Clinical trial NCT02629965
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim
Start date: 2016-02-12; Completion date: 2017-04-17
Enrollment: 184 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a multi-centre, randomised, double-blinded, active-controlled, 2-way cross over trial to assess the effects of once daily administration of orally inhaled tiotropium + olodaterol FDC or tiotropium (both delivered by the RESPIMAT Inhaler) on pulmonary function (lung hyperinflation), exercise capacity (6-minute walk distance) and physical activities after 6 weeks of treatment in Japanese patients with Chronic Obstructive Pulmonary Disease.

Detailed description:

Arms: arm 1: inhalation two puffs from the RESPIMAT inhaler, once a day, in the morning arm 2: inhalation two puffs from the RESPIMAT inhaler, once a day, in the morning
Interventions: intervention 1: tiotropium intervention 2: olodaterol intervention 3: tiotropium
Intervention descriptions: intervention 1: fixed dose combination intervention 2: fixed dose combination intervention 3: None

Protocol documents:
Prot_001.pdf: 
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03397161-01
BI Trial No.:
1237.33
BI Investigational 
Product:
Spiolto® Respimat®, Tiotropium+olodaterol RESPIMAT fixed 
dose combination inhalation solution
Title:
A randomised, double-blinded, active-controlled 2-way cross over 
trial to assess the effects of 6 weeks treatment of once daily orally 
inhaled tiotropium + olodaterol fixed dose combination delivered 
by RESPIMAT Inhaler compared with tiotropium delivered by 
RESPIMAT Inhaler on lung hyperinflation, exercise capacity and
physical activity in Japanese patients with Chronic Obstructive 
Pulmonary Disease (COPD)
Brief Title:
Japanese Physical Activity Study [VESUTOTM]
Clinical Phase:
IIIb
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
, 
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version:
Date:
1.0
30 October 2015
Page 1 of 96
Proprietary confidential information.
2015 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: 
Spiolto®
Name of active ingredient:
Tiotropium + olodaterol fixed 
dose combination solution for 
inhalation
Protocol date:
30 OCT 2015
Trial number:
1237.33
Revision date:
Title of trial:
A randomised, double-blinded, active-controlled 2-way cross over trial to assess the 
effects of 6 weeks treatment of once daily orally inhaled tiotropium + olodaterol fixed 
dose combination (FDC) delivered by RESPIMAT Inhaler compared with tiotropium 
delivered by RESPIMAT Inhaler on lung hyperinflation, exercise capacity and
physical activity in Japanese patients with Chronic Obstructive Pulmonary Disease 
(COPD)
Coordinating
Investigator:
 
Trial sites:
Multi-centre trial in Japan
Clinical phase:
IIIb
Objectives:
The primary objective of this trial is to investigate the effect of 6 weeks treatment 
with tiotropium + olodaterol FDC therapy compared to tiotropium monotherapy on 
lung hyperinflation (measured by an inspiratory capacity [IC]) in Japanese patients 
with COPD
The second objective is to evaluate the effect of 6 weeks treatment with tiotropium 
+ olodaterol FDC compared to tiotropium monotherapy on exercise tolerability
(measured by a 6-minute walk test [6MWT]) and amount of daily physical activity 
(measured by an activity monitor [3-axis accelerator]) in Japanese patients with 
COPD
Methodology:
Double-blinded, randomised, active-controlled, two-way cross over design
No. of patients:
total entered:
180 patients (240 patients enrolled)
each treatment:
Tiotropium + olodaterol FDC: 180 patients 
Tiotropium : 180 patients
Diagnosis :
Chronic Obstructive Pulmonary Disease (COPD)
Main criteria
for inclusion:

Patients must have relatively stable airway obstruction with a post-bronchodilator 
FEV1 < 80% of predicted normal and post-bronchodilator FEV1/FVC < 70% at 
Visit 1.

Male or female patients, aged ≥ 40 years.

Patients must be current or ex-smokers with a smoking history of more than 10 
pack years.

Patients with score on the modified Medical Research Council (mMRC) ≥1.

Patients who walk <400 meters of 6MWT and have a score on the modified Borg 
≥4 at the end of 6MWT at Visit 2.


Boehringer Ingelheim
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001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim 
Name of finished product: 
Spiolto®
Name of active ingredient:
Tiotropium + olodaterol fixed 
dose combination solution for 
inhalation
Protocol date:
30 OCT 2015
Trial number:
1237.33
Revision date:
Test product:
Tiotropium + olodaterol fixed dose combination (FDC) solution for inhalation
dose:
[5 µg tiotropium + 5 µg olodaterol] once daily
mode of 
administration:
Oral inhalation
Comparator product:
Tiotropium solution for inhalation
dose:
5 µg once daily
mode of 
administration:
Oral inhalation
Duration of treatment:
- Screening period (Visit 1 to Visit 2): 2 weeks
- Double-blind treatment period: 12 weeks (2 x 6 weeks treatment periods) 
- Follow up period: 3 weeks
Endpoints
Primary Endpoint:
•
IC at rest measured at 60 minutes post-dose, after 6 weeks of treatment
Secondary Endpoints
•
6 minute walk distance (m) after  6 weeks of treatment
•
Average number of step per day (step/ day) measured by the activity 
monitor in the 2 weeks prior to Week 6
•
Average daily duration (minutes) of ≥4 metabolic equivalents (METs) 
measured by the activity monitor in the 2 weeks prior to Week 6
•
Average daily duration (minutes) of ≥3 METs measured by the activity 
monitor in the 2 weeks prior to Week 6
•
Average daily duration (minutes) of ≥2 METs measured by the activity 
monitor in the 2 weeks prior to Week 6
•
Average daily active strength (METs·minutes) of ≥3 METs measured by 
the activity monitor in the 2 weeks prior to Week 6
•
60 minutes post-dose Slow vital capacity (SVC), after 6 weeks of treatment
•
30 minutes post-dose FEV1, after 6 weeks of treatment.
•
30 minutes post-dose FVC, after 6 weeks of treatment.
Safety criteria:
Adverse events, Physical examination, Heart rate and SpO2 in conjunction with 
6MWT
Statistical methods:
Primary endpoint will be analysed using a mixed effect repeated measures model, 
with treatment and period as categorical fixed effects, study baseline as a covariate 
and patient as a random effect. 
Secondary and further endpoints for efficacy will be analysed using the same model 
as the primary endpoint.
Descriptive statistics will be used for safety and efficacy endpoints.


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FLOW CHART
Trial Periods
Screening 
Period
Treatment period 1
Treatment period 2
Trial 
Follow-Up
Visit Number
01
1
2
☎
☎
3
☎
☎
4/ EOT
5
Week of treatment
-2
0
4
5
6
10
11
12
EOT+3
Day of treatment
-14
1
28
35
43
70
77
85
106
Visit window (days)
-7
N/A
-3
±1
+3
-3
±1
+3
+7
Informed consent
X2
Demographics
X
Medical history / 
concomitant diagnosis
X
Smoking status
X
X3
In-/ exclusion criteria4
X
X
Physical examination
X
X
X
X3
X5
Laboratory tests 
X
X3
X5
12-lead ECG
X
X
X
X3
X5
Pregnancy test6
X
X3
X5
Training in use of 
RESPIMAT7
X
X
Dispense and explain 
use of rescue 
medication8
X
X
X
X
Collect rescue 
medication/accountabili
ty check8
X
X
X
X3
Medication washout 
check
X
X
X
X
Administration (dosing) 
of trial medication at 
the site
X
X18
X18
X
X
X
mMRC20
X
Pulmonary Function 
Testing (PFT); 
FEV1/FVC and
SVC/IC)
X9
X10
X11
X3,11
Vital signs (seated)12
X
X
X
X3
X5
6MWT
X21
X
X
X
 
X21
X
X
X


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Trial Periods
Screening 
Period
Treatment period 1
Treatment period 2
Trial 
Follow-Up
Visit Number
01
1
2
☎
☎
3
☎
☎
4/ EOT
5
Week of treatment
-2
0
4
5
6
10
11
12
EOT+3
Day of treatment
-14
1
28
35
43
70
77
85
106
Visit window (days)
-7
N/A
-3
±1
+3
-3
±1
+3
+7
Physical activity 
monitoring14
X
X
X
X
X
X
X
X
X
X
X
X
Patient Diary23
X
X
X
X3
X
X
X
Muscle amount (% in 
BW)
X
Telephone contacts17
X
X
X
X
Patient registration 
(IRT)
X
Randomisation (via 
IRT)
X
Dispense double-
blinded trial medication
X
X
Collect double-blinded 
trial medication and 
accountability check
X
X3
Adverse events
X
X
X
X
X
X
X
X3
X
Concomitant therapy
X
X
X
X
X
X
X
X3
X
EOT: End of Treatment, IRT: Interactive Response Technology, PFT: Pulmonary Function Testing, 
 
 mMRC: modified Medical Research Council,
 
, 6MWT: 6 minute walk test
1 
Visit 1 may be scheduled 1-28 days after Visit 0 (depending on medication washout requirement as described in Section 
4.2.2.1. Patients who are treated with LABA and LAMA should be treated at least 3 weeks with one of its’component, i.e. 
LABA or LAMA.).
2
All patients must sign an informed consent consistent with ICH-GCP guidelines and Japanese GCP regulations prior to 
participation in the trial, which includes medication washout and restrictions.
3
EOT examinations are completed by all patients who took at least one dose of trial medication and who discontinue early. 
Pulmonary Function Testing (PFT) is to be performed if possible. 
4
A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid unnecessary washout procedures in non-
eligible patients.
5
To be performed only if relevant findings at Visit 4/EOT.
6
Women of child-bearing potential: pregnancy test at Visit 1 and Visit 4/EOT
7
The patient will be instructed in the use of the RESPIMAT, but patient should not inhale from the training inhaler at Visit 2.
8
Rescue medication as salbutamol is prescribed at visit 0. Rescue medication will be collected and prescribed on subsequent 
visits by investigators as needed. All rescue medication for the trial to be confirmed to be collected at Visit 4/EOT. 
9
Pre- and post-bronchodilator (400 µg salbutamol) [note: reversibility is not an inclusion criterion], Spirometry measurement; 
FVC and FEV1 only.
10
Baseline spirometry measurement FEV1, FVC, SVC, and IC.
11
Morning post-dose spirometry 


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- FEV1 and FVC: 30 min post-morning dose as starting time
- IC and SVC measurement: 60 min post-morning dose as starting time
12
Prior to the start of PFTs are performed.
13
14
Patients should wear and measure activity monitor (3-axis accelerator) every day for 2 weeks prior to Visit 2, Visit 3 and 
Visit 4/EOT.
15
16
17
Site staff will telephone the patients 15 days and 8 days prior to the next planned Visit and remind them to wear physical 
activity monitor every day. An assessment of adverse events and of concomitant therapy should be performed from the last 
assessment.
18
Trial medication dispensed at Visit 2 should be administrated at clinic at Visit 3 and trial medication dispensed at Visit 3 
should be administrated at clinic at Visit 4/EOT. Newly assigned trial medication at Visit 3 should be administered next day 
of Visit 3. 
19
20
Refer to Appendix 10.8. mMRC
21
Training of 6MWT
22
Refer to Appendix 10.11
23
Training of patient diary at Visit 1. Dispense of the diary at Visit 1, Visit 2 and Visit 3. Reviewing and collection of the 
diary at Visit 2, Visit 3 and Visit 4/EOT.


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TIMING OF PROCEDURES: VISIT1 _SCREENING
1
mMRC questionnaires will be completed prior to all other procedures after medical washout compliance.
2
The vital signs (seated) and ECG should be conducted following 5 minutes rest and prior to blood sampling
3
Patients will be asked to rate breathing discomfort and leg discomfort using the modified Borg Scale before, during every 1 
minute, and at the end of the 6MWT as outlined in Appendix 10.7.
4
The inhalation of 4 puffs of salbutamol will be conducted between 7:00 a.m.-10:00 a.m.
5
Administration current medication will be done after post-dosing PFT before at noon
Start time
-
More than 30 
min prior to
Pre-dosing PFT
-10 to 0 min 
prior to
administration
salbutamol
administration
salbutamol
(0 min)
10 to 15 min after
administration
salbutamol
-
Medication washout 
compliance
X
mMRC1
X
Physical examination, vital sign 
and 12-lead ECG2
X
Laboratory test and Pregnancy 
test
X
6MWT (training)
X
Breathlessness/leg discomfort
(modified Borg scale)3
X
Pre-dosing PFT (FEV1, FVC)
X
Administration 400 µg 
salbutamol4
X
Post-dosing PFT (FEV1, FVC)
X
Administration current 
medication5
X


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TIMING OF PROCEDURES: VISIT2 _BASELINE 
1
 
2
 
3
First administration trial medication will be done after 6MWT before at noon
Start time 
-
0 min
30 min
(± 5 min )
60 min
(+ 10 min )
-
Medication washout compliance
X
 
X
Physical examination, vital sign and 
12-lead ECG
X
PFT (FEV1, FVC)
X
PFT (IC, SVC)
X
6MWT
X
X
Administration trial medication3
X


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TIMING OF PROCEDURES: VISIT3, VISIT 4_ENDPOINT
1
 
2
The vital signs (seated) and ECG should be conducted following 5 minutes rest and prior to blood sampling.
3
Study medication will be administration within ± 30 min of administration time of next day at Visit 2 and between 07:00 
and 10:00 am.
4
 
Start time
-
Administration
of medication
(0 min)
30 min
(± 5 min)
60 min
(± 10 min)
90 min
(+ 15 min)
Medication washout compliance
X
 
X
Physical examination, vital sign and 12-
lead EGC2
X
Laboratory test and Pregnancy test
(only Visit 4/EOT)
X
Administration trial medication3
X
PFT (FEV1, FVC)
X
PFT (IC, SVC)
X
6MWT
X
 
X


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................17
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....20
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................20
2.2
TRIAL OBJECTIVES........................................................................................20
2.3
BENEFIT - RISK ASSESSMENT.....................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................23
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................23
3.1.1
Administrative structure of the trial .................................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................26
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................27
3.3.3
Exclusion criteria ................................................................................................27
3.3.3.1
Contraindications to exercise:...............................................................................30
3.3.4
Removal of patients from therapy or assessments...........................................31
3.3.4.1
Removal of individual patients .............................................................................31
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................31
4.
TREATMENTS...................................................................................................33
4.1
TREATMENTS TO BE ADMINISTERED.....................................................33
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........33
4.1.2
Method of assigning patients to treatment groups...........................................34
4.1.3
Selection of doses in the trial..............................................................................34
4.1.4
Drug assignment and administration of doses for each patient......................34
4.1.5
Blinding and procedures for unblinding...........................................................36
4.1.5.1
Blinding.................................................................................................................36
4.1.5.2
Unblinding and breaking the code ........................................................................36
4.1.6
Packaging, labelling, and re-supply...................................................................36
4.1.7
Storage conditions...............................................................................................37
4.1.8
Drug accountability.............................................................................................38


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
TREATMENT.....................................................................................................39
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....39
4.2.1.1
Rescue Medication................................................................................................39
4.2.1.2
Emergency procedures..........................................................................................39
4.2.1.3
Additional treatments............................................................................................39
4.2.2
Restrictions ..........................................................................................................40
4.2.2.1
Restrictions regarding concomitant treatment ......................................................40
4.2.2.2
Restrictions on diet and life style..........................................................................44
4.3
TREATMENT COMPLIANCE........................................................................44
5.
VARIABLES AND THEIR ASSESSMENT ....................................................46
5.1
TRIAL ENDPOINTS..........................................................................................46
5.1.1
Primary Endpoint ...............................................................................................46
5.1.2
Secondary Endpoints..........................................................................................46
...........................................................................................46
5.2
ASSESSMENT OF EFFICACY........................................................................47
5.2.1
Pulmonary Function Testing..............................................................................47
5.2.2
Six-minute walk test (6MWT)............................................................................48
5.2.3
Activity monitoring.............................................................................................48
8
9
9
 
0
5.2.8
Patient diary ........................................................................................................50
5.3
ASSESSMENT OF SAFETY.............................................................................50
5.3.1
Physical examination ..........................................................................................50
5.3.2
Vital Signs............................................................................................................50
5.3.3
Safety laboratory parameters ............................................................................50
5.3.4
Electrocardiogram ..............................................................................................51
5.3.5
Other safety parameters.....................................................................................52
5.3.6
Assessment of adverse events.............................................................................52
5.3.6.1
Definitions of AEs ................................................................................................52
5.3.7
Adverse event collection and reporting.............................................................54
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................55
5.4.1
Assessment of Pharmacokinetics.......................................................................55
5.4.2
Methods of sample collection .............................................................................56
5.4.3
Analytical determinations ..................................................................................56
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................56
5.5
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................56
5.5.1
Biobanking...........................................................................................................56
5.6
OTHER ASSESSMENTS...................................................................................56
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................56
6.
INVESTIGATIONAL PLAN.............................................................................57


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6.1
VISIT SCHEDULE.............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................57
6.2.1
Screening period..................................................................................................57
6.2.2
Treatment periods...............................................................................................60
6.2.3
Follow Up Period and Trial Completion...........................................................61
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................62
7.1
STATISTICAL DESIGN - MODEL.................................................................62
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................62
7.3
PLANNED ANALYSES.....................................................................................62
7.3.1
Primary endpoint analyses.................................................................................62
7.3.2
Secondary and further endpoint analyses ........................................................63
7.3.3
Safety analyses.....................................................................................................63
7.3.4
Pharmacokinetic analyses ..................................................................................63
7.4
INTERIM ANALYSES ......................................................................................63
7.5
HANDLING OF MISSING DATA ...................................................................64
7.6
RANDOMISATION ...........................................................................................64
7.7
DETERMINATION OF SAMPLE SIZE .........................................................64
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........65
8.1
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...........................................................................................................65
8.2
DATA QUALITY ASSURANCE ......................................................................66
8.3
RECORDS...........................................................................................................66
8.3.1
Source documents ...............................................................................................66
8.3.2
Direct access to source data and documents.....................................................66
8.3.3
Storage period of records ...................................................................................67
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS67
8.4.1
Listedness.............................................................................................................67
8.4.2
Expedited reporting to health authorities and IRB.........................................67
8.5
STATEMENT OF CONFIDENTIALITY........................................................67
8.6
END OF TRIAL..................................................................................................68
8.7
PROTOCOL VIOLATIONS .............................................................................68
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY..............................................................................68
9.
REFERENCES....................................................................................................69
9.1
PUBLISHED REFERENCES............................................................................69
9.2
UNPUBLISHED REFERENCES......................................................................72
10.
APPENDICES.....................................................................................................73
10.1
THE RESPIMAT INHALER ............................................................................73
10.2
RETURN OF INHALERS/CARTRIDGES......................................................78
...........79
...........80


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10.5
ADDITIONAL INFORMATION REGARDING IN/EXCLUSION 
CRITERIA...........................................................................................................87
10.6 
SIX-MINUITE WALK DISTANCE .................................................................88
...............................................................................89
10.8
MODIFIED MEDICAL RESEARCH COUNCIL (MMRC) .........................91
....................................92
10.10
INSPIRATORY CAPACITY.............................................................................93
10.11
PATIENT GLOBAL PHYSICAL ACTIVITY RATING AND GLOBAL 
IMPRESSION OF CHANGE ............................................................................94
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................96


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ABBREVIATIONS
ACCP
American College of Chest Physician
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline phosphatase
ALT 
Alanine aminotransferase
AMP
Auxiliary Medicinal Product
ATS
American Thoracic Society
AST
Aspartate aminotransferase
AUC
Area under the Curve
BAC
benzalkonium chloride
BI
Boehringer-ingelheim
b.i.d
bis in die (twice daily dosing)
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
CA
Competent authority
CCDS
Company Core Data Sheet
CI
Confidence Interval
CML
Local Clinical Monitor 
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRO
Contract research organization
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DEDP
Drug exposure during pregnancy
DILI
Drug induced liver injury
DMC
Data Monitoring Committee
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
EDC
Electronic Data Capture
EELV
End expiratory lung volume
EOT
End of Treatment
ePRO
Electronic Patient Reported Outcome
ERS
European Respiratory Society
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDC
Fixed dose combination
FEV1
Forced expiratory volume in one second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GOLD
Global initiative for chronic Obstructive Lung Disease


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HPC
Human Pharmacology Center
HR
Heart Rate
IB
Investigator’s Brochure
IC
Inspiratory capacity
ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intervenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
LABA
Long acting β2-agonists
LAMA
Long acting muscarinic antagonist
LDH
Lactate dehydrogenase
LoEE
List of Essential Element 
MACE
Major adverse cardiovascular event
MCID
Minimal clinically important difference
MDI
metered dose inhaler
MedDRA
Medical Dictionary for Drug Regulatory Activities
METs
Metabolic equivalents
MST
Medical Sub team
mMRC
modified Medical Research Council
MMRM
mixed model repeated measures
OPU
Operative Unit
PA
Physical activity
PEFR
Peak expiratory flow rate
PFT
Pulmonary function testing
p.o.
per os (oral)
PPS
Per–Protocol Set
q.d.
quaque die (once a day)
RDC
remote data capture
REP
Residual effect period
SABA
Short-acting β2–agonist
SAE
Serious Adverse Event
SAMA
Short-acting anticholinergic
SOP
standard operation procedure
6MWD
Six-minute walk distance
6MWT
Six-minute walk test
SPC
Summary of Product Characteristics
SUSAR
Suspected serious unexpected adverse reactions
SVC
Slow vital capacity
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan


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TLC
Total lung capacity
TMF
Trial Master File
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Global initiative for chronic Obstructive Lung Disease (GOLD) treatment guidelines [P14-
01052] place bronchodilators as the foundation of pharmacologic management of COPD. In 
patients with moderate to very severe pulmonary impairment (i.e., GOLD Stage II to IV) 
whose symptoms are not adequately controlled with as-needed short-acting bronchodilators, 
adding regular treatment with one or more long-acting inhaled bronchodilators is 
recommended (long acting β2-agonists, LABAs; long acting muscarinic antagonists, 
LAMAs). 
The rationale for combining bronchodilators with different mechanisms is based on the 
notion of additive relaxation of airway smooth muscle by direct inhibition of cholinergic 
activity and functional antagonism of bronchoconstriction through β2-adrenergic pathways, 
with the expectation of an increase in the degree of bronchodilation for equivalent or lesser 
side effects. Several recent studies have provided evidence in support of this increased 
bronchodilatory effect when LABAs are added to LAMAs.
When beta-agonists and muscarinic antagonists with similar or equivalent posologies are 
combined, the opportunity exists for offering a simpler and more convenient administration 
regimen with the development of fixed combinations within the same inhaler device. The 
development of the novel once daily LABA olodaterol (quaque die [q.d.]) now offers the 
opportunity for a once daily (FDC) LABA/LAMA including the well-established LAMA
tiotropium.
The complementary modes of action of tiotropium and olodaterol have previously been 
demonstrated in human clinical trials. The application for marketing authorisation has been 
approved in the EU, US, Japan and a number of other countries.
1.2
DRUG PROFILE
Tiotropium 
Tiotropium is an established once-daily LAMA that improves the main functional and 
patient-orientated outcomes of COPD [P08-12524, P10-08261, P13-04267, P11-07562, P11-
03885, P13-11053]. Tiotropium has also been demonstrated to moderate disease progression, 
even in the early stages of COPD (e.g. patients not receiving maintenance therapy[P10-
02376] or patients with GOLD Stage II [P09-11278]).
Tiotropium in the dry powder inhaler HandiHaler has been approved in more than 100 
countries worldwide. An alternative aqueous formulation for use in the RESPIMAT inhaler 
(tiotropium 5μg q.d..) is approved in more than 80 countries worldwide including EU, US
and Japan. Further information about tiotropium can be found in the Investigators Brochure 
(IB) for the product.


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Olodaterol
Olodaterol is a highly selective and nearly full β2 agonist [P10-07776, P11-07720] that 
provides 24-h bronchodilation in patients with COPD [P13-11467, P13-14112, P13-11346, 
P13-11345] Olodaterol is also associated with symptomatic benefit [P13-11341] and 
enhanced exercise capacity [P13-14109]. Olodaterol RESPIMAT 5 μg once daily has so far 
been approved in more than 40 countries worldwide (Olodaterol is not approved in Japan).
Tiotropium + olodaterol fixed dose combination
Tiotropium + olodaterol FDC is an aqueous solution of tiotropium and olodaterol. It is 
administered by using the RESPIMAT inhaler. 
In the pivotal studies (1237.5/.6) participating Japanese COPD patients, tiotropium + 
olodaterol FDC showed statistically significant improvements in FEV1 Area under the curve 
(AUC0-3h) response and trough expiratory volume in one second (FEV1) response after 24 
weeks compared to the mono-components and these improvements were maintained up to 52 
weeks. The bronchodilatory profile of the combination was confirmed in a supportive 6-week 
study (1237.20), in which the mean FEV1 improvements over 24 hours were superior to the 
mono-components, with improvements in forced vital capacity (FVC), inspiratory capacity 
(IC), functional residual capacity (FRC), morning peak expiratory flow rate (PEFR) and 
evening PEFR supporting the results for FEV1.
Tiotropium + olodaterol FDC showed statistically significant improvements in health-related 
quality of life (SGRQ) and dyspnoea experienced during everyday activities (TDI) after 24 
weeks compared to the mono-components. More patients treated with the combination had an 
improvement in SGRQ total score and TDI greater than the Minimal clinically important 
difference (MCID).
Treatment with tiotropium + olodaterol FDC resulted in reductions in both daytime and night 
time rescue bronchodilator use compared to the mono-components and patients treated 
perceived a greater improvement in their respiratory condition, as measured by a Patient´s 
Global Rating scale.
Tiotropium + olodaterol FDC was shown to be safe and well tolerated over 1 year in a 
moderate to very severe COPD population. The overall incidences of adverse events (AEs), 
serious adverse event (SAEs), fatal AEs, frequencies for cardiac events and Major adverse 
cardiovascular event (MACE) in the tiotropium + olodaterol FDC treatment group were 
similar to the mono-components. The nature and frequency of AEs in general was consistent 
with the disease under study. There were no results in the clinical development program 
suggesting the need for absolute contraindications for the combination product.
In conclusion, the clinical trials conducted to date have shown tiotropium + olodaterol FDC 
to be a safe, well tolerated and efficacious combination therapy according to treatment 
guidelines in a moderate to very severe COPD patient population that included patients with 
concomitant cardiovascular diseases. The observed incremental bronchodilator response for 


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the combination compared to the individual components translated into benefits that were 
meaningful to the patient, with improvements in several patient-reported outcomes. For 
further information please refer to the IB for the Tiotropium + olodaterol FDC.
RESPIMAT Inhaler
Boehringer Ingelheim’s RESPIMAT Inhaler will be used for administration of tiotropium + 
olodaterol FDC and tiotropium. One cartridge is used per inhaler, which is inserted into the 
device prior to first use. In pivotal clinical trials and for the intended marketed product, the 
clinical dose consists of two actuations once daily. The RESPIMAT inhaler uses mechanical 
energy to create a soft mist which is released over a period of approximately 1.5 seconds. The 
fraction of fine particles accessible to lungs and airways is very high compared with many 
metered dose aerosols or dry powder devices. The solution is adjusted to pH 2.9 because the 
drug in solution is stable at acidic pH values. Due to the multi-dose characteristics of the 
RESPIMAT Inhaler, the drug formulation contains the chelating agent disodium edentate 
(EDTA) and the antimicrobial preservative benzalkonium chloride (BAC). However, the 
concentrations of EDTA and BAC in tiotropium + olodaterol FDC solution and tiotropium 
solution for inhalation with the RESPIMAT Inhaler are well below the levels, which have 
been reported to induce bronchospasms in some patients inhaling aerosols of solutions from a 
nebulizer.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Lung hyperinflation is an important factor to cause exercise-associated symptoms such as 
dyspnea and fatigue. These symptoms as a result of lung hyperinflation are believed to induce 
a reduction of exercise tolerability and daily physical activity (PA) being strong predictors of 
the rise of mortality in patients with COPD. Therefore, an improvement in lung 
hyperinflation is one of desirable therapeutic goals for the COPD patients with symptomatic 
dyspnea.
Previous global Phase III studies including Japanese COPD patients, tiotropium + olodaterol 
FDC were shown to be superior in improving airflow over 24 hours, QOL, and breathlessness
compared with tiotropium or olodaterol monotherapy (ref 1237.5/6). Moreover, the other 
studies (ref 1237.13/14) have shown statistically significant improvement of lung 
hyperinflation (i.e. an increase in inspiratory capacity, IC) for tiotropium + olodaterol FDC 
compared with tiotropium or olodaterol monotherapy. However, no Japanese patients with 
COPD have participated in these two studies: trial 1237.13/14. As a consequence, the 
pharmacological impact of these bronchodilators on lung hyperinflation in Japanese patients
with COPD has not been demonstrated yet.
In this trail, we are planning to investigate the effects of tiotropium + olodaterol FDC 
compared with tiotropium on IC as an index of lung hyperinflation in Japanese patients with 
COPD. Moreover, the effect of these bronchodilators on exercise tolerability and amount of 
daily physical activities are also evaluated in parallel. For purpose of evaluation of exercise 
tolerability and daily physical activity, we will perform a 6-minute walk test (6MWT) and 
activity monitor (3-axis accelerator) assessment, respectively. 
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to demonstrate investigate the effect of 6 weeks 
treatment with tiotropium + olodaterol FDC therapy compared to tiotropium monotherapy 
on lung hyperinflation (measured by IC) in Japanese patients with COPD
The secondary objective is to evaluate the effect of  6 weeks treatment with tiotropium + 
olodaterol FDC therapy compared to tiotropium monotherapy on exercise tolerability  
(measured by 6MWT) and amount of daily physical activities (measured by activity monitor) 
in Japanese patients with COPD
2.3
BENEFIT - RISK ASSESSMENT


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The potential benefits of a treatment with tiotropium + olodaterol FDC (5 µg/5 µg) and 
tiotropium from the RESPIMAT have been described in Section 1.2. Tiotropium is a well-
established maintenance treatment for patients with COPD across broad severities. 
The clinical trials conducted to date have shown tiotropium + olodaterol FDC (5 µg/5 µg) to 
be a safe, well tolerated and efficacious combination therapy in a moderate to very severe 
COPD patient population (including patients with concomitant cardiovascular diseases). The 
observed incremental bronchodilator response for the combination compared to the 
monotherapy translated into benefits that were meaningful to the patient, with improvements 
in several patient-reported outcomes.
Potential risks associated with administration of the combination of tiotropium and olodaterol 
include the listed adverse events for the IB for the Tiotropium + olodaterol FDC.
Women of childbearing potential may be included in clinical trials for tiotropium + olodaterol 
FDC (5 µg/5 µg) provided appropriate precautions are taken to minimize the risk of 
pregnancy. These precautions include pregnancy testing and use of a highly effective method 
of birth control. Continued testing and monitoring during the trial should be sufficient to 
ensure compliance with the measures not to become pregnant during the period of drug 
exposure (which may exceed the length of study until the follow-up visit at 21 days after 
discontinuation of study medication [R05-0370]). 
The trial design requires that patients will be randomised at Visit 2 (1:1) to one of the 
following treatments:

Tiotropium + olodaterol FDC inhalation solution (2.5 µg/2.5 µg per actuation)

Tiotropium  inhalation solution (2.5 µg per actuation)
At Visit 3, the patients will receive the other treatment which has not been received in 
previous treatment without any washout period. There is no placebo comparator in this trial.
Patients receiving inhaled corticosteroids before enrolment will continue their treatment (or 
the inhaled corticosteroids component alone if taken as a fixed combination with 
bronchodilator) at an equivalent dose and regimen by the end of treatment period. The only 
medications that are excluded during the treatment period are anticholinergic and long-acting 
β2-adrenergic other than the study drugs.
During the whole course of the trial, salbutamol is prescribed to be used as rescue medication 
for all patients after they have signed their informed consent. The proposed medication 
restriction scheme is considered ethically acceptable given the availability of rescue short-
acting β2-adrenergic (SABA) and permitted use of the other maintenance medications.
Patients who treat with LAMA/LABA combination at informed consent are desired to switch 
to LAMA or LABA monotherapy after informed consent, but patient’ safety are secured 
since SAMA or SABA are available at least during the screening period.


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Safety will be monitored (as described in Section 5.3) at site visits as well as at each 
telephone contact. Patients will be contacted by site staff and asked for adverse events and 
change in concomitant therapy.
Given the good tolerability seen in the clinical trials for the combination of tiotropium and 
olodaterol and the careful monitoring during the study visits and phone contacts, the sponsor 
considers the risks to the participating patients would be minimised.


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3.
DESCRIPTIO
3.1
OVERALL TRIA
This is a multi-centre, random
to assess the effects of once da
FDC 5 μg/5 μg or tiotropium 5
function (lung hyperinflation)
physical activities after 6 week
After signing Informed Conse
after appropriate stable treatm
treated with combination of L
monotherapy component.) and
start a 2-week screening perio
baseline physical activity asse
and 6MWT (Visit 1 and Visit 
Patients who meet all the inclu
randomised (1:1 ratio) at Visit
portion of the study, in which 
Sequence AB; Tiotropium
Sequence BA; Tiotropium
for a total of 12 weeks of treat
Figure 3.1: 1 Trial design
Trial Protocol
2015 Boehringer Ingelheim International GmbH or one or more of i
001-MCS-40-106-RD-0
ON OF DESIGN AND TRIAL POPUL
AL DESIGN AND PLAN
mised, double-blinded, active-controlled, 2-wa
aily administration of orally inhaled tiotropiu
5 μg (both delivered by the RESPIMAT Inha
, exercise capacity (6-minute walk distance [6
ks of treatment in Japanese patients with COP
ent (Visit 0) and completing an initial screenin
ment with LAMA or LABA mono therapy (In 
ABA and LAMA need to be treated at least 3
d ensuring clinical stability (i.e. no exacerbati
od. During the screening visit (Visits 1), they w
essments (between Visit 1 to Visit 2) and base
2). 
usion criteria and none of the exclusion criter
t 2 into the 2-period 6-week double-blind, cro
they will receive one of two treatment sequen
m followed by Tiotropium + olodaterol FDC
m + olodaterol FDC followed by Tiotropium
tment (Figure 3.1: 1).
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its affiliated companies
03 (12.0) / Saved on: 30 Jan 2015
LATION
ay cross over trial
um + olodaterol 
aler) on pulmonary 
6MWD]) and 
PD. 
ng visit (Visit 1)
case, patients who 
3 weeks with only 
ions), patients will 
will conduct 
eline IC (Visit 2) 
ria will be 
oss-over treatment 
nces as follows:


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An Interactive Response Technology (IRT) will be used for randomisation to a treatment 
sequence in this trial and for appropriate re-supply of medication to patients.
In this trial, patients who complete first 6-week treatment period will subsequently start 
second 6-week treatment period. There is no washout period between each treatment periods.
Pulmonary function testing (PFT) will be conducted at Visit 1, just before (within 10 min)
and 10-15 min after inhalation of sulbtamol for inclusion, at Visit 2 for baseline and at Visit 3 
and Visit 4/EOT during the treatment period (30 min post-dosing and 60 min post-dosing)
Physical examination will be performed together with an evaluation of the patient's smoking 
status and COPD background characteristics at Visit 1. Blood samples for clinical laboratory 
testing will be obtained and a 12-lead ECG will be recorded at Visit 1 to evaluate the patient's 
eligibility. Pregnancy testing will be performed at Visit 1 and 4/EOT in females of child 
bearing potential. 
A 6MWT will be performed at Visit 1 (more than 30 min before PFT of post-dose salbutamol
inhalation) for training in the study. The 6MWT will also be performed at Visit 2 for 
inclusion. Additional tests will be conducted at Visit 3 and Visit 4/EOT during the treatment 
period (90 minutes post-dosing).
 
Physical activity assessment for baseline will be performed between Visit 1 and Visit 2. 
Physical activity assessments during the treatment period will be conducted for
approximately 2 weeks prior to Visit 3 and Visits 4/EOT.
Adverse events and concomitant therapies will be documented throughout the trial, i.e. 
starting with informed consent and ending 21 days after actual last administration of trial 
medication.
3.1.1
Administrative structure of the trial
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
order the materials as needed for the trial, 
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
A list of responsible persons and relevant local information (as protocol reference, if 
applicable) can be found in the ISF.


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A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicentre trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in ISF.
Boehringer Ingelheim (BI) will be responsible for the monitoring of the study. 
Clinical Research Organisation (CRO)
IRT system will be used for randomisation in this trial and for allocation of trial medication 
to patients throughout the treatment period. The ability to unblind will be available to the 
investigator via IRT during emergency.
Spirometer, Flowscreen (eRT), which meets ATS/ERS Criteria (P05-12782) will be provided 
by BI.
All contracts and relevant meeting minutes will be stored by BI in the trial master file (TMF).
A physical activity monitor (Omron healthcare), a mobile pulse oximeter (Fukuda denshi) 
and a body composition meter (Omron healthcare) are provided by BI.
The following local facilities/equipment are required at the investigational site: body weight 
scale, height scale, sphygmomanometer, 12-lead ECG device will be used on all patients
during the trial. Sites have to be able to perform 6MWT. 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Since patients may be randomised to a treatment arm that includes both a LABA (olodaterol) 
and a LAMA (tiotropium), it is necessary to restrict the use of LABA (e.g. salmeterol, 
formoterol, indacaterol) and LAMA or SAMA (e.g. tiotropium, ipratropium) during the 
treatment period. Patients will continue to receive treatment with inhaled corticosteroids as 
required. SABA medication (salbutamol MDI) will be prescribed at the trial site to all 
patients for rescue use, and appropriate medications will be allowed to control acute 
exacerbations as medically necessary.
A 6-week treatment period is considered sufficient to evaluate the effects of tiotropium + 
olodaterol FDC at pharmacodynamic steady state (based on results from previous studies 
evaluating the effects of tiotropium + olodaterol FDC on spirometric parameters). 
The cross-over design allows for each patient to serve as his/her own control. As such, 
treatment comparisons are within patient rather than between patients, which removes the 
inter-patient variability from the comparison between treatment regimens [R94-1529].


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Patients participating in this trial should perform exercise tolerance test for every visit. In 
order to decrease the burden on patients, medication restrictions such as a longer washout 
period have not been included in this trial. All participants are treated with tiotropium in both 
treatment periods, so a washout period for tiotropium before treatment 2 has not been 
included in this trial. In terms of olodaterol, we set the efficacy endpoints in the 2 weeks prior 
to Week 6 in order to avoid a carryover effect of olodaterol in the previous period. It is also 
considered sufficient to evaluate the effects of tiotropium + olodaterol FDC at the efficacy 
endpoints in the 2 weeks prior to Week 6 because a pharmacodynamic steady state of 
olodaterol has been reached.
3.3
SELECTION OF TRIAL POPULATION
A sufficient number of patients will be enrolled (sign informed consent) to ensure that at least 
180 patients (90 patients per each treatment sequence) of either sex, aged ≥ 40 years with a 
diagnosis of COPD are randomised into the study.
Enrolment will be competitive. Additional sites may be initiated may be closed to ensure 
sponsor's timelines. 
Patients who treated with LABA/LAMA combination (both fixed-dose and free-dose) at Visit 
0, at the time of informed consent, and are able to be switched their medication to LAMA or 
LABA monotherapy (one of component of their used LABA/LAMA) as judged by 
investigators can be switched to monotherapy.
Patients will be required to perform 6MWT on several occasions during the trial. Patients 
with any contraindication to exercise (as stipulated in the ERS guidelines [R98-0973], and 
supported by the ATS/American College of Chest Physician (ACCP) guidelines [P03-01262] 
will be excluded from participation. 
Patients can only be randomised if their COPD has been clinically stable for screening phase.
All log of patients 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
Outpatients with a history of COPD are eligible for inclusion if they fulfil all the inclusion 
criteria (Section 3.3.2) and do not present with any of the exclusion criteria (Section 3.3.3). 
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
regarding to the in- and exclusion criteria.


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3.3.2
Inclusion criteria
1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to 
participation in the trial, which includes medication washout and restrictions.
2. All patients must have a diagnosis of chronic obstructive pulmonary disease (P11-05865) 
and must meet the following spirometric criteria:
Patients must have relatively stable airway obstruction with a post-bronchodilator FEV1 <
80% of predicted normal (ECSC [R94-1408]); GOLD grade II-IV (P11-05865) and post-
bronchodilator FEV1/FVC < 70% at Visit 1 (see Appendix 10.5 for ECSC predicted 
normal equations).
3. Male or female patients, aged ≥ 40 years.
4. Patients must be current or ex-smokers with a smoking history of more than 
10 pack-years (see Appendix 10.5 for calculations). Patients who have never smoked 
cigarettes must be excluded.
5. Patients with score on the modified Medical Research Council (mMRC) ≥1.
6. Patients who walk < 400 meters of 6MWT and have a score on the modified Borg ≥4 at 
the end of 6MWT at Visit 2.
7. Patients must be able to perform technically acceptable pulmonary function tests 
(spirometry), to use the physical activity monitor and must be able to complete 6MWT 
during the study period as required in the protocol.
8. Patients must be able to inhale medication in a competent manner from the RESPIMAT
Inhaler (Appendix 10.1) and from a metered dose inhaler (MDI).
3.3.3
Exclusion criteria
1.
Patients with a significant disease other than COPD; a significant disease is defined 
as a disease which, in the opinion of the investigator, may:

put the patient at risk because of participation in the study

influence the results of the study

cause concern regarding the patient’s ability to participate in the study.
2.
Patients with clinically relevant abnormal baseline haematology, blood chemistry，
urinalysis or creatinine > x2 ULN will be excluded regardless of clinical condition 
(a repeat laboratory evaluation can be conducted if deemed necessary by the 
investigator).
3.
Patients with a current documented diagnosis of asthma. For patients with allergic 
rhinitis or atopy, source documentation is required to verify that the patient does 
not have asthma.


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Patients with any of the following conditions:
4.
A diagnosis of thyrotoxicosis (due to the known class side effect profile of β2-
agonists).
5.
A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to the known 
class side effect profile of β2-agonists).
6.
A history of myocardial infarction within 1 year of screening visit (Visit 1).
7.
Life-threatening cardiac arrhythmia as judged by the investigator.
8.
Hospitalized for heart failure within the past year.
9.
Known active tuberculosis.
10.
Any malignancy unless free of disease at least 5 years (patients with treated basal 
cell carcinoma or squamous cell skin cancers are allowed).
11.
A history of life-threatening pulmonary obstruction and patients with chronic 
respiratory failure.
12.
A history of cystic fibrosis.
13.
Clinically evident bronchiectasis as judged by the investigator.
14.
Patients with severe emphysema requiring endobronchial interventions within 6 
months prior to screening visit (Visit 1).
15.
A history of significant alcohol or drug abuse as judged by the investigator.
16.
Any contraindications for exercise testing as outlined below (see Section 3.3.3.1
below “Contraindications to exercise”).
17.
Patients who have undergone thoracotomy with pulmonary resection (patients 
with a history of thoracotomy for other reasons should be evaluated as per 
exclusion criterion No. 1).
18.
Patients being treated with any oral and patch β-adrenergics.
19.
Patients being treated with oral corticosteroid medication at unstable doses (i.e., 
less than 6 weeks on a stable dose) or at doses in excess of the equivalent of 
10 mg of prednisone per day or 20 mg every other day.
20.
Patients who regularly use daytime oxygen therapy for more than one hour per 
day and in the investigator’s opinion will be unable to abstain from the use of 
oxygen therapy during clinic visits


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21.
Patients who have completed a pulmonary rehabilitation program in the 6 weeks 
prior to the screening visit (Visit 1) or Patients whose pulmonary rehabilitation 
program is planned to be changed during the trial.
22.
Patients who have a limitation of exercise performance as a result of factors other 
than muscle fatigue or exertional dyspnea, such as arthritis in the leg, angina 
pectoris or claudication or morbid obesity. 
23.
Patients who have taken an investigational drug within one month or six half-lives 
(whichever is greater) or in case the investigator drug (sub) class is listed with in 
washout period specified in Table 4.2.2.1: 1 prior to screening visit (Visit 1).
24.
Patients with known hypersensitivity to β-adrenergic and/or anticholinergics 
drugs, BAC, EDTA, or any other component of the RESPIMAT inhalation 
solution.
25.
Pregnant or nursing women.
26.
Women of childbearing potential not using highly effective methods of birth 
control.*Female patients will be considered to be of childbearing potential unless 
surgically sterilised by hysterectomy or bilateral tubal ligation, or post-
menopausal for at least two years.
* as per ICH M3(R2) [R10-5669]: a highly effective method of birth control is 
defined as those which result in a low failure rate (i.e. less than 1% per year) when 
used consistently and correctly.
27.
Patients who have previously been randomised in this study or are currently 
participating in another study.
28.
Patients who are unable to comply with pulmonary medication restrictions prior to 
randomisation.
29.
Patient who have dysuria, narrow-angle glaucoma, prostatic hyperplasia or 
bladder-neck obstruction (contraindications for Tiotropium as an anticholinergic 
drug, tiotropium may potentially worsen the symptoms and signs)
Note: 
1. Extreme caution should be used when including patients:
-
with cardiovascular disorders, especially coronary insufficiency and hypertension*  
-
being treated with monoamine oxidase inhibitors or tricyclic antidepressants.*
2. Caution should be used when including patients on treatment with non-potassium-sparing 
diuretics.*


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3. Beta-blockers not only block the pulmonary effect of beta-agonists, but may also produce 
severe bronchospasm in patients with COPD. Therefore, patients should not normally be 
treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis 
after myocardial infarction, there may be no acceptable alternatives to the use of beta-
adrenergic blocking agents in patients with COPD. In this setting, cardio selective beta-
blockers could be considered, although they should be administered with caution.* 
*cf. prescribing information for registered LABAs
4. As a predominantly renally excreted drug, patients with moderate to severe renal 
impairment (creatinine clearance 50 mL/min) treated with tiotropium should be 
monitored closely.
3.3.3.1
Contraindications to exercise:
Patients are not allowed to perform an exercise challenge if they are known to have or are 
suspected of having one of the following contraindications to exercise at the investigator’s 
discretion (R98-0973):
-
unstable angina
-
uncontrolled arrhythmias causing symptoms or haemodynamic compromise
-
active endocarditis
-
acute myocarditis or pericarditis
-
symptomatic severe aortic stenosis
-
uncontrolled heart failure
-
acute non-cardiac disorder that may affect exercise performance or be aggravated by 
exercise (i.e., infection, renal failure, thyrotoxicosis)
-
thrombosis of lower extremities
-
left main coronary stenosis or its equivalent
-
moderate stenotic valvular heart disease
-
electrolyte abnormalities
-
severe untreated arterial hypertension (>200 mmHg systolic, >120 mmHg diastolic)
-
significant pulmonary hypertension
-
tachyarrhythmias or bradyarrhythmias
-
hypertrophic cardiomyopathy
-
mental impairment leading to inability to cooperate
-
high-degree atrioventricular block


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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient may be withdrawn from the trial prior to completion if any of the 
following criteria apply:
1. The patient withdraws consent, without the need to justify the decision.
2. The patient is no longer able to participate for medical reasons (e.g. pregnancy, surgery, 
adverse events, or other diseases), or contraindications for exercise testing have occurred.
3. Administrative reasons (protocol violations, persistent non-compliance).
-
Investigators must carefully consider withdrawal from the treatment of an individual
patient if any of the following criteria apply:

At least 3 courses (or increases) of systemic (oral, i.v.) corticosteroids are required to 
treat a COPD exacerbation.

When, during trial participation, a second hospital admission (at least 2 overnight 
stays) for a COPD exacerbation occurs.

Clinical deterioration requiring maintenance treatment not allowed per protocol.
No patient should be discontinued from the trial for a protocol violation before discussion of 
patient’s withdrawal with the clinical monitor.
Data of patients who discontinue or withdraw prior to randomisation will be entered in the 
trial database and will be listed. Data of patients who discontinue or withdraw after 
randomisation must be documented and the reason for withdrawal must be recorded in the 
eCRF. The data must be included in the trial database and must be reported. 
Refer to Section 6.2.3 for procedures to be completed for patients prematurely terminating 
the trial.
Pregnancy
If a patient becomes pregnant during the trial the investigational product needs to be stopped 
and follow to pregnancy of Section 5.3.7
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site


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2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The trial medication will be provided from Nippon Boehringer ingelheim.
Patients will receive both of the following treatments in random order:

tiotropium + olodaterol FDCinhalation solution (2.5 µg/2.5 µg per actuation)

tiotropium inhalation solution (2.5 µg per actuation)
During the 12-week treatment period (2-period, 6-week) patients will inhale two puffs from 
the RESPIMAT inhaler, once a day, in the morning.
4.1.1
Identity of BI investigational product(s) and comparator product(s)
Table 4.1.1: 1 Investigational product (Test)
-
Substance (INN):
-
Tiotropium + olodaterol fixed dose combination
-
Pharmaceutical form:
-
Inhalation solution
-
Unit strength:
-
2.5/2.5 µg per actuation
-
Total daily dose Route of 
administration:
-
5/5 µg q.d.. oral inhalation via RESPIMAT 
Inhaler
-
Dose regimen:
-
2 inhalations once daily (a.m. dosing)
Table 4.1.1: 2 Investigational product (Reference)
-
Substance (INN):
-
Tiotropium
-
Pharmaceutical form:
-
Inhalation solution
-
Unit strength:
-
2.5 µg per actuation
-
Total daily dose Route of 
administration:
-
2.5 µg q.d.. oral inhalation via RESPIMAT 
Inhaler
-
Dose regimen:
-
2 inhalations once daily (a.m. dosing)


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4.1.2
Method of assigning patients to treatment groups
When a patient is qualified for entry into randomised treatment periods, the treatment 
sequence assignment will be performed by IRT at Visit 2. To facilitate the use of the IRT, the 
investigator will receive all necessary instructions.
Patient assignment to the treatment sequences will be determined by a computer generated 
random sequence. Access to the randomisation code will be controlled and documented – for 
further details please see Sections 4.1.5.1 and 4.1.5.2.  
The assigned medication number which will be assigned via IRT will be entered in eCRF, 
and the corresponding medication kit should be given to the patient. Using this procedure, all 
relevant parties will be blinded to the treatment group assignment.
4.1.3
Selection of doses in the trial
The doses of Tiotropium + olodaterol FDC or Tiotropium are based on the marketed dose in 
Japan. These doses were selected based on the results from previous dose finding studies and 
pivotal studies for submission for registration (please refer to the current version of the IB).
4.1.4
Drug assignment and administration of doses for each patient
Dispensing of medication
Trial medication will be dispensed to the patient by the investigator/pharmacist. At Visit 2 
eligible patients will be randomised to one of two double-blinded treatment sequences (1:1 
ratio) by the IRT. At Visit 2 and Visit 3, the IRT will assign 3 boxes of a RESPIMAT
treatment box to each patient and each RESPIMAT treatment box will have a unique number.
One of these RESPIMAT treatment boxes is a reserve RESPIMAT inhaler. This reserve kit 
allows the patient the flexibility of not having to return to the clinic immediately to replace a 
lost or malfunctioning RESPIMAT inhaler. In the event that a patient may need additional 
extra RESPIMAT inhalers and cartridges due to rescheduled visits, inhaler loss or 
malfunction, these will be supplied on an 'on demand' basis via the IRT. Dispensing of these 
extra RESPIMAT inhalers will also be managed via the IRT.
Site personnel will enter all medication numbers dispensed to each patient in the Medication 
Record page of the eCRF. 
Priming of the RESPIMAT Inhaler
Each newly assembled RESPIMAT Inhaler needs to be primed prior to first time use. The 
inhaler should be primed by actuating it until an aerosol is visible plus three additional 
actuations. All priming actuations should be directed to the ground. Priming should NOT take 
place in the same room where the patient is inhaling trial medication. For detailed priming 
instructions please refer to the RESPIMAT Inhaler handling instructions in Appendix 10.1.
Once assembled, the shelf-life of the RESPIMAT with study medication is 3 months. Once 
assembled, the shelf-life of the RESPIMAT with training medication is also 3 months. 
Therefore it is important to ALWAYS enter the date of the cartridge insertion on the 
medication label of the RESPIMAT immediately after the cartridge is inserted.


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Note: At Visit 2 and Visit 3, patients will receive 3 medication boxes; only one RESPIMAT 
Inhaler should be ready for use (= cartridge inserted and primed). Once a cartridge is inserted 
in a RESPIMAT Inhaler, the shelf-life is limited. 
Testing of the rescue medication (salbutamol prescribed at sites)
Before using for the first time, one actuation should be released into the air to make sure the 
device is working. 
Instructing the patient
Detailed written instructions and training for the use of the RESPIMAT Inhaler will be given 
to the patient at Visit 1 (see Appendix 10.1). At Visits 2 and 3, detailed instructions on the 
use of the device will be repeated, but patients should not inhale from the training device on 
those visit days. The investigator or qualified study personnel will observe the inhalation 
procedure and will reinforce a correct inhalation technique.
Study medication administration at clinic visits
The utmost care should be taken to ensure that during the treatment period, the study 
medication is not taken prior to coming to the site for a visit. 
At Visit 2 the study medication will be self-administered after all necessary measurement 
until 12:00 pm (noon). Oral inhalation of two puffs of the study medication from the assigned 
RESPIMAT Inhaler will be self-administered by the patient in a seated position under the 
direct supervision of the investigating physician or study personnel. 
At Visits 3 and Visit 4/EOT, the RESPIMAT Inhaler that is in current use, must be bring to 
the site and used for administration of the study medication at that visit. Study medication 
will be self-administered within ± 30 min of administration time of next day at Visit 2 and 
between 7:00 a.m. and 10:00 a.m. The clock time of the start of inhalation of test medication 
will be captured on the source documents and in the eCRF.
At Visit 2, site personnel should discuss with the patient about the preferred regular time of 
day that the patient will be taking the morning dose of study medication at home.
Study medication administration at home
Each morning between clinic visits, oral inhalation of two puffs of the study medication from 
the assigned RESPIMAT Inhaler will be self-administered by the patient in a seated position.
The doses of study medication will be self-administered preferably within ±30 minutes of
time of administration next day of Visit 2 AND between 7:00 a.m. and 10:00 a.m. throughout
the trial. If the patient forgot to take study medication within the specified time window, the 
patient is allowed to administer the dose until 12:00 pm (noon). After 12:00 pm the patient 
should skip the dose and take the next dose at the next scheduled time the following day. 
Medication accountability will be done using the counter on the RESPIMAT device. 
RESPIMAT Inhaler return
The RESPIMAT Inhalers dispensed during the treatment period will contain sufficient 
medication for 30 days of treatment. All used and unused test medication will be returned to 
the medication boxes and must be brought to each clinic visit by the patient.


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Any RESPIMAT Inhaler that has been reported as malfunctioning by a patient or investigator 
will be returned to Boehringer Ingelheim for investigation. See the ISF for specific 
instructions and for details regarding drug accountability requirements. A detail of the 
procedure for the return of malfunctioning inhalers is provided in Appendix 10.2.
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.
BI will generate and store the randomisation schedule, and prepare and code the medication 
in a blinded fashion. Trial supplies will be assigned to the patients via IRT.
However, due to the requirements to report suspected serious unexpected adverse reactions 
(SUSARs), it may be necessary for a representative from BI’s drug safety group to access the 
randomisation code for individual patients during study conduct. In such cases, access to the 
code will only be permitted by authorised drug safety representatives. Access to the code will 
be via the IRT.
The randomisation code will be kept secret by Clinical Trial Support up to database lock. 
Please see Section 4.1.5.2 for the rules regarding breaking the code for an individual or for all 
patients in emergency situations.
4.1.5.2
Unblinding and breaking the code
In this blinded trial, an emergency code break will be available to the investigator via the IRT 
system. This code break may only be accessed in emergency situations when the identity of 
the trial drug must be known to the investigator in order to provide appropriate medical 
treatment or if required to assure the safety of trial participants. Each site receives a manual 
from the IRT provider that contains instructions on how to unblind the treatment of a patient 
via the IRT (via 24-hour Emergency helpline). If the code break for a patient is accessed, the 
Sponsor must be informed immediately. The reason for accessing the code break, together 
with the date, must be documented on the appropriate eCRF page. In case third party needs to 
break the code, however, when the investigator cannot be reached, the code can be opened by 
calling emergency code manager (see Emergency Code Break Manual) in the ISF.
4.1.6
Packaging, labelling, and re-supply
Boehringer Ingelheim will provide study supplies including blinded study medication and 
RESPIMAT inhaler training kits.
Open-label supplies= Auxiliary Medicinal Products (AMPs)


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
Training RESPIMAT inhaler and placebo cartridges for training purposes are 
supplied. The training RESPIMAT can be used until 3 months after first insertion of 
the cartridge or until the device is empty. The date of the cartridge insertion should be 
entered on the medication label of the RESPIMAT immediately after the cartridge is 
inserted. 
RESPIMAT inhaler for training purposes will be provided by IRT along with the 
initial supply order.
Blinded study medication= Investigational Medicinal Product (IMP)

Packaging: the RESPIMAT treatment box will contain one RESPIMAT inhaler plus 
one drug-filled cartridge and contains sufficient medication for 30 days of treatment. 
The RESPIMAT inhaler will lock after 60 actuations have been administered and will 
no longer actuate any medication. 

Labelling: individual RESPIMAT treatment box will have a three-part tear-off label. 
One part of each tear-off label should be attached to the drug accountability form 
which will be part of the ISF, and one part will remain on the box (an extra part is 
available as well). The investigator or designee should fill out the following 
information: 
o
date of cartridge insertion should be entered at time of cartridge insertion on 
the cover page of the cartridge booklet
o
Investigator’s name should be entered at time of dispense on the cover page of 
the booklet on the RESPIMAT treatment box.
For details of the packaging and the description of the label, refer to the ISF.
!" #$%&&'( 
Each site will receive a first supply at or after the initiation visit and will be resupplied upon 
demand by IRT.
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, CML (as provided in the 
list of contacts) must be contacted immediately.”


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4.1.8
Drug accountability
The 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
The 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 patient, 

the return to the sponsor or alternative disposition of used/unused trial medication.  

the adequate documentation that the patients were provided the doses specified by the 
CTP

the reconciliation of all investigational products received from the sponsor
At the time of return to the sponsor and/or appointed CRO, the investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.
The investigator/pharmacist will record on the drug accountability forms the following 
information.
RESPIMAT inhaler:

dates (dispense and return), 

dispenser’s initials

batch/serial numbers, 

expiry dates, 

the unique RESPIMAT treatment box number assigned by IRT

trial patient number assigned by the RDC system. 
See Section 4.1.2 for the randomisation. It is important to enter the date of priming on the 
medication label of the RESPIMAT.  
Rescue medication (salbutamol MDI prescribed at sites) and training RESPIMAT:
AMP accountability form for each will be provided to the trial site. This record will include:

dates (dispense and return)

dispenser’s initials

quantities,

batch/serial numbers,


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
expiry date,

the trial patient number assigned by the RDC system. 
The patient will be asked to return all used/unused rescue medication inhalers at each clinic 
visit. Source data documentation and full drug accountability in regard to dispensed and 
returned medication to investigational site and to patients are required. Only used inhalers 
will be replaced at each clinic visit. For further details, please refer to Section 4.2.1 (Rescue 
medication).
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
4.2.1.1
Rescue Medication
Administration of rescue medication can occur at any point during the trial as deemed 
necessary by the patient or the investigator. Salbutamol will be prescribed as rescue 
medication in the trial site; only the salbutamol prescribed in the trial site is allowed for 
rescue medication use. If the patient requires rescue medication during the pulmonary 
function test (PFT) days (Visits 1, 2, 3, and 4), the PFTs will be discontinued. The visit 
should be rescheduled if possible. The medication used, route and 24-hour clock time of 
administration will be recorded on the Rescue Medication eCRF page.
4.2.1.2
Emergency procedures
There are no special emergency procedures to be followed.
4.2.1.3
Additional treatments
Medications allowed to controlling acute exacerbations as medically necessary during the 
treatment period:

Salbutamol inhalation aerosol from MDI for p.r.n. use

Temporary increases in the dose or addition of oral steroids are allowed during the 
treatment portion of the study. PFT should not occur within 7 days of the last 
administered dose of an increase or addition of oral steroids. These tests may be 
postponed up to 14 days to meet this restriction. Subsequent visits will be scheduled 
according to the patient's regular schedule.

Temporary additions of theophylline preparations are allowed during the treatment 
portion of the study. PFT should not occur within seven days of the last dose. These 
tests may be postponed up to 14 days to accommodate this restriction. Subsequent 
visits will be scheduled according to the patient's regular schedule.


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
The use of antibiotics is not restricted and may be prescribed as medically necessary 
for exacerbations and / or infections. If antibiotics are prescribed for a respiratory 
infection prior to PFT, these tests will be postponed for at least 2 days but not more 
than 7 days after the last dose is given. Subsequent visits will be scheduled according 
to the patient's regular schedule.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
-
The following Table 4.2.2.1:1 provides an overview of permitted and restricted
medication.


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Table 4.2.2.1: 1 Permitted Medications and Medication Restrictions 
Drug Class
Sub-class
Prior to study
Study Period
Run-in Period
Treatment Period
Follow up Period
Corticosteroids
Inhaled corticosteroids (ICS)
(stabilized 6 wks. prior to V1)
Permitted 
Permitted
Permitted
Permitted
Oral corticosteroids 
[≤10 mg prednisone per day or ≤20 mg 
prednisone every other day (or 
equivalent); stabilized 6 wks. prior to 
V1]
Permitted
Permitted
Permitted
Permitted
Injected corticosteroids – local 
administration
(for treatment of e.g. bursitis)
Permitted
Permitted
Permitted
Permitted
β-adrenergics
SABA(e.g. sulbtamol)
Permitted
Rescue1
Rescue1
Permitted
LABA (bid, qd)2
(e.g. formoterol / salmeterol / 
indacaterol)
Permitted as 
monotherapy3
Permitted as 
monotherapy3
NOT permitted
Permitted
Oral and patch beta-adrenergics
Not Permitted
(w.o. 4wks. prior to V1)
Not Permitted
NOT permitted
Permitted
Beta blockers  
(cautionary statement, Section 3.3.3;
stabilized 6 wks. prior to V1)
Permitted
Permitted 
Permitted 
Permitted 


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Table 4.2.2.1: 1 Permitted Medications and Medication Restrictions (cont’d)
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment Period
Follow up Period
Anticholinergics
SAMA
(e.g. inhalation aerosol, nasal spray)
Permitted4
Permitted4
NOT permitted
Permitted
LAMA (bid, qd)2 (e.g. tiotropium, 
aclidinium, glycopyronnium, 
umeclidinium)
Permitted as 
monotherapy3
Permitted as 
monotherapy3
Study medication
Permitted
Combinations
ICS/LABA (bid, qd)
(Switch to ICS mono-product at the 
same dose or equivalent dose)
Permitted
NOT permitted
NOT permitted
Permitted
ICS/SABA
(Switch to ICS mono-product at the 
same dose or equivalent dose)
Permitted
NOT permitted
NOT permitted
Permitted
LABA3
(i.e. tiotropium+olodaterol, 
glycopyrronium+indacaterol, 
umeclidinium+vilanterol)
Not Permitted
(w.o. 3 wks prior to 
V1)
NOT permitted
(w.o. 5 wks prior to V2)
Study medication
Permitted
Antibiotics
Any infection
Permitted
(w.o 4 wks prior to V1)
Permitted
Permitted
Permitted


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Table 4.2.2.1: 1 Permitted Medications and Medication Restrictions (cont’d)
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment Period
Follow up Period
Miscellaneous
Other investigational drugs (see 
exclusion criterion)
NOT permitted
NOT permitted
NOT permitted
NOT permitted
Cromolyn sodium / nedocromil 
sodium
(if prescribed for non-asthma condition)
Permitted 
Permitted
Permitted
Permitted
Antihistamines, antileukotrienes
( if prescribed for non-asthma condition)
Permitted
Permitted 
Permitted
Permitted 
Methylxanthines/Theophyllines
(if prescribed for non-asthma condition)
Permitted
Permitted
Permitted1
Permitted
Mucolytics 
(not containing bronchodilators; 
stabilized 6 wks prior to V1)
Permitted
Permitted
Permitted
Permitted
1.
Use rescue medication (salbutamol) delivered by each visit.
2.
Commercial long-acting bronchodilators will be discontinued prior to Visit 2 in accordance with drug restriction for PFTs.
3.
Patients on LAMA/LABA combination therapy (FDC or free dose combination) should be treated with either LAMA or LABA at Visit 0. Patients treated with LAMA or 
LABA monotherapy for at least 3 weeks are proceeded to Visit 1 and Visit 2.
4.
SAMA is allowed to be used in patients who do not use any LAMA from Visit 0 until Visit 2.


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Medication restrictions for pulmonary function testing 
-
At least an 8-hour washout of SABA bronchodilators.
-
At least an 8-hour washout of SAMA bronchodilators prior to Visit 1 and 2 (Not 
allowed during treatment periods).
-
At least a 48-hour washout of LABA (BID or QD) prior to Visit 1 and Visit 2 (Not 
allowed during treatment periods).
-
At least a 48-hour washout of LAMA (BID or QD) prior to Visit 1 and Visit 2 (Not 
allowed during treatment periods).
-
The morning dose of ICS should not be taken in the 1-hour period prior to PFTs.
-
Morning doses of study medication should not be taken prior to test-day (Study 
medication  should be taken on previous day of the visit)
-
A patient visit may be re-scheduled twice due to lack of medication washout 
compliance.
-
At least a 24-hour washout of short-acting (BID or more frequent administration) 
theophylline preparations.
-
At least a 48-hour washout of long-acting (QD administration) theophylline preparation.
4.2.2.2
Restrictions on diet and life style
Medication washout restrictions should be adhered to as described in Table 4.2.2.1:1.
Patients must remain in the building where the PFT is performed and must return to the 
laboratory at least 10 minutes prior to the start of each test.
On PFT days (including the Screening Visit), patients must refrain from strenuous activity for 
at least 2-3 days prior to PFT and throughout the testing period. Patients should 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 should be avoided the morning of or during the PFT period. Decaffeinated 
beverages are acceptable.
Smoking should be discouraged for the 12 hours prior to lung function testing and throughout 
the study day and will not be permitted in the 30-minute period prior to PFT.
4.3
TREATMENT COMPLIANCE
On visit days, compliance will be guaranteed by administration of the trial drug under 
supervision of the investigating physician or designee. Each patient will be trained in the 


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correct use of the RESPIMAT Inhaler using the training RESPIMAT Inhaler with inserted 
placebo cartridge on Visit 1.
The patient will complete a patient Diary confirming that trial medication has been taken and 
indicating the number of puffs of salbutamol MDI use. Compliance should be emphasised 
with a goal of within 80% to 120% compliance rate with treatment in the patient Diary. The 
investigator or designee will review these records with the patient at all visits to assess rescue 
medication use and treatment compliance in treatment phase. However, randomised patients 
will not be discontinued for lack of compliance without prior discussion with CML.


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5.
VARIABLES AND THEIR ASSESSMENT 
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint
Inspirational Capacity (IC) at rest measured at 60 minutes post-dose, after 6 weeks of 
treatment 
This is no safety issue.
5.1.2
Secondary Endpoints
The following secondary endpoints will be assessed:
-
6-minute walk distance (6MWD [m]) after 6 weeks of treatment
-
Average number of step per day (step/day) in the 2 weeks prior to Week 6
-
Average daily duration (minute) of ≥4 metabolic equivalents (METs) in the 2 weeks 
prior to Week 6
-
Average daily duration (minute) of ≥3 METs in the 2 weeks prior to Week 6
-
Average daily duration (minute) of ≥2 METs in the 2 weeks prior to Week 6
-
Average daily active strength (METs·minute) of ≥3 METs in the 2 weeks prior to Week 
6
-
60 minutes post-dose Slow vital capacity (SVC), after 6 weeks of treatment
-
30 minutes post-dose FEV1, after 6 weeks of treatment
-
30 minutes post-dose FVC, after 6 weeks of treatment
These are no safety issue.


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5.2
ASSESSMENT OF EFFICACY
5.2.1
Pulmonary Function Testing
These tests will be performed using spirometers (Flowscreen, eResarch Technology GmbH) 
provided by BI. Spirometers and their use, including daily calibration, must meet ATS/ERS 
criteria (P05-12782). Baseline PFT will be conducted at Visit 2. PFT will also be conducted 
post-dose and before 6MWT (at Visit 3 and Visit 4). Patient will be in a seated position and it 
is preferable that the same trained individual performs the pulmonary function tests for a 
given patient. 
Baseline IC and SVC measurement (Visit 2) should be done 30 minutes before 6MWT. IC 
and SVC measurement (at Visit 3 and Visit 4) should also be done 30 minutes before 6MWT, 
which is on 60 minutes post-dosing. For IC and SVC at least three reproducible 
measurements should be obtained with a maximum of 5 measurements to be performed. The 
resting IC and SVC should be recorded as the mean of the two highest acceptable efforts. For 
additional details on the IC maneuvers, please refer to Appendix 10.11.
Baseline FEV1 and FVC measurement (Visit 2) should be done 60 minutes before 6MWT.
FEV1 and FVC measurement (at Visit 3 and Visit 4) should also be done 60 minutes before 
6MWT, which is on 30 minutes post-dosing. The best of three efforts will be defined as the 
highest FEV1 and the highest FVC each obtained on any of three manoeuvres meeting the 
ATS criteria (to a maximum of five attempts). The highest FEV1 and the highest FVC will be 
selected regardless of whether they come from different spirometric manoeuvres or from the 
same manoeuvre. 
If a patient is unable to complete the PFTs during a visit, the CML should be notified as soon 
as possible. The eCRF will be completed indicating the reason for stopping testing, rescue 
medication given (if any) and time of rescue medication. Patients who are unable to complete 
the study visit may leave the clinic only upon instruction from the supervising physician.


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Reversibility testing (P05-12782) for the qualifying PFT at the Screening Visit (Visit 1): the 
procedure is described in Appendix 10.5. The post-bronchodilator measurements must meet 
the inclusion criteria specified in Section 3.3.2.
5.2.2
Six-minute walk test (6MWT)
The test will be conducted according to the methodology described by ATS guideline (R03-
0725, R13-4735, R13-2807). At Visit 1, a training for 6MWT before administration of 400 
µg salbutamol will be done. At Visit 2, 6MWT for eligibility assessment will be performed
before administration of the study medication. The 6MWT will be repeated at Visit 3 and 
Visit 4, starting 90 minutes (+15 minutes) after inhalation of the study medication. 
During 6MWT, oxygen saturation and heart rate are monitored to measure 
 and recovery 
time for SpO2 (%, see Section 5.1.3) using a mobile pulse oximeter, which is provided by BI.
During 6MWT and at the end of 6MWT, the intensity of breathing discomfort and leg 
discomfort will be assessed (modified Borg Scale as outlined in Appendix 10.7) by the 
patients. The outline of 6MWT is described in Appendix 10.6.
5.2.3
Activity monitoring 
A physical activity monitor (HJA-750C, OMRON) is an accelerometer that is used to 
measure the overall movement of a patient and provided by BI.
Patients will wear the physical activity monitor every day for 2 weeks and 3 times repeat
during the trial i.e. in the 2 weeks prior to Visit 2, Visits 3 and Visit 4. The device will not be 
worn during bathing or water sport activities. Activities that may hamper proper functioning 
of the equipment are limited and not likely to happen in the population studied, but should be 
discussed with the investigator and eventually avoided. (e.g. high impact sports).
Muscle amount (% in BW) will be measured before activity monitor measurement at Visit 1.


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5.2.8
Patient diary
Patient daily will be used to collect and the study medication (salbutamol) and rescue 
medication, steps, and weather throughout trail.
5.3
ASSESSMENT OF SAFETY
The safety endpoints will be assessed:
•
All adverse events (including physical examination) until the end of the study
•
Heart rate and SpO2 in conjunction with 6MWT
5.3.1
Physical examination
At start of screening (Visit 1), Visit 2, Visit 3 and Visit 4/EOT, a complete physical 
examination (including cardiac, neurological, dermatological, pulmonological) will be 
performed by the investigator. Documentation of, and findings from the physical 
examination, must be part of the source documents available at the site. Follow-up 
examination will be performed at Visit 5 if there are any clinically significant findings at 
Visit 4/EOT.
5.3.2
Vital Signs
Measurements of heart rate and blood pressure will be obtained prior to 6MWT and 
spirometry measurement, with the patient seated and rested for a minimum of 5 minutes.
5.3.3
Safety laboratory parameters
Laboratory tests


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Safety laboratory testing will be conducted (non-fasting) on all patients at the screening visit 
(Visit 1), and at Visit 4/EOT. Follow-up clinical laboratory testing will be performed at Visit 
5 if there are any clinically significant findings at Visit 4/EOT. The laboratory tests at Visit 1 
will be considered as the baseline measurements. Laboratory specimens will be collected in 
the morning prior to the exercise testing. Patients should be instructed not to do any 
unaccustomed physical exercise 36 hours prior to laboratory testing. 
Haematology, blood chemistry, urinalysis will be analysed by the local laboratory. 
Haematology
Haemoglobin, haematocrit, red blood cell count, white blood cell count including differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), total eosinophil count and 
platelet count.
Blood chemistry
Alkaline phosphatase, LDH, Gamma- glutamyl transferase (GT), aspartate
aminotransaminase AST (SGOT), alanine aminotransaminase ALT (SGPT), glucose, 
calcium, inorganic phosphorus, uric acid, urea nitrogen, creatinine, total protein, potassium, 
sodium, chloride, total bilirubin, creatine kinase.
Urinalysis
Specific gravity, pH, glucose, protein, occult blood.
Pregnancy Testing
Pregnancy tests to be performed at Visit 1 and Visit 4/EOT. If a patient discontinues early, a 
pregnancy test will also be conducted.
Local laboratory will be used and the laboratory data will not be collected or captured in the 
eCRF. All laboratory values will be evaluated, (signed, dated and commented upon) by the 
investigator and stored locally. Any clinically relevant changes in the laboratory values will 
be reported as AEs (see Section 5.3.6) and followed up and/or treated locally until returning 
to normal or stable condition.
Any laboratory abnormalities will be carefully monitored and if necessary the patient will be 
removed from the trial and medically treated.
5.3.4
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) at rest will be performed on all patients at Visit 
1, Visit 2, Visit 3 and Visit 4/EOT. An ECG will be repeated at Visit 5 in case of any findings 
at Visit 4/EOT.


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The purpose of the screening ECG (Visit 1) is to obtain information about the patient’s 
baseline conditions. Therefore, any significant findings from the examination are recorded on 
the baseline condition page. In case of indication of a disease listed under the exclusion 
criteria, the patient should not be randomised for treatment.
ECG will be completed using site´s own equipment and ECG data will not be collected or 
captured in the eCRF. All ECGs will be evaluated, (signed, dated and commented upon) by 
the investigator and stored locally. Any clinically relevant changes in the ECG will be 
reported as AEs (see Section 5.3.6) and followed up and/or treated locally until returning to 
normal or stable condition.
Any ECG abnormalities will be carefully monitored and if necessary the patient will be 
removed from the trial and medically treated.
5.3.5
Other safety parameters
Other safety parameters
Heart Rate Monitoring and Oxygen Saturation (SpO2): A mobile pulse oximeter will be 
provided by sponsor for use during the 6MWT. Both heart rate and SpO2 will be monitored 
during 6MWT.
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 


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require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
Every new occurrence of cancer must be reported as a serious event regardless of the duration 
between discontinuation of the drug and the occurrence of the cancer.
The following events will be handled as “deemed serious for any other reason”. An AE which 
possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC system. These events 
should always be reported as SAEs as described in Section 5.3.7.
Adverse events of special interest (AESIs)
There are no AESIs in this study.
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
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. 
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


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Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the eCRFs. The reason for 
the decision on causal relationship for unlisted AEs needs to be provided in the eCRF.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
5.3.7
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
•
From signing the informed consent onwards through the Residual Effect Period (REP), 
until individual patient’s end of trial:
- all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only
report relevant SAEs and relevant AESIs of which the investigator may become aware of.
The REP is defined as 21 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 will be considered 
as post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
Sponsor’s unique entry point (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.
All SAEs and AESIs must be reported immediately to the head of the trial site.
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.


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Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, outcome, 
seriousness, and action taken with the investigational drugs. The Investigator should 
determine the causal relationship to the trial medication, and any possible interactions 
between the investigational drugs and AMPs.
The following should also be recorded as an (S)AE in the eCRF and SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the investigator must report immediately (within 24 hours) the
drug exposure during pregnancy (DEDP) to the sponsor’s unique entry point (specific contact 
details will be provided the ISF). Pregnancy Monitoring Form for Clinical Trials (Part A) 
should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying 
SAE/AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is 
to be completed. If there is an SAE/AESI associated with the pregnancy, then the SAE/AESI
has to be reported on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Not Applicable


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5.4.2
Methods of sample collection
Not Applicable
5.4.3
Analytical determinations
Not Applicable
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Not Applicable
5.5
ASSESSMENT OF EXPLORATORY BIOMARKER(S)
Not Applicable
5.5.1
Biobanking
Not Applicable
5.6
OTHER ASSESSMENTS
Not applicable in this trials
5.7
APPROPRIATENESS OF MEASUREMENTS
Six-Minute Walk Test
6MWT is a standard test to assess treatment changes in patients with COPD (R03-0725, R13-
4735, R13-2807).
Activity monitoring
HJA-750C provided by BI will be used as physical activity monitor in this trial. This is an 
electronic device used to measure physical activity levels of the patient. The devices are 
standard method to assess various output parameters (i.e. steps, METs, etc.) of activity in
patients during the trial.
Spirometry
PFT are a validated and well established measurement tool for lung function testing. PFT will 
be conducted at clinic visits using the equipment which meets ATS/ERS criteria (P05-12782)
provided by BI. FEV1, FVC, SVC and IC are standard measurements for the assessment of 
lung function. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
This trial consists of a screening period, two period 6-week treatment periods, and a 3-week 
follow-up period. Following the screening visit (Visit 1) and 2-week screening period, 
patients will be randomised into the first of double-blind treatment period (Visit 2). 
Additional clinic visits will be scheduled after 6 weeks of treatment (Visits 3 and Visit 
4/EOT) and once 3 weeks post-treatment (Visit 5). 
Patients should make every attempt to complete the protocol as specified. Investigators 
should encourage patient treatment compliance and adherence to other protocol specific 
activities. All deviations from the planned visit schedule will be documented. Refer to the 
Flow chart for time windows for the visits.
Rescheduling in general
A patient may be rescheduled twice (within one week of the scheduled visit date) due to lack 
of medication washout compliance or no intake of study medication on the day preceding the 
clinic visit.
Rescheduling after randomisation
Subsequent visits should always be planned to take place to assure a minimum 6 week 
treatment period.
If rescheduling of visits after randomisation is necessary, the total daily doses of the 
RESPIMAT inhaler need to be obeyed. Reserve medication is dispensed at each treatment 
period to avoid intermediate visits.
If rescue medication is administered during a visit day within 8 hours prior to administration 
of trial medication, the visit will be rescheduled once. Further rescheduling should be 
discussed with the local clinical monitor. 
Refer to Section 4.2.1 for details on medications allowed to control acute COPD 
exacerbations and restrictions for these medications prior to PFTs.
In case a visit needs to be rescheduled outside the allowed time window (e.g. in order to meet 
PFT washout requirements following treatment of an acute exacerbation), the CML should be 
contacted.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Visit 0 (Informed Consent Visit )

Informed consent will be obtained prior to patient participation in the trial, which 
includes any medication washout procedures or restrictions (e.g., for exercise testing 


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or lung function testing).  Upon obtaining consent, the patient will be instructed on 
the medication washout and other restrictions for the screening PFT and 6MWT
(Visit 1).  Rescue medication will be dispensed.

The patient will receive directions on the as needed use of the salbutamol (as rescue 
medication) that will be dispensed at this visit.

A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid 
unnecessary washout procedures in non-eligible patients.
Visit 1 (Screening visit)

Medication washout compliance will be verified as described in Section 4.2.

mMRC questionnaire will be completed in the order noted prior to all other 
procedures.

Demographic data (gender, race, year of birth, height, weight, muscle amount, 
duration of COPD, pack years, and smoking status) will be recorded.

COPD background characteristics will be recorded.

All adverse events experienced since signed informed consent will be reviewed and
recorded.

In/Exclusion criteria will be reviewed

Any change of concomitant therapy since signed informed consent will be reviewed
and recorded.

A relevant medical history, and physical examination including vital signs (blood
pressure and pulse rate) and 12-lead ECG will be conducted. The vital signs (seated) 
and ECG should be conducted following 5 minutes rest and prior to blood sampling.

Blood and urine samples will be collected. A pregnancy test will be performed for 
women of child-bearing potential. Blood samples need to be taken prior to the 
salbutamol dosing.

6MWT should be performed as mentioned in Flow chart and respective protocol 
sections.

 
 

PFT will be conducted both immediately prior to within 10 min. and 10 - 15 min.
after the inhalation of 4 puffs of salbutamol between 7:00 a.m.-10:00 a.m..

Patients qualified to enter the 2-week screening period of the trial will be issued 
additional rescue medication if needed.

Patient takes current concomitant medication after post-dosing PFT until noon.


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
Patients will receive training and instructions on 
-
the use of rescue medication (salbutamol)
-
the use of the RESPIMAT Inhaler using the training kit
-
medication restrictions and washout requirements for the screening period 
and subsequent visits
-
the use of patient diary 
-
the use of activity monitor and starting physical activity measurement

Patients will be asked to return all issued medication, diary, activity monitor, etc. to 
the clinic on all subsequent visits.
Visit 2 (Baseline visit and randomisation)  

Medication washout compliance will be verified as described in Section 4.2.

 

All adverse events experienced since the last visit will be reviewed and recorded.

In/Exclusion criteria will be reviewed

Any change of concomitant therapy since the last visit will be reviewed and recorded.

Physical examination, vital signs (blood pressure and pulse rate) followed by 12-lead 
ECG will be measured before start of PFT and with the patient seated and rested for at 
least five minutes.

PFT should be performed as mentioned in Flow chart and respective protocol sections 

6MWT should be performed as mentioned in Flow chart and respective protocol 
sections.

 
 

Patients will be instructed to return a trail medication, a rescue medication, a diary 
and an activity monitor to the clinic on the next scheduled visit. 
Randmisation

Patients will receive instructions on restrictions for the treatment period and 
subsequent visits. Patients will be instructed to bring all study-related treatments to 
the clinic at the next visit.

Trial medication will be dispensed to the patient by IRT. 

Dispense/collect rescue medication as needed.


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
The patient will be instructed in the use of the RESPIMAT, but patient should not 
inhale from the training inhaler at this visit.
6.2.2
Treatment periods
Clinic visits after 6 weeks of each treatment period (Visits 3 and 4):
Telephone Visit
The investigator or a designated site staff member will telephone the patients 15 days and 
8 days prior to the next planned Visit and remind them to wear physical activity monitor 
every day. An assessment of adverse events including concomitant therapy should be 
performed from the last assessment.The investigator should ask the patient to visit the 
clinic, if determined by the investigator as concerning the patient’s safety.
Observations / procedures:
Patients will be contacted prior to each of the visits to remind the patient of medication 
washout times, exercise test restrictions and to bring back all study medication at their 
next visit.

Medication washout compliance will be verified at every visit as described in 
Section 4.2.

 

Patient’s smoking status will be recorded only at Visit 4/EOT. 

All adverse events experienced since the last visit will be reviewed and recorded.

Any change of concomitant therapy since the last visit will be reviewed and recorded.

A complete physical examination including vital signs (blood pressure and pulse 
rate) and 12-lead ECG will be conducted. The vital signs and ECG should be 
conducted following 5 minutes rest and prior to blood sampling.

Blood and urine samples will be collected (only Visit 4/EOT). A pregnancy test will 
be performed for women of child-bearing potential.

Study medication will be self-administered within ± 30 minutes of time of 
administration next day of Visit 2 and between 7:00 a.m. and 10:00 a.m.; start-time 
of inhalation will be recorded. Administration of trial medication during these visits 
will be done using medication that was dispensed at the beginning of the treatment 
period.

PFT should be performed as mentioned in Flow chart and respective protocol 
sections.

6MWT should be performed as mentioned in Flow chart and respective protocol 
sections.


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
 

All trial medications should be collected at Visit 3 and Visit 4/EOT. At Visit 3, new 
trail medications for the patients should be dispensed via IRT.
6.2.3
Follow Up Period and Trial Completion
Following the end of final treatment period, patients will be followed up for an additional 21 
days. They will be seen at the end of this period (Visit 5) and their adverse events and
concomitant therapies will be reviewed and recorded (see Flow chart). If the physical 
examination, clinical laboratory tests, Pregnancy test (if applicable) or ECG performed at 
Visit 4/EOT yield abnormal values representing clinically significant changes from baseline, 
they will be repeated at the follow-up visit (Visit 5). Any persistently abnormal test must be 
fully explained by the investigator and follow-up evaluation performed, if necessary. 
The clinical monitor must be consulted on all persistently abnormal tests and SAEs until it is 
agreed that follow-up is no longer necessary.
Observations and procedures in case of premature withdrawal:
The following procedures of Visit 4/EOT should be performed after any premature 
withdrawal of patients
that took at least one dose of trial medication.

Physical examination including 12-lead ECG and vital signs (blood pressure and 
pulse rate) will be conducted.

Adverse events and changes in concomitant therapies will be recorded. Any 
ongoing (serious) adverse events should be followed until the event is resolved or 
there is a mutual agreement between the investigator and CML that follow-up is 
sufficient. 

Smoking status will be assessed.

Laboratory testing

Pregnancy test in women of child-bearing potential

Study and rescue medication (used and unused), activity monitor and patient 
diary will be collected.

If possible, a spirometry will be performed.
The investigator should make every effort to perform a follow-up visit 21 days after the 
last dose of study medication in patients that withdrew prematurely, as described earlier in 
this section.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The primary objective of this trial is to confirm that bronchodilator FDC therapy 
(LABA/LAMA FDC) will improve Inspiratory Capacity (i.e., IC) at rest as compared to 
bronchodilator monotherapy (LAMA) in patients with COPD.
The secondary objective of this trial is to evaluate the effect on two domains of physical 
activity: (1) amount of physical activity as measured with the activity monitor described in 
Section 5.1.2.; (2) perceived difficulties associated with physical activity as measured by 
some questionnaires described in Section 5.1.3. 
A mixed effects model repeated measures (MMRM) approach with treatment and period as 
fixed effects, study baseline as a covariate and patient as a random effect will be used for the 
primary analysis. Study baseline was defined as the measurement at the baseline (Visit 2).
7.2
NULL AND ALTERNATIVE HYPOTHESES
The following hypothesis (two-sided α = 0.05) will be tested for the primary endpoint - IC at 
rest measured at 60 minutes post-dose - after 6 weeks of treatment:
H0: Mean IC for Tiotropium + Olodaterol (5 μg/5 μg) = Mean IC for Tiotropium (5 μg) vs.
H1: Mean IC for Tiotropium + Olodaterol (5 μg/5 μg) ≠Mean IC for Tiotropium (5 μg)
7.3
PLANNED ANALYSES
Details will be described in the Trial Statistical Analysis Plan(TSAP).
7.3.1
Primary endpoint analyses
Primary analysis will be performed in all patients who signed informed consent, are 
randomised (RS) and are documented to have taken any dose of study medication (TS), and 
have non-missing baseline at Visit 2 and non-missing post-dose baseline measurements of IC 
at rest for primary endpoint. This set is called Full Analysis set (FAS) and assignment to the 
FAS will be done after implementation of any data handling rules which set measurements to 
missing.
The primary analysis will be conducted using MMRM including treatment and period as 
categorical fixed effects, study baseline as a covariate and patient as a random effect
treatment. Compound symmetry will be used as a covariance structure for within patient 
variation. The SAS procedure MIXED will be used involving the restricted maximum 
likelihood estimation and the Kenward-Roger approximation for denominator degrees of 
freedom. This approach is described in [R10-4391]. Adjusted mean values as well as 


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treatment contrasts will be presented together with the 95% confidence intervals (CI) and p-
values.
After blinded review of the magnitude and potential impact of any serious protocol violations, 
a subset of the data corresponding to those patients without serious deviations from the 
protocol will be created. This will be called the Per–Protocol Set (PPS). If the number of 
patients in PPS is less than 90% of the number of patients in FAS, the primary analyses will 
also be performed on PPS. These will be supportive analyses to assess the robustness of the 
primary analysis using FAS.
7.3.2
Secondary and further endpoint analyses
All secondary and further endpoints (described in Section 5.1.2 and Section 5.1.3) will be 
analysed using a similar MMRM model as for the primary endpoint. Descriptive statistics 
will be provided for each of the two treatment groups.
7.3.3
Safety analyses
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned 
prospectively. 
Adverse events will be coded using the Medical Dictionary for regulatory Activities 
(MedDRA) coding dictionary. The number of patients with adverse events during the 
treatment period will be summarized. Standard BI summary tables and listings will be 
produced to compare the incidence of adverse events across the treatment groups. All events 
with an onset after the first dose of trial medication up to a period of 21 days after the last 
dose of trial medication will be assigned to the treatment period for evaluation. AEs before 
the treatment period will be assigned to screening. AEs after 21 days from the last study drug 
intake up to and including trial completion date will be assigned to post-treatment. AEs after 
trial completion date will be assigned to post-study.  
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding to the current version of MedDRA.
Blood pressure and pulse rate measured in conjunction with PFT testing will be presented for 
each treatment using descriptive statistics.
7.3.4
Pharmacokinetic analyses
No pharmacokinetic analysis is planned for this trial.
7.4
INTERIM ANALYSES
No interim analysis is planned for this trial.


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7.5
HANDLING OF MISSING DATA
Every effort should be made to collect complete data on each test day, except if the patient 
has used rescue medication. Missing data at a given visit will be imputed by the available 
data based on BI standard approaches. Completely missing visits will be handled through the 
statistical model described in Section 7.3.1. 
Additional details on the imputation of missing data will be specified in the Trial Statistical 
Analysis Plan (TSAP) prior to unblinding.
7.6
RANDOMISATION
This is a cross-over trial with two treatment groups and two groups. Patients who meet the 
inclusion criteria and do not violate any exclusion criteria will be randomised in equal ratio to 
one of the two treatment sequences. Randomisation will not be stratified. BI will arrange for 
the randomisation, the packaging and labelling of study medication. Patients, investigators 
and everyone involved in analysing or with an interest in this double-blind study will remain 
blinded with regard to the randomised treatment assignments until database lock.
The randomisation list will be generated using a validated system, which involves a pseudo 
random number generator so that the resulting treatment will be both reproducible and non-
predictable.  Access to the codes will be controlled and documented. Practical aspects of the 
treatment allocation process and methods to carry out blinding are detailed in Sections 4.1.2
and 4.1.5.
7.7
DETERMINATION OF SAMPLE SIZE
For the primary endpoint of IC at rest after Week 6, results from the recent two BI studies (BI 
no.:1237.13[c02094185] and 1237.14[c02094318]) suggest that the standard deviation is 
approximately 0.4[L]. However, a little conservative 0.41[L] is deemed more appropriate due 
to uncertain prediction of drop-outs during tests for physical activities. In addition the IC at 
rest after Week 6 is estimated at 0.1 L for the difference between tiotropium + Olodaterol
(LAMA/LABA FDC) and tiotropium (LAMA).  To detect a difference of 0.1 L with the 
standard deviation of 0.41 L in the IC at rest between the two treatments with 90% power at 
the 2-sided alpha of 0.05, 180 patients will be required. Nquery Advisor nTerim ver.2.0
(MOT0-1, 1-sample t-test) was used for the sample size calculation.
Table 7.7: 1 Summary of sample size considerations
primary endpoint
⊿[L]
SD [L]
N (power)
IC at rest[L] 
0.1
0.41
180 (90%)
0.40
171 (90%)


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and the 
Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 
1997). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 
in the responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the study subjects against any immediate hazard, and also of any serious breaches of 
the protocol/ICH GCP and the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997).
The rights of the investigator / the trial site and of the sponsor with regard to publication of 
the results of this trial are described in the investigator contract/the trial site’s contract. As a 
general rule, no trial results should be published prior to finalisation of the Clinical Trial 
Report.
The certificate of the insurance cover is made available to the investigator and the patients, 
and is stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) and competent authority (CA) 
according to national and international regulations. The same applies for the implementation 
of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’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 patient or the 
patient’s legally accepted representative.”
The Investigator must give a full explanation to trial patients by using the patient information 
form, which is prepared avoiding the use of technical terms and expressions. The patient is 
given sufficient time to consider participation in the trial. The investigator obtains written 
consent of the patient’s own free will with the informed consent form after confirming that 
the patient understands the contents. The investigator must sign and date the informed 


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consent form. If a trial collaborator has given a supplementary explanation, the trial 
collaborator also signs and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, the 
sponsor’s designees, IRBs 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
eCRF for individual patients will be provided by the Sponsor via remote data capture. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For eCRF, all data must be derived from source documents. 
Additionally, the following source documents must be collected and filed at the investigator’s 
trial site:
•
ECG results (original or copies of printouts)
•
Physical examinations (original documentation)
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB review and 
regulatory inspection, providing direct access to all related source data / documents. eCRFs
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the Sponsor’s clinical trial monitor, 
auditor and inspection by health authorities (e.g. FDA). The CRA / on site monitor and 


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auditor may review all eCRFs, and written informed consents. The accuracy of the data will 
be verified by reviewing the documents described in Section 8.3.1.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source documents and essential documents for a period defined 
by the Japanese GCP regulation and trial site’s contract with the sponsor.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For the tiotropium inhalation solution, this is the current version of the IB (c01860006). For 
the tiotropium + olodaterol FDC inhalation solution, this is the current version of the IB
(c01735808). For salbutamol, the reference document is the SmPC. The current versions of 
these reference documents are provided in the ISF. No AEs are classified as listed for 
matching placebo, study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IRB, will be done according to local regulatory 
requirements. Further details regarding this reporting procedure are provided in the ISF.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB and the regulatory authorities.


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8.6
END OF TRIAL
The end of the trial is defined as last patient out.
When the trial is completed, the Investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
Sponsor of the completion in writing.
8.7
PROTOCOL VIOLATIONS
The investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the Sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R94-1408
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. 
Lung volumes and forced ventilatory flows. Report Working Party 
Standardization of Lung Function Tests, European Community for Steel 
and Coal. Official Statement of the European Respiratory Society. Eur
Respir J 1993;6(Suppl 16):5-40
R98-0973
Roca J, Whipp BJ, Agusti AGN, Anderson SD, Casaburi R, Cotes JE, et al.
Clinical exercise testing with reference to lung diseases: indications,
standardization and interpretation strategies. Eur Respir J 1997. 10: 2662-
2689.
R94-1529
Chow SC, Liu JP, editors. Design and Analysis of Bioavailability and 
Bioequivalence Studies.  New York: Marcel Dekker Inc 1992
R02-0127
Zigmond AS, Snaith RP. The Hospital Anxiety and Depression scale. Acta 
Psychiatr Scand 67, 361 - 370 (1983)
R02-2232
Redelmeier DA, Guyatt GH, Goldstein RS, Assessing the minimal 
important difference in symptoms: a comparison of two techniques. J Clin 
Epidemiol 49 (11), 1215 - 1219 (1996)
R03-0725
Crapo RO, Enright PL, Zeballos RJ; ATSstatement: guidelines for the six-
minute walk test. This official statement of the American Thoracic Society 
was approved by the ATS Board of Directors March 2002. Am J Respir 
Crit Care Med 166, 111 - 117 (2002)
R05-0370
ICH harmonised tripartite guideline: maintenance of the ICH guideline on 
non-clinical safety studies for the conduct of human clinical trials for 
pharmaceuticals M3(M) (recommended for adoption at step 4 of the ICH 
process on 16 July 1997 and amended on 9 November 2000 by the ICH 
Steering Committee). Int Conf on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
R10-4391
Kenward, M.G. The use of baseline covariates in crossover studies. 
Biostatistics 11(1),1-17 (2010)
R10-5669
ICH Expert Working Group; ICH harmonised tripartite guideline: guidance 
on nonclinical safety studies for the conduct of human clinical trials and 
marketing authorization for pharmaceuticals, M3 (R2) (current step 4 
version, dated 11 June 2009). 
webpage:ich.org/LOB/media/MEDIA5544.pdf (access date:11.10.2010) 
(2009)
 
 


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R13-2807
Puhan MA, Mador MJ, Held U, Goldstein R, Guyatt GH, Schunemann HJ. 
Interpretation of treatment changes in 6-minute walk distance in patients 
with COPD. Eur Respir J 32 (3), 637 - 643 (2008) 
R13-4735
Jenkins S, Cecins N, Camarri B, Williams C, Thompson P, Eastwood P. 
Regression equations to predict 6-minute walk distance in middle-aged and 
elderly adults. Physiother Theor Pract 25 (7), 516 - 522 (2009)
R14-0975
Hareendran A, Leidy NK, Monz BU, Winnette R, Becker K, Mahler DA, 
Proposing a standardized method for evaluating patient report of the 
intensity of dyspnea during exercise testing in COPD. Int J Chronic 
Obstruct Pulm Dis 7, 345 - 355 (2012)
P03-01262
ATS/ACCP Statement on Cardiopulmonary Exercise Testing. Am J Respir 
Crit Care Med. 2003. 167(2): 211-277.
P05-12646
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al.
Interpretative strategies for lung function tests. Eur Respir J 26 (5), 948 -
968 (2005)
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al.
Wanger JStandardisation of spirometry. Eur Respir J 26 (2), 319 - 338 
(2005)
P08-12524
Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al.
UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic 
obstructive pulmonary disease. N Engl J Med 359 (15), 1543 - 1554 (2008)
P09-11278
Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP, UPLIFT 
Investigators. Effect of tiotropium on outcomes in patients with moderate 
chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup 
analysis of a randomised controlled trial. Lancet, (2009)
P10-02376
Troosters T, Celli B, Lystig T, Kesten S, Mehra S, Tashkin DP, et al.
UPLIFT Investigators. Tiotropium as a first maintenance drug in COPD: 
secondary analysis of the UPLIFT trial. Eur Respir J 36 (1), 65 - 73 (2010)
P10-07776
Bouyssou T, Casarosa P, Naline E, Pestel S, Konetzki I, Devillier P, et al.
Pharmacological characterization of olodaterol, a novel inhaled beta2-
adrenoceptor agonist exerting a 24-hour-long duration of action in 
preclinical models. J Pharmacol Exp Ther 334 (1), 53 - 62 (2010)
P10-08261
Bateman ED, Tashkin D, Siafakas N, Dahl R, Towse L, Massey D, et al. A 
one-year trial of tiotropium Respimat plus usual therapy in COPD patients. 
Respir Med 104, 1460 - 1472 (2010)
P11-03885
Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Moelken 
MPMH, Beeh KM, et al. POET-COPD Investigators. Tiotropium versus 
salmeterol for the prevention of exacerbations of COPD. N Engl J Med 364 
(12), 1093 - 1103 (2011)
P11-05865
Global Initiative for Chronic Obstructive Lung Disease (GOLD) Global 
strategy for the diagnosis, management, and prevention of chronic 
obstructive pulmonary disease: updated 2010. Website:goldcopd.com/ 
(access date: 12 May 2011) (2010)
P11-07562
Yohannes AM, Willgoss TG, Vestbo J. Tiotropium for treatment of stable
COPD: a meta-analysis of clinically relevant outcomes. Respir Care 56 (4),
477 - 487 (2011)


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P11-07720
Casarosa P, Kollak I, Kiechle T, Ostermann A, Schnapp A, Kiesling R, et al. 
Functional and biochemical rationales for the 24- hour-long duration of 
action of olodaterol. J Pharmacol Exp Ther 337 (3), 600- 609 (2011)
P11-08788
Antoniu SA Effects of inhaled therapies on health-related quality of life in 
stable chronic obstructive pulmonary disease. Expert Rev 
Pharmacoeconomics Outcomes Res 10 (2), 155 - 162 (2010)
P13-02399
Global Initiative for Chronic Obstructive Lung Disease (GOLD); Global 
strategy for the diagnosis, management, and prevention of chronic 
obstructive pulmonary disease (updated 2013)
weblink: .goldcopd.org/uploads/users/files/GOLD_Report_2013Feb13.pdf 
(access date: 20 February 2013)
P13-04267
Cooper CB, Celli BR, Jardim JR, Wise RA, Legg D, Guo J, et al. Treadmill 
endurance during 2-year treatment with tiotropium in patients with COPD: 
a randomized trial. Chest 144 (2), 490 - 497 (2013)
P13-11053
Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, et al. TIOSPIR 
Investigators. Tiotropium Respimat inhaler and the risk of death in COPD. 
N Engl J Med 369 (16), 1491 - 1501 (2013)
P13-11341
Koch A, Paggiaro P, Hamilton A, Hart L, Korducki L, Salvo MC de, et al. 
Symptomatic benefit of olodaterol QD delivered via Respimat vs placebo 
and formoterol BID in patients with COPD: combined analysis from two 
48-week studies. 23rd Ann Cong of the European Respiratory Society 
(ERS), Barcelona, 7 - 11 Sep 2013
P13-11345
Koch A, Pizzichini E, Hamilton A, Hart L, Korducki L, Salvo MC de, 
Paggiaro P. Lung function efficacy of olodaterol QD delivered via 
Respimat vs placebo and formoterol BID in patients with COPD: two 48-
week studies. 23rd Ann Cong of the European Respiratory Society (ERS), 
Barcelona, 7 – 11 Sep 2013
P13-11346
Ferguson G, Feldman G, Hofbauer P, Hamilton A, Allen L, Korducki L, et 
al. Lung function efficacy of olodaterol QD delivered via Respimat in 
COPD patients: results from two 48-week studies. 23rd Ann Cong of the 
European Respiratory Society (ERS), Barcelona, 7 - 11 Sep 2013
P13-11467
Lange P, Aumann JL, Derom E, Hamilton A, Tetzlaff K, Ting N, et al. The 
24-h FEV1 time profile of olodaterol QD delivered via Respimat in COPD: 
results from two 6-week studies. 23rd Ann Cong of the European 
Respiratory Society (ERS), Barcelona, 7 - 11 Sep 2013
P13-14109
Maltais F, Kirsten AM, Hamilton A, Sousa D de, Wang F, Decramer M.
Evaluation of the effects of olodaterol on exercise endurance in patients 
with COPD: results from two 6-week studies. Chest 2013, 79th Ann Mtg of 
the American College of Chest Physicians, Chicago, 26 - 31 Oct 2013. 
Chest 144 (4) (Suppl), 748A, Abstr (2013)
P13-14112
Feldman G, Bernstein JA, Hamilton A, Nivens C, LaForce C, The 24-hour 
FEV1 time profile of olodaterol once daily (QD) via Respimat and 
formoterol twice daily (BID) via Aerolizer in patients with COPD: results 
from two 6-week studies. Chest 2013, 79th Ann Mtg of the American 
College of Chest Physicians, Chicago, 26 - 31 Oct 2013, Chest 144 (4) 
(Suppl), 749A, Abstr (2013)


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P14-01052
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
strategy for the diagnosis, management, and prevention of chronic 
obstructive pulmonary disease (updated 2014). Website: 
goldcopd.org/uploads/users/files/GOLD_Report_2014.pdf (access date: 22 
January 2014) ; Global Initiative for Chronic Obstructive Lung Disease 
(GOLD) (2014)
9.2
UNPUBLISHED REFERENCES
c02094185
 A randomised, double-blind, 5 treatment
arms, 4-period, incomplete cross-over study to determine the effect of 6 
weeks treatment of orally inhaled tiotropium + olodaterol fixed dose 
combination (FDC) (2.5 /5 μg and 5 / 5 μg) (delivered by the Respimat® 
Inhaler) compared withtiotropium (5 μg), olodaterol (5 μg ), and placebo 
(delivered by the Respimat® Inhaler) on lung hyperinflation and exercise 
endurance time during constant work rate cycle ergometry in patients with 
Chronic Obstructive Pulmonary Disease (COPD) [MORACTO™ 1] 
(1237.13) 08 April 2014.
c02094318
. A randomised, double-blind, 5 treatment
arms, 4-period, incomplete cross-over study to determine the effect of 6 
weeks treatment of orally inhaled tiotropium + olodaterol fixed dose 
combination (FDC) (2.5 /5 μg and 5 / 5 μg) (delivered by the Respimat® 
Inhaler) compared with tiotropium (5 μg), olodaterol (5 μg ), and placebo 
(delivered by the Respimat® Inhaler) on lung hyperinflation and exercise 
endurance time during constant work rate cycle ergometry in patients with 
Chronic Obstructive Pulmonary Disease (COPD) [MORACTO™ 2] 
(1237.14) 07 April 2014.
c01860006
. Investigator's Brochure: Tiotropium 
Bromide, Ba 679 BR. Version 21, 07 October 2014
c01735808
. Investigator’s brochure- BI 1744 and tiotropium - 1237.P1 -
Version 7, 12 Sept 2014


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10.
APPENDICES
10.1
THE RESPIMAT INHALER  
Instructions for Use
RESPIMAT inhaler
How to use your RESPIMAT inhaler
This leaflet explains how to use and care for your RESPIMAT inhaler. Please read and carefully 
follow these instructions.
The RESPIMAT inhaler releases medication slowly and gently, making it easy to inhale it into your 
lungs.
The RESPIMAT inhaler enables you to inhale the medicine contained in a cartridge. You will need to 
use this inhaler only ONCE A DAY. Each time you use it take 2 PUFFS. In the box you will find 
the RESPIMAT inhaler and the RESPIMAT cartridge. Before the RESPIMAT inhaler is used for the 
first time, the cartridge provided must be inserted.
RESPIMAT inhaler and the RESPIMAT cartridge


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Inserting the cartridge and preparation for use 
The following steps 1-6 are necessary before first use:
1
1
With the grey cap closed, press the safety catch (E) and pull off 
the clear base (G).
2a
2
Take the cartridge (H) out of the box.  Push the narrow end of 
the cartridge into the inhaler until it clicks into place (2a). The 
cartridge should be pushed gently against a firm surface to 
ensure that it has gone all the way in (2b).
Do not remove the cartridge once it has been inserted into the 
inhaler.
2b
  3
3
Replace the clear base (G). 
Do not remove the clear base again.
Safety catch


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To prepare the RESPIMAT inhaler for first-time use
4
4
Hold RESPIMAT  inhaler upright, with the grey cap (A) closed. 
Turn the clear base (G) in the direction of the red arrows on the 
label until it clicks (half a turn).
5
5
Open the grey cap (A) until it snaps fully open.
6
6
Point the RESPIMAT inhaler towards the ground. 
Press the dose release button (D).  Close the grey cap (A).
Repeat steps 4, 5 and 6 until a cloud is visible. 
Then repeat steps 4, 5 and 6 three more times to ensure the 
inhaler is prepared for use. 
Your RESPIMAT inhaler is now ready to use.  
These steps will not affect the number of doses available. After 
preparation your RESPIMAT inhaler will be able to deliver 
60 puffs.


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Using the RESPIMAT inhaler
You will need to use this inhaler only ONCE A DAY. 
Each time you use it take 2 PUFFS.
I
I
Hold RESPIMAT inhaler upright, with the grey cap (A) closed, 
to avoid accidental release of dose. Turn the clear base (G) in 
the direction of the red arrows on the label until it clicks (half a 
turn).
II
II
Open the grey cap (A) until it snaps fully open. Breathe out 
slowly and fully, and then close your lips around the end of the 
mouthpiece without covering the air vents (C). Point your 
RESPIMAT inhaler to the back of your throat.  
While taking in a slow, deep breath through your mouth, press 
the dose release button (D) and continue to breathe in slowly 
for as long as you can. Hold your breath for 10 seconds or for 
as long as comfortable.
III
Repeat steps I and II so that you get the full dose.
You will need to use this inhaler only ONCE A DAY.
Close the grey cap until you use your RESPIMAT inhaler 
again.
If the RESPIMAT inhaler has not been used for more than 3 days 
release one puff towards the ground. If the RESPIMAT inhaler has not 
been used for more than 21 days repeat steps 4 to 6 until a cloud is 
visible. Then repeat steps 4 to 6 three more times.
When to get a new RESPIMAT inhaler
The RESPIMAT inhaler contains 60  puffs (30 doses). The dose 
indicator shows approximately how many doses are left.  When the 
pointer enters the red area of the scale, there is, approximately, 
medication for 14 puffs (7 days) left.  
Once the dose indicator has reached the end of the red scale (i.e. all 30 
doses have been used), the RESPIMAT inhaler is empty and locks 
automatically. At this point, the base cannot be turned any further. 


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What if...
What if...
I can’t turn the base easily.
I can’t press the dose release 
button.
The clear base springs back 
after I have turned it.
I can turn the clear base past the 
point where it clicks.
How to care for your inhaler
Clean the mouthpiece including t
at least once a week.
Any minor discoloration in the m
inhaler.
  
If necessary, wipe the outside of 
Further information
The RESPIMAT inhaler must no
base.
Do not touch the piercing elemen
Keep out of the reach and sight o
Do not freeze.
Boehringer Ingelheim Pharma G
D - 55216 Ingelheim, Germany
  0123 HI-Master-Version-
Trial Protocol
2015 Boehringer Ingelheim International GmbH or one or more of 
001-MCS-40-106-RD-0
Reason
What to do
a) The RESPIMAT inhaler is 
already prepared and ready 
to use. 
b) The RESPIMAT inhaler is 
locked after 60 puffs (30 
doses).
a) The RE
be used 
b) Prepare 
RESPIM
The clear base has not been 
turned.
Turn the cle
clicks. (half
The clear base was not turned 
far enough.
Prepare the 
for use by tu
until it click
Either the dose release button 
has been pressed, or the clear 
base has been turned too far.
With the gr
the base unt
turn) 
r
the metal part inside the mouthpiece with a damp
mouthpiece does not affect the performance of you
f your RESPIMAT inhaler with a damp cloth.
ot be disassembled after inserting the cartridge an
nt inside the base.
of children.
GmbH & Co. KG
-04-BI 1744+tiotropium combination-Respimat
30 OCT 2015
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f its affiliated companies
03 (12.0) / Saved on: 30 Jan 2015
o
SPIMAT inhaler can 
as it is.
and use your new  
MAT inhaler.
ear base until it 
f a turn)
RESPIMAT inhaler 
urning the clear base 
ks. (half a turn)
rey cap closed, turn 
til it clicks. (half a 
p cloth or tissue only, 
ur RESPIMAT
nd replacing the clear 
t-20090831


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10.2
RETURN OF INHALERS/CARTRIDGES 
Return of Malfunctioning RESPIMAT Inhalers
RESPIMAT inhalers, with the used cartridge in situ, that appeared to malfunction, will be 
returned to BI as soon as possible. Details of the procedures for the return of malfunctioning 
inhalers are provided in the ISF.


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10.5
ADDITIONAL INFORMATION REGARDING IN/EXCLUSION 
CRITERIA 
Reversibility testing [P05-12782]
At the screening visit (Visit 1), following the completion of three acceptable pre-
bronchodilator forced expiratory manoeuvres, salbutamol will be administered to each patient 
in order to document the degree of reversibility. Immediately after (within 10 min) pre-
bronchodilator forced expiratory manoeuvres and after a gentle and incomplete expiration, a 
dose of 100 μg of salbutamol is inhaled in one breath to total lung capacity (TLC). The breath 
is then held for 5–10s before the subject exhales. Four separate doses (total dose 400 μg) are 
delivered at approximately 30-s intervals (this dose ensures that the response is high on the 
salbutamol dose–response curve). Three additional, acceptable post-bronchodilator forced 
expiratory manoeuvre tests are recorded ≥10 min and up to 15 min later after the last dose of 
salbutamol is inhaled.
Calculation of predicted normal values according to ECSC [R94-1408]
For height measured in inches
Males:
FEV1 predicted (L) = 4.30 x [height (inches)/39.37] - 0.029 x [age (yrs)] - 2.49
Females: FEV1 predicted (L) = 3.95 x [height (inches)/39.37] - 0.025 x [age (yrs)] - 2.60
For height measured in meters
Males:
FEV1 predicted (L) = 4.30 x [height (m)] - 0.029 x [age (yrs)] - 2.49
Females: FEV1 predicted (L) = 3.95 x [height (m)] - 0.025 x [age (yrs)] - 2.60
Ethnic adjustments may be made as appropriate as per ATS/ERS recommendations (P05-
12646, R94-1408).
Calculation of number of pack years
Pack years =
Number of cigarettes/day
X      years of smoking
20


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10.6
SIX-MINUITE WALK DISTANCE
-
Testing should be performed at Visits 1 (for training), Visit 2, Visit 3 and Visit 4/EOT
in a location where a rapid, appropriate response in the event of an emergency is 
possible. The appropriate location of a crash cart should be determined by the physician 
supervising the facility.
-
Supplies that must be available include oxygen, sublingual nitroglyercine, aspirin, and
salbutamol in metered dose inhaler or nebulizer. A telephone or other means should be 
in place to enable a call for help.
-
Physicians are required to be present for the first test and for subsequent tests as needed. 
-
During the 6MWT patients will be monitored for both HR and SpO2 using mobile pulse 
oximeter.
-
If SpO2 decreases to below 83% at any time after the patients begins walking:
• The walk should be terminated. Supplemental oxygen should be administered.
• The patient should then be seated and allowed to rest for 5 minutes. If the resting SpO2
after 5 minutes is not ≥83% then the O2 flow rate should be increased another 2 L/min 
and the resting SpO2 reassessed after 5 minutes. This should be repeated until the 
resting SpO2 is ≥83 % for 5 minutes.
Mandatory stopping rules for the 6MWT include the following (ATS guideline):
• Chest pain
• Intolerable dyspnea
• Leg cramps
• Staggering
• Diaphoresis
• Pale or ashen appearance.
-
The distance walked will be measured in meters (m) and will be recorded. If the test is 
stopped prematurely, the distance (m), the duration (min), and the reason for stopping
will be recorded.
-
Patients will be asked to rate the intensity of breathing discomfort and leg discomfort 
using the modified Borg Scale (see Section 10.7) prior to exercise (i.e., before the start 
of walking), every one minutes during exercise and at end-exercise.


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10.8
MODIFIED MEDICAL RESEARCH COUNCIL (MMRC)
Grade
Description of Breathlessness
0
I only get breathless with strenuous exercise.
1
I get short of breath when hurrying on level ground or walking up a slight hill.
2
On level ground, I walk slower than people of the same age because of 
breathlessness, or have to stop for breath when walking at my own pace.
3
I stop for breath after walking about 100 yards or after a few minutes on level 
ground.
4
I am too breathless to leave the house or I am breathless when dressing.


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10.10
INSPIRATORY CAPACITY
In this trial inspiratory capacity measurements will be done at rest in combination with dosing 
of trial medication. A baseline measurement will be completed at Visit 2 prior to the exercise 
tests. IC measurements will also be performed 1.0 hours post morning dose on Visits 3 and 4
after measurement of FEV1 and FVC. To supplement the information on IC manoeuvres in 
this chapter, a manual of procedures has been developed. More detailed information on IC 
measurements, calculations and post-test corrections etc. can be found in this manual which 
is filled in the ISF.
Resting IC 
At each required visit, IC maneuvers will first be fully explained to the patient and then 
practiced at rest to confirm proper technique. Patients will be given a few breaths warning 
before an IC maneuver, a prompt for the maneuver (i.e., “At the end of the next normal 
breath out, take a deep breath all the way IN”), and then strong verbal encouragement to 
make a maximal effort before relaxing.
The patient will breathe through a mouthpiece attached to the spirometer. The patient should 
breathe quietly for a few breaths to achieve stable end expiratory lung volume (EELV) and 
then perform the inspiratory maneuver from EELV to TLC. The patient can be taken off the 
mouthpiece between maneuvers. The patient should return to stable EELV prior to 
preforming the next maneuver. At least three reproducible IC measurements should be 
obtained (i.e., IC s.d. /IC mean values is 0.06 or less than 0.06) with a maximum of 5 
measurements to be performed. The resting IC should be recorded as the mean of the two 
highest acceptable efforts.
Analysis / acceptability of IC maneuvers 
If the effort appears sub-maximal or if anticipatory changes in breathing pattern occur 
immediately preceding a maneuver, then the IC should not be accepted unless it can be 
corrected post-test.


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10.11
PATIENT GLOBAL PHYSICAL ACTIVITY RATING AND GLOBAL 
IMPRESSION OF CHANGE
-
Patient Global Rating of physical activity experience (Visit 2; baseline)
-
Instruction: This question should be used immediately before the patient completes 
other visit specific questionnaires. The investigator is to read out the question and 
response options to the patient. The patient’s response should be noted in the eCRF.
-
Overall, how would you describe your experience of physical activity in the last 
week? 
-
By physical activity we mean all activities that require movement of your body. 
Examples are household activities, walking, going out and about. (please select one 
answer)
Not limited at all
Slightly  limited
Quite limited
Severely limited
Patient Global rating of change (Visit 3 and 4/EOT)
-
Instruction: This question should be used immediately before the patient completes 
other visit specific questionnaires. The investigator is to read out the question and 
response options to the patient. The patient’s response should be noted in the e-CRF.
-
Rating of change; overall concept
-
The comparison to the time at which the patient answered the global rating of severity 
question (study start/ randomisation) should be emphasised and the patient asked to 
think about the last week. 
-
Compared to the start of the study –mention day and month-, how would you describe 
your overall experience of physical activity in the past week?  (please select one 
answer)
Much worse
Worse
Slightly worse
No change
Slightly better
Better
Much better


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BI Trial No.: 1237.33
c03397161-01
Trial Protocol
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-
Rating of change; amount domain
-
The comparison to the time at which the patient answered the global rating of severity 
question (study start/ randomisation) should be emphasised and the patient asked to 
think about the last week. 
-
Compared to the start of the study –mention day and month-, how physically active 
have you been in the last week? (amount)  (please select one answer)
Much less active
Less active
A little less active
No change
A little more active
More active
Much more active
-
Rating of change; difficulty domain
-
The comparison to the time at which the patient answered the global rating of severity 
question (study start/ randomisation) should be emphasised and the patient asked to 
think about the last week. 
-
Compared to the start of the study, how difficult have you found it  to conduct physical 
activity in the last week: (difficulty)  (please select one answer)
Much more difficult
More difficult
A little more difficult
No change
A little easier
Easier
Much easier


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
“This is the original protocol.”
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03397161
1.0
clinical-trial-protocol
A randomised, double-blinded, active-controlled 2-way cross over trial to assess the
effects of 6 weeks treatment of once daily orally inhaled tiotropium + olodaterol
fixed dose combination delivered by RESPIMAT Inhaler compared with tiotropium
delivered by RESPIMAT Inhaler on lung hyperinflation, exercise capacity and
physical activity in Japanese patients with Chronic Obstructive Pulmonary...
Author-Trial Clinical Monitor
02 Nov 2015 01:37 CET
Author-Trial Statistician
02 Nov 2015 08:40 CET
Approval-Therapeutic Area 
02 Nov 2015 10:46 CET
Approval-Team Member Medical
Affairs
03 Nov 2015 11:10 CET
Verification-Paper Signature
Completion
04 Nov 2015 00:21 CET


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Document Number: 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03397161
1.0

SAP_000.pdf: 
Reference Document “Template Trial Statistical Analysis Plan – template”
001-MCG-160_RD-06 (7.0) / Saved on: 08 Jun 2015
TITLE PAGE
Trial Statistical Analysis Plan
c08927535-01
BI Trial No.:
1237.33
Title:
A randomised, double-blinded, active-controlled 2-way cross over 
trial to assess the effects of 6 weeks treatment of once daily orally 
inhaled tiotropium + olodaterol fixed dose combination delivered 
by RESPIMAT Inhaler compared with tiotropium delivered by 
RESPIMAT Inhaler on lung hyperinflation, exercise capacity and 
physical activity in Japanese patients with Chronic Obstructive 
Pulmonary Disease (COPD)
Investigational
Product(s):
Japanese Physical Activity Study [VESUTOTM]
Responsible trial 
statistician(s):
.
Address:
 
Phone: 
 Fax: 
Date of statistical 
analysis plan:
10 APR 2017
Version:
Final
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2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................6
......................7
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINT .......................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoint .......................................................................................8
5.2.2
Secondary endpoints.............................................................................................8
.....................................................................................8
5.4
OTHER VARIABLES..........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
PATIENT SETS ANALYSED...........................................................................15
6.4
SUBGROUPS ......................................................................................................16
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................18
7.
PLANNED ANALYSIS......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........20
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINT .....................................................................................20
7.5
SECONDARY ENDPOINTS.............................................................................21
7.5.1
Key secondary endpoint .....................................................................................21
7.5.2
Secondary endpoints...........................................................................................21
7.5.2.2
Average number of step per day (step/day) in the 2 weeks prior to Week 6........21
7.5.2.3
Average daily duration (minute) of ≥4 metabolic equivalents (METs) in the 2 
weeks prior to Week 6 ..........................................................................................21
7.5.2.4
Average daily duration (minute) of ≥3 METs in the 2 weeks prior to Week 6 ....21
7.5.2.6
Average daily active strength (METs·minute) of ≥3 METs in the 2 weeks prior 
to Week 6 ..............................................................................................................21
...................................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse events.....................................................................................................22
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................23


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7.8.4
ECG......................................................................................................................23
7.8.5
Others...................................................................................................................23
8.
REFERENCES....................................................................................................24
9.
ADDITIONAL SECTIONS ...............................................................................25
10.
HISTORY TABLE..............................................................................................26


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LIST OF TABLES
Table 6.2: 1
Important protocol violations ...........................................................................13
Table 6.2: 1 (cont’d)
Important protocol violations ..............................................................14
Table 6.2: 1 (cont’d)
Important protocol violations ..............................................................15
Table 6.3: 1
Patient sets analysed .........................................................................................16
Table 6.7: 1
Planned and actual study days, and time windows...........................................19
Table 10: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
BRPM
Blinded report planning meeting
CRF
Case Report Form
COPD
Chronic Obstructive Pulmonary Disease
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
ECG
Electrocardiogram
FAS
Full analysis set
IC
Inspiratory capacity
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
METs
Metabolic equivalents
MQRM
Medical Quality Review Meeting
PPS
Per protocol set
PT
Preferred term
PV
Protocol violation
RS
Randomised set 
SAE
serious adverse event
6MWD
Six-minute walk distance
6MWT
Six-minute walk test
SD
Standard deviation
SOC
System organ class
TS
Treated set
TSAP
Trial statistical analysis plan


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3.
INTRODUCTION
As per International Council for Harmonisation (ICH) E9, the purpose of this document is to 
provide a more technical and detailed elaboration of the principal features of the analysis 
described in the protocol, 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 Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint of efficacy will be used as described in the CTP, Section 5.1.1 “Primary 
endpoint”
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
This section is not applicable since there are no key secondary endpoints specified in the CTP.
5.2.2
Secondary endpoints
Secondary endpoints of efficacy will be used as described in the CTP, Section 5.1.2 
“Secondary endpoints”


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5.4
OTHER VARIABLES
Treatment compliance

Percent compliance

Percent missing compliance
Treatment compliance will be based on data from the patient diary. The patients will report 
whether they took study medication for each day during the treatment period. For each 
patient, percent compliance will be calculated as the number of times they reported taking 
study medication divided by the number of times a non-missing response was given 
(excluding clinic visit days for both numerator and denominator) times 100. The percent of 
missing compliance data will also be calculated as the number of occasions of missing 
compliance data divided by the expected number of non-clinic occasions times 100. In case 
there are multiple records with the same diary date, the responses will be compared within 
that date. If all of the responses are identical (yes, no, or missing) to a common value, then 
that common value will be used. If not all of the responses are identical, then the response will 
be set to missing. Two examples are given in Table 5.4: 1.
Table 5.4: 1
Examples for duplicate compliance data
Date
Study drug 
Taken
Case 1
Original data
25Sep2014
Yes
25Sep2014
Yes
Collapsed data
25Sep2014
Yes
Case 2
Original data
15Jan2015
No
15Jan2015
Yes
Collapsed data
15Jan2015
.
Due to the nature of how compliance data is collected, the value for percent treatment 
compliance can never be more than 100%. This is because yes/no responses for taking study 
medication are collected rather than the number of doses taken. The ranges on the compliance 
table will be <80% and 80% - 100%.
Safety

pulse rate and blood pressure in conjunction with Pulmonary function testing


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
pulse rate and SpO2 in conjunction with 6MWT

For vital signs in conjunction with spirometry, frequency tables will be presented with the 
number and percentage of patients with marked changes in vital signs (decrease, increase) 
at any time and for each time point separately by treatment. Marked changes are defined 
in Table 5.4: 2.
Table 5.4: 2
Definition of marked changes in vital signs in conjunction with spirometry
Variable
Criteria
Systolic blood 
pressure increase
value > 150 mmHg and an increase >= 25 mmHg 
above baseline
Systolic blood 
pressure decrease
value < 100 mmHg and a decrease >10 mmHg 
below baseline
Diastolic blood 
pressure increase
value > 90 mmHg and an increase > 10 mmHg 
above baseline
Diastolic blood 
pressure decrease
value < 60 mmHg and a decrease > 10 mmHg below 
baseline
Pulse rate increase
> 100 bpm and an increase > 10 bpm above baseline
Pulse rate decrease
< 60 bpm and a decrease > 10 bpm below baseline

all adverse events (AEs), including any clinically relevant changes/abnormalities in 
physical examination, vital signs, laboratory values, and electrocardiogram (ECG)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
The doses to be administered are described in Section 4 of the CTP. 
This is a crossover trial consisting of a two-week screening period followed by two six-week 
treatment periods and a three-week post-treatment period.  The day after the follow-up visit 
will be considered the start of the post-study period in case there are any subsequent AE data 
we become aware of.  In this study, there will be no washout between treatment periods. 
For the main safety analysis, data occurring during the treatment periods and within 21 days 
of stop of study drug for that period will be assigned to the respective treatment for that 
period. Data occurring before the first drug intake date is assigned to "screening".  If the next 
treatment period starts within 21 days of the end of the last period, data after the start of 
treatment for the next period will be assigned to the treatment for that period. In this trial, next 
treatment will be started after end of treatment of first period as soon as possible because
there is no washout period as planned. Data more than 21 days after drug stop date for a 
period but before the start of the next period will be assigned to washout. Data more than 21 
days after the end of the last treatment period and up to and including the date of the study 
termination will be assigned to post-treatment. Data after study termination will be assigned 
to post-study.
Any cases of patient being treated with the wrong study medication will be identified and 
summarised as an important protocol violation (PV).

If a patient was treated with a treatment sequence different from the randomised 
treatment sequence throughout the on-treatment period, i.e., a patient was treated with
incorrect study medication during every treatment period, this patient will be included 
in the treated set and will be analysed as treated for both efficacy and safety analyses, 
including patient disposition. Such a case will be reported as an important PV and this 
patient will be excluded from the per-protocol set (PPS).

If a patient was treated with incorrect study medication throughout one treatment 
period only, but not both treatment periods, this patient will be included in the treated 
set and will be analysed as treated for safety analysis. For efficacy analysis, only 
efficacy data collected in the correct treatment period will be used and efficacy data 
collected in the other treatment period with the duplicate study medication will not be 
used. For patient disposition, such a patient will be analysed as randomised. Such a 
case will also be reported as an important PV but this patient will not be excluded 
from the PPS.
If a patient was treated with incorrect study medication during part of a treatment period, data 
of this patient will be discussed case by case at final Blinded report planning meeting
(BRPM).


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6.2
IMPORTANT PROTOCOL VIOLATIONS
A patient’s deviation from the trial protocol is considered “important” if it can be expected 
that the deviation had a distorting influence on the assessment of the treatment effect on the 
primary endpoint of the trial or could affect the patient’s safety/rights.
Table 6.2: 1 lists the important PVs for this trial. Some of the important PVs can be checked 
automatically through the electronic case report form or through programming of relevant 
data in the database; others will need information gained from investigator comments or site 
monitoring reports and will need a decision at a Medical Quality Review Meeting (MQRM) 
or BRPM or through team review of the manual PV log.
In the case that a patient was randomised in both this trial and another trial or was randomised 
at two different sites in this trial, the patient will be indicated as having an important PV (IPV, 
see Table 6.2: 1-Exclusion Criterion 27). The following process will be followed with regards 
to the patient’s data.

All efficacy data will be excluded from the analysis and the patient will be excluded 
from the Full Analysis Set (FAS) (for this trial or both trials as appropriate).

The only safety data which will be reported is exposure and serious adverse events 
(SAEs). These will be analysed according to the treatment which the patient actually 
received. If the patient was randomised twice in this study and both treatments are the 
same, the patient’s data will be combined (i.e. the patient is only counted once). If the 
patient participated in two different trials in the same project, he/she will be reported 
separately for each trial. As well, care will be taken with regard to the SAE narratives 
as to whether data for one patient number is relevant for an SAE under the other 
patient number.

For disposition, demographics, baseline characteristics and important PVs, the patient 
will be analysed as treated. If the patient was randomised twice in this study and the 
treatments are different, the patient will be counted under each treatment. A footnote 
will be included in the disposition table identifying the situation and noting that the 
patient is counted twice for disposition as well as demographics, baseline data and 
important PVs.
The final decision with regards to important PVs and exclusion from the PPS will be made at 
the final BRPM or database lock meeting before unblinding.


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Table 6.2: 1
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded from
Automatic/ 
Manual
A
Entrance criteria not met
A1
Inclusion criteria violated
Inclusion Criteria 
2,3,4,5,6,7,8 not met
Exclude from 
PPS:
2,3,4,5,6,7,8
Criteria 3 ,5 
and 6 are 
Automatic. 
Otherwise 
Manual.
A2
Exclusion criteria 
violated
Exclusion Criteria 2-14,16-
29 not met
Exclude from  
PPS: 
3,9-14,17-
20,23,27,28
Keep in PPS:
2,4-8,15, 16, 21, 
22, 24-26,29
Manual
B
Informed consent
B1
Informed consent not 
available/not done
B1.1
Informed consent to study 
not available/not done
Informed consent date 
missing; no signature on ICF.
All
Manual
B2
Informed consent too late
Date of informed consent 
was after a patient signed the 
correct version of the ICF 
after Visit 0, such cases will 
be discussed at 
MQRM/BRPM/DBL 
meetings.
None
Automatic
ICF = Informed Consent Form
DBL = Database Lock
BRPM = Blinded report planning meeting
MQRM = Medical Quality Review Meeting
PPS = Per protocol set


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Table 6.2: 1 (cont’d)
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded from
Automatic/ 
Manual
C
Trial medication and 
randomisation
C1
Incorrect trial medication 
taken
Not throughout study; could 
be at a clinic visit or between 
clinic visits.
External vendor will check 
before unblinding.
PPS (decision at 
BRPM)
Automatic 
and Manual
C2
Randomisation order not 
followed and incorrect 
trial medication taken
Throughout the study
PPS
Automatic 
and Manual
C3
Non-compliance with 
study medication
C3.2
Serious non-compliance 
with study medication as 
reported in monitoring 
report or manual PV 
spreadsheet
Decision at BRPM/MQRM. 
PPS if at Visit 3 or 4
Manual
C4
Medication code broken 
inappropriately
To be discussed and decided 
during MQRM/BRPM.
Only inappropriate code 
breaks are IPVs (e.g. 
unblinding by Global 
Pharmacovigilance is not).
PPS
Manual
D
Concomitant medication
D1
Improper medication 
washout at baseline visit 
or primary endpoint 
visit(s)
Visit 2, 3 or 4. Refer to Table 
4.2.2.1: 1 in CTP. Decision at 
BRPM
PPS
Manual
D2
Prohibited medication use 
during study
Check CT. Decision at 
BRPM.
PPS if in the week 
prior to Visit 3 or 
Visit 4
Manual
F
Incorrect timing
F3
Primary endpoint 
recorded outside time 
window
F3.6
PFT measurement at 60 
minutes planned time taken 
<30 minutes or > 3 hours 
after dosing
Visit 3 or 4
PPS
Automatic
CT = Concomitant Therapy
BRPM = Blinded report planning meeting
MQRM = Medical Quality Review Meeting
PPS = Per protocol set


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Table 6.2: 1 (cont’d)
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded from
Automatic/ 
Manual
Z
Other
Z1
Serious GCP non-
compliance
Manual PVs reported by 
CML/CRA which are 
considered as important. 
Carefully reviewed, 
described and documented in 
DBL meeting minutes.
PPS
Manual
Z2
Other PV affecting 
efficacy and possibly 
safety
Additional PV identified 
through monitoring which 
impacts the primary analysis 
and possibly patient’s rights 
or safety. Carefully reviewed 
and documented in BRPM 
minutes and comment field 
of IPV ADS.
PPS
Manual
Z3
Other PV affecting safety 
only
Additional PV identified 
through monitoring which 
impacts patient’s rights or 
safety. Carefully reviewed 
and documented in BRPM 
minutes and comment field 
of IPV ADS.
None
Manual
Z4
Missing value of all 
primary and secondary 
endpoints
Patients who had baseline 
measurement and at least one 
post-baseline measurement 
for the primary endpoint or a 
secondary endpoint will be 
included FAS. Patient who 
does not have above 
measurement is IPV.
FAS
Automatic
CML = Local Clinical Monitor
CRA = Clinical Research Associate
Note: Missing visits, evaluations, and tests are considered as missing data, but not protocol deviations.
DBL = Data Base Lock
ADS = Analysis Data Set
6.3
PATIENT SETS ANALYSED
The following nested patient sets are defined:

Randomised set (RS):
This patient set includes all patients who signed informed consent form and were also 
randomised, regardless whether the patient was treated with study medication or not.

Treated set (TS):
This patient set is nested within RS and includes all patients who were dispensed study 
medication and were documented to have taken any dose of study medication. TS will 
be used for patient disposition, demographics and baseline disease characteristics, 
concomitant therapies, treatment compliance, treatment exposure and safety analyses 
(including AEs and vital signs).


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
Full analysis set (FAS):
This patient set is nested within TS and includes patients who had baseline 
measurement and at least one post-baseline measurement for the primary endpoint or a 
secondary endpoint. The FAS will be used for the efficacy analyses. Assignment to 
the FAS will be done after implementation of any data handling rules which set 
measurements to missing.

Per protocol set (PPS):
This patient set is nested within FAS and includes only patients who had no important 
PVs which are specified to be excluded from the PPS (Table 6.3: 1). The PPS will be 
used for sensitivity analysis if PPS less than 90% of FAS.
The final decision regarding which patients are excluded from PPS will be made at 
BRPM prior to data unblinding. 
Table 6.3: 1
Patient sets analysed
Patient Sets
Class of endpoint
TS
FAS
PPS
Primary endpoint
primary 
analysis
supportive 
analysis*
Secondary endpoints 
X
Further endpoints 
X
Safety endpoints
X
Demographic/baseline 
endpoints/exposure
X
* Adding only when the number of patients in PPS is less than 90% of the number of patients in FAS as 
sensitivity analysis.
6.4
SUBGROUPS
No subgroups are defined and no subgroup analyses are planned.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Completely missing visits not due to worsening of study disease will not be imputed and will 
stay as missing, because such missing data are considered as randomly missing data and will 
be handled in the mixed model repeated measures model.


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Completely missing visits/weeks due to the patient discontinuing due to worsening of study 
disease will be imputed with the baseline value.
It could happen that a patient needed therapy for COPD symptoms at a clinic visit. This 
therapy was entered on the rescue medication of electronic Case Report Form (eCRF). This 
may or may not be the rescue medication provided by Boehringer Ingelheim (BI). For 
purposes of the imputation rules this will be termed “rescue medication” regardless of 
whether or not it was BI-supplied rescue medication.
For spirometry data, the records which are flagged as “unacceptable” by the vendor (ERT) 
will be administratively set to missing and treated as randomly missing data for imputation 
purpose.
The following rules are used for exercise data:

 
 

Measurements of oxygen saturation, blood pressure and heart rate which are missing 
during recovery will not be imputed.

 
 
 
 
 
 
The following rules will be used for spirometry data which were collected at Visits 2, 3 and 4:

Since there is only one spirometry measurement at each on-treatment clinic visit, 
rescue medication use on or before the spirometry measurement or rescue use with 
unknown time will both result in all spirometry measurements for the visit being set to 
missing.  In these cases the entire visit will be imputed with baseline.

If spirometry measurements for an entire visit are completely missing because a 
patient discontinued due to worsening of study disease, then all data for this visit will 
be imputed with baseline.

Randomly missing spirometry measurements will not be imputed.


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Missing safety data will not be imputed with the exception of missing or incomplete AE dates 
which will be imputed according to BI guideline 'Handling of missing and incomplete AE 
dates' (1).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Measurements collected at Visit 2 will be used as baseline with the exception of the activity 
endpoints which are averaged over 2 weeks. For endpoints of physical activity monitoring, 
baseline will be the average value in two weeks prior the day before first administration (Visit 
2) except for Day -2 and Day -1. These will be defined as "Study baseline" which will be 
common baseline for both period 1 and period 2.
Planned and actual study day will be included in the analysis data sets. These will both be 
calculated relative to the beginning of the study and to the beginning of respective study 
periods in the crossover design as indicated in the following table.


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Table 6.7: 1
Planned and actual study days, and time windows
Relative to period start
Relative to study start
Visit
Planned 
day
Actual day
Planned 
day
Actual day
2
1
1
1
1
3
43
Visit 3 date – Visit 2 date + 1
43
Visit 3 date – Visit 2 date + 1
4
43
Visit 4 date – Visit 3 date + 1
85
Visit 4 date – Visit 2 date + 1
5
3
Visit 5 date – Visit 4 date + 1
106
Visit 5 date – Visit 2 date + 1


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7.
PLANNED ANALYSIS
For End-Of-Text tables, the set of summary statistics is: N / Mean / Standard deviation (SD) / 
Min / Median / Max.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics for the treated set are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Use of pulmonary medications during treatment period and testing will be summarised in the 
end-of-text tables in the Clinical Trial Report (CTR) and a subject data listing of all 
concomitant medications will be provided in Appendix 16.2.
A table of number (%) of patients with concomitant diagnoses by system organ class (SOC) 
and preferred term (PT) will be included along with a supporting subject data listing. 
Concomitant diagnoses will be coded with the most recent version of the Medical Dictionary 
for Regulatory Activities (MedDRA) in effect at database lock.
Descriptive statistics and frequency tables (%) will be presented for history of trial indication.
Frequency tables (%) will be presented for COPD background characteristics.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. Summary statistics will be 
given for percent compliance along with the number (%) of patients with compliance in the 
categories <80%, 80% - 100% (cf. Section 5.4 for calculation of treatment compliance).
7.4
PRIMARY ENDPOINT
The primary analysis for Inspiratory capacity (IC) will be conducted using mixed effect 
repeated measurement including treatment and period as categorical fixed effects, study 
baseline as a covariate and patient as a random effect treatment. Compound symmetry will be 
used as a covariance structure for within patient variation. The SAS procedure MIXED will 
be used involving the restricted maximum likelihood estimation and the Kenward-Roger 
approximation for denominator degrees of freedom. This approach is described in (2). 
Adjusted mean values as well as treatment contrasts will be presented together with the 95% 
confidence intervals and p-values.


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If the number of patients in PPS is less than 90% of the number of patients in FAS, the 
primary analyses will also be performed on PPS. These will be supportive analyses to assess 
the robustness of the primary analysis using FAS.
Descriptive statistics by treatment will be displayed.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoints
The analysis will be performed as defined in the CTP, Section 7.3.2.
Descriptive statistics by treatment will be displayed.
Additional analysis are described follows.
7.5.2.1
Average number of step per day (step/day) in the 2 weeks prior to Week 6
 
7.5.2.2
Average daily duration (minute) of ≥4 metabolic equivalents (METs) in the 2 weeks 
prior to Week 6
7.5.2.3
Average daily duration (minute) of ≥3 METs in the 2 weeks prior to Week 6
7.5.2.4
Average daily duration (minute) of ≥2 METs in the 2 weeks prior to Week 6
7.5.2.5
Average daily active strength (METs·minute) of ≥3 METs in the 2 weeks prior to
Week 6


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7.7
EXTENT OF EXPOSURE
Extent of exposure is calculated as drug stop date minus drug start date plus one day and 
treatment interruptions are not taken into account in the calculation.
Extent of exposure will be summarised using descriptive statistics for the total treatment 
exposure in days as well as tabulation of number of patients with total exposure fall into the 
following categories:

1 day

2 – 21 days

22 – 42 days

43 – 63 days

64 - 84 days

>=85 days.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature and will be based on BI guideline 'Handling 
and summarisation of AE data for CTRs and integrated summaries' (3). All analyses of AE 
will be based on the number of patients with AEs and NOT on the number of AEs. For this 
purpose, AE data will be combined in a 2-step procedure into AE records.
In the first step, AE occurrences, i.e. AE entries collected in the eCRF, will be collapsed into 
AE episodes provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences

The occurrences are time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence.
In the second step, AE episodes will be condensed into AE records provided that the episodes 
were reported with the same term on the respective MedDRA level and that the episodes are 
assigned to the same treatment. For further details on summarisation of AE data, please refer 


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to BI guideline 'Handling and summarisation of AE data for CTRs and integrated summaries'
(3).
Analyses of AEs are based on the concept of treatment emergent adverse events. This means 
that all AEs occurring between first drug intake and 21 days after last drug intake are assigned 
to the respective analysing treatment. All AEs occurring before first drug intake are assigned 
to ‘screening’ and all AEs occurring after last drug intake + 21 days up to and including trial 
completion date are assigned to ‘post-treatment’. AEs more than 21 days after drug stop date 
for a period but before the start of the next period will be assigned to 'washout'. AEs starting 
after trial completion date are assigned to ‘post-study’. Screening, post-treatment and post-
study AEs are presented in subject data listings only. For details on the treatment definition, 
see Section 6.1.
An overall summary of AEs will be presented.
The frequency of patients with AEs will be summarised by treatment, primary SOC and PT. 
Separate tables will be provided for patients with other significant adverse s according to ICH 
E3 (4), for patients with AEs leading to treatment discontinuation, for patients with AEs 
leading to death, for patients with investigator determined drug-related adverse events, and for 
patients with SAEs.
According to ICH E3 (4), AEs classified as ‘other significant’ include those non-serious and 
non-significant adverse events with
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or that lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator and confirmed at a BRPM.
The system organ classes will be sorted according to the standard sort order specified by the 
European Medicines Agency, PTs will be sorted by frequency (within SOC).
Standard AE analyses requested for public disclosure at CT.gov and European Union Drug 
Regulating Authorities Clinical Trials will also be provided in Section 16.1.9.2 of the CTR.
7.8.2
Laboratory data
Clinically significant findings in laboratory data will be reported as “baseline conditions” or 
“adverse events” and will be analysed accordingly.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Clinically significant findings in ECG data will be reported as “baseline conditions” or 
“adverse events” and will be analysed accordingly.
7.8.5
Others
This section is not applicable.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
R10-4391: Kenward, M.G. The use of baseline covariates in crossover studies. 
Biostatistics 11(1),1-17 (2010)
3
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", version 5; IDEA for CON.
4
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version


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9.
ADDITIONAL SECTIONS
PROGRAMMING CODE FOR INFERENTIAL ANALYSIS

SAS codes for primary analysis:
PROC MIXED data=indata order=internal method=reml cl covtest;
     CLASS trtgrp period usubjid;
     MODEL ept = trtgrp period eptbase / ddfm=kr solution;
     repeated period / type=cs subject=usubjid r rcorr;
     LSMEANS trtgrp / pdiff cl;
RUN;
The endpoint is denoted by ept, eptbase denotes the baseline value of the endpoint, trtgrp
denotes treatment, period denotes the treatment period, and usubjid denotes patient number. 


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
10-APR-2017
 
None
This is the final TSAP without any 
modification.