Conditions: Pulmonary Disease, Chronic Obstructive
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 106
Healthy volunteers: no

Brief summary:
The primary objective of the present study is to evaluate the effect of tiotropium + olodaterol fixed dose combination (FDC) compared to tiotropium monotherapy on the intensity of breathlessness during the 3min constant speed shuttle test (CSST).

A secondary objective is to explore the relationship between reductions in breathlessness during the 3min CSST and reductions in breathlessness during activities of everyday living as measured by the dyspnea domain of the Chronic Respiratory Questionnaire (CRQ) following bronchodilator therapy.

Detailed description:

Arms:
arm 1: Patients will receive tiotropium 5mcg + olodaterol 5mcg in a fixed dose combination once daily. arm 2: None

Interventions: intervention 1: Tiotropium intervention 2: Olodaterol intervention 3: Tiotropium
Intervention descriptions: intervention 1: fixed dose combination once daily intervention 2: fixed dose combination once daily intervention 3: None

Protocol document:
Prot_001.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c03207491-01
EudraCT No.:
2015-002974-20
BI Trial No.:
1237.28
BI Investigational 
Product(s):
Tiotropium + olodaterol fixed dose combination solution for     
inhalation - Respimat®
Title:
A randomised, double-blind, cross-over study to evaluate the effect 
of 6 weeks treatment of orally inhaled tiotropium + olodaterol  
fixed dose combination (5/5 µg) compared with tiotropium (5 µg), 
both delivered by the Respimat® Inhaler, on breathlessness during 
the three minute Constant Speed Shuttle Test (3min CSST) in 
patients with Chronic Obstructive Pulmonary Disease (COPD)
[OTIVATOTM]
Brief Title:
Effect of tiotropium + olodaterol on breathlessness in COPD 
patients.
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone: 
  Fax:
Coordinating 
Investigator:
Status:
Final Protocol
Version and Date:
Version 1.0
Date: 15 APR 2016
Page 1 of 137
Proprietary confidential information.
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Tiotropium + olodaterol 
fixed dose combination 
solution for inhalation  -
Respimat®
Protocol date:
15 APR 2016
Trial number:
1237.28
Revision date:
Title of trial:
A randomised, double-blind, cross-over study to evaluate the effect of 6
weeks treatment of orally inhaled tiotropium + olodaterol  fixed dose 
combination (5/5 µg) compared with tiotropium (5 µg), both delivered 
by the Respimat® Inhaler, on breathlessness during the three minute 
Constant Speed Shuttle Test (3min CSST) in patients with Chronic 
Obstructive Pulmonary Disease (COPD) [OTIVATOTM]
Principal Investigator
Trial sites:
Multi-centre
Clinical phase:
IV
Objectives:
The primary objective of the study is to evaluate the effect of   
tiotropium + olodaterol FDC compared to tiotropium monotherapy on 
the intensity of breathlessness during the 3min CSST.
A secondary objective is to explore the relationship between reductions 
in breathlessness during the 3min CSST and reductions in 
breathlessness during activities of everyday living as measured by the 
dyspnea domain of the Chronic Respiratory Questionnaire (CRQ)
following bronchodilator therapy. 
Methodology:
Randomised, double-blind, active-controlled, cross-over design 
comparing two treatments after 6 weeks of treatment.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Tiotropium + olodaterol 
fixed dose combination 
solution for inhalation  -
Respimat®
Protocol date:
15 APR 2016
Trial number:
1237.28
Revision date:
No. of patients: 
102
total entered:
102
each treatment:
102
Diagnosis :
Chronic Obstructive Pulmonary Disease (COPD)
Main criteria
for inclusion:
Outpatients of either sex, aged ≥ 40 years and ≤ 75 years with a 
smoking history > 10 pack years, post-bronchodilator 30% ≤ FEV1 < 
80% predicted, post-bronchodilator FEV1/ FVC< 0.70, BDI < 8, FRC
>120% predicted.
Test products:
Tiotropium + olodaterol fixed dose combination solution for inhalation 
– Respimat®
dose:
[5 μg tiotropium  + 5 μg olodaterol] once daily
mode of 
administration:
Oral inhalation
Comparator products:
Tiotropium solution for inhalation – Respimat®
dose:
5 µg once daily
mode of 
administration:
Oral inhalation 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Tiotropium + olodaterol 
fixed dose combination 
solution for inhalation  -
Respimat®
Protocol date:
15 APR 2016
Trial number:
1237.28
Revision date:
Duration of treatment:
2 x 6-week treatment periods (total treatment duration of 12 weeks)
Endpoints
The primary endpoint is the change from baseline in intensity of 
breathlessness measured using the Modified BORG Scale (MBS-S) at 
the end of the 3 minute Constant Speed Shuttle Test (3min CSST) after 
6 weeks of treatment.
Change from baseline is defined as change from patient baseline.
Secondary Endpoints include:
Change from baseline in Inspiratory Capacity (IC) measured prior to 
exercise, after 6 weeks of treatment.
Change from baseline in IC measured at the end of exercise, after 6 
weeks of treatment
Change from baseline in 1 hour post-dose FEV1, after 6 weeks of 
treatment.
Change from baseline in 1 hour post-dose FVC, after 6 weeks of 
treatment.
Change from baseline in intensity of Breathlessness (MBS-S) at 1, 2 
and 2.5 min during the 3min CSST after 6 weeks of treatment. 
Change in CRQ-SAI dyspnea subscale score after 6 weeks of treatment.
Change in CRQ-SAS dyspnea subscale score after 6 weeks of 
treatment.
None of the primary or secondary endpoints are safety issues.
Safety criteria:
Heart rate, blood pressure and SpO2 in conjunction with lung function 
and exercise testing as applicable, adverse events and physical 
examination. 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Tiotropium + olodaterol 
fixed dose combination 
solution for inhalation  -
Respimat®
Protocol date:
15 APR 2016
Trial number:
1237.28
Revision date:
Statistical methods:
Restricted Maximum Likelihood Estimation based Mixed-effects Model 
for Repeated Measures (MMRM) analysis will be used to obtain 
adjusted means for the treatment effects.
This model will include treatment and period as fixed effects, patient as 
a random effect and period baseline as well as patient baseline as 
covariates. The patient baseline will be obtained by calculating the 
mean of period baselines for each patient. Compound symmetry will be 
used as a covariance structure for within patient variation. 
Descriptive statistics for the safety analyses.


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FLOW CHART
Screening
Treatment Period1
Follow-
up
Visit
0
1
2
3
4, 7
5, 8
6, 9 
(V9-
EOT)
10
Week of treatment
-
-
-
-
0
3
6
V9-EOT
+ 3 
weeks 
Day of treatment
Time Window 
(days)
-
-21 
to  
-14
-13 
to -9
-8 to 
-1
1
22
+7
43
+ 7
V9-EOT
+ 21
+ 7
Informed consent,
patient information
X2
Demographics
X
Baseline Conditions
X
COPD Characteristics
X
Smoking status
X
X
X3
In-/Exclusion Criteria
X
X
X
X (visit 
4 only)
Physical examination
X
X3
X26
Laboratory tests 
X
X3
X26
Pregnancy testing4
X
X
X3
X
12-lead ECG5
X
X3
X26
Body 
Plethysmography6
(IC, FRC, TLC)
X
Screening call (IRT)
X
Training in use of 
Respimat® inhaler
X
X7
Randomisation (IRT)
X (visit 
4 only)


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Screening
Treatment Period1
Follow-
up
Visit
0
1
2
3
4, 7
5, 8
6, 9 
(V9-
EOT)
10
Week of treatment
-
-
-
-
0
3
6
V9-EOT
+ 3 weeks 
Day of treatment
Time Window 
(days)
-
-21 
to  
-14
-13 
to -9
-8 to 
-1
1
22
+7
43
+ 7
V9-EOT
+ 21
+ 7
Assign and Dispense 
IMP (IRT)
X
Dispense rescue 
medication (as 
needed)
X8
X
X
X
X
X
X 
Administer trial 
medication at clinic
X
X
X
Collect trial 
medication
X3,9
Incremental Shuttle 
Walk Test  (ISWT)
X10
3min Constant Speed 
Shuttle Test (3min 
CSST)
X11
X12
X13
X14
Breathing discomfort 
/ 
 
(Modified BORG 
Scale) during 3min 
CSST15
X
X
X
X
Inspiratory Capacity 
(IC) measurements16
X
X
X
X
 
 
 
 


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Screening
Treatment Period1
Follow-
up
Visit
0
1
2
3
4, 7
5, 8
6, 9 
(V9-
EOT)
10
Week of treatment
-
-
-
-
0
3
6
V9-EOT
+ 3 weeks 
Day of treatment
Time Window 
(days)
-
-21 
to  
-14
-13 
to -9
-8 to 
-1
1
22
+7
43
+ 7
V9-EOT
+ 21
+ 7
 
Chronic Respiratory 
Questionnaire 
(CRQ)-  dyspnea 
domain, self-
administered, 
individualized and 
standardized
X
X
Modified Medical 
Research Council
(mMRC) Dyspnea 
Scale
X
Baseline Dyspnea 
Index (BDI)
X19
 
 
Spirometry (FEV1, 
FVC)
X20
X21
X3,22
Vital signs (seated)23
X
X
X
X3
Adverse events
X
X
X
X
X
X3
X
Concomitant therapy
X
X
X
X
X
X3
X
Medication wash-out
X
X
X
X
X
X


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1.
Treatment Period: In this cross-over design, each treatment period (period 1, period 2) will follow the same flow chart:
•
procedures during visits 4 and 7 will be identical (except for inclusion/exclusion check, randomisation and BDI at 
V4 only)
•
procedures during visits 5 and 8 will be identical
•
procedures during visits 6 and 9 will be identical
2.
Informed Consent: All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in 
the trial, which includes medication washout and restrictions.
3.
Procedures: To be completed at the end of each treatment period and / or by all patients who took at least one dose of trial 
medication including those who discontinue early. PFTs are to be performed if possible.
4.
Pregnancy Testing: Women of child-bearing potential: serum pregnancy test at visit 1; urine pregnancy test at visits 4, 6, 7, 
9, 10.
5.
ECG: 12-lead ECG recording at screening (visit 1) and end of treatment periods (visits 6 and 9) to be measured pre-dose.
6.
Body Plethysmography: Conducted prior to dosing with salbutamol for inclusion. 
7.
Device Training: The patient will be instructed in the use of the Respimat® inhaler, but the patient should not inhale from 
the placebo inhaler at these visits.
8.
Rescue Medication: To be supplied to all patients starting at visit 0.
9.
Trial Medication Collection: Last dose of trial medication for the respective treatment period will be the morning dose, 
taken in the clinic on Day 43. All medication is collected after this dosing.
Screening
Treatment Period1
Follow-
up
Visit
0
1
2
3
4, 7
5, 8
6, 9 
(V9-
EOT)
10
Week of treatment
-
-
-
-
0
3
6
V9-EOT
+ 3 weeks 
Day of treatment
Time Window 
(days)
-
-21 
to  
-14
-13 
to -9
-8 to 
-1
1
22
+7
43
+ 7
V9-EOT
+ 21
+ 7
Rescue Medication 
Use
X
X
X
X
X
X3
Trial Medication 
Adherence24
X
X3
Telephone contacts25
X
X
X
X
X
X
Trial medication 
termination
X3
(call IRT 
at V9 only)
Trial completion
X


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10. Measurements during ISWT:
•
BORG measurements conducted at rest, every 2 minutes during exercise and at the end of exercise. Refer to Appendix
10.5 for further details.
•
IC to be conducted at rest, every 2 minutes during exercise and at the end of exercise using mobile cardiopulmonary 
exercise equipment. IC measurements are to be done after the BORG measurements. Refer to Appendix 10.7 and 
manual of procedures for further details.
 
11. V2 3min CSST: Speed to be determined at visit 2 by conducting up to three tests at select speeds.
12. V3 3min CSST: Practice test for the 3min CSST at speed selected from V2.
13. 3min CSST timing V4 and V7: 3min CSST conducted prior to dosing (period baseline).
14. 3min CSST timing V5, V6, V8 and V9: 3min CSST conducted 2 hours post-dose (+15 minutes).
15. BORG measurements during 3min CSST: BORG measurements conducted at rest, 1, 2, 2.5 minutes during exercise and at 
3min or end of exercise (if 3 minutes not achieved). Refer to Appendix 10.5 for further details.
16. Inspiratory Capacity measurements: IC measurements performed at rest and at end exercise during 3min CSSTs using 
mobile cardiopulmonary exercise equipment. IC measurements are to be done after the BORG measurements. 
Refer to Appendix 10.7 and manual of procedures for further details.
19. BDI score: Score <8 is required for inclusion.
20.   Reversibility Testing: Pre- and post-bronchodilator FEV1 and FVC (400 µg salbutamol (albuterol)). [note: reversibility is 
not an inclusion criterion]
21.   Baseline spirometry measurements: Conducted prior to exercise testing.
22.   Post-dose FEV1 and FVC: 1 hr post-dose (±10 minutes) and prior to exercise testing
23. Vital Signs: Immediately prior to PFTs.
24. Medication Use: Measured using the counter on the Respimat® device.
25. Telephone Contacts: Site staff will telephone the patient 1-2 days prior to clinic visits to remind them of medication washout 
and any other requirements.
26. To be completed in the event of any clinically relevant findings at the End of Trial (EOT) visit.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ......................................................................................................11
ABBREVIATIONS................................................................................................................15
1.
INTRODUCTION...............................................................................................18
MEDICAL BACKGROUND.............................................................................18
1.1
DRUG PROFILE................................................................................................18
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....20
RATIONALE FOR PERFORMING THE TRIAL.........................................20
2.1
TRIAL OBJECTIVES........................................................................................21
2.2
BENEFIT - RISK ASSESSMENT.....................................................................22
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.1
3.1.1
Administrative structure of the trial .................................................................25
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................27
SELECTION OF TRIAL POPULATION .......................................................28
3.3
3.3.1
Main diagnosis for trial entry ............................................................................28
3.3.2
Inclusion criteria .................................................................................................29
3.3.3
Exclusion criteria ................................................................................................29
Contraindications to exercise................................................................................32
3.3.3.1
3.3.4
Removal of patients from therapy or assessments...........................................32
Removal of individual patients .............................................................................32
3.3.4.1
Discontinuation of the trial by the sponsor ...........................................................33
3.3.4.2
4.
TREATMENTS...................................................................................................34
TREATMENTS TO BE ADMINISTERED.....................................................34
4.1
4.1.1
Identity of BI investigational products and comparator products.................34
4.1.2
Method of assigning patients to treatment groups...........................................35
4.1.3
Selection of doses in the trial..............................................................................35
4.1.4
Drug assignment and administration of doses for each patient......................36
4.1.4.1 
Priming of the Respimat® inhaler ........................................................................36
4.1.4.2 
Study medication administration ..........................................................................37
4.1.4.3 
Inhaler devices training.........................................................................................38
Respimat® malfunctioning....................................................................................38
4.1.4.4


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4.1.5
Blinding and procedures for unblinding...........................................................39
Blinding.................................................................................................................39
4.1.5.1
Unblinding and breaking the code ........................................................................39
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................39
4.1.7
Storage conditions...............................................................................................40
4.1.8
Drug accountability.............................................................................................41
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................42
4.2.1
Rescue medication, emergency procedures, and additional treatments........42
4.2.2
Restrictions ..........................................................................................................44
Restrictions for PFT and shuttle tests ...................................................................47
4.2.2.1
Restrictions on diet and life style..........................................................................47
4.2.2.2
Restrictions regarding women of childbearing potential ......................................48
4.2.2.3
4.3
TREATMENT COMPLIANCE........................................................................48
5.
VARIABLES AND THEIR ASSESSMENT ....................................................49
TRIAL ENDPOINTS..........................................................................................49
5.1
5.1.1
Primary Endpoint ...............................................................................................49
5.1.2
Secondary Endpoints..........................................................................................49
...........................................................................................49
ASSESSMENT OF EFFICACY........................................................................50
5.2
ASSESSMENT OF SAFETY.............................................................................53
5.3
5.3.1
Physical examination ..........................................................................................53
5.3.2
Vital Signs............................................................................................................54
5.3.3
Safety laboratory parameters ............................................................................54
5.3.4
Electrocardiogram ..............................................................................................55
5.3.5
Other safety parameters.....................................................................................55
5.3.6
Assessment of adverse events.............................................................................55
Definitions of AEs ................................................................................................55
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................58
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................60
5.4.1
This study will not analyse pharmokinetic or pharmodynamic parameters. 60
ASSESSMENT OF EXPLORATORY BIOMARKERS.................................60
5.5
OTHER ASSESSMENTS...................................................................................60
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................61
5.7
6.
INVESTIGATIONAL PLAN.............................................................................62
VISIT SCHEDULE.............................................................................................62
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................63
6.2
6.2.1
Screening and run-in period ..............................................................................63
6.2.2
Treatment periods...............................................................................................67
6.2.3
Follow-up Period and Trial Completion...........................................................73


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE75
STATISTICAL DESIGN - MODEL.................................................................75
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................75
7.2
PLANNED ANALYSES.....................................................................................75
7.3
7.3.1
Primary endpoint analyses.................................................................................76
7.3.2
Secondary endpoint analyses .............................................................................76
7.3.3
Safety analyses.....................................................................................................76
7.3.4
Pharmacokinetic analyses ..................................................................................77
INTERIM ANALYSES ......................................................................................77
7.4
HANDLING OF MISSING DATA ...................................................................77
7.5
RANDOMISATION ...........................................................................................77
7.6
DETERMINATION OF SAMPLE SIZE .........................................................78
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........79
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................79
DATA QUALITY ASSURANCE ......................................................................80
8.2
RECORDS...........................................................................................................80
8.3
8.3.1
Source documents ...............................................................................................80
8.3.2
Direct access to source data and documents.....................................................81
8.3.3
Storage period of records ...................................................................................81
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................82
8.4
STATEMENT OF CONFIDENTIALITY........................................................82
8.5
TRIAL MILESTONES.......................................................................................82
8.6
9.
REFERENCES....................................................................................................84
PUBLISHED REFERENCES............................................................................84
9.1
UNPUBLISHED REFERENCES......................................................................87
9.2
10.
APPENDICES.....................................................................................................89
THE RESPIMAT® INHALER..........................................................................89
10.1
RETURN OF INHALERS/CARTRIDGES......................................................95
10.2
ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA...........96
10.3
EXERCISE TESTING – ISWT AND 3MIN CSST.........................................97
10.4
10.4.1
General considerations for exercise testing ......................................................97
10.4.2
Shuttle Test........................................................................................................100
Incremental Shuttle Walk Test............................................................................101
10.4.2.1
Constant Speed Shuttle Test ...............................................................................103
10.4.2.2
MODIFIED BORG SCALE (MBS-S).............................................................105
10.5
INSPIRATORY CAPACITY AND FRC........................................................108
10.7
MODIFIED MEDICAL RESEARCH COUNCIL DYSPNEA SCALE 
10.8
(MMRC).............................................................................................................110


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CHRONIC RESPIRATORY QUESTIONNAIRE – SELF ADMINISTERED 
10.9
STANDARDIZED - DYSPNEA DOMAIN ONLY........................................111
CHRONIC RESPIRATORY QUESTIONNAIRE – SELF ADMINISTERED 
10.10
INDIVIDUALIZED ..........................................................................................118
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................137


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ABBREVIATIONS
ACCP
AE
American College of Chest Physicians
Adverse Event
AESI
Adverse Event of Special Interest
AMP
ATS
AUC
β-HCG
BAC
BDI
BI
Auxiliary Medicinal Products
American Thoracic Society
Area under the Curve
Beta-Human Chorionic Gonadotropin
Benzalkonium Chloride
Baseline Dyspnea Index
Boehringer Ingelheim
bid
bis in die – twice daily
CA
Competent Authority
CI
Confidence Interval
CML
Local Clinical Monitor 
COPD
CPR
CRA
CRO
Chronic Obstructive Pulmonary Disease
Cardiopulmonary Resuscitation
Clinical Research Associate
Contract Research Organization
CRQ-SAS
CRQ-SAI
CSST
Chronic Respiratory Questionnaire - Self Administered Standardized
Chronic Respiratory Questionnaire - Self Administered Individualized
Constant Speed Shuttle Test
CTP
Clinical trial Protocol
DOMS
eCRF
Delayed Onset Muscular Soreness
Electronic Case Report Form
ECG
ECSC
EDTA
EELV
EOT
ERS
EudraCT
Electrocardiogram
European Coal and Steel Community
Ethylenediaminetetraacetic acid
End expiratory lung volume
End of Trial
European Respiratory Society
European Clinical Trials Database
FAS
FC
FDC
FEV1
FRC
FVC
Gamma-GT
GOLD
Full Analysis Set
Flow Chart
Fixed Dose Combination
Forced Expiratory Volume in 1st second
Functional Residual Capacity
Forced Vital Capacity
Gamma-Glutamyl Transpeptidase
Global Initiative for Chronic Obstructive Lung Disease


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HFA
hrs
IB
Hydrofluoroalkane
Hours
Investigator’s Brochure
IC
ICH-GCP
ICS
IEC
Inspiratory Capacity
International Conference on Harmonization - Good Clinical Practice
Inhaled corticosteroid
Independent Ethics Committee
IMP
IRB
Investigational Medicinal Product
Institutional Review Board
IRT
Interactive Response Technology
ISF
ISWT
LABA
LAMA
LDH
MBS-S
MCID
MDI
Investigator Site File
Incremental Shuttle Walk Test
Long Acting β2-Agonists
Long Acting Muscarinic Antagonists
Lactate Dehydrogenase
Modified BORG Scale
Minimum clinically important difference
Metered Dose Inhaler
MedDRA
Min
mg
mMRC
Medical Dictionary for Drug Regulatory Activities
Minute
milligram
Modified Medical Research Council Dyspnea Scale
mmHg
Millimetres mercury
MMRM
MOP
mth
PDE-4
PFT
Mixed Effect Repeated Measures Model
Manual of Procedures
Month
Phosphodiesterase Type 4
Pulmonary Function Test
PRN
Pro re nata – as needed
qd
quaque die (once a day)
RDC
REML
REP
Remote Data Capture
Restricted Maximum Likelihood
Residual effect period
SAE
SGOT
SGPT
Serious Adverse Event
Serum glutamic-oxaloacetic transaminase
Serum glutamic-pyruvic transaminase
SOP
Standard Operating Procedure
SpO2
SQ
TCM
Oxygen saturation 
Sensory Quality
Trial Clinical Monitor
TLC
Total Lung Capacity


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TMF
Trial Master File
TS
TSAP
ULN
wks
w.o.
Treated Set
Trial Statistical Analysis Plan
Upper Limit Normal
Weeks
Washout


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
European Respiratory Society (ERS), American Thoracic Society (ATS) and Global Initiative for 
Chronic Obstructive Lung Disease (GOLD) treatment guidelines all place bronchodilators as the 
foundation of pharmacologic management of COPD. In patients with moderate to very severe 
pulmonary impairment (i.e., GOLD Stage 2 to 4) 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. 
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 
recently completed clinical development program for tiotropium + olodaterol fixed dose 
combination (FDC) was based on the hypothesis that the combination of the LAMA, tiotropium, 
and the LABA, olodaterol, inhaled once daily, is superior in improving airflow over 24 hours 
compared with tiotropium monotherapy once daily and olodaterol monotherapy once daily.
DRUG PROFILE
1.2
Tiotropium
Tiotropium is an established once-daily (QD) 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 those with GOLD [P14-01052] 2 disease [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 
QD) is approved in more than 80 countries worldwide including European Union (EU), Japan, 
United States (US) and Canada. Further information about tiotropium can be found in the 
respective prescribing information for the product.


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Tiotropium + olodaterol combination
Tiotropium + olodaterol FDC is an aqueous solution of tiotropium and olodaterol contained in a 
cartridge. It is administered by using the Respimat® inhaler. The same device is used for 
tiotropium (Spiriva® Respimat®). One cartridge is used per inhaler, which is inserted into the 
device prior to first use. 
In the pivotal studies (1237.5/.6) [c01735218-03/c01735249-03] tiotropium + olodaterol FDC 
showed statistically significant improvements in Forced Expiratory Volume in one second
(FEV1) Area Under the Curve (AUC0-3h) response and trough FEV1 response after 24 weeks 
compared to the mono-components and these improvements were maintained up to 52 weeks.
Tiotropium + olodaterol FDC showed statistically significant improvements in health-related 
quality of life [St. George's Respiratory Questionnaire (SGRQ)] and dyspnea experienced during 
everyday activities [Transitional Dyspnea Index (TDI)] after 24 weeks compared to the mono-
components. More patients treated with the combination had an improvement in SGRQ total 
score and TDI focal score greater than the Minimal Clinically Important Difference (MCID).
Treatment with tiotropium + olodaterol FDC also resulted in reductions in both daytime and 
night time rescue bronchodilator use compared to the mono-components.
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.
For a more detailed description of the drug profile, please refer to the current Investigator’s 
Brochure (IB) which is included in the Investigator Site File (ISF).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Breathlessness upon exertion is the most troublesome symptom reported by COPD patients. 
Furthermore, reduced breathlessness during exercise as a result of reductions in lung 
hyperinflation is believed to be the primary mechanistic explanation for increases in exercise 
endurance time in patients with COPD following treatment with bronchodilators. 
Previous studies have shown significant reductions in lung hyperinflation (increases in 
Inspiratory Capacity (IC)) for tiotropium + olodaterol FDC compared with placebo, tiotropium 
and olodaterol.  However, while the improvement in IC with tiotropium + olodaterol FDC 
compared with placebo was associated with a reduction in breathlessness and an increase in 
symptom-limited endurance time, this was not the case for the increases in IC for tiotropium +
olodaterol FDC compared with the monocomponents [c02094185-02 , c02094318-02 , 
c01735246-02]. Contrasting findings have been observed in the pivotal TONADOTM studies
[c01735218-03 , c01735249-03 ], with significant increases in the Mahler TDI focal score for 
tiotropium + olodaterol FDC compared with tiotropium and olodaterol, providing evidence of 
incremental benefit in activity-related breathlessness for the combination over the 
monotherapies. Therefore, there is a need to better understand the relationship between 
improvements in lung function and activity-related breathlessness for tiotropium + olodaterol 
FDC compared to the monocomponents. 
Traditional constant work rate exercise tests (e.g. endurance shuttle walking, constant work rate 
cycle ergometry) are conducted to the point of symptom limitation, which presents challenges 
regarding the evaluation of symptoms during exercise due to the open-ended nature of these 
tests. To address this issue, a novel exercise methodology, the 3min CSST, has been developed
that allows specific focus on the assessment of activity-related breathlessness (using the MBS-S) 
at specific pre-defined timepoints in patients with COPD. The feasibility and reproducibility of 
the 3min CSST in providing a standardized physical stimulus and a measurable level of 
breathlessness in patients with moderate to severe COPD has been reported [R15-4319]. In one 
study, the responsiveness of the 3min CSST to bronchodilation was confirmed, with a 
statistically significant reduction in the intensity of breathlessness with ipratropium bromide 
compared to placebo [P12-12739].
Breathlessness or dyspnea1 is characterised as “a subjective experience of breathing discomfort 
that consists of qualitatively distinct sensations that vary in intensity [and] vary in their 
                                                
1 In this protocol, the terms “breathlessness” and “dyspnea” are used interchangeably as the general term to describe the subjective experience of 
breathing discomfort [R15-4208 ]; the specific sensation that patients will be asked to attend to during the 3 min CSST is “breathing discomfort” 
(see Appendix 10.5).  In the ATS statement on dyspnea, keywords are identified as “breathlessness”, “shortness of breath” and “respiratory 
sensation”.


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unpleasantness and in their emotional and behavioral significance” [1]. There is increasing 
recognition that dyspnea is a multidimensional experience [R15-4209, R15-4207, R15-4211] and 
that, while unidimensional scales can capture the overall severity of dyspnea at a particular time-
point (current or recalled), they do not capture information about the quality of breathing 
discomfort, its unpleasantness or the associated emotional responses. The recent development of 
a conceptual model for dyspnea (figure 1; [R15-4211]) suggests that clinical trials that 
specifically focus on exertional breathlessness should not limit the evaluation solely to the 
intensity dimension, but should conduct a comprehensive assessment that also attends to the 
sensory quality (SQ) and emotional impact of dyspnea in patients with COPD.
Figure 1 Model of the components of dyspnea underlying the Multidimensional Dyspnea Profile
(MDP). 
Reproduced from Banzett et al. Multidimensional Dyspnea Profile: an instrument for clinical and 
laboratory Research. [R15-4210]
TRIAL OBJECTIVES
2.2
The primary objective of the study is to evaluate the effect of tiotropium + olodaterol FDC 
compared to tiotropium monotherapy on the intensity of breathlessness during the 3min CSST. 


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A secondary objective is to explore the relationship between reductions in breathlessness during 
the 3min CSST and reductions in breathlessness during activities of everyday living as measured 
by the dyspnea domain of the Chronic Respiratory Questionnaire (CRQ) following 
bronchodilator therapy. 
BENEFIT - RISK ASSESSMENT
2.3
The clinical trials conducted to date have shown tiotropium + olodaterol 5/5 μg 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 tiotropium + olodaterol 5/5 μg compared 
to the individual components translated into benefits that were meaningful to the patient, with
improvements in several patient centred outcomes. As such, tiotropium + olodaterol 5/5 μg will 
be a valuable additional therapeutic option for patients with COPD, offering increased treatment
benefit compared to the monotherapies with a comparable safety profile.
Based on the overall assessment of benefit to risk, the application for marketing authorization for 
tiotropium + olodaterol FDC was submitted in the EU and the US in May 2014, and then 
subsequently in several other countries, including Canada. At the time of the final protocol for 
1237.28, marketing authorization has been granted in Belgium, Canada, Germany, Netherlands, 
as well as the US and several other countries.
Potential risks associated with exercise testing will be avoided by implementing standard 
monitoring procedures under appropriate supervision [R13-2820, R13-4694].  
The trial design requires that all eligible patients complete a 3 to 4 week screening period in 
which LABAs and LAMAs are withdrawn prior to randomisation. At the investigator´s 
discretion, ipratropium may be provided to patients who are required to wash out LAMA during 
the washout period prior to randomisation and during the washout period prior to visit 7; 
Boehringer Ingelheim (BI) will provide open-label salbutamol (albuterol) as needed (PRN)
rescue medication for all patients who have signed Informed Consent.
All patients will receive active treatment with either tiotropium + olodaterol FDC (5 µg / 5 µg) 
or tiotropium (5 µg) inhalation solution (control group) during the treatment periods. There is no 
placebo comparator in this trial.
Patients receiving inhaled corticosteroids (ICS) before enrolment will continue their treatment 
(or the ICS component alone if taken as a fixed combination with bronchodilator) at the same or 
equivalent dose and regimen during the study. The only medications that are excluded during the 
treatment period are anticholinergic and long-acting β-adrenergic other than the study drugs.


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The proposed medication restriction scheme is considered ethically acceptable given the 
availability of ipratropium metered dose inhaler (MDI) during the wash-out periods, salbutamol 
(albuterol) as rescue medication and permitted use of ICS during the treatment period.  
Safety will be monitored (as described in section 5.2) at site visits and withdrawal criteria are 
provided for investigators’ consideration (as listed in section 3.3.4.1).
According to the prescribing information for Spiolto® (Stiolto® in US, Inspiolto® in Canada), as 
a precautionary measure, it is preferable to avoid the use of Spiolto® during pregnancy. Women 
of childbearing potential may be included in clinical trials for tiotropium + olodaterol (5/5 μg) 
FDC 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]. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a multi-centre, multi-national, randomised, double-blind, active-controlled, two-period
cross-over, Phase IV study to evaluate the effects of once daily administration of orally inhaled 
tiotropium + olodaterol FDC (5 / 5 μg) (delivered by the Respimat® Inhaler) compared with  
tiotropium  (5 µg) (delivered by the Respimat® Inhaler) on the intensity of breathlessness in
patients with Chronic Obstructive Pulmonary Disease (COPD). 
The trial consists of a run-in period, two 6-week treatment periods, each separated by a 3-week 
wash-out period and a follow-up period.
Figure 3.1:1. Overview of the trial design
After signing Informed Consent and completing an initial screening visit (visit 1), patients will 
enter a 3 to 4-week run-in period to ensure clinical stability (i.e. no exacerbations).  During this 
screening period, they will conduct an Incremental Shuttle Walk Test (ISWT) at visit 1, up to 
three x 3min CSSTs to establish the shuttle test speed at visit 2 and a practice 3min CSST at visit 
3.


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Patients who meet all the inclusion criteria and none of the exclusion criteria will be randomised 
at visit 4 into the first of 2 x 6-week double-blind, cross-over treatment portion of the study, in 
which they will receive one of two treatment sequences with the treatment codes as follows: 
A. tiotropium + olodaterol ( 5 / 5  μg) FDC inhalation solution, delivered once daily via the 
Respimat®
B. tiotropium (5  μg) inhalation solution, delivered once daily via the Respimat®
The randomised treatment sequences are AB and BA. An interactive voice/web response system 
named 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.
IRT will also be set-up to ensure that the number of GOLD Stage II patients is capped at 
approximately 50% and the number of GOLD Stage III patients is capped at approximately 50%.  
This will allow a better representation of the different stages of pulmonary impairment in the 
trial.
The patient’s GOLD stage will be entered in IRT at the screening call that should take place at 
visit 1.  The following classification of severity of airflow limitation should be used to determine 
the GOLD stage of the patient [P11-05865]:
GOLD Stage
Severity of Disease
Degree of airflow limitation 
(FEV1)
GOLD 2
Moderate
50% ≤ FEV1 < 80%
GOLD 3
Severe
30% ≤ FEV1 < 50%
Additional clinic visits will be scheduled after 3 and 6 weeks of treatment (visits 5 and 6 
respectively). The first treatment period will be followed by a 3-week wash-out period and then 
the second treatment period will commence (visits 7-9). Patients will be evaluated for an 
additional 21 days following completion of the last 6-week treatment period, or, in case of early 
discontinuation, after the final dose of study medication. The patient’s trial participation will be 
concluded with the follow-up visit 21 days after the end of treatment. For visit details please 
refer to section 6.2.
All study-related documentation will be stored in the BI clinical trial master file (TMF). Trial 
relevant documentation for the study sites will be filed in the ISF at the investigational sites.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI)


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Sponsor: BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating all 
required activities, in order to:
•
manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedure (SOPs),
•
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
•
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and internal SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation of 
the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be defined 
according to BI SOPs. A list of responsible persons and relevant local information can be found 
in the ISF.
Coordinating Investigator: 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 the ISF.
Targeted group of Investigators: Pulmonologists/qualified sites with experience in conducting 
studies involving exercise in patients with COPD and access to the desired patient population. 
Local Facilities/Equipment: The following local facilities/equipment is required at the 
investigational site: 
•
scale and sphygmomanometer,
•
a spirometer which meets ATS Criteria [P05-12782],
•
a portable pulse oximeter for use during exercise testing,
•
body plethysmograph,
•
a standard 12-lead electrocardiogram (ECG),
•
access to local lab facility for safety testing.
Staff training on exercise procedures: Given the importance to perform the shuttle test in a
harmonised and standardised way in all participating countries and centers, a global exercise 
trainer has been contracted to advise the sponsor and trial team and assure that local training will 
be performed in a standardised way.


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Local Laboratory: Blood samples for safety evaluation will be analysed at a local lab.
IRT: An IRT vendor will be used in this trial for randomisation to a treatment group and for 
appropriate re-supply of medication to patients. The ability to unblind will be available to the 
investigator via the IRT. Details will be provided in IRT Manual available in the ISF.
Mobile cardiopulmonary exercise equipment: Will be leased by the sponsor for all sites for the 
duration of the trial. The provision of this equipment will be handled by BI and an external 
vendor.
All contracts and relevant meeting minutes will be stored by BI in the TMF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
Randomisation will be used to avoid systematic differences between groups with respect to 
patient characteristics that could affect the outcomes of interest.  The double-blind design will be 
used to ensure that patients, investigators and BI personnel are unaware of each patient’s 
assigned treatment, thus minimising any potential biases resulting from differences in 
management, treatment or assessment of patients, or interpretation of results that could arise as a 
result of patient or investigator knowledge of the assigned treatment [R03-2273].
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].
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 restriction of long-acting β2-agonist and a long-acting anti-cholinergic during the run-in 
period is necessary to determine the appropriate speed for the 3min CSST, perform the practice 
3min CSST, and measures of breathlessness.  
During the run-in and treatment periods, patients will continue to receive treatment with ICS as 
required. Short-acting β2-agonist medication (salbutamol / albuterol) will be provided to all 
patients for rescue use, and appropriate medications will be allowed to control acute 
exacerbations as medically necessary. Ipratropium may be provided to patients who are required 
to wash out of LAMAs during the run-in and washout periods. 
Eligible patients may be randomised to a treatment arm that includes both a LABA(olodaterol) 
and a LAMA (tiotropium), therefore it is necessary to restrict the use of LABAs (e.g. salmeterol, 


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formoterol, indacaterol, olodaterol) and anti-cholinergics (e.g. tiotropium, ipratropium) during 
the treatment period. 
The inclusion of the tiotropium 5 µg monotherapy treatment arm allows for an appropriate 
comparison of the combination product to the commonly used individual product to determine 
the additional effect of adding LABA to an anticholinergic on breathlessness.
SELECTION OF TRIAL POPULATION
3.3
A sufficient number of patients will be enrolled (sign informed consent) at approximately 15
sites to ensure that a minimum of 102 patients of either sex, 40 to 75 years of age, with a 
diagnosis of COPD are randomised into the study. 
Enrolment will be competitive. Additional sites may be initiated and 'non-productive' sites may 
be closed to ensure sponsor's timelines.  The distribution of patients between countries will be 
dependent on the access to the suitable patient population as well as the operational feasibility of 
performing the trial in the country.  It is anticipated that each site will enrol an average of 
approximately 8 patients. 
Patients will be required to perform shuttle tests on several occasions during the trial. For this 
reason, 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. 
A log of all 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 with moderate to severe pulmonary impairment (according 
to GOLD guidelines [P11-05865]), including hyperinflation at rest during screening and a 
reported degree of breathlessness are eligible for inclusion if they fulfill 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 pertaining 
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 International Conference on 
Harmonisation - Good Clinical Practice (ICH-GCP) guidelines prior to participation in the 
trial, which includes medication washout and restrictions.
2. All patients must have a diagnosis of COPD [P11-05865] and must meet the following 
spirometric criteria:
Patients must have relatively stable airway obstruction with a post-bronchodilator 30% ≤ 
FEV1 < 80% of predicted normal (European Coal and Steel Community (ECSC), [R94-1408]
see Appendix 10.3 for ECSC predicted normal equations); GOLD 2 - 3, [P11-05865] and a 
post-bronchodilator FEV1/FVC < 0.70 at visit 1.
3. Male or female patients, between 40 and 75 years of age (inclusive) on day of signing 
informed consent.
4. Patients must be current or ex-smokers with a smoking history of more than 10 pack-years 
(see Appendix 10.3 for calculations). Patients who have never smoked cigarettes must be 
excluded.
5. Patients with a score on the Baseline Dyspnea Index (BDI) < 8 at visit 0.
6. Patients with hyperinflation at rest, defined as Functional Residual Capacity (FRC) >120% 
predicted at visit 1 (see Appendix 10.7).
7. BORG dyspnea score ≥4 at the end of 3min CSST at visit 2 (refer to Appendix 10.4.2.2 and 
manual of procedures for further details).
8. Patients must be able to perform technically acceptable pulmonary function tests (PFTs)
(spirometry and body plethysmography), must be able to complete multiple shuttle tests 
during the study period as required in the protocol.
9. Patients must be able to inhale medication in a competent manner from the Respimat® inhaler 
(Appendix 10.1) and from a 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 (i) put the patient at risk because of 
participation in the study, (ii) influence the results of the study, or (iii) cause concern 
regarding the patient’s ability to participate in the study.


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2. Patients with a, in the opinion of the investigator, clinically relevant abnormal baseline 
haematology, blood chemistry, or creatinine >x2 Upper Limit Normal (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. 
4. Patients with a COPD exacerbation in the 6 weeks prior to screening (visit 1).
Patients with any of the following conditions:
5. A diagnosis of thyrotoxicosis (due to the known class side effect profile of 
ß2-agonists).
6. A history of myocardial infarction within 6 months of screening visit (visit 1).
7. Life-threatening cardiac arrhythmia as judged by the investigator.
8. Known active tuberculosis.
9. Any malignancy unless free of disease for at least 5 years (patients with treated basal cell 
carcinoma or squamous cell skin cancers are allowed).
10. A history of cystic fibrosis.
11. Clinically relevant bronchiectasis, as judged by the investigator.
12. Patients with severe emphysema requiring endobronchial interventions within 6 months prior 
to screening.
13. A history of significant alcohol or drug abuse, as judged by the investigator.
14. Any contraindications for exercise testing as outlined below (see section 3.3.3.1 below 
“Contraindications to exercise”).
15. 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).
16. Patients being treated with any oral or patch β-adrenergics.
17. Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than 
four weeks on a stable dose prior to visit 1) or at doses in excess of the equivalent of 10 mg 
of prednisone per day or 20 mg every other day.


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18. Patients being treated with antibiotics for any reason (not limited to exacerbation infection) 
within 4 weeks of screening visit (visit 1).
19. Patients being treated with PDE4 inhibitors within 3 months of screening visit 1 (e.g. 
roflumilast) should not be enrolled and PDE4 inhibitors should not be withdrawn for the 
purpose of enrolling in this study.
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.
21. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to 
the screening visit (visit 1) or patients who are currently in a pulmonary rehabilitation 
program.
22. Patients who have a limitation of exercise performance as a result of factors other than 
fatigue or exertional dyspnea, such as arthritis in the leg, angina pectoris or claudication or 
morbid obesity.  
23. Patients with an endurance time 12 minutes during the ISWT (visit 1).
24. Patients with oxygen saturation SpO2 < 85% (on room air) at rest or during exercise (no 
CSST will be conducted with supplemental oxygen).
25. Patients who have taken an investigational drug within one month or six half-lives
(whichever is greater) or in case the investigational drug (sub) class is listed within the 
washout period specified in table 4.2.2.1 prior to screening visit (visit 1).
26. Patients with known hypersensitivity to β-adrenergics and/or anticholinergic drugs, 
Benzalkonium Chloride (BAC), Ethylenediaminetetraacetic acid (EDTA) or any other 
component of the Respimat® inhalation solution.
27. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
28. Women of childbearing potential not using a highly effective method 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.  
29. Patients who have previously been randomised in this study or are currently participating in 
another study.


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30. Patients who are unable to comply with pulmonary medication restrictions prior to 
randomisation.
Contraindications to exercise
3.3.3.1
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 [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.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:
•
The patient withdraws consent for study treatment or study participation, without the 
need to justify the decision.
•
The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.
•
The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs, other diseases, or pregnancy).
•
The patient has repeatedly shown to be non-compliant with important trial procedures
and, in the opinion of both, the investigator and sponsor representative, is not willing or
able to stick to the trial requirements in the future.


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If a patient becomes pregnant or a pregnancy is suspected during the trial, the patient will be 
permanently discontinued from study treatment and will be followed up until birth or otherwise 
termination of the pregnancy. For further information on reporting on pregnancy and the 
outcome of pregnancy, please see section 5.3.7.
Investigators must carefully consider withdrawal from the treatment of an individual patient if 
any of the following criteria apply: 
•
More than 3 courses (or increases) of systemic (oral, intravenous) 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 with 
the clinical monitor. 
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and section 6.2.3.
For all patients the reason for withdrawal (e.g. AEs) must be recorded in the electronic case 
report form (eCRF). These data will be included in the trial database and reported.
Discontinuation of the trial by the sponsor
3.3.4.2
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk-
assessment that could significantly affect the continuation of the trial.
3. Violation of ICH-GCP, the Clinical Trial Protocol (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
TREATMENTS TO BE ADMINISTERED
4.1
The study medication below will be supplied by Boehringer Ingelheim Pharma GmbH &
Co.KG.
Patients will receive of the following treatments in random order:
•
Tiotropium + olodaterol FDC (2.5 μg / 2.5 μg per actuation) inhalation solution.
•
Tiotropium (2.5 μg / per actuation) inhalation solution.
The patients inhale two puffs from the Respimat®inhaler, once a day, in the morning.
4.1.1
Identity of BI investigational products and comparator products
Table 4.1.1: 1
Test products
Substance:
Tiotropium + olodaterol FDC
Pharmaceutical formulation:
Inhalation Solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG.
Unit strength:
2.5 µg / 2.5 µg  per actuation
Posology
2 inhalations once daily (a.m. dosing)
Route of administration:
Oral inhalation via Respimat® inhaler (A5)


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Table 4.1.1: 1
Test products (cont’d)
Substance:
Tiotropium
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
2.5 µg  per actuation
Posology
2 inhalations once daily (a.m. dosing)
Route of administration:
Oral inhalation via Respimat® inhaler (A5)
4.1.2
Method of assigning patients to treatment groups
During visit 4 and after the patient’s eligibility has been confirmed, the treatment sequence will 
be assigned via a third party phone/web-based system.  This will involve the use of an IRT
system which will implement a randomisation scheme generated using a validated system. 
Access to the codes will be controlled and documented. All necessary instructions for using the 
IRT system will be described in a user guide/manual, a copy of which will be available in the 
ISF.
Note that the Respimat® treatment box numbers assigned to the patient by the IRT is different 
from the study patient number assigned by the Remote Data Capture (RDC) system upon signing 
informed consent.
4.1.3
Selection of doses in the trial
The clinical trials conducted during the Phase III program for tiotropium + olodaterol FDC 5/5 
μg have shown that this dose is a safe, well tolerated and efficacious combination therapy. The 
observed incremental bronchodilator response for the combination compared to the individual 
components translated into benefits that were meaningful to the patient, with improvements in 
several patient centred outcomes. 
At the time of the final protocol for 1237.28, tiotropium + olodaterol  FDC (5/5 µg) delivered by 
the Respimat® Inhaler has been approved in Belgium, Canada, Germany, Netherlands, as well as 


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the US and several other countries. Therefore the marketed dose is considered to be the 
appropriate dose to be studied in this trial. 
Tiotropium 5μg (2.5 μg / per actuation) inhalation solution Respimat® has been approved in more 
than 80 countries worldwide including Europe, US, Canada and Japan as an antimuscarinic 
bronchodilator with a once daily posology. Therefore the marketed dose of tiotropium Respimat®
is deemed an adequate comparator for the study.
4.1.4
Drug assignment and administration of doses for each patient
Trial medication will be dispensed to the patient by the investigator/pharmacist or designee. At 
visit 4 eligible patients will be randomised to one of two double-blinded treatment sequences 
(1:1 ratio) by the IRT. At visits 4 and 7, the IRT will assign 3 Respimat® treatment boxes to each 
patient. Each Respimat® treatment box consists of a Respimat® inhaler and a cartridge and will 
have a unique medication number with 6 digits.
One of the Respimat® treatment boxes is a reserve Respimat® inhaler. The 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. 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.
4.1.4.1 
Priming of the Respimat® inhaler
Each newly assembled Respimat® inhaler has to be primed when appropriate. The Respimat®
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 and priming should NOT take
place in the same room where the patient is inhaling trial medication.
Once assembled, the shelf-life of the Respimat® inhaler with study medication or training 
medication (placebo) is 3 months. Therefore it is important to ALWAYS enter the date of the 
cartridge insertion on the medication label of the Respimat® inhaler immediately after the 
cartridge is inserted.
For detailed priming instructions please refer to the Respimat® inhaler handling instructions
in Appendix 10.1


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4.1.4.2 
Study medication administration
At visit 4 the study medication will be self-administered between 7:00 a.m. and 10:00 a.m. At 
subsequent clinic visits, study medication will be self-administered preferably within ±30 
minutes of time of administration at visit 4 AND between 7:00 a.m. and 10:00 a.m. The clock 
time of the start of inhalation of study medication will be captured on the source documents and 
in the eCRF. 
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 visits 6 and 9 (last visit of each treatment period), the Respimat® Inhaler that is in current use, 
must be used for administration of the study medication at that visit since no new Respimat®
treatment box will be assigned.
When planning the time of the morning dose of study medication at visit 4, 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 clinic visits
Dispensation and Respimat® inhaler assembling
Trial medication will be dispensed at visits 4 and 7. Patients will receive 2 new Respimat®
treatment boxes + 1 Respimat® inhaler reserve. During the clinic visit only one new Respimat®
inhaler should be primed (= cartridge inserted and primed) under the oversight of the site staff. 
The other Respimat® inhalers should NOT be assembled prior to leaving the clinic.
Drug administration
At each clinic visit, oral inhalation of two puffs of the study medication from the new assigned 
Respimat® inhaler will be self-administered by the patient under the direct supervision of the 
investigating physician or designee. The investigator or qualified study personnel will observe 
the inhalation procedure. For training session please refer to section 4.1.4.3.
Respimat® inhalers return
At visits 6 and 9 all used and unused Respimat® inhalers will be returned to the clinic by the
patient. The reserve Respimat® inhaler should also be returned at each clinic visit to be replaced 
if it has been used or primed.
For rescue medication dispensation, please refer to section 4.2.1
Study medication administration at home
Each morning, oral inhalation of two puffs on the study medication from the assigned Respimat®
inhaler will be self-administered by the patient. Patients should be encouraged to take their study 


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medication at approximately the same time in the morning (morning dose window until noon). If 
a patient misses the daily dose he/she should take the next dose the day after. The patient must 
assemble and prime the Respimat® inhaler at home once the current used Respimat® inhaler is 
empty and the device is locked.
4.1.4.3 
Inhaler devices training
SPECIAL CONSIDERATION:
Most severe to very severe COPD patients are currently using different inhalation medications at 
the same time. This may cause technical challenges and affect their treatment adherence. 
Respimat®
Training on the use of the Respimat®inhaler will be provided to patients.
•
At visit 1: The first patient’s training session will be performed with the intention
to familiarise the patient with the Respimat®inhaler training medication (placebo). 
Detailed written instructions for the use of the Respimat® inhaler will also be given. (See 
Appendix 10.1).
•
At visit 4: After randomisation, the patient’s training session will be performed from the 
new assigned Respimat® inhaler. Instructions on how to assemble and prime the 
Respimat® inhaler at home should also be reviewed.
•
At visit 7: Observance of the inhalation procedure will occur. The correct inhalation 
technique should be reinforced in case of inadequate use of Respimat® inhaler. It is also 
important to remind the patient on how to assemble and prime the Respimat®inhaler at 
home.
Rescue medication
Before using for the first time the salbutamol (albuterol) hydrofluoroalkane (HFA) MDI 
inhalation aerosol, one actuation should be released into the air to make sure the device is 
working. The patient’s inhaler technique should be reviewed and corrected if needed at each 
clinic visit.
Respimat® malfunctioning
4.1.4.4
Any Respimat® inhaler that has been reported as malfunctioning by a patient or investigator will 
be returned to BI for investigation. See the ISF for specific instructions and for details regarding 
drug accountability requirements. Details of the procedure for the return of malfunctioning 
inhalers are provided in Appendix 10.2.


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4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
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.
The randomisation code will be kept secret by Clinical Trial Support up to database lock.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the investigator / pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of the 
trial drug must be known to the investigator in order to provide appropriate medical treatment or 
otherwise assure safety of trial participants. The reason for unblinding must be documented in 
the source documents and/or appropriate eCRF page along with the date and the initials of the 
person who broke the code.  Patients unblinded to treatment will be withdrawn from the trial. 
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions (SUSARs), 
it may be necessary for a representative from BI’s Pharmacovigilance group to access the 
randomisation code for individual patients during trial conduct. The access to the code will only 
be given to authorised Pharmacovigilance representatives and not be shared further.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be
packaged and labelled in accordance with the principles of Good Manufacturing Practice
(GMP).
BI will provide all study supplies including blinded study medication, rescue medication, 
ipratropium bromide and Respimat® inhaler training kits. Expiry date will be pre-printed on the 
trial supplies labels.
Open-label supplies = Auxiliary Medicinal Products (AMPs)
•
Training Respimat® inhaler, placebo cartridges and disposable mouthpieces for training
purposes. A training device may be used for multiple training sessions. The training 
Respimat® inhaler 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® inhaler immediately after the cartridge is inserted. A 
new mouthpiece should be used for each patient.


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•
Salbutamol (albuterol*) HFA MDI inhalation aerosol (100μg per actuation) for use
during reversibility testing at V1 and as rescue medication during screening, treatment 
and follow-up periods. The rescue medication will be provided locally by BI.
•
Ipratropium bromide to be dispensed at the discretion of the investigator. For use by 
patients on LAMAs during the screening period and during the wash-out period between 
the treatment periods.  This medication will be provided locally by BI.
* NOTE: Albuterol sulphate is the official generic name in the US and salbutamol sulphate is
the WHO recommended generic name.
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 study specific booklet with a 
two-part tear-off label (including one extra portion).  One part of each tear-off label 
should be attached to the drug accountability form which will be part of the ISF. 
The investigator or designee should fill out the following information:
•
Date of cartridge insertion should be entered at time of cartridge insertion on the inside
page of the booklet on the Respimat® Inhaler.
•
Investigator’s name should be entered at time of dispense on the inside page of the 
booklet on the Respimat® treatment box.
For details of the packaging and the description of the label, refer to the ISF.
Re-supply
Each site will receive a first supply at or after the initiation visit and resupply will be managed 
via an IRT system which will also monitor expiry dates of supplies available at the sites.
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. 
The Respimat® inhaler and cartridges and training kits should be stored as indicated on the 
country specific booklet page. A temperature log must be maintained at the site to make certain 
that the drug supplies are stored at the correct temperature. If the storage conditions are found to 
be outside the specified range, the CML (as provided in the list of contacts) must be contacted 
immediately.


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Further details are provided in the IB (tiotropium + olodaterol), prescribing information
(tiotropium) and on the country-specific labels, a sample of which will be part of the ISF.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:
•
Approval of the trial protocol by the institutional review board (IRB) / independent ethics 
committee (IEC).
•
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 (CA).
•
Availability of the curriculum vitae of the principal investigator.
•
Availability of a signed and dated CTP.
•
Where applicable:  availability of the proof of a medical license for the principal 
investigator.
•
For USA availability of Form 1572.
The investigator / pharmacist / investigational drug storage manager must maintain records of the 
product’s delivery to the trial site, the inventory at the site, the use by each patient, and the return 
to the Sponsor or warehouse / drug distribution centre or alternative disposal of used or unused 
products. If applicable, the sponsor or warehouse / drug distribution centre will maintain records 
of the disposal.
For the Respimat® Inhaler, these records for the drug accountability forms will include:
•
dates (dispense and return),
•
dispenser’s initials,
•
quantities,
•
batch / serial numbers,
•
expiry (‘use- by’) dates,
•
the unique Respimat® treatment box number assigned by IRT,
•
The trial patient number assigned by the RDC system.
For the rescue medication and ipratropium bromide, accountability form 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.  
Patients will be asked to return all used/unused ipratropium bromide at the end of screening and 
washout periods. 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).
The investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor or appointed CRO, the investigator / pharmacist / investigational drug storage manager 
must verify that all unused or partially used drug supplies have been returned by the clinical trial 
patient and that no remaining supplies are in the investigator’s possession.
See section 4.1.2. It is important to enter the date of priming on the medication label of the 
Respimat® inhaler.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
Administration of rescue medication can occur at any point during the trial as deemed necessary 
by the patient or the investigator. Open label salbutamol / albuterol MDI (100 μg per puff) will 
be provided as rescue medication by BI; only the salbutamol / albuterol MDI provided by BI is 
allowed for rescue medication use. If the patient requires rescue medication during the PFT days 
(visits 4 - 9), the PFTs will be discontinued. The exercise testing 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. 
There are no special emergency procedures to be followed.
Medications allowed to control acute exacerbations as medically necessary during the treatment 
period:
•
Salbutamol inhalation aerosol from MDI for PRN use provided by BI.
•
Temporary increases in the dose or addition of oral steroids are allowed during the 
treatment portion of the study. Pulmonary function testing should not occur within seven 
days of the last administered dose of an increase or addition of oral steroids. Pulmonary 


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function testing 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. Pulmonary function testing should not occur within seven days of 
the last dose. Pulmonary function testing may be postponed up to 14 days to 
accommodate this restriction. Subsequent visits will be scheduled according to the 
patient's regular schedule.
•
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 pulmonary function testing days, the testing will be postponed for at least two 
days but not more than seven days after the last dose is given. Subsequent visits will be 
scheduled according to the patient's regular schedule.


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4.2.2
Restrictions
Table 4.2.2:1 
Restrictions regarding concomitant treatment
Drug Class
Sub-class
Prior to study
Study Period
Screening
Period
Treatment 
Period
Wash-out 
Period
Follow up 
Period
Corticosteroids
Inhaled corticosteroids
(stabilized 4 wks prior to V1)
Permitted1&5
Permitted1&5
Permitted1&
5
Permitted1&
5
Permitted1&5
Oral corticosteroids
[≤10 mg prednisone per day or 
≤20 mg prednisone every other day 
(or equivalent); stabilized 4 wks
prior to V1]
Permitted
Permitted
Permitted
Permitted
Permitted
Injected Corticosteroids – local 
administration
(for treatment of e.g. bursitis)
Permitted
Permitted
Permitted
Permitted
Permitted
Nasal Corticosteroid sprays
Permitted5
Permitted5
Permitted5
Permitted5
Permitted5
β-adrenergics
Inhaled short-acting β-
adrenergics
Permitted1
Rescue1
Rescue1
Rescue1
Permitted
Inhaled long-acting β-adrenergics 
(bid)
(e.g. formoterol / salmeterol)
Permitted1
(w.o. 48 hrs 
prior to V1)
NOT 
permitted
NOT 
permitted
NOT 
permitted
Permitted
Inhaled long-acting β-adrenergics 
(qd)
(i.e. indacaterol, olodaterol)
Permitted1
(w.o.1 wk 
prior to V1)
NOT 
permitted
(w.o.3wks 
prior to V4)
NOT 
permitted
NOT 
permitted
Permitted


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Drug Class
Sub-class
Prior to study
Study Period
Screening
Period
Treatment 
Period
Wash-out 
Period
Follow up 
Period
Oral and patch beta-adrenergics
NOT 
permitted6
NOT 
permitted
NOT 
permitted
NOT 
permitted
NOT 
permitted
Beta blockers
(stabilized 6 wks prior to V1)
Permitted
Permitted 
Permitted 
Permitted
Permitted 
Anti-cholinergics
Short-acting anticholinergics
(inhalation aerosol, nasal spray)
Permitted1
Permitted1
(w.o. 8 hrs 
prior to V2, 
V3,V4)
NOT 
permitted
Permitted1
(w.o. 8 hrs 
prior to V7)
Permitted
Long-acting anticholinergics 
(bid/qd)
(i.e. tiotropium, aclidinium, 
glycopryonnium, umeclidinium)
Permitted
(w.o. 1 wk 
prior to V1)
NOT 
permitted
(3 wks prior 
to V4)
Study 
medication
NOT 
permitted
Permitted
Combinations
ICS/LABA (bid)
(* switch to ICS mono-product, at the 
same or equivalent dose, at least 48 hrs 
prior to V1)
Permitted1
NOT 
permitted*
NOT 
permitted
NOT 
permitted
Permitted
ICS/LABA (qd)
(*switch to ICS mono-product, at the 
same or equivalent dose, at least 1 wk 
prior to V1) (e.g. fluticasone 
+vilanterol)
Permitted 
NOT 
permitted*
NOT 
permitted
NOT 
permitted
Permitted
ICS/SABA
(* switch to ICS mono-product, at the 
same or equivalent dose, at least 8 hrs 
prior to V1)
Permitted1
NOT 
permitted*
NOT 
permitted
NOT 
permitted
Permitted
short-acting anticholinergic/ SABA
(* 8 hrs prior to V1)
Permitted1
NOT 
permitted*
NOT 
permitted
NOT 
permitted
Permitted


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Drug Class
Sub-class
Prior to study
Study Period
Screening
Period
Treatment 
Period
Wash-out 
Period
Follow up 
Period
Long-acting anticholinergics/long-
acting β-adrenergics2(e.g. 
glycopyrronium+indacaterol, 
umeclidinium+vilanterol)
Permitted
(w.o. 1 week 
prior to V1)
NOT 
permitted 
(w.o. 3 wks 
prior to V4)
Study 
medication
NOT 
permitted
Permitted
Antibiotics
For respiratory infections
The use of antibiotics is not restricted and may be 
prescribed as medically necessary for COPD 
exacerbation episodes and / or infections.
Permitted
(w.o. 4 wks 
prior to V1)
Permitted
(except antibiotics for prevention of exacerbation of COPD)
Any other infections
Permitted
(w.o. 4 wks 
prior to V1)
Permitted
Permitted
Permitted
Permitted
Miscellaneous
Other investigational drugs
(* 1 mth or 6 half-lives (whichever is 
greater) prior to V1)
NOT 
permitted*
NOT 
permitted
NOT 
permitted
NOT 
permitted
NOT 
permitted
Cromolyn sodium / nedocromil 
sodium5
Permitted
Permitted
Permitted
Permitted
Permitted
Antihistamines (including nasal 
route), antileukotrienes5
Permitted
Permitted
Permitted
Permitted
Permitted
Methylxanthines5
Permitted3
Permitted3
Permitted3
Permitted3
Permitted3
Mucolytics
(not containing bronchodilators; 
stabilized 4 wks prior to V1)
Permitted
Permitted
Permitted
Permitted
Permitted
Mucolytics containing 
bronchodilators
NOT 
permitted6
NOT 
permitted
NOT 
permitted
NOT 
permitted
NOT 
permitted
Phosphodiesterase type 4 (PDE4) 
inhibitor4 (e.g. roflumilast)
NOT 
permitted
NOT 
permitted
NOT 
permitted
NOT 
permitted
NOT 
permitted


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1 Refer to section 4.2.2.1 for washout period prior to PFTs.
2 Patients may be switched to bid LABA and short acting anticholinergic. Refer to section 4.2.2.1 for washout period prior to 
   PFTs.
3 For theophyllines: Refer to section 4.2.2.1 for washout period prior to PFTs.
4 Patients currently using PDE4-inhibitors (e.g. roflumilast) should not be enrolled and roflumilast should not be withdrawn for 
   the purpose of enrolling in this study.  Patients who were using roflumilast in the past may be included if their last use was a 
   minimum of 3 months prior to visit 1. In the event a patient with prior use of roflumilast is enrolled, past medical records are 
   required to support and document why and when roflumilast was stopped.
5 Permitted if prescribed for non-asthma condition
6 Not permitted within 4 weeks prior to screening visit (w.o. 4 wks prior to V1)
Refer to section 4.2.1 for washout period prior to PFTs in case of treatment of a COPD exacerbation
Restrictions for PFT and shuttle tests
4.2.2.1
•
At least an 8-hour washout of short-acting beta-adrenergic bronchodilators.
•
At least an 8-hour washout of short-acting anticholinergic bronchodilators prior to visits
1, 2, 3 and 4 (Not allowed during treatment periods but permitted during the wash-out 
period, with at least an 8-hour washout prior to V7).
•
At least a 1-week washout of long-acting anticholinergic bronchodilators twice daily 
(bid) or once daily (qd) prior to visit 1 and a 3-week washout prior to visit 4. (Not 
allowed between visits 1 to 9).
•
At least a 1-week washout of long-acting beta-adrenergic bronchodilators (qd) prior to 
visit 1 and a 3-week washout prior to visit 4 (Not allowed between visits 1 to 9).
•
At least a 48-hour washout of long-acting beta-adrenergic bronchodilators (bid) prior to 
visit 1 (Not allowed between visits 1 to 9).
•
The morning dose of inhaled steroids 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 pre-dose PFT.
•
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.
A patient visit may be re-scheduled twice due to lack of medication washout compliance. After 
this, a discussion with the Clinical Monitor should take place regarding the patient continuing 
in the trial
Restrictions on diet and life style
4.2.2.2
•
Medication washout restrictions should be adhered to as described in table 4.2.2.1.
•
Patients must remain in the building where the exercise and lung function testing is 
performed and must return to the laboratory at least 10 minutes prior to the start of each 
test.


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•
On PFT and exercise testing days (including the screening visit), patients must refrain 
from strenuous activity for at least 2-3 days prior to pulmonary function and exercise 
testing and throughout the testing period. Patients should also avoid cold temperatures, 
environmental smoke, dust or areas with strong odours (e.g. perfumes).
•
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 lung 
function and exercise testing. If a patient has smoked in the 30-minute period prior to 
lung function and exercise testing, the visit should be rescheduled.  
•
Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, and ice-
cold beverages are not allowed the morning of and during the lung function and exercise 
testing period. Decaffeinated beverages are acceptable.
Restrictions regarding women of childbearing potential
4.2.2.3
Women of childbearing potential must use the contraception methods described in the patient
information.
4.3
TREATMENT COMPLIANCE
On visit days, compliance will be guaranteed by administration of the trial drug under 
supervision of the investigator or designee. Each patient will be trained in the correct use of the 
Respimat® Inhaler using the training Respimat® Inhaler with inserted placebo cartridge on 
visit 1.
Compliance will be measured using the counter on the Respimat® device. Patients are requested 
to bring all used and unused trial medication with them when attending visits. The investigator or 
designee will review these records with the patient at all visits to assess treatment compliance in 
treatment phase. However, randomised patients will not be discontinued for lack of compliance 
without prior discussion with the (CML).
If the number of doses taken is not between 80-120%, site staff will explain the patient the
importance of treatment compliance.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary endpoint is the change from baseline in intensity of breathlessness measured using 
the MBS-S at the end of the 3min Constant Speed Shuttle Test (CSST) after 6 weeks of 
treatment.
Change from baseline is defined as change from patient baseline. See Section 7.3.1.
5.1.2
Secondary Endpoints
The following secondary endpoints will also be evaluated:
•
Change from baseline in Inspiratory Capacity (IC) measured prior to exercise, after 6 
weeks of treatment.
•
Change from baseline in IC measured at the end of exercise, after 6 weeks of treatment
•
Change from baseline in 1 hour post-dose FEV1, after 6 weeks of treatment.
•
Change from baseline in 1 hour post-dose FVC, after 6 weeks of treatment.
•
Change from baseline in intensity of Breathlessness (MBS-S) at 1min, 2min, and 2.5min
during the 3min CSST after 6 weeks of treatment.
•
Change in Chronic Respiratory Questionnaire - Self Administered Individualized (CRQ-
SAI) dyspnea domain score after 6 weeks of treatment.
•
Change in Chronic Respiratory Questionnaire - Self Administered Standardized (CRQ-
SAS) dyspnea domain score after 6 weeks of treatment.
None of the primary or secondary endpoints are safety issues.


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ASSESSMENT OF EFFICACY
5.2
Constant Speed Shuttle Test
At all sites, an ISWT will be performed at visit 1 for each patient. The test will be conducted 
according to the methodology described by Singh et al [R04-4259] with IC and physiological 
parameters measured using the mobile cardiopulmonary exercise equipment. At visit 2, starting 
at 4 km/h, the patient will complete up to three x 3min CSST at different sets of speeds (2.5, 
3.25, 4, 5 or 6 km/h) to determine the highest speed that meet the following parameters:
•
The patient can complete the entire three minutes of the test, and
•
The patient achieves a BORG breathlessness rating of ≥ 4.
The test will be conducted according to the methodology developed by Maltais et al, [ P12-
12739]. This speed selected at visit 2 will be used for all subsequent tests.   At visit 3, a training 
3min CSST will be performed using the speed selected at visit 2. At visits 4 and 7, a period
baseline 3min CSST will be completed prior to dosing. At visits 5, 6, 8 and 9 a constant speed
test will be conducted 2 hours (+ 15 minutes) after inhalation of the study medication. 
 
 
 
 
 
 
 
 
 
 
The 3min CSST test methodology and speed selection is described in detail in Appendix 10.4
and manual of procedures.


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Modified BORG Scale
Before, during and at end-exercise, patients will be asked to estimate the intensity of breathing
discomfort 
 that they are experiencing by matching their subjective estimate to 
descriptive phrases that best describe the intensity of each sensation using the MBS-S.  
Details of the MBS-S are provided in Appendix 10.5.
Pulmonary Function Testing
Spirometers and their use, including daily calibration, must meet ATS/ERS criteria [P05-12782]. 
Spirometry will be conducted using the site’s own equipment. Patient will be in a seated position 
and it is preferable that the same trained individual performs the PFT for a given patient. 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 FVC will be selected regardless of whether they come from different spirometric 
manoeuvres or from the same manoeuvre. 
Predicted normal FEV1 values will be calculated for patients using the ECSC equations (R94-
1408, see Appendix 10.3). 
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.
Reversibility testing [P05-12782] will be performed for the qualifying PFT at the Screening visit 
(visit 1): the procedure is described in Appendix 10.3. The post-bronchodilator measurements 
must meet the inclusion criteria specified in section 3.3.2.
Inspiratory Capacity Measurements
IC measurements will be performed during exercise testing as follows: 

ISWT - at rest, during exercise and at the end of exercise

3min CSSTs – at rest and at the end of exercise
IC measurements will be taken using mobile cardiopulmonary exercise equipment capable of 
measuring IC during the shuttle tests.
For IC taken at rest prior to exercise, at least three reproducible measurements should be 
obtained with a maximum of 5 measurements to be performed. The resting IC should be 
recorded as the mean of the two highest acceptable efforts.
For additional details on the IC maneuvers, please refer to Appendix 10.7 and manual of 
procedures.


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Body Plethysmography 
Constant-volume variable-pressure body plethysmography will be used in the trial at visit 1 to 
assess eligibility and parameters to be measured will be FRC, IC and total lung capacity (TLC). 
Measurements should be done in triplicate. The mean FRC value from the three manoeuvres will 
be recorded. The largest IC will be recorded. TLC will be calculated as mean FRC + largest IC.
Body plethysmography should be done before spirometry. 
CRQ Questionnaires
The CRQ questionnaires should be administered at the visits outlined in the FC and completed 
by the patients.  They should be completed first during a study visit, prior to dosing and all study 
procedures.  The CRQ-SAI should be completed prior to the CRQ-SAS. Please see Section 6.2
for the detailed order of administration of questionnaires at each visit.
The CRQ-SAS is a questionnaire that assesses the patients’ perception of their COPD and 
measures the impact of COPD on their life. The CRQ-SAS refers to the CRQ-Self-administered 
format and contains 20 standardised dyspnea questions. The first part of the questionnaire 
contains 5 standardized activities and the patients must indicate how much shortness of breath 
they have experienced while performing each of the activities.

Patients will also complete the CRQ-SAI questionnaire which contains a dyspnea domain 
that is individualized to each patient.  Dyspnea items may be selected from a list of 26 
suggested items or may be written in by the patients. The patients are asked to select the 5 
activities associated with breathlessness that they perform frequently and are most important 
to them.

Details of the CRQ-SAS are provided in Appendix 10.9.

Details of the CRQ-SAI are provided in Appendix 10.10.
Mahler Dyspnea Indices [R96-2117]
  The BDI performed at 
visit 0 will be performed to determine eligibility. 
 
 
 
 
 
 
 


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Details of the Mahler Dyspnea Indices are provided in Appendix 10.12.
 
  
 
 
 
 
  
 
 
 
 
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
Physical examinations are conducted at visit 1, at the end of each treatment period and at visit 10
in case of any findings at the end of treatment visit.  The physical exam includes vital signs 
(blood pressure and pulse rate), height and weight.


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5.3.2
Vital Signs
Measurements of heart rate and blood pressure will be obtained immediately prior to forced 
spirometry measurement (FEV1 and FVC), with the patient seated and rested for a minimum of 5 
minutes.
5.3.3
Safety laboratory parameters
Safety laboratory testing will be conducted (non-fasting) on all patients at the screening visit 
(visit 1), and at visits 6 and 9 (or at the withdrawal visit if the patient does not complete all study 
visits). Follow-up clinical laboratory testing will be performed at visit 10 if there are any 
clinically significant findings at visit 9. 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 and ß-HCG will be analysed by the local laboratory of each 
participating site or, where appropriate, locally selected central laboratory. Laboratory data will 
be collected but not captured in the eCRF or transferred to the sponsor. It is the responsibility of 
the investigator to evaluate changes in laboratory values and reporting of adverse event should be 
followed according to the definitions outlined in section 5.3.6.1.
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, Lactate Dehydrogenase (LDH), Gamma-Glutamyl Transpeptidase 
(Gamma-GT), Serum glutamic-oxaloacetic transaminase (SGOT), Serum glutamic-pyruvic 
transaminase (SGPT), glucose, calcium, inorganic phosphorus, uric acid, urea nitrogen, 
creatinine, total protein, potassium, sodium, chloride, total bilirubin, creatinine phosphokinase.
Pregnancy Testing
A serum human chorionic gonadotropin (HCG) test will be done at visit 1 in all females of 
childbearing potential. Urine pregnancy testing will be performed at visit 4, 6, 7, 9, and 10 in 
females of childbearing potential.


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5.3.4
Electrocardiogram
A standard 12-lead ECG at rest will be performed on all patients at visits 1, 6 and 9. An ECG 
will be repeated at visit 10 in case of any findings at visit 9.
The purpose of the screening ECG (visit 1) is to obtain information about the patient´s baseline 
conditions that may have not been elicited in obtaining the baseline conditions. Therefore, any 
significant findings from the examination are recorded on the Baseline Condition page.
ECG will be completed using site´s own equipment and ECG data will not be collected or 
captured in the eCRF. It is the responsibility of the investigator to evaluate the ECG and 
reporting of adverse events should be followed using the definitions outlined in section 5.3.6.1.
In case of indication of a disease listed under the exclusion criteria, the patient should not be 
randomised for treatment.
5.3.5
Other safety parameters

Heart rate, blood pressure in conjunction with spirometry

Heart rate, SpO2, blood pressure in conjunction with exercise testing
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to ta medicinal product which is noxious and 
unintended.  Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility.  Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure.  Conditions of use outside the marketing authorization include off-label 
use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A 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 
require medical or surgical intervention to prevent one of the other outcomes listed in the
above definitions.
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalisation but might jeopardise the patient or might 
require intervention to prevent one of the other outcomes listed above.  Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalisation or development of dependency or 
abuse.  Any suspected transmission via a medicinal product of an infectious agent is also 
considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of 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.  These events should always 
be reported as SAEs.
Adverse events of special interest (AESIs)
No AESIs have been defined for this trial.
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


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Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event.  An adverse reaction, 
in contrast to an adverse event, is characterised by the fact that a causal relationship between a 
medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history.
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.


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Arguments that may suggest that there is a reasonable possibility of a causal relationship could 
be: 

The event is consistent with the known pharmacology of the drug

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative etiologies that could explain the event (e.g. pre existing 
or concomitant disease, or co-medications)

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (Stevens-Johnson Syndrome)
Arguments that may suggest that there is no reasonable possibility of a causal relationship could 
be: 

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treament cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying disease appear to provide a more likely 
explanation for the observed event than the drug concernted)

Disapperance of the event event though the study drug treatment continues or remains 
unchanged 
5.3.7
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate eCRF by the investigator:
•
From signing the informed consent onwards through the Residual Effect period (REP), 
until individual patient’s end of trial:
o
All AEs (serious and non-serious).
•
After the individual patient’s end of trial: 
o
The Investigator does not need to actively monitor the patient for AEs but should 
only report relevant SAEs of which the Investigator may become aware of.


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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 7.3.3. Events which occurred after the REP will be considered as post treatment 
events.
AE reporting to sponsor and timelines
The investigator must report SAEs and non-serious AEs which are relevant for the reported SAE
on the BI SAE form via fax immediately (within 24 hours ) to the Sponsor’s unique entry point 
(country specific contact details will be provided in the ISF). The same timeline applies if 
follow-up information becomes available. In specific occasions the investigator could inform the 
Sponsor upfront via telephone. This does not replace the requirement to complete and fax the BI 
SAE form.
Information required
For each AE, the investigator should provide the information requested on the appropriate eCRF 
pages and the BI SAE form. The Investigator should determine the causal relationship to the trial 
medication and any possible interactions between the investigational drugs and a Non-
Investigational Medicinal Product (NIMP)/Auxiliary Medicinal Product (AMP).
The following should also be recorded as an SAE 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.


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All (S)AEs, including those persisting after individual patient’s end of trialmust be followed up 
until they have resolved, have been sufficiently characterized, or no further information can be 
obtained.
Pregnancy
In rare cases pregnancy might occur in a clinical trial.  Once a patient has been enrolled into a 
clinical trial after having taken trial medication the investigator must report immediately (within 
24 hours) a potential drug exposure during pregnancy to the sponsor’s unique entry point 
(country specific contact details will be provided in the ISF). The Pregnancy Monitoring Form
for Clinical Trials (Part A) should be used.   
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring Form 
for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, only 
the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. If 
there is an SAE associated with the pregnancy then the SAE 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).
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
This study will not analyse pharmokinetic or pharmodynamic parameters.
ASSESSMENT OF EXPLORATORY BIOMARKERS
5.5
This study will not analyse biomarkers.
OTHER ASSESSMENTS
5.6
 


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Modified Medical Research Council Dyspnea Scale 
The mMRC Dyspnea Scale uses a simple grading system to assess a patient´s level of dyspnea. 
All questions relate to everyday activities and are generally easily understood by patients. Scores 
range from 0 (none) to 4 (very severe) and are usually obtained in a few seconds. Patients will be 
asked to score their dyspnea at Visit 1.
 
 
 
  
APPROPRIATENESS OF MEASUREMENTS
5.7
Measurements of efficacy parameters will be consistent with the following generally recognized 
standards: 
Shuttle Test
The ISWT will be conducted according to the methodology described by Singh et al [R04-4259].
The 3min CSST will be conducted according to the methodology developed by Maltais et al
[P12-12739].
Spirometry
PFTs are a validated and well established measurement tool for lung function testing. PFTs will 
be conducted at clinic visits using the site’s own equipment which meets ATS/ERS criteria [P05-
12782]. FEV1, FVC and IC are standard measurements for the assessment of lung function.
Body Plethysmography 
Constant-volume variable-pressure body plethysmography will be used in the trial following the 
methodology and calibration procedures described by Coates et al. 1997 [R98-1487].


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
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 FC for time 
windows for the visits. After this, a discussion with the Clinical Monitor should take place
regarding the patient continuing in the trial.
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 prior to randomisation
The screening period (between visit 1 and visit 4) may be extended by an additional 2 weeks for 
administrative reasons.
If a patient experiences a COPD exacerbation or respiratory tract infection in the 6 weeks prior to 
visit 1, the visit will be postponed until 6 weeks following recovery from the infection or 
exacerbation. 
If a patient experiences a COPD exacerbation or respiratory tract infection during the screening 
period (between visit 1 and 4), randomisation will be postponed until 6 weeks following 
recovery from the infection or exacerbation. To be eligible, patients should be clinically stable in 
the opinion of the investigator for 3 weeks prior to the randomisation visit. 
If the screening period is extended by more than an additional 4 weeks, but not more than an 
additional 8 weeks, the screening examination has to be repeated prior to randomisation. The 
repeat screening examination will include a physical examination, vital signs (blood pressure and 
pulse rate), 12-lead ECG and clinical laboratory evaluation (haematology, serum chemistry, and 
pregnancy test). The patient should return for these evaluations 2 weeks prior to the re-scheduled 
randomisation visit (visit 4). All AEs and concomitant therapies will be recorded. If the 
screening period is to be extended more than an additional 8 weeks, the sponsor should be 
contacted. A decision whether the patient can continue in the trial will be made on a case by case 
basis. Clinically unstable COPD should be considered as a reason for discontinuation of the 
patient.
Refer to sections 4.2.1 and 4.2.2 for details on medications allowed to control COPD 
exacerbations and restrictions for these medications prior to PFTs. 


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Rescheduling after randomisation 
Subsequent visits should always be planned to take place to assure a minimum 6 week treatment 
period and a minimum 3 week wash-out period between treatment periods.
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 CML. 
Refer to sections 4.2.1 and 4.2.2 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 wash-out requirements following treatment of an acute exacerbation), the CML should be 
contacted.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening and run-in period
Screening Period
If there is any indication during the screening period that the patient is not stable enough, in the 
opinion of the investigator, to complete the trial or that the patient will be non-compliant with the 
trial medication or restrictions, the patient should not be randomised. This evaluation should be 
completed by the investigator.
Details of any patient who is screened for the trial but is found to be ineligible must be entered in 
the enrolment log and documented in the eCRF.
Patients must satisfy all inclusion and not meet any of the exclusion criteria prior to 
randomisation at visit 4 (see section 3.3.2 and section 3.3.3).


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Visit 0 Procedures and Observations
A preliminary check of in-/exclusion criteria is recommended at visit 0 to avoid unnecessary 
washout procedures in non-eligible patients.
Informed 
Consent
Informed consent will be obtained prior to patient participation in the trial, 
which includes any medication washout procedures or restrictions.
See section 6.1 for pulmonary test restrictions and section 3.3.3.1 for exercise 
test restrictions. 
BDI
Completed to ascertain eligibility for the trial (Appendix 10.12).
Rescue 
Medication
Rescue medication will be issued to all patients.  Please refer to section 4.2.1.
The patient will receive directions on the as needed use of the salbutamol 
(albuterol) MDI (as rescue medication) that will be dispensed at this visit.
Ipratropium 
Will be dispensed at the discretion of the investigator for patients washing out 
of LAMAs.
Patients will be contacted prior to each of the screening period visits to remind the patient of 
medication washouts and restrictions, and to bring back all rescue medication.
Visit 1 Procedures and Observations
Incremental Shuttle Walk Test and Reversibility Testing
Medication 
washout
Medication washout compliance for prohibited medications will be 
verified and visits may be rescheduled as appropriate (section 6.1)
Background 
Information
Demographic data, COPD background characteristics, baseline conditions 
and smoking status will be recorded.
mMRC 
Questionnaire
To be completed prior to study procedures.
Refer to Appendix 10.8.
Adverse Events
All AEs experienced since signing informed consent will be reviewed and
recorded.
Concomitant 
Therapy
Medication use for the previous 3 months will be recorded in the eCRF.
Inclusion / 
Exclusion
To be reviewed.
Physical 
Examination and 
12- Lead ECG
The physical examination includes measurements of blood pressure and 
pulse rate.  Refer to section 5.3.1.
The vital signs (seated) and ECG should be conducted following five 


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minutes rest and prior to blood sampling and to salbutamol (albuterol) 
dosing.
Laboratory tests 
Will be collected and submitted to the local laboratory for haematology, 
serum chemistry and pregnancy testing (if applicable). 
A fasted condition is not required. 
Blood samples need to be taken prior to the salbutamol (albuterol) dosing. 
Body 
Plethysmography
(Appendix 10.7)
Measurements (FRC, IC, TLC) will be taken prior to spirometry. 
Vital Signs
Blood pressure and pulse rate will be measured immediately before PFTs 
with the patient seated and rested for at least five minutes.
Spirometry 
•
The 24-hour clock time of the last cigarette smoked during the 12 
hours prior to the start of lung function measurements will be recorded.
•
Will be conducted between 7:00 a.m.-10:00 a.m. immediately prior to 
(-10 min) and ≥10 minutes and up to 15 minutes after the inhalation of 
4 puffs of salbutamol (albuterol). 
•
Please refer to inclusion criteria 2 and Appendix 10.3.
ISWT
To be performed 1 hour after spirometry. Please refer to Appendix 10.4.1.
The duration and the number of shuttles for each patient will be recorded 
in the eCRF.
The following will be measured during ISWT (please refer to FC):
•
BORG measurements - at rest, every 2 minutes during exercise and 
at the end of exercise. Refer to Appendix 10.5 for further details.
•
IC - at rest, every 2 minutes during exercise and at the end of 
exercise using mobile cardiopulmonary exercise equipment. Refer 
to Appendix 10.7 for further details.
•
Physiological parameters using mobile cardiopulmonary exercise 
equipment.
•
MDP to be performed at end of exercise. Refer to Appendix 10.11.
•
Locus of Symptom Limitation Visual Analog Scale (VAS) to be 
administered at the end of exercise. Refer to Appendix 10.6.
Training and 
Instructions
Patients will receive training and instructions on
•
The use of rescue medication (salbutamol/albuterol)
•
The use of the Respimat® Inhaler using the training kit


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•
Medication restrictions and washout requirements for the screening 
period and subsequent visits
•
Returning all issued medication to the clinic on all subsequent visits.
Rescue 
Medication
Patients qualified to enter the 3-week screening period of the trial will be 
issued additional rescue medication if needed.
IRT
Call IRT to register the patient in screening.  The patient’s GOLD stage 
will need to be entered into the IRT system.  Please refer to section 3.1.
Visit 2 Procedures and Observations
3 min CSST Speed Selection Visit 
Medication 
washout
Medication washout compliance for prohibited medications will be 
verified and visits may be rescheduled as appropriate (section 6.1)
Adverse Events
All AEs experienced since the previous visit will be reviewed and 
documented.
Concomitant 
Therapy
Any changes in concomitant medications since the last visit will be 
reviewed and documented.
Inclusion / 
Exclusion
To be reviewed.
3min CSST
Patients will conduct the 3min CSST at various speeds as outlined in 
Appendix 10.4.2.2. The speed selected at this visit will be used for all 
subsequent visits. 
The following will be measured during 3min CSST (please refer to FC):
•
BORG measurements - at rest, 1, 2, 2.5 minutes during exercise and 
at 3 min or the end of exercise. Refer to Appendix 10.5 for further 
details.
•
IC - at rest and at end of exercise using mobile cardiopulmonary 
exercise equipment. Refer to Appendix 10.7 for further details
•
Physiological parameters using mobile cardiopulmonary exercise 
equipment.
Rescue 
Medication
Patients will be issued additional rescue medication if needed and 
instructed to return all rescue medication to the clinic on the next 
scheduled visit.


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Visit 3 Procedures and Observations
Training 3min CSST Visit 
Medication 
washout
Medication washout compliance for prohibited medications will be 
verified and visits may be rescheduled as appropriate (section 6.1).
Adverse Events
All AEs experienced since the previous visit will be reviewed and 
documented.
Concomitant 
Therapy
Any changes in concomitant medications since the last visit will be 
reviewed and documented.
Inclusion / 
Exclusion
To be reviewed.
3min CSST
A training 3min CSST will be conducted after spirometry using the speed 
selected at visit 2 (Appendix 10.4.2.2).
The following will be measured during 3min CSST (please refer to FC):
•
BORG measurements - at rest, 1, 2, 2.5 minutes during exercise and 
at 3 min or the end of exercise. Refer to Appendix 10.5 for further 
details.
•
IC - at rest and at end of exercise using mobile cardiopulmonary 
exercise equipment. Refer to Appendix 10.7 for further details
•
Physiological parameters using mobile cardiopulmonary exercise 
equipment. 
•
MDP to be performed at end of exercise. Refer to Appendix 10.11.
Rescue 
Medication
Patients will be issued additional rescue medication if needed and 
instructed to return all rescue medication to the clinic on the next 
scheduled visit.
6.2.2
Treatment periods
Patients will be contacted prior to each of the visits to remind the patient of medication washout 
requirements, and to bring back all study and rescue medication. Patients must return study 
medication at visits 6 and 9
Visits 4 and 7 Procedures and Observations
First visit of each treatment period
Medication 
washout
Medication washout compliance for prohibited medications will be 
verified and visits may be rescheduled as appropriate (section 6.1)
Questionnaires
To be completed in the following order: CRQ-SAI (Appendix 10.10), 


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CRQ-SAS (Appendix 10.9), 
To be performed prior to dosing and study procedures.
 
Adverse Events
All AEs experienced since the previous visit will be reviewed and 
documented.
Concomitant 
Therapy
Any changes in concomitant medications since the last visit will be 
reviewed and documented.
Inclusion / 
Exclusion
Visit 4 only
To be reviewed.
Smoking Status
Will be recorded
Urine Pregnancy
Will be performed if needed.
Vital Signs
Blood pressure and pulse rate will be measured immediately before PFTs 
with the patient seated and rested for at least five minutes.
Spirometry 
Baseline spirometry measurements will be performed between 7:00 and 
10:00am and prior to exercise testing. Refer to FC.
The 24-hour clock time of the last cigarette smoked during the 12 hours 
prior to the start of lung function measurements will be recorded.
3min CSST
To be performed prior to dosing at the speed selected at visit 2.
Please refer to Appendix 10.4.1.
The following will be measured during 3min CSST (please refer to FC):
•
BORG measurements - at rest, 1, 2, 2.5 minutes during exercise and 
at 3 min or the end of exercise. Refer to Appendix 10.5 for further 
details.
•
IC - at rest and at end of exercise using mobile cardiopulmonary 
exercise equipment. Refer to Appendix 10.7 for further details
 
 
Randomisation 
Call
Visit 4 only
To be performed by calling IRT.


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Assignment and 
dispensing of 
trial drug 
Allocate the appropriate medication kits using IRT.
2 Respimat® treatment boxes and 1reserve Respimat® inhaler are assigned.
Trial drug 
training and 
administration
The patient will self-administer the trial drug (from the new assigned 
Respimat® inhaler) under the oversight of site staff. Instructions on how to
assemble and prime the Respimat® inhaler at home should also be 
reviewed.
Please refer to section 4.1.4.3.
First dose of study medication for the treatment period will be self-
administered between 07:00 and 10:00 a.m.; start-time of inhalation will 
be recorded. Note that at subsequent clinic visits, study medication will be 
self-administered preferably within ±30 minutes of time of administration 
at visit 4 AND between 7:00 a.m. and 10:00 a.m.
Training and 
Instructions
Patients will receive training and instructions on
•
Medication restrictions and washout requirements for the screening 
period and subsequent visits
•
Returning all issued medication to the clinic on all subsequent visits.
Rescue 
Medication
Patients will be issued additional rescue medication if needed and 
instructed to return all rescue medication to the clinic on the next 
scheduled visit.
Visits 5, and 8 Procedures and Observations
Clinic visits after 3 weeks of each treatment period
No new study medication will be dispensed at these visits.
Medication washout
Medication washout compliance for prohibited medications will be 
verified and visits may be rescheduled as appropriate (section 6.1)
Adverse Events
All AEs experienced since the previous visit will be reviewed and 
documented.
Concomitant 
Therapy
Any changes in concomitant medications since the last visit will be 
reviewed and documented.
Trial Drug 
Administration
Study medication will be self-administered within ±30 minutes of time 
of administration at visit 4 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.


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Vital Signs
Blood pressure and pulse rate will be measured immediately before 
PFTs with the patient seated and rested for at least five minutes.
 
 
 
 
 
 
 
 
 
 
 
 
 
Training and 
Instructions
Patients will receive training and instructions on
•
Medication restrictions and washout requirements for the screening 
period and subsequent visits
•
Returning all issued medication to the clinic on all subsequent 
visits.
Rescue Medication
Patients will be issued additional rescue medication if needed and 
instructed to return all rescue medication to the clinic on the next 
scheduled visit.
If the patient is unable to complete the entire test-day visit, the eCRF will be completed 
indicating the reason for stopping testing, rescue medication given and time of rescue 
medication. Patients, who are unable to complete the test-day visit, may leave the clinic only 
upon instruction from the supervising physician. 


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Visits 6 and 9 (EOT) Procedures and Observations
Clinic visits after 6 weeks of each treatment period
No new study medication will be dispensed at these visits.
Medication washout
Medication washout compliance for prohibited medications will be 
verified and visits may be rescheduled as appropriate (section 6.1)
Questionnaires
To be completed in the following order: CRQ-SAI (Appendix 10.10), 
CRQ-SAS (Appendix 10.9),
To be performed prior to dosing and study procedures.
Adverse Events
All AEs experienced since the previous visit will be reviewed and 
documented.
Concomitant 
Therapy
Any changes in concomitant medications since the last visit will be 
reviewed and documented.
Physical 
Examination and 
12- Lead ECG
The physical examination includes measurements of blood pressure and 
pulse rate.  Refer to section 5.3.1.
The vital signs (seated) and ECG should be conducted following five 
minutes rest and prior to blood sampling and to salbutamol (albuterol) 
dosing.
Laboratory tests
Will be collected and submitted to the local laboratory for haematology 
and serum chemistry. 
A fasted condition is not required. 
Smoking Status 
Will be recorded
Urine Pregnancy
Will be performed if applicable. 
Trial Drug 
Administration
Study medication will be self-administered within ±30 minutes of time 
of administration at visit 4 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. 
Vital Signs
Blood pressure and pulse rate will be measured immediately before 
PFTs with the patient seated and rested for at least five minutes.
Spirometry 
Lung function measurements will be performed 1-hour (±10 minutes)
post-dose and prior to exercise testing.  Refer to FC.


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The 24-hour clock time of the last cigarette smoked during the 12 hours 
prior to the start of lung function measurements will be recorded.
3min CSST
To be performed 2 hours (+15 min) post-dose using the speed selected 
at visit 2.
Please refer to FC and Appendix 10.4.1.
The following will be measured during 3min CSST (please refer to 
FC):
•
BORG measurements - at rest, 1, 2, 2.5 minutes during exercise 
and at 3 min or the end of exercise. Refer to Appendix 10.5 for 
further details.
•
IC - at rest and at end of exercise using mobile cardiopulmonary 
exercise equipment. Refer to Appendix 10.7 for further details
 
 
 
 
 
 
Training and 
Instructions
Patients will receive training and instructions on
•
Medication restrictions and washout requirements for the wash-out 
period (visit 7) and subsequent visits
•
Returning all issued medication to the clinic on all subsequent 
visits.
Trial Drug 
Collection
All study medication will be collected at visits 6 and 9.
Rescue Medication
Patients will be issued additional rescue medication if needed and 
instructed to return all rescue medication to the clinic on the next 
scheduled visit.
IRT
Visit 9 only
Call IRT to register the patient as completed.  
If the patient is unable to complete the entire test-day visit, the eCRF will be completed 
indicating the reason for stopping testing, rescue medication given and time of rescue 


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medication. Patients, who are unable to complete the test-day visit, may leave the clinic only 
upon instruction from the supervising physician. 
6.2.3
Follow-up Period and Trial Completion
Premature Discontinuation Procedures and Observations
These procedures should be performed after any premature withdrawal of patients that took at 
least one dose of trial medication.
Adverse Events
All AEs experienced since the previous visit will be reviewed and 
documented.
Concomitant 
Therapy
Any changes in concomitant medications since the last visit will be 
reviewed and documented.
Physical 
Examination and 
12- Lead ECG
The physical examination includes measurements of blood pressure and 
pulse rate.  Refer to section 5.3.1.
The vital signs (seated) and ECG should be conducted following five 
minutes rest and prior to blood sampling and to salbutamol (albuterol) 
dosing.
Laboratory tests
Will be collected and submitted to the local laboratory for haematology 
and serum chemistry. 
A fasted condition is not required. 
Smoking Status 
Will be recorded
Urine Pregnancy
Will be performed if applicable. 
Vital Signs
Blood pressure and pulse rate will be measured immediately before PFTs 
with the patient seated and rested for at least five minutes.
Spirometry 
Will be conducted if possible. Refer to FC.
The 24-hour clock time of the last cigarette smoked during the 12 hours 
prior to the start of lung function measurements will be recorded.
Trial Drug 
Collection
All study medication will be collected.
IRT
Call IRT to register the patient as discontinued.  


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Follow-up Visit 10 Procedures and Observations
At the completion of Visit 9, the follow-up visit should be performed as described in the FC.
The investigator should make every effort to perform a follow-up visit 21 days after the last dose 
of study medication in patients that withdraw prematurely.
Adverse Events
All AEs experienced since the previous visit will be reviewed and 
documented.
Concomitant 
Therapy
Any changes in concomitant medications since the last visit will be 
reviewed and documented.
Physical 
Examination and 
12- Lead ECG
•
The physical examination includes measurements of blood pressure and 
pulse rate.  Refer to section 5.3.1.
•
The vital signs (seated) and ECG should be conducted following five 
minutes rest and prior to blood sampling and to salbutamol (albuterol) 
dosing.
•
To be completed in the event of any clinically relevant findings at the 
EOT visit.
Laboratory tests
•
Will be collected and submitted to the local laboratory for haematology 
and serum chemistry. 
•
A fasted condition is not required. 
•
To be completed in the event of any clinically relevant findings at the 
EOT visit.
Urine Pregnancy
Will be performed if applicable. 
Trial Completion
Trial completion is defined as last dose of trial medication followed 21 
days later by the follow-up visit.
The clinical monitor must be consulted on all persistently abnormal tests and SAEs until it is 
agreed that follow-up is no longer necessary.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a randomised, double-blind, cross-over study to determine the effect of 6 weeks treatment 
of orally inhaled tiotropium + olodaterol FDC (5/5 µg) delivered by the Respimat® Inhaler, on 
breathlessness during the three minute shuttle test in patients with COPD.  The effect of two 
treatments (T+O vs. tiotropium) in this cross-over study will be compared.
Based on these design considerations, a mixed effect repeated measures model (MMRM) with 
treatment and period as fixed effects and patient as a random effect will be used for the primary 
analysis. Detailed specifications will be provided in section 7.3. 
NULL AND ALTERNATIVE HYPOTHESES
7.2
The following hypotheses (two-sided α = 0.05) will be tested for the primary endpoint – change 
from baseline in intensity of breathlessness measured using the MBS-S at the end of the 3min 
CSST - after 6 weeks of treatment.
H0: Mean MBS-S3 for (Tiotropium + Olodaterol) = Mean MBS-S3 for Tiotropium
H1: Mean MBS-S3 for (Tiotropium + Olodaterol) ≠ Mean MBS-S3 for Tiotropium
Where MBS-S3 is the primary endpoint, the MBS-S at the end of the 3 minute shuttle test after 6 
weeks of treatment. 
PLANNED ANALYSES
7.3
The efficacy analysis will be performed in all randomised patients who were documented to have 
received any dose of trial medication and who have both baseline and any evaluable post-
baseline measurement for the primary endpoint. This set will be called Full Analysis Set (FAS).
All randomised patients taking any dose of the trial medication will be included in the safety 
evaluation (Treated Set).
The handling of randomised patients who received the wrong treatment will be specified in the 
TSAP.


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7.3.1
Primary endpoint analyses
In the primary analysis, the two-sided hypotheses as given in section 7.2 will be tested based on 
MBS-S using a restricted maximum likelihood (REML)-based MMRM. This model will include 
treatment and period as fixed effects, patient as a random effect and period baseline as well as 
patient baseline as covariates. 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 
treatment contrasts will be presented together with the 95% confidence intervals (CI) and p-
values.
Period baseline
The period baseline is defined as the pre-dose measurement, the MBS-S at the end of the 3 
minute CSST, performed prior to dosing on the first day of each period.
Patient baseline
The patient baseline is defined as the mean of non-missing period baselines for each patient.
7.3.2
Secondary endpoint analyses
The MMRM model described for the primary analysis will be performed for secondary 
endpoints as listed in section 5.1. Adjusted mean values as well as treatment contrasts will be 
presented together with the 95% CI. All calculated p-values should be considered descriptive for 
the analysis of the secondary endpoints.
7.3.3
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary. Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the residual effect period (REP), a period of 
21 days after the last dose of trial medication, will be assigned to the treatment period for 
evaluation.
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.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end of 
the residual effect period will be considered ‘treatment-emergent’.  The residual effect period is 
defined as 21 days after last dose of study medication (separately for each treatment period in the 


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crossover). Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system organ 
class and preferred term after coding according to the current version of 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.
INTERIM ANALYSES
7.4
No interim analysis is planned.
HANDLING OF MISSING DATA
7.5
In general, missing data at a given visit will be imputed by the available data from the patient at 
that visit and completely missing visits will be handled through the statistical model.
Additional details on the imputation of missing data will be specified in the Trial Statistical 
Analysis Plan (TSAP) prior to unblinding.
RANDOMISATION
7.6
Patients will be randomised in blocks to double-blind treatment. Approximately equal numbers 
of patients will be randomised to each treatment sequence. BI will arrange for the randomisation
and the packaging and labelling of trial medication. 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. The block size will be documented in 
the CTR. Access to the codes will be controlled and documented.
IRT will also be set-up to ensure that the number of GOLD Stage II patients is capped at 
approximately 50% and the number of GOLD Stage III patients is capped at approximately 50%.


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DETERMINATION OF SAMPLE SIZE
7.7
Based on a pilot study [P12-12739], the standard deviation of within-subject treatment difference
(measured by 10-point modified BORG scale) for 3min CSST is approximately 1.776 for COPD 
patients. The pilot study was a placebo controlled, double-blind cross-over study in patients with 
COPD to investigate the effect of administration of 500 μg nebulized ipratropium bromide vs. 
saline placebo. It is deemed reasonable to assume that the variability for within-patients 
difference should be similar for this trial.
Assuming a delta of 0.5 BORG units and various choices of power, nQuery Advisor® 7.0 
MOT0-1 (one-sample t-test) yielded the following results.
Table 7.7: 1
Total calculated sample size
Power
Std. Dev. (1.776)
80%
101
90%
135
Since patient drop out over 12 weeks of treatment is expected to be quite low and the MMRM 
model specified for the primary analysis naturally accounts for missing data, there has been no 
sample size inflation to account for patient attrition in the sample size calculations. Based on the 
standard deviation of 1.776 and a type one error rate of 0.05 (two-sided), the ability to detect a 
difference of 0.5 BORG units would require a sample size of 101 to maintain 80% power to 
reject the null hypothesis. Since there are two sequences of treatments, the sample sizes are 
rounded up to the nearest even number. The required sample size is 102.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) and 
the harmonized standards for Medical Devices (ISO 14155-01 and ISO 14155-02).
The trial will be carried out in compliance with the protocol, the ethical principles laid down in 
the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for 
Good Clinical Practice (GCP), and relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor 
with regard to publication of the results of this trial are described in the Investigator contract.
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/ IEC and 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.”


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Re-consenting may become necessary when new relevant information becomes available and
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
RECORDS
8.3
eCRF for individual patients will be provided by the Sponsor. See section 4.1.5.2 for rules about 
emergency code breaks. For drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and other 
data pertinent to the investigation on each trial subject. Source data as well as reported data 
should follow good documentation practices and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail). Data reported on the 
CRF must be consistent with the source data or the discrepancies must be explained.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))


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
Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and pulmonary function testing reports, with 
proper documented medical evaluation 

Completion of Patient’s Participation in the trial” (end date; in case of premature
discontinuation document the reason for it)

Prior to allocation of a patient to a treatment into a clinical trial, there must be
documented evidence in the source data (e.g. medical records) that the trial participant
meets all inclusion criteria and does not meet any exclusion criteria. The absence of
records (either medical records, verbal documented feedback of the patient or testing
conducted specific for a protocol) to support inclusion/exclusion criteria does not make
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and inhouse 
data quality review. The frequency of on-site monitoring will be determined by assessing all 
characteristics of the trial, including its nature, objective, methodology and the degree of any 
deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g. 
FDA). The CRA and auditor may review all CRFs and informed consents. The accuracy of the 
data will be verified by direct comparison with the source documents described in section 8.3.1.
The sponsor will also monitor compliance with the protocol and ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient data obtained as a result of this trial is considered confidential and disclosure 
to third parties is prohibited with the exceptions noted below. Patient privacy will be ensured by 
using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
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 / IEC and the regulatory authorities. 
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment pf the first patient in the whole trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the last 
patient at an individual trial site ends trial medication (as scheduled per protocol or prematurely). 
Individual Investigators will be notified of SUSARs occurring with the trial medication until 30 
days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.


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The IEC / CA in each participating EU member state will be notified about the trial milestones 
according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed the 
trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one year 
from the end of a clinical trial as a whole, regardless of the country of the last patient (EU or 
non-EU).


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P03-01262
ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit 
Care Med 167 (2), 211 - 277 (2003)
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.
Standardisation 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)
P10-08261
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. http://www.goldcopd.com/ (access date: 12 May 2011) 
(2010)


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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)
P11-08042
Bedard ME, Brouillard C, Pepin V, Provencher S, Milot J, Lacasse Y, et. al.  
Tiotropium improves walking endurance in chronic obstructive pulmonary 
disease.  Eur Respir J 39 (2), 265 - 271 (2012)
P12-12739
Sava F, Perrault H, Brouillard C, Darauay C, Hamilton A, Bourbeau J, et. al. 
Detecting improvements in dyspnea in COPD using a three-minute constant rate 
shuttle walking protocol. COPD J Chronic Obstruct Pulm Dis 9 (4), 395 - 400 
(2012)
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)
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). 
http://www.goldcopd.org/uploads/users/files/GOLD_Report_2014.pdf (access 
date: 22 January 2014); Global Initiative for Chronic Obstructive Lung Disease 
(GOLD) (2014)
R03-2273
Draft consensus guideline: choice of control group in clinical trials (released for 
consultation at step 2 of the ICH process on 7 May 1999 by the ICH steering 
committee).
R04-4259
Singh SJ, Morgan MDL, Scott S, Walters D.  Hardman AE Development of a 
shuttle walking test of disability in patients with chronic airways obstruction. 
Thorax 47, 1019 - 1024 (1992)
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


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R10-4391
Kenward MG, Roger JH 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).  http://www.ich.org/LOB/media/MEDIA5544.pdf (access date:11.10.2010) 
(2009)
R13-2820
Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, et. al.  
Exercise and physical activity in the prevention and treatment of atherosclerotic 
cardiovascular disease: a statement from the Council on Clinical Cardiology 
(Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on 
Nutrition, Physical Activity, and MetabolismL (Subcommittee on Physical 
Activity).  Circulation 107 (24), 3109 - 3116 (2003)
R13-4694
Spruit MA, et al.   ATS/ERS Task Force on Pulmonary Rehabilitation An official 
American Thoracic Society/European Respiratory Society statement: key 
concepts and advances in pulmonary rehabilitation.  Am J Respir Crit Care Med 
188 (8), e13 - e64 (2013)
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)
R15-4207
Laviolette L, Laveneziana P. Dyspnoea: a multidimensional and multidisciplinary 
approach. Eur Respir J 2014; 43: 1750–1762.
R15-4208
Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic 
Society statement: update on the mechanisms, assessment, and management of 
dyspnea. Am J Respir Crit Care Med 2012; 185: 435–452.
R15-4209
Scano G, Stendardi L, Grazzini M. Understanding dyspnoea by its language. Eur 
Respir J 2005; 25: 380–385.
R15-4210
Banzett et al. Multidimensional Dyspnea Profile: an instrument for clinical and 
laboratory Research. Eur Respir J 2015; 45: 1681–1691.
R15-4211
Banzett RB, Pedersen SH, Schwartzstein RM, et al. The affective dimension of 
laboratory dyspnea: air hunger is more unpleasant than work/effort. Am J Respir 
Crit Care Med 2008; 177: 1384–1390.


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R15-4319
Perrault H, Baril J, Henophy S, Rycroft A, Bourbeau J, Maltais F
Paced-walk and step tests to assess exertional dyspnea in COPD.
COPD J Chronic Obstruct Pulm Dis 6 (5), 330 - 339 (2009).
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 6 (Suppl 16), 5 - 40 (1993)
R94-1529
Chow SC, Liu JP, Design and Analysis of Bioavailability and Bioequivalence 
Studies.   New York: Marcel Dekker Inc (1992)
R96-2117
Mahler DA, Weinberg DH, Wells CK, Feinstein AR
The measurement of dyspnea. Contents, interobserver agreement, and physiologic 
correlates of two new clinical indexes.  Chest 85 (6), 751 - 758 (1984)
R98-0973
Roca J, Whipp BJ, Agusti AGN, Anderson SD, Casaburi R, Cotes JE, et. 
Al.Weisman I Clinical exercise testing with reference to lung diseases: 
indications, standardization and interpretation strategies. Eur Respir J 10, 2662 -
2689 (1997)
R98-1487
Coates AL, Peslin R, Rodenstein D. Stocks J Measurement of lung volumes by 
plethysmography.  Eur Respir J 10, 1415 - 1427 (1997)
R99-0401 
Crapo RO, Morris AH, Clayton PD, Nixon CR. Lung volumes in healthy 
nonsmoking adults. Bull Eur Physiopathol Respir 18, 419 - 425 (1982)
UNPUBLISHED REFERENCES
9.2
c01735218-03
  Clinical Trial Report: Tiotropium + 
olodaterol fixed dose combination inhalation solution – Respimat®.  TOnado™ 1 
1237.5. 10 April 2014.
c01735246-02
  Clinical Trial Report: Tiotropium + olodaterol
fixed dose combination inhalation solution – Respimat®.  TORRACTO™ 
1237.15. 2 April 2014.
c01735249-03
 Clinical Trial Report: Tiotropium + 
olodaterol fixed dose combination inhalation solution – Respimat®.  TOnado™ 2 
1237.6. 10 April 2014.


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c02094185-02
 Clinical Trial Report: Tiotropium + olodaterol
fixed dose combination inhalation solution – Respimat®. MORACTO™ 1 1237.   
13.  08 April 2014.
c02094318-02
  Clinical Trial Report: Tiotropium + olodaterol
fixed dose combination inhalation solution – Respimat®. MORACTO™ 2 1237. 
14.  07 April 2014.


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10.
APPENDICES
THE RESPIMAT® INHALER  
10.1
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 (A) 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 firmly against a firm surface to 
ensure that it has gone all the way in (2b).
The cartridge will not be flush with the inhaler; you will still 
see the silver ring on the lower end of the cartridge.
2b
Do not remove the cartridge once it has been inserted into the 
inhaler.
  3
3
Replace the clear base (G). 
Do not remove the clear base again.


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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 (30 
medicinal doses).


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Daily use of your Respimat® inhaler
You will need to use this inhaler only ONCE A DAY. 
Each time you use it take TWO PUFFS.
I
I
Hold the Respimat® inhaler upright, with the grey cap (A) 
closed, to avoid accidental release of dose. Turn the 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.


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When to get a new Respimat® inhaler
The Respimat® inhaler contains 60  puffs (30 medicinal doses). The 
dose indicator shows approximately how much medication is left.  
When the pointer enters the red area of the scale, there is, 
approximately, medication for 7 days (14 puffs) 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. 
What if...
What if...
Reason
What to do
I can’t turn the base easily.
a) 
The Respimat®
inhaler is already prepared 
and ready to use. 
b) 
The Respimat®
inhaler is locked after 60 
puffs (30 doses).
a) 
The Respimat®
inhaler can be used as it is.
b) 
Prepare and use your 
new  Respimat® inhaler.
I can’t press the dose 
release button.
The clear base has not been 
turned.
Turn the clear base until it 
clicks. (half a turn)
The clear base springs back 
after I have turned it.
The clear base was not 
turned far enough.
Prepare the Respimat®
inhaler for use by turning 
the clear base until it 
clicks. (half a turn)
I can turn the clear base 
past the point where it 
clicks.
Either the dose release 
button has been pressed, or 
the clear base has been 
turned too far.
With the grey cap closed, 
turn the base until it clicks. 
(half a turn) 
How to care for your inhaler
Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, at 
least once a week.
Any minor discoloration in the mouthpiece does not affect the performance of your Respimat® inhaler.
  
If necessary, wipe the outside of your Respimat® inhaler with a damp cloth.


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Further information
The Respimat® inhaler must not be disassembled after inserting the cartridge and replacing the clear 
base.
Do not touch the piercing element inside the base.
Keep out of the reach and sight of children.
Do not freeze.
Boehringer Ingelheim Pharma GmbH & Co. KG
D - 55216 Ingelheim, Germany
  0123 HI-Master-Version-06-tiotropium+olodaterol-combination-Respimat-20140516


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RETURN OF INHALERS/CARTRIDGES
10.2
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. Procedures for this return, including name, address and 
contact person are provided in the ISF.


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ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA
10.3
Reversibility testing [P05-12782]
At the screening visit (visit 1), following the completion of three acceptable pre-bronchodilator
forced expiratory manoeuvres, salbutamol (albuterol) 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 (albuterol) is inhaled in one breath to TLC. The breath is then 
held for 5–10s before the patient exhales. Four separate doses (total dose 400 μg) are delivered 
at approximately 30-second intervals (this dose ensures that the response is high on the
salbutamol (albuterol) 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 (albuterol) is inhaled. !"# $%&'()*%+,"%-./0'%* 1#0&2*#1#+'& 12&' 1##' '"# 
.+,/2&.%+ ,*.'#*.0 &$#,.3.#- .+ &#,'.%+ 454565
The spirometers and their use, including daily calibration, must meet American Thoracic Society 
(ATS)/ European Respiratory Society (ERS) criteria.
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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EXERCISE TESTING – ISWT AND 3MIN CSST
10.4
To supplement the information on exercise testing using the ISWT and 3min CSST described 
in this chapter, a Manual of Procedures (MOP) has been developed. More detailed information 
on the procedure, on staffing, site and equipment requirements, patient preparation, IC
measurements, and calculations etc. can be found in this MOP, which is filed in the ISF.
10.4.1
General considerations for exercise testing
Exercise performance variability
A number of physiological and psychological factors are known to affect exercise 
performance. Lack of attention to controlling these extraneous factors may result in an 
unacceptable degree of variability in exercise performance. As such, certain requirements have 
been put in place to reduce exercise performance variability:
Physiological:
Pre-exercise diet: Patients are to be encouraged to eat breakfast before coming to the clinic. 
However, patients should not eat within 2 hours of exercise tests.
•
Hydration state: Patients are to be encouraged to maintain an adequate hydration state 
during the morning of the exercise tests (i.e., drink lots of water).
•
Environmental conditions (temperature, humidity): Temperature and humidity should be 
controlled within the laboratory at comfortable levels, and should be recorded each 
testing day.
Previous exercise:
•
Fatigue: Patients should be encouraged to stay well-rested and to refrain from any 
strenuous, fatiguing or exhausting activities (e.g., walking up hills, walking up many 
flights of stairs, running, cycling, shovelling snow, strenuous household chores) on the 
morning of exercise tests.
•
Delayed onset muscular soreness (DOMS): Very strenuous, heavy type of activities, 
especially activities to which the patient is unaccustomed, can lead to muscle soreness 
24-48 hours after the activity. Patients should be encouraged to refrain from any type of 
heavy lifting, exhaustive digging in the garden etc., for 2-3 days prior to each clinic visit, 
especially if the patient has not performed these activities recently.
Psychological:
•
External motivational cues: Motivational cues provided to the patient can have profound 
effects on exercise performance. It is imperative that external motivational cues are 
controlled across patients and across sites.


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•
Time of exercise: No visual cues regarding the time of exercise should be provided to the 
patient. The patient’s watch should be removed prior to exercise, and all other 
timekeeping devices (e.g., trial staff watches, wall clocks, stopwatch etc.) should be kept 
away from the patient’s view.
•
Verbal encouragement: During exercise testing, the wording and intensity of verbal 
encouragement provided to the patient will be standardized, and will preferably only be 
provided by one member of the trial team, who is blinded to the results of the lung 
function tests. Appropriate positive words should be used to encourage the patient to 
continue walking. The tone of the encouragement should be enthusiastic and supportive, 
but not overbearing, overly loud or coercive in nature. Examples would be "good work", 
"well done", "excellent job so far" and "keep up the good work". Reinforcement could 
also consist of "that's a good walking rate" or, if the walking rate is dropping, "keep up 
the walking rate - that's great".
•
Familiarity with surroundings: Trial staff should allow as much time as necessary for the 
patient to become comfortable with the laboratory surroundings.
•
Distractions: During the exercise tests, access to the laboratory should be restricted to 
trial staff as much as possible. The noise level in the laboratory should be kept to a 
minimum, except for those sounds specifically related to the conduct of the test. This will 
ensure that the patient is able to concentrate on the task at hand, and will also ensure that 
the patient is attentive to the verbal encouragement provided by the designated member 
of the trial team.
•
Comfort with equipment: Patients should be appropriately dressed for exercise (e.g., 
shorts or track pants, gym shoes, T-shirt or sweat shirt), and trial staff should ensure that 
the patient is comfortable with the equipment prior to starting the exercise.
•
Familiarity with test: Before starting exercise, a member of the trial team should make 
sure that the patient is completely familiar with the type of exercise that is to be 
performed; for the incremental test, patients should be told that during the test they will 
have to walk progressively faster. For the constant speed tests, patients should be told that 
the speed of walking will be constant throughout the test. It is important that the patient
understands the difference between the incremental test and the constant speed tests.
•
For the ISWT: It is extremely important that the patient understands that there is no 
specific time limit to the exercise test, and that the test will continue as long as the patient
is able to. It must be stressed to the patient that the trial team will not stop the test unless 
there is concern for the patient’s safety, or the patient is unable to maintain the required 
walking pace.


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•
Performance incentives: No external incentives for performance (i.e., rewards for 
performance) should be given to the patient, especially as the patient nears the point of 
limitation, but also prior to or at any time during the exercise.
Heart rate and safety monitoring:
•
Heart rate and oxygen saturation will be monitored during shuttle tests using a mobile 
pulse oximeter. 
•
Blood pressure will be determined before exercise, at end-exercise, five minutes after 
termination of exercise and when, for clinical reasons, it is required.
Personnel qualifications:
•
Exercise challenges should be conducted by adequately trained personnel with a basic 
knowledge of exercise physiology.
•
Technicians familiar with normal and abnormal responses during exercise and trained in 
CPR should be present throughout the test.
•
The supervising physician must be readily available to respond as needed. The degree of 
patient supervision should be increased if warranted by the clinical status of the patient.
Safety issues:
Cardiac (bradyarrhythmias, ventricular tachycardia, myocardial infarction, heart failure, 
hypotension, and shock) and non-cardiac (musculoskeletal trauma, severe fatigue, dizziness, 
fainting, body aches) complications of exercise challenges have been reported.
Consequently during the test, study personnel should be alert to any abnormal event.
Indications to stop the test must be clearly established and known by the personnel involved in 
testing.
Symptoms such as:
•
acute chest pain,
•
sudden pallor,
•
loss of co-ordination,
•
mental confusion,
•
extreme dyspnea.
If the exercise test has been stopped for one of these reasons, the patient should be monitored 
in the laboratory until signs / symptoms / ECG modifications have completely cleared. Full 
CPR equipment should be available in the laboratory. The patient will be withdrawn from the 
study.


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10.4.2
Shuttle Test 
Shuttle tests will be performed in all patients of this trial. Selection of sites is based on past 
experience with the test and/or the availability of suitable infrastructure and qualified 
personnel. 
The shuttle test is performed on a flat, straight walking track, in a quiet treatment area that is at 
least 12 meters in length and approximately 2 meters wide, and clear of hospital traffic and 
obstacles. The standard instructions are given by trained site staff. Patients are required to 
walk, jog or run back and forth, in loops of 10 meters long. Cones are placed half a meter from 
the end, so they are 9 meters apart. The patient must keep pace with the pre-recorded auditory 
signal such that he/she completes a turn as each audio signal sounds.
Figure 10.4.2:1: Set up for the shuttle test
During the test oxygen saturation and heart rate will be monitored using a pulse oximeter 
(fingertip or ear lobe sensor).  Patients will also wear mobile cardiopulmonary exercise 
equipment. A chair should be placed in the immediate surroundings of the track for the patient 
to rest before and at the end of the test.
For the ISWT at visit 1, the end of the test will be signaled
a) by the patient, when he feels too breathless or fatigued to continue at the required speed.
b) by the operator when the patient fails to keep up to auditory signals after repeated 
warnings and encouragements (patient is more than 0.5 meter from the cone at the beep) 
and is unable to catch up within 3 shuttles.
c) when the patient is unable to continue safely (in the opinion of the supervising technician 
or physician).
For the 3min CSST, the end of the test will be signaled
a) by the patient, when he feels too breathless or fatigued to continue at the required speed.
b) by the operator when the three minutes of testing is completed.
c) by the operator when the patient fails to keep up to auditory signals after repeated 
warnings and encouragements (patient is more than 0.5 meter from the cone at the beep) 
and is unable to catch up within 3 shuttles.
d) when the patient is unable to continue safely (in the opinion of the supervising technician 
or physician).
nine metres
nine metres


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The test should also be interrupted when symptoms occur as described in the safety section 
above.
Patient preparation:
•
Patients should not eat for at least 2 hours before any exercise challenge and should avoid 
caffeine-containing products the morning of and during the testing period.
•
Patients should dress appropriately for the exercise challenge (i.e., comfortable shoes and 
clothing).
•
On arrival in the laboratory, a detailed explanation of the testing procedure should be 
given to the patient, outlining the risks involved and potential complications (see safety 
issues section above).
•
Before exercise, blood pressure and heart rate are measured; the pulse oximetry sensor is 
carefully placed and secured to ensure good recordings. Nail polish and acrylic nails do 
not allow correct measurements and should be removed.
•
Good communication with the patient throughout the whole procedure increases the 
patient’s confidence and helps to ensure a good effort by the patient. Standardized 
instructions from the CD/ instruction sheet should be used during the test. Standardized 
and continuous encouragement to the patient should preferably be provided by only one 
member of the trial team who is blinded to the results of the spirometry.
Incremental Shuttle Walk Test
10.4.2.1
In addition to adhering to the general considerations for exercise challenges described above, 
the following specific procedures should be adhered to during the ISWT at visit 1:
The ISWT is a progressive test: the patient walks/jogs/runs up and down a 10 meter course at a 
speed dictated by an audio signal. Every minute the speed increases. Every change in speed 
will be indicated by a triple audio signal (triple bleep).
The test starts with a triple bleep [start the stopwatch: Timing starts at the first triple beep, 
when the patient starts walking at the slowest speed (level 1)]; the patient starts at one of the 
cones. Thereafter, the CD emits a single bleep at regular intervals; the patient is advised to 
walk at a steady pace, aiming to turn around at the cone at the opposite end of the course when 
he/she hears the signal (single bleep). When the signal sounds the patient should be turning 
around the cone and proceed back down the course.


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Each minute the speed of walking is increased by a small increment; a change of speed to the 
next level is indicated by a triple bleep from the CD, and the operator asks the patient to 
increase his speed slightly. There are 12 levels of speed beginning at 0.50 m/s and ending at 
2.37m/s.
To help the patient to establish the routine of the test, the operator walks alongside the patient 
for the first minute (3 shuttles the first minute). When the patient reaches the cone before the 
signal, he/she is instructed to wait until the signal indicates that he/she can proceed. When the 
patient did not reach the cone within 0.5 meter when the signal sounds, the operator asks the 
patient to increase his speed (“You’re not going fast enough; try to make up the speed this 
time”); if the patient fails to keep up the required pace after repeated warnings and 
encouragements, the test ends.
During the test patients should be encouraged (in a standardized way) to keep the pace or to 
catch up when lagging behind.
Patients will be asked to rate the intensity of breathing and leg discomfort using the MBS-S
(see section 10.5) prior to exercise, every two minutes during exercise and at end-exercise.
This is a maximal test. The patient will exercise until:
•
limited by symptoms (i.e., is unwilling to continue exercising because of the discomfort 
associated with the exercise); OR
•
unable to maintain the walking pace emitted by the CD (even with repeated 
encouragement): patient is not within 0.5 meter from the cone at the beep and not able to 
catch up within 3 shuttles; OR
•
unable to continue safely (in the opinion of the supervising technician or physician). 
The duration of exercise will be recorded using a stopwatch (in minutes and seconds). 
At the end of exercise, after having taken the peak blood pressure measurement, the patient can 
rest on the chair, or walk around if he/she prefers.
At end-exercise the following parameters will be recorded immediately: oxygen saturation, 
(SpO2%), blood pressure, heart rate and rating of the intensity of breathing discomfort and leg 
discomfort (MBS-S), followed by the MDP and locus of symptom limitation VAS (Appendix 
10.6). Repeat blood pressure, heart rate and SpO2% measurements will be taken five minutes
later to assess recovery rate.
The number of completed shuttles is recorded on the ISWT recording sheet. One shuttle is 10 
meters, the distance covered between two bleeps. The last shuttle is considered complete if at 
least ¾ of the distance was covered when the patient stopped the test. The total distance 
covered is calculated (distance in meters = number of complete shuttles x10). 


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The patient should remain in a clinical area for at least 15 minutes following an uncomplicated 
test or for at least 30 minutes after resolution of any symptoms. 
Note that patients who complete level 12 will not be eligible to continue in the study (exclusion 
criterion 22).
Constant Speed Shuttle Test
10.4.2.2
The following procedure is to be followed for the 3min CSST conducted throughout the study.
Determination of speed for the 3min CSST:
The methodology for the execution of the 3min CSST is described by 
group [P12-12739]. Based on the findings from the initial study, the current protocol was 
designed as described.
At visit 2, a test consisting of one bout of three minutes of walking at the initial speed of 4.0 
km/h is completed. Thirty minutes after this first test, a second test will be performed at a 
speed of either 5.0 or 3.25 km/h. 
The second walking rate will be determined by the ability to complete the full 3 minutes of the 
test at 4.0 km/h. If a patient cannot complete the first test, then the second speed will be 
stepped down to 3.25 km/h. If a patient is able to complete the full 3 minutes in the first test, 
then the second speed will be increased to 5.0 km/h. Patients will be asked to perform up to 
three tests at different speeds in order to determine, amongst the 3 different speeds, the highest 
speed that meet the following parameters:
•
can be sustained for the entire 3 minutes, and
•
achieves a BORG breathlessness rating of ≥4.
In doing so, the objective is to induce a level of dyspnea that is sufficiently high to be 
amenable to therapy.
Depending on the patient’s ability to complete 3 minutes OR achieve a BORG breathlessness 
rating ≥4 then the speed can be further adjusted up to 6.0 km/h or down to 2.5 km/h to achieve 
these requirements. Please consult the Manual of Procedures for more detailed instructions for 
speed selection. 
An appropriate speed will be determined based on patients’ ability to complete the entire 3 
minutes of a speed and achieve a BORG rating ≥4.  If these 2 parameters are not fulfilled at 
any speed, the patient will be considered a screen failure.


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These speeds are selected based on previous work by 
’ group showing that these 
were sufficiently demanding to induce measurable levels of dyspnea and that most moderate to 
severe patients with COPD are able to complete the test for the desired duration [R15-4319].
Patients will be directed to follow the audio signal for the entire 3 minutes of the test. They will 
be instructed to walk/jog/run around the two cones set-up in the hospital hallway pacing their 
walk/jog/run in a way not to wait at the cones for the following audio signal.
The values for the completed 3min CSST tests will be recorded in the eCRF, and will be used 
for all subsequent 3min CSSTs: the training 3min CSST (visit 3) and for the subsequent 3min 
CSSTs conducted.
No adjustments to the speed selected at visit 2 are permitted throughout the trial.
Physiological parameters will be taken during the 3min CSSTs using mobile cardiopulmonary 
exercise equipment.


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MODIFIED BORG SCALE (MBS-S)
10.5
[R14-0975]
PATIENT INSTRUCTIONS
We will be using the BORG Scale to help us understand the intensity or severity of your breathing
discomfort and the intensity or severity of your leg discomfort. We will ask you to use this scale to rate
the intensity of your breathing discomfort and your leg discomfort before, during, and after your 
exercise test.
Please review the scale to see the various levels from which you can choose. 
For breathing discomfort:
The top of the scale, “0 or nothing at all,” means no breathing discomfort at all. 
The bottom of the scale, “10 or maximal,” means the most severe breathing discomfort that you have 
ever experienced or could imagine experiencing.  
For leg discomfort:
The top of the scale, “0 or nothing at all,” means no leg discomfort at all.
The bottom of the scale, “10 or maximal,” means the most severe leg discomfort that you have ever 
experienced or could imagine experiencing.  
When we ask you to rate the intensity of your breathing discomfort and your leg discomfort, please 
place the tip of your finger on the number that best describes the intensity that you are experiencing at 
that moment. You may also place a finger between 2 numbers if that better describes the intensity of 
your breathing discomfort or your leg discomfort.
Please let us know if you have any questions before we begin.
0
Nothing at all
0.5
Very, very slight (just noticeable)
1
Very slight
2
Slight 
3
Moderate
4
Somewhat severe
5
Severe 
6
7
Very severe 
8
9
Very, very severe (almost maximal)
10
Maximal


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Instructions for the Modified BORG Scale
Prior to the start of exercise test, each subject will be told that they will be asked to rate the
intensity of sensations at rest, during exercise and at end-exercise.  The sensations will be 
described to the subject as: 
•
Discomfort with your breathing
Use of the BORG Scale to rate these sensations will be explained to the subject. While showing 
the scale to the subject, the study coordinator or blinded tester will explain that the subject 
should relate the wording on the BORG Scale to the level of the sensation that he / she is 
experiencing, and then place the end of a finger on a number that best describes the intensity of 
the sensation - explain that placing a finger between 2 numbers is allowed. (BORG Scale 
numbers will be recorded to the nearest 0.5 units). 
The study coordinator or blinded tester will anchor the endpoints of the scale for both sensations. 
The study coordinator or blinded tester will explain that for the sensation of “discomfort with 
your breathing”, “0 or nothing at all” corresponds to “no discomfort with your breathing” and 
“10 or maximal” corresponds to the “most severe discomfort with your breathing that you have 
ever experienced or could imagine experiencing”. 
 
Subjects are to be given no further information about these sensations. If a subject requests 
further clarification, he/she will be told to use his/her own individual interpretation as to the 
meaning of the sensory descriptors. This will ensure that the sensory descriptors are presented 
to each subject in a standard format.


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INSPIRATORY CAPACITY AND FRC
10.7
In this trial FRC measurements will be done at visit 1 in the body box to determine eligibility.
FRC predicted equations according to Crapo [R99-0401]:
Males: Y=0.0472(Ht in cm) + 0.009 (Age) – 5.29
Females: Y=0.036(Ht in cm) + 0.0031(Age) - 3.182
Inspiratory Capacity measurements:
IC measurements will be performed during exercise testing as follows: 

ISWT - at rest, during exercise and at the end of exercise 

3min CSSTs – at rest and at the end of exercise
IC measurements will be taken using mobile cardiopulmonary exercise equipment capable of 
measuring IC during the shuttle tests.
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 be performing these IC maneuvers in the “Rest phase” of the exercise test
using mobile cardiopulmonary exercise equipment.  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., within ± 10% 
or ± 100 mL whichever is larger) with a maximum of 5 measurements to be performed. The 
resting IC should be recorded as the mean of the two highest acceptable efforts.
Exercise IC for the ISWT
These IC maneuvers will be carried in a manner similar to that at rest. For the end-exercise IC 
maneuver specifically, the BORG scale intensity of breathing discomfort and leg discomfort 
ratings should precede IC maneuver by at least 5 breaths to avoid interfering with pre-IC 
breathing patterns.


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End exercise IC 
An IC maneuver should be performed directly after having performed the BORG scale 
measurements after end-exercise (i.e., first 15 seconds of recovery) and used as the “end-
exercise” measurement. However, for the ISWT, if during the exercise test, a scheduled IC 
maneuver is performed within 30 seconds prior to the end of exercise, the final IC maneuver 
during exercise will be considered as the “end-exercise” measurement.
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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MODIFIED MEDICAL RESEARCH COUNCIL DYSPNEA SCALE (MMRC)
10.8
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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CHRONIC RESPIRATORY QUESTIONNAIRE – SELF ADMINISTERED 
10.9
STANDARDIZED - DYSPNEA DOMAIN ONLY
Instructions for the self –administered standardised CRQ
1. Please read these instructions carefully if you distribute the questionnaire to respondents in 
person.
2. This is a questionnaire that respondents should complete. It asks about breathing difficulties 
they might have experienced.
3. Please ask the respondent to take time, read over the instructions and answer the questions as 
best as they can by placing an “X” in the corresponding response box. Reassure them that this 
is not a test. There are no right or wrong answers to any of the questions, you would just like 
them to choose the best answer that describes how they have been feeling during the past 2 
weeks.
4. If a question seems unclear to the respondent, we suggest that they read the question once or 
twice more. We have found that reading the question again helps understanding the questions.
5. In summary, we suggest that you tell the respondent the following when you give out the 
questionnaire: “This is a questionnaire that we would like you to complete. Please take your 
time, read over the instructions and answer the questions as best you can. It is not a test. There 
are no right or wrong answers to any of the questions, we would just like to you choose the 
best answer that describes how you have been feeling during the past 2 weeks. If a question 
seems unclear to you, we suggest that you read the question once or twice more. We have 
found that this helps understanding the questions.”
6. Please also review the detailed background information and instructions prior to start using 
the questionnaire.
7. Please remove this sheet if it is attached to the questionnaire prior to handing questionnaire 
to respondent for completion.


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CHRONIC RESPIRATORY QUESTIONNAIRE – SELF ADMINISTERED 
10.10
INDIVIDUALIZED


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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 
 
 
 
 
 
c03207491
1.0
clinical-trial-protocol
A randomised, double-blind, cross-over study to determine the effect of 6 weeks
treatment of orally inhaled tiotropium + olodaterol  fixed dose combination  (5/5 µg)
compared with tiotropium (5 µg), both delivered by the Respimat® Inhaler, on
breathlessness during the three minute Constant Speed Shuttle Test (3min CSST) in
patients with Chronic Obstructive Pulmonary Disease (COPD) [OTIVATO®]
Approval-Trial Clinical Monitor
15 Apr 2016 19:52 CEST
Author-Team Member Medicine
15 Apr 2016 20:39 CEST
Approval-Therapeutic Area
19 Apr 2016 09:32 CEST
Approval-Biostatistics
19 Apr 2016 15:35 CEST
Verification-Paper Signature
Completion
19 Apr 2016 16:52 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03207491
1.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c13175053-01
BI Trial No.:
1237.28
Title:
A randomised, double-blind, cross-over study to evaluate the effect 
of 6 weeks treatment of orally inhaled tiotropium + olodaterol  
fixed dose combination (5/5 µg) compared with tiotropium (5 µg), 
both delivered by the Respimat® Inhaler, on breathlessness during 
the three minute Constant Speed Shuttle Test (3min CSST) in 
patients with Chronic Obstructive Pulmonary Disease (COPD)
[OTIVATOTM]
Investigational
Product(s):
Tiotropium + olodaterol fixed dose combination solution for     
inhalation - Respimat®
Responsible trial 
statistician(s):
Telephone: 
Fax: 
Date of statistical 
analysis plan:
21 JUL 2017 SIGNED
Version:
FINAL
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
....................................................................................9
.......................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
PATIENT SETS ANALYSED...........................................................................14
.................................................................................................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......................................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........21
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................21
7.3
TREATMENT COMPLIANCE........................................................................21
7.4
PRIMARY ENDPOINT(S) ................................................................................22
7.5
SECONDARY ENDPOINT(S) ..........................................................................22
7.5.1
Key secondary endpoint(s).................................................................................22
7.5.2
(Other) Secondary endpoint(s) ..........................................................................22
............................................................................22
7.7
EXTENT OF EXPOSURE.................................................................................23
7.8
SAFETY ANALYSIS..........................................................................................23
7.8.1
Adverse events.....................................................................................................23
7.8.2
Laboratory data ..................................................................................................25
7.8.3
Vital signs.............................................................................................................25
7.8.4
ECG......................................................................................................................25
7.8.5
Others...................................................................................................................25
8.
REFERENCES....................................................................................................26
..............................................................................27
10.
HISTORY TABLE..............................................................................................28


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LIST OF TABLES
..10
Table 6.2: 1
Important protocol violations ...........................................................................13
Table 6.3: 1
Patient sets analysed .........................................................................................15
Table 6.7: 1 
Planned and actual study days..........................................................................20
Table 10: 1
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP 
Term
Definition / description
ACCP
AE
American College of Chest Physicians
Adverse Event
AESI
Adverse Event of Special Interest
AMP
ATS
AUC
β-HCG
BAC
BDI
BI
Auxiliary Medicinal Products
American Thoracic Society
Area under the Curve
Beta-Human Chorionic Gonadotropin
Benzalkonium Chloride
Baseline Dyspnea Index
Boehringer Ingelheim
bid
bis in die – twice daily
BRPM
Blinded report planning meeting
f
Breathing Frequency
CA
Competent Authority
CI
Confidence Interval
CML
Local Clinical Monitor 
COPD
CPR
CRA
CRO
Chronic Obstructive Pulmonary Disease
Cardiopulmonary Resuscitation
Clinical Research Associate
Contract Research Organization
CRQ-SAS
CRQ-SAI
CSST
Chronic Respiratory Questionnaire - Self Administered Standardized
Chronic Respiratory Questionnaire - Self Administered Individualized
Constant Speed Shuttle Test
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DOMS
DRA
Delayed Onset Muscular Soreness
Drug Regulatory Affairs
DMG
Dictionary Maintenance Group
eCRF
Electronic Case Report Form
ECG
ECSC
EDTA
EELV
EMEA
EOTERS
ERS
Electrocardiogram
European Coal and Steel Community
Ethylenediaminetetraacetic acid
End expiratory lung volume
European Agency for the Evaluation of Medicinal Products
End of Trial
European Respiratory Society
EudraCT
European Clinical Trials Database
FAS
FC
FDC
FEV1
Full Analysis Set
Flow Chart
Fixed Dose Combination
Forced Expiratory Volume in 1st second


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Term
Definition / description
FRC
FVC
Gamma-GT
GOLD
Functional Residual Capacity
Forced Vital Capacity
Gamma-Glutamyl Transpeptidase
Global Initiative for Chronic Obstructive Lung Disease
HFA
hrs
IB
Hydrofluoroalkane
Hours
Investigator’s Brochure
IC
ICH
ICH-GCP
ICS
IEC
Inspiratory Capacity
International Conference on Harmonisation
International Conference on Harmonization - Good Clinical Practice
Inhaled corticosteroid
Independent Ethics Committee
IMP
IRB
Investigational Medicinal Product
Institutional Review Board
IRT
Interactive Response Technology
ISF
ISWT
LABA
LAMA
LDH
LOCF
MBS-S
MCID
MDI
MDP
Investigator Site File
Incremental Shuttle Walk Test
Long Acting β2-Agonists
Long Acting Muscarinic Antagonists
Lactate Dehydrogenase
Last observation carried forward
Modified BORG Scale
Minimum clinically important difference
Metered Dose Inhaler
Multidimensional Dyspnea Profile
MedDRA
Min
mg
mMRC
Medical Dictionary for Drug Regulatory Activities
Minute
milligram
Modified Medical Research Council Dyspnea Scale
mmHg
Millimetres mercury
MMRM
MOP
MQRM
mth
O*C
PDE-4
PFT
PK
Mixed Effect Repeated Measures Model
Manual of Procedures
Medical Quality Review Meeting
Month
Oracle Clinical
Phosphodiesterase Type 4
Pulmonary Function Test
Pharmacokinetics
PPS
Per protocol set
PRN
PSTAT
PT
PV
Q1
Q3
Pro re nata – as needed
Project Statistician
Preferred term
Protocol violation
Lower quartile
Upper quartile
qd
quaque die (once a day)
RDC
Remote Data Capture


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Term
Definition / description
REML
REP
Restricted Maximum Likelihood
Residual effect period
SA
Statistical analysis
SAE
SD
SGOT
SGPT
SMQ
SOC
Serious Adverse Event
Standard deviation
Serum glutamic-oxaloacetic transaminase
Serum glutamic-pyruvic transaminase
Standardised MedDRA query
System organ class
SOP
Standard Operating Procedure
SpO2
SQ
TCM
TDI
TESS
Oxygen saturation 
Sensory Quality
Trial Clinical Monitor
Transitional Dyspnea Index
Treatment emergent signs and symptoms
TLC
Total Lung Capacity
TMF
TMW
ToC
Trial Master File
Trial Medical Writer
Table of contents
TS
TSAP
ULN
VAS
Ve
VT
wks
w.o.
Treated Set
Trial Statistical Analysis Plan
Upper Limit Normal
Visual Analog Scale
Minute Ventilation
Tidal Volume
Weeks
Washout


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3.
INTRODUCTION
As per 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 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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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
 
 
 
The protocol includes the following as secondary/
 endpoints.

Change in Chronic Respiratory Questionnaire - Self Administered Individualized 
(CRQ-SAI) dyspnea domain score after 6 weeks of treatment.

Change in Chronic Respiratory Questionnaire - Self Administered Standardized 
(CRQ-SAS) dyspnea domain score after 6 weeks of treatment.
 
To further clarify, it is revised to: 

Change from baseline in Chronic Respiratory Questionnaire - Self Administered 
Individualized (CRQ-SAI) dyspnea domain score after 6 weeks of treatment.

Change from baseline in Chronic Respiratory Questionnaire - Self Administered 
Standardized (CRQ-SAS) dyspnea domain score after 6 weeks of treatment.
 


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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.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
No key secondary endpoints were specified.
5.2.2
Secondary endpoints
Secondary endpoints of efficacy will be used as described in the CTP, Section 5.1.2.
CRQ scores are calculated according to “CRQ Package_English” (1).  


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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 3 to 4-week run-in 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.  There will be 3-week 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 the 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 21days 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.  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 “relevant” 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 gives the important protocol violations (IPVs) for the trial. The final decision with 
regards to important PVs and exclusion from the PPS will be made at the final blinded report 
planning meeting (BRPM) or data base lock meeting (DBLM). 
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 29). 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, the patient’s data of 
periods with the same treatment 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 in periods 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.
“Automatic” in the column “Automatic/Manual” means that the IPV can be checked 
automatically through the eCRF or through programming of relevant data in the database. 
“Automatic and Manual” and ”Manual” in the column ‘Automatic/Manual’ means that to 
check the IPV, other information gained from investigator comments or CRA comments will 
be used. 


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Table 6.2: 1
Important protocol violations
Category /
Code
Description
Requirements
Excluded 
from
Automatic/
Manual
A
Entrance criteria not met
A1
Inclusion criteria not met
Inclusion Criteria 2-9 not met
as specified in the protocol.
Exclude 
from PPS*:
2-9
Automatic
and Manual
A2
Exclusion criteria not met
Exclusion Criteria 1-30
not met as specified in the 
protocol
Exclude 
from  PPS*: 
3, 4, 8-12, 14-
25, 29, 30
Automatic
and Manual
B
Informed consent
B1
Informed consent 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 the date of any study-
related procedure, or a patient 
signed the correct version of the 
ICF after Visit 0. If date of 
informed consent equals to date 
of Visit 1, such cases will be 
discussed at 
MQRM/BRPM/DBL meetings.
None
Automatic
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
Throughout the study
PPS
Automatic
and Manual
C3
Non-compliance with study 
medication
C3.1
Serious non-compliance 
with study medication as 
reported in monitoring 
report or manual PV 
spreadsheet
Decision at BRPM/MQRM.
PPS if at 
Visit 6 or 9
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


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Table 6.2: 1 (continued)
Important protocol violations
Category
/ Code
Description
Example/Comment
Excluded from
Automatic/
Manual
D
Concomitant medication
D1
Improper medication 
washout at baseline visit or 
primary endpoint visit(s)
Visit 4,6,7,9. Decision at 
BRPM
PPS
Automatic
and Manual
D2
Prohibited medication use 
during study
Check CT. Decision at 
BRPM.
PPS if in the week 
prior to Visit 4,6,7,9
Automatic
and Manual
F
Incorrect timing
F3
Primary endpoint recorded 
outside time window
F3.5
Constant speed shuttle test 
<1 hour or >3 hours after 
inhalation
Only at Visits 6, 9
PPS
Automatic
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
Automatic 
and 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
Automatic 
and Manual
KEY:
CT = Concomitant Therapy, BRPM = Blinded report planning meeting, CML = Local Clinical Monitor, CRA = 
Clinical Research Associate, ICF = informed consent form, MQRM = Medical Quality Review Meeting, PPS = Per protocol 
set, DBL = Data Base Lock, ADS = Analysis Data Set
*Final decision will be discussed and determined prior to database lock.
Note: Missing visits, evaluations, and tests are considered as missing data, but not protocol deviations.
6.3
PATIENT SETS ANALYSED
The following nested patient sets are defined:

Randomised set (RS):


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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).

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. 
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 final 
decision regarding which patients are excluded from PPS will be made at BRPM prior 
to data unblinding. 
If the number of patients in PPS is less than 90% of the number of patients in FAS, the 
primary analysis for the primary endpoint will also be performed on the PPS as supportive 
analyses.
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
* Performed only when the number of patients in PPS is less than 90% of the number of patients in FAS as 
sensitivity analysis.


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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
As noted in the protocol, in general, missing data at a given visit will be imputed by the 
available data from the patient at that visit and completely missing visits will be handled 
through the statistical model.
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.
Completely missing visits due to the patient discontinuing due to worsening of study disease 
will be imputed with the least favourable prior visit during that period.
It could happen that a patient needed therapy for COPD symptoms at a clinic visit. This 
therapy was entered on the rescue medication 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.
The following rules are used for exercise data:
In situations where the full 3-min of exercise was completed:

Measurements of Borg breathing discomfort scale, 
 
which are missing for 
the 3 minute time point will be imputed using the last non-missing observation during 
exercise (but not non-missing measurements at rest) for that visit.

Measurements of Borg breathing discomfort scale, 
 
which are missing for
all other time points during exercise will not be imputed (i.e. left as missing).
In situations where exercise is terminated prematurely:


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
Borg breathing discomfort 
 scores will be imputed from end-
of-exercise value for all time points beyond the exercise termination (including the 3 
minute time point).
In addition, the following rules apply:
 

If rescue medication was used prior to exercise testing or if the time of rescue 
medication use is unknown, measurements taken at rest and during exercise, i.e., -
Borg scale of breathing discomfort, 
 
blood pressure, and IC will be set to missing 
and not imputed. If rescue medication was used during exercise testing, measurements 
of Borg scale of breathing discomfort 
 will be set to 
missing for those time points after the first use of rescue medication and imputed 
using the worst non-missing observation during exercise (but not non-missing 
measurements at rest) for that visit before rescue medication use.
The following rules will be used for spirometry data which were collected at Visits 4, 5, 6, 
7, 8, and 9:

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 using the least favourable prior 
non-missing measurement from previous visits during that period.

If the spirometry measurement for a visit is completely missing because a patient 
discontinued due to worsening of study disease, then all data for this visit will be 
imputed with the least favourable prior observation from previous visits during that 
period.

Randomly missing spirometry measurements at Visits 5, 6, 8 and 9, e.g., due to a 
mechanical failure, will not be imputed.
Also,

For endpoints with two period baselines, if one period baseline is missing, it will be 
imputed by the other period baseline.


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
For CRQ-SAI, at visits where dyspnoea activities were selected differently than the 
baseline (at visit 4), those dyspnoea activity values will be set as missing values. 
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (2).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Period baseline
The period baseline is defined as the pre-dose measurement, performed prior to dosing on the
first day of each period.
Patient baseline
The patient baseline is defined as the mean of non-missing period baselines for each patient.
Study baseline
For endpoints with only one baseline measurements prior to the first treatment period, this 
baseline will be called study baseline. 
More specifically,
Baselines for Primary Endpoint
The primary endpoint is the change from baseline in intensity of breathlessness measured 
using the MBS-S at the end of the 3min Constant Speed Shuttle Test (CSST) after 6 weeks of 
treatment.

Period baselines are measured at the end of the 3 min CSST at visits 4 and 7 
Period Baselines for Secondary Endpoints
Change from baseline in Inspiratory Capacity (IC) measured prior to exercise, after 6 weeks 
of treatment.

Period baselines are measured in resting IC (Omnia) prior to exercise at visits 4 and 7 
Change from baseline in IC measured at the end of exercise, after 6 weeks of treatment 

Period baselines are measured in IC at the end of exercise at visits 4 and 7


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Change from baseline in 1 hour post-dose FEV1, after 6 weeks of treatment.

Period baselines are measured in pre-dose FEV1 at visits 4 and 7
Change from baseline in 1 hour post-dose FVC, after 6 weeks of treatment.

Period baselines are measured in pre-dose FVC at visits 4 and 7
Change from baseline in intensity of Breathlessness (MBS-S) at 1min, 2min, and 2.5min 
during the 3min CSST after 6 weeks of treatment.

Period baselines are measured at the corresponding time point during the 3 min CSST 
at visits 4 and 7 
Change from baseline in Chronic Respiratory Questionnaire - Self Administered 
Individualized (CRQ-SAI) dyspnea domain score after 6 weeks of treatment.

Period baselines are collected at visits 4 and 7
Change from baseline in Chronic Respiratory Questionnaire - Self Administered Standardized 
(CRQ-SAS) dyspnea domain score after 6 weeks of treatment.

Period baselines are collected at visits 4 and 7
 
  
 
 
 
 
 
 
 
 


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Time windows and calculated visits
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 (Table 6.7: 1).
Table 6.7: 1 
Planned and actual study days
Relative to period start
Relative to study start
      
Visit
Planned 
day
                          
Actual day
Planned 
day
                          
Actual day
  4
  1
1
    1
1
  5
22
Visit 5 date - Visit 4 date + 1
  22
Visit 5 date - Visit 4 date + 1
  6
  43
Visit 6 date - Visit 4 date + 1
  43
Visit 6 date - Visit 4 date + 1
  7
1
1
64
Visit 7 date - Visit 4 date + 1
  8
  22
Visit 8 date - Visit 7 date + 1
85
Visit 8 date - Visit 4 date + 1
  9
43
Visit 9 date - Visit 7 date + 1
106
Visit 9 date - Visit 4 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 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. Only descriptive statistics, 
i.e. the number (%) and percent of patients with compliance in the range of 80% - 120% will 
be provided. (cf. Section 5.4 for calculation of treatment compliance).


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7.4
PRIMARY ENDPOINTS
For the primary analysis, a mixed effect model repeated measures (MMRM) is specified in 
the protocol. This model will include treatment and period as fixed effects, patient as a 
random effect and period baseline as well as patient baseline as covariates. 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 (3). Adjusted mean values as well as treatment contrasts will be presented 
together with the 95% confidence intervals (CI) and p-values.
         
 
 
 
 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Other Secondary endpoints
The MMRM described for the primary endpoint will be performed for all secondary 
continuous endpoints. Adjusted mean values as well as treatment contrasts will be presented 
together with the 95% CIs and nominal p-values. All p-values will be considered as 
descriptive.


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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 adverse events will be descriptive in nature and will be based on BI guideline 
“Handling and summarisation of adverse event data for clinical trial reports and integrated 
summaries” (4). All analyses of AEs will be based on the number of patients with AEs (not 
the number of AEs). For this purpose, AE data will be combined in a 2-step procedure into 
AE records.
In a first step, AE occurrences, i.e. AE entries on the CRF, will be collapsed into AE episodes 
provided that all of the following applies:


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
The same MedDRA lowest level term was reported for the occurrences

The occurrences were 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 a 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 summarization of AE data, please refer 
to BI guideline 'Handling and summarization of adverse event data for clinical trial reports 
and integrated summaries' (4).
Analyses of adverse events are based on the concept of treatment emergent adverse events. 
This means that all adverse events occurring between first drug intake and 21 days after last 
drug intake are assigned to the respective analysing treatment. All adverse events occurring 
before first drug intake are assigned to “screening” and all adverse events 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 completing date are assigned 
to “post-study”. Screening, post-treatment and post-study AEs are presented in subject data 
listings only.
An overall summary of adverse events will be presented. A detailed description of the 
assignment of AE’s to treatment can be found in Section 6.1.
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class and preferred term. Separate tables will be provided for patients with other 
significant adverse events according to ICH E3 (5), for patients with adverse events leading to 
treatment discontinuation, for patients with adverse events leading to death, for patients with 
investigator determined drug-related adverse events, and for patients with serious adverse 
events.
According to ICH E3 (5), 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 
EMEA, preferred terms will be sorted by frequency (within system organ class).
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.


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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
None.


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8.
REFERENCES
1
R17-2573: “CRQ Package_English”.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", version 5; 
IDEA for CON.
3
R10-4391: Kenward, M.G. The use of baseline covariates in crossover studies.
Biostatistics 11(1),1-17 (2010)
4
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
5
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports,
current version


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
23-AUG-16
None
This is the initial TSAP with necessary 
information for trial conduct
Final
21-JUL-17
None
This is the final TSAP without any 
modification