmillan Press , 206 - 213 (1990)
R96-0686
Jones PW, Quirk FH. A self-complete measure of health status for chronic 
airflow limitation. Am Rev Respir Dis 145, 1321 - 1327 (1992)
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 1996;153:1530-1535.


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R15-5349 
Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King M, 
Edwards LJ, Helms RW, Boucher RC. A pilot study of aerosolized 
amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med. 
1990;322(17):1189-94
9.2
UNPUBLISHED REFERENCES
c02337864 
Investigators Brochure: BI 443651 Cystic Fibrosis, COPD
c10884768-01 
Safety, tolerability and pharmacokinetics of single rising inhaled doses of
BI 443651 in healthy male volunteers in a partially randomised, single
blind, placebo-controlled trial (Trial 1363.1). Clinical Trial Report. 
c18572722-01 
A Phase Ib, multicentre, double blind, randomised, two-part study, first part 
multiple rising dose and second part two-way cross-over, to assess safety, 
tolerability, efficacy and pharmacokinetics of BI 443651 compared to 
placebo via Respimat® in healthy volunteers and cystic fibrosis subjects 
(Trial 1363.2). Summary Interim Report. 
c09837286
 Clinical overview: BI 443651 to support clinical trial application 
for study 1363.2. Contains safety, tolerability and PK data from first-inman
study 1363.1
n00248843
Influence of BI 443651 on hERG-mediated potassium current in HEK293 
cells (13_0032_HRG). Non Clinical Report. 
001-MCS-36-472 
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics.


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10.
APPENDICES
10.1
HANDLING INSTRUCTIONS FOR RESPIMAT INHALER FOR USE IN 
CLINICAL TRIALS
Instructions For Demonstration
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.
Figure 10.1:1
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
Figure 10.1:2
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.
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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Prepare for first use
Figure 10.1: 3
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.


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  Daily use
Figure 10.1:4
TURN

Keep the cap closed.

TURN the clear base in the direction of 
the arrows on the label until it clicks 
(half a turn).
OPEN

OPEN the cap until it snaps fully open.
PRESS

Breathe out slowly and fully.

Close your lips around the mouthpiece 
without covering the air vents.

While taking a slow, deep breath through 
your mouth, PRESS the dose-release 
button and continue to breathe in.

Hold your breath for 10 seconds or for as 
long as comfortable.

Repeat Turn, Open, Press for a total of 
puffs required by the clinical trial 
protocol.


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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.
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.


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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   


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10.4
PHARMACOKINETIC ANALYSES
N/A
10.5
HANDLING PROCEDURE OF BLOOD SAMPLES FOR PLASMA 
CONCENTRATION-TIME MEASUREMENTS
N/A
10.6
CF EXACERBATION
A CF Pulmonary exacerbation is defined as a new or change in antibiotic therapy (IV, 
inhaled, or oral) for any 4 or more of the above signs/symptoms: 

Change in sputum

New or increased hemoptysis

Increased cough

Increased dyspnea

Malaise, fatigue, or lethargy

Temperature above 38°C (equivalent to approximately 100.4°F)

Anorexia or weight loss

Sinus pain or tenderness

Change in sinus discharge

Change in physical examination (PE) of the chest

Decrease in pulmonary function by 10%

Radiographic changes indicative of pulmonary infection
10.7
CONTRACEPTION SECTION
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, bilateral 
oophorectomy, confirmed tubal occlusion or tubal ligation. 
All female subjects of child bearing potential must use two acceptable methods of 
contraception with their partners, from screening until 30 days after the last dose of IMP. 
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 female subjects: 
• Condoms 
• Established hormonal contraception in the form of combined oral monophasic contraception 


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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 dose of IMP


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
13 October 2016
EudraCT number
2016-001504-31
BI Trial number
1363.2
BI Investigational Product(s)
BI 443651
Title of protocol
A Phase Ib, multicentre, double blind, randomized, 
two-part study, first part multiple rising dose and 
second part two-way cross-over, to assess safety, 
tolerability, efficacy and pharmacokinetics of BI 
443651 compared to placebo via Respimat® in 
healthy volunteers, and COPD and CF subjects.
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flow Chart I, II & III; Sections 3.1.2, 4.1.4, 4.2.2.3, 
5.1.2, 5.1.3, 5.3.9, 5.4.2.3, 6.1, 6.2.2, 7.1, 7.3
Description of change
Reduction to 7 days treatment for healthy 
volunteers, removal of body plethysmography time 
points, 
Rationale for change
Review of data from 1363.1.
Section to be changed
Section 5.3.4, 5.3.7, 5.3.10
Description of change
Clarity over details entered in the database: 
spirometry ex-clinic, local laboratory values, AEs 
considered ”always serious”, 
 in 
appendices
Rationale for change
Clarification.
Section to be changed
Flow Chart I, II & III; Sections 3.1.2, 
Description of change
Clarification over follow-up period and REP.
Rationale for change
Response to MHRA questions / clarification,


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Number of global amendment
2
Date of CTP revision
01 December 2016
EudraCT number
2016-001504-31
BI Trial number
1363.2
BI Investigational Product(s)
BI 443651
Title of protocol
A Phase Ib, multicentre, double blind, randomized, 
two-part study, first part multiple rising dose and 
second part two-way cross-over, to assess safety, 
tolerability, efficacy and pharmacokinetics of BI 
443651 compared to placebo via Respimat® in 
healthy volunteers, and COPD and CF subjects.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flow Charts I, II & III; Sections 3.1.2, 
Description of change
Extension of follow-up period and REP from 14 to 
30 days. Extension of wash-out period for CF 
cohort from 14 to 30 days.
Rationale for change
Response to MHRA questions /clarification,
Section to be changed
Section 1.2 
Description of change
Clarifications on safety margins and drug profile.
Rationale for change
Response to MHRA questions /clarification,
Section to be changed
Section 3.3.4 
Description of change
Addition of one criterion for individual withdrawal: 
subject experiencing a serious adverse event or any 
AE that, in the opinion of the investigator, may 
jeopardise the safety of the trial participant.
Rationale for change
Response to MHRA questions /clarification,
Number of global amendment
3
Date of CTP revision
08 March 2017


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EudraCT number
2016-001504-31
BI Trial number
1363.2
BI Investigational Product(s)
BI 443651
Title of protocol
A Phase Ib, multicentre, double blind, randomized, 
two-part study, first part multiple rising dose and 
second part two-way cross-over, to assess safety, 
tolerability, efficacy and pharmacokinetics of BI 
443651 compared to placebo via Respimat® in 
healthy volunteers, and COPD and CF subjects.
Comment
A CTP version 4 (revision 3) exists but this version 
will not be submitted to IRB/ IEC / CA. It has been 
issued by error but the archiving system doesn’t 
allow to disregard the corresponding version 
numbering.
Number of global amendment
4
Date of CTP revision
31 March 2017
EudraCT number
2016-001504-31
BI Trial number
1363.2
BI Investigational Product(s)
BI 443651
Title of protocol
A Phase Ib, multicentre, double blind, randomized, 
two-part study, first part multiple rising dose and 
second part two-way cross-over, to assess safety, 
tolerability, efficacy and pharmacokinetics of BI 
443651 compared to placebo via Respimat® in 
healthy volunteers, and COPD and CF subjects.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
TCM name
Description of change
 replaced 
 as TCM
Rationale for change
Administrative change
Section to be changed
Section 2.3.2 Drug-related risks and safety
measures


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Description of change
1) Modification of the safety margins (dose 
multiples) for the NOAEL dose in the 4-week 
rat study and for the NOAEL dose in the 4-
week dog study.
2) Change in the values for the multiples for the 
starting dose for both HV and COPD 
populations
Rationale for change
To align with the values indicated in the IB dated 
of 16 Dec 2016
Number of global amendment
5
Date of CTP revision
20 April 2017
EudraCT number
2016-001504-31
BI Trial number
1363.2
BI Investigational Product(s)
BI 443651
Title of protocol
A Phase Ib, multicentre, double blind, randomized, 
two-part study, first part multiple rising dose and 
second part two-way cross-over, to assess safety, 
tolerability, efficacy and pharmacokinetics of BI 
443651 compared to placebo via Respimat® in 
healthy volunteers and CF subjects.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Title and all subsequent mentions of COPD patients, 
pathology except in section 1.
Description of change
Deletion of the word COPD and references to COPD 
subjects.
Rationale for change
COPD cohorts will not be performed then the whole 
references to COPD subjects assessments have been 
removed
Section to be changed
Flowcharts I and II and footnotes
Description of change
Visit 1 timeframe changed as well as first day of 


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Visit 2. The footnotes where this time windows
appear have been changed accordingly.
Rationale for change
To guarantee safety laboratory results review before 
first dosing within the protocol requirements
Section to be changed
Flowchart I 
Description of change
1) Footnote 6 : Add the opportunity to perform 
screening ECG on the site’s device and then to 
transfer the data to the vendor
2) ECG Day -7 to -3 : deleted 
3) Footnote 8 added for day 7, pre-dose 
measurement. Footnote also corrected
Rationale for change
1) To allow more flexibility
2) Not necessary as already taken at screening and 
then pre-dose
3) To correct a mistake
Section to be changed
Flowchart II
Description of change
1) Deletion of footnote 24 to first laboratory sample 
on Day -7 to -3
2) First laboratory samples taken on Day 1 moved 
from 7.45 am to 6 am and footnote 4 replaced by 
24
3) Footnote 2 added to pre dose PK sampling at Day 
1
 
 
5) Dosing time changed from 7.45 am to 8 am and 
move from 8 am to 7.45 am of pre-dose safety 
laboratory samples and PK samples 
6) Addition of evening calls
Rationale for change
1) To correct an omission
2) To allow more time to perform the assessments
3) To correct an omission
4) To correct an omission
5) To be consistent with timepoints at every visit
6) To secure the study drug compliance
Section to be changed
Abbreviations
Description of change
Adjustment of abbreviations list
Rationale for change
To fit the abbreviations actually used into the 
protocol 
Section to be changed
Section 3.1.2
Description of change
Deletion of the mention of the need to have 20 CF 
subjects for a review
Rationale for change
No dose escalation meeting will be performed based 


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on CF subjects data then no reason to be mentioned 
in this section.
Section to be changed
Section 3.2
Description of change
Maximum wash out period between treatment period 
1 and 2 for CF subjects decreased from 8 to 6 weeks
Rationale for change
To limit the length of this wash out period
Section to be changed
Section 3.3.2
Description of change
Inclusion criteria 3 for every population: Change of 
timeframe to obtain the progesterone measurement
Rationale for change
To align with the change of timeframe globally
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria 11: Change of timeframe for the 
first safety laboratory sample taken at Visit 2
Rationale for change
To align with the change of timeframe globally
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria 13: and changed to or for the 
timepoint of assessment of pre dose ECGs
Rationale for change
To ensure not to enter any patient with a potential 
pre-existing ECG abnormality
Section to be changed
Section 3.3.4
Description of change
1) Maximum wash out period between treatment 
period 1 and 2 for CF subjects decreased from 8 
to 6 weeks.
2) Addition of the request that the site contacts the 
sponsor in case of patient’s withdrawal indicating 
the reason of discontinuation.
Rationale for change
1) To limit the length of the wash out period.
2) To ensure the sponsor is informed in a timely 
manner.
Section to be changed
Section 4.1.2
Description of change
1) Deletion of a sentence defining safety margin for 
the starting dose (100µg).
2) Correction of the dose group of healthy 
volunteers which has to be evaluated before 
starting CF part.
Rationale for change
1) To delete unnecessary information as already 
included in section 2.3.2.
2) To correct a mistake.
Section to be changed
Section 4.3
Description of change
Retraining of the patient needed in case he/she has a 


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compliance over 120% instead of 100%.
Rationale for change
To align with other part of the CTP.
Section to be changed
Section 5.1.3
Description of change
Indication of PK parameters which will be 
determined at Day 7 for CF subjects.
Rationale for change
To clarify the objective of the PK sampling done at 
Day 7 for CF subjects.
Section to be changed
Footnote Table 5.3.7: 1
Description of change
 
Rationale for change
To correct a mistake
Section to be changed
Section 5.3.7
Description of change
1) Indication that the safety samples which are 
expected to be performed locally in addition to 
central laboratory are serum electrolytes
2) Deletion of reference to section 10 as this pointed 
to the section 10 of the CTP when this refers to 
section 10 of the ISF.
Rationale for change
1) To clarify which samples have to be analysed 
locally
2) To correct a mistake
Section to be changed
Section 5.3.8
Description of change
Deletion of the mention that all ECG will be centrally 
evaluated
Rationale for change
To clarify that all ECGs will be collected centrally 
but that screening ones will not be evaluated by the 
vendor.
Section to be changed
Section 5.3.9
Description of change
 
 
Rationale for change
To correct an omission and make the explanation 
clearer.
Section to be changed
Section 5.3.10.2
Description of change
Deletion of a mention that a sentence can be deleted
Rationale for change
To correct a missing adaptation from the protocol 
template
Section to be changed
Description of change
 
 


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Rationale for change
1) To allow more flexibility to the sites and allow 
them to stick to their usual practices.
2) To clarify that a different container will be used 
per sampling interval.
Section to be changed
Section 5.5.1 Biobanking (header)
Description of change
Header deleted
Rationale for change
Only extended storage of sample is proposed in the 
protocol and not biobanking properly then the header 
is not applicable
Section to be changed
Section 6.2.2
Description of change
Washout period for CF patient changed from 14 days 
to 30 days as minimum
Rationale for change
To align on changes done in revision 2 (omission 
here
Section to be changed
Section 7.4, Section 4.1.5, Section 3.1.3 and 
Statistical Methods Part within Synopsis
Description of change
Added different timepoints for final analyses of part 
1 (HV) and part 2 (CF) depending on their 
completion.
Rationale for change
To enhance further project planning.
Section to be changed
Section 7.4
Description of change
Added blinded interim analysis of BA data from CF 
subjects
Rationale for change
To enhance planning of upcoming Phase II trial.
Section to be changed
Appendix 10.1
Description of change
Instruction for use of Respimat® adapted to the test 
drug used in this study
Rationale for change
As the dose of study drug is higher than with other 
drug inhaled with Respimat®, the instructions for use 
have been adapted to ask for a daily priming.
Section to be changed
Description of change
 
Rationale for change
 
Number of global amendment
6
Date of CTP revision
06 September 2017


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EudraCT number
2016-001504-31
BI Trial number
1363.2
BI Investigational Product(s)
BI 443651
Title of protocol
A Phase Ib, multicentre, double blind, randomized, 
two-part study, first part multiple rising dose and 
second part two-way cross-over, to assess safety, 
tolerability, efficacy and pharmacokinetics of BI 
443651 compared to placebo via Respimat® in 
healthy volunteers and CF subjects.
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
X
Section to be changed
3.3.2 Inclusion criteria #7 Part 2
Description of change
In the c criteria, deletion of be as written twice.
Rationale for change
To correct a typo.
Section to be changed
3.3.4 Removal of Subject from therapy or assesment
Description of change
Clarification of the type of antibiotics which have to 
be stopped prior to re start of treatment period 2.
Rationale for change
To clarify the use of antibiotics during the trial.
Section to be changed
3.3.4.1 Discontinuation of the trial
Description of change
In the second potential reason for discontinuation, the 
timing of the baseline ECG for treatment Period 2 
has been changed from Day –3 to -1 to Day 1.
Rationale for change
To correct a typo.
Section to be changed
4.2.2.1 Restrictions regarding concomitant treatment
Description of change
1) Clarification on the permitted use of oral/injected 
antibiotics if not prescribed for exacerbation or 
infection and in a chronic way.
2) Visit 2 changed into Visit 3 in the section for 
inhaled antibiotics and clarification of restart for 
treatment period 2.


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Rationale for change
1) To clarify that the use of oral/injected antibiotics 
is only excluded in the case of exacerbation or 
infection but not when use chronically.
2) To correct a typo and clarify when the treatment 
has to be restarted.
Section to be changed
4.2.2.2 Medication restrictions for all lung function 
testing
Description of change
Deletion of mention of Day 7 for a visit where serial 
PFTs occur.
Rationale for change
To correct a typo, no PFT +2hr on Day 7.
Section to be changed
4.2.2.3 Restrictions on diet and life style
Description of change
Clarification of the restrictions related to diet.
Rationale for change
To clarify the fact that dietary supplement are 
allowed as used as replacement in the case of CF 
patients. Other dietary restrictions have also been 
clarified to fulfil study requirements.


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Number of global amendment
7
Date of CTP revision
09 November 2017
EudraCT number
2016-001504-31
BI Trial number
1363.2
BI Investigational Product(s)
BI 443651
Title of protocol
A Phase Ib, multicentre, double blind, randomized, 
two-part study, first part multiple rising dose and 
second part two-way cross-over, to assess safety, 
tolerability, efficacy and pharmacokinetics of BI 
443651 compared to placebo via Respimat® in 
healthy volunteers and CF subjects.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as 
changes involve logistical or 
administrative aspects only
Section to be changed
Flowchart II - header
Description of change
1) Planned time relative to drug intake of the day
added.
2) Deletion of columns 
 
bodyplethysmography and sputum collection.
Rationale for change
1) To be clearer for the investigators.
2) Cancellation 
, bodyplethysmography
and sputum collection to restrict the burden for the 
patients to what is only necessary for safety 
monitoring.
 
 
Body plethysmography is no longer required as no 
relevant changes in any of the lung function 
parameters was observed in healthy volunteers at any 
timepoints.


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Section to be changed
Flowchart II – deletion of several lines
Description of change
1) Deletion of several assessments during main clinic 
visits (Day 1, Day 7 and Day 14) as PFT post dose 
after +2 hr) Removal of  PK samples with the 
exception of predose, 30 and 45 minutes postdose on 
Days1 and 14, predose and 30 min postdose on Day 7 
and sample at EOS and ECGs after +30 min (Day 1).
2) Replacement of intermediate on-site visits by 
twice daily phone contact with patients as well as 
during wash-out/follow up period.
3) Vital signs measurements at +5min cancelled on 
Day 1 and Day 14.
Rationale for change
1) To limit the length of on-site visits for the patients 
as these assessments are considered as no longer 
required. And burden of PK sampling
2) To limit the number of in-clinic visits and then the 
burden for the patients while maintaining an 
appropriate safety monitoring of the patients.
3) Not feasible because of the requirement to have a 
minimum of 5 min rest in supine position.
Section to be changed
Flowchart II – addition of time windows 
Description of change
Allowance of time windows for Day 7 (+/- 2 days), 
Day 14 (- 1/+ 3 days), Day 23 (+/- 2 days), Day 30 
(+/- 5 days).
Rationale for change
To allow more flexibility for the patients to come on 
site.
Section to be changed
Flowchart II – changes in footnotes
Description of change
1) Deletion of footnotes (8, 10, 11), adaptation of 
some others (2, 22).
2) changes in footnotes 5 and 24.
Rationale for change
1) To meet the changes implemented in the flowchart 
in this amendment.
2) to correct a mistake (5) or to avoid 
misunderstanding (24)
Section to be changed
Sections 2.1, 2.2, 5.1.2, 5.1.3, 5.4.2.3, 6.2.3
Description of change
All PK sampling times removed with the exception 
of predose, 30 and 45 minutes postdose on Days 1 
and 14, predose and 30 minutes postdose on Day 7 
and EOS PK sample.  This resulted in removal of PK 
parameters for CF patients, as they no longer can be 
calculated. The PK concentrations will be listed by 
time point along with descriptive statistics will be 
provided.  The CF dose normalised concentration 
data will be shown graphically with the HV PK data 


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to investigate whether systemic exposures are similar 
or different in the two different populations.
Rationale for change
To reduce PK burden on CF patients. 
Section to be changed
Section 2.3.1 Procedure related risks
Description of change
Change of maximum volume of blood taken.
Rationale for change
As the number of PK points decreases in the CF part, 
the maximum volume of blood is taken in the HV 
part and is then lower than initially mentioned.
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
Change in exclusion criteria #16 to limit this criteria 
to concomitant medication not clearly allowed in the 
table 4.2.2.1:1
Rationale for change
To clarify that oral antibiotic as Azythromycin are 
allowed as prophylactic treatment despite their long 
half-life.
Section to be changed
Section 4.1.5.1 Blinding
Description of change
Clarification of a sentence explaining that analyses of 
part I will not have an impact conduct of part II.
Rationale for change
It is clarified that the term conduct in that sentence 
refers to randomisation, blinding and analyses of the 
primary endpoint. That is there is no conflict for this 
amendment.
Section to be changed
Section 4.2.2.2 Medication restriction for all lung 
function testings 
Description of change
Change of wording and timing for PFTs. 
Rationale for change
Due to the decrease of the number of PFT 
assessments, the wording has been reviewed.
Section to be changed
Section 4.2.2.3 Restrictions on diet and lifestyle. 
Description of change
Addition of “excess” in the sentence refraining CF 
patients from their alcoholic consumption.
Rationale for change
To be more realistic and allow a reasonable alcoholic 
intake during the course of the study.
Section to be changed
Section 5.3.5 Body Plethysmography
Description of change
Deletion of the mention of Flowchart II or subjects
Rationale for change
Body plethysmography will no more be performed 
for CF subjects then correction required.
Section to be changed
Section 5.3.6 CF control during the trial
Description of change
Few corrections in the “telephone visits” subsection 
to be clear that there will have twice daily calls when 
the patient will not have an in-clinic visit.


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BI Trial No.: 1363.2
c09013915-08
Trial Protocol
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Rationale for change
To be online with the twice a day phone call 
planning.
Section to be changed
Table 5.3.7: 1 Routine laboratory tests
Description of change
1) Addition of the mention of HV patients only for 
the manual differential white blood cell count of 
polymorphnuclear neutrophils.
 
Rationale for change
1) To correct a mistake.
 
Section to be changed
Description of change
Rationale for change
 
Section to be changed
Section 7.1.1 Objectives, 
Description of change
Rationale for change
Section to be changed
Section 7.4 Interim analyses
Description of change
Removed analyses of PK data from CF subjects by 
trial pharmacometrician
Rationale for change
This is not needed any longer due to reduced PK 
sampling in Part 2.
Section to be changed
Section 9.2 Unpublished references
Description of change
Some references deleted and some others added.
Rationale for change
To support the changes of the CTP.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09013915
8.0
clinical-trial-protocol-version-08
A Phase Ib, multicenter, double blind,  randomized, two-part study, first part multiple
rising dose and second part two-way cross-over, to assess safety, tolerability, efficacy
and pharmacokinetics of BI 443651 compared to placebo via Respimat® in healthy
volunteers and CF subjects.
Author-Trial Statistician
13 Nov 2017 09:17 CET
Approval-Team Member Medicine
13 Nov 2017 09:20 CET
Approval-Therapeutic Area 
13 Nov 2017 10:04 CET
Author-Trial Clinical Monitor
13 Nov 2017 10:42 CET
Approval-Clinical Pharmacokinetics
13 Nov 2017 18:09 CET
Verification-Paper Signature
Completion
15 Nov 2017 10:40 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09013915
8.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c13382205-03
BI Trial No.:
1363.2
Title:
A Phase Ib, multicentre, double blind, randomized, two-part study, 
first part multiple rising dose and second part two-way cross-over, to 
assess safety, tolerability, efficacy and pharmacokinetics of BI 
443651 compared to placebo via Respimat® in healthy volunteers 
and CF subjects including Protocol Amendment 7 (c09013915 -08)
Investigational
Product:
BI 443651
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
18SEP2018 REVISED
Version:
Revised 3.0
Page 1 of 38
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT .....................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoints....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
5.3.2
Safety endpoints ..................................................................................................12
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................15
6.1
TREATMENTS...................................................................................................15
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................16
6.3
PATIENT SETS ANALYSED...........................................................................21
.....................................................................................................22
6.5
POOLING OF CENTRES .................................................................................22
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................22
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................22
7.
PLANNED ANALYSIS......................................................................................25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........26
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................26
7.3
TREATMENT COMPLIANCE........................................................................26
7.4
PRIMARY ENDPOINT .....................................................................................26
7.5
SECONDARY ENDPOINTS.............................................................................26
7.5.1
Key secondary endpoints....................................................................................26
7.5.2
Secondary endpoints...........................................................................................26
7.6.1
Safety endpoints ..................................................................................................28


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7.7
EXTENT OF EXPOSURE.................................................................................29
7.8
SAFETY ANALYSIS..........................................................................................29
7.8.1
Adverse events.....................................................................................................29
7.8.2
Laboratory data ..................................................................................................31
7.8.3
Vital signs.............................................................................................................31
7.8.4
ECG......................................................................................................................31
7.8.5
Others...................................................................................................................32
7.8.5.1
Spirometry.............................................................................................................32
7.8.5.2
Physical examination ............................................................................................33
 
 
8.
REFERENCES....................................................................................................35
9.1
DETAILED DESCRIPTION OF ENDPOINTS FOR ECG...........................36
10.
HISTORY TABLE..............................................................................................38


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for adverse events, laboratory tests, vital signs 
and spirometry for healthy volunteers..............................................................15
Table 6.1: 2
Flow chart of analysis phases for adverse events, laboratory tests, vital 
signs, ECG and spirometry for CF subjects .....................................................16
Table 6.2: 1
Important protocol deviations for healthy volunteers.......................................17
Table 6.2: 2
Important protocol deviations for CF subjects .................................................19
Table 6.3: 1
Analysis Sets.....................................................................................................21
Table 6.7: 1
12-lead ECG recordings for HV.......................................................................23
Table 6.7: 2
12-lead ECG recordings for CF subjects..........................................................24
Table 10: 1
History table .....................................................................................................38


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
CARE
Clinical data analysis and reporting environment
CF
Cystic fibrosis
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
EudraCT
European union drug regulating authorities clinical trials
FEF25-75
Forced expiratory flow
FEV1
Forced expiratory volume in 1 second
FEV1pp
FEV1 percent predicted
FRC
Functional residual capacity
FVC
Forced vital capacity
gCV
Geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IPD
Important protocol deviation


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Term
Definition / description
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PEF
Peak expiratory flow
PFT
Pulmonary function testing
PK
Pharmacokinetic(s)
PKS
PK analysis set
QTcB
QT interval corrected for heart rate using the method of Bazett (QTcB)
QTcF
QT interval corrected for heart rate using the method of Fridericia 
(QTcF)
RAGe
Report appendix generator
RPM
Report planning meeting
RS
Randomised set
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
TEAE
Treatment emergent adverse event
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E9 (10), the purpose of this document is to provide a 
more technical and detailed elaboration of the principal features of the analysis described in 
the revised 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 revised 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.
Within the earlier version 2.0 of the TSAP, the planned analyses for the healthy volunteer 
(HV) cohort has been specified. All descriptions and planned analyses for this trial part are
based on CTP Version 6.0 (20 April 2017) even though part 1 was conducted according to
CTP Version 3.0 (01 December 2016) which was applicable when recruitment for part 1 
started. Planned analyses for CF subjects were described as detailed as possible in version 2.0 
of the TSAP. At the time of recruitment of the first CF subjects for part 2 of the study, CTP 
Version 7.0 (06 September 2017) was applicable and the CTP was amended to Version 8.0 
(09 November 2017) during conduct of part 2. Within the current revised version of the TSAP 
the planned analyses for the CF subjects were updated or added based on CTP Version 8.0.
For further details refer to Section 4.
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). 
Non-compartmental pharmacokinetic (PK) parameters will be calculated using WinNonlinTM
software (professional Network version 5.2, Pharsight Corporation, Mountain View, CA 
94041-1530, USA). Population PK, PK/PD analysis will be conducted with appropriate 
software, which will be documented in the population PK, PK/PD report.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Changes implemented within TSAP Version 2.0:
CTP Version 6.0 ( dated 20 April 2017) was the basis for planned analyses of HV part (trial 
part 1). The corresponding amendment implemented the following changes which also affect 
the planned analysis of the study:

The COPD cohort was not performed. All planned analyses will be based on healthy 
volunteers and CF subjects only.

After completion of part 1 with healthy volunteers (HV) the final unblinded analysis 
of this data will be performed to enhance further project planning. Logistical details 
are described in a separate Logistics Plan (9). Data obtained from part 1 will be 
cleaned and an interim database lock will be made before unblinding and finalization 
of the outputs. A final TSAP for the analyses of HV was provided before interim 
database lock. 
For PK parameters assessed on Day 7 of part 1 for HV itwas not clear at the time of analysis 
whether steady state had beenreached. Therefore, for the purpose of the final analysis and 
reporting the parameters Cmax,ss and AUCτ,ss at Day 7, which are defined as secondary 
endpoints for HV, will now be referred to as Cmax,13 and AUCτ,13.
Changes implemented within this TSAP Version 3.0:
Since planned analyses for CF subjects were not completely described in TSAP version 2.0, 
all details on planned analyses for CF subjects are described in this revised TSAP prior to 
final database lock at the end of the trial.
CTP Version 7.0 (dated 06 September 2017) was applicable at the time of first recruitment of 
CF subjects in part 2 of the trial. It implemented changes to facilitate trial logistics which did 
not affect the planned analyses of the trial.
The Final Version 8.0 of the CTP (dated 09 November 2017) implemented the following 
changes which also affect the planned analysis of the study part 2 with CF subjects:
 
 
 
 
 
 
 


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
Planned times for pre-dose assessments on Days 1, 7 
 were changed as listed 
below:
Planned time according to
Study day
CTP V7.0
CTP V8.0
Day 1
-2:00
-1:00
-1:00
-0:30
Day 7
142:00
143:00
143:00
143:30
Pre-dose measurements collected according to planned times of CTP Version 7.0 will 
be set to the corresponding planned time of CTP Version 8.0 for analyses.
 
 
 
Further changes/clarifications to the planned analyses of CF subjects (not based on a CTP 
amendment):

In addition to the further safety endpoints regarding PFT, FEV1/FVC ratio will be 
evaluated as further safety endpoint similar to FEV1 and FVC.
 
 
 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint to assess safety and tolerability of BI 443651 is the frequency (in 
percent) of subjects with treatment-emergent adverse events (TEAE) over the treatment 
period. The primary endpoint will be reported separately for HV and CF subjects.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
No applicable.
5.2.2
Secondary endpoints
The following pharmacokinetic parameters of BI 443651 will be determined after first dose 
(morning of Day 1) in HV in Part 1:

Cmax (maximum measured concentration of the analyte in plasma after first dose)

AUC0-12 (area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to 12 h after first dose)
The following pharmacokinetic parameters of BI 443651 will be determined after last dose 
(13th dose, morning of Day 7) in HV in Part 1:

Cmax,13 (maximum measured concentration of the analyte in plasma over the time interval 
from 0 to 12 h after the 13th dose)

AUCτ,13 (area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to 12 h after the 13th dose)


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5.3.2
Safety endpoints
The following endpoints are further safety criteria of interest:

Related AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Pulmonary function tests (FEV1, FVC, FEV1/FVC ratio (CF subjects only), FEF25-75)
12-lead ECG endpoints
For the definition of baseline and a summary of time points please refer to Section 6.7.
Quantitative ECG endpoints:
The following quantitative ECG endpoints will be determined for the ECG variables RR, PR, 
QRS, QT, HR, QTcF and QTcB derived as described in Section 9.1:

absolute values (per time point)

changes from baseline (per time point)

percent changes from baseline (per time point; only for HR, PR, QRS)
Categorical ECG endpoints
The following categorical ECG endpoints will be determined based on the quantitative ECG 
endpoints:

New onset (meaning that this or a higher category was not present at baseline) of 
maximum QTcF interval > 450 to 480 msec, > 480 to 500 msec, or > 500 msec on 
treatment. For assignment of a particular subject to one of the above categories, all time 
points on-treatment will be considered. If baseline is missing, but the maximum absolute 
QT(c) interval falls in a category other than normal (i.e. when QTcF > 450 msec), then 
this is categorized as a new onset in the respective category. If baseline is missing, but the 
maximum absolute QT(c) interval is normal, then it is categorized as ‘No new onset’.

Maximum change from baseline in QT interval of ≤ 60 msec, or > 60 msec on treatment

Maximum change from baseline in QTcF interval of ≤ 30 msec, > 30 to ≤ 60 msec, or 
> 60 msec on treatment


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The occurrence of any of the following will be viewed as "notable findings":

New onset (not present at baseline) of uncorrected QT interval > 500 msec at any time on 
treatment
If baseline is missing, any occurrence of QT interval > 500 msec at any time on treatment 
will be a notable finding

New onset of QTcF interval > 500 msec at any time on treatment
If baseline is missing, any occurrence of QTcF interval > 500 msec at any time on 
treatment will be a notable finding

Increase in QTcF interval from baseline by > 60 msec at any time on treatment

Increase in HR from baseline by ≥ 25%, when corresponding on-treatment value of HR is 
> 100 beats/min, or decrease in HR by ≥ 25%, when corresponding on-treatment value of 
HR is < 50 beats/min, at any time on treatment

Increase in the PR interval from baseline by ≥ 25%, when corresponding on-treatment 
value of PR interval is > 200 msec, at any time on treatment

Increase in the QRS complex from baseline by ≥ 10%, when corresponding on-treatment 
value of QRS complex is > 110 msec, at any time on treatment
Findings from the morphologic analyses of the ECGs (done for CF subjects in Part 2) will be 
determined and categorized based on SDTM terminology.
 
 
 
 
 
 
 
 
 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered please refer to Section 4 of the 
CTP.
The trial is composed of two parts, a multiple rising-dose (MRD) and a cross-over part. Both 
parts are randomised, placebo-controlled and double-blind.
During the MRD part, healthy volunteers (40 subjects planned to be included) will be treated 
with doses of 100, 400, 1200 and 1800 µg b.i.d. of BI 443651 or placebo.
For the cross-over part, a total of 24 subjects with CF will be included in the study. Each 
subject will receive both placebo and active drug at the dose level 600 µg b.i.d. of BI 443651.
Measurements (such as ECG, spirometry, vital signs, or laboratory parameters) or adverse 
events (AE) will be assigned to treatments and study periods by applying the following rules:

Screening: measurements made or AEs which started prior to first administration of trial 
medication.

On-treatment: measurements made or AEs which started between first administration of 
trial medication in a treatment period and first administration of trial medication in the 
next treatment period or end of REP will be assigned to the preceding treatment. The REP 
for BI 433651 is defined as 30 days after the last trial medication application.

Follow-up: measurements made or AEs which started between the end of REP and first 
administration of trial medication in the next treatment period or trial termination date. In 
case of 2 or more treatments, the follow-up will be summarized according to the previous 
treatment.
Table 6.1: 1
Flow chart of analysis phases for adverse events, laboratory tests, vital signs 
and spirometry for healthy volunteers
Study analysis 
phase
Start
End
Screening
Date of informed consent 
Date/time of first device actuation for
administration of BI 443651 or placebo
On treatment
Date/time of first device actuation for
administration of BI 443651 or placebo
0:00 AM on day after end of REP or
0:00 AM on day after trial termination 
date 
Whatever comes first
Follow-up (not 
identical to time 
points acc. To CTP)
0:00 AM on day after end of REP
trial completion date


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Table 6.1: 2
Flow chart of analysis phases for adverse events, laboratory tests, vital signs, 
ECG and spirometry for CF subjects
Study analysis 
phase*
Start
End
Screening
Date of informed consent 
Date/time of first device actuation for
administration of BI 443651 or placebo
(first treatment period)
On treatment
(period 1/2)
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
0:00 AM on day after trial termination 
date
or 
date/time of first drug intake in the next 
treatment period
whatever comes first
Follow-up
0:00 AM on day after end of REP
0:00 AM on day after trial termination 
date
or 
date/time of first drug intake in the next 
trial period
*In case measurements (baseline or on-treatment) scheduled for period 2 were obtained within the on-treatment phase of 
treatment period 1 deviations in the assignment to study phases or possible exclusions will be discussed in the BRPM.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects entered and 
randomized who did not fail during screening.
Consistency check listings (for identification of deviations 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 Medical Quality Review Meetings (MQRM) and Blinded 
Report Planning Meetings (BRPMs). At these meetings, all manual deviations identifyed at 
the sites by the CRAs and deviations too complex to program will be reviewed by the trial 
team to decide which are considered important. For definition of important protocol 
deviations (iPD), and for the process of identification of these, refer to the Boehringer 
Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" (1).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the MQRM/BRPM minutes via an accompanying Excel spreadsheet (2). The following tables
contain the categories which are considered to be iPDs in this trial, separately for healthy 
volunteers and CF subjects. The column “Excluded from” specifies a general rule when an 
iPD results in exclusion from analysis datasets, but the final decision with regard to iPDs and 
exclusion from analysis datasets should be made at the BRPM or Database Lock Meeting 
(DBLM). If the data show other iPDs, these tables will be supplemented accordingly by the 
time of the DBLM at the latest.


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Table 6.2: 1
Important protocol deviations for healthy volunteers
Category /
Code
Description
Example/Comments
Excluded from
A
Entrance criteria not met
A1
Inclusion criteria not met
None
A2
Exclusion criteria not met
None
B
Informed consent
B1
Informed consent not 
available/not done
Missing informed consent (ICF); 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 
subject signed the correct version of the 
ICF after Visit 1. To be discussed at 
MQRM/BRPM/DBL meetings.
None
C
Trial medication and 
randomization
C1
Incorrect trial medication 
taken *
Medication kit assigned not matching 
treatment subject was randomized to 
and/or not matching IVRS assignment
None
C2
Randomisation order not 
followed*
None
C3
Non-compliance
Compliance <80% or >120%
Decisions at MQRM/BRPM.
None
C4
Medication code broken 
inappropriately *
To be discussed and decided during 
MQRM/BRPM. Only inappropriate code 
breaks at iPDs (e.g., unblinding by 
Global Pharmacovigilance is not).
None
C5
Incorrect intake of trial 
medication
None


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Table 6.2: 1
Important protocol deviations for healthy volunteers (cont.)
Category 
/ Code
Description
Example/Comments
Excluded from
D
Concomitant 
medication
D1
Prohibited medication 
use *
Decision at MQRM/BRPM
None
D3
Improper medication 
washout at baseline visit 
or primary endpoint 
visit(s) *
Decisions at MQRM/BRPM. 
None
E
Missing data (for 
primary and secondary 
endpoints)1
E1
Certain deviations of 
procedures used to 
measure primary or 
secondary data
Decision at MQRM/BRPM
None
F
Incorrect timing2
F1
Certain deviations of 
time schedule used to 
measure primary or 
secondary data
Incorrect timing for PK sampling *
Decision at MQRM/BRPM
None
G
Other trial specific 
important deviations
G1
Incorrect intake of meal*
None
G2
protocol deviations 
affecting safety and 
rights. *
Manual deviationss reported by 
CML/CRA which are considered as 
important. Carefully reviewed, 
described and documented in DBL 
meeting minutes.
None
*not programmed
1 Missing visits, evaluations, and tests will be considered missing data, not protocol violartions
2 Time deviations will only be flagged as iPD, when leading to exclusion of the entire subject from an analysis set


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Table 6.2: 2
Important protocol deviations for CF subjects
Category /
Code
Description
Example/Comments
Excluded from
A
Entrance criteria not met
A1
Inclusion criteria not met
A1.1
Age limitation not met or 
women with childbearing 
potential (with no confirmed 
menstrual period prior to 
dosing) 
IN3, IN4
None
A1.2
CF diagnosis not met
IN2
None
A1.3
Pre-bronchodilator parameter 
at screening not met.
IN6
None
A1.5
Ability to perform technically 
acceptable pulmonary 
function tests not given
IN8
None
A1.6
Other reason
IN5, IN7
None
A2
Exclusion criteria not met
A2.1
Co-morbidity conditions not 
met
EX1,EX2
None
A2.2
Cardiovascular related 
conditions not met
EX4, EX5, EX13, EX14
None
A2.3
Safety lab not met
EX11
None
A2.4
Substance abuse
EX19, EX20, EX21 
None
A2.5
Use of restricted medication
EX15, EX16, EX17
None
A2.6
Other reasons
EX3, EX6, EX7, EX8, EX9, EX10, 
EX18, EX22, EX23, EX24, EX25, 
EX26, EX27, EX28, EX29 
None
B
Informed consent
B1
Informed consent not 
available/not done
Missing informed consent; 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 subject signed the 
correct version of the ICF after Visit 
1. To be discussed at 
MQRM/BRPM/DBL meetings.
None
C
Trial medication and 
randomization
C1
Incorrect trial medication 
taken *
Medication kit assigned not 
matching treatment subject was 
randomized to and/or not matching 
IVRS assignment
None
C2
Randomisation order not 
followed
None


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Table 6.2: 2
Important protocol deviations for CF subjects (cont.)
Category 
/ Code
Description
Example/Comment
Excluded from
C3
Non-compliance
Compliance <80% or >120%
Decisions at MQRM/BRPM.
None
C4
Medication code broken 
inappropriately *
To be discussed and decided during 
MQRM/BRPM. Only inappropriate 
code breaks at iPDs (e.g., unblinding 
by Global Pharmacovigilance is not).
None
C5
Incorrect intake of trial 
medication
None
C6
Improper washout 
between treatments
None
D
Concomitant 
medication
D1
Prohibited medication 
use *
Decision at MQRM/BRPM
None
D3
Improper medication 
washout at baseline visit 
or primary endpoint 
visit(s) *
Decisions at MQRM/BRPM. 
None
D4
Improper use of rescue 
medication
Decisions at MQRM/BRPM.
None
E
Missing data1
E1
Certain deviations of 
procedures used to 
measure primary,
secondary or efficacy
data
Decision at MQRM/BRPM
None
F
Incorrect timing2
F1
Certain deviations of 
time schedule used to 
measure primary,
secondary or efficacy
data
Incorrect timing for PK sampling *
Decision at MQRM/BRPM
None
G
Other trial specific 
important deviations
G1
Incorrect intake of meal
None
G2
protocol deviations
affecting efficacy, safety 
and rights. *
Manual protocol deviations reported 
by CML/CRA which are considered 
as important. Carefully reviewed, 
described and documented in DBL 
meeting minutes.
None
*not programmed
1 Missing visits, evaluations, and tests will be considered missing data, not protocol deviations
2 Time deviations will only be flagged as iPD, when leading to exclusion of the entire subject from an analysis set


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6.3
PATIENT SETS ANALYSED
The statistical analysis will be based on the following analysis set:

Enrolled set (ES): all subjects who signed informed consent and underwent screening 
procedures

Randomized set (RS): all randomised subjects, whether treated or not

Treated set (TS): all subjects who were randomized and treated with at least one dose 
of study drug (active or placebo). The treatment assignment (for CF part: within each 
treatment period) will be determined based on the first treatment the subjects received.
 

Pharmacokinetic set (PKS): all HVs in the TS who provide at least one PK parameter 
that was not excluded according to the description in Section 7.3.2 of the CTP. 
Excluded subjects will be listed with their individual plasma concentrations and 
individual pharmacokinetic parameters, however, will not be included in descriptive 
statistics for plasma concentrations, pharmacokinetic parameters or other statistical 
assessment.
Table 6.3: 1
Analysis Sets
Analysis Set
Class of endpoint
ES
RS
TS
PKS
Disposition
X
Exposure
X
iPDs
X
Demographic/baseline endpoints
X
Safety endpoints 
X
Secondary PK endpoints
X
Further PK endpoints
X
 
 
 


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6.5
POOLING OF CENTRES
For HV there is only one centre. 
For CF subjects all planned analyses will be performed across all centres. 
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Generally, it is not planned to impute missing values for safety or efficacy evaluations with 
the exception of missing or incomplete AE dates and missing data of PK data. These will be 
handled according to BI standards (see SOP 001-MCG-156_RD-01 for missing AE dates (3)
and SOP 001-MCS-36-472 for missing PK data (4)).
Plasma 
 drug concentration data identified with NOS (no sample available), NOR 
(no valid result), NOA (not analysed), BLQ (below the lower limit of quantification), or NOP 
(no peak detectable) will be displayed as such and not replaced by zero at any time point (this 
rule also applies to the lag phase, including the predose values).
For the non-compartmental analysis of pharmacokinetic parameters, concentration data 
identified with NOS, NOR or NOA will generally not be considered. Concentration values in 
the lag phase identified as BLQ or NOP will be set to zero. All other BLQ/NOP values of the
profile will be ignored. The lag phase is defined as the period between time zero and the first 
time point with a concentration above the quantification limit.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For endpoints regarding pulmonary function testing (e.g. FEV1) in-clinic, baseline is defined 
as the last measurement taken on Day 1 before first study drug administration within each 
treatment period.
For pulmonary function testing using the home spirometer, baseline is defined as the last 
measurement taken between Day -7 and -3 before first study drug administration within each 
treatment period.
For ECG endpoints, baseline is defined as the mean of the last triplicate measurement taken 
on Day 1 before first study drug administration within each treatment period.
For all other endpoints, baseline is defined as the last measurement before first study drug 
administration within each trial period. I.e., in case the pre-dose measurement on Day 1 is 
missing, the measurement between Day -7 and Day -3 will be used as baseline.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the MQRM.


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There will be a centralised evaluation of all 12-lead ECG recordings at the time points 
identifyed in Tables 6.7:1 and 6.7:2 for HV and CF subjects, respectively.
Table 6.7: 1
12-lead ECG recordings for HV
Visit
Day
Planned time 
[hh:mm]
(relative to drug 
administration)
Approximate 
clock time 
[hh:mm]
of actual day
Study 
phase
Triplicate 
ECG 1
1
-21 to -1
Screening
2
-3 to -1
1
-01:00
07:00
Baseline
X
00:45
08:45
On-
treatment
X
02:00
10:00
X
04:00
12:00
X
11:00
19:00
X
2
23:00
07:00
X
4
71:00
07:00
7
143:00
07:00
X
144:45
08:45
X
146:00
10:00
X
148:00
12:00
X
155:00
19:00
X
8
167:00
07:00
X
16
360:00
08:00
23
528:00
08:00
30
696:00
08:00
4
37-44
9999:00
08:00
e.o.s.
Note: Times are based on Flow Chart I – Healthy Volunteers of CTP Version 3.0 (01 
December 2016)
1 Triplicate ECGs on Day 1, 2, 7 and 8 will be evaluated centrally.


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Table 6.7: 2
12-lead ECG recordings for CF subjects
Per
iod
Visi
t
Day
Planned time 
[hh:mm]
(relative to 
drug 
administration
)
CTP Version 
8.0(7.0)
According 
to CTP, 
Version 7.0
Approxima
te clock 
time 
[hh:mm]
of actual 
day
Accordin
g to CTP, 
Version 
8.0
Approxi
mate 
clock time 
[hh:mm]
of actual 
day
Study 
phase
Triplic
ate 
ECG
1
-21 to -
3
Screen
ing
1/2
2/3
1
-1:00(-02:00)
06:00
7:00
Period
Baseli
ne 1/2
X
00:30
08:30
08:30
On-
treatm
ent 1/2
04:00
12:00
11:00
19:00
7
143:00(142:00)
06:00
7:00
11
239:00
07:00
14
311:00(310:00)
06:00
7:00
23
528:00
08:00
30
696:00
08:00
8:00
37
864:00
08:00
4
44-51
9999:00
08:00
8:00
e.o.s.
Note: at the end of Visit 2 (period 1), subjects will washout for at least 30 days prior to 
crossing-over and commencing Day 1 of Visit 3 (period 2). At the end of Visit 3 (period 2), 
subjects will continue to the end of study visit (Visit 4).
Note: Times are based on Flow Chart II – CF subjects of CTP Version 7.0 (06 September 
2017) and Version 8.0 (09 November 2017); all ECGs (single and triplicate) will be evaluated 
centrally


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7.
PLANNED ANALYSIS
This version of the TSAP describes analyses for HV and CF subjects. 
Generally, HV and CF subjects will be evaluated separately. For safety analyses a total active 
treatment column will be displayed, if applicable.
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (7).
The individual values of all subjects will be listed, sorted by treatment group, subject number 
and visit (if visit is applicable in the respective listing). AE listings will be sorted by assigned 
treatment (see Section 7.8.1 below for details). The listings will be contained in Appendix 
16.2 (SDL) of the CTR.
Inferential statistical analyses of PK endpoints will be presented in Section 15.5 of the CTR 
and in Appendix 16.1.9.3.
Descriptive data analysis of PK endpoints will be presented in Section 15.6 of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
 
 
 
 
For plasma concentrations as well as for all PK parameters, the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.


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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.
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.
Only frequency tables 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 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 MQRM/BRPM (cf. Section 6.2) and described in the 
CTR.
7.4
PRIMARY ENDPOINT
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis of 
the frequency of subjects with TEAEs, which is the primary endpoint of this trial.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
Not applicable.
7.5.2
Secondary endpoints
According to CTP Version 8.0 secondary endpoints are only defined for HV and not for CF 
subjects.
The analysis of secondary endpoints will be based on the PKS.
Dose proportionality of secondary endpoints (AUC0-12, Cmax, AUCτ,13, Cmax,13 for HV) over the 
entire dose range will be evaluated as defined in the CTP, Section 7.3.2, by use of the power 


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model for healthy volunteers. For each of the secondary endpoints tables displaying geometric 
means of pairwise ratios together with 95% confidence intervals will be provided by dose 
group. A summary of results of the power model as described in the CTP, Section 7.3.2 will 
be displayed by a table. The relationship between the dose and the respective PK parameters 
will additionally be visualized graphically.


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7.6.1
Safety endpoints
Further safety endpoints will be analysed as described in Section 7.8 of this TSAP.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.7
EXTENT OF EXPOSURE
Treatment exposure will be listed by means of the date and time of drug administration.
Additionally, tables displaying descriptive statistics for treatment exposure (number of doses 
and total dose administered) will be given separately for HV and CF subjects. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
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:

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)


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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' (5) 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 
5.3.10.1 of the CTP.
The frequency of subjects with AEs will be summarised by treatment (dose), 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), subjects with AESIs and subjects with other significant AEs (according 
to ICH E3). 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).
A further table will present AEs by preferred term, dose group and intensity, sorted by 
descending relative frequency in any dose group.
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.
Tables prepared for public disclosure (ClinicalTrial.gov and EudraCT) will include subjects
of both trial parts combined (HV and CF subjects).


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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 for HV will be based on original values. If multiple reference ranges 
apply for one parameter (e.g. due to different age groups) for HV, analyses will be based on 
normalised values, which means transforming to a standard unit and a standard reference 
range. Analyses for CF subjects will be based on normalized values. If references ranges are 
not available, analyses will be based on original values.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will be 
done over comparing laboratory data to their reference ranges. Values outside the reference 
range will be highlighted in the listings. 
Dose groups will be compared with descriptive statistics of laboratory values over time and 
by analysing differences from baseline (see Section 6.7 for definition of baseline). 
Additionally, frequency tables of changes between baseline and last values on treatment with 
respect to the reference ranges will be presented. For electrolytes, descriptive statistics of 
values over time and differences from baseline will be provided comparing all active doses 
versus placebo for HV. Furthermore graphical representations over time will be generated for 
serum electrolytes for HV and CF subjects and for urine electrolytes for HV subjects.
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 12-lead ECG or continuous ECG monitoring will be reported as 
baseline conditions (at screening) or as AEs (during the trial) if judged clinically relevant by 
the investigator.
The evaluation of 12-lead ECG data will be based on the TS.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. 
Occurrences of notable findings will be flagged. For all subjects with any notable finding of 
quantitative ECG recordings, a separate listing will be created as end-of-text display (same 
display as in Appendix 16.2), and the corresponding time profiles will be shown. Comments 
regarding the ECGs will be listed.
Analysis of central tendency


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For quantitative ECG endpoints (RR, PR, QRS, QT, HR, QTcF and QTcB) descriptive 
statistics for absolute values and absolute changes from baseline will be provided for HV and 
CF subjects.
For QTcF, QT and HR of HV, a repeated measurements analysis of the changes from baseline 
with baseline as a covariate will be performed. The model will include the fixed effects 
“base”, “dose group”, “base*time” interaction, and “dose group*time” interaction. The 
covariance model for the repeated effect “time” will be unstructured. For each dose group and 
each time point, the contrast of the means for “treatment-placebo” will be estimated by the 
difference in the corresponding adjusted means (Least Squares Means); two-sided 90% CIs 
based on the t-distribution will also be computed. For each of the above ECG variables, the 
time profiles of the mean differences to placebo in the changes from baseline and the 
corresponding 90% CIs will be presented in a figure.
For QTcF, QT and HR of CF subjects, a repeated measurements analysis of the changes from 
baseline with subject and period baseline as covariates will be performed, if feasible, for time-
points defined in CTP Version 8.0:
The model will include the fixed effects “base 1” as the subject baseline (i.e. the arithmetic 
mean of the respective period baselines per subject), “base2” as the period baseline, 
“treatment”, “time”, “Period”, “base1*time” and “base2*time” interaction, “period*time” 
interaction, and “treatment*time” interaction. Subject is included as a random effect on the 
intercept. The covariance model for the repeated effect “time” will be unstructured, using the 
blocking factor ‘subject-by-period’. For each time point, the contrast of the means for 
“treatment-placebo” will be estimated by the difference in the corresponding adjusted means 
(Least Squares Means); two-sided 90% CIs based on the t-distribution will also be computed. 
For each of the above ECG variables, the time profiles of the mean differences to placebo in 
the changes from baseline and the corresponding 90% CIs will be presented in a figure.
Categorical Endpoints
For the categorical endpoints, frequency tables will be provided.
Categorical endpoints will also include morphological findings that might be attributable to 
treatment. In particular, new onsets of findings not present at baseline will be explored. A 
morphological finding observed on treatment that was not reported at baseline will be 
categorized as a ‘new onset’ of this finding.
For subjects with notable findings, the individual time courses of RR, PR, QRS, QT, HR, 
QTcF and QTcB of these subjects will be presented in figures.
7.8.5
Others
7.8.5.1
Spirometry
For HV and CF subjects descriptive statistics of spirometry endpoints (FEV1, FVC, 
FEV1/FVC (CF subjects only) and FEF25-75) over time and their change from baseline will be 
presented for data obtained in-clinic and with the home spirometer separately (see Section 6.7
for definition of baseline). Time courses of individual subject data and median of FEV1 and 


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changes from baseline per dose group will additionally presented graphically separately for 
data obtained in-clinic and with the home spirometer.
Furthermore, the changes from pre-dose values up to two hours post-dose on Days 1, 7 and 14 
will be analysed descriptively.
Clinically relevant findings in spirometry data will be reported as AEs and will be analysed as 
part of AE analysis.
7.8.5.2
Physical examination
Descriptive statistics of body weight obtained e.o.s and its changes from baseline (see Section 
6.7) will be provided for CF subjects.
Other physical examination findings will be reported as relevant medical history/baseline 
condition (i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.
 
 
 
 
 
 
 
 


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8.
REFERENCES
1
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", 
current version, BIRDS
2
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; BIRDS
4
001-MCS-36-472_1: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; BIRDS
5
001-MCG-156: "Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries", current version; BIRDS
6
001-MCG-157: "Display and Analysis of Laboratory Data", current version, BIRDS
7
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; BIRDS.
8
BI position paper: “Statistical Methods for PK”, current version
9
TDMAP: “8-07-other-HV-analyses-logistics-plan”
10
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical 
Trialss, current version
11
CASA-Q User Manual. Boehringer Ingelheim (v4.0 2015), [R18-2689]
12
CFQ-R – General Scoring Instructions, [R18-2688]


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9.1
DETAILED DESCRIPTION OF ENDPOINTS FOR ECG
RR, PR, QRS and QT baseline and on-treatment measurements (see Table 6.7: 1+2) are 
included in the centralised ECG evaluation. For CF subjects also recordings at screening and 
end of study are included in addition.
For each single ECG with centralised evaluation, measurements of QT, PR, QRS and 
preceding RR intervals of four cardiac cycles will be determined and stored in the database as 
raw data.
QTcF, HR and QTcB will be calculated based on the derivation rules as follows:
From the four cardiac cycles of a single ECG, the HR (measured in beats/min) will be 
calculated as
 [	] = 60 000


where RR is the mean of the four RR intervals (measured in msec).
Similarly, the QT interval corrected for HR according to Fridericia’s formula (QTcF) for a 
single ECG will be derived as
 [	] = 1000




 ,
where QT is the mean of the four QT intervals and RR is the mean of the corresponding 
preceding RR intervals of the four cardiac cycles for this ECG.
Likewise, the HR-corrected QT interval according to Bazett’s formula (QTcB) for a single 
ECG is given by
 [	] = 1000




 .
The PR and QRS values for a single ECG are derived as the means of the PR and QRS values, 
respectively, of the four cardiac cycles for this ECG. 
In case of triple ECGs at a time point, the respective ECG variable will be averaged over the 
triple ECG measurements at this time point (arithmetic mean). Note that in case of missing
values the averaging is simply done for the available values.


Boehringer Ingelheim
TSAP for BI Trial No: 1363.2
Page 37 of 38
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No: 1363.2
Page 38 of 38
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial 
Version
(1.0)
09-Jan-17
None
This is the initial TSAP 
Final 2.0
04-Jul-17
All
This is the final TSAP (for HV 
analyses)
Revised 3.0
18-Sep-18
All
This is the final revised TSAP (for 
HV analyses and CF subject 
analyses)