Clinical trial NCT03055988
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim
Start date: 2017-03-29; Completion date: 2018-03-26
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The objectives of the study are to explore the effect of treatment with tiotropium + olodaterol fixed dose combination (FDC) compared to fluticasone propionate + salmeterol FDC on:

* reversal of left ventricular diastolic dysfunction assessed with cardiac magnetic resonance (CMR) imaging,
* measures of arterial stiffness assessed by CMR and pulse wave analysis (PWA),
* reduction of hyperinflation assessed with body plethysmography and
* post dose spirometry.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Tiotropium intervention 2: Olodaterol intervention 3: Fluticasone propionate intervention 4: Salmeterol
Intervention descriptions: intervention 1: Fixed Dose Combination intervention 2: Fixed Dose Combination intervention 3: Fixed Dose Combination intervention 4: Fixed Dose Combination

Protocol documents:
Prot_001.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c03560350-04
EudraCT No.:
EU Trial No:
2015-002641-66
BI Trial No.:
1237.36
BI Investigational 
Product(s):
Tiotropium + olodaterol fixed dose combination inhalation 
solution - Respimat®
Title:
An exploratory, randomised, double-blind, double-dummy, 
active-controlled, two period cross-over study to investigate the 
effect of 6 weeks treatment of orally inhaled tiotropium + 
olodaterol fixed dose combination (FDC) delivered by the 
Respimat® Inhaler with fluticasone propionate + salmeterol FDC 
delivered by the Accuhaler® Inhaler, on left ventricular function 
and arterial stiffness in patients with Chronic Obstructive 
Pulmonary Disease (COPD)
Lay Title:
Cardiovascular function in COPD patients
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone:
, Fax: 
Coordinating 
Investigator:
Phone: 
, Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment 3)
Version and Date:
Version: 4.0
Date: 30 November 2017
Page 1 of 99
Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
Spiolto® Respimat®
inhalation solution
Name of active ingredient:
Tiotropium + olodaterol 
fixed dose combination 
inhalation solution -
Respimat®
Protocol date:
25 Oct 2016
Trial number:
1237.36
Revision date:
30 Nov 2017
Title of trial:
An exploratory, randomised, double-blind, double-dummy, active-
controlled, two period cross-over study to investigate the effect of  6 
weeks treatment of orally inhaled tiotropium + olodaterol fixed dose 
combination (FDC) delivered by the Respimat® Inhaler with 
fluticasone propionate + salmeterol FDC delivered by the Accuhaler®
Inhaler, on left ventricular function and arterial stiffness in patients 
with Chronic Obstructive Pulmonary Disease (COPD)
Coordinating
Investigator
Phone: 
, Fax: 
Trial site(s):
Multi-centre trial (approximately10 centres in Germany)
Clinical phase:
IV
Objective(s):
The primary objective of the study is to explore the effect of treatment 
with tiotropium + olodaterol FDC compared to fluticasone propionate 
+ salmeterol FDC on reversal of left ventricular diastolic dysfunction 
assessed with cardiac magnetic resonance (CMR) imaging.
A secondary objective is to explore the effect of tiotropium + 
olodaterol FDC compared to fluticasone propionate + salmeterol FDC 
on measures of arterial stiffness assessed by CMR and central blood 
pressure assessed by pulse wave analysis (PWA), and on reduction of 
lung hyperinflation assessed with body plethysmography (pleth) and 
post dose spirometry.
Methodology:
Exploratory, randomised, double-blind, double-dummy, 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:
Spiolto® Respimat®
inhalation solution
Name of active ingredient:
Tiotropium + olodaterol 
fixed dose combination 
inhalation solution -
Respimat®
Protocol date:
25 Oct 2016
Trial number:
1237.36
Revision date:
30 Nov 2017
No. of patients: 
Approximately 74
total entered:
Approximately 74
each treatment:
Approximately 74
Diagnosis :
Chronic Obstructive Pulmonary Disease (COPD)
Main criteria
for inclusion:
Outpatients of either sex, aged ≥ 40 years and ≤ 75 years with smoking 
history > 10 pack years, post bronchodilator FEV1 < 70% predicted, 
post–bronchodilator FEV1/FVC < 70%, FRCpleth > 120% predicted 
normal, with post–bronchodilator reversibility which improves by 
greater than or equal to 7,5 percentage points, clinically free of 
cardiovascular (CV) disease.
Test product(s):
Tiotropium + olodaterol FDC inhalation solution - Respimat®
dose:
[5 µg tiotropium + 5 µg olodaterol]
(2.5 µg / 2.5 µg per actuation)
mode of 
administration:
Oral inhalation (2 inhalations in the morning)
Comparator products:
Fluticasone propionate + salmeterol FDC dry powder for inhalation  -
Accuhaler®
dose:
[1000 µg fluticasone propionate + 100 µg salmeterol] 
(500 µg / 50 µg per actuation)
mode of 
administration:
Oral inhalation (2 x 1 inhalation daily) bid


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Name of company:
Boehringer Ingelheim
Name of finished product:
Spiolto® Respimat®
inhalation solution
Name of active ingredient:
Tiotropium + olodaterol 
fixed dose combination 
inhalation solution -
Respimat®
Protocol date:
25 Oct 2016
Trial number:
1237.36
Revision date:
30 Nov 2017
Duration of treatment:
2 x 6-week treatment periods (total treatment duration of 12 weeks)
Endpoints
Primary endpoint is change from baseline in left ventricular end 
diastolic volume index (LVEDVI) after 6 weeks of treatment.
Secondary endpoints, all calculated as change from baseline, include:
Aortic distensibility, pulmonary artery pulsatility.
Central systolic, pulse and augmentation index.
FRCpleth % predicted after 6 weeks of treatment.
1,5 hour post dose FEV1, after 6 weeks of treatment.
1,5 hour post dose FVC, after 6 weeks of treatment.
Safety criteria:
Heart rate and blood pressure in conjunction with lung function testing 
as applicable, adverse events and physical examination.
Statistical methods:
Restricted Maximum Likelihood (REML) 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 baseline as a covariate. (Unstructured covariance 
structure will be used for within patient variation).
Descriptive statistics for the safety analyses/assessment.


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FLOW CHART
Screening 
period Run-in 
Period
Treatment phase
Disconti
nuation3
Follow-
up
Period 1 and 2
Visit
0
1
2
31
41
5
Week of treatment (cumulative)
-
-3 to -
1
0
6
12
EoT
V4 + 3
EoO
Day of treatment 
-
-21 to 
-7
1
43
85
106
Day of treatment (cumulative)
Time window (days)*
-
-21 to 
-7
1
43 
±3
85
±3
V4 + 21
+7
Informed consent, patient information
X2
Register patient in screening (IRT)
X
Demographics
X
Medical history/Baseline Conditions
X
COPD/patient characteristics
X
Smoking status
X
X
X
X
X
In-/Exclusion criteria
X
X
Physical examination
X
X
X
X
X4
Laboratory tests
X
Pregnancy test5
X
X
X
X
X
X
12 lead-ECG6
X
Training in use of Respimat® and Accuhaler®
X
X7
X7
Randomisation (IRT)
X
Medication washout check
X
X
X
X
Dispense and explain use of rescue medication
X8
X
X
X
Collect rescue medication
X
X
X
X
X
Dispense trial medication (IRT)
X
X
Administer trial medication at clinic
X
X
X
Collect trial medication
X9
X9
X
Drug and/or rescue med. accountability check
X
X
X
X
mMRC 
  
10
X
Cardiac Magnetic Resonance (CMR)11
X11a
X11b
X11b
Body Plethysmography (FRC, RVol, TLC, IC)
X12
X13
X13
X13
Spirometry (FEV1, FVC)
X12
X13
X13
X13
X
Vital signs (seated)14
X
X
X
X
X
Blood pressure and PWA15
X
X
X
X
Adverse events
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
Medication washout
X
X
X
X
Rescue Medication Use16
X
X
X
X
X
Trial Medication Adherence16
X
X
X
Telephone contacts17
X
X
X
X
Trial medication termination (IRT)
X
X
Completion of patient participation
X


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* 
Site should make every effort to attain 6 weeks treatment exactly when scheduling the visit days with the patient at the 
beginning of the trial.
1
Treatment phase: Procedures during visits 3 and 4 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 medical washout and restrictions.
3
Premature discontinuation procedures and observations: To be completed by all patients who took at least one dose of 
trial medication including those who discontinue early (see Section 6.2.3).
4
End of observation (EoO) examinations: To be performed in the event of any clinically relevant findings at Visit 4.
5
Pregnancy testing: Women of child-bearing potential: serum pregnancy test at Visit 1; urine pregnancy test at Visits 2, 
3, 4 and 5.
6
ECG: 12-lead ECG recording at screening (Visit 1) for inclusion in the study.
7 
Device training: The patient will be instructed in the use of the Respimat® inhaler and Accuhaler® inhaler, but the 
patient should not inhale from the placebo/demonstrational inhaler at these visits.
8 
Rescue medication: To be supplied to all patients 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 visit day (Visit 3 – day 43 and Visit 4 – day 85). All medication is collected after this dosing.
10 
mMRC 
: Refer to Appendix 10.4 and 10.5, respectively.
11
Cardiovascular MR:
11a
- baseline evaluation - in a week prior to randomisation (Visit 2) but at the latest 3 days prior to the Visit
2 to allow for the assessment of ejection fraction level for inclusion.
11b
- end of treatment evaluation - in a week prior to end of treatment period visits or on the visit day (Visit 3 
and 4) after the visit procedures have been completed and within the time frame 1-8 hours post morning study 
medication dose.
Washouts planned for baseline Visit 2 should be reached also for baseline CMR evaluation conducted in a week prior 
to visit 2. For CMRs prior to Visits 3 and 4 rescue medication washout needed as for respective clinic visits. 
12
Reduction of hyperinflation and reversibility testing: Pre- and post-bronchodilator (400 μg salbutamol (albuterol))
spirometry and body plethysmography at Visit 1. [note: hyperinflation at rest defined as FRCpleth > 120% predicted, 
with post-bronchodilator reversibility greater than or equal to 7,5 percentage points at Visit 1 is an inclusion criterion].
Refer to Appendix 10.3.
13 
Body plethysmography followed by spirometry measurements:
Visit 2 - Pre-dose measurement: 1 hour prior to inhalation of morning dose of study medication at Visit 2.
Visits 3 and 4 - Post-dose measurement:  1.5 hour post morning dose of trial medication at Visits 3 and 4.
14
Vital Signs: immediately prior to body plethysmography.
15
Blood pressure measurement and pulse wave analysis: should be performed during vital signs assessment prior to 
body plethysmography.
16
Medication Use: From medication counter for IMP and rescue medication.
17
Telephone contacts: Site staff will telephone the patient prior to patient´s scheduled CMR examination and 1-2 days 
prior to clinic visits to remind them of medication washout and any other requirements.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................10
1.
INTRODUCTION...............................................................................................13
MEDICAL BACKGROUND.............................................................................13
1.1
DRUG PROFILE................................................................................................15
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....17
RATIONALE FOR PERFORMING THE TRIAL.........................................17
2.1
TRIAL OBJECTIVES........................................................................................17
2.2
BENEFIT - RISK ASSESSMENT.....................................................................17
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
OVERALL TRIAL DESIGN AND PLAN .......................................................20
3.1
3.1.1
Administrative structure of the trial .................................................................21
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................22
SELECTION OF TRIAL POPULATION .......................................................23
3.3
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................24
3.3.3
Exclusion criteria ................................................................................................25
3.3.4
Removal of patients from therapy or assessments...........................................27
Removal of individual patients .............................................................................27
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................28
3.3.4.2
4.
TREATMENTS...................................................................................................29
INVESTIGATIONAL TREATMENTS ...........................................................29
4.1
4.1.1
Identity of the Investigational Medicinal Products..........................................29
4.1.2
Selection of doses in the trial..............................................................................31
4.1.3
Method of assigning patients to treatment groups...........................................31
4.1.4
Drug assignment and administration of doses for each patient......................31
Dispensing of trial medication..............................................................................31
4.1.4.1
Study medication administration ..........................................................................32
4.1.4.2
Inhaler devices training.........................................................................................34
4.1.4.3
Respimat® malfunctioning....................................................................................35
4.1.4.4
4.1.5
Blinding and procedures for unblinding...........................................................35
Blinding.................................................................................................................35
4.1.5.1
Unblinding and breaking the code ........................................................................35
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................35
4.1.7
Storage conditions...............................................................................................37


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4.1.8
Drug accountability.............................................................................................37
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................39
4.2.1
Other treatments and emergency procedures..................................................39
4.2.2
Restrictions ..........................................................................................................40
Restrictions regarding concomitant treatment ......................................................40
4.2.2.1
Restrictions for pulmonary function testing and CMR assessment ......................45
4.2.2.2
Restrictions on diet and life style..........................................................................45
4.2.2.3
TREATMENT COMPLIANCE........................................................................45
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................47
TRIAL ENDPOINTS..........................................................................................47
5.1
5.1.1
Primary Endpoint(s)...........................................................................................47
5.1.2
Secondary Endpoint(s) .......................................................................................47
...........................................................................................47
ASSESSMENT OF EFFICACY........................................................................48
5.2
ASSESSMENT OF SAFETY.............................................................................50
5.3
5.3.1
Physical examination ..........................................................................................50
5.3.2
Vital Signs............................................................................................................50
5.3.3
Safety laboratory parameters ............................................................................50
5.3.4
Electrocardiogram ..............................................................................................51
5.3.5
Other safety parameters.....................................................................................51
5.3.6
Assessment of adverse events.............................................................................51
Definitions of AEs ................................................................................................51
5.3.6.1
Adverse event collection and reporting ................................................................54
5.3.6.2
COPD Exacerbations ............................................................................................55
5.3.6.3
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................56
5.4.1
Assessment of Pharmacokinetics.......................................................................56
ASSESSMENT OF BIOMARKER(S) ..............................................................56
5.5
OTHER ASSESSMENTS...................................................................................56
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................57
5.7
6.
INVESTIGATIONAL PLAN.............................................................................58
VISIT SCHEDULE.............................................................................................58
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................59
6.2
6.2.1
Screening and run-in period(s)..........................................................................59
6.2.2
Treatment period(s)............................................................................................61
6.2.3
Follow Up Period and Trial Completion...........................................................66
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................68
STATISTICAL DESIGN - MODEL.................................................................68
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................68
7.2
PLANNED ANALYSES.....................................................................................68
7.3
7.3.1
Primary endpoint analyses.................................................................................69
7.3.2
Secondary endpoint analyses .............................................................................69
................................................................................69


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7.3.4
Safety analyses.....................................................................................................69
7.3.5
Pharmacokinetic analyses ..................................................................................70
INTERIM ANALYSES ......................................................................................70
7.4
HANDLING OF MISSING DATA ...................................................................70
7.5
RANDOMISATION ...........................................................................................70
7.6
DETERMINATION OF SAMPLE SIZE .........................................................70
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................72
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................72
DATA QUALITY ASSURANCE ......................................................................73
8.2
RECORDS...........................................................................................................73
8.3
8.3.1
Source documents ...............................................................................................73
8.3.2
Direct access to source data and documents.....................................................74
8.3.3
Storage period of records ...................................................................................74
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................74
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........74
8.5
TRIAL MILESTONES.......................................................................................75
8.6
9.
REFERENCES....................................................................................................76
PUBLISHED REFERENCES............................................................................76
9.1
UNPUBLISHED REFERENCES......................................................................79
9.2
10.
APPENDICES.....................................................................................................80
THE RESPIMAT® INHALER ..........................................................................80
10.1
THE ACCUHALER® INHALER......................................................................85
10.2
ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA...........87
10.3
MODIFIED MEDICAL RESEARCH COUNCIL DYSPNEA SCALE........88
10.4
NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
10.6
CLASSIFICATION ............................................................................................90
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................91


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AI
Augmentation Index
AMP
Auxiliary Medicinal Product
ATS
American Thoracic Society
AUC
Area under the Curve
BAC
Benzalkonium chloride
BI
Boehringer Ingelheim
bid
bis in die (twice daily dosing)
BMI
Body Mass Index
BSA
body surface area
CABG
Coronary Artery Bypass Graft
CI
Confidence Interval
CML
Local Clinical Monitor
CMR
Cardiac Magnetic Resonance
COPD
Chronic Obstructive Pulmonary Disease 
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organisation
CT
Computer tomography
CTMF
Clinical trial master file
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
DEDP
drug exposure during pregnancy
DPI
Dry Powder Inhaler
ECG
Electrocardiography
eCRF
Electronic Case Report Form
ECSC
European Coal and Steel Community
ED
end diastolic
EDTA
Disodium edentate
EF
ejection fraction
EFL
Expiratory flow limitation
EoO
End of Observation
EoT
End of Treatment
ERS
European Respiratory Society
ERV
Expiratory reserve volume
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
FDC
Fixed Dose Combination
FEV1
Forced Expiratory Volume in 1st second
FRC
Functional Residual Capacity


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FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HCG
human chorionic gonadotropin
HFA
hydrofluoroalkane
IB
Investigator’s Brochure
IC
Inspiratory capacity
ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IVC
inspiratory vital capacity
LABA
Long-acting β2-agonist
LAMA
Long-acting muscarinic antagonists
LBBB
Left bundle branch block
LDH
Lactate Dehydrogenase
LPDD
Last Patient Drug Discontinuation
LV
Left Ventricle
LVEDVI
Left Ventricular End Diastolic Volume Index 
LVH
Left ventricular hypertrophy
MACE
Major adverse cardiovascular event
MCID
Minimal clinically important difference
MD
Medical Degree
MDI
Metered Dose Inhaler
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMI
Myocardial mass index
mMRC
Modified Medical Research Council Dyspnoea Scale
MMRM
Mixed-effects Model for Repeated Measures
MST
Medical Sub Team
NIMP
Non Investigational Medicinal Product
NYHA
New York Heart Association
PD
Pharmacodynamics
PA
pulmonary artery
PDE-4
Phosphodiesterase Type 4
Pleth
Body Plethysmography
PFT
Pulmonary function testing
PRN
pro re nata (as needed)
PWA
Pulse Wave Analysis
qd
quaque die (once a day)
REML
Restricted Maximum Likelihood
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RV
right ventricular
RVol
Residual Volume


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SAE
Serious Adverse Event
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SGRQ
St. George´s Respiratory Questionnaire
SOP
Standard operating procedures
SmPC
Summary of Product Characteristics
STORM
storage conditions for trial medication
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVI
Stroke volume index
TCM
Trial Clinical Monitor
TDI
Transitional dyspnoea index
TLC
Total Lung Capacity
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
UK
United Kingdom
US
United States


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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.
Cardiovascular disease in COPD
COPD is a chronic inflammatory disease of the lungs known to have systemic features, 
among which is an increased risk of CV disease. Large population studies have confirmed the 
importance of COPD as an independent risk factor for ischemic heart disease and sudden 
cardiac death [R12-4840, R16-3513 and R16-3514]. Besides traditional risk factors, as 
smoking, leading to inflammation and dysfunctionality in the lungs there is increasing 
evidence of systemic inflammation and further more physiologic stresses and abnormalities 
of the vascular wall that accelerate cardiovascular pathology in COPD.
Bronchial obstruction and hypoxia play important role in inducing hemodynamic stress that 
contribute to cardiovascular morbidity and mortality.  It is evident that developing an 
obstructive lung pattern early in life is associated with an underfilling in the left heart and low 
cardiac output [R16-3515, R16-3516 and R16-3517]. Reversing of functional impairment of 
lungs with bronchodilation would reduce lung hyperinflation and would have an effect on 
hemodynamic stress on the heart and abnormalities of arterial wall that could be assessed and 
used as a control in provision of treatment and in prognosis of COPD especially with respect 
to cardiovascular comorbidity typical for COPD.


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COPD and lung hyperinflation
Expiratory flow limitation (EFL) is the pathophysiological hallmark of COPD and is caused 
by parenchymal destruction (emphysema) and airway dysfunction which is a consequence of 
small airway inflammation, airway remodelling, mucus impaction and possibly increased 
cholinergic airway muscle tone. Emphysema results in reduced elastic recoil which together 
with increased airway resistance leads to a reset of relaxation volume of respiratory system to 
a higher level than in age-matched healthy individuals. This is so called “static” lung 
hyperinflation. In laboratory gas trapping is defined as Residual Volume (RVol) or Residual 
Volume/Total Lung Capacity (RVol/TLC) above the upper limits of normal and 
hyperexpansion as FRC or TLC above the upper limits of normal or IC/TLC below the lower 
limit of normal. Isolated hyperexpansion is associated with greater percent emphysema, 
lower Body Mass Index (BMI) and a higher blood haemoglobin concentration [R16-3518] 
and hyperinflation as measured with RVol or RVol/TLC is associated with greater LV mass 
[R15-2161]. Decreasing of hyperinflation in the lungs would have an effect on cardiac and 
arterial dysfunction that could be measured comparing two alternative treatments and used to 
explore further the separate effects of diastolic dysfunction vs reduced left ventricle (LV)
preload due to pulmonary causes [R16-3519].
Arterial stiffness and diastolic dysfunction as important predictors of CV events
Arterial stiffness is increasingly recognised as a surrogate end point for CV disease. As 
measured by the carotid-femoral pulse wave velocity as a “gold standard” it is a strong 
predictor of future CV events especially in persons with higher baseline CV risk. Increased 
large artery stiffness results in greater central aortic systolic pressures, increased left 
ventricular afterload and reduced diastolic coronary artery filling. Even in the present absence 
of evidence that pharmacological treatment of COPD has direct beneficial effect lowering the 
pulse wave velocity there are other measures indirectly connected to arterial stiffness of 
central arteries (central pressure, pulse pressure, augmentation index) that allow us to explore 
further the measures of the effect of arterial stiffness particularly on the left heart failure with 
preserved ejection fraction [R16-3528].
Diagnostic modalities in assessing cardiac function and arterial stiffness in COPD
Assessment of early changes of cardiac function in COPD is challenging and validated gold 
standard is missing. Due to hyperinflation echocardiography has been proven to have 
limitations and is replaced more and more with cardiac magnetic resonance (CMR) 
established as a gold standard for the measurements of volumes, mass and ejection fraction of 
both left and right ventricles and particularly left atrium [R16-3556, R16-3557]. It also allows 
the assessment of pulmonary artery pulsatility and aortic distensibility that are local measures 
of arterial stiffness [R16-3558].


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DRUG PROFILE
1.2
Tiotropium + olodaterol combination
Tiotropium + olodaterol FDC (Spiolto® Respimat®) 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/c01735249] tiotropium + olodaterol FDC 
showed statistically significant improvements in Forced Expiratory Volume in first 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.
Supportive evidence characterizing the bronchodilating profile of tiotropium + olodaterol 
FDC over 24- hour dosing interval, with similar 24-hour FEV1- time profiles and an 
increased bronchodilatory activity compared to twice daily fluticasone propionate + 
salmeterol FDC, was provided from a 6-week cross-over trial (1237.11) [P16-01440].
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 events (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 refer to the current Summary of Product 
Characteristics (SmPC) for Spiolto® which is included in the Investigator Site File (ISF).
Fluticasone propionate + salmeterol combination
Fluticasone propionate and salmeterol are the constituents in the FDC product Seretide®
(Viani®, Atmadisc®). Seretide® Accuhaler® (50 µg salmeterol and 500 µg fluticasone 
propionate in a dry powder inhaler- DPI) given twice daily is approved in the EU for the 
symptomatic treatment of patients with severe COPD and a history of repeated exacerbations, 
who have significant symptoms despite regular bronchodilator. More information can be 
found in the SmPC for Seretide®, included in the ISF.
The FDC of fluticasone and salmeterol is registered for the maintenance treatment of patients 
with severe to very severe COPD and frequent exacerbations in many countries. Despite this 


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labeled indication, the real world use of LABA/Inhaled corticosteroids (ICS) combinations is 
different and comparable doses to those in the trial are being used from maintenance 
initiation onwards in many EU countries, including Germany. Therefore we believe that it is 
justified to use the comparator product as specified in the trial protocol.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Diastolic dysfunction of the heart carries a substantial risk of heart failure and reduced 
survival, even when it is asymptomatic. Diastolic dysfunction is defined as functional 
abnormalities that exist during ventricular relaxation and filling and carries a mortality rate 
that is similar to that seen in systolic failure. In the last 20 years, the survival of patients with 
systolic heart failure has improved, whereas the prognosis of diastolic heart failure has not 
changed.
The hypothesis in our trial is that in absence of any clinically evident cardiovascular disease 
COPD patients would have sub-clinical cardiac dysfunction and arterial wall stiffness that 
would be related to the severity of airways obstruction and air trapping and would change 
under influence of treatment.
Evidence that pharmacological treatment of COPD has consistent beneficial and plausible 
effects on cardiac function and pulmonary vasculature that may contribute to favourable 
effects of inhaled therapies is already published. The trial was of short duration (7-14 days of 
treatment), using a combination of LABA/ICS against placebo [R16-3512].
In this study we want to go explore further if cardiac function improves even more if two 
bronchodilators (a long-acting 2-agonist and long-acting muscarinic antagonist) are used, 
and if these are better compared to LABA/ICS combination, and also in longer treatment 
duration [P16-08905].
TRIAL OBJECTIVES
2.2
The primary objective of the study is to explore the effect of treatment with tiotropium + 
olodaterol FDC compared to fluticasone propionate + salmeterol FDC on reversal of left 
ventricular diastolic dysfunction assessed by cardiac magnetic resonance (CMR) imaging.
A secondary objective is to explore the effect of tiotropium + olodaterol FDC compared to 
fluticasone propionate + salmeterol FDC on:

measures of arterial stiffness assessed by CMR and

central blood pressure assessed by PWA and

reduction of lung hyperinflation assessed with body plethysmography and

post dose spirometry.
BENEFIT - RISK ASSESSMENT
2.3
The clinical trials conducted to date have shown tiotropium + olodaterol 5 μg / 5 μg to be a 
safe, well tolerated and efficacious combination therapy according to treatment guidelines in 


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a moderate to very severe COPD patient population that included patients with concomitant 
cardiovascular diseases.
The observed incremental bronchodilator response for tiotropium + olodaterol 5 μg / 5 μg 
compared to the individual components translated into benefits that were meaningful to the 
patient, with improvements in several patient centered outcomes. As such, tiotropium + 
olodaterol 5 μg / 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. At the time of the final protocol for 1237.36, 
marketing authorization has been granted in almost all EU countries, United States (US), 
Japan and several other countries.
The trial design requires that all eligible patients complete a 3 or 4 week screening period in
which LABAs, LAMAs and inhaled corticosteroids (ICS) are withdrawn prior to 
randomisation. Boehringer Ingelheim (BI) will provide open-label salbutamol (albuterol) and 
ipratropium metered dose inhalers as needed (PRN) rescue medication for all patients who 
have signed Informed Consent. At the investigator´s discretion, ipratropium metered dose 
inhaler (MDI) may be provided to patients who are primarily required to wash out LAMA 
during the washout period prior to baseline CMR and Visit 2. In spite of provision of 
salbutamol and/or ipratropium there is approximately 1% risk that patients may withdraw in 
the screening period because of intolerance to their prescribed medication withdrawal.
All patients will receive active treatment with either tiotropium + olodaterol FDC (5 µg / 5 
µg) or fluticasone propionate + salmeterol FDC (1000 µg / 100 µg) inhalation solution 
(control group) during the treatment periods. There is no separate placebo arm in this trial and 
placebo is used for the double-dummy treatment design.
The potential benefits for patients outweigh potential risks and justify inclusion of tiotropium 
+ olodaterol FDC Respimat® as intervention in the study.
The FDC of fluticasone and salmeterol is registered in many countries for the maintenance 
treatment of patients with COPD, with a FEV1 < 60% predicted normal (pre-bronchodilator) 
and a history of repeated exacerbations, who have significant symptoms with regular 
bronchodilatory therapy. Despite this labeled indication, the real world use of LABA/ICS 
combinations is different and comparable doses to those in the trial are being used from 
maintenance initiation onwards in many EU countries, including Germany. The use of 
LABA/ICS in COPD patients with post-bronchodilator FEV1 less than 70% predicted normal
as a comparator product in our trial was also decided because this was effective therapy for 
COPD, leading to change in cardiac function, in already published short term study [R16-
3512].
Therefore, both treatment regimens are considered options for long-term therapy of COPD 
and comparison of both regimens regarding the effects of lung deflation on cardiovascular 


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function is of importance for the treatment of COPD patients and development of CV 
comorbidities in patients with COPD.
The proposed medication restriction scheme is considered ethically acceptable given the 
availability of ipratropium MDI (primarily during the washout period) and/or salbutamol 
(albuterol) as rescue medication.
According to the prescribing information for Spiolto®, 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 µg / 5 µg) FDC provided 
appropriate precautions are taken to minimize the risk of pregnancy. These precautions
include pregnancy testing and use of highly effective methods of birth control. Continued 
testing and monitoring during the trial should be sufficient to ensure compliance with the 
measures not to become pregnant during the period of drug exposure (which may exceed the 
length of study until the follow-up visit at 21 days after discontinuation of study medication)
[R05-0370].
The subjects participation in the study requires standard medical procedures known to 
patients with respiratory diseases. The examinations include common procedures like 
physical examination, 12-lead ECG, spirometry and body plethysmography. Other 
procedures include common medical practices such as disease-specific questionnaires and 
routine blood sampling for safety assessment. All these procedures are known to have an 
acceptable safety risk. An amount of 50 ml of blood will be drawn during study (once for 
safety assessment and three times for determination of
 
 and no safety–related risk to the patient is expected from this blood 
withdrawal.
Safety will be monitored (as described in Section 5.3) at site visits and withdrawal criteria 
will be provided for investigators’ consideration (as listed in Section 3.3.4.1).
Cardiac Magnet Resonance imaging (CMR) will be conducted in all subjects. CMR uses 
strong magnetic fields and radio waves to generate cross-sectional images of the body. In this 
study, CMR will be used to acquire morphological and functional information of the heart, 
aorta and pulmonary artery. In contrast to Computer tomography (CT), CMR does not use 
ionizing radiation (X-rays) and there are no known harmful effects associated with temporary 
exposure to the strong magnetic field of CMR scanners in patients without metal foreign 
bodies. Potential safety concerns are related to implanted medical devices (i.e. heart 
pacemaker and metal implants like vascular clips, metal silver in patient´s eye), which may 
dislodge and can malfunction or heat up during the exams. Dyes from tattoos and tattooed 
eyeliners can cause skin or eye irritation, and medication patches can cause skin burn due to 
heating effects. Some subjects might suffer from claustrophobia during the examination. 
Subjects in the CMR scanner will be exposed to some noise, which will be minimized by ear 
protection but can still cause some discomfort. No contrast or stress agent will be used during 
the examinations. Potential risks associated with CMR will be avoided by implementing 
standards CMR procedure under appropriate supervision [R16-3555].


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is an exploratory, randomised, double-blind, double-dummy, active-controlled, two-
period complete cross-over study to investigate the effect of 6 weeks treatment  of orally 
inhaled tiotropium + olodaterol FDC (5 μg / 5 μg) (delivered by the Respimat® Inhaler) 
compared with fluticasone propionate + salmeterol (1000 μg / 100 μg) (delivered by the 
Accuhaler® Inhaler) on left ventricular function and arterial stiffness in patients with COPD.
The trial consists of a run-in period, two 6-week treatment periods with no washout in 
between the treatments 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 reach their baseline level of diastolic heart function 
prior to changes under treatment. In a week prior to randomisation, patients will conduct an 
assessment of heart (left ventricular) function with CMR examination.
Patients who meet all the inclusion criteria and none of the exclusion criteria will be 
randomised at Visit 2 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 treatments with the treatment codes as 
follows:
A. tiotropium + olodaterol (5 μg / 5 μg) FDC inhalation solution, delivered once daily 
via the Respimat®
B. fluticasone propionate + salmeterol (1000 μg / 100 μg) dry powder for inhalation, 
delivered twice daily via the Accuhaler®
The randomised treatment sequences are AB and BA. An interactive voice/web response 
B FP/Sal (1000/100 mcg) A
B
A
Tio/Olo (5/5 mcg)
V1
V5
V2
V3
V4
3 weeks
Scr.
6 weeks
6 weeks
FP/Sal (1000/100 mcg)
Follow up
EOT
R
Tio/Olo (5/5 mcg)
EOS
3 weeks


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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.
Patients will be evaluated for an additional 21 days following completion of the last 6-week 
randomised treatment period, or in case of discontinuation, after the final dose of study 
medication. In this follow-up period patients may return to their medication prescribed prior 
to participating in the study. 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.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim.
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 procedures (SOPs),

direct the clinical trial team in the preparation, conduct, and reporting of the trial, and

ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and investigators.
All study-related documentation will be stored in the BI clinical trial master file (CTMF). 
Trial relevant documentation for the study sites will be filed in the investigator site file (ISF) 
at the investigational sites.
Boehringer Ingelheim will be responsible for the monitoring of the study. Management of
clinical trial supply including an IRT system will be handled by BI and an external vendor.
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 ISF.
Targeted group of Investigators: Pulmonologists/qualified sites with experience in 
conducting studies with own body plethysmography and spirometry equipment and access to 
the desired patient population of patients with COPD. 


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Local Facilities/Equipment: Sites should also have access to MRI facility that has capacity to 
conduct CMR for trial purpose. The following local facilities/equipment is required at the 
investigational site:

scale and stadiometer

a standard 12-lead electrocardiogram (ECG)

a body plethysmograph which meets ATS/ERS Criteria [R08-1121]

a spirometer which meets ATS/ERS Criteria [P05-12782]

access to local lab facility for safety testing

access to local radiology unit for CMR examination 
Contract Research Organisation (CRO): A CRO will provide the device and staff training for 
peripheral blood pressure measurement and PWA for central blood pressure assessment for 
complete duration of the trial. A CRO will also provide logistical support for organizing and 
conducting centralized imaging service for timely assessment of CMR protocols and 
acquisition of parameters and support of the independent central reader.
Local Laboratory: Blood samples for safety evaluation will be analyzed at a local lab.
 
IRT: An IRT vendor will be used for randomisation to a treatment sequence AB or BA in this 
trial 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 
ISF.
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 are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
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 minimizing 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].


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A 6 week treatment period is considered sufficient to evaluate the effects of both tiotropium +
olodaterol FDC and of fluticasone propionate+salmeterol FDC at pharmacodynamic steady 
state (based on results from previous studies evaluating the effects of tiotropium + olodaterol 
FDC on spirometric parameters). A 6 week treatment period was therefore also accepted as 
sufficient for the evaluation of the longer term effects of the reduced lung hyperinflation on 
the cardiovascular changes.
The inclusion of the fluticasone propionate + salmeterol FDC allows a comparison of a 
LABA (in combination with an ICS), as used in previous positive study, to the combination 
product of both β2-agonist and anti-cholinergic. This selection will only allow us to explore 
the effect of two different combinations on the improvement of lung hyperinflation and 
cardiac function.
Pure placebo arm was not planned in this study. Based on the evidence of dual 
bronchodilation from previous similar comparisons the effect on reduction of lung 
hyperinflation is expected to be of similar size. How this translates in hemodynamic changes 
over longer treatment duration in presently unknown.
Because the duration of each treatment is 6 weeks, the pharmacodynamic steady state on lung 
function and hyperinflation would sufficiently be reached without the washout between the 
treatment periods. It is expected that in the treatment change from tiotropium + olodaterol to 
fluticasone propionate + sameterol (AB sequence) there will be some additional 
bronchodilatory effect of tiotropium, lasting at most a couple of days that will rapidly and 
completely disappear when pahrmacodynamic steady state of both treatments in the second 
treatment periods will be reached. No measurements are planned in this period but only at the 
end of each treatment period.
Since patients will be randomised to a treatment sequence AB or BA that includes either both 
a long-acting β2-agonist (olodaterol) and a long-acting anti-cholinergic (tiotropium) or an 
intermediate acting β2-agonist (salmeterol) and inhaled corticosteroid (fluticasone), it is 
necessary to restrict the use of long-acting β2-agonists (e.g. salmeterol, formoterol, 
indacaterol), anti-cholinergics (e.g. tiotropium, ipratropium) and inhaled corticosteroids (iCS)
during the entire treatment phase. Short-acting β2-agonist medication (salbutamol / albuterol) 
and /or short acting anticholinergic (ipratropium; primarily to patients who are required to 
washout LAMAs during run-in periods) will be provided to patients for rescue use (as 
needed, PRN) in run-in and treatment periods with short washout of short-acting 
bronchodilators prior to CMR and PFT assessments.
SELECTION OF TRIAL POPULATION
3.3
A sufficient number of patients will be enrolled (sign informed consent) to ensure that 
approximately 74 patients of either sex, 40 to 75 years old, with a diagnosis of COPD are
randomised into the study. All patients are expected to be randomised within eight months of
overall trial initiation (i.e. initiation of the first site), which requires a minimum enrollment of 
2 patients per month at each site.
Enrolment will be competitive and conducted at approximately 10 study sites. Additional 


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sites may be initiated and 'non-productive' sites may be closed to ensure sponsor's timelines.
It is anticipated that each site will enroll an average of approximately 8 patients.
Patients will be required to perform lung function testing with body plethysmography on 
several occasions in the study. They will also be performing CMR 3 times in the trial. Each 
examination is estimated to last up to one hour and will be conducted as a non-contrast and 
non-stress MRI procedure. For this reason any patients with general contraindications to 
magnetic resonance procedure 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 FEV1 < 70% predicted, including hyperinflation at 
rest during screening, with documented reversibility of hyperinflation are eligible for 
inclusion if they fulfil all the inclusion criteria (Section 3.3.2) and do not present with any of 
the exclusion criteria (Section 3.3.3).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to 
participation in the trial, which includes medication washout and restrictions.
2. All patients must have a diagnosis of chronic obstructive pulmonary disease [P16-13658]
for which they are treated with one or more long-acting inhaled bronchodilators prior to 
enrolment and must meet the following spirometric criteria:
Patients must have stable airway obstruction with a post-bronchodilator FEV1 < 70% of 
predicted normal calculated with European Coal and Steel Community (ECSC) formulas, 
[R94-1408], and a post-bronchodilator FEV1/FVC < 70% at Visit 1 (see Appendix 10.3
for ECSC predicted normal equations).
3. Patients with hyperinflation at rest defined as FRC > 120% predicted, with post-
bronchodilator reversibility which improves by greater than or equal to 7,5 percentage
points at Visit 1 (see Appendix 10.3 for predicted normal FRC values).
4. Male or female patients between 40 and 75 years of age (inclusive) on day of signing 
informed consent.
5. Patients with a smoking history of more than 10 pack-years (see Appendix 10.3 for
calculations).
6. Patients with Modified Medical Research Council Dyspnoea Scale (mMRC) score > 1 at 
Visit 1.
7. Patients must be able to perform technically acceptable pulmonary function tests (body 
plethysmography and spirometry), cardiac magnetic resonance, brachial blood pressure 


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measurements with PWA and other tests during the study period as required in the 
protocol.
8. Patients must be able to inhale medication in a competent manner, as assessed by the 
Investigator, from the Respimat® and Accuhaler® inhalers (Appendix 10.1 and 10.2) 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.
2. Patients with a, in the opinion of the investigator, clinically relevant abnormal baseline 
hematology, blood chemistry, or creatinine will be excluded regardless of clinical 
condition (a repeat laboratory evaluation will not be conducted in these patients).
3. Patients with a current 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) and 
patients who experience COPD exacerbation or respiratory tract infection during the 
washout phase prior to randomisation.
5. A history of myocardial infarction, cerebrovascular event or coronary artery intervention 
other than Coronary Artery Bypass Graft (CABG) within 1 year of screening Visit 1.
6. Abnormal and clinically significant 12-lead ECG (e.g. Left bundle branch block (LBBB)
and left ventricular hypertrophy (LVH)).
7. Hospitalized for heart failure within the past year. Current severe heart failure (New York 
Heart Association (NYHA) class IV [New York Heart Association, 1994]. Ejection 
fraction ≤ 40% from CMR baseline assessment.
8. Patients with systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90
mmHg at Visit 1.
9. A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists).
10. Known active tuberculosis, cardiac sarcoidosis.
11. Any malignancy unless free of disease for at least five years (patients with treated basal 
cell carcinoma or squamous cell skin cancers are allowed).
12. A history of cystic fibrosis.
13. Clinically evident bronchiectasis, as judged by the Investigator.


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14. Patients with severe emphysema requiring endobronchial interventions within 6 months 
prior to screening.
15. A history of significant alcohol or drug abuse as judged by the investigator.
16. 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).
17. Patients being treated with any oral β-adrenergics.
18. Patients being treated with oral corticosteroid medication within 6 weeks prior to Visit 1.
19. Patients being treated with Phosphodiesterase Type 4 (PDE-4) inhibitors within 3 months 
of screening Visit 1 (e.g. roflumilast) should not be enrolled and PDE-4 inhibitors should 
not be withdrawn for the purpose of enrolling in this study.
20. Patients being prescribed long-term home oxygen treatment 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 taken an investigational drug within one month, six half-lives or 
(whichever is greater) or in case the investigational drug (sub) class is listed within the 
washout period specified in Table 4.2.2.1:1 prior to screening Visit 1.
23. Patients with known hypersensitivity to β-adrenergics drugs, anticholinergic drugs,
fluticasone propionate or to any of the excipients: Benzalkonium chloride (BAC), 
Disodium edentate (EDTA) or Lactose monohydrate (which contains milk proteins) or 
any other component of the Respimat® or Accuhaler® delivery systems.
24. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
25. Women of childbearing potential not using highly effective methods of birth 
control*during the period of drug exposure and until the follow-up visit at 21days after 
the discontinuation of study medication. Female patients will be considered to be of 
childbearing potential unless permanently sterilised by hysterectomy, bilateral 
salpingectomy or bilateral oophorectomy, or post-menopausal (12 months with no menses 
without an alternative cause).
* 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. A list of contraception methods meeting these criteria is provided in the patient 
information.


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26. Patients who have previously been enrolled in this study or are currently enrolled in 
another study.
27. Patients who are unable to comply with pulmonary medication restrictions, as per 
Investigator´s judgment, prior to randomisation.
28. Patients with pacemakers and metal implants (i.e. vascular clips and stents, metal silver in 
patient’s eye) and patients with claustrophobia, due to contraindications for CMR.
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, adverse events, 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.
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 of pregnancy 
and the outcome of pregnancy, please see Section 5.3.6.2.
Investigators must carefully consider withdrawal from the treatment of an individual patient 
if any of the following criteria apply:

More than 3 courses of systemic (oral, intravenous) corticosteroids are required to 
treat a COPD exacerbation.

When, during trial participation, a second hospital admission (at least 2 overnight 
stay) for a COPD exacerbation occurs.

Clinical deterioration requiring maintenance treatment not allowed per protocol.
Details of all COPD exacerbations will be captured in the source notes and on AE/SAE 
pages.
No patient should be discontinued from the trial for a protocol violation before discussion 
with the Sponsor.
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.


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For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the 
electronic case report form (e)CRF. These data will be included in the trial database and 
reported.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
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
INVESTIGATIONAL TREATMENTS 
4.1
The study medication below will be supplied by Boehringer Ingelheim Pharma GmbH & Co.
KG.
After screening, eligible patients will be randomly assigned to a treatment sequence AB or 
BA in two 6 week periods, with no washout in between the two treatment periods.
Patients will receive one of the following treatments:
Tiotropium + olodaterol FDC (2.5 μg / 2.5 μg) inhalation solution via Respimat®
inhaler
followed by
B. Fluticasone propionate +salmeterol FDC (500 mcg / 50 mcg) inhalation powder via 
Accuhaler® inhaler
or vice versa, depending on randomized treatment sequence.
During each treatment period the patient will inhale two puffs from the Respimat® inhaler, 
once per day, in the morning immediately followed by one inhalation from the Accuhaler®. 
Each evening the patient will take one inhalation from the Accuhaler® only. The Respimat®
inhaler is not to be used in the evening.
In order to assure blinded treatment during each treatment period with only one medication 
matching placebo will be used for both products for double dummy-design of the study.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product 1:
Substance:
Tiotropium plus 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: 2
Placebo for test product 1:
Substance:
Placebo matching Tiotropium plus olodaterol FDC
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG.
Unit strength:
Not applicable
Posology
2 inhalations once daily (a.m. dosing)
Route of administration:
Oral inhalation via Respimat® inhaler (A5)
Table 4.1.1: 3
Test product 2:
Substance:
Fluticasone propionate /salmeterol FDC
Pharmaceutical formulation:
Inhalation powder
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG.
Unit strength:
500 µg / 50 µg per inhalation
Posology
One inhalation in the morning and evening (a.m. and 
p.m. dosing)
Route of administration:
Oral inhalation via Accuhaler® inhaler
Table 4.1.1: 4
Placebo for test product 2:
Substance:
Placebo matching Fluticasone propionate /salmeterol 
FDC
Pharmaceutical formulation:
Inhalation powder
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG.
Unit strength:
Not applicable
Posology
One inhalation in the morning and evening (a.m. and 
p.m. dosing)
Route of administration:
Oral inhalation via Accuhaler® inhaler


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4.1.2
Selection of doses in the trial
The clinical trials conducted during the Phase III program for tiotropium + olodaterol FDC 5
μg / 5 μg have shown that this dose is a safe, well tolerated and efficacious combination 
therapy. Tiotropium + olodaterol FDC 5 μg / 5 μg demonstrated statistically significant and 
clinically relevant benefit over the individual components in all primary and secondary 
endpoints. On the other hand, the lung function improvement for lower dose tiotropium + 
olodaterol FDC 2.5 μg / 5 μg was more modest and a statistically significant benefit was not 
demonstrated in the pre-specified symptomatic primary endpoint, SGRQ total score. Based 
on these observations, the tiotropium + olodaterol FDC 5 μg / 5 μg has been submitted for 
regulatory approval and was approved in this dosage and is therefore considered to be the
most appropriate dose to be studied in this trial.
4.1.3
Method of assigning patients to treatment groups
Once the patient has provided written informed consent, the medication washout can occur 
according to Table 4.2.2.1:1. When a patient is qualified for entry into the randomised 
treatment sequence, the intervention assignment will be by means of a third-party phone/web-
based randomisation at Visit 2.
Patients will be assigned a unique patient number using the remote data capture system. 
During Visit 2 and after the patient’s eligibility has been confirmed, one of the two treatment 
sequences will randomly be assigned via IRT. To facilitate the use of the IRT, the 
Investigator will receive all necessary instructions. Patients will then be assigned the 
alternative treatment again at Visit 3. Each time patients will be assigned treatment 
medication boxes and each medication box will have a unique number. Refer to Section 4.1.6
for details on packaging and labelling.
Please note that the medication number is different from the patient number. Site personnel 
will enter all the medication numbers dispensed to each patient in the electronic case report 
form (eCRF).
Details on the IRT are provided in the ISF.
4.1.4
Drug assignment and administration of doses for each patient
Dispensing of trial medication
4.1.4.1
Trial medication will be dispensed to the patient by the investigator/pharmacist. At Visit 2
eligible patients will be randomised to one of two double-blinded treatment sequences AB or 
BA (1:1 ratio) by the IRT. IRT will assign three Respimat® kits (two for treatment and one 
for reserve) and three Accuhaler® kits (two for treatment and one for reserve). Matching 
placebo kits will be used in assignment so that in one treatment period only one product of 
the two will contain active substance (double-dummy design). This will be used for six weeks 
of treatment. At Visit 3, the IRT will assign additional Respimat®and Accuhaler treatment 
boxes so that alternate treatment sequence will be supported. Each Respimat®and Accuhaler®
treatment box will have a unique medication number with 6 digits.


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One of these Respimat® and Accuhaler® treatment boxes is a reserve Respimat®and 
Accuhaler® kit (Explanation: Respimat kit contains Respimat® inhaler and cartridge or 
respective Accuhaler® inhaler). This allows the patient the flexibility of not having to return 
to the clinic immediately to replace a lost or malfunctioning inhaler. In the event that a 
patient may need additional extra inhalers and cartridges due to rescheduled visits, inhaler 
loss or malfunction, these will be supplied on an ‘on demand’ basis. Dispensing of these extra
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 electronic case report form (eCRF) and on the drug accountability forms.
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. If the cloud of mist is not 
seen, the priming process shall be repeated until a cloud is visible. These steps will not affect 
the number of doses available and the Respimat® inhaler will deliver enough doses for 1 
month supply.
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.
The Accuhaler® containing fluticasone propionate + salmeterol discus being a DPI does not 
require priming and has no shelf-life other than labeled Use-by date.
Testing of the MDI (rescue medication)
Before using for the first time, one actuation should be released into the air to make sure the 
device is working.
Study medication administration
4.1.4.2
For the patient’s sake of convenience regarding the trial drug administration, the clinic visit 
must be scheduled in the morning. During the treatment phase the patient will be instructed to 
withhold the morning dose of the trial medication in current use prior to come to visits 3 and 
4 to avoid overdosing.
The last administration of the study medication will be taken at visit 4 (EoT) from the 
Respimat® inhaler and from Accuhaler® that is in current use since no new Respimat® and 
Accuhaler® treatment box will be assigned.


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Study medication administration at clinic visits
Detailed written instructions and training for the use of the Respimat® inhaler and Accuhaler®
will be given to the patient at Visit 1 (see Appendix 10.1 and 10.2). At Visits 2 and 3 detailed 
instructions on the use of the device will be repeated, but patient should not inhale from a 
training device that day. The investigator or qualified personnel will observe the inhalation 
procedure and will reinforce a correct inhalation technique. For training session please refer 
to Section 4.1.4.3.
Trial medication will be dispensed at visits 2 and 3. 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. Patient will also receive 2 new Accuhaler® treatment boxes + 1 Accuhaler® inhaler 
reserve.
At each clinic visit and in this order, oral inhalation of two puffs of the trial medication from 
the assigned Respimat® inhaler followed by one puff of trial medication from the assigned 
Accuhaler® will be self-administered by the patient under the direct supervision of the 
investigating physician or designee. In addition, the evening dose of one puff from the 
Accuhaler® will be self-administered by the patient. The utmost care should be taken to 
ensure that during the treatment in the study medication is not taken prior to coming to the 
site. At treatment period end visits (Visit 3 and 4) the Respimat® and Accuhaler® that is in 
current use must be used for administration of the trial medication at that visit.
When planning the time of the morning dose of trial medication at Visit 2, site personnel 
should discuss with the patient about the preferred regular time of day that the patient will be 
taking the morning dose of trial medication at home as this will also affect the time the 
patient will take the evening dose at home.
At Visit 2, the trial medication will be self-administered between 7:00 a.m. and 10:00 a.m. At 
subsequent clinic visits, the morning dose of trial medication will be self-administered within 
±30 minutes of time of administration at Visit 2. The evening dose of trial medication will be 
self-administered at home by the patient between 7:00 p.m. and 10:00 p.m., twelve hours 
(±30 minutes) after the administration of the morning dose of trial medication.
For rescue medication dispensation, please refer to Section 4.2.1.
Study medication administration at the CMR visits prior to Visits 3 and 4
CMR assessment will be performed in a week prior to Visit 3 and Visit 4, 1 to 8 hours after 
self-administered morning medication dosing within ±30 minutes of time of administration at 
visit 2 AND between 7:00 a.m. and 10:00 a.m.


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Study medication administration at home
Each morning between clinic visits and in this order, oral inhalation of two puffs of the trial 
medication from the assigned Respimat® inhaler and one puff of trial medication from the 
assigned Accuhaler® (inhaled according to the instructions provided in Appendix 10.1 and 
10.2) will be self-administered by the patient within±30 minutes of time of administration at 
visit 2 AND between 7:00 a.m. and 10:00 a.m.
Each evening, one additional inhalation of trial medication from the Accuhaler® (inhaled 
according to the instructions provided in Appendix 10.2) will be self-administered by the 
patient, twelve hours (±30 minutes) after administration of the morning dose of trial 
medication.
If the patient forgot to take the trial medication within the specified time window, the patient 
is allowed to administer the morning dose up until 12:00 p.m. (morning dose window until 
noon). After 12:00 p.m. the patient should skip the dose and take the next dose at the next 
scheduled time the following day. If the patient forgot to take the evening trial medication 
within the specified time window, the patient is allowed to administer the evening dose up 
until 12:00 midnight (evening dose window until midnight). After midnight the patient 
should skip the dose and take the next dose at the next scheduled time the following day.
The patient must assemble and prime the Respimat® inhaler at home once the current used
Respimat® inhaler is empty and the device is locked.
Respimat® and Accuhaler® inhalers return
The Respimat® and Accuhaler® dispensed for treatment periods can be used for 
approximately 30 days each. All used and unused trial medication must be returned to the 
patient treatment boxes and must be brought to the subsequent site visit by the patient. The 
reserve inhalers should also be returned at each clinic visit to be replaced if it has been used 
or primed.
All used and unused Respimat® and Accuhaler® inhalers dispensed at Visit 2 will be returned 
at Visit 3 at the end of first treatment period (and those newly dispensed at Visit 3 will be 
returned at Visit 4 respectively), after administration of morning trial medication at the site.
This procedure allows for prompt recording on the drug accountability forms by the site staff 
and ensures that during the next treatment period trial medication of the previous treatment 
period could not be administered by the patient.
Inhaler devices training
4.1.4.3
Training on the use of the Respimat® and Accuhaler® inhalers will first be provided to the 
site staff who will subsequently train the patients.

At visit 1: the first patient’s training session will be performed with the intention to 
familiarize the patient with the Respimat® and Accuhaler® inhaler training medication 
(placebo). Detailed written instructions for the use of the inhalers will also be given
(Appendix 10.1 and 10.2).


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
Subsequent clinic visits: observance of the inhalation procedure. The correct 
inhalation technique should be reinforced in case of inadequate use of Respimat® and 
/or Accuhaler® inhalers. It is also important to remind the patient on how to assemble 
and prime the Respimat® inhaler at home.
Respimat® malfunctioning
4.1.4.4
Any Respimat® inhaler or Accuhaler® that has been reported as malfunctioning by a patient 
or investigator will be returned to Boehringer Ingelheim for investigation. See the ISF for 
specific instructions and for details regarding drug accountability requirements. 
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.
Boehringer Ingelheim will generate the randomisation scheme. Packaging and labelling of 
trial medication in a blinded fashion will be performed by a contractor. Trial supplies will be 
assigned to the patients via IRT.
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 CRF page along with the date and 
the initials of the person who broke the code.
4.1.6
Packaging, labelling, and re-supply
Boehringer Ingelheim will provide all study supplies including blinded study medication, 
rescue medication and Respimat® and Accuhaler® inhaler training kits. Expiry date will be 
pre-printed on the trial supplies labels

Training Respimat® inhaler, placebo cartridges and disposable mouthpieces for 
training purposes. A training device may be used for more than one training session. 
The training Respimat® can be used until 3 months after first insertion of the cartridge 
or until the device is empty. The date of the cartridge insertion should be entered on 
the medication label of the Respimat® immediately after the cartridge is inserted. A 
new mouthpiece should be used for each patient.


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
Accuhaler® training: Training placebo Accuhaler® kits will be used for training 
purposes and can be used until empty or used by date is reached. The device should 
be cleaned with antiseptic wipes, followed by a dry tissue after each patient use.
Blinded study medication , Investigational Medicinal Product (IMP)
All study medication (also containing blinded placebo medication) will be contained in 
Respimat® or Accuhaler® treatment boxes identified with the trial number and a medication 
number.
The boxes will have a two-part tear-off label. One part of each tear-off label will remain on 
the box, and the other part will be attached to a special drug dispensing log which will be part 
of the ISF. Examples of the labels are provided in the ISF.
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.

The Accuhaler® treatment box will contain one Accuhaler® inhaler. Each Accuhaler®
contains sufficient medication for 30 days of treatment.
Labelling
Individual treatment box will have a medical identification label and a two-part tear-off label. 
One part of each tear-off label should be attached to the drug accountability form which will 
be part of the ISF, and one part will remain on the box (an extra part is available as well). The 
investigator or designee should fill out the following information:

date of cartridge insertion, patient number and visit number should be entered at time 
of cartridge insertion on the inside page of the cartridge booklet

Investigator’s name should be entered at time of dispense on the label of the booklet 
on the treatment box.
For details of packaging and the description of the label, refer to the ISF.
Medication dispensing
The assignment of Respimat® and Accuhaler® treatment boxes dispensed at the beginning of 
each treatment period (Visit 2 and 3) will be handled by an IRT system.
At randomisation (Visit 2), as well as at Visits 3 the site staff will phone IRT and obtain 
medication numbers for each of the 3 Respimat® treatment kits and 3 Accuhaler® treatment 
kits to be dispensed to the patient for daily use during the 6 weeks between visits. This will 
include one reserve Respimat® kit and one reserve Accuhaler®. The Respimat® and 
Accuhaler® medication and reserve kits will have unique medication numbers.
One Respimat® inhaler will be primed by the site staff (see Section 4.1.4) and used to dose 
the patient at that site visit, and will be continued to be used at home until 30 days of 
treatment has been reached. The Accuhaler® does not have to be primed and will be used for 


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30 days of treatment. The second Respimat® will be primed and used by the patient to cover 
the remaining few weeks until the next visit (end of treatment visit). The third Respimat® and 
Accuhaler® are reserve medication. This is to allow the patient the flexibility of not having to 
return to the site immediately to replace a lost or malfunctioning Respimat® or Accuhaler®.
NOTE: The Respimat® and drug-filled cartridge that is not yet in use by the patient 
(including the reserve) should NOT be assembled prior to leaving the site. These devices 
must be assembled and primed by the patient at home when needed.
The investigator or designee should fill in investigator's name on the medication label of all 
three Respimat® and Accuhaler® treatment boxes at time of dispensing to the patient (Visit 2 
and 3 respectively). In contrast, date of cartridge insertion should be entered (label of 
Respimat® inhaler only) at time of cartridge insertion only, i.e. for the first Respimat® inhaler 
this is entered by site staff (during Visit 2 and 3), for the second Respimat® inhaler the patient 
is advised to do so when assembling this device at home during the treatment period, as well 
as for the third (reserve) Respimat® device, if necessary.
Re-supply
Each site will receive a first supply at or after the initiation visit and will be resupplied upon 
demand by IRT.
4.1.7
Storage conditions
All clinical trial supplies will be stored in a locked, secure cabinet and must be kept under the 
recommended storage conditions on the medication label. Clinical trial supplies may only be 
dispensed to trial subjects according to the protocol.
The Respimat® inhaler and cartridges and Accuhaler® 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 as specified in storage 
conditions for trial medication (STORM) document. If the storage conditions are found to be 
outside the specified range, immediately contact the local clinical monitor
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
Further details are provided in the STORM document and on the country-specific labels, a 
sample of which will be part of the ISF.
Throughout the trial, drug receipt, usage and return must be documented and verified. Any 
discrepancies in drug supplies will be noted and explained.
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 IRB / ethics committee,


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
Availability of a signed and dated clinical trial contract between the Sponsor and the 
head of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol
The 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 alternative disposal of used or unused products.
For the Respimat® and Accuhaler® Inhaler, these records for the drug accountability forms 
will include:

dates (dispense and return),

dispenser’s initials, 

quantities, 

expiry (‘use- by’) dates,

the unique Respimat treatment box number assigned by IRT

patient number assigned by the remote data capture system.
For the rescue medication, one Non Investigational Medicinal Product (NIMP) accountability 
form will be provided for salbutamol and ipratropium to the trial site. This record will 
include:

dates (dispense and return)

dispenser’s initials

quantities,

batch/serial numbers,

expiry date,

patient number.
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®.


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OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Non Investigational Medicinal Product (NIMP) (open label supplies)

Salbutamol (albuterol*) HFA MDI inhalation aerosol (100 μg per actuation) for use as 
rescue medication during screening and treatment (visit 0 to Visit 4) will also be used 
for reversibility testing at Visit 1. The rescue medication will be provided by BI.
* NOTE: Albuterol sulphate is the official generic name in the US and salbutamol sulphate is
the WHO recommended generic name.

Ipratropium bromide HFA MDI inhalation aerosol (20 μg per actuation) will be 
provided to be dispensed at the investigators discretion primarily for use by patients 
on a LAMA during the 4-week washout period of the LAMA preceding Visit 2.
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 and/or 
ipratropium bromide MDI will be provided by BI and allowed for rescue medication use. If 
the patient requires rescue medication during the PFT days (Visits 2 - 4), the PFTs will be 
discontinued and PFTs repeated on another day. The medication used, route and 24-hour 
clock time of administration will be recorded on the Rescue Medication eCRF page.
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.
There are no special emergency procedures to be followed.
Medications Allowed to Control Acute Exacerbations as Medically Necessary during the 
Treatment Period (Refer to Section 5.3.6.3 for definition of COPD exacerbations):

Salbutamol inhalation aerosol and/or Ipratropium bromide inhalation aerosol, both 
from MDI for PRN use, provided by BI.

Temporary addition of oral steroids is allowed during the treatment portion of the 
study. CMR assessment and pulmonary function testing should not occur within seven 
days of the last administered dose of an increase or addition of oral steroids. CMR 
assessment and subsequent pulmonary 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. CMR assessment and pulmonary function testing should not 
occur within seven days of the last dose. CMR assessment and subsequent 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.


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
The use of antibiotics is not restricted and may be prescribed as medically necessary 
for exacerbations and / or infections. If antibiotics are prescribed for a respiratory 
infection prior to pulmonary function testing days and /or CMR assessment, the 
testing/assessment will be postponed for at least two days. Subsequent visits will be 
scheduled according to the patient´s regular schedule.
Non study medication like oral steroids, theophylline preparations and antibiotics will not be 
provided by BI.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
The following Table 4.2.2.1:1 provides an overview of permitted and restricted medication.


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Table 4.2.2.1: 1
Permitted medications and Medications Restrictions
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment 
Period
Follow up 
Period
Corticosteroids
Inhaled corticosteroids
(not allowed for 2 weeks prior to V1)
Permitted1
NOT permitted
NOT 
permitted
Permitted1
Oral corticosteroids
(not allowed for at least 6 weeks prior to Visit1;
permitted intermittently during the treatment phase in 
a case of COPD exacerbation)
Permitted
NOT permitted
NOT 
permitted
Permitted
Injected Corticosteroids – local administration
(for treatment of e.g. bursitis)
Permitted
Permitted
Permitted
Permitted
β-adrenergics
Inhaled short-acting β-adrenergics
Permitted1
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
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 
baseline CMR and
V2)
NOT 
permitted
Permitted


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Table 4.2.2.1: 1
Permitted medications and Medications Restrictions (cont.)
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment 
Period
Follow up 
Period
Oral and patch beta-adrenergics
Permitted1
(w.o.4 wks prior 
to V1)
NOT permitted
NOT 
permitted
NOT 
permitted
Beta blockers
(stabilized 6 wks prior to V1)
Permitted
Permitted 
Permitted 
Permitted 
Anti-
cholinergics
Short-acting anticholinergics
(inhalation aerosol, nasal spray)
Permitted1
Rescue1
Rescue1
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 
baseline CMR and
V2)
NOT 
permitted
Permitted
Combinations
ICS/LABA (bid)
(* switch to LABA mono-product 2 weeks prior to V1, and 
then discontinue LABA at least 48 hrs prior to V1) (if 
switched to e.g. salmeterol, formoterol)
Permitted1
NOT permitted*
Study 
medication
Permitted
ICS/LABA (qd)
(*switch to LABA mono-product 2 weeks  prior to V1, and 
then discontinue at least 1 wks prior to V1) (if switched to 
e.g. indacaterol, olodaterol)
Permitted 
NOT permitted*
NOT 
permitted
Permitted
ICS/SABA
(* switch to SABA only 2 weeks prior to V1, and then 
discontinue SABA at least 8 hrs prior to V1)
Permitted1
NOT permitted*
NOT 
permitted
Permitted


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Table 4.2.2.1: 1
Permitted medications and Medications Restrictions (cont.)
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment 
Period
Follow up 
Period
short-acting anticholinergic/ SABA
(* 8 hrs prior to V1)
Permitted1
NOT permitted*
NOT 
permitted
Permitted
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 
baseline CMR and
V2)
Study 
medication
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
Cromolyn sodium / nedocromil sodium
(* if prescribed for non-asthma condition)
Permitted*
Permitted*
Permitted*
Permitted*
Antihistamines, antileukotrienes
(* if prescribed for non-asthma condition)
Permitted*
Permitted*
Permitted*
Permitted*
Methylxanthines*
(* if prescribed for non-asthma condition)
Permitted3
Permitted3
Permitted3
Permitted3
Mucolytics
(not containing bronchodilators; stabilized 6 wks prior to 
V1)
Permitted
Permitted
Permitted
Permitted
Phosphodiesterase type 4 (PDE-4) inhibitor4 (e.g. 
roflumilast)
NOT permitted
NOT permitted
NOT 
permitted
NOT 
permitted
Strong inhibitors of CYP3A45
NOT permitted 
(w.o.4 wks prior 
to V2)
NOT permitted
NOT 
permitted
NOT 
permitted


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1 Refer to Section 4.2.2.2 for washout period prior to PFTs.
2 Patients may be switched to qid LABA and short acting anticholinergic. Refer to Section 4.2.2.2 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 PDE-4-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 Strong CYP3A4 inhibitors e.g. boceprevir, danoprevir, elvitegrevir, clarithromycin, cobicistat (GS-9350), conivaptan, grapefruit juice DS, idelalisib, indinavir, itraconazole, ketoconazole,
  LCL161, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin and voriconazole are not permitted 4 weeks
  prior to first trial drug administration (Visit 2) and during the trial. All concomitant medication has to be checked by the investigator whether it is a strong inhibitor of CYP3A4 based on the
  SPC, if applicable. Specific questions of eligibility based on this criterion should be clarified by the clinical monitor prior to inclusion.


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Restrictions for pulmonary function testing and CMR assessment
4.2.2.2

At least 2 weeks washout of inhaled steroids prior to PFT s at visit 1, (Inhaled steroids 
are not allowed after Visit 1)

At least an 8-hour washout of short-acting beta-adrenergic bronchodilators and short-
acting anticholinergic bronchodilators.

At least a 1-week washout of long-acting anticholinergic bronchodilators (bid or qd) 
prior to Visit 1 and a 3-week washout prior to baseline CMR and Visit 2. (Not 
allowed between Visits 1 to 4)

At least a 1-week washout of long-acting beta-adrenergic bronchodilators (qd) prior to 
Visit 1 and a 3-week washout prior to baseline CMR and Visit 2 (Not allowed
between Visits 1 to 4).

At least a 48-hour washout of long-acting beta-adrenergic bronchodilators (bid) prior 
to Visit 1 (Not allowed between Visits 1 to 4).

At least a 4-week washout of oral and patch beta adrenergics prior to visit 1.

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.
Restrictions on diet and life style
4.2.2.3

On pulmonary function testing days (including the Screening Visit), patients must 
refrain from strenuous activity for at least 2-3 days prior to pulmonary function 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 
spirometry.

Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, and 
ice-cold beverages are not allowed the morning of or during the lung function testing 
period. Decaffeinated beverages are acceptable.
TREATMENT COMPLIANCE
4.3
On visit days, compliance will be guaranteed by administration of the trial drug under 
supervision of the investigating physician or designee.
Each patient will be trained at the screening Visit 1 as to the correct priming and inhalation 
using a training Respimat® Inhaler and on use of the Accuhaler®, both containing placebo. 
Compliance will be measured using the counter on the Respimat® and Accuhaler® devices. 
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 


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assess treatment compliance in treatment phase. However, randomised patients will not be 
discontinued for lack of compliance without prior discussion with the Sponsor.
	
 	
(%) =
	  
ℎ
  
  100
	  
ℎ
 ℎℎℎ ℎ! 
 
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(s)
The primary endpoint is change from baseline in LVEDVI in the 6th week of treatment with 
tiotropium+olodaterol FDC versus fluticasone propionate+salmeterol FDC.
LVEDVI is normalized left ventricular end diastolic volume (LVEDV), divided by body
surface area (BSA) (Appendix 10.3).
Baseline is defined as the value obtained during the assessment performed in a week prior to 
Visit 2. The change from baseline is calculated as the value obtained in a week prior to Visits 
3 and 4 (end of each treatment periods) minus the baseline value.
5.1.2
Secondary Endpoint(s)
The following secondary endpoints will be evaluated, all calculated as a change from baseline 
after 6 weeks of treatment:

Aortic distensibility and pulmonary artery (PA) pulsatility.

Central systolic pressure, pulse pressure and augmentation index (AI).

FRCpleth % predicted.

1,5 hour post dose FEV1.

1,5 hour post dose FVC.
None of the primary or secondary endpoints are safety issues.


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ASSESSMENT OF EFFICACY
5.2
CMR imaging
The CMR at 1.5 or 3 Tesla will be performed as indicated in a flowchart at rest as non-
enhanced, non-stress procedure lasting up to one hour in order to assess cardiac functional 
parameters and structure using a cardio-pulmonary acquisition protocol according to 
specifications detailed in the Imaging Manual prepared by a Central Imaging Vendor. 
Cardiac cine images will be acquired in two and four chamber view as well as in short-axis 
view. Strain and strain-rate of RV, LA and LV will be assessed.
Aortic distensibility and pulmonary artery pulsatility as measures of arterial stiffness will be 
derived from cine images acquired at end-expiration in planes perpendicular to the thoracic 
aorta at the level of the PA (ascending and descending section of thoracic aorta), abdominal 
aorta, and perpendicularly to the main, right, and left pulmonary arteries.
All scans on each subject will be completed on the same MR scanner used for the baseline 
MRI with the same settings and accredited for use by the Imaging Vendor. All scans should 
be performed preferably in a time window between 1 and 8 hours after morning trial 
medication dosing at visits 3 and 4.
All scans will be digitally transferred for central review performed by the independent 
reviewer within a pre-specified time period. All parameters will be captured and recorded at 
the Sponsor before the database lock and unblinding of the study. Further information is 
provided in a Study Procedure Manual filed in the ISF.
Pulse pulse wave analysis (PWA)
PWA will be performed with vendor device in conjunction with measurement of blood 
pressure at Visit 1 for inclusion and at Visit 2 to obtain baseline measurement and then it will 
be repeated at visits 3 and 4 at the end of each treatment period. Measurements will be batch 
uploaded from the vendor. All parameters will be captured and recorded at the Sponsor 
before the database lock and unblinding of the study. Further information is provided in a 
Study Procedure Manual filed in the ISF.
Body plethysmography
Body plethysmography will be done in line with ATS/ERS standards [R08-1121] using the 
device of the investigational site for assessment of lung volumes and capacities.
The measurement of functional residual capacity (FRC) will be repeated at least 3 times, until
3 obtained FRC values show ≤≥ 5% variability.


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Expiratory reserve volume (ERV) will be measured immediately after the FRC, followed by
slow inspiratory vital capacity (IVC) manoeuver, without the subject coming off the 
mouthpiece prior to the completion (as a linked maneuvre).
COPD patients who cannot perform linked manoeuvers will be instructed to have few cycles
of quiet breathing before initiation of the ERV/IVC manoeuvers.
Mean FRC value of at least 3 technically satisfactory FRC measurements, linked to the
technically satisfactory ERV and IVC manoeuvers used for calculating the RVol and TLC 
will be reported. RVol will be calculated as a difference between the reported FRC value and 
the mean of the technically acceptable ERV measurements, linked to technically acceptable 
FRC determinations. Total lung capacity (TLC) will be calculated by adding the reported 
value for RVol and the largest of the technically acceptable IVCs.
Inspiratory capacity (IC) will be derived from IVC and ERV, and IC/TLC will be calculated.
RVol % predicted will also be reported.
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 for FRC must meet the inclusion criteria specified in Section 3.3.2.
Pulmonary Function Testing
Spirometers and their use, including daily calibration on measurement days, 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 Sponsor 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.


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ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
Physical examinations are conducted at visit 1, at the end of each treatment (Visits 3 and 4) 
and at Visit 5 (Follow-up Visit) in case of any findings at the end of treatment visit (Visit 4). 
The physical exam includes vital signs (blood pressure and pulse rate), height and weight.
5.3.2
Vital Signs
Measurements of heart rate and blood pressure will be obtained immediately prior to body 
plethysmography, 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 will be collected in the morning prior to the reduction of hyperinflation and 
reversibility testing.
Haematology, blood chemistry and ß-HCG will be analyzed 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. It is 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 performed at visit 1 in all females 
of childbearing potential. Urine pregnancy testing will be performed at visits 2, 3, 4 and 5 in 
females of childbearing potential.


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5.3.4
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) at rest will be performed on all patients at the 
screening visit (Visit 1) for inclusion in the study.
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 body plethysmography and spirometry.
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 subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or 

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the remote data capture system. 
These events should always be reported as SAEs as described in Section 5.3.6.
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
Moderate:
Enough discomfort to cause interference with usual activity


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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.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged.


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Adverse event collection and reporting
5.3.6.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:

From signing the informed consent onwards through the Residual Effect Period (REP),
until individual patient’s end of trial:
- All AEs (serious and non-serious).

After the individual patient’s end of trial: 
- The Investigator does not need to actively monitor the patient for AEs but should 
only report relevant SAEs and relevant AESIs of which the Investigator may become 
aware of.
Figure 5.3.6.2: 1 AE collection in 1237.36
The REP is defined as 21 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see Section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs 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 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 


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to the trial medication and any possible interactions between the investigational drug(s) and a 
Non-Investigational Medicinal Product (NIMP) / Auxiliary Medicinal Product (AMP).
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In the rare case that a female subject participating  in this clinical trial becomes pregnant after 
having taken trial medication, the investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (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 an SAE form must be completed 
in addition.
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
COPD Exacerbations
5.3.6.3
For the purpose of this study, a COPD exacerbation is defined as a complex of lower 
respiratory events / symptoms (increase or new onset) related to the underlying COPD, with 
duration of three days or more, requiring prescription of antibiotics and/or systemic steroids 
and/or hospitalisation
A complex of lower respiratory events is defined as at least two of the following:

Shortness of breath

Sputum production (volume)

Change in sputum colour

Cough


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
Wheezing

Chest tightness
“Onset of exacerbation” will be defined by the onset of first recorded symptom. The “end of 
exacerbation” will be decided by the investigator based on clinical judgment. 
Exacerbations will be classified as follows:
Mild:
a new prescription of maintenance bronchodilator only
Moderate: 
patient receiving an exacerbation-related prescription of oral corticosteroids 
and/ or antibiotic not requiring hospitalisation.
Severe:
COPD-related hospitalisation.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
This study will not analyse pharmacokinetic or pharmacodynamic parameters
ASSESSMENT OF BIOMARKER(S) 
5.5
 
 
OTHER ASSESSMENTS
5.6
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’s 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 (Appendix 10.4). 
Patients will be asked to score their dyspnea first during an in-clinic visit, prior to
 
 pulmonary function testing and all other procedures (see Section 6.2). The 
results will be reported in the eCRFs.
 
 
 
 


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New York Heart Association functional classification
The New York Heart Association (NYHA) functional classification will be used to check and 
classify the severity of the patients’ function capacity (Appendix 10.6). The investigator 
should place the patients in one of the four categories based on how limited their physical 
activity is. Candidates for screening are required not to have a NYHA functional class IV.
The classification of patient’s physical activity according to NYHA will be performed at 
Visit 1.
APPROPRIATENESS OF MEASUREMENTS
5.7
Measurements of efficacy parameters will be consistent with the following generally 
recognized standards:
CMR
Cardiac magnetic resonance imaging will be performed according to current standardized 
protocols [R16-3841].
PWA
Non-invasive brachial cuff based assessment of central aortic pressure and waveform features 
will be used in this trial according to current recommendations [R16-3840]. The vendor 
device used provides measurements of brachial pressure and the estimation of central aortic 
pressure waveform by mathematical transformation of brachial artery tonometry. The method 
is reproducible and central pressure waveform indices correlate strongly with Doppler 
indexes of LV function [R16-3842 and R16-3843].
Body Plethysmography
Body plethysmography will be conducted at clinic visits using the site´s own equipment and 
used following the ATS/ERS methodology and calibration procedures [R08-1121].
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 standard measurements for the assessment of lung 
function.


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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 visit 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 2) 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 2) washout should be stopped and patient will be 
assessed for severity and treated with bronchodilators, inhaled or systemic corticosteroids, 
antibiotics and other appropriate management interventions, as indicated according to current 
guidelines (P16-13658). Patient should also be excluded from further participation in the trial.
Rescheduling after randomisation
Subsequent visits should always be planned to take place to assure a minimum 6 week 
treatment period.
If rescheduling of visits after randomisation is necessary, the total daily doses of the 
Respimat® inhaler and/or Accuhaler® 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 Sponsor.
Refer to Section 4.2.2 for restrictions prior to PFTs and CMRs during study treatment.
In case a visit needs to be rescheduled outside the allowed time win Sponsor should be 
contacted.


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Pulmonary function testing (PFT) and body plethysmography will be conducted at the 
screening visit (Visit 1) to determine patient eligibility. PFTs and body plethysmography will 
also be conducted at Visits 2, 3 and 4 during the treatment period; vital signs will be
measured in conjunction with pulmonary function tests at all visits.
Physical examination will be performed together with an evaluation of the patient's smoking
status and COPD background characteristics at Visit 1. A 12-lead EGC will be recorded at 
Visit 1 and blood samples for clinical laboratory testing will be obtained to evaluate the 
patient's eligibility. The physical exam will be repeated at Visit 3 and also at Visit 4 on 
completion of patient's participation in the randomised treatment period of the trial.
Serum pregnancy testing will be done at Visit 1 in females of childbearing potential. Urine 
pregnancy testing will be performed at Visit 2, 3, 4 and 5 in females of child bearing
potential. 
Peripheral blood pressure measurements together pulse wave analysis assessment will be 
obtained at Visit 1 for inclusion and on Visit 2 as baseline and at subsequent Visits 3 and 4 at 
the end of each 6 week treatment period.
CMR will be performed in a week prior to Visit 2 to obtain baseline parameters and then in a 
week prior to subsequent Visits 3 and 4, or at the latest on the day of respective visits, at the 
end of each treatment periods for assessment of left and right global and regional systolic and 
diastolic cardiac function and arterial stiffness.
Adverse events will be documented throughout the trial, i.e. starting with informed consent 
and ending 21 days after actual last administration of trial medication. COPD exacerbations
according to protocol-specific definition (Section 5.3.6.3) will be documented together with 
additional observations including adverse events and concomitant therapies.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening and run-in period(s)
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 2 (see Section 3.3.2 and Section 3.3.3).
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.


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Informed
Consent
Informed Consent will be obtained prior to patient participation in the trial, 
which includes any medication washout procedures or restrictions.
See Section 4.2.2.2 for pulmonary test restrictions.
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 and/or ipratropium (primarily to patients who are required 
to washout LAMAs during run-in periods) (as rescue medication) that will 
be dispensed at this visit.
IRT
Call IRT to register the patient in screening.
Visit 1 Procedures and Observations
Reversibility and Hyperinflation Testing
(Phone contact 1-2 days prior to the visit
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 
 
questionnaires 
To be completed prior to study procedures. Refer to Appendix 10.5
and 10.6.
Adverse Events
All AEs experienced since signing informed consent will be reviewed 
and recorded.
Smoking Status
Will be 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) with blood pressure measurement should be 
performed. 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 
hematology, 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.


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Vital Signs
Blood pressure (together with pulse wave analysis) and pulse rate will 
be measured immediately before body plethysmography with the 
patient seated and rested for at least five minutes.
Body 
Plethysmography 
followed by 
Spirometry 
(hyperinflation 
reduction and 
reversibility 
testing)

Lung volumes including FRC measurement will be taken prior 
to 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 (-30 min) and ≥10 minutes and up to 20 minutes after 
the inhalation of 4 puffs of salbutamol (albuterol).

Please refer to inclusion criteria 2 and Appendix 10.3.
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

The use of the Accuhaler® Inhaler using the training kit

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 (if not already done at 
Visit 0).
Plan for baseline 
CMR prior to 
Visit 2
Schedule for the baseline CMR assessment in coordination with the 
patient and the CMR unit. Assign patient a card for washout 
requirements and instructions for baseline CMR assessment. Instruct 
the patient about handling of the patient card.
6.2.2
Treatment period(s)
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 3 and 4
Visit 2 Procedures and Observations
Randomisation, medication dispensing. 
CMR baseline assessment will be performed in a week prior to Visit 2 but at the latest 3 
days prior to the Visit 2 to allow for the assessment of ejection fraction level for 
inclusion.


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(Phone contact prior to CMR and 1-2 days prior to the visit)
Medication 
washout
Medication washout compliance for prohibited medications will be
verified and visits may be rescheduled as appropriate (Section 6.1)
mMRC 
 
questionnaires
To be completed prior to study procedures. Refer to Appendix 10.4
and 10.5.
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.
Smoking Status
Will be recorded.
CMR patient card
Evaluate patient card for baseline CMR issued at Visit 1.
 
 
Urine Pregnancy
Will be performed if needed.
Vital Signs
Blood pressure (together with pulse wave analysis) and pulse rate will 
be measured immediately before PFTs with the patient seated and 
rested for at least five minutes.
Body 
Plethysmography
followed by 
Spirometry
Baseline pre-dose body plethysmography will be performed between 
7:00 and 10:00 am (1 hour prior to inhalation of morning dose of study 
medication) followed by baseline pre-dose spirometry. Refer to FC.
The 24-hour clock time of the last cigarette smoked during the 12 
hours prior to the start of body plethysmography measurements will be 
recorded.
Randomisation 
Call  (IRT)
To be performed by calling IRT.
Assignment and 
dispensing of trial 
drug
Allocate the appropriate medication kits using IRT.
2 Respimat® treatment boxes and 1 reserve Respimat® inhaler are 
assigned and 
2 Accuhaler® treatment boxes and 1 reserve Accuhaler® inhaler
Trial drug
training and
administration
The patient will self-administer the trial drug (from the new assigned
Respimat® inhaler followed by Accuhaler® 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 


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will be recorded. Note that at subsequent clinic visits, study 
medicatiokn will be self-administered preferably within ±30 minutes 
of time of administration at Visit 2 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 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.
Plan for the 
second CMR 
prior to/at Visit 3
Schedule for the second CMR assessment in coordination with the 
patient and the CMR unit. Assign patient a card for washout 
requirements and time point of intake of morning study medication at 
the CMR assessment day. Instruct patient about handling of the patient 
card.
Visit 3 Procedures and Observations
End of first treatment period assessments and medication change.
CMR assessment will be performed in a week prior to or at the latest at Visit 3 (1 to 8 
hours after morning medication dosing).
(Phone contact prior to CMR and 1-2 days prior to the visit)
Medication 
washout
Medication washout compliance for prohibited medications will be 
verified and visits may be rescheduled as appropriate (Section 6.1)
mMRC 
 
questionnaires
To be completed prior to study procedures. Refer to Appendix 10.4
and 10.5.
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.
Smoking Status
Will be recorded.
CMR patient card
Evaluate patient card for the second CMR issued at Visit 2.
Physical 
Examination 
The physical examination includes measurements of blood pressure 
and pulse rate. Refer to Section 5.3.1.
The vital signs (seated) with blood pressure measurement should be 
performed.
 
Urine pregnancy
Will be recorded.


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Trial Drug 
Administration
Study medication will be self-administered within ±30 minutes of time 
of administration at visit 2 AND between 7:00 a.m. and 10:00 a.m.; 
start-time of inhalation will be recorded. Administration of trial 
medication during these visits will be done using medication that was 
dispensed at the beginning of the treatment period.
Vital Signs
Blood pressure (together with pulse wave analysis) and pulse rate will 
be measured immediately before body plethysmography with the 
patient seated and rested for at least five minutes.
Body 
Plethysmography
followed by 
Spirometry
Post-dose plethysmography will be performed 1,5 hour post inhalation 
of morning dose of study medication followed by post-dose 
spirometry. 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 and 
Compliance 
check
Collect all dispensed trial medication and perform Compliance check.
IRT Call
Change of trial medication.
Assignment and
dispensing of
trial drug 
Allocate the appropriate medication kits using IRT.
2 Respimat® treatment boxes and 1 reserve Respimat® inhaler are 
assigned and 
2 Accuhaler® treatment boxes and 1 reserve Accuhaler® inhaler
Training and
Instructions
Patients will receive training and instructions on

Medication restrictions and washout requirements for 
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.
Plan for the third
CMR prior to/at 
Visit 4
Schedule for the third CMR assessment in coordination with the 
patient and the CMR unit. Assign patient a card for washout 
requirements and time point of intake of morning study medication at 
CMR assessment day. Instruct patient about handling of the patient 
card.
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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Visit 4 (EoT) Procedures and Observations
End of second treatment period assessments and trial medication collection.
CMR assessment will be performed in a week prior to or at the latest at Visit 4 (1 to 8 
hours after morning medication dosing).
(Phone contact prior to CMR and 1-2 days prior to the visit)
Medication 
washout
Medication washout compliance for prohibited medications will be 
verified and visits may be rescheduled as appropriate (Section 6.1)
mMRC 
 
questionnaires
To be completed prior to study procedures. Refer to Appendix 10.4
and 10.5.
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.
Smoking Status
Will be recorded.
CMR patient card
Evaluate patient card for the third CMR issued at Visit 3.
Physical 
Examination
The physical examination includes measurements of blood pressure 
and pulse rate. Refer to Section 5.3.1.
The vital signs (seated) with blood pressure measurement should be 
performed.
 
Urine pregnancy
Will be recorded.
Trial Drug 
Administration
Study medication will be self-administered within ±30 minutes of time 
of administration at Visit 2 AND between 7:00 a.m. and 10:00 a.m.; 
start-time of inhalation will be recorded. Administration of trial 
medication during these visits will be done using medication that was 
dispensed at the beginning of the treatment period.
Vital Signs
Blood pressure (together with pulse wave analysis) and pulse rate will 
be measured immediately before body plethysmography with the 
patient seated and rested for at least five minutes.
Body 
Plethysmography
followed by 
Spirometry
Post-dose body plethysmography will be performed 1,5 hour post 
inhalation of morning dose of study medication followed by post-dose 
spirometry. 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.
IRT Call
Call IRT to register the patient as completed.
Trial Drug
Collection and 
All study medication will be collected at visit 4. Compliance check 
will be performed.


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Compliance 
check
Rescue 
Medication 
Collection
All study medication will be collected
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.
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
The physical examination includes measurements of blood pressure 
and pulse rate. Refer to Section 5.3.1.
The vital signs (seated) with blood pressure measurement should be 
performed.
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.
Body 
Plethysmography 
followed by 
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
Call IRT to register the patient as discontinued.
Visit 5 (End of observation) Follow-up Procedures and Observations
At the completion of Visit 4, 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.


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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
The physical examination includes measurements of blood pressure 
and pulse rate. Refer to Section 5.3.1.
The vital signs (seated) with blood pressure measurement should be 
performed.
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 an exploratory, randomised, double-blind, double-dummy, active-controlled, two 
period complete cross-over study to investigate the effect of 6 weeks treatment of orally 
inhaled tiotropium + olodaterol FDC (5 µg/5 µg) compared with fluticasone propionate + 
salmeterol FDC (1000 µg /100 µg) on left ventricular function and arterial stiffness in 
patients with COPD.
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 are 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 LVEDVI.
H0: Mean change from baseline in LVEDVI for (Tiotropium + Olodaterol) = Mean change 
from baseline in LVEDVI for (Fluticasone propionate + Salmeterol)
H1: Mean change from baseline in LVEDVI for (Tiotropium + Olodaterol) ≠ Mean change 
from baseline in LVEDVI for (Fluticasone propionate + Salmeterol)
Where LVEDVI is the primary endpoint 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 or secondary endpoints. This set will be 
called Full Analysis Set (FAS).
The data from patients who have had an exacerbation during the treatments will be excluded 
from the analyses, 
 
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 Trial Statistical Analysis Plan (TSAP).


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7.3.1
Primary endpoint analyses
In the primary analysis, the two-sided hypothesis as given in Section 7.2 will be tested based 
on adjusted mean change from baseline in LVEDVI, as listed in Section 5.1.1, using a 
restricted maximum likelihood (REML)-based MMRM. This model will include treatment 
and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured 
covariance structure will be used for within patient variation. If convergence is not achieved, 
the compound symmetry covariance structure will be used. 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.
 
Baseline
The baseline is defined as the (pre-dose) measurement in, the LVEDVI performed in a week 
prior to Visit 2 (or prior to dosing on the Visit 2).
7.3.2
Secondary endpoint analyses
The MMRM model described for the primary analysis will be performed for secondary 
endpoints as listed in Section 5.1.2. 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.
7.3.4
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 considered 
‘treatment-emergent’. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’. Adverse events with an onset from 
the start of treatment to Visit 3 will be assigned to the first treatment, and adverse events with 
an onset on a day after Visit 3 to the end of REP to the second treatment.   
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.


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Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA.
Blood pressure and pulse rate measured in conjunction with PFT testing will be presented for 
each treatment using descriptive statistics. 
7.3.5
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 TSAP prior to 
unblinding.
RANDOMISATION
7.6
Approximately 74 patients will be randomised in blocks to double-blind treatment sequence
so that approximately equal numbers of patients will be randomised to each treatment 
sequence. BI will arrange for the randomization and the packaging and labelling of trial
medication. The randomization 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.
DETERMINATION OF SAMPLE SIZE
7.7
This is an exploratory trial and only limited data exist about LVEDVI. A cross-over study in 
COPD patients evaluated the effect of fluticasone furoate and vilanterol versus placebo on 
mean change from baseline in LVEDVI [R16-3512]. The mean difference was 3.63 mL/m2
with a standard deviation of approximately 7.3 mL/m2. Assuming a 2-sided alpha of 5% and 
a within-patient standard deviation of 7.5 mL /m2, a sample size of approximately 74 patients 
would have 80% to 90% power to reject the null hypothesis if the true treatment difference is 
2.5 to 3.0 mL/m2. If the SD is 20% larger (9.0 mL /m2), then the power would still be 80% 
for a treatment difference of 3.0 mL/m2. This results in a sample size of 74 patients.


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Table 7.7: 1
Sample size for 80% and 90% power, 2-sided alpha= 0.05
Power
Difference 
[ml/m2]
SD
Sample Size
80%
3.0
7.5
52
90%
3.0
7.5
68
80%
3.0
9.0
74
90%
3.0
9.0
98
80%
2.5
7.5
74
90%
2.5
7.5
98
Calculations were performed using nQuery Advisor® 7.0 statistical package by Statistical 
Solutions Ltd.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonised standards for Medical Devices (ISO 14155 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), relevant BI Standard Operating Procedures (SOPs) 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 BI 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, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to 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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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.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure patient confidentiality.
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))

Serious adverse events (onset date (mandatory), and end date (if available))


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
Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

Completion of 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 in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g.
FDA). The CRA and auditor may review all CRFs and informed consents. The accuracy of 
the data will be verified by direct comparison with the source documents described in Section 
8.3.1. The Sponsor will also monitor compliance with the protocol and ICH GCP.
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.
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 AND PATIENT PRIVACY
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 


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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 Suspected Unexpected Serious 
Adverse Reactions (SUSARs) occurring with the trial medication until 30 days after LPDD at 
their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / CA in Germany 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 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.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P05-12646
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates 
A, Grinten CPM van der, Gustafsson P, Hankinson J, Jensen R, Johnson DC, 
MacIntyre N, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J. 
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, Crapo 
R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson DC, 
MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, 
Wanger J; Standardisation of spirometry. Eur Respir J 26 (2), 319 - 338 (2005)
P16-01440
Beeh KM, Derom E, Echave-Sustaeta J, Groenke L, Hamilton A, Bjemer L. 
The lung function profile of once-daily tiotropium and olodaterol vis Respimat 
is superior to that of twice-daily salmeterol and fluticasone propionate via 
Accuhaler (ENERGITO study). Int J Chronic Obstruct Pulm Dis 11,  193 –
205 (2016)
 
 
 
 
 
P16-08905
Watz H. Chronic Obstructive Pulmonary disease: when Pulmologists do 
Something Good for the Heart. Am J Respir Crit Care Med 2016; 193(7): 703-
716.
P16-13658
Global strategy for the diagnosis, management, and prevention of chronic 
obstructive pulmonary disease 2017 report. http: // goldcopd.org/gold-2017-
global-strategy-diagnosis-management-prevention-copd/ (access date: 22 
November 2016); Global Initiative for Chronic Obstructive Lung Disease 
(GOLD) (2017).
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)
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 


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Steering Committee, Int. Conf Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 2000)
R06-1245
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 
1987; 317(17):1098.
R08-1121
Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, 
Casaburi R, Crapo R, Enright P, Grinten CPM van der, Gustafsson P, 
Hankinson J, Jensen R, Johnson D, MacIntyre N, McKay R, Miller MR, 
Navajas D, Pellegrino R, Viegi G. Standardisation of the measurement of lung 
volumes. Eur Respir J 26 (3), 511 - 522 (2005)
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). weblink: ich.org/LOB/media/MEDIA5544.pdf (access 
date:11.10.2010) (2009)
 
 
R12-4840
Divo M, Cote C, Torres JP de, Casanova C, Marin JM, Pinto-Plata V, Zulueta 
J, Cabrera C, Zagaceta J, Hunninghake G, and Celli B; for the BODE 
Collaborative Group. Comorbidities and risk of mortality in patients with 
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186:
155-161.
R15-2161
Smith BM, Kawut SM, Bluemke DA, Basner RC, Gomes AS, Hoffman E,  
Kalhan R, Lima JAC, Liu CY, Michos ED, Prince MR, Rabbani L, Rabinovitz 
D, Shimbo D, Shea S, Barr RG, Pulmonary Hyperinflation and Left Venticular 
Mass. The Multi-Ethnic Study of Atherosclerosis COPD Study, Circulation 
2013; 127: 1503-1511. 
R16-3512
Stone IS, Barnes NC, James W-L, Midwinter D, Boubertakh R, Follows R, 
John L, Petersen SE. Lung deflation and cardiovascular structure and function 
in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2016;
193: 717-726.
R16-3513
Negewo NA, McDonald VM, Gibson PG. Comorbidity in chronic pulmonary 
disease, Respiratory Investigation 2015; 53: 249-258.
R16-3514
Chen W, Thomas J, Sadatsafavi M, FitzGerald JM. Risk of cardiovascular 
comorbidity in patients with chronic obstructive pulmonary disease: a 
systematic review and meta-analysis. Lancet Respir Med 2015; 3: 631-39.


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R16-3515
Cuttica MJ, Colangelo LA, Shah SJ, Lima J, Kishi S, Arynchyn A, Jacobs DR 
JR, Thyagarajan B, Liu K, Lloyd-Jones, and Kalhan R. Loss of Lung Health 
from Young Adulthood and Cardiac Phenotypes in Middle Age. Am J Respir 
Crit Care Med 2015; 192(1); 76-85.
R16-3516
Watz H. The Lungs and the Heart. Am J Respir Crit Care Med 2015; 192(1);
7-8.
R16-3517
Watz H, Waschki B, Meyer T, Kretschmar G, Kirsten A, Claussen M,  
Magnussen H. Decreasing cardiac chamber sizes and associated heart 
dysfunction in COPD; role of hyperinflation. Chest 2010; 138: 32-38.
R16-3518
Smith BM, Hoffman EA, Basner RC, Kawut SM, Kalhan R, and Barr RG. Not 
all measures of Hyperinflation Are Created Equal. Lung structure and clinical 
Correlates of Gas Trapping and Hyperexpansion in COPD: The Multi-Ethnic 
Study of Atherosclerosis (MESA) COPD Study. Chest 2014; 145(6): 1305-
1315. 
R16-3519
Smith BMPrince MR, Foffman EA, Bluemke DA, Liu CY, Rabinovitz D, 
Hueper K, Parikh MA, Gomes AS, MIchos ED, Lima JAC, Barr RG. Impaited 
Left Ventricular Filling in COPD and Emphysema: Is It the Heart or the 
Lungs? The Multi-Ethnic Study of Atherosclerosis COPD Study. Chest 2013; 
144(4): 1143-1151. 
R16-3528
Chirinos JA, Zamani P. The Nitrate-Nitrite-NO Pathway and Its Implications 
for heart Failure and Preserved Ejection Fraction. Curr Heart Fail Rep 2016;
13: 47. DOI 10.1007/s11897-016-0277-9.
R16-3555
Frydrychowicz A, Wieben O. Safety issues in MRI. In: ERS Monograph 
Imaging. Edited by Ghram Barr R, Parr DG, Vogel-Claussen J. 2015; 70: 263-
270.
R16-3556
Caudron J, Fares J, Bauer F, Dacher JN. Evaluation of Left Ventricular 
Diastolic Function with Cardiac MR imaging. Radiographics 2011; 31: 239-
261.
R16-3557
Rutten FH , Vonken EJ, Cramer MJ, Moons KG,Velthuis BB, Niek HP, 
Lammers JW,  Grobbee DE, Mali WP, Hoes AWH. Cardiovascular magnetic 
resonance imaging to identify left-sided chronic heart failure in stable patients 
with chronic obstructive pulmonary disease. Amerrican Heart Journal 2008;
156 (3), 506–512.
R16-3558
Sanz J, Kariisa M, Dellegrottaglie S, Prat-Gonzales S, Garcia MJ, Fuster V, 
Rajagopalan S. Evaluation of Pulmonary Artery Stiffness in Pulmonary 
Hypertension With Cardiac Magnetic Resonance. JACC: Cardiovascular 
Imaging 2009; 2(3): 286-95.
R16-3840
Townsend RR, Wilkinson IB, Schiffrin EL, Avolio AP, Chirinos JA, Cockroft 
JR, Heffernan KS, Lakatta EG, McEniery CM, Mitchell GF, Najjar SS, 


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Nichols WW, Urbina EM, Weber T. Recommendations for improving and 
standardizing vascular research on arterial stiffness. A scientific statement 
from the American Heart Association. Hypertension 2015; 66: 698-722.
R16-3841
Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E. Standardised 
cardiovascular magnetic resonance (CMR)protocols 2013 update. Journal of 
Cardiovascular Magnetic Resonance 2013; 15: 91 (http: // jcmr-
online.com/content/15/1/91).
R16-3842
Cauwenberghs N, Knez J, Tikhonoff V, D´hooge JD, 
Kloch-Badek M, Thijs L, Stolarz-Skzypek K, Haddad F, Wojciechowska W, 
Swierblewska E, Casiglia E, Kawecka-Jaszcz K, Narkiewicz K, Staessen JA, 
Kuznetsova T. Dopper indexes of left ventricular systolic and diastolic 
function in relation to the arterial stiffness in a general population. J Hipertens 
2015; 34: 762-771.
R16-3843
Avolio A, Butlin M. Indices of central aortic pressure waveform and 
ventricular function: an intimate conversation changing direction with age. J 
Hipertens 2016; 34: 634-636.
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)
UNPUBLISHED REFERENCES
9.2
c01735218
 Clinical Trial Report: Tiotropium + 
olodaterol fixed dose combination inhalation solution – Respimat®. TOnado™ 
1 1237.5. 10 April 2014.
c01735249
. Clinical Trial Report: Tiotropium +
olodaterol fixed dose combination inhalation solution – Respimat®. 
TOnado™ 2 1237.6. 10 April 2014.
U13-1917
Randomised, double-blind, placebo-
controlled, 6 treatment, 4 period, incomplete cross-over trial to characterise the 
24-hour lung function profiles of tiotropium + olodaterol fixed dose 
combination (2.5/5 μg, 5/5 μg), tiotropium (2.5 μg, 5 μg) and olodaterol (5 μg)
(oral inhalation, delivered by the Respimat® Inhaler) after 6 weeks once daily 
treatment in patients with Chronic Obstructive Pulmonary Disease (COPD) 
[VIVACITOTM] (1237.20).


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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 closed, press the safety catch € and pull the
clear base (G).
2a
2
Take the cartridge (H) out of the box.  Push the narrow end of 
the cartridge into the inhaler until it clicks into place (2a). The 
cartridge should be pushed gently against a firm surface to 
ensure that it has gone all the way in (2b).
Do not remove the cartridge once it has been inserted into the 
inhaler.
2b
  3
3
Replace the clear base (G). 
Do not remove the clear base again.
Safety catch


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


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


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What if...
What if...
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.
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-04-BI 1744+tiotropium combination-Respimat-20090831


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THE ACCUHALER® INHALER
10.2
Version 1.0
Instructions for use


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ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA
10.3
Reversibility and reduction of hyperinflation testing [P05-12782]
At the screening visit (Visit 1) plethysmography is conducted first to obtain FRC 
measurement. Spirometry is conducted next and following the completion of three acceptable 
pre-bronchodilator forced expiratory manoeuvres, salbutamol will be administered to each 
patient in order to document the degree of reversibility. Immediately after (within 15 min) 
pre-bronchodilator forced expiratory manoeuvres and after a gentle and incomplete expiration, 
a dose of 100 μg of salbutamol is inhaled in one breath to total lung capacity (TLC). The 
breath is then held for 5–10s before the subject exhales. Four separate doses (total dose 400 
μg) are delivered at approximately 30-s intervals (this dose ensures that the response is high 
on the salbutamol dose–response curve).
Post-bronchodilator plethysmography for the assessment of hyperinflation reduction (FRCpleth
reversibility) is conducted ≥10 min and up to 20 min later after the last dose of salbutamol 
(albuterol) is inhaled followed by three additional, acceptable post-bronchodilator forced 
expiratory manoeuvre tests.
Calculation of FEV1 predicted normal values according to ECSC [R94-1408]
Males:
"#$%   (&) = 4.30  *+ℎ (	) −0.029  /+ () −2.49
Females:
"#$%   (&) = 3.95  *+ℎ (	) −0.025  /+ () −2.60 
Ethnic adjustments of FEV1 predicted may be made as appropriate as per ATS/ERS 
recommendations [P05-12646, R94-1408].
Calculation of FRC predicted normal values according to ECSC [R94-1408] 
Males:
"23    (&) = 2.34  *+ℎ (	) + 0.009  /+ () −1.09
Females:
"23    (&) = 2.24  *+ℎ (	) + 0.001  /+ () −1.00
Calculation of RVol predicted normal values according to ECSC [R94-1408] 
Males:
2$    (&) = 1.31  *+ℎ (	) + 0.022  /+ () −1.23
Females:
2$    (&) = 1.81  *+ℎ (	) + 0.016  /+ () −2.00
Calculation of number of pack years
6  = 	  +   
20
  7  	
+
For calculation of Body Surface Area the following (Mosteller) formula should be used [R06-
1245]
89/ (	:) = ;
<=>?@A (BC)D E=>?@A (F?)
GHII
J
%/:
 


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MODIFIED MEDICAL RESEARCH COUNCIL DYSPNEA SCALE
10.4
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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NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
10.6
CLASSIFICATION
Class
New York Association functional classification
I
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea 
(shortness of breath) or anginal pain
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain
III
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea or anginal pain
IV
Unable to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
3
Date of CTP revision
30 Nov 2017
EudraCT number
2015-002641-66
BI Trial number
1237.36
BI Investigational Product(s)
Tiotropium + Olodaterol fixed dose combination 
inhalation solution (Respimat®)
Title of protocol
An exploratory, randomised, double-blind, double-
dummy, active-controlled, two period cross-over 
study to investigate the effect of 6 weeks treatment 
of orally inhaled tiotropium + olodaterol fixed dose 
combination (FDC) delivered by the Respimat®
Inhaler with fluticasone propionate + salmeterol 
FDC delivered by the Accuhaler® Inhaler, on left 
ventricular function and arterial stiffness in patients 
with Chronic Obstructive Pulmonary Disease 
(COPD)
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
All changes have already been implented in the 
trial conduct in the checklists and worksheets and 
in other parts of the protocol. The correction of 
FAS definition for secondary enpoints also is not a 
change of endpoints and considered rational
approach in this exploratory trial.
Section to be changed
1. Abbreviations
2. Section 3.3.3 (Exclusion criteria)
3. Section 4.1.4.2 (Study medication 
administration)
4. Section 4.2.1 (Other treatments and emergency 


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procedures)
5. Table 4.2.2.1: 1 (Permitted medications and 
Medication Restrictions)
6. Section 5.1.1 (Primary Endpoint (s))
7. Section 5.2 (Assessment of Efficacy)
8. Section 6.2.1 (Screening and run-in period (s))
9. Section 6.2.1 (Follow Up Period and Trial 
Completion)
10. Section 7.3 (Planned analyses)
Description of change
 
2. Exclusion criterion 18 modified to match the 
restrictions Section 4.2.2 (detailed Table 4.2.2.1:1 
Permitted medications and Medications 
Restrictions) and also washout worksheets.
3. Use of paper diary removed.
4. Time interval of CMR assessment and PFT 
testing after the use of antibiotics for acute COPD 
exacerbation treatment was modified.
5. Table was corrected for: 
a. tio+olo was deleted as LAMA mono product.
b. LABA mono product (qd) discontinuation 
corrected to 1 week prior to V1 also when switched 
from ICS/LABA (qd).
c. LABA/LAMA combination discontinuation 
corrected to 3 weeks prior to baseline CMR and 
V2.
6. Reference to Appendix section for calculation of 
BSA was corrected.
7. Repeatability of FRC measurements requirement 
was corrected to lest than or equal to 5%.
8. Training video replaced with training kit for the 
demonstration of Accuhaler® use.
9. Missing text...and documented... entered under 
AEs procedure at the study site. 
10. FAS set definition extended to patients with 


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baseline and post baseline secondary endpoints.
Rationale for change
1. Missing information in the Abbreviation list.
2. Discrepancy to the detailed restriction Section 4 
corrected.
3. Medication diary not used in this trial.
4. Restriction on assessments within one week of 
antibiotic use is not feasible due to other logistical 
requirements.
5. Medication restrictions inconsistencies have 
been corrected.
6. Reference corrected and hyperlink updated.
7. Sign less than or equal to was corrected as 
required in guidelines and implemented in study 
LF calculator. 
8. Training video for comparator was not feasible 
for this study so training kits is used for this 
purpose.
9. Missing text deleted in copying was entered.
10. FAS definition based on primary endpoints was 
extended to secondary endpoints not to limit the 
exploratory analysis unnecessary (not a change in 
any endpoint).


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Number of global amendment
2
Date of CTP revision
11 Jan 2017
EudraCT number
2015-002641-66
BI Trial number
1237.36
BI Investigational Product(s)
Tiotropium + Olodaterol fixed dose combination 
inhalation solution (Respimat®)
Title of protocol
An exploratory, randomised, double-blind, double-
dummy, active-controlled, two period cross-over 
study to investigate the effect of 6 weeks treatment 
of orally inhaled tiotropium + olodaterol fixed dose 
combination (FDC) delivered by the Respimat®
Inhaler with fluticasone propionate + salmeterol 
FDC delivered by the Accuhaler® Inhaler, on left 
ventricular function and arterial stiffness in patients 
with Chronic Obstructive Pulmonary Disease 
(COPD)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
Written to accommodate the requirements of 
CA (BfArM) and EC.
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
1. Synopsis (Main criteria for inclusion) 
2. Flow chart footnote
3. Section 3.3 (Selection of trial population)
4. Section 3.3.2 (Inclusion criteria)
5. Section 3.3.3 (Exclusion criteria)
6. Section 4.2.2 (Restrictions)
7. Section 6.1 (Visit schedule) 
8. Section 6.2.2 (Treatment period)


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Description of change
1. Patient age interval was limited to include 
patients only up to the age of 75 years (inclusive).
2. In footnote 13 timing of the post dose LF 
measurement was corrected.
3. Patient age interval was limited to include 
patients only up to the age of 75 years (inclusive).
4. Inclusion criterion number 2 was updated to 
include also the requirement that patients should be 
treated with one or more long-acting 
bronchodilators prior to enrolment. Inclusion 
criterion number 4 was updated to include patients 
only up to the age of 75 years (inclusive).
5. Exclusion criterion number 4 was updated to
exclude patients who experience COPD 
exacerbation or respiratory tract infection during 
the washout phase prior to randomisation. 
Exclusion criterion number 28 was updated to 
exclude also patients with claustrophobia from the 
study due to contraindication for CMR assessment.
6. In Table 4.2.2.1:1 page 42 ICS/LABA (qd) 
washout was updated.
7. Updated to contain information that patients with 
COPD exacerbation or respiratory tract infection in 
the washout phase prior to randomization should be 
excluded from further participation in the trial. 
8. Timing of the post dose LF measurement was 
corrected for Visits 3 and 4 to 1,5 hours post dose. 
Rationale for change
1. Request of CA and EC to limit the upper age 
level of participants.
2. Correction to match with the timing in the CTP 
text.
3. Same as 1.
4. Request of the CA and EC to include patients 
treated with long-acting bronchodilators and same 
as 1.
5. Request of CA and EC to exclude patients who 


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experience COPD exacerbation or respiratory tract 
infection during the washout phase prior to 
randomisation and to exclude patients with 
claustrophobia due to contraindication for CMR 
assessment.
6. Discontinuation of LABA mono-product for V1 
was corrected to match description in 4.2.2.2.
7. Request of CA and EC to exclude patients who 
experience COPD exacerbation or respiratory tract 
infection during the washout phase prior to 
randomisation.
8 Correction to match with the timing in the CTP 
text (Synopsis and Secondary endpoints 
description).


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Number of global amendment
1
Date of CTP revision
09 Dec 2016
EudraCT number
2015-002641-66
BI Trial number
1237.36
BI Investigational Product(s)
Tiotropium + Olodaterol fixed dose combination 
inhalation solution (Respimat®)
Title of protocol
An exploratory, randomised, double-blind, double-
dummy, active-controlled, two period cross-over 
study to investigate the effect of 6 weeks treatment 
of orally inhaled tiotropium + olodaterol fixed dose 
combination (FDC) delivered by the Respimat®
Inhaler with fluticasone propionate + salmeterol 
FDC delivered by the Accuhaler® Inhaler, on left 
ventricular function and arterial stiffness in patients 
with Chronic Obstructive Pulmonary Disease 
(COPD)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
Written to accommodate the requirements of 
CA (BfArM) and EC.
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
1. Flow chart (including footnote)
2. Section 2.3 (Benefit-risk assessment) 
3. Section 3.1.1 (Administrative structure of the 
trial)
4. Section 3.3.3 (Exclusion criteria)
5. Section 4.2.1 (Other treatments and emergency 
procedures)
6. Table 4.2.2.1:1 (Permitted medications and 


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medications restrictions) 
7. Section 4.2.2.2 (Restrictions for pulmonary 
function and CMR assessment)
8. Section 5.1.2 (Secondary Endpoints)
9. Section 5.3.6.3 (COPD Exacerbations)
10. Section 6.1 (Visit schedule)  
11. Section 6.2.1 (Screening and run-in period)
12. Section 6.2.3 (Follow Up Period and Trial 
Completion)
13. Section 9.1 (Published references)
Description of change
1. Trial follow-up time window was corrected to be 
aligned with the requirements in Section 5.3.6.2. 
Footnote number 11 was updated to clarify the 
timing of CMR assesments. Footnote number 12 to 
the flowchart was updated to contain percentage 
points as a required change of FRC. 
2. Washout required for baseline CMR and Visit 2. 
Update of existing CMR benefit-risk information.
 
4. Exclusion criterion number 25 was updated to 
clarify the duration of highly effective birth control 
until the follow-up visit at 21 days after the 
discontinuation of study medication. Tubal 
occlusion was deleted as permanent sterilisation. 
An exclusion criterion 28 was added for CMR 
contraindications. 
5. Use of antibiotics restricted also prior to CMR 
assessment as for pulmonary function testing.
6. Updated to contain also washout requirement for 
baseline CMR prior to Visit 2. Updated to contain 
restriction for strong and moderate inhibitors of 
CYP3A4 during the trial with additional footnote 
number 5 to address the restricted medications. 
7. Updated to contain also washout requirement of 
LAMAs for baseline CMR prior to Visit 2.


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8. ´Pressure´ added for clarity. 
9. Description of mild COPD exacerbation added 
to classification.
10. Updated to include more instructions on COPD 
exacerbation and potential withdrawal of the 
patient.
11. IRT call added to Visit 0 to register the patient 
in screening. Details on planning of CMRs added.
12. Laboratory testing deleted from description of 
visit 5 procedures. 
13. Updated reference to the new GOLD guideline 
2017.
Rationale for change
1. Correction to align with BI standard. 
Clarification of timing of CMRs and of change in 
FRC for reversibility.
2. Clarification of washout requirement for CMR 
assessment and risk-benefit in CMR assessment.
4. Clarification on duration of contraception as 
required for this study.
5. Clarification of antibiotic restriction prior to 
CMR assessment.
6. Washout requirements for baseline CMR 
assessment and restriction of CYP3A4inhibitors 
during this study.
7. Washout requirement for CMR assessment.
8. Clarification.
9. Correction to align with BI standard.
10. To avoid prolonging unnecessary suboptimal 
treatment in screening due to intolerance of 
washout.
11. Corrections and clarifications.
12. Deleted to align with CTP text.
13. Update of guideline reference.


 
 
 
 
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Title: 
 
 
 
 
                                                                                                                   
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03560350
4.0
clinical-trial-protocol-revision-03
An exploratory, randomised, double-blind, double-dummy, active-controlled, two
period cross-over study to investigate the effect of 6 weeks treatment of orally
inhaled tiotropium + olodaterol fixed dose combination (FDC) delivered by the
Respimat Inhaler with fluticasone propionate + salmeterol FDC delivered by the
Acchaler Inhaler, on left venticular function and arterial stiffness in ...
Approval-Trial Clinical Monitor
30 Nov 2017 15:12 CET
Approval-Therapeutic Area 
30 Nov 2017 16:38 CET
Approval-Team Member Medicine
30 Nov 2017 17:35 CET
Approval-Biostatistics
04 Dec 2017 05:44 CET
Verification-Paper Signature
Completion
06 Dec 2017 11:03 CET


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Document Number: 
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c03560350
4.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c14108328-02
BI Trial No.:
1237.36
Title:
An exploratory, randomised, double-blind, double-dummy, active-
controlled, two period cross-over study to investigate the effect of 6 
weeks treatment of orally inhaled tiotropium + olodaterol fixed 
dose combination (FDC) delivered by the Respimat® Inhaler with 
fluticasone propionate + salmeterol FDC delivered by the 
Accuhaler® Inhaler, on left ventricular function and arterial stiffness 
in patients with Chronic Obstructive Pulmonary Disease (COPD)
Investigational
Product(s):
Tiotropium + olodaterol fixed dose combination inhalation solution 
- Respimat®
Responsible trial 
statistician(s):
Telephone:  
Fax:  
Date of statistical 
analysis plan:
13 MAR 2018 SIGNED
Version:
Final
Page 1 of 27
Proprietary confidential information
2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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TSAP for BI Trial No: 1237.36
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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.................................................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ....................10
5.
ENDPOINT(S).....................................................................................................11
5.1
PRIMARY ENDPOINT......................................................................................11
5.2
SECONDARY ENDPOINT(S)...........................................................................11
5.2.1
Key secondary endpoint(s) .................................................................................11
5.2.2
Secondary endpoints ...........................................................................................11
...............................................................................11
...............................................................................11
6.
GENERAL ANALYSIS DEFINITIONS...........................................................13
6.1
TREATMENT(S) ................................................................................................13
6.2
IMPORTANT PROTOCOL VIOLATIONS....................................................14
6.3
PATIENT SETS ANALYSED ...........................................................................17
......................................................................................................18
6.5
POOLING OF CENTRES..................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................18
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................19
7.
PLANNED ANALYSIS ......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........20
7.2
CONCOMITANT DISEASES AND MEDICATION......................................20
7.3
TREATMENT COMPLIANCE ........................................................................20
7.4
PRIMARY ENDPOINT(S).................................................................................21
7.5
SECONDARY ENDPOINT(S)...........................................................................21
7.5.1
Key secondary endpoint(s) .................................................................................21
7.5.2
(Other) Secondary endpoint(s)...........................................................................21
...............................................................................21
7.7
EXTENT OF EXPOSURE .................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse events .....................................................................................................22
7.8.2
Laboratory data...................................................................................................23
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG ......................................................................................................................24
7.8.5
Others ...................................................................................................................24
8.
REFERENCES ....................................................................................................25
................................................................................26
10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.2: 1
Important protocol violations ...........................................................................15
Table 6.3: 1
Patient sets analysed .........................................................................................18
Table 6.7: 1 
Planned and actual study days..........................................................................19
Table 10: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP 
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
AI
Augmentation Index
AMP
Auxiliary Medicinal Product
ATS
American Thoracic Society
AUC
Area under the Curve
BAC
Benzalkonium chloride
BI
Boehringer Ingelheim
bid
bis in die (twice daily dosing)
BMI
Body Mass Index
BRPM
Blinded report planning meeting
BSA
body surface area
CABG
Coronary Artery Bypass Graft
CI
Confidence Interval
CML
Local Clinical Monitor
CMR
Cardiac Magnetic Resonance
COPD
Chronic Obstructive Pulmonary Disease 
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organisation
CT
Computer tomography
CTC
Common Terminology Criteria
CTMF
Clinical trial master file
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
DEDP
drug exposure during pregnancy
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DMG
Dictionary Maintenance Group


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Term
Definition / description
DPI
Dry Powder Inhaler
DRA
Drug Regulatory Affairs
ECG
Electrocardiography
eCRF
Electronic Case Report Form
ECSC
European Coal and Steel Community
ED
end diastolic
EDTA
Disodium edentate
EF
ejection fraction
EFL
Expiratory flow limitation
EMEA
European Agency for the Evaluation of Medicinal Products
EoO
End of Observation
EoT
End of Treatment
ERS
European Respiratory Society
ERV
Expiratory reserve volume
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
FDC
Fixed Dose Combination
FEV1
Forced Expiratory Volume in 1st second
FRC
Functional Residual Capacity
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HCG
human chorionic gonadotropin
HFA
hydrofluoroalkane
IB
Investigator’s Brochure
IC
Inspiratory capacity
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product


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Term
Definition / description
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IVC
inspiratory vital capacity
LABA
Long-acting β2-agonist
LAMA
Long-acting muscarinic antagonists
LBBB
Left bundle branch block
LDH
Lactate Dehydrogenase
LOCF
Last observation carried forward
LPDD
Last Patient Drug Discontinuation
LV
Left Ventricle
LVEDVI
Left Ventricular End Diastolic Volume Index 
LVH
Left ventricular hypertrophy
MACE
Major adverse cardiovascular event
MCID
Minimal clinically important difference
MD
Medical Degree
MDI
Metered Dose Inhaler
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMI
Myocardial mass index
mMRC
Modified Medical Research Council Dyspnoea Scale
MMRM
Mixed-effects Model for Repeated Measures
MQRM
Medical Quality Review Meeting
MST
Medical Sub Team
NIMP
Non Investigational Medicinal Product
NYHA
New York Heart Association
O*C
Oracle Clinical
PD
Pharmacodynamics
PA
pulmonary artery
PDE-4
Phosphodiesterase Type 4
Pleth
Body Plethysmography
PFT
Pulmonary function testing
PK
Pharmacokinetics


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Term
Definition / description
PPS
Per protocol set
PRN
pro re nata (as needed)
PSTAT
Project Statistician
PT
Preferred term
PV
Protocol violation
PWA
Pulse Wave Analysis
Q1
Lower quartile
Q3
Upper quartile
qd
quaque die (once a day)
REML
Restricted Maximum Likelihood
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RV
right ventricular
RVol
Residual Volume
SA
Statistical analysis
SAE
Serious Adverse Event
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SGRQ
St. George´s Respiratory Questionnaire
SOC
System organ class
SOP
Standard operating procedures
SmPC
Summary of Product Characteristics
SMQ
Standardised MedDRA query
STORM
storage conditions for trial medication
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVI
Stroke volume index
TCM
Trial Clinical Monitor
TDI
Transitional dyspnoea index
TESS
Treatment emergent signs and symptoms 
TLC
Total Lung Capacity
TMF
Trial Master File
TMW
Trial Medical Writer


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Term
Definition / description
ToC
Table of contents
TSAP
Trial Statistical Analysis Plan
UK
United Kingdom
US
United States


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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
All analyses described in the TSAP are outlined in the CTP.
 
 
 
 
 
   


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT
Primary endpoint of efficacy will be used as described in the CTP, Section 5.1.1 “Primary 
endpoint”.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
No key secondary endpoints were specified in the CTP.
5.2.2
Secondary endpoints
Secondary endpoints of efficacy will be used as described in the CTP, Section 5.1.2 
“Secondary Endpoints”.


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
All adverse events (AEs), including any clinically relevant changes/abnormalities in 
physical examination, vital signs, laboratory values, and electrocardiogram (ECG)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
The doses to be administered are described in Section 4 of the CTP. 
This is a crossover trial consisting of a one to three-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. In this study, there will be no washout between treatment periods. 
In general, the first period will be considered last until 12 hours after the last intake of 
medication assigned for the first period, then the second period will start 
For the main safety analysis, data occurring during the treatment periods and within 21 days 
of stop of study drug for that period will be assigned to the respective treatment for that 
period. Data occurring before the first drug intake date is assigned to "screening".   If the next 
treatment period starts within 21 days of the end of the last period, data after the start of 
treatment for the next period will be assigned to the treatment for that period. In this trial, next 
treatment will be started after end of treatment of first period as soon as possible because 
there is no washout period planned. The last day of the first period is the day of the last intake 
of medication for the first period. AEs occurring at the last day of the first period will be 
assigned to the first period even if the medication of the evening dose already belongs to the 
second 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 
follow-up. 
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.


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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) or data base lock meeting (DBLM).
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 26). 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.


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Table 6.2: 1
Important protocol violations
Category / 
Code
Description
Requirements
Excluded from*
A
Entrance criteria not met
A1
Inclusion criteria not met
Inclusion Criteria 2-8 not met as 
specified in the protocol.
Exclude from PPS*:
2-8
A2
Exclusion criteria not met
Exclusion Criteria 1-28 
not met as specified in the protocol
Exclude from PPS*: 
3-8, 10-14, 16-22, 26-
28
B
Informed consent
B1
Informed consent not 
available/not done
Informed consent date missing; no 
signature on ICF.
All
B2
Informed consent too late
Date of informed consent was after the 
date of any study-related procedure, or 
a patient signed the correct version of 
the ICF after Visit 0. If date of 
informed consent equals to date of 
Visit 1, such cases will be discussed at 
MQRM/BRPM/DBL meetings.
None
C
Trial medication and 
randomisation
C1
Incorrect trial medication 
taken
Not throughout the entire study 
treatment period; could be at a clinic 
visit or between clinic visits.
External vendor will check before 
unblinding.
PPS (decision at 
BRPM)
C2
Randomisation order not 
followed
Throughout the study
PPS
C3
Non- compliance with 
study medication
C3.1
Serious non-compliance 
with study medication as 
reported in monitoring 
report or issue listing 
(formerly manual PV 
spreadsheet)
Decision at BRPM/MQRM.
PPS if at Visit 3 or 4 
and at respective 
second and third CMR 
assessments
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 considered 
inappropriate code break).
PPS


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Table 6.2: 1 (continued)
Important protocol violations
Category / 
Code
Description
Example/Comment
Excluded from*
D
Concomitant medication
D1
Improper medication 
washout for CMR 
assessment (at baseline 
CMR or on-treatment 
CMRs for primary 
endpoint)
Washout not met for baseline CMR 
assessment and for on-treatment 
CMRs. Decision at BRPM*
PPS
D2
Prohibited medication use 
during study
Check CT. Decision at BRPM.
PPS if in the week 
prior to Visit 2, 3, and 
4 
F
Incorrect timing
F3
Primary endpoint recorded 
outside time window 
A. With respect to treatment duration:
1) CMR < 35 days of treatment in 
each period
B. With respect to clinic visits: 
1) CMR baseline assessment at or 
after Visit 2 date, and/or
2) second CMR assessment after 
Visit 3 date, and/or
3) third CMR assessment after Visit 4 
date, and/or
4) second CMR assessment < 1 hour 
or > 8 hours post morning dose of 
study medication at Visit 3 and/or
5) third CMR assessment < 1 hour or 
> 8 hours post morning dose of study 
medication at Visit 4
PPS
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
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
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
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.


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6.3
PATIENT SETS ANALYSED
The following nested patient sets are defined:

Randomised set (RS):
This patient set includes all patients who signed informed consent form and were also 
randomised, regardless whether the patient was treated with study medication or not.

Treated set (TS):
This patient set is nested within RS and includes all patients who were dispensed study 
medication and were documented to have taken any dose of study medication. TS will 
be used for patient disposition, demographics and baseline disease characteristics, 
concomitant therapies, treatment compliance, treatment exposure and safety analyses 
(including AEs and vital signs).

Full analysis set (FAS):
This patient set is nested within TS and includes patients who had baseline 
measurement and at least one post-baseline measurement for the primary endpoint or 
secondary endpoints.  Assignment to the FAS will be done after implementation of 
any data handling rules which set measurements to missing.
 

Full analysis set excluding exacerbation (FAS-EE):
This patient set is nested within FAS and the data from patients who have had an 
exacerbation during the treatments will be excluded from this data set. FAS-EE will be 
used for the efficacy analyses. 

Per protocol set (PPS):
This patient set is nested within FAS-EE 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 or data base lock meeting (DBLM) prior to data unblinding. 
 
 


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Table 6.3: 1
Patient sets analysed
Patient Sets
Class of endpoint
TS
FAS-EE
Primary endpoint
 
primary 
analysis
 
Secondary endpoints 
X
 
Safety endpoints
X
Demographic/baseline 
endpoints/exposure
X
 
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 will not be imputed and will stay as missing, and will be handled in 
the mixed model repeated measures model.
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 will be used for spirometry data which were collected at Visits 2, 3 and 4:

Since there is only one spirometry measurement at each on-treatment clinic visit, rescue 
medication use on or before the spirometry measurement or rescue use with unknown time 
will both result in all spirometry measurements for the visit being set to missing.  


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
Randomly missing spirometry measurements at Visits 2, 3, and 4, e.g., due to a 
mechanical failure, will not be imputed.
The rules used for spirometry data will also be applied to Body Plethysmography. CMR data 
will not be imputed.
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (3).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baselines for Primary Endpoint
The primary endpoint is change from baseline in LVEDVI in the 6th week of treatment with
tiotropium+olodaterol FDC versus fluticasone propionate+salmeterol FDC.

The baseline is defined as the (pre-dose) measurement of the LVEDVI performed in a 
week prior to Visit 2 (or prior to dosing on the Visit 2).
Baseline for endpoints not related to CMR is defined as the pre-dose measurement at Visit 2.
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 
Planned and actual study days
Relative to period start
Relative to study start
      
Visit
Planned 
day
                          
Actual day
Planned 
day
                          
Actual day
  2
  1
1
    1
1
  3
43
Visit 3 date - Visit 2 date + 1
  43
Visit 3 date - Visit 2 date + 1
  4
43
Visit 4 date - Visit 3 date + 1
85
Visit 4 date - Visit 2 date + 1


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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 ENDPOINT(S)
In the primary analysis, the two-sided hypothesis as given in Section 7.2 in the CTP will be 
tested based on adjusted mean change from baseline in LVEDVI, as listed in Section 5.1.1 in 
the CTP, using a restricted maximum likelihood (REML)-based MMRM. This model will 
include treatment and period as fixed effects, patient as a random effect and baseline as 
covariate. Unstructured covariance structure will be used for within patient variation. If 
convergence is not achieved, the compound symmetry covariance structure will be used. The 
SAS procedure MIXED will be used involving the restricted maximum likelihood estimation 
and the Kenward-Roger approximation for denominator degrees of freedom. This approach is 
described in (2). Adjusted mean values as well as treatment contrasts will be presented 
together with the 95% confidence intervals (CI) and p-values. The primary analysis will be 
performed on FAS-EE.
 
 
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
The MMRM described for the primary endpoint will be performed for 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.
Extent of exposure will also be summarised using descriptive statistics into the following 
categories:

1 – 39  days

40 – 46 days

>=47 days.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of subjects with AEs and NOT on the number of 
AEs.
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:
•
All AE attributes are identical ((LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome.


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•
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). 
For further details on summarization of AE data, please refer to (3, 4).
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till last drug 
intake + residual effect period will be assigned to the randomised treatment. All adverse 
events occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after the residual effect period will be assigned to ‘post-treatment’ (for listings 
only). For details on the treatment definition, see Section 6.1.
According to ICH E3 (5), AEs classified as ‘other significant’ needs to be reported and will 
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 lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting.
An overall summary of adverse events will be presented. 
The frequency of subjects with adverse events will be summarised by treatment, primary 
system organ class and preferred term (mention MedDRA levels to be displayed in the tables). 
Separate tables will be provided for subjects with other significant adverse events according 
to ICH E3 (5), for subjects with adverse events of special interest (only if defined), for 
subjects with serious adverse events, for subjects with adverse events leading to 
discontinuation, for subjects with drug-related adverse events, and for subjects with related 
serious adverse events.
The system organ classes will be sorted alphabetically, preferred terms will be sorted by 
frequency (within system organ class).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature. 
In general lab data will not be analyzed.
Clinically significant findings in other 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.


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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
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
R10-4391: Kenward, M.G. The use of baseline covariates in crossover studies.
Biostatistics 11(1),1-17 (2010)
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
4
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
5
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports,
current version
6
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.


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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-MAR-17
None
This is the initial TSAP with necessary 
information for trial conduct
Final
13-MAR-18
Overall
This is the final TSAP without any
Modification.