Clinical trial NCT03240575
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim
Start date: 2017-08-14; Completion date: 2019-05-06
Enrollment: 302 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the trial is to show superiority in lung function of once daily (2 inhalations) treatment with orally inhaled tiotropium+olodaterol fixed dose combination to twice daily (one inhalation) treatment with fluticasone propionate+salmeterol fixed dose combination over 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD).

A Digital Health (DH) exploratory study has been integrated into the main study as a site specific study. The DH exploratory study will be performed at a single site; the site is also participating in the main study. The DH exploratory study site will enter (randomize) approximately 20 patients (subjects) (in addition to the patients to be enrolled in the main study at this site). The patients enrolled in the DH exploratory study are not considered to be part of the main study (i.e. data collected in the DH exploratory study will be analyzed separately from the data collected in the main study).

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:
c13020187-03
BI Trial No.:
1237-0063
BI Investigational 
Product(s):
Stiolto®, Tiotropium+olodaterol fixed dose combination –
Respimat®
Title:
A randomized, double-blind, double-dummy, active-controlled, 
multi-center, parallel group study to show the superiority in lung 
function of 12 weeks once daily treatment with orally inhaled 
tiotropium+olodaterol fixed dose combination delivered by the 
Respimat® inhaler vs. 12 weeks twice daily treatment with orally 
inhaled fluticasone propionate+salmeterol fixed dose combination 
delivered by the Diskus® in patients with Chronic Obstructive 
Pulmonary Disease (COPD) [ENERGITO® 2]
Lay Title:
The ENERGITO® 2 study compares 2 inhaled medicines for 
Chronic Obstructive Pulmonary Disease (COPD). One medicine 
is a combination of tiotropium and olodaterol (Stiolto®) taken 
using the Respimat® inhaler and the other medicine is a 
combination of fluticasone and salmeterol taken using the 
Diskus®
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone: 
Fax:
Coordinating 
Investigator:
Phone:
Fax:
Status:
Final Protocol (Revised Protocol based on global amendment 2)
Version and Date:
Version: 3.0
Date: 06 March 2018
Page 1 of 125
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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Stiolto®
Name of active ingredient:
Tiotropium+olodaterol 
(5µg/5µg) fixed dose 
combination inhalation 
solution – Respimat®
Protocol date
09 May 2017
Trial number:
1237-0063
Revision date:
06 March 2018
Title of trial:
A randomized, double-blind, double-dummy, active-controlled, multi-
center, parallel group study to show the superiority in lung function of 
12 weeks once daily treatment with orally inhaled 
tiotropium+olodaterol fixed dose combination delivered by the 
Respimat® inhaler vs. 12 weeks twice daily treatment with orally 
inhaled fluticasone propionate+salmeterol fixed dose combination 
delivered by the Diskus® in patients with Chronic Obstructive 
Pulmonary Disease (COPD) [ENERGITO® 2]
Coordinating
Investigator:
 
Phone:
Fax: 
Trial site(s):
Multi-center trial conducted in the US
Clinical phase:
IV
Objective(s):
The primary objective of the trial is to show superiority in lung 
function of once daily treatment with orally inhaled 
tiotropium+olodaterol (5µg/5µg) fixed dose combination to twice 
daily treatment with fluticasone propionate+salmeterol (250µg/50µg) 
fixed dose combination over 12 weeks in patients with Chronic 
Obstructive Pulmonary Disease (COPD).
Methodology:
Randomized, double-blind, double-dummy, active-controlled 
parallel group design
No. of patients: 
350 enrolled
 
Total entered:
288
 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Stiolto®
Name of active ingredient:
Tiotropium+olodaterol 
(5µg/5µg) fixed dose 
combination inhalation 
solution – Respimat®
Protocol date
09 May 2017
Trial number:
1237-0063
Revision date:
06 March 2018
Each treatment:
144
Diagnosis :
Chronic Obstructive Pulmonary Disease (COPD)
Main criteria
for inclusion:
Outpatients of either sex, aged ≥ 40 years with a diagnosis of COPD; 
smoking history >10 pack years, post-bronchodilator 30% ≤ FEV1
(Forced Expiratory Volume in one second) <80% predicted, post-
bronchodilator FEV1/FVC <70%
Test product(s):
Tiotropium+olodaterol FDC solution for inhalation – Respimat®
Dose:
5µg tiotropium + 5µg olodaterol daily
(2.5 μg /2.5 μg per actuation administered as 2 actuations once 
daily)
Mode of administration: Oral inhalation (2 inhalations in the morning)
Comparator products:
Fluticasone propionate + salmeterol FDC dry powder for inhalation 
– Diskus®
Dose:
500µg fluticasone propionate + 100µg salmeterol daily
(250 μg /50 μg per actuation administered as 1 actuation twice a day )
Mode of administration: Inhalation
Duration of treatment:
12 weeks
Endpoints:
Primary endpoint:
FEV1 AUC (Area under the curve) 0-24hours response (change from 
baseline) [L] after 12 weeks of treatment
Secondary endpoints:
•
FEV1 AUC 0-12h response (change from baseline) [L] after 12 
weeks treatment
•
Trough FEV1 response (change from baseline) [L] after 12 weeks 
treatment


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Stiolto®
Name of active ingredient:
Tiotropium+olodaterol 
(5µg/5µg) fixed dose 
combination inhalation 
solution – Respimat®
Protocol date
09 May 2017
Trial number:
1237-0063
Revision date:
06 March 2018
•
Peak 0-3h FEV1 response (change from baseline) [L] after 12 
weeks treatment
Safety criteria:
Adverse Events, Serious Adverse Events, Physical Exam
Statistical methods:
The primary and secondary endpoints at week 12 will be analyzed 
using a mixed effects model repeated measures (MMRM) approach.
DH exploratory study data will be analyzed separately and analysis 
will be descriptive only.


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FLOW CHART
Trial Periods
Screening/
Run-in Period
Randomized Treatment
Period
Follow-
up (FU)
Period 
Visit
0
1
V2
V3
V4/EOT
V5/FU
Week
1
6
12
15
Day1
-28
1
42
84
105
Visit window (days)
+318
±3
±3
±7
Informed Consent2
x
Inclusion/ exclusion criteria
x
x
x
Demographics/Baseline Conditions
x
Physical examination incl. vital signs14
x
x3
x4
COPD/patient characteristics
x
Register patient in screening (IRT)
x
Issue Trial Identification Card
x
Dispense and explain use of ProAir®
HFA (rescue medication)
x
x13
x13
x13
Dispense Atrovent HFA per 
investigator discretion16
x
Collect Atrovent HFA, if applicable
X16
Medication washout check9
x
x
x
x
Collect rescue medication8
x
x
x
x3
12 lead-ECG14, 15
x
Laboratory tests 14
x
x
Pregnancy test5
x
x
x3
x
Review smoking status
x
x
x
x3
COPD Assessment Test CAT14
x
x3
Saint George’s Respiratory 
Questionnaire SGRQ14
x
x3
Training in use of Respimat® and 
Diskus® 
x
x6
x6
x6
PFTs (FEV1 & FVC)*14
x10
x7, 11
x7, 12
x7, 12
Adverse events
x
x
x
x
x3
x
Concomitant therapy
x
x
x
x
x3
x
Telephone Contact7
x
x
x
Randomization (IRT)
x
Medication kit allocation (IRT)
x
x


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Trial Periods
Screening/
Run-in Period
Randomized Treatment
Period
Follow-
up (FU)
Period 
Visit
0
1
V2
V3
V4/EOT
V5/FU
Week
1
6
12
15
Day1
-28
1
42
84
105
Visit window (days)
+318
±3
±3
±7
Drug accountability check9
x
x
x3
Medication compliance check17
x
x3
Dispense trial medication
x
x
Administration (dosing) of trial  
medication at the site
x
x
x
Collect trial medication
x
x3
Trial medication termination (IRT)
x3
Trial Completion
x
Guidance Notes:
1.
Visit 1 may be scheduled from 1 day to 6 weeks after Visit 0 (depending on 
medication washout requirements).  The visit interval may also be extended for 
administrative reasons to allow for recovery from respiratory infections (See 
Section 6.1). If no medication washout is required, Visits 0 and 1 could take place 
on the same day.
2.
All patients must sign an informed consent consistent with ICH-GCP guidelines 
prior to participation in the trial, which includes medication washout and 
restrictions. Re-consenting may become necessary when new relevant information 
becomes available as should be conducted according to the sponsor’s instructions.
3.
For patients who discontinue early, EOT visit should be performed instead of the 
scheduled visit at time of discontinuation and all indicated procedures are to be 
performed if possible.
4.
To be performed only if relevant findings at Visit 4.
5.
Women of child-bearing potential:  Serum pregnancy test is to be completed at 
Visit 1.  Urine pregnancy test (dipstick) is to be completed at Visits 2, 4, and 5.  
Pregnancy testing is to be completed prior to study drug administration.
6.
If needed, the patient will be re-instructed/re-educated in the use of the Respimat®
and Diskus® devices but the patient should not inhale from the placebo inhaler at 


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these visits.
7.
Site staff will telephone the patient 1 – 2 days prior to visits 2, 3 and 4 to remind 
the patient of medication restriction requirements and that they should not inhale 
trial medication at home on the morning of a clinic visit.
8.
Collect dispensed rescue medication during the course of the trial (whenever 
applicable).
9.
Including drug accountability check of dispensed ProAir® HFA rescue medication 
and Atrovent HFA (if applicable).
10.
Visit 1:  Reversibility testing using 400µg albuterol [Note: reversibility is not an 
inclusion criterion]. See Appendix 10.5
11.
Visit 2*:  

Two pre-dose PFTs:  One at 1hour pre-dose and a second at 10 minutes 
prior to inhalation of dose of trial medication.

Post-dose PFTs: 30 min, 1, 2 and 3h post-dose
12.  
Visits 3 and 4**:
Pre-dose PFT:  10 minutes prior to dosing

Post-dose PFTs: 30 min, 1, 2, 3, 4, 6, 8, 10, 11h50´

Inhalation of evening dose of study medication (12:00)  

Post evening dose PFTs: 12h30´, 13, 14, 22, 23h and 24h
13.
Dispense rescue medication as needed.  
14.
The preferred sequence of procedures is as follows:
1. CAT (where applicable)
2. SGRQ (where applicable)
3. Physical Exam (where applicable)
4. 12-lead ECG (where applicable)
5. Labs (where applicable)
6. Pulmonary Function Test (pre-dose)
15.
ECG: 12-lead ECG recording at screening (Visit 1) for inclusion in the study.
16.
Patients on treatment with a LAMA at study entry will receive open label 
Atrovent HFA during the run-in period, per Investigator’s discretion.  This 
medication must be collected at Visit 2.
17.
Medication use:  From dose counter on Respimat® and Diskus® devices.
18.
The 4-week screening period (between Visit 1 and Visit 2) may be extended by up 
to 4 weeks for administrative reasons and/or to meet wash-out requirements. (see 
Section 6.1).


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* For reversibility testing instructions see Appendix 10.5.
**Time windows for PFT Measurements:
PFT Time Windows: Visit 2:
The 1h pre-dose measurement will be obtained at -15 minutes and + 5 minutes of the 
scheduled time point; the 10 minute pre-dose and the 30 min and 1h post dose measurements 
will be obtained within  ± 5 minutes of the scheduled time point. 
The 2h and 3h post- dose measurement will be obtained within ± 10 minutes of the scheduled 
time point.
PFT Time Windows: Visits 3 and 4
The 10 minute pre-dose measurement will be obtained within ± 5 minutes of the scheduled 
time point.  
The 30 minute and 1h post-dose measurements will be obtained within ± 5 minutes of the 
scheduled time point.  The post dose measurements from 2h through 11h50´ pre evening dose 
and from 12h30´ through 24 post evening dose measurements will be performed ± 10 minutes 
of the scheduled time point.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................15
MEDICAL BACKGROUND.............................................................................15
1.1
DRUG PROFILE................................................................................................16
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....18
RATIONALE FOR PERFORMING THE TRIAL.........................................18
2.1
TRIAL OBJECTIVES........................................................................................18
2.2
BENEFIT-RISK ASSESSMENT.......................................................................18
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................21
OVERALL TRIAL DESIGN AND PLAN .......................................................21
3.1
3.1.1
Administrative structure of the trial .................................................................22
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S) ......................................................................................23
SELECTION OF TRIAL POPULATION .......................................................24
3.3
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................25
3.3.4
Removal of patients from therapy.....................................................................28
3.3.4.1
Removal of individual patients .............................................................................28
3.3.4.2
Discontinuation of the trial by the sponsor ...........................................................29
4.
TREATMENTS...................................................................................................30
4.1
INVESTIGATIONAL TREATMENTS ...........................................................30
4.1.1
Identity of the investigational medicinal products...........................................30
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......................32
4.1.4.1   
Study Medication Administration.........................................................................33
4.1.5
Blinding and procedures for unblinding...........................................................35
4.1.5.1
Blinding.................................................................................................................35
4.1.5.2
Unblinding and breaking the code ........................................................................36
4.1.6
Packaging, labelling, and re-supply...................................................................36
4.1.7
Storage conditions...............................................................................................38
4.1.8
Drug accountability.............................................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................40


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4.2.1
Rescue Medication, emergency procedures and additional treatments.........40
4.2.1.1
Rescue medication ................................................................................................40
4.2.1.2
Emergency procedures..........................................................................................40
4.2.1.3
Additional treatment .............................................................................................40
4.2.2
Restrictions ..........................................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment ......................................................42
4.2.2.2
Restrictions on diet and lifestyle...........................................................................47
4.2.2.3
Restriction regarding women of childbearing potential........................................48
4.3
TREATMENT COMPLIANCE ........................................................................48
5.
VARIABLES AND THEIR ASSESSMENT ....................................................49
5.1
TRIAL ENDPOINTS..........................................................................................49
5.1.1
Primary Endpoint(s)...........................................................................................49
5.1.2
Secondary Endpoint(s) .......................................................................................49
5.2
ASSESSMENT OF EFFICACY........................................................................50
5.2.1
Pulmonary function testing (PFT).....................................................................50
5.2.2
Saint George’s Respiratory Questionnaire (SGRQ)........................................50
5.2.3
COPD health status.............................................................................................51
5.3
ASSESSMENT OF SAFETY.............................................................................51
5.3.1
Physical examination ..........................................................................................52
5.3.2
Laboratory parameters ......................................................................................52
5.3.3
Electrocardiogram ..............................................................................................52
5.3.4
Other safety parameters.....................................................................................52
5.3.5
Assessment of adverse events.............................................................................52
5.3.5.1
Definition of adverse events .................................................................................52
5.3.5.2
Adverse event collection and reporting ................................................................55
5.3.5.3
COPD Exacerbations ............................................................................................56
5.4
DRUG CONCENTRATION MESUREMENTS AND 
PHARMACOKINETICS ...................................................................................57
5.5
ASSESSMENT OF BIOMARKERS.................................................................57
5.6
OTHER ASSESSMENTS...................................................................................57
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................57
6.
INVESTIGATIONAL PLAN.............................................................................58
6.1
VISIT SCHEDULE.............................................................................................58
6.2
DETAIL OF TRIAL PROCEDURES AT SELECTED VISITS ...................59
6.2.1
Screening and run-in period(s) ..........................................................................59
6.2.2
Treatment period(s) ............................................................................................60
6.2.3
Follow up period and trial completion..............................................................61
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................62
7.1 
STATISTICAL DESIGN - MODEL.................................................................62
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................62
7.3
PLANNED ANALYSES.....................................................................................62
7.3.1
Primary endpoint analyses.................................................................................63


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7.3.2
Secondary endpoint analyses .............................................................................63
7.3.4
Safety analyses.....................................................................................................63
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................64
7.4
INTERIM ANALYSES ......................................................................................64
7.5
HANDLING OF MISSING DATA ...................................................................64
7.6
RANDOMISATION ...........................................................................................64
7.7
DETERMINATION OF SAMPLE SIZE .........................................................65
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................66
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................66
8.2
DATA QUALITY ASSURANCE ......................................................................66
8.3
RECORDS...........................................................................................................67
8.3.1
Source documents ...............................................................................................67
8.3.2
Direct access to source data and documents.....................................................68
8.3.3
Storage period of records ...................................................................................68
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................68
8.5 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........68
8.6
TRIAL MILESTONES.......................................................................................69
9.
REFERENCES....................................................................................................70
9.1
PUBLISHED REFERENCES............................................................................70
9.2
UNPUBLISHED REFERENCES......................................................................72
10.
APPENDICES.....................................................................................................73
10.1
HANDLING INSTRUCTIONS FOR RESPIMAT® INHALER....................73
10.2
THE DISKUS® INHALER.................................................................................79
10.3
COPD ASSESSMENT TEST (CAT).................................................................81
10.4
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ)...................82
10.5
ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA...........91


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................121
11.1
GLOBAL AMENDMENT 1 ............................................................................121
11.2
GLOBAL AMENDMENT 2 ............................................................................123


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ABBREVIATIONS
AE
Adverse Event
AESI
App.
AMP
ATS/ERS
Adverse Event of Special Interest
An application, downloaded to patient iPhone
Auxiliary Medicinal Product
American Thoracic Society/European Respiratory Society
AUC
BI
Area under the Curve
Boehringer Ingelheim
b.i.d.
bis in die (twice daily dosing)
CAT
COPD Assessment Test
CCDS
Company Core Data Sheet
CML
COPD
Local Clinical Monitor 
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRF
CRO
Case Report Form
Contract Research Organization
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
ECG
eCRF
ECSC
Electrocardiogram
Electronic Case Report Form
European Coal and Steel Community
EDC
EOT
Electronic Data Capture
End of Trial
 
FAS
Full Analysis Set
FC
FDC
FEV1
FU
FVC
Flow Chart
Fixed Dose Combination
Forced Expiratory Volume in one second
Follow-up
Forced Vital Capacity
GCP
GOLD
HCG
Good Clinical Practice
Global Initiative for Chronic Obstructive Lung Disease
Human Chorionic Gonadotrophin
IB
IC
ICH-GCP
ICS
Investigator’s Brochure
Informed Consent
International Council for Harmonisation – Good Clinical Practice
Inhaled Corticosteroid
IEC
IMP
INN
Independent Ethics Committee
Investigational Medicinal Product
International Non-proprietary Name
IRB
Institutional Review Board
IRT
Interactive Response Technology


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ISF
Investigator Site File
i.v.
L
LABA
LAMA
Intravenous
Liter
Long-acting β2-agonist
Long-acting antimuscarinic antagonist
LPDD
LRTI
PRN
Last Patient Drug Discontinuation
Lower Respiratory Tract infection
Pro re nata (as occasion requires)
q.d.
q.i.d
quaque die (once a day)
quater in die (4 times a day)
REP
SABA
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
Short acting beta agonist
SAE
Serious Adverse Event
SmPC
STORM
Summary of Product Characteristics
Storage conditions for Trial Medications
TCM
Trial Clinical Monitor
TMF
Trial Master File
TSAP
URTI
WHO
Trial Statistical Analysis Plan
Upper Respiratory Tract infection
World Health Organization


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Chronic obstructive pulmonary disease (COPD) is a chronic and progressive disease 
characterized by persistent airflow limitation (Global Initiative for Chronic Obstructive Lung 
Disease 2017 (GOLD) [P16-13658].
Long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-
acting beta-agonists (LABAs), are the cornerstone of maintenance therapy for patients with 
COPD, whose symptoms are not adequately controlled by short-acting bronchodilators alone 
[P13-05794, P16-13658]. Treatment with inhaled corticosteroids (ICS) is only recommended 
for patients with a history of exacerbations despite appropriate treatment with long-acting 
bronchodilators (GOLD group C and D patients) [P16-13658]. In clinical practice, however, 
ICS/LABA is also commonly used as maintenance treatment for individuals with low 
exacerbation risk who have less severe COPD, despite a lack of evidence to show that this is 
the optimal treatment approach for this group.
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. Fixed dose combinations of a short-acting β2-agonist and a short-acting 
anticholinergic have been developed and have been shown to be safe, efficacious and 
convenient for the patient (e.g., Combivent®: albuterol+ipratropium bromide; [P94-1346]). 
The recent interest in the development of LABAs and LAMAs with a once daily posology
has presented the opportunity for the development of LABA/LAMA fixed dose combinations 
with a once daily posology.
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. In the pivotal studies, this combination has been shown to improve 
bronchodilation as compared with their respective monotherapies. The addition of a second 
bronchodilator has been seen to provide additional benefits in terms of enhanced 
bronchodilation, inspiratory capacity, improved dyspnea, quality of life and a decline in 
rescue medication use [P15-04531, P15-03349]. Importantly, superiority in lung function 
improvement with once-daily tiotropium+olodaterol FDC compared to twice-daily salmeterol 
+ fluticasone propionate FDC was demonstrated over the full 24-hour dosing period [P16-
01440].


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Therefore, the combination of tiotropium+olodaterol in a single Respimat® Inhaler device 
provides a rational target for optimizing bronchodilator treatment of COPD. In this context 
and given the increasing number of treatment options available, generating additional 
evidence may facilitate clinicians´ decision to choose the appropriate approach for 
individuals who require initiation of maintenance treatment for COPD.
DRUG PROFILE
1.2
Tiotropium+olodaterol combination
Tiotropium+olodaterol FDC (Stiolto® 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.
Based on these observations, marketing authorization for tiotropium+olodaterol (5μg /5μg) 
FDC (total daily dose) has so far been granted in US, Canada, Australia and in all European 
countries within the decentralized procedure (DCP) as well as in a number of other countries 
worldwide.
For a more detailed description of the drug profile refer to the current Summary of Product 
Characteristics (SmPC) for Stiolto® which is included in the Investigator Site File (ISF).


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Boehringer Ingelheim’s Respimat® inhaler will be used for administration of study drug. The 
medication is provided as an aqueous solution in a cartridge, which is inserted into the device 
prior to first use. A propellant-free device, the Respimat® inhaler generates a soft mist which 
is released over a period of approximately 1.5 seconds. The fraction of fine particles 
accessible to the lungs and airways is very high compared with many metered dose aerosols 
or dry powder devices. The use of the Respimat® inhaler has been shown to be safe with 
regards to paradoxical bronchoconstriction during chronic use in patients with COPD [P05-
08465].
Fluticasone propionate + salmeterol combination
Fluticasone propionate and salmeterol are the constituents in the fixed dose combination 
product Advair® (Seretide®, Viani®). In the US Advair® (50μg salmeterol and 250μg 
fluticasone proprionate) given twice daily via the Diskus® inhaler is approved for the 
maintenance treatment of airflow obstruction and reducing exacerbations in patients with 
chronic obstructive pulmonary disease (COPD). 
More information can be found in the SmPC for US PI for Advair®, included in the 
Investigator Site File (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 
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 the US as well as in many EU countries. 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
This study will be a randomized, 12 weeks, parallel study to evaluate the lung function and 
symptom improvements following treatment with tiotropium+olodaterol FDC 5µg/5µg
compared to fluticasone + salmeterol FDC 500/100 µg.
In a previous BI study (ENERGITO 1,1237.11), tiotropium+olodaterol FDC 5/5µg was 
shown to be superior to twice-daily fluticasone + salmeterol FDC 250µg/50µg and 500
µg/50µg with respect to FEV1 AUC0-12 response after 6 weeks of treatment. With the 
growing evidence of once-daily LABA/LAMA FDC having shown superior efficacy vs 
ICS/LABA FDC in several COPD trials, further assessment of the lung function profile 
over 24 hours with once daily tiotropium+olodaterol FDC 5/5µg in comparison with a 
commonly used twice daily ICS/LABA FDC is warranted. This study will use a different 
formulation of fluticasone+ salmeterol than ENERGITO 1. A 12-week parallel group study 
was chosen for this trial to avoid repeated washout periods for the patients, which would be
necessary in a cross-over trial (design of ENERGITO 1).
There is a specific need for the US to generate further local data on LAMA/LABA vs.
LABA/ICS to confirm that LAMA/LABA is significantly superior to LABA/ICS in terms 
of lung function. In addition, the study will also conduct an initial exploration of the effects 
of LABA/LAMA compared with LABA/iCS regarding symptom improvement.
TRIAL OBJECTIVES
2.2
The primary objective of the trial is to show superiority in lung function of once daily (2 
inhalations) treatment with orally inhaled tiotropium+olodaterol (5µg/5µg) fixed dose 
combination to twice daily (one inhalation) treatment with fluticasone propionate+salmeterol 
(250µg/50µg) fixed dose combination over 12 weeks in patients with Chronic Obstructive 
Pulmonary Disease (COPD).
Safety will be assessed as a further objective.
BENEFIT-RISK ASSESSMENT
2.3
Clinical trials conducted to date have shown tiotropium+olodaterol (5μg/5μg) fixed dose 
combination to be a safe, well tolerated and efficacious combination therapy according to 
treatment guidelines in a moderate to severe COPD population. The observed incremental 
bronchodilator response for the fixed dose combination compared to the individual 
components translated into benefits that were meaningful for the patient, with improvements 
in several patient centred outcomes. 
Further potential benefits of tiotropium+olodaterol FDC include:


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-
improved airflow over a complete 24 hour period compared with twice daily 
treatment with fluticasone propionate+salmeterol FDC
-
improved convenience and compliance compared with the free combination of 
tiotropium and olodaterol
Both tiotropium and olodaterol offer a 24 hour duration of action profile.
Potential risks associated with administration of the combination of tiotropium and olodaterol 
include the listed (expected) adverse events for tiotropium / olodaterol (5μg/5μg) fixed dose 
combination. The most frequently reported adverse reactions were nasopharyngitis and 
cough.
Potential risks associated with administration of tiotropium include the listed (expected)
adverse events for tiotropium monoproduct. The most frequently reported adverse reactions
were nasopharyngitis, dry mouth and cough.
Potential risks associated with administration of olodaterol include the listed (expected) 
adverse events for olodaterol monoproduct.
Furthermore, the β2-mimetic class effects described in the international product information 
of β2-agonists such as formoterol [R04-4303, R04-4304, and R04-4305] may also be relevant 
for olodaterol, both as monoproduct and in combination with tiotropium. As noted in Section 
7.1 of the Investigator’s Brochure [c01730070-04], careful assessment of cardiovascular 
function has to be ensured in planned clinical studies of the combination of tiotropium and 
olodaterol.
The potential benefits for patients outweigh potential risks and justify clinical development of
tiotropium+olodaterol FDC.
The fixed-dose combination of fluticasone and salmeterol is registered for the maintenance 
treatment of patients with severe to very severe COPD and frequent exacerbations in many 
countries.
Therefore, both treatment regimens are considered options for long-term therapy of COPD 
and a comparison of both regimens regarding efficacy and safety is of importance for the 
future treatment of COPD patients.
Women of childbearing potential may be included in clinical trials for tiotropium+olodaterol
(5μg/5μg) fixed dose combination provided appropriate precautions are taken to minimise the 
probability of becoming pregnant. These precautions include pregnancy testing and use of a 
highly effective method of birth control. Continued testing and monitoring during the trial 
should be sufficient to ensure compliance with the measures not to become pregnant during 
the period of drug exposure (which may exceed the length of the study until the follow-up 
visit at 21 days after discontinuation of the study medication) [R10-5669].


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The trial design requires that all eligible patients complete a four week baseline/run-in period 
in which LABAs, LAMAs and ICS are withdrawn prior to randomization. At the 
Investigator’s discretion, Atrovent® HFA may be provided to patients who are taking a 
LAMA previous to trial entry for use during the 4 week run-in period; Boehringer Ingelheim 
(BI) will provide open-label Atrovent® HFA for this purpose.
During the entire course of the trial Boehringer Ingelheim will provide open-label albuterol 
as PRN rescue medication for all patients who have signed Informed Consent.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a randomized, double-blind, double-dummy, active-controlled, multi-center, parallel 
group, Phase IV study to show superiority in lung function of 12 weeks once daily treatment 
with orally inhaled tiotropium+olodaterol fixed dose combination (5µg/5µg) delivered by the 
Respimat® inhaler vs. 12 weeks twice daily orally inhaled treatment with fluticasone 
propionate+salmeterol fixed dose combination (250µg/50µg) delivered by the Diskus®
inhaler in patients with Chronic Obstructive Pulmonary Disease (COPD).
The study will consist of a screening and run-in period of at least 4 four week duration, a 12-
week randomised treatment period and a three week follow up period.
After signing Informed Consent (IC) at Visit 0 and completing an initial screening visit (Visit 
1), patients enter a four-week screening (baseline) period to ensure clinical stability (i.e. no 
exacerbations). Patients who meet all inclusion criteria and do not present with any of the 
exclusion criteria will be randomised into the 12-week treatment period (at Visit 2) in which 
they will be assigned randomly to one of two treatments. An interactive response technology 
(IRT) system will be used for randomisation to treatment in this trial and for allocation of 
medication to patients throughout the treatment period.  Additional clinic visits will be 
scheduled after 6 and 12 weeks of treatment (Visits 3 and 4).  A follow-up visit (Visit 5) will 
be scheduled approximately three weeks after the last dose of study medication. 
Individual patient participation is concluded when the patient has completed the last planned 
visit.  The “last-patient-last-visit-primary-endpoint” is the last scheduled primary endpoint 
visit at Week 12 completed by the last patient.  The end of the trial is defined as “last patient 
out”, i.e. last scheduled visit completed by the last patient.  
All randomised patients who withdraw prematurely are encouraged to have an end of 
treatment (EOT) visit and a follow-up visit, three weeks after the EOT visit. 
Site staff will contact the patients by telephone approximately one to two days prior to 
scheduled PFT visits (Visits 2, 3 and 4) to remind them of medication washout and any other 
requirements in preparation for the visit (see Figure 3.1: 1).


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Figure 3.1: 1 Study design flow diagram
Pulmonary function testing (PFT) will be conducted at the screening visit (Visit 1) to 
determine patient eligibility.
Analysis of clinical laboratory samples will be performed by a Central Lab. Any abnormal 
laboratory finding at Visit 2, which is considered by the investigator to be clinically relevant, 
will be recorded as baseline condition. 
Adverse events will be documented throughout the trial, i.e. starting with informed consent
and ending 21 days after administration of the last dose of trial medication.
Further details of the assessments conducted throughout the study period are provided in the
Flow Chart and Section 6.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
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 SOPs
(Standard Operating Procedures).
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitor (CML), 
Clinical Research Associates (CRAs), and Investigators.


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All study-related documentation will be stored in the BI clinical trial master file (TMF). 
Trial relevant documentation for the study sites will be filed in the 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 performed by BI according to BI SOPs.
Tasks and functions assigned in order to organize, 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 is selected by the sponsor. Tasks and 
responsibilities will be defined in a contract.  Relevant documentation on the participating 
(principal) investigators and other important participants, including their curricula vitae, 
will be filed in the ISF.
Targeted group of Investigators: Pulmonologists/qualified sites with access to the requested 
patient population. They must have the logistical infrastructure in place to be able to 
perform 24-hour pulmonary function testing in patients with COPD, including adequate 
facilities to accommodate overnight stays of patients and site staff over the full course of 
the study.  To facilitate the inclusion of the patients and ease the burden on the study staff, 
sites might include patients in cohorts, where more than one patient is performing the 24-
hour PFT visits at the same day at the same site. This approach requires that adequate site 
staff and equipment are available during the 24-hour serial spirometry testing days.
The following local facilities/equipment is required at the investigational site:
-
scale 
-
12-lead electrocardiogram (ECG)
-
Barometer for use in calibration of the spirometer
A central laboratory service and vendors for spirometry, and IRT (Interactive Response 
Technology) will be used in this trial. Details will be provided in the applicable manuals 
available in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
Patients with COPD with moderate to severe pulmonary impairment will be included in this 
trial.  Pharmacotherapy with long-acting bronchodilators (as single-agent therapy or as 
combination therapy) is the recommended maintenance treatment for these patients according 
to various international medical guidelines for the management of this disease [P01-02794, 
P04-07409].


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Since patients may be receiving combination therapy that includes both a long-acting ß-
agonist (olodaterol), and a long-acting anti-cholinergic (tiotropium) or a long-acting ß-agonist 
(salmeterol) and ICS (fluticasone propionate) it is necessary to restrict the use of long-acting
ß-agonists (e.g. salmeterol, formoterol, indacaterol), anti-cholinergics (e.g. tiotropium, 
ipratropium) and inhaled corticosteroids (ICS) during the entire treatment phase. Short-acting 
ß-agonist medication (salbutamol/albuterol) will be provided to all patients for rescue use 
(PRN), and appropriate medications will be allowed to control acute exacerbations as 
medically necessary.  A short-acting anticholinergic medication (Atrovent HFA) will
be provided for use during the LAMA washout prior to the randomisation visit on 
investigator’s discretion.
Randomisation will be used to avoid any systemic 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 consequence of patient or investigator knowledge of the assigned treatment [R03-2273].
SELECTION OF TRIAL POPULATION
3.3
A sufficient number of patients of either sex, 40 years of age or older, with a diagnosis of 
COPD will be enrolled in the study to ensure that a minimum of 288 patients are entered 
(randomized) into the study.
 
 
 
Clinical trials contribute toward reducing health disparities through improved knowledge
about treatment among diverse populations. Greater diversity in clinical trial samples allows
for broader generalization of trial results, increased minority access to trials, improved
standards of care, decreased disparities in disease treatment and outcomes, and improved
external validity supported by a more representative sample. Each Investigator should 
develop a recruitment strategy that ensures the recruitment of a representative patient 
population and takes into consideration gender, race and ethnicity.
Enrolment will be competitive and conducted at approximately 45 study sites. Additional
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 6 – 8 patients over an 
approximate 8 month enrollment period.


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A log of all patients enrolled into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Outpatients with a history of COPD with moderate to severe pulmonary impairment
(according to GOLD guideline [P11-05865]) 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 inclusion and exclusion criteria.
`
3.3.2
Inclusion criteria
1. 
All patients must sign an informed consent consistent with FDA regulations prior to 
participation in the trial, which includes medication washout and restrictions.
  2.
All patients must have a diagnosis of chronic obstructive pulmonary disease [P11-
05865] and must meet the following spirometric criteria:
Patients with a post-bronchodilator 30% ≤ FEV1<80% of predicted normal 
(ECSC, [R94-1408]); and a post-bronchodilator FEV1/FVC <70% at Visit 1
(see Appendix 10.5 for ECSC predicted normal equations)
3.
Male or female patients, 40 years of age or older.
4.
Patients must be current or ex-smokers with a smoking history of more than 10 
pack years. (see Appendix10.5 for calculation):  Patients who have never smoked 
cigarettes must be excluded.
5.
Patients must be able to perform, according to investigator’s judgment, all trial
related procedures including:

Technically acceptable pulmonary function tests (spirometry)

Completion of study questionnaires
6.
Patients must be able to inhale medication in a competent manner (in the 
opinion of the investigator) from the Respimat® and Diskus® inhalers 
(Appendix 10.1 and 10.2) and from a metered dose inhaler (MDI). 
3.3.3
Exclusion criteria
1.
Patients with a significant disease other than COPD; a significant disease is 
defined as a disease which, in the opinion of the investigator, may (i) put the 
patient at risk because of participation in the study, (ii) influence the results of the 
study, or (iii) cause concern regarding the patient’s ability to participate in the 
study.


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2.
Patients who have had a COPD exacerbation that required treatment with 
antibiotics, systemic steroids (oral or intravenous) or hospitalization in the last 3 
months prior to Visit 1 and/or between Visit 1 and Visit 2.
3.
Patients with a history of asthma. For patients with allergic rhinitis or atopy,
source documentation is required to verify that the patient does not have asthma. 
If a patient has a total blood eosinophil count ≥ 600/mm3, source documentation 
is required to verify that the increased eosinophil count is related to a non-
asthmatic condition.
Patients with any of the following conditions:
4.
A diagnosis of thyrotoxicosis (due to the known class side effect profile of 
ß2-agonists).
5.
A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to 
the known class side effect profile of ß2-agonists).
6.
A history of myocardial infarction within 1 year of screening visit (Visit 1).
7.
Unstable or life-threatening cardiac arrhythmia.
8.
Hospitalization for heart failure within the past year.
9.
Known active tuberculosis.
10.
A malignancy for which patient has undergone resection, radiation therapy or 
chemotherapy within last five years (patients with treated basal cell carcinoma 
are allowed).
11.
A history of life-threatening pulmonary obstruction.
12.
A history of cystic fibrosis.
13.
Clinically evident bronchiectasis.
14.
A history of significant alcohol or drug abuse.
15.
Patients who have undergone thoracotomy with pulmonary resection (patients 
with a history of thoracotomy for other reasons should be evaluated as per 
exclusion criterion No. 1).
16.
Patients being treated with oral or patch β-adrenergics.
17.
Patients being treated with oral corticosteroid medication within 6 weeks prior to
Visit 1.  


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18.
Patients who regularly use daytime oxygen therapy for more than one hour per 
day and in the investigator’s opinion will be unable to abstain from the use of 
oxygen therapy during clinic visits.  
19.
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.
20.
Patients who have taken an investigational drug within one month, six half-lives or 
(in case the investigational drug (sub) class is listed in Table 4.2.2.1:1) within the 
wash out period specified in Table 4.2.2.1:1 (whichever is greater) prior to
screening visit (Visit 1).
21.
Patients with known hypersensitivity to β-adrenergic drugs, BAC, EDTA, or 
any other component of the Respimat® inhalation solution. In addition, 
patients with known hypersensitivity to Lactose monohydrate (which contains
milk proteins).
22.
Pregnant or nursing women.
23.
Women of childbearing potential not using a method of birth control classified at 
least as “acceptable”*. Female patients will be considered to be of childbearing 
potential unless surgically sterilized by hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy, or post-menopausal (defined as no menses for 12 months 
without an alternative medical cause). Tubal ligation is NOT a method of 
permanent sterilisation.
* 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. As 
per CTFG  Recommendations related to contraception and pregnancy testing in clinical trials 
(http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf ), sections 2.2.4, 
4.1, 4.2 and 4.3, “highly effective” or “acceptable” methods include:

combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:

oral

intravaginal

transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation :

oral

injectable

implantable 

intrauterine device (IUD) 

intrauterine hormone-releasing system ( IUS) 

vasectomised partner 

progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action

male or female condom with or without spermicide 

cap, diaphragm or sponge with spermicide 


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24.
Patients who have previously been randomized in this study or are 
currently participating in another study.
25.
Patients who are unable to comply with pulmonary medication restrictions 
prior to randomization.
3.3.4
Removal of patients from therapy 
3.3.4.1
Removal of individual patients
An excessive withdrawal rate can have a severe negative impact on the scientific value of the
trial. Every effort should be made to keep patients in the trial as scheduled. This includes
careful patient selection and appropriate explanation of the trial requirements and procedures
prior to enrolment as well as an explanation of the consequences of premature withdrawal.
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for trial treatment or trial 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 5.3.5.2.
Investigators must carefully consider withdrawal from the treatment of an individual 
patient if any of the following criteria apply:

More than 3 courses (or increases) of systemic (oral, i.v.) corticosteroids are 
required to treat a COPD exacerbation

When, during trial participation, a second hospital admission (at least 2 
overnight stays) for a COPD exacerbation occurs

Clinical deterioration requiring maintenance treatment not allowed per protocol
No patient should be discontinued from the trial for a protocol violation before 
discussion with the local clinical monitor.
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(s) 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.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
After screening, eligible patients will be randomly assigned to one of two study 
medications for 12 weeks.
1. tiotropium+olodaterol FDC, a once daily dose of 2 actuations of 2.5µg /2.5µg
inhalation solution via the Respimat® inhaler.
2. Fluticasone propionate+salmeterol FDC, a twice daily dose of one actuation of 
250µg/50µg inhalation powder via the Diskus® inhaler.
-
During each treatment the patient will inhale two puffs from the Respimat® inhaler, 
once daily, in the morning followed by one inhalation from the Diskus® inhaler. 
-
Each evening the patient will take one inhalation from the Diskus® inhaler only. 
-
The Respimat® inhaler is not to be used in the evening.
4.1.1
Identity of the investigational medicinal products
Table 4.1.1: 1
Test product 1: tiotropium+olodaterol FDC
Substance:
Tiotropium+olodaterol fixed dose combination
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
Placebo for test product 1:
Substance:
Tiotropium+olodaterol fixed dose combination
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
NA
Posology
2 inhalations once daily (a.m. dosing)
Route of administration:
Oral inhalation via Respimat® inhaler


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Test product 2:  Fluticasone propionate+salmeterol FDC
Substance:
Fluticasone propionate+salmeterol fixed dose 
combination
Pharmaceutical formulation:
Inhalation powder
Source:
GlaxoSmithKline, Zebulon, North Carolina 
Unit strength:
250 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 Diskus® 
Placebo for test product 2:  
Substance:
Fluticasone propionate+salmeterol fixed dose 
combination
Pharmaceutical formulation:
Inhalation powder 
Source:
GlaxoSmithKline France
Unit strength:
NA
Posology
One inhalation in the morning and evening (a.m. and 
p.m. dosing)
Route of administration:
Oral inhalation via Diskus® 
4.1.2
Selection of doses in the trial
Tiotropium Respimat® 5μg once daily and tiotropium+olodaterol Respimat® 5μg/5μg once
daily are approved dose regimens for the treatment of COPD in many countries and these
doses were selected for the trial. The clinical trials conducted during the Phase III program 
for tiotropium+olodaterol FDC 5μg/5μg have shown that this dose is a safe, well tolerated 
and efficacious combination therapy. The observed incremental bronchodilator response for 
the combination compared to the individual components translated into benefits that were 
meaningful to the patient, with improvements in several patient-centered outcomes.
4.1.3
Method of assigning patients to treatment groups
Patients are randomised to treatment at Visit 2. After assessment of all in- and exclusion 
criteria, each eligible patient will be assigned kits that will have unique medication numbers.
Note that the medication number is different from the patient number (the latter is assigned 
directly after informed consent is obtained). Site personnel will enter the medication number 
on the case report form.


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During visit 2, eligible patients will be randomised to receive tiotropium+olodaterol FDC or 
fluticasone propionate+salmeterol FDC in a 1:1 ratio according to a randomization plan. The 
assignment will occur in a blinded fashion via Interactive Response Technology (IRT).
The treatment for each patient is determined by random assignment.
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
Patients will be randomized at Visit 2 to one of two treatments, tiotropium+olodaterol FDC 
and placebo fluticasone propionate+salmeterol FDC or fluticasone propionate+salmeterol 
FDC and placebo tiotropium+olodaterol FDC. At Visit 2 the IRT will assign three Respimat®
Kits (two for treatment and one for reserve) and three Diskus® Kits (two for treatment and 
one for reserve). At Visit 3 the patient will bring in all treatment kits (including the reserve 
kits) that were dispensed at Visit 2. At Visit 3, two new Respimat® and Diskus® treatment 
kits will be dispensed in addition to the reserve kit which was previously dispensed at Visit 2.  
If the reserve kit dispensed at Visit 2 was used by the patient, a new reserve kit will be 
dispensed as well. Each treatment kit will have a unique medication ID number.  Trial 
medication will be dispensed to the patient by the investigator/pharmacist at these visits.  The 
amount of trial medication dispensed will be recorded on the drug accountability forms.
The reserve kits allow 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 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.
Priming of the Respimat®Inhaler
Each newly assembled Respimat®Inhaler has to be primed.  Priming should NOT take place 
in the same room where the patient is inhaling trial medication.  The inhaler should be primed 
by actuating it until an aerosol is visible plus three additional actuations.  All priming 
actuations should be directed to the ground.  For detailed priming instructions please refer to 
the Respimat®Inhaler handling instructions in Appendix 10.1.
Once assembled, the shelf-life of the Respimat® Inhaler with trial medication is 3 months.  
Once assembled, the shelf-life of the Respimat® Inhaler with training medication is also 3 
months. Therefore it is important to ALWAYS enter the date of the cartridge insertion on the 
medication label of the Respimat® Inhaler immediately after the cartridge is inserted.
Fluticasone propionate+salmeterol Inhaler - Diskus®
The Diskus® is a dry powder inhaler (DPI) and does not require priming and has no shelf-life 
restriction other than labelled use-by date. The Diskus® Inhaler should not be used beyond 
one month after removal from the moisture-protective foil overwrap, or after all blisters have 
been used (when indicator reads “0”), whichever comes first.


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Rescue Medication: ProAir® HFA:  Testing of the MDI 
Before using for the first time, one actuation should be released into the air to make sure the 
device is working.
4.1.4.1   
Study Medication Administration
Trial medication administration at site visits
Detailed written instructions and training for the use of the Respimat® Inhaler and
Diskus® Inhaler will be given to the patient at Visit 1 (see Appendices 10.1 and 10.2). At 
Visits 2 - 4 detailed instructions on the use of the devices will be repeated if needed, but 
patients should not inhale from a training device that day.  The investigator or qualified study 
personnel will observe the inhalation procedure and will reinforce a correct inhalation 
technique.
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 
Diskus® Inhaler (inhaled according to the instructions provided in Appendix 10.1 and 10.2) 
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 Diskus® will be 
self- administered by the patient under the direct supervision of the investigating physician or 
designee at Visits 3 and 4.  The utmost care should be taken to ensure that during the 
treatment phase the study medication is not taken prior to coming to the site. The exact time-
point of trial medication inhalation (i.e. end inhalation procedure which consists of one 
inhalation from the fluticasone propionate+salmeterol Diskus®) for both the morning and 
evening doses on visit days at the site will be captured in the MasterScope® CT spirometer.
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.
At Visits 3 and 4 (i.e., 24-hour PFT visits), for the evening dosing, oral inhalation of one puff 
of medication from the Diskus® (inhaled according to the instructions provided in Appendix 
10.2) will be self-administered by the patient between 7:00 p.m. and 10:00 p.m., twelve hours 
(±30 minutes) after administration of the morning dose of trial medication. This evening dose 
will be inhaled after the 11h50min PFT and prior to the 12hr30min PFT time point.
The last administration of the study medication will be taken at the clinic at Visit 4 (EOT)
from the Respimat® inhaler and Diskus® inhaler that is in current use since no new 
medication treatment boxes will be dispensed at this visit.


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Trial medication administration at home
Each morning between clinic visits and in this order, oral inhalation of two inhalations of the 
trial medication from the assigned Respimat®Inhaler and one puff of trial medication from 
the assigned Diskus® Inhaler (inhaled according to the instructions provided in Appendices 
10.1 and 10.2) will be self-administered by the patient.
Patients are to be instructed that the morning and evening doses of trial medication will be 
self-administered within ±30 minutes of time of administration at Visit 2.
Each evening, one additional inhalation of trial medication from the Diskus® Inhaler (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 forgets to take the morning dose of trial medication within the specified time 
window, the patient can take the morning dose up until 12:00 p.m. (noon). After 12:00 p.m. 
the patient should skip the morning dose and take evening dose per protocol. The patient 
should then take the next morning dose at the scheduled time the following day.  If the patient 
forgets to take the evening dose of trial medication within the specified time window, the 
patient can take the evening dose up until 12:00 midnight. After midnight the patient should 
skip the evening dose and take the next evening dose at the scheduled time the following 
evening.
Patients are to be instructed that on the day preceding Visits 3 and 4 that the doses of trial 
medication must be self-administered within ±30 minutes of time of administration at Visit 2 
AND between 7:00 a.m. and 10:00 a.m. for the morning dose to avoid influence on the data 
collected on the site visit day. Patients should also be instructed that on the day preceding 
Visits 3 and 4 the evening dose of trial medication must be self-administered within ±30 
minutes of time of administration at Visit 2 AND between 7:00 p.m. and 10:00 p.m. to avoid 
influence on the data collected on the site visit day. 


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Table 4.1.4.1: 1
tiotropium+olodaterol and fluticasone+salmeterol treatments
Treatment Group
Morning Dose
Evening Dose
Tiotropium+Olodaterol
FDC
5µg/5µg
2 puffs – Tio+Olo 2.5µg/2.5µg
inhaler
plus
1 puff – placebo
fluticasone propionate+salmeterol
1 puff – placebo fluticasone 
propionate+salmeterol
Fluticasone 
propionate+salmeterol 
FDC  250µg/50µg
2 puffs – Tio+Olo placebo inhaler
plus
1 puff fluticasone 
propionate+salmeterol 250µg/50µg
1 puff fluticasone 
propionate+salmeterol 
250µg/50µg
Respimat®and Diskus® Return
The Respimat® and Diskus® Inhalers dispensed for treatment can be used for approximately 
30 days each.  
All used and unused Respimat®and Diskus® Inhalers dispensed at Visit 2 and 3 must be 
returned to the patient treatment boxes and returned at Visit 3 and 4 respectively, after 
administration of trial medication at the site.
Any Respimat® Inhaler or Diskus®Inhaler that has been reported as malfunctioning by a 
patient or investigator will be returned to Boehringer Ingelheim for investigation. See the ISF 
for specific instructions and for details regarding drug accountability requirements. A detail 
of the procedure for the return of used inhalers is provided in Appendices 10.1 and 10.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators and everyone involved in analyzing or with an interest in this 
double-blind study will remain blinded with regard to the randomized treatment 
assignments until after database lock.
Boehringer Ingelheim will generate the randomization scheme using validated 
randomization software, and prepare and code the medication in a blinded fashion.  Study 
medication will be assigned for the patients via the IRT. Refer to Section 4.1.5.2 for rules 
for breaking the code for an individual or for all patients in emergency situations.  


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4.1.5.2
Unblinding and breaking the code
The ability to unblind will be available to the investigator via the IRT. Unblinding must only 
be used in emergency situations when the identity of the study drug must be known by the 
investigator to provide appropriate medical treatment. Each site receives a manual from the 
IRT provider that contains instructions on how to unblind the treatment of a patient via the 
IRT (via 24-hour Emergency helpline). If possible, the sponsor, i.e. Clinical Monitor Local 
(CML) and Trial Clinical Monitor (TCM) must be contacted prior to the site unblinding a 
patient's treatment. Patients unblinded to treatment will be withdrawn from the trial. 
4.1.6
Packaging, labelling, and re-supply
Boehringer Ingelheim will provide all study supplies including blinded study medication,
open-label Atrovent® HFA, open-label ProAir® HFA and Respimat® and Diskus® training 
kits.  They will be packaged and labelled in accordance with the principles of Good 
Manufacturing Practice (GMP). Re-supply to the sites will be managed via an IRT system, 
which will also monitor expiry dates of supplies available at the sites.
Training Materials

Respimat training: Training Respimat® Inhaler, placebo cartridges and 
disposable mouthpieces will be provided for training purposes: A training 
device may be used for more than one training session. The training Respimat®
Inhaler can be used until 3 months after first insertion of the cartridge or until the 
device is empty. The date of the cartridge insertion should be entered on the 
medication label of the Respimat® immediately after the cartridge is inserted. A 
new mouthpiece should be used for each patient.

Diskus® training: Training placebo Diskus® Inhaler kits will be provided for 
training purposes. The Diskus® Inhaler should not be used beyond one month 
after removal from the moisture-protective foil overwrap, or after all blisters 
have been used (when indicator reads “0”), whichever comes first. The device 
should be cleaned with antiseptic wipes, followed by a dry tissue after each 
patient use.
Open-label supplies = Auxiliary Medicinal Product (AMP)

Atrovent® HFA for use as run-in medication will be provided by BI and 
purchased locally. This medication (Atrovent® HFA) will be provided for use 
during the LAMA washout prior to the randomization visit, on investigator’s 
discretion.

ProAir® HFA MDI inhalation aerosol (100 µg per actuation) for use as rescue 
medication during the screening/run-in and treatment period.  The rescue 
medication will be provided by BI and purchased locally.


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Blinded study medication = Investigational Medicinal Product (IMP)
All study medication (also containing blinded placebo medication) will be contained in 
Respimat® or Diskus® treatment boxes identified with the trial number and a unique 
medication number. 
The treatment boxes will have a tear-off label.  This tear-off label will be attached to the 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 1 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 Diskus® treatment box will contain one Diskus® inhaler. Each Diskus® contains 
sufficient medication for 30 days of treatment. The Diskus® inhaler will be contained
inside a foil pouch which will be heat-sealed and labelled, before being placed into 
the treatment box.
Labelling
Individual treatment boxes will have a medication identification label and a tear-off label. 
Each tear-off label should be attached to the drug accountability form which will be part of 
the ISF. The investigator or designee should complete the following information:
-
Date of cartridge insertion, patient number and visit number should be entered at time 
of cartridge insertion on the inhaler booklet label.
-
Investigator’s name should be entered at the time of dispensing on the label of the 
treatment box.
For details of packaging and the description of the label, refer to the ISF.
Medication Dispensing
The assignment of Respimat® and Diskus® treatment boxes dispensed at the beginning of 
each treatment visit (Visit 2 and Visit 3) will be handled by an IRT system.
At randomisation (Visit 2), the site staff will phone or use the web to access the IRT and 
obtain medication numbers for each of the 3 Respimat® treatment kits and 3 Diskus®
treatment kits to be dispensed to the patient for daily use during the 6 weeks between visits. 
Two of the treatment kits will be used by the patient and the third is a reserve kit.
The Respimat® and Diskus® 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 continue to be used at home until 30 days of 


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treatment has been reached.  The Diskus® Inhaler does not have to be primed and will be used 
for 30 days of treatment.  
The second Respimat® kit will be primed and used by the patient to cover the remaining 
weeks until the next visit. The third Respimat® kit and the third Diskus® kit 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 Diskus®.  
NOTE: The Respimat® Inhaler 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 the investigator’s name on the medication label of all three Respimat® and 
Diskus® treatment boxes at time of dispensing to the patient (Visit 2 and 3 respectively).
Please note that the 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® inhaler, if necessary.
Re-Supply
Each site will receive a first supply after the first patient is registered in the IRT and will be 
resupplied upon demand by the 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 Diskus® Inhaler 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, trial drug receipt and rescue drug receipt, usage and return must be 
documented and verified. Any discrepancies in drug supplies will be noted and explained.


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4.1.8
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:

Approval of the trial protocol by the IRB / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the principal Investigator,

Availability of Form FDA 1572
The investigator and/or pharmacist and/or investigational drug storage manager must
maintain records of:

the product’s delivery to the trial site,

the inventory at the site,

the use by each patient,

the return to the sponsor or alternative disposal of unused products. If applicable, the
sponsor or warehouse / drug distribution centre will maintain records of the disposal,

dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, and the unique code
numbers assigned to the investigational product and trial patients,

adequate documentation that the patients were provided the doses specified by the CTP,

reconciliation of all investigational products received from the sponsor.
At the time of return to the sponsor and/or appointed CRO, the investigator / pharmacist /
investigational drug storage manager must verify that all unused or partially used drug
supplies have been returned by the clinical trial patient and that no remaining supplies are in
the Investigator’s possession.
The investigator/ pharmacist will record on the drug accountability forms the following
information:
For Respimat® inhaler and Diskus® inhaler 

dates (dispense and return)

dispenser’s initials

batch/serial numbers

expiry dates

the unique Respimat® and Diskus® treatment box number assigned by IRT

trial patient number 
It is important to enter the date of priming on the medication label of the Respimat®
see Section 4.1.6.
Rescue medication and run-in medication


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AMP accountability forms will be provided for albuterol (rescue medication) and
Atrovent HFA (run-in medication-if applicable). This record will include:

dates (dispense and return)

dispenser’s initials

quantities

batch/serial numbers

expiry dates

trial patient number 
Patients will be asked to return all run-in medication (if dispensed, at Visit 2) and used 
/unused rescue medication and inhalers at each clinic visit. Source data documentation and 
full drug accountability in regard to dispensed and returned medication to investigational site 
and to patients is required. Only used inhalers will be replaced at each clinic visit. For further 
details, please refer to Section 4.2.1.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Rescue Medication, emergency procedures and additional treatments
4.2.1.1
Rescue medication
Administration of rescue medication can occur at any point during the trial as deemed 
necessary by the patient or the investigator. Open label albuterol HFA MDI (100 µg per 
actuation) will be provided as rescue medication by BI; only the albuterol MDI provided by 
BI is allowed for rescue medication use. If the patient requires rescue medication during the 
pulmonary function test (PFT) days (Visits 2, 3 and 4), the PFTs will be continued if 
possible. The medication used, route and 24-hour clock time of administration will be 
recorded on the Rescue Medication eCRF page. The visit should not be re-scheduled.
In the case where the investigator decides to discontinue a patient from a PFT visit or rescue 
treatment is administered please contact the sponsor (e.g. the Local Clinical Monitor) prior to 
discontinuing the patient.
Rescue Medication on and before Pulmonary Function Test Days
All test-day rescue medication administered before the conclusion of pulmonary function 
testing will be recorded on a specific source data worksheet and captured in the eCRF.
4.2.1.2
Emergency procedures
There are no special emergency procedures to be followed.
4.2.1.3
Additional treatment
Medications allowed to control acute exacerbations as medically necessary during the 
treatment period:


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
PRN albuterol HFA inhalation aerosol (MDI) provided by BI.

Temporary additions of oral steroids are allowed during the treatment portion of the 
study. Pulmonary function testing visits should not occur within seven days of the last 
administered dose of an addition of oral steroids. Pulmonary function testing visits 
may be postponed up to 14 days to meet this restriction. Subsequent visits will be 
scheduled according to the patient’s regular schedule.

Temporary additions of theophylline preparations are allowed during the treatment 
portion of the study. Pulmonary function testing visits should not occur within seven 
days of the last dose. Pulmonary function testing visits may be postponed up to 14 
days to accommodate this restriction. Subsequent visits will be scheduled according to 
the patient’s regular schedule.

The use of antibiotics is not restricted and may be prescribed as medically necessary 
for exacerbations and / or infections. If antibiotics are prescribed for a respiratory 
infection prior to pulmonary function testing visits, the visit will be postponed for at 
least two days but not more than seven days after the last dose is given. Subsequent 
visits will be scheduled according to the patient’s regular schedule.
Oral steroids, theophylline preparations and antibiotics will not be provided by BI.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The following table provides an overview of permitted and restricted medication over the different study periods.
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)
Permitted
NOT 
permitted
NOT 
permitted
Permitted
Oral corticosteroids
(not allowed for at least 6 weeks prior to V1; 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


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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
β-adrenergics
Inhaled short-acting β-adrenergics
Permitted1
Rescue1
Rescue1
Permitted
Inhaled long-acting β-adrenergics (b.i.d.)
(e.g. formoterol / salmeterol)
Permitted1
(w/o 48 hrs. prior 
to V1)
NOT 
permitted 
NOT 
permitted 
Permitted
Inhaled long-acting β-adrenergics (q.d.)
(i.e. indacaterol, olodaterol)
Permitted1
(w/o1 wk prior 
to V1)
NOT 
permitted
(w/o 3wks.
prior to V2)
NOT 
permitted
Permitted
β-adrenergics
Oral and patch beta-adrenergics
Permitted1
(w/o 4 wks. prior 
to V1)
NOT 
permitted
NOT 
permitted
NOT 
permitted
Beta blockers
(If stabilized 6 wks. prior to V1)
Permitted
Permitted 
Permitted 
Permitted 
Anti-
cholinergics
Short-acting anticholinergics
(inhalation aerosol, nasal spray)
Permitted1
Permitted1
(w/o 8 hours 
prior to V2)
NOT 
permitted
Permitted
Long-acting anticholinergics (b.i.d./q.d.)
(i.e. tiotropium, aclidinium, glycopryonnium, 
umeclidinium, tio+olo)
Permitted
(w/o 1 wk prior 
to V1)
NOT 
permitted 
(w/o 3 wks.
prior to 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
Combinations
ICS/LABA (b.i.d.)
(*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 (q.d.)
(*switch to LABA mono-product 2 weeks  prior to V1, 
and then discontinue at least 1 wk. 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
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 3wks.
prior to V2)
Study 
medication
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
Miscellaneous
Other investigational drugs
(*1 month 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
Biologic or other immunomodulators
NOT 
permitted
NOT 
permitted
NOT 
permitted
NOT 
permitted


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Table 4.2.2.1: 1
Permitted medications and medications restrictions (cont.)
1.
Refer to Section 4.2.2.2 for washout period prior to PFTs.
2.
Patients may be switched to q.d. LABA and short acting anticholinergic. Refer to Section 4.2.2.2 for washout 
period prior to PFTs.
3.
For theophyllines: Refer to Section 4.2.2.2 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.


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Medication restrictions for pulmonary function testing:
•
Morning dose of trial medication should not be taken prior to test-day pre-dose PFT.
•
At least a 2 week washout of inhaled steroids prior to PFTs at Visit 1.
(Inhaled steroids are not allowed after Visit 1).
•
At least an 8-hour washout of short-acting beta-adrenergic bronchodilators
•
At least a 48-hour washout of long-acting beta-adrenergic bronchodilators (b.i.d.) 
prior to Visit 1 (not allowed between Visit 1 and 5).
•
At least a 1-week washout of long-acting beta-adrenergic bronchodilators (q.d.) 
prior to Visit 1 and a 3-week washout prior to Visit 2.
•
At least an 8-hour washout of short-acting anticholinergic bronchodilators prior 
to Visit 1 and 2 (not allowed during treatment periods)
•
At least a 1-week washout of long-acting anticholinergic bronchodilators (b.i.d. or 
q.d.) prior to Visit 1 and a 3-week washout prior to Visit 2.
•
At least a 4-week washout of oral and patch anticholinergics prior to Visit 1.
•
At least a 24-hour washout of short-acting (b.i.d. or more frequent administration)
theophylline preparations.
•
At least a 48-hour washout of long-acting (q.d. administration) 
theophylline preparation.
4.2.2.2
Restrictions on diet and lifestyle
Restrictions prior to PFT visits:
•
Medication washout restrictions should be adhered to as described in Section 4.2.2.1.
•
The patient must remain in the building where the pulmonary function testing is 
performed and must return to the laboratory at least ten minutes prior to the start of 
each test. An exception is the travel to and from the overnight accommodation,
which of course is allowed.
•
On pulmonary function test days (including the Screening Visit), patients must 
refrain from strenuous activity for at least 12 hours prior to pulmonary function 
testing and throughout the testing period. Patients should also avoid cold 
temperatures, environmental smoke, dust or areas with strong odors (e.g. perfumes).
•
Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, and 
ice-cold beverages are not allowed at least 2 hours prior to and during the 
pulmonary function testing at clinic visits.  Decaffeinated beverages are acceptable.
•
Smoking should be discouraged for the 12 hours prior to pulmonary function testing 
and throughout the test day and will not be permitted in the 30-minute period prior 
to spirometry.
A patient visit may be re-scheduled twice due to lack of medication washout 
compliance.


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4.2.2.3
Restriction regarding women of childbearing potential
Women of childbearing potential must use the contraception methods described in the patient 
information.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits. Trial medication adherence should be reviewed by 
the investigator and reported in the eCRF.
Estimating compliance to trial medication
Respimat® Inhaler compliance:  Knowing the time interval between clinic visits, it is possible 
to calculate the number of puffs that should have been administered by the patient. The 
Respimat® Inhaler contains 60 actuations (30 daily doses). The dose indicator shows
approximately how much medication is left. The dose indicator scale is divided into 4
quarters. One quarter used accounts for 7 days of treatment (14 actuations). When the pointer 
enters the red area of the scale, there is approximately medication for 7 days (14 actuations 
left).   Once the dose indicator has reached the end of the red scale (i.e. all 30 daily doses 
have been used) the Respimat® inhaler is empty.
Diskus® Inhaler compliance:  There is a counter on top of the Diskus® which indicates how 
many doses are left.  It counts down to 0.  
The acceptable medication compliance should have an overall value in the range 80% to 
120%. If the compliance is less than 80% the patient needs to be re-trained.
Randomised patients should not be discontinued for lack of medication compliance without
prior discussion with the sponsor.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint(s)
The primary efficacy variable will be forced expiratory volume in one second (FEV1), 
obtained during pulmonary function testing.
The primary endpoint is FEV1 Area Under the Curve (AUC)0-24 h response (change from 
baseline) [L] after 12 weeks of treatment.
FEV1 AUC0-24 h is calculated as the area under the FEV1-time curve from 0-24 hours post-
dose using the trapezoidal rule, divided by the duration (24 hours) and reported in Liters. 
FEV1 AUC0-24 hr  response (change from baseline) is defined as FEV1 AUC0-24 h minus 
baseline FEV1.
The same definition applies to FEV1 AUC 0-12h.
The mean of the two pre-dose pulmonary function test measurements at Visit 2, 1 hour prior 
and 10 minutes prior to the administration of the first dose of the randomised treatment, is 
defined as the baseline FEV1.
5.1.2
Secondary Endpoint(s)

FEV1 AUC 0-12 h response (change from baseline) [L] after 12 weeks treatment

Trough FEV1 response (change from baseline) [L] after 12 weeks treatment

Peak 0-3h FEV1 response (change from baseline) [L] after 12 weeks treatment
-
Trough FEV1 is defined as the mean of the FEV1 value measured at 23 hrs and 
at 24 hrs after trial medication administration. Trough FEV1 response (change 
from baseline) is defined as trough FEV1 minus baseline FEV1.
-
Peak 0-3h is defined as the maximum value measured within the first three 
hours post dosing.


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5.2
ASSESSMENT OF EFFICACY 
5.2.1
Pulmonary function testing (PFT)
MasterScope® CT spirometers will be provided to sites for the on-site spirometry 
measurements. The spirometers and their use, including daily calibration on test days, must 
meet ATS/ERS criteria [P05-12782]. Spirometry will be conducted with the patient in a 
seated position having abstained from medications as specified in Section 4.2.2.1, and it is 
preferable that the same trained individual performs the PFTs 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 blows meeting the ATS criteria (with a maximum of five attempts). The highest FEV1
and FVC will be selected regardless of whether they come from different spirometric 
maneuvers or from the same maneuver. The 24-hour clock time of the first maneuver for 
each PFT time point will be recorded.
The clock time of the start and end of inhalation procedure of trial medication will be 
captured by the MasterScope® CT spirometer.
At Visit 2, pulmonary function tests will be performed to determine patient eligibility and
assess bronchial reversibility (for patient characterization). Further details of reversibility
testing are described in Appendix 10.5. At Visit 2 the study medication will be self-
administered between 07: 00 a.m. and 10:00 a.m. At Visits 3 and 4 the study medication is to 
be self-administered within ± 30 minutes of the time of administration at Visit 2 (please refer 
to Section 4.1.4.1 for time window in inhalation of trial medication).
At Visits 3 and 4 the PFT will be measured up to 24 hours after dosing of trial medication 
(please see specified time points in the Flow Chart). Also refer to the Flow Chart for the time 
windows for the PFTs.
Refer to Section 4.2.2.2 for restrictions regarding concomitant therapy prior to PFTs. Refer to 
Section 4.2.2.2 for restrictions on diet and life style prior to PFTs. Refer to the Flow Chart for 
the timing of PFTs.
5.2.2
Saint George’s Respiratory Questionnaire (SGRQ)
The Saint George’s Respiratory Questionnaire (SGRQ) [R96-0686] will be completed at 
Visit 2 and repeated after 12 weeks of treatment (Visit 4).
The SGRQ measures health status in patients with chronic airflow limitation. It comprises 
two parts which cover three domains (symptoms, activities and impacts) with scores ranging 
from 0 (no impairment to 100 (worst possible). Part 1 produces the Symptom score and Part 2 
the Activity and Impacts scores. A Total score is also produced.


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Part 1 (Questions 1 to 8), covers the patients’ recollection of their symptoms over the past 
four weeks. It is not designed to be an accurate epidemiological tool; its purpose is to assess 
the patient’s perception of their recent respiratory problems. The original version was 
validated using a 12-month recall period.  More recently a 4-week recall version 
(appropriately worded) has been validated. This has slightly weaker psychometric properties 
than the 12-month version and produces marginally lower Symptoms score and Total score.
Part 2 (Sections 1 – 7) addresses the patients’ current state (i.e. how they are these days).  The 
Activity score just measures disturbances to patients’ daily activity. The Impacts score covers 
a wide range of disturbances of psycho-social function. Validation studies showed that this 
component relates in part to respiratory symptoms, but is also correlates quite strongly with 
exercise performance (6-minute walking test), breathlessness in daily life (MRC 
breathlessness score) and disturbances of mood (anxiety and depression). The Impacts score 
is, therefore, the broadest component of the questionnaires, covering the whole range of
disturbances that respiratory patients experience in their lives. The results will be reported in 
the eCRFs
Details of the SGRQ are provided in Appendix 10.4.
The baseline for SGRQ will be the measurement made prior to the first dosing at Visit 2.
5.2.3
COPD health status
The COPD Assessment Test ™ (CAT) is a short 8-item questionnaire for assessment and
monitoring of COPD health status in routine practice. Its scale is 0-40 (high score = poor
health). The CAT questionnaire has the advantage of a reduced-number of items and could be 
used to assess the effects of inhaled therapies [P11-08788]. A sample CAT is provided in
Appendix 10.3).
The CAT will be performed at Visits 2 and 4.
The test will be performed according to the “HEALTHCARE PROFESSIONAL USER
GUIDE; CATTM; COPD Assessment Test; Expert Guidance on frequently asked questions;
Issue 3 February 2012” [R13-0957] provided in the ISF.
Site staff will check the answered CAT questionnaire for completeness. Site staff must not
exercise any influence on the patient’s answers.
The patient’s answers will be transcribed from the CAT questionnaire into the eCRF. The
CAT score is the sum of the values corresponding to the answers in the eight questions.
5.3
ASSESSMENT OF SAFETY
There is no endpoint for safety in a statistical sense in this trial. Instead, safety and
tolerability will be assessed in a descriptive way based on:

Adverse events

Serious adverse events

Physical examination


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5.3.1
Physical examination
A complete, head-to-toe physical examination will be completed on all patients at Visits 1
and 4 (or EOT visit in case of premature withdrawal). Another Physical Examination should 
be performed at the follow-up visit (Visit 5) only if relevant findings are found at Visit 4.  All 
abnormal findings at Visit 1 will be recorded in the patients’ source documents and on the
Baseline Conditions eCRF, if applicable. New abnormal findings or worsening of Baseline 
Conditions during the trial will be recorded as adverse events on the appropriate eCRF page.
The physical examination will also include measurements of systolic and diastolic blood
pressure and pulse rate, which will be measured with the patient seated and after having
rested for at least five minutes.
5.3.2
Laboratory parameters
Lab assessments will be performed by the central laboratory service provider.

An absolute Eosinophil count will be performed at the screening visit (Visit 1) and 
randomization visit (Visit 2) to confirm stability of eosinophil counts.  

Pregnancy testing - A serum human chorionic gonadotrophin (HCG) test will be 
performed on all females of child-bearing potential at Visit 1. A urine dip stick 
pregnancy test will be performed at Visits 2, 4 and 5.
5.3.3
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed on all patients at the
screening visit (Visit 1). The purpose of the screening ECG is to obtain information about the 
patient’s baseline condition that may not have been elicited in obtaining the medical history. 
Therefore, any significant findings from this examination not associated with a baseline 
condition are recorded on the Baseline Conditions eCRF page. The ECG will be evaluated 
by the PI and stored in the patient record.
5.3.4
Other safety parameters
Not applicable for this trial.
5.3.5
Assessment of adverse events
5.3.5.1
Definition of adverse events
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.


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Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the 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 EDC system.
These events should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)


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The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
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
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.


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•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
5.3.5.2
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
•
From signing the informed consent onwards through the Residual Effect Period (REP)
until 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 of which the Investigator may become aware of.
Figure 5.3.5.2: 1
All adverse 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.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 


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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 conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Studies (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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Studies (Part A and 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 Studies 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.
Exemptions to SAE reporting
Not applicable for this trial.
5.3.5.3
COPD Exacerbations  
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 hospitalization:
A complex of lower respiratory events is defined as at least two of the following:

Shortness of breath

Sputum production (volume)

Change in sputum color

Cough

Wheezing

Chest tightness


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“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 hospitalization.
Severe: 
COPD-related hospitalization
5.4
DRUG CONCENTRATION MESUREMENTS AND 
PHARMACOKINETICS
Not applicable for this trial.
5.5
ASSESSMENT OF BIOMARKERS
Not applicable for this trial.
5.6
OTHER ASSESSMENTS
Not applicable for this trial.
5.7
APPROPRIATENESS OF MEASUREMENTS
Measurements of efficacy parameters will be consistent with the following generally
recognized standards:
Spirometry
Pulmonary function tests are a validated and well established measurement tool for lung
function testing. Pulmonary function tests will be conducted at clinic visits using standardised 
spirometry equipment. FEV1 is a standard measurement for the assessment of lung function.
Questionnaires

The SGRQ is a well-established and validated questionnaire for the measurement of 
health status in patients with chronic airflow limitation.

The COPD Assessment Test™ (CAT) is a short 8-item questionnaire for assessment 
and monitoring of COPD health status in routine practice.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients should make every attempt to complete the protocol as specified.  Each visit date 
(with its window) is to be counted from Day 1 (Day 1 = Visit 2 / Randomization). If any visit 
has to be rescheduled, subsequent visits should follow the original visit date schedule.  
Additional visits for the purpose of re-testing or AE monitoring may be included as deemed 
necessary by the investigator. Investigators should encourage patient treatment compliance 
and adherence to other protocol specific activities.  Refer to the Flow Chart for time windows 
for the visits. All deviations from the planned visit schedule will be documented. After this, a 
discussion with the Clinical Monitor should take place.
Following the screening visit (Visit 1) and the required minimum of 4 week screening period, 
eligible patients will be randomised into the 12-week treatment portion of the trial (Visit 2). 
Visit 3 will take place after approximately 6 weeks of treatment and Visit 4 will take place 
after approximately 12 weeks of treatment. Approximately three weeks, i.e. 21 days after 
completion of the end of treatment period (Visit 4), there will be one post-treatment follow-
up visit (Visit 5).
Patients should make every attempt to complete the protocol as specified. Investigators 
should encourage patient treatment compliance and adherence to all protocol specific 
activities.
Rescheduling in general
A patient visit may be rescheduled twice within the permitted time window of the scheduled 
visit date (See Flow Chart) due to the lack of medication washout compliance or no intake of 
study medication the day preceding Visit 3 and 4.
Rescheduling prior to randomisation
The 4-week screening period (between Visit 1 and Visit 2) may be extended by up to 4 weeks 
(i.e. total up to 8 weeks or 56 days) for administrative reasons and/or to meet wash-out 
requirements.
If a patient experiences an upper respiratory tract infection (URTI) between Visit 1
and Visit 2, Visit 2 may be postponed until 4 weeks following recovery from the
infection.
Note: Patients who experience a lower respiratory tract infection (LRTI) or symptoms of
a COPD exacerbation during screening period (Visits 1-2) are not eligible for randomisation 
and must be withdrawn (screen failure).
If the screening is extended by more than an additional 4 weeks (but not
more than an additional 8 weeks), the safety screening examinations have to be repeated prior
to randomisation. The repeat screening examination will include a physical examination,
measurement of vital signs (blood pressure and pulse rate), 12-lead ECG and clinical
laboratory evaluation (total eosinophil count and pregnancy test). The patient should return 
for these evaluations within 1 week prior to the re-scheduled randomization visit (Visit 2). 
All adverse events and concomitant therapies will be recorded.  If the screening period cannot 


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be completed within an extension period of 8 weeks, the patient should be considered a 
screen failure.
Rescheduling after randomisation
Subsequent visits after randomisation should take place at the originally scheduled dates to 
assure required treatment. 
If rescheduling of visits after randomisation is necessary, the adherence to the correct total 
daily doses of the Respimat® Inhaler and/or Diskus® Inhaler must be observed. Reserve 
medication is dispensed at each treatment visit to avoid intermediate visits.
In case a visit needs to be re-scheduled outside the allowed time window (e.g. in order to 
meet PFT wash-out requirements following treatment of an acute exacerbation), the CML 
should be contacted.
6.2
DETAIL OF TRIAL PROCEDURES AT SELECTED VISITS
A complete overview of assessments to be performed at each visit is provided in the trial
Flow Chart. Refer to Section 5 for explanations of procedures.  Additional details on 
procedures at selected visits are provided below.
6.2.1
Screening and run-in period(s)
To keep the number of screen failures and patients with avoidable washout procedures as low
as possible, patients should be very carefully selected for this trial. Therefore, investigators
should make a preliminary check of major inclusion and exclusion criteria when considering
patients for enrolment in the trial.
Patient numbers will be assigned in the IRT system and transferred from there to/into EDC, 
thereby creating the subject in EDC.
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.
Eligibility will be assessed at Visits 0 and 1 and confirmed at the randomization visit (Visit 
2).
Run-in Period
•
Informed Consent will be obtained at Visit 0, prior to patient participation in the trial, 
which includes any medication washout procedures or restrictions. Upon obtaining 
Informed Consent, the patient will be instructed on the medication washout and other 
restrictions needed for the screening pulmonary function test at Visit 1.
•
The patient will receive instructions on the as needed use of the albuterol MDI (as rescue 
medication) that will be dispensed at this visit.
•
In case the patient has to wash-out of a LAMA in the run-in, at the discretion of the 
investigator, Atrovent HFA will be dispensed at this visit.
•
A preliminary check of inclusion/exclusion criteria is recommended at Visit 0 to avoid 
unnecessary washout procedures in non-eligible patients.


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•
Any adverse events and concomitant therapies will be recorded
•
The patient will receive a trial identification card.
Observations and procedures at Visit 1
Refer to the Flow Chart for procedures to be conducted at this visit:
•
Demographics/Baseline conditions, Physical, COPD characteristics, lab testing, 
pregnancy testing, ECG, review of smoking status and concomitant medications and AE 
check.
•
Pulmonary function testing with the MasterScope® CT spirometer will be conducted 
between 7:00 and 10:00 a.m. immediately prior to (-10 min) and ≥10 minutes and up to 
45 minutes after the inhalation of 4 puffs of salbutamol (albuterol), (reversibility testing).
•
Patients qualified to enter the 4-week (up to 12-week) screening period of the trial will be 
issued additional rescue medication if needed.
•
Patients will receive training and instructions on:
-
the use of the Respimat® Inhaler using the training Respimat® Inhaler containing 
placebo
-
the use of the Diskus® Inhaler using the training Diskus® Inhaler containing placebo
-
medication restrictions and washout requirements for the screening period and 
subsequent visits
-
returning all issued medication to the site on all subsequent visits
•
Site staff will perform “Screening” call in IRT. 
Screening Period
If there is any indication during the screening period that the patient is not stable enough to 
complete the trial or that the patient will be non-compliant with the trial medication or 
restrictions, the patient should not be randomised. 
A telephone contact is required approximately 1-2 days before Visit 2 to remind the patient of 
medication restriction requirements.
6.2.2
Treatment period(s)
The treatment period is from Visit 2 (Randomization) though the EOT (End of Treatment).
Applicable eligibility criteria will be re-confirmed prior to randomization. Patients that
experienced a COPD exacerbation during the screening period (as per exclusion #2) will not
be eligible for randomization.
At the beginning of each visit, the investigator and site personnel should ensure that the 
wellbeing of the patient as well as all requirements for conduct of the visit are applicable:
•
Any adverse events and changes in concomitant therapies will be recorded.
•
Medication washout compliance and lifestyle restrictions will be verified.
•
The 24-hour clock time of the last cigarette smoked during 12 hours prior to start of lung 
function measurement procedures will be recorded (and smoking status as well).
•
Before dosing with trial medication site personnel should ensure that the patient knows 
how to inhale properly from the Respimat® Inhaler and the Diskus® Inhaler. The patient 
should not inhale from a placebo training device on visit days.
•
At the close of each visit during treatment visit, the investigator and site personnel should 
ensure that the patient is provided with all instructions for the next visit.


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•
Patient will be instructed at each visit to bring all rescue medication to the site.
Note:
If the patient is unable to complete any of the entire test-day visits, the electronic case report 
form 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 site only upon instruction from the supervising physician.
Observations and procedures:
•
At Visit 2, inclusion and exclusion criteria will be reviewed again prior to randomisation. 
At Visit 2 only: Site staff will perform “Randomization” call in IRT.
•
At Visit 2 and 3 the patient will receive instructions on use of Respimat® and Diskus®
devices and will be instructed to bring all trial medication to the site in the next visit.
•
Approximately 1-2 days prior to visits 2, 3 and 4, a telephone contact will be made to 
each patient in order to remind him/ her of the medication restrictions and to adhere to the 
correct time of intake of the trial medication administration the day before the site visit. 
Please refer to Section 4.1.4 (“trial medication administration at home”). It should be 
pointed out that trial medication administration on the site visit day will only be 
performed on site.
•
Dosing of trial medication is to be performed on timing pre-determined at Visit 2 (i.e. day 
1) (± 30 minutes).
•
At Visit 4 only, site staff will make the “Trial Medication Termination” call to the IRT. 
At Visit 4, rescue medication must be returned and all patients can go back to normal 
medications after this visit.
6.2.3
Follow up period and trial completion
For all randomised patients termination of trial medication and trial completion must be 
recorded on the corresponding eCRFs.
Patients who discontinue treatment prior to the planned Flow Chart visit schedule will 
complete EOT visit procedures instead of the planned treatment period visit. They will also 
have a follow-up visit approximately 21 days after last treatment.
Following the end of the 12 weeks of treatment, patients will be followed up for an additional 
21 days. They will be seen at the end of this visit (Visit 5) and adverse events and
concomitant therapies will be reviewed and recorded. If the physical examination performed 
at Visit 4 yields abnormal values representing clinically significant changes from baseline, it
will be repeated at the follow-up visit (Visit 5). Any persistently abnormal test must be fully 
explained by the investigator and follow-up evaluation performed if necessary. Additionally, 
all (S)AEs that occur within 21 days after a patient terminates trial medication must be 
reported according to Boehringer Ingelheim SAE procedures.
The sponsor must be consulted on all persistently abnormal tests and (S)AEs until it is agreed 
that follow-up is no longer necessary.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1 
STATISTICAL DESIGN - MODEL
Design
This is a  Phase IV, randomized, double-blind, double-dummy, multi center, active-controlled 
parallel group study of 12 weeks once daily treatment with orally inhaled 
tiotropium+olodaterol fixed dose combination delivered by the Respimat® inhaler and 12 
weeks twice daily treatment with fluticasone propionate+salmeterol fixed dose combination 
delivered by the Diskus® in patients with Chronic Obstructive Pulmonary Disease (COPD)
Objective
To show superiority in lung function of once daily treatment with orally inhaled tiotropium 
(LAMA) +olodaterol (LABA) (5µg/5µg) fixed dose combination to twice daily treatment 
with fluticasone propionate(LABA) +salmeterol (ICS) (250µg/50µg) fixed dose combination 
over 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD).
7.2
NULL AND ALTERNATIVE HYPOTHESES
The following primary hypothesis will be tested at 5% level of significance (two-sided):
H0: Mean FEV1 AUC 0-24h response (change from baseline) [L] after 12 weeks of treatment 
for tiotropium (LAMA) +olodaterol (LABA) (5µg/5µg) = Mean FEV1 AUC 0-24h response 
(change from baseline) [L] after 12 weeks of treatment for fluticasone propionate(LABA) 
+salmeterol (ICS) (250µg/50µg) 
H1: Mean FEV1 AUC0-24h response (change from baseline) [L] after 12 weeks of treatment for 
tiotropium (LAMA) +olodaterol (LABA) (5µg/5µg)≠Mean FEV1 AUC0-24h response 
(change from baseline) [L] after 12 weeks of treatment for fluticasone propionate(LABA) 
+salmeterol (ICS) (250µg/50µg)
The secondary analyses will be performed using the same methodology as the primary 
analysis.
7.3
PLANNED ANALYSES
The efficacy analysis will be performed in all randomized patients who were documented to 
have received any dose of trial medication and who have both baseline and any evaluable 
post-baseline measurement for at least one of the efficacy endpoints. This set will be called 
Full Analysis Set (FAS).
After blinded review of the magnitude and potential impact of any important protocol 
violations, a subset of the data corresponding to those patients without any important 
deviations from the protocol will be created. This will be called the Per-Protocol Set (PPS). 
If the number of patients in PPS is less than 90% of the number of patients in FAS, the 


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primary analyses for the primary efficacy endpoint will also be performed on PPS. These 
will be supportive 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 TSAP”
7.3.1
Primary endpoint analyses
In the primary analysis, the two-sided hypothesis as given in Section7.2 will be tested on the 
adjusted means of FEV1 AUC 0-24h change from baseline. As PFT measurements will be 
collected over time, a restricted maximum likelihood (REML)-based mixed-effects model 
repeated measures (MMRM) model will be used. This model will include treatment, visit and 
treatment by visit interaction as fixed effects, and baseline as well as baseline by visit 
interaction as covariates. The mean of the two pre-dose pulmonary function test 
measurements at Visit 2, 1 hour prior and 10 minutes prior to the administration of the first 
dose of the randomised treatment, is defined as the baseline FEV1.
An unstructured covariance structure will be used to model the within patient errors. The 
SAS procedure MIXED will be used for the restricted maximum likelihood estimation and 
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 95% confidence intervals. The primary treatment comparisons
will be the contrasts between treatments after 12 weeks of treatment.
7.3.2
Secondary endpoint analyses
Secondary and other endpoints:
The MMRM model described for the primary analysis will be performed for the continuous 
secondary endpoints. Adjusted mean values as well as treatment contrasts will be presented 
together with the 95% confidence intervals. All calculated p-values should be considered 
descriptive for the analysis of the secondary endpoints. Sensitivity analyses will be defined 
in the TSAP, which will be signed off prior to data base lock. The TSAP will include 
details of sensitivity analyses designed to assess the impact of various assumptions 
concerning missing data.
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 


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(REP), a period of 21 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation.
All randomized patients who have taken at least one dose of study drug (i.e., the treated set)
will be included in the safety analysis. In general, safety analyses will be descriptive in nature
and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect 
period is defined as 21 days. Adverse events that start before first drug intake and deteriorate 
under treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
7.3.5
Pharmacokinetic and pharmacodynamic analyses
No pharmacokinetic analysis is planned.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
The REML-based MMRM model described in Section 7.3.1 will handle missing data due to 
early drop outs or missing data in between visits which are assumed to be missing at random. 
Additional details on the imputation of missing data will be specified in the TSAP prior to 
unblinding.
If the patient requires rescue medication during the pulmonary function test (PFT) days 
(Visits 2, 3 and 4), the PFTs will be continued if possible. The data obtained within the 
required wash out period of the rescue medication (= 8 hours for albuterol) will be censored.
Missing answers for CAT and SGRQ will be handled based on related manuals [R12-1915
and R12-2870].
7.6
RANDOMISATION
Patients will be randomised in blocks to double-blind treatment. Approximately equal 
numbers of patients will be randomised to each treatment group. 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.


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7.7
DETERMINATION OF SAMPLE SIZE
Calculations were performed using nQuery Advisor® 6.1 statistical package by Statistical 
Solutions Ltd.
Assuming a standard deviation of 0.22L a total sample size of 274 completed patients, will 
be able to detect a treatment difference of .075 L, for FEV1 AUC0-24h with 80% power, using 
a two-sided test at α=0.05 for superiority testing. The assumptions for sample size 
calculation are based on the results of 1237.5, 1237.6, and 1237.11 studies. Assuming a 
maximum 5% drop-out rate, in order to ensure that 274 completers, 288 patients will be 
randomized.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
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 Boehringer Ingelheim transparency and publication policy can be found on the following 
web page:  trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. Prior to patient 
participation in the trial, written informed consent must be obtained from each patient (or the 
patient’s legally accepted representative) according to ICH / GCP and to the regulatory and 
legal requirements of the participating country. Each signature must be personally dated by 
each signatory and the informed consent and any additional patient-information form retained 
by the Investigator as part of the trial records. A signed copy of the informed consent and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
The patient must be given sufficient time to consider participation in the trial. The 
Investigator or designee obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
Investigator or designee must sign (or place a seal on) and date the informed consent form. 
Re-consenting may become necessary when new relevant information becomes available and
should be conducted according to the sponsor’s instructions.  The consent and re-consenting 
process should be properly documented in the source
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 


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have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRF) for individual patients will be provided by the sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).  
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
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

Baseline conditions (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of 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 


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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.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.


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8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P01-02794
Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS. Global 
strategy for the diagnosis, management, and prevention of chronic 
obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit 
Care Med 2001;163(5):1256-1276.
P04-07409
Celli BR, MacNee W. Standards for the diagnosis and treatment of patients 
with COPD: a summary of the ATS/ERS position paper. Eur Respir J 
2004;23(6):932-946.
P05-08465
Hodder R, Pavia D, Dewberry H, Alexander K, Iacono P, Ponitz H, Beck E. 
Low incidence of paradoxical bronchoconstriction in asthma and COPD 
patients during chronic use of Respimat Soft Mist inhaler. Respir Med 
2005;99:1087-1095.
P05-12782 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Standardisation of spirometry. Eur Respir J 2005;26(2):319-338.
P11-05865
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
strategy for the diagnosis, management, and prevention of chronic 
obstructive pulmonary disease: updated 2010. http://www.goldcopd.com/ 
(access date: 12 May 2011); 2010.
P11-08788
Antoniu SA. Effects of inhaled therapies on health-related quality of life in
stable chronic obstructive pulmonary disease. Expert Rev 
Pharmacoeconomics Outcomes Res 2010;10(2):155-162.
P13-05794
Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the 
management   of chronic obstructive pulmonary disease. Respir Res (Lond) 
2013;14:49
P15-03349
Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G, 
Tiotropium and olodaterol fixed-dose combination versus mono-
components in COPD (GOLD 2-4). Eur Respir J 2015;45:969-979.
P15-04531
Beeh KM, Westerman J, Kirsten AM, Hebert J, Groenke L, Hamilton A, 
Tetzlaff K, Derom E. The 24-h lung-function profile of once-daily 
tiotropium and   olodaterol fixed-dose combination in chronic obstructive 
pulmonary disease.  Pulmonary Pharmacology & Therapeutics, Accepted 
Manuscript, Available online 5 May 2015, doi: 10.1016/j.pupt.2015.04.002; 
2015. p. 53-59.


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P16-01440
Zhai, D and et al. The lung function profile of once-daily tiotropium and 
olodaterol via 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)
P16-09960
Rodriguez-Roisin R, Tetzlaff K, Watz H, Wouters EFM, Disse B, Finnigan 
H, et al Daily home-based spirometry during withdrawal of inhaled 
corticosteroid in severe to very severe chronic obstructive pulmonary 
disease. Int J Chronic Obstruct Pulm Dis 11, 1973 - 1981 (2016)
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.
P94-1346
Bone R. In chronic obstructive pulmonary disease, a combination of 
ipratropium and albuterol is more effective than either agent alone: an 85-
day multicenter trial. Chest 105 (5), 1411 - 1419 (1994).
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). 1999:1-29.
R04-4303
Foradil Aerolizer (Schering) (formoterol fumarate inhalation powder), Rx 
only (rev. June 2003). http://pdrel.thomsonhc.com ; In: PDR Electronic 
Library. Thomson; 2004.
R04-4304
Rote Liste Win 2003/II, Version 3.2, Editio Cantor, Freigabedatum: 
01.07.2003; 2003.
R04-4305
Rote Liste Win 2003/II, Version 3.2, Editio Cantor, Freigabedatum: 
01.07.2003 ; 2003.
R10-4391
Kenward MG, Roger JH. The use of baseline covariates in crossover 
studies.  Biostatistics 2010;11(1):1-17.
R10-5669
ICH Expert Working Group. ICH harmonised tripartite guideline: guidance 
on nonclinical safety studies for the conduct of human clinical trials and
marketing authorization for pharmaceuticals, M3 (R2) (current step 4
version, dated 11 June 2009). 
http://www.ich.org/LOB/media/MEDIA5544.pdf (access date:11.10.2010); 
2009.
R12-1915
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. 
Development and first validation of the COPD Assessment Test. Eur Respir 
J 2009;34(3):648-654.


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R12-2870
Jones PW. St George's Respiratory Questionnaire manual (version 2.3, June 
2009).
http://www.healthstatus.sgul.ac.uk/SGRQ_download/SGRQ%20Manual%2
0June%202009.pdf (access date: 27 June 2012); 2009.
R13-0957
CAT: COPD assessment test (healthcare professional user guide), expert 
guidance on frequently asked questions (issue 3: February 2012).
http://www.catestonline.org/images/UserGuides/CATHCPUser%20guideE
n.pdf (access date: 28 February 2013); GlaxoSmithKline; 2012.
R94-1408
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. 
Lung volumes and forced ventilatory flows. Report Working Party 
Standardization of Lung Function Tests, European Community for Steel 
and Coal. Official Statement of the European Respiratory Society. Eur 
Respir J 1993;6(Suppl 16): 5-40.
R96-0686 
Jones PW, Quirk FH. A self-complete measure of health status for chronic
airflow limitation. Am Rev Respir Dis 1992: 145: 1321-1327.
9.2
UNPUBLISHED REFERENCES
c01735218-03
 Clinical Trial Report: 
Tiotropium+olodaterol fixed dose combination inhalation solution –
Respimat®. TOnado™ 1 1237.5. 10 April 2014.
c01735249-03
Clinical Trial Report: 
Tiotropium+olodaterol fixed dose combination inhalation solution –
Respimat®. TOnado™ 2 1237.6. 10 April 2014.
c01730070-04
Investigator's Brochure. Boehringer Ingelheim, (1237.P1).
Tiotropium+olodaterol fixed dose combination. Version 9, 13Dec2016


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10.
APPENDICES
10.1
HANDLING INSTRUCTIONS FOR 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.
  
How to store my RESPIMAT®

Keep your RESPIMAT® out of the sight and reach of children.

Do not freeze your RESPIMAT®.

If RESPIMAT® has not been used for more than 7 days release one puff towards the 
ground.

If RESPIMAT® has not been used for more than 21 days repeat steps 4 to 6 under 
‘Prepare for first Use’ until a cloud is visible. Then repeat steps 4 to 6 three more 
times.

Do not use your RESPIMAT® after the expiry date


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When to get a new RESPIMAT®
•
Your RESPIMAT® inhaler contains 60 puffs if used as indicated.
•
The dose indicator shows approximately how much medication is left.
•
When the dose indicator enters the red area of the scale you need to get a new
prescription; there are approximately 14 puffs left.
•
Once the dose indicator reaches the end of the red scale, your RESPIMAT® locks
automatically – no more doses can be released. At this point, the clear base cannot be
turned any further.
•
Three months after first use, the RESPIMAT® should be discarded even if it has not
been used.
Prepare for first use
1. Remove clear base

Keep the cap closed.

Press the safety catch while 
firmly pulling off the clear base 
with your other hand.
2. Insert cartridge

Insert the narrow end of the 
cartridge into the inhaler.

Place the inhaler on a firm 
surface and push down firmly 
until it snaps into place.


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


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


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Answers to Common Questions
It is difficult to insert the cartridge deep enough.
Did you accidentally turn the clear base before inserting the cartridge? Open the cap,
press the dose-release button then insert the cartridge.
Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow 
end first.
I cannot press the dose-release button.
Did you turn the clear base? If not, turn the clear base in a continuous movement until it 
clicks (half a turn).
Is the dose indicator on the RESPIMAT® pointing to zero? The RESPIMAT® inhaler is 
locked after 60 puffs. Prepare and use your new RESPIMAT® inhaler.
I cannot turn the clear base.
Did you turn the clear base already? If the clear base has already been turned, follow steps 
“OPEN” and “PRESS” under “Daily Use” to get your medicine. 
Is the dose indicator on the RESPIMAT® pointing to zero? The RESPIMAT® inhaler is 
locked after 60 puffs. Prepare and use your new RESPIMAT® inhaler.
The dose indicator on the RESPIMAT® reaches zero too soon. 
Did you use RESPIMAT® as indicated (two puffs/Once daily)? RESPIMAT® will last 30 
days if used at two puffs once daily.
Did you turn the clear base before you inserted the cartridge? The dose indicator counts 
each turn of the clear base regardless whether a cartridge has been inserted or not.
Did you spray in the air often to check whether the RESPIMAT® is working? Once you 
have prepared RESPIMAT®, no test-spraying is required if used daily.
Did you insert the cartridge into a used RESPIMAT®? Always insert a new cartridge into 
a NEW RESPIMAT®.
My RESPIMAT® sprays automatically.
Was the cap open when you turned the clear base? Close the cap, then turn the clear base.
Did you press the dose-release button when turning the clear base? Close the cap, so the 
dose-release button is covered, then turn the clear base.
Did you stop when turning the clear base before it clicked? Turn the clear base in a 
continuous movement until it clicks (half a turn).
My RESPIMAT® doesn’t spray.
Did you insert a cartridge? If not, insert a cartridge.
Did you repeat Turn, Open, Press less than three times after inserting the cartridge?
Repeat Turn, Open, Press three times after inserting the cartridge as shown in the steps 4 to 6 
under “Prepare for first Use”.


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Is the dose indicator on the RESPIMAT® pointing to 0? If the dose indicator points to 0, 
you have used up all your medication and the inhaler is locked.
Once your RESPIMAT® is assembled, do not remove the clear base or the cartridge. Always 
insert a new cartridge into a NEW RESPIMAT®.
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.
Boehringer Ingelheim Pharma GmbH & Co. KG
D - 55216 Ingelheim, Germany   
Return of malfunctioning RESPIMAT Inhalers
Respimat® inhalers, with the used cartridge in situ, that appeared to malfunction, will be 
returned to Boehringer Ingelheim as soon as possible. Procedures for this return, including 
name, address and contact person are provided in the ISF.


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10.2
THE DISKUS® INHALER
Instructions for use

Your doctor, nurse or pharmacist will show you how to use your inhaler. They will 
check how you use it from time to time. Not using the Diskus® properly or as 
prescribed may mean that it will not help your COPD as it should.

The Diskus® inhaler holds blisters containing medication.

There is a counter on top of the Diskus® which tells you how many doses are left. It 
counts down to 0. The numbers 5 to 0 will appear in red to warn you when there are 
only a few doses left. Once the counter shows 0, your inhaler is empty.
Using your inhaler
1
To open your Diskus®, hold the outer 
case in one hand and put the thumb of 
your other hand on the thumb grip. Push 
your thumb away from you as far as it 
will go. You will hear a click. This will 
open a small hole in the mouthpiece.
2
Hold your Diskus® with the mouthpiece 
towards you. You can hold it in either 
your right or left hand.  Slide the lever 
away from you as far as it will go. You 
will hear a click. This places a dose of 
your medicine in the mouthpiece. Every 
time the lever is pulled back a blister is 
opened inside and the powder made ready 
for you to inhale. Do not play with the 
lever as this opens the blisters and wastes 
medicine.


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3
Hold the Diskus® away from your 
mouth, breathe out as far as is 
comfortable. Do not breathe into your 
Accuhaler.
4
Put the mouthpiece to your lips; 
breathe in steadily and deeply through 
the Diskus®, not through your nose.
Remove the Diskus® from your 
mouth. Hold your breath for about 10 
seconds or for as long as is 
comfortable. Breathe out slowly.
5
Afterwards rinse your mouth with
water and spit it out. This may help to
stop you getting thrush and being 
hoarse.
6
To close the Diskus®, slide the thumb
grip back towards you, as far as it will 
go. You will hear a click. The lever 
will return to its original position and 
is reset. Your Diskus® is now ready 
for you to use again.


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10.3
COPD ASSESSMENT TEST (CAT)
TOTAL SCORE
SCORE


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10.4
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ) 
What is the St George’s Respiratory Questionnaire?
The SGRQ is designed to measure health impairment in patients with asthma and COPD. It is 
also valid for use in bronchiectasis and has been used successfully in patients with
kyphoscoliosis and sarcoidosis. It is not suitable for cystic fibrosis. It is in two parts. Part I
produces the Symptoms score, and Part 2 the Activity and Impacts scores. A Total score is
also produced.
Part 1 (Questions 1 to 8) covers the patients’ recollection of their symptoms over the past 4 
weeks. It is not designed to be an accurate epidemiological tool, its purpose is to assess the 
patient’s perception of their recent respiratory problems.  The original version was validated 
using a 12-month recall period. More recently a four week recall version (appropriately 
worded) has been validated. This has slightly weaker psychometric properties than the 12-
month version and produces a marginally lower Symptom score and Total score.
Part 2 (Questions 9 to 16) addresses the patients’ current state (i.e. how they are these days).  
The Activity score just measures disturbances to patients daily physical activity. The Impacts 
score covers a wide range of disturbances of psycho-social function. Validation studies 
showed that this component relates in part to respiratory symptoms, but it also correlates 
quite strongly with exercise performance (6-minute walking test), breathlessness in daily life 
(MRC breathlessness score) and disturbances of mood (anxiety and depression).  The Impacts 
score is, therefore, the broadest component of the questionnaires, covering the whole range of 
disturbances that respiratory patients experience in their lives.
How should it be administered?
The questionnaire should be completed in a quiet area free from distraction and the patient
should ideally be sitting at a desk or table. Explain to the patient why they are completing the 
questionnaire, and how important it is for us to understand how they feel about their illness 
and the effect it has on their daily life. Ask the patient to complete the questionnaire as 
honestly as possible and stress that there are no right or wrong answers, simply the answer 
that the patient feels applies to them. Explain that they must answer every question and that 
someone will be close at hand to answer any queries.
The SGRQ is designed as a supervised self-administered questionnaire. This means that the
patients should complete the questionnaire themselves but someone should be available to
give advice if it is required. The patient’s responses should not be influenced by the opinions 
of family, friends or members of staff. The questionnaire is designed to elicit the patient’s 
opinion of his/her health, not someone else’s opinion of it. If the spouse or partner has 
accompanied the patient they should be asked to wait in a separate area. Similarly, do not 
allow patients to take the SGRQ home to be completed since you cannot be sure that it will 
be completed without the help of family or friends.
It is very important, once the patient has finished, that you check the questionnaire to make
sure a response has been given to every question and return it the patient for completion of
missed items, before the patient leaves.


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What should I do about queries regarding completion of the questionnaire?
If a patient asks for help with a question, do not provide an answer for them. The point of the 
questionnaire is to get an understanding of how the patient views his or her illness. It is
appropriate to clarify a question but not to provide an answer. Questions may be read aloud if 
patients have difficulty with reading, but the responses must be theirs alone. It is their view of 
their condition we are interested in – no matter how strange the response!
The following are notes which may help you explain to patients what is required
1.
In Part 1 of the questionnaire, emphasise to patients that you are interested in how much
chest trouble they have had over the last 4 weeks.
2.
Asthma and COPD can vary day-to day. In Part 2, we want to know about the patient’s
current state (these days).
3.
A severe or very unpleasant attack of chest trouble (Part 1, Question 5) is any attack 
that could be described that way in the patient’s own judgement. Not ‘severe’ as 
defined by medical staff.
4.
For Question 7 emphasise that you are interested in the number of good days that they
have had.
5.
Question 10 regarding employment can cause patients some problems. We are 
interested in how a patient’s chest trouble affects their current working life or how it 
affected life when they were working. For example, if a patient took early retirement 
because of their chest condition, the response would be 10a – ‘My chest trouble made 
me stop work’, if a patient’s retirement was unrelated to their chest trouble, their 
response would be 10c ‘My chest trouble does not affect my work’.
6.
Questions 11 to 16 require a response to every question. It may be worth emphasising 
this to the patient.
7.
Many patients do not engage in physical activity. It is important to determine whether 
this is because they do not wish to (in which case the answer would be ‘False’) or 
cannot engage in these activities because of their chest trouble (in which case the 
answer would be ‘True’).
8.
Medication questions refer to medications and treatments given for a patient’s chest
disease and may interfere with their life if, for example, they are on oxygen support and
have to carry it around with them.
9.
It should be emphasised that responses to Question 15 are in terms of breathing
difficulties and not any other problems. If patients do not engage in activities described 
in certain items, they should tick ‘False’. Patients who do not engage in these activities
because they are limited by their breathlessness, should tick ‘True’.


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EXAMPLE OF QUESTIONNAIRE
This questionnaire is designed to help us learn much more about how your
breathing is troubling you and how it affects your life. We are using it to find out
which aspects of your illness cause you the most problems, rather than what the
doctors and nurses think your problems are.
Please read the instructions carefully and ask if you do not understand anything. 
Do not spend too long deciding about your answers.
Before completing the rest of the questionnaire:
Please check one box to show how you describe 
your current health:
Very good

Good

Fair

Poor

Very poor

Copyright reserved
P.W. Jones, PhD FRCP 
Professor of Respiratory Medicine, 
St. George’s University of London,
Jenner Wing,
Cranmer Terrace, 
Tel.  +44 (0) 20 8725 5371
London SW17 ORE, UK. 
Fax  +44 (0) 20 8725 5955


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St. George’s Respiratory Questionnaire
PART 1
Please describe how often your respiratory problems have affected you over the past 4 
weeks.
Please check () one box for each question:
almost 
every
day 
several 
days 
a week
a few
days 
a month
only with 
respiratory 
infections
not 
at 
all
1.
Over the past 4 weeks, I have coughed:





2.
Over the past 4 weeks, I have brought up 
phlegm (sputum):





3.
Over the past 4 weeks, I have had shortness 
of breath: 





4.
Over the past 4 weeks, I have had wheezing 
attacks: 





5.
How many times during the past 4 weeks have you suffered from 
severe or very unpleasant respiratory attacks?
Please check () one:
more than 3 times 
3 times 
2 times 
1 time 
none of the time 
6.
How long did the worst respiratory attack last?
(Go to Question 7 if you did not have a severe attack)
Please check () one:
a week or more 
3 or more days 
1 or 2 days 
less than a day 
7.
Over the past 4 weeks, in a typical week, how many good days
(with few respiratory problems) have you had?
Please check () one:
No good days 
1 or 2 good days 
3 or 4 good days 
nearly every day was good 
every day was good 


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8.
If you wheeze, is it worse when you get up in the morning?
Please check () one:
No 
Yes 


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St. George’s Respiratory Questionnaire
PART 2
SECTION 1
How would you describe your respiratory condition?
Please check () one:
The most important problem I have 
Causes me quite a lot of problems 
Causes me a few problems 
Causes no problems 
If you have ever held a job:
Please check () one:
My respiratory problems made me stop working altogether 
My respiratory problems interfere with my job or made me change my job 
My respiratory problems do not affect my job 
SECTION 2
These are questions about what activities usually make you feel short of breath these 
days.
For each statement please 
check () the box that 
applies
to you these days:
True
False
Sitting or lying still


Washing or dressing yourself


Walking around the house


Walking outside on level ground


Walking up a flight of stairs


Walking up hills


Playing sports or other physical activities




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SECTION 3
These are more questions about your cough and shortness of breath these days.
For each statement please check () the 
box that applies to you these days:
True
False
Coughing hurts


Coughing makes me tired


I am short of breath when I talk


I am short of breath when I bend over


My coughing or breathing disturbs my sleep


I get exhausted easily


SECTION 4
These are questions about other effects that your respiratory problems may have on you 
these days.
For each statement, please check () the 
box that applies to you these days:
True
False
My cough or breathing is embarrassing in public 

My respiratory problems are a nuisance to my family, friends or neighbours 

I get afraid or panic when I cannot catch my breath 

I feel that I am not in control of my respiratory problems 

I do not expect my respiratory problems to get any better 

I have become frail or an invalid because of my respiratory problems 

Exercise is not safe for me 

Everything seems too much of an effort 

SECTION 5
These are questions about your respiratory treatment.  If you are not receiving 
treatment go to section 6.
For each statement, please check () the 
box that applies to you these days:
True
False
My treatment does not help me very much


I get embarrassed using my medication in public


I have unpleasant side effects from my medication


My treatment interferes with my life a lot




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SECTION 6
These are questions about how your activities might be affected by your respiratory 
problems.
For each statement, please check () the 
box that applies to you because of your 
respiratory problems:
True False
I take a long time to get washed or dressed


I cannot take a bath or shower, or I take a long time to do it


I walk slower than other people my age, or I stop to rest


Jobs such as household chores take a long time, or I have to stop to rest


If I walk up one flight of stairs, I have to go slowly or stop


If I hurry or walk fast, I have to stop or slow down


My breathing makes it difficult to do things such as walk up hills,
carry things up stairs, light gardening such as weeding,
dance, bowl or play golf


My breathing makes it difficult to do things such as carry heavy loads,
dig in the garden or shovel snow, jog or walk briskly (5 miles per hour),
play tennis or swim


My breathing makes it difficult to do things such as very heavy
manual work, ride a bike, run, swim fast, or play competitive sports


SECTION 7
We would like to know how your respiratory problems usually affect your daily life.
For each statement, please check () the 
box that applies to you because of your 
respiratory problems:
True
False
I cannot play sports or do other physical activities


I cannot go out for entertainment or recreation


I cannot go out of the house to do the shopping


I cannot do household chores


I cannot move far from my bed or chair




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Here is a list of other activities that your respiratory problems may prevent you from doing.
(You do not have to check these, they are just to remind you of ways your shortness of breath 
may affect you):
Going for walks or walking the dog
Doing activities or chores at home or in the garden
Sexual intercourse
Going to a place of worship, or a place of entertainment
Going out in bad weather or into smoky rooms
Visiting family or friends or playing with children
Please write in any other important activities that your respiratory problems may stop 
you from doing:
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Now please check the box (one only) that you think best describes how your respiratory 
problems affect you:
They do not stop me from doing anything I would like to do

They stop me from doing one or two things I would like to do

They stop me from doing most of the things I would like to do

They stop me from doing everything I would like to do

Thank you for completing this questionnaire. Before you finish would you please make sure 
that you have answered all the questions.


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10.5
ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA
Reversibility testing (P05-12782)
At the screening visit (Visit 1), following the completion of three acceptable pre-
bronchodilator forced expiratory manoeuvres, albuterol will be administered to each patient 
in order to document the degree of reversibility. Immediately after (within 10 min) pre-
bronchodilator forced expiratory manoeuvres and after a gentle and incomplete expiration, a
dose of 100 μg of salbutamol (albuterol) is inhaled in one breath to total lung capacity
(TLC). The breath is then held for 5–10 s before the subject exhales. Four separate doses 
(total dose 400 μg) are delivered at approximately 30-s intervals (this dose ensures that the 
response is high on the salbutamol dose–response curve). Three additional, acceptable post-
bronchodilator forced expiratory manoeuvre tests are recorded ≥10 minutes and up to 45 
minutes later after the last dose of albuterol is inhaled.
Calculation of predicted normal values according to ECSC (R94-1408)
For height measured in inches
Males:
FEV1 predicted (L) = 4.30 x [height (inches)/39.37] - 0.029 x [age (yrs)] - 2.49
Females:
FEV1 predicted (L) = 3.95 x [height (inches)/39.37] - 0.025 x [age (yrs)] - 2.60
For height measured in meters
Males:
FEV1 predicted (L) = 4.30 x [height (m)] - 0.029 x [age (yrs)] - 2.49
Females:
FEV1 predicted (L) = 3.95 x [height (m)] - 0.025 x [age (yrs)] - 2.60
Calculation of numberof pack years
Pack years =
Number of cigarettes/day
x years of smoking
20


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Number of global amendment
1.0
Date of CTP revision
11 August 2017
EudraCT number
N/A
BI Trial number
1237-0063
BI Investigational Product(s)
Stiolto® Tiotropium+olodaterol
Title of protocol
A randomized, double-blind, double-dummy, 
active-controlled, multi-center, parallel group study 
to show the superiority in lung function of 12 
weeks once daily treatment with orally inhaled 
tiotropium+olodaterol fixed dose combination 
delivered by the Respimat® inhaler vs. 12 weeks 
twice daily treatment with orally inhaled 
fluticasone propionate+salmeterol fixed dose 
combination delivered by the Diskus® in patients 
with Chronic Obstructive Pulmonary Disease 
(COPD) [ENERGITO® 2]
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Section 3.3
Description of change
Exclusion criterion updated to soften contraception
requirements.
Rationale for change
To be consistent with current guidance on trials 
with approved drugs, and to reduce discrepancies 
in messaging for contraception / fertility / etc. 
between the IC / protocol and the publically 


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available drug label.
Section to be changed
Section 3.3.4.1
Description of change
Removal of the sentence:  Details of all COPD 
exacerbations will be captured in the source notes 
and on AE/SAE pages.
Rationale for change
As it is not an exacerbation trial, details of 
exacerbation events will not be collected in this 
trial.
Section to be changed
Section 5.1.3 and Section 7.3
Description of change
FVC added to further endpoints
FAS updated 
Rationale for change
To analyse collected endpoints and to keep 
consistency with 1237.11.
To be able to have in the full analysis dataset and 
therefore to analyze the patients for efficacy if they 
have missing PFTs but they have other efficacy 
endpoints collected like SGRQ or CAT.
Section to be changed
Description of change
Revised sentences to add “or designee” and 
removed the following sentence: If a trial 
collaborator has given a supplementary 
explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Rationale for change
In the US, per FDA regulations, the PI can delegate 
responsibilities, including consenting of subjects to 
 study team.
Section to be changed
Appendix 10.1
Description of change
Replace Respimat® instructions for use
Rationale for change
Respimat® instructions have been updated


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11.2
GLOBAL AMENDMENT 2
Date of amendment
06 March 2018
EudraCT number
EU number
NA
BI Trial number
1237-0063
BI Investigational Product(s)
Stiolto® Tiotropium+olodaterol
Title of protocol
A randomized, double-blind, double-dummy, 
active-controlled, multi-center, parallel group study 
to show the superiority in lung function of 12 
weeks once daily treatment with orally inhaled 
tiotropium+olodaterol fixed dose combination 
delivered by the Respimat® inhaler vs. 12 weeks 
twice daily treatment with orally inhaled 
fluticasone propionate+salmeterol fixed dose 
combination delivered by the Diskus® in patients 
with Chronic Obstructive Pulmonary Disease 
(COPD) [ENERGITO® 2]
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed


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randomized at one site.
Section to be changed
Flow Chart and Guidance notes – pages 5-6
Description of change
1. Register patient in screening (IRT) changed from 
visit 1 to visit 0; 2. #16: remove “once daily”3. 
Footnote 6 – added “if needed”
Rationale for change
1. Patient numbers must be received when the 
patient consents, which is at visit 0; 2. Error in 
guidance notes; 3. clarification
Section to be changed
Section 4.1.4.1
Description of change
“if  needed” added to the following sentence:  ).  At 
Visits 2 - 4 detailed instructions on the use of the 
devices will be repeated if needed, but patients 
should not inhale from a training device that day.  
Rationale for change
Clarification
Section to be changed
Table 4.2.2.1:1    
Description of change
1.Footnote 2 - corrected q.i.d to qd; 
2. LAMA/LABA combination during screening, 
NOT permitted (w/o 4 wks. prior to V2) changed to 
3 weeks prior to V2
Rationale for change
errors
Section to be changed
Section 7.3
Description of change
Added: This set will be called Full Analysis Set 
(FAS).
Rationale for change
Inadvertently left out of protocol
Section to be changed
RDC updated to EDC in several places
Description of change
RDC (Remote Data Capture) is the brand name of 
Oracle’s EDC (electronic Data Capture System)
Rationale for change
Correctness
Section to be changed
Section 4.3
Description of change
Medication compliance updated from 80-100% to 
80-120%
Rationale for change
Correction
Section to be changed
Section 4.1.4
Description of change
The Diskus Inhaler should not be used beyond one 
month after removal from the moisture-protective 
foil overwrap, or after all blisters have been used 
(when indicator reads “0”), whichever comes first.


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Rationale for change
Clarification on timeframe to use Diskus device 
once opened
Section to be changed
Section 4.1.6
Description of change
The Diskus Inhaler should not be used beyond one 
month after removal from the moisture-protective 
foil overwrap, or after all blisters have been used 
(when indicator reads “0”), whichever comes first.
Rationale for change
Clarification on timeframe to use Diskus training 
device once opened
Section to be changed
Section 6.2.1
Description of change
Patients will be assigned a study patient number in 
the EDC system once consent is signed. This is 
populated from the IRT system; therefore, the site 
should also register the patients as screened in IRT.
Rationale for change
Corrected based in implementation of  new systems


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13020187
3.0
clinical-trial-protocol-version-03
A randomized, double-blind, double-dummy, active-controlled, multi-center , parallel
group study to show the superiority in lung function of 12 weeks once daily treatment
with orally inhaled tiotropium+olodaterol fixed dose combination delivered by the
Respimat® inhaler vs. 12 weeks twice daily treatment with orally inhaled fluticasone
propionate+salmeterol fixed dose combination delivered by ...
Approval-Trial Clinical Monitor
06 Mar 2018 16:03 CET
Approval-Biostatistics
06 Mar 2018 16:39 CET
Approval-Team Member Medicine
08 Mar 2018 14:54 CET
Approval-Therapeutic Area 
08 Mar 2018 15:05 CET
Verification-Paper Signature
Completion
08 Mar 2018 15:29 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13020187
3.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c23758242-01
BI Trial No.:
1237-0063
Title:
A randomized, double-blind, double-dummy, active-
controlled, multi-center, parallel group study to show the 
superiority in lung function of 12 weeks once daily 
treatment with orally inhaled tiotropium+olodaterol fixed 
dose combination delivered by the Respimat® inhaler vs. 12 
weeks twice daily treatment with orally inhaled fluticasone 
propionate+salmeterol fixed dose combination delivered by 
the Diskus® in patients with Chronic Obstructive 
Pulmonary Disease (COPD) [ENERGITO® 2]
Including Protocol global amendment 2 [c13020187-03]
Investigational
Product:
Stiolto®, Tiotropium+olodaterol fixed dose combination –
Respimat®
Responsible trial 
statistician:
Telephone: 
Date of statistical 
analysis plan:
14 May 2018 SIGNED
Version:
Final
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2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written 
permission.


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1. TABLE OF CONTENTS
TITLE PAGE
1
1.
TABLE OF CONTENTS
2
LIST OF TABLES
4
2.
LIST OF ABBREVIATIONS
4
3.
INTRODUCTION
7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
7
5.
ENDPOINTS
7
5.1
PRIMARY ENDPOINTS.....................................................................7
5.2
SECONDARY ENDPOINTS...............................................................7
5.2.1
Key secondary endpoints...........................................................................7
5.2.1
(Other) Secondary endpoints ....................................................................8
6.
GENERAL ANALYSIS DEFINITIONS
8
6.1
TREATMENTS.....................................................................................8
6.2
IMPORTANT PROTOCOL VIOLATIONS .....................................9
6.3
PATIENT SETS ANALYZED...........................................................13
6.5
POOLING OF CENTRES .................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................14
6.6.1
Spirometry data........................................................................................14
6.6.2
SGRQ and CAT data ...............................................................................16
6.6.3
Safety data.................................................................................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...16
7.
PLANNED ANALYSIS
17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................17
7.3
TREATMENT COMPLIANCE ........................................................18
7.4
PRIMARY ENDPOINT .....................................................................18
7.4.1
Adjusted Multiple Imputation sensitivity analysis for missing data ...19
7.5
SECONDARY ENDPOINTS.............................................................19
7.5.1
Key secondary endpoint...........................................................................19
7.5.2
(Other) Secondary endpoints ..................................................................19
7.7
EXTENT OF EXPOSURE.................................................................20
7.8
SAFETY ANALYSIS..........................................................................20
7.8.1
Adverse events ..........................................................................................20
7.9
LABORATORY DATA......................................................................21
7.10
VITAL SIGNS.....................................................................................21
7.11
ECG......................................................................................................21
7.12
OTHERS..............................................................................................21


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8.
REFERENCES
22
10.
HISTORY TABLE
23


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LIST OF TABLES
Table 6.1: 1  Treatment and labels..............................................................................................9
Table 6.2: 1  Important Protocol Violations .............................................................................11
Table 6.3: 1 Patient sets analyzed.............................................................................................14
Table 6.7: 1 Planned and actual study days ..............................................................................17
Table10:1 History table.............................................................................................................23
2. LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP 
Term
Definition / description
ADS
Analysis Data Set
AE
Adverse event
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BDI
Baseline Dyspnoea Index (Mahler)
BRPM
Blinded report planning meeting
CD
Concomitant diagnosis
CML
Clinical Monitor Local
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CT
Concomitant treatment
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Data Base Lock
DH
Digital Health
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DRA
Drug Regulatory Affairs
eCRF
electronic Case Report Form
EoT
End of Text
EMEA
European Agency for the Evaluation of Medicinal Products
FAS
Full analysis set


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Term
Definition / description
FDC
Fixed Dose Combination
FEV1
Forced Expiratory Volume in One Second
FVC
Forced Vital Capacity
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
(I)PV
(Important) Protocol Violation
IVRS
Interactive Voice Response System
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed effects model repeated measures
MQRM
Medical Quality Review Meeting
PEF
Peak Expiratory Flow
PFT
Pulmonary Function Test
PK
Pharmacokinetics
PPS
Per protocol set
PRN
Pro re nata (when necessary)
PSTAT
Project Statistician
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
REML
Restricted maximum likelihood
RS
Randomised set
SABA
Short-acting beta agonist
SAE
Serious Adverse Event
SAMA
Short-acting muscarinic antagonist
SD
Standard deviation
SGRQ
Saint George’s Respiratory Questionnaire
SMQ
Standardised MedDRA query
SOC
System organ class
TDI
Transitional Dyspnoea Index
TS
Treated set


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Term
Definition / description
TSAP
Trial statistical analysis plan
TTM
Termination of trial medication


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3. INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (1) , the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the protocol, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size.” Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
SAS® Version 9.4 or later will be used for all analyses.
4. CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
In addition to the further endpoints described in the protocol, the following further endpoints 
will be added.
-
FEV1 AUC 0-12 h response (change from baseline) [L] after 6 weeks treatment
-
FVC AUC0-24h response (change from baseline) [L] after 6-weeks treatment
-
FVC AUC0-12h response (change from baseline) [L] after 6-weeks treatment
-
FVC AUC 12-24h response (change from baseline) [L] after 6-weeks of treatment
5. ENDPOINTS
5.1PRIMARY ENDPOINTS
Primary endpoint of efficacy will be used as described in the clinical trial protocol, section 
5.1.1.
5.2SECONDARY ENDPOINTS
5.2.1 Key secondary endpoints
There are no key secondary endpoints in this trial.


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5.2.1 (Other) Secondary endpoints
Secondary endpoints of efficacy will be used as described in the clinical trial protocol, 
Section 5.1.2.
6. GENERALANALYSIS DEFINITIONS
6.1TREATMENTS
As described in Section 4 of the CTP, the following treatments are planned to be investigated 
in this study:


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Table 6.1: 1 Treatment and labels
Treatment
Label
Tiotropium + olodaterol FDC (5 μg / 5 μg) inhalation solution
T+O 5/5
Fluticasone propionate + salmeterol FDC   (250 μg / 50 μg) 
inhalation powder
F+S 250/50
This is a parallel-group trial consisting of a screening and run-in period of at least 4 four 
week duration, a 12-week randomised treatment period and a three week (21 days) follow up 
period
For the main safety analysis, data occurring during the treatment period between first double-
blind drug intake date and within 21 days after the last drug intake date is assigned to and 
analysed under the respective treatment. Data occurring before the first drug intake date is 
assigned to screening/run-in period. 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 
summarized as an important protocol violation.

If a patient was treated with a study medication different from the randomized 
treatment throughout the on-treatment period, this patient will be included in the 
treated set and will be analysed as treated under the initial study medication received 
on Day 1 for both efficacy and safety analyses. Such a case will be reported as an 
important protocol violation and this patient will be excluded from the per-protocol 
set (PPS)

If a patient was treated with incorrect study medication during part of the on-
treatment period, this patient will be included in the treated set and will be analysed 
under the initial study medication received on Day 1 for both efficacy and safety 
analyses. For safety analyses, the actual incorrect study medication is listed as the 
actual treatment at onset of any adverse event in the subject data listings. Such a case 
will be reported as an important protocol violation and a decision will be made 
whether to exclude this patient from the PPS at the blinded report planning meeting 
(BRPM) on a case-by case basis before unblinding.
6.2IMPORTANT PROTOCOL VIOLATIONS
A patient’s deviation from the trial protocol is considered “important” if it can be expected 
that the deviation had a distorting influence on the assessment of the treatment effect on the 
primary endpoint of the trial or could affect the patient’s safety or rights.
Table 6.2: 1 gives the important PVs for this trial. The final decision with regard to important 
PVs and exclusion from the PPS will be made at the final BRPM. Some important PVs will 
be set automatically; others will need a decision at a Medical Quality Review Meeting 
(MQRM) or BRPM or through team review of the manual PV log. 


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In the case that a patient is randomized in both this trial and another trial or is randomized at 
two different sites in this study the patient will be indicated as having IPV A2 (see Table 6.2: 
1). 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) (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 is randomized twice in this study and both treatments are the 
same, the patient’s data will be combined (i.e., the patient is only counted once). If the 
patient participates in two different trials in the 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 and baseline characteristics the patient will be analysed 
as treated. If the patient is randomized twice in this study and the treatments are 
different, the patient will be counted under each treatment. A footnote will be 
included in the disposition table identifying the situation and noting that the patient is 
counted twice for disposition as well as baseline data and important protocol 
violations.
The final decision with regards to important protocol violations and exclusion from the PPS 
will be made at the final BRPM or database lock meeting before unblinding.


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Table 6.2: 1  Important Protocol Violations 
Category 
Code
Description
Requirement
Excluded from
A
Entrance criteria not met
A1
Inclusion Criteria not met
Any of inclusion criteria 2 through 
6 not met as specified in the 
protocol.
PPS
A2
Exclusion Criteria not met
Any of exclusion criteria 2, 3, 9, 
12,13, 15, 16, 17, 19, 20, 24, 25 not 
met as specified in the protocol
Any of exclusion criteria 1,4, 5, 6, 
7, 8, 10, 11, 12, 14, 18, 21, 22, 23 
not met as specified in the protocol
PPS
None
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. If the date of informed 
consent equals to date of Visit 1, such 
cases are discussed at MQRM/ 
BRPM/DBL meetings. Patient 
signed the wrong version of ICF and 
then signed correct version with date 
after randomisation 
None
C
Trial medication and 
randomisation
C1
Incorrect trial medication taken
Not throughout study; could be at a 
clinic visit or between clinic visits
PPS (decision at 
BRPM )
C2
Randomisation order not 
followed and incorrect trial 
medication taken
Throughout the study, check IVRS
PPS
C3
Non-compliance with study 
medication
C3.2
Serious non-compliance with study 
medication as reported in 
monitoring report
Decision at MQRM/BRPM
If at visit 4
PPS 
C4
Medication code broken 
inappropriately
To be discussed and decided during 
MQRM/BRPM.
Only inappropriate code breaks are 
IPVs (e.g. unblinding by Global 
Pharmacovigilance is not).
PPS


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Table 6.2: 1 (cont.)
Important protocol violations
Category 
Code
Description
Requirement
Excluded from 
D
Concomitant medication
D1
Improper medication washout at 
baseline visit or at primary 
endpoint visits
Visit 2 and Visit 4, refer to Section 
4.2.2.2 and Table 4.2.2.1:1 in 
CTP. Decision at BRPM
PPS
D2
Prohibited medication use during 
the study
Refer to Table in 4.2.2.1:1 in 
CTP. Decision at BRPM if in week 
prior to Visit 2 or Visit 4. 
PPS
F
Incorrect timing
F3
Primary endpoint recorded 
outside time window
F.3.1
PFT measurement at 12-hour time 
point performed more than 13  
hours after dosing
Visit 4
Decision at BRPM
PPS
F3.2
PFT measurement at 23:00 or 24:00 
planned time performed earlier than 
22 hours after dosing at primary 
endpoint visit(s)
Visit 4
Decision at BRPM
PPS
F4
Trial medication
F4.1
Trial medication taken prior to pre-
dose measurement at baseline visit
Visit 2
Decision at BRPM
PPS
F4.2
Trial medication taken prior to pre-
dose measurement at primary 
endpoint visit(s)
Visit 4
Decision at BRPM
PPS
F4.3
Evening dose of trial medication 
taken prior to 12h measurements 
Visit 4
Decision at BRPM
PPS
F4.4
Drug administration outside time 
window at randomisation visit and 
primary endpoint visit.
Visit 2 and Visit 4 start times are 
both outside 0600 to 1100 inclusive 
OR 
(One of Visit 2/Visit 4 start times is 
outside 6 am to 11 am inclusive 
AND
Visit 2 and 4 morning doses are more 
than 30 min apart) OR
(Visit 4 morning and evening doses 
do not meet the 12 hours+/- 30 
minutes criterion) 
Decision at BRPM
PPS
Z
Other
Z1
Serious GCP non-compliance
Manual PVs reported by CML/CRA. 
Carefully reviewed, described and 
documented in the DBL meeting 
minutes
Decision at BRPM
PPS
Z2
Other PV affecting efficacy and 
possible 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


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Table 6.2: 1 (cont.)
Important protocol violations
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
Note:
Missing visits, evaluations, and tests will be considered missing data, not protocol deviations.
IPV categories B2, C1, C2, C3.2, C4, D1, D2, Z1, Z2 and Z3 cannot be checked 
programmatically and need to be done manually
6.3PATIENT SETS ANALYZED
There are four patient sets defined in this trial:

Randomised Set (RS)
This patient set includes all patients who signed the informed consent form and were 
also randomised, regardless whether the patient was treated with trial medication or 
not.

Treated Set (TS)
All randomized patients who were dispensed trial medication and were documented to 
have taken any dose of trial medication.

Full Analysis Set (FAS)
This patient set is nested within the TS and includes patients who had baseline and at 
least one post-baseline measurement for at least one  efficacy endpoint. The FAS will 
be used for the primary analyses of the primary efficacy endpoint and for all other 
efficacy endpoints.

Per Protocol Set (PPS)
This patient set is nested within the FAS and only includes patients who had no 
important PVs which are specified to be excluded from the efficacy analysis. (see 
Table 6.2: 1).

The final decision regarding which patients are included in PPS will be made at 
BRPM prior to data unblinding.
  If the number of patients in PPS is less than 90% of the number of patients in FAS, the 
primary analysis for the primary endpoint will also be performed on the PPS as supportive 
analyses.
The analysis will be compliant with ICH guideline (5)


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Table 6.3: 1 Patient sets analyzed
Patient set
Class of endpoint
Treated 
set
FAS
PPS
Primary endpoint
primary 
analysis
*supportive 
analysis
Key secondary, (other) 
secondary and further 
endpoints 
X
Safety
X
Demographic/baseline 
X
* If the number of patients in PPS is less than 90% of the number of patients in FAS, the 
primary analysis for the primary endpoint will also be performed on the PPS as supportive 
analyses.
6.5POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6HANDLING OF MISSING DATA AND OUTLIERS
Every effort should be made to collect complete data for each time point on each test day. 
6.6.1 Spirometry data 
The REML-based MMRM model described in Section 7.3.1 will handle missing data due to 
early drop outs or missing data in between visits which are assumed to be missing at random.
Adjusted multiple imputation will be used to handle missing data in a sensitivity analysis. 
Details are described in Section 7.4. 
FEV1 and FVC measurements
FEV1 and FVC measurements at individual time points that are flagged as unacceptable by 
the vendor will be set to missing prior to applying any missing data imputation rules. Missing 
FEV1 and FVC measurements at a given in-clinic visit will be imputed by the available data 
from the patient at that visit. Completely missing visits will not be imputed and will be 
handled through the MMRM statistical model expect for cases where a patient discontinues 
due to an AE indicative of worsening of COPD. For the case of discontinuing due to an AE 
indicative of worsening of COPD, completely missing visits will be imputed with the worst 
observation observed before discontinuation. 


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Discontinuation due to an AE indicative of worsening of COPD will be determined as 
follows.

Check that the reason for discontinuation on the termination of trial medication is 
adverse event.

Get the AE flagged by the investigator as the primary reason for discontinuation of 
trial medication.

Check whether this AE belongs to the group of AEs identified as corresponding to 
either COPD exacerbation or lower respiratory disorders.  This will be based on the 
BI system in place for grouping MedDRA preferred terms into medical concepts 
(currently referred to as pharmacovigilance endpoints).
Additional details on the imputation of missing data for specific cases are provided below:

Any visit occurring more than one day after discontinuation of study medication which 
has non-missing data will not be used in the analysis. 

For patients taking a short-acting beta agonist (SABA) or short-acting anticholinergic 
(SAMA) as rescue medication during Visit 3 and 4, any subsequent FEV1 and FVC 
measurements from the time of rescue use until time of rescue plus 8 hours (e.g., 2:17 to 
10:17) will be set to missing and imputed by the worst non-missing (either observed or 
imputed) observation for that visit strictly prior to the administration of the rescue 
medication (even if it is a pre-dose value, either observed or imputed). If there are FEV1
and FVC measurements after the 8-hour window they will be considered valid and not 
imputed provided that they are not in the 8-hour window for a subsequent rescue 
medication use. If rescue medication is taken at any on-treatment in-clinic visit and there 
is no rescue medication time given, data for the entire visit will be considered missing and 
it will be handled the same way as the case where all measurements after rescue use are 
set to missing.

For randomly missing data (not due to worsening of study disease or rescue medication 
use), the following rules will be applied:

If one of the two pre-dose measurements at Visit 2 is missing, it will be imputed with 
the other predose measurement.

Missing 10 minute pre-dose measurement at Visits 3 and 4 will be imputed with the 
average of the 23h and 24h post-dose measurements at the same visit if both 23h and 
24h time points have non-missing values, or will be imputed with the non-missing 
measurement at 23h or 24h.

If one of the post-dose 23h and 24h measurements is missing at a visit, then impute 
the missing post-dose measurement with the non-missing one.


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
If both of the post-dose 23h and 24h measurements are missing and the 10-min pre-
dose measurement is non-missing at a visit, then impute missing 23h and 24h 
measurements with the non-missing 10-min pre-dose measurement from the same 
visit.
6.6.2 SGRQ and CAT data
Missing answers for COPD Assessment Test (CAT) and St. George’s Respiratory 
Questionnaire (SGRQ) will be handled based on related manuals [R12-1915R12-2870].
If the baseline SGRQ and CAT is missing the patient will be excluded from all SGRQ and 
CAT analyses, respectively.
Completely missing visits will not be imputed and will be handled through the MMRM 
statistical model. 
In cases where an entire on-treatment visit is missing after a patient discontinues due to an 
AE indicative of worsening COPD, all SGRQ component scores and the SGRQ total score as 
well as CAT score will be imputed using the least favorable prior values for the respective 
scores.
If SGRQ total score and the CAT score is missing at a visit, the patient will be counted as 
non-responder for the SGRQ and CAT responder analysis, respectively, at that visit.  
6.6.3 Safety data
Missing safety data will not be imputed with the exception of missing AE dates which will be 
imputed according to BI standards (see Boehringer Ingelheim Data Management and 
Statistics Manual (DM&SM) “Handling of missing and incomplete AE dates” (2),(3),(4).
6.7BASELINE, TIME WINDOWS AND CALCULATED VISITS
The definition of baseline values for FEV1 can be found in Section 5 of the CTP. The mean 
of the two pre-dose pulmonary function test measurements at Visit 2, 1 hour prior and 10 
minutes prior to the administration of the first dose of the randomised treatment, is used as 
the baseline FEV1 and FVC, respectively. For CAT and SGRQ the measurements at Visit 2 is 
defined as baseline.
Planned and actual study day will be included in the analysis data sets. These will both be 
calculated relative to the beginning of study as indicated in the following table (nominal 
visits). See Table 6.7: 1


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Table 6.7: 1 Planned and actual study days
Visit
Planned Study Day
Actual Study Day
2
1
1
3
42
Visit 3 date – Visit 2 date + 1
4
84
Visit 4 date – Visit 3 date + 1
5
105
Visit 5 date – Visit 4 date + 1
7. PLANNED ANALYSIS
For End-of-Text (EoT) tables, the set of summary statistics for descriptive displays is: N / 
Mean / 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.
7.1DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. COPD background 
characteristics will be listed only.
GOLD A-D 2017 classifications will be summarized by treatment group.
7.2CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. A table of number (%) of 
patients with concomitant diagnoses (CDs) by system organ class (SOC) and preferred term 
(PT) will be included along with a supporting listing. Concomitant diagnoses will be coded 
with the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) 
in effect at database lock.
Frequency tables (%) will be presented for medical history and COPD background 
characteristics. 
Pulmonary medication will be summarized as the number (%) of patients taking pulmonary 
medications within the last three months before visit 0 and during the treatment periods.


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7.3TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. Summary statistics will 
be given for percent compliance along with the number (%) of patients with compliance in 
the categories <80% or >120%, 80% - 120%.
7.4PRIMARY ENDPOINT
In the primary analyses, comparisons between treatment groups for the primary endpoint will 
be based on a mixed effects model repeated measures (MMRM). Change from baseline in 
FEV1 AUC0-24h, will be analysed using a restricted maximum likelihood (REML)-based 
repeated measures approach. This model will include treatment, visit and treatment by visit 
interaction as fixed effects, and baseline as well as baseline by visit interaction as covariates. 
An unstructured covariance structure will be used to model the within patient errors. The 
SAS procedure MIXED will be used for the restricted maximum likelihood estimation and 
Kenward-Roger approximation for denominator degrees of freedom. Adjusted mean values 
as well as treatment contrasts will be presented together with 95% confidence intervals. The 
primary treatment comparisons will be the contrasts between treatments after 12 weeks of 
treatment.
PROC MIXED DATA=alldat cl method=reml order=formatted; 
CLASS usubjid ptrsort tptno; 
MODEL ept = ptrsort*tptno eptbase*tptno 
/ ddfm=kr solution; 
REPEATED tptno / subject=usubjid type=un r rcorr; 
LSMEANS tptno*ptrsort / pdiff=all om cl alpha=0.05 slice=tptno; 
RUN; 
Here tptno is the planned analysis day number for each visit. The endpoint is ept, baseline 
value of the endpoint is eptbase, treatment is ptrsort and patient number is usubjid.  
In the event of non-convergence, the following methods will be attempted (in order) to 
overcome it:
1. Add the ‘singular=1e-10’ option in the model statement – This raises the threshold at 
which columns are declared linearly dependent (from typically 1e-12). 
2. Set ‘maxiter=100’ in the Proc Mixed statement – This increases the number of 
convergence iterations used from a default of 50. 
3. Set ‘scoring=4’ to specify use of the Fisher scoring algorithm in the first 4 iterations. 
4. Include the statement ‘performance nothread’ – this removes multi-threading from the
calculations. 
If the number of patients in PPS is less than 90% of the number of patients in FAS, then the 
primary analyses for the primary efficacy endpoints will be repeated using PPS and the 
results will be presented as supportive analyses


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7.4.1 Adjusted Multiple Imputation sensitivity analysis for missing data
The MMRM primary analysis implicitly accounts for missing observations under the MAR 
(missing at random) assumption. The robustness of the primary analysis to the MNAR 
(missing not at random) assumption will be assessed by performing an adjusted multiple 
imputation sensitivity analysis.
The aim of the multiple imputation approach is to assess the robustness of the primary 
analysis with respect to departures from MAR by applying specific shift parameters to 
missing data in the T+O 5/5 arm, corresponding to substantially worse outcomes for these 
patients. 
As a first step non-monotone missing data will be imputed m = 100 times using MCMC 
(Markov Chain Monte Carlo) under an assumption of MAR to generate m data sets with 
monotone missingness. This large number of imputations is chosen to minimize the standard 
error of the estimates. The seed number will be set to 123763. 
The monotone missing data in the 100 generated datasets will then be imputed once per each 
of the 100 imputations using sequential regression including baseline FEV1 and Week 6 
FEV1 AUC0-24h as covariates in the model, with a shift parameters S applied to the treatment 
arm T+O 5/5 at the first missing visit and no shift applied to the F+S 250/50 treatment arm. 
Subsequent visits will have no additional shift but due to the sequential method, the impact of 
the initial shift will propagate to all future visits.
Point estimates for treatment differences and respective p-values will be reported for all S.
Selection of S
a. -250 ml (large shift, conservative analysis)
b. -125 ml,
c. negative treatment difference from the primary analysis
7.5SECONDARY ENDPOINTS
7.5.1 Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2 (Other) Secondary endpoints
The MMRM model described for the primary analysis will be performed for the continuous
secondary endpoints. Adjusted mean values as well as treatment contrasts will be presented
together with the 95% confidence intervals. All calculated p-values should be considered
descriptive for the analysis of the secondary endpoints.


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7.7EXTENT OF EXPOSURE
Extent of exposure will be summarized using descriptive statistics for days of exposure as 
well as number (%) of patients whose total exposure falls in the categories specified in 
Section 5.4.
7.8SAFETY 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).

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).


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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 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 and for subjects with serious adverse events.
The system organ classes will be sorted alphabetically, preferred terms will be sorted by 
frequency (within system organ class).
7.9LABORATORY DATA
The absolute eosinophil count recorded at Visit 1 and 2 will be analysed descriptively.
7.10
VITAL SIGNS
Only descriptive statistics are planned for this section of the report.
7.11
ECG
Not applicable since ECG data will not be collected in the database.
7.12
OTHERS
Not applicable since there were no additional endpoints.


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8. REFERENCES
1. CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
2. 001-MCS-80-606: “Handling of Non-Compliances in Clinical Development, 
Medicine and QRPE”, current version; IDEA for CON.
3. 001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
4. 001-MCG-156: "Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
5. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version.


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10.HISTORY TABLE
Table 10:1 History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Initial
31-Aug-2017
None
This is the initial TSAP with necessary 
information for trial conduct
Final
14-May-2018
7
This is the final TSAP