Clinical trial NCT02296138
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim
Start date: 2015-01-13; Completion date: 2017-03-29
Enrollment: 7903 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall objective is to assess the effect of once daily tiotropium + olodaterol fixed dose combination compared to 5 µg tiotropium (both delivered with the Respimat® inhaler) on moderate to severe COPD exacerbation in patients with severe to very severe COPD.

Detailed description:

Arms: arm 1: Once daily 2 puffs solution for inhalation Respimat arm 2: Once daily 2 puffs solution for inhalation Respimat
Interventions: intervention 1: olodaterol intervention 2: tiotropium intervention 3: tiotropium
Intervention descriptions: intervention 1: fixed dose combination intervention 2: fixed dose combination intervention 3: None

Protocol documents:
Prot_001.pdf: 
Clinical Trial Protocol
Doc. No.: c02247259-03
EudraCT No.:
BI Trial No.:
2014-002275-28
1237.19
BI Investigational
Products:
Tiotropium + olodaterol fixed dose combination inhalation solution-
RESPIMAT®
Title:
A randomised, double-blind, active-controlled parallel group study to 
evaluate the effect of 52 weeks of once daily treatment of orally inhaled 
tiotropium + olodaterol fixed dose combination compared with 
tiotropium
on Chronic Obstructive Pulmonary Disease (COPD) 
exacerbation in patients
with severe to very severe COPD.
[DYNAGITO]
Clinical Phase:
IIIb
Trial Clinical 
Monitor:
Phone: 
                      Fax:
E-mail: 
Co-ordinating 
Investigator:
 
Phone: 
Status:
Revised Protocol (based on global amendment 1)
Version and Date:
Version:
2.0
         
Date: 15 July 2015
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredients:
-
Tiotropium + olodaterol fixed dose 
combination inhalation solution Respimat® 
-
Tiotropium 5 μg inhalation solution
Respimat® 
Protocol date:
Trial number:
Revision date:              
15 July 2015
29 September 2014
1237.19
Title of trial:
A randomised, double-blind, active-controlled parallel group study to evaluate the 
effect of 52 weeks of once daily treatment of orally inhaled tiotropium + olodaterol 
fixed dose combination compared with tiotropium on Chronic Obstructive Pulmonary 
Disease (COPD) exacerbation in patients with severe to very severe COPD. 
[DYNAGITO]
Co-ordinating 
Investigator 
Trial sites:
Multi-centre, multi-national trial
Clinical phase:
IIIb
Objective:
The overall objective is to assess the effect of once daily tiotropium + olodaterol fixed 
dose combination compared to 5 μg tiotropium (both delivered with the Respimat®
inhaler) on moderate to severe COPD exacerbation in patients with severe to very 
severe COPD.
Methodology:
Randomised, double-blind, active-controlled parallel group design
No. of patients: 
total entered:
Approximately 7800 subjects
each treatment:
Approximately 3900 subjects
Diagnosis :
Severe to very severe Chronic Obstructive Pulmonary Disease (COPD)
Main criteria
for inclusion:
1.
Outpatients of either sex, aged ≥ 40 years with a post-bronchodilator FEV1 < 60 
% predicted and a post- bronchodilator FEV1/FVC <70% 
2.
Documented history of at least 1 moderate to severe COPD exacerbation in the 
previous 12 months.
3.
Current or ex-smokers with smoking history >10 pack years
Exclusion: Patients with a current documented diagnosis of asthma.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredients:
-
Tiotropium + olodaterol fixed dose 
combination inhalation solution Respimat® 
-
Tiotropium 5 μg inhalation solution
Respimat® 
Protocol date:
Trial number:
Revision date:              
15 July 2015
29 September 2014
1237.19
Test products:
Tiotropium + olodaterol fixed dose combination (FDC) inhalation solutionRespimat®
inhaler
dose:
[5 μg tiotropium  + 5 μg olodaterol] once daily
mode of admin.:
Oral inhalation 
Comparator product:
Tiotropium inhalation solution– Respimat® inhaler
dose:
5 μg once daily
mode of admin.:
Oral inhalation
Duration of treatment: 52-week.
In case of early drop-out, each patient will be followed up for exacerbations and vital 
status up to the predicted end of treatment date (52 weeks) + 21 days follow-up.
Criteria for efficacy:
Primary endpoint

Annualised rate of moderate to severe COPD exacerbation during the 
treatment period (within 1 day after the last drug administration date)
Key secondary endpoint

Time to first moderate to severe COPD exacerbation during the treatment 
period (within 1 day after the last drug administration date)
Secondary endpoints 

Annualised rate of exacerbation leading to hospitalisation during the 
treatment period (within 1 day after the last drug administration date)

Time to first COPD exacerbations leading to hospitalisation during the 
treatment period (within 1 day after the last drug administration date)

Time to all-cause mortality (within 1 day after the last drug administration
date)


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredients:
-
Tiotropium + olodaterol fixed dose 
combination inhalation solution Respimat® 
-
Tiotropium 5 μg inhalation solution 
Respimat® 
Protocol date:
29 September 2014
Trial number:
1237.19
Revision date:              
15 July 2015
Criteria for efficacy: 
Criteria for safety:

Adverse events , serious adverse events and fatal adverse events 
Statistical methods:
For analysis of annualised rate of exacerbation, a negative binomial model accounting 
for exposure will be used. For analysis of time to event data for exacerbation, Cox’s 
proportional hazard model will be used for hazard ratio estimations and confidence 
intervals, while log-rank test will be used to obtain p-values.  Descriptive statistics 
and exploratory analyses for safety data.


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FLOW CHART
Study periods
Screening*
Randomised 52-week treatment period
Follow-
up ****
Study visits** (V) and 
phone call ()***
V1
V2

V3

V4

V5

V6
EoT4
V6a12
Study day from Visit 2 
(Days)
-1 to
-7
Day1
D45
±7
D90
±7
D135
±7
D180 
±7
D225
±7
D270
±7
D315
±7
D360
+7
+ 1 day
from 
V6/EoT
+21 days 
after 
V6/EoT 
(+7)
Informed Consent
X1
Demographics
X
Cardiovascular risk-factors
X
Concomitant Diagnosis
X
2
Physical examination
X
X
X6
Laboratory tests 
X9
X9
X6
Smoking status
X
X
12-lead ECG
X
Review of in-/exclusion 
criteria
X
X
Serum pregnancy test 11
X
X
Urine pregnancy test
X
X
X
X
X
Screening call (IRT)
X
Inhalation device trainings 10
X10a
X10b
X10c
X10c
X10c
Rescue medication 
dispensation
X8
X
X
X
X
X
Medication restriction review 
X3
X3
Trial patient’s card
X
Randomisation call  (IRT) 
X
Administration of trial drugs 
in clinic
X
X
X
X
Last administration of trial 
drugs in clinic
X
Assign trial drugs (IRT)
X
X
X
X
Dispense Patient’s reminder 
card
X
X
X
X
X
COPD exacerbation interview
X
X
X
X
X
X
X
X
X
X
Collect trial 
drugs/accountability
X
X
X
X
Collect rescue 
medication/accountability
X
X
X
X
X
Compliance check
X
X
X
X
Discontinuation assessment
Vital status collection. 
X13
X13
Discontinuation assessment
COPD exacerbation collection
X14
X14
X14
X14
X14
X14
X14
X14
Trial drug termination call 
(IRT)
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
Conclusion of patient 
participation
X
Trial Completion
X


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STUDY PERIODS
*
The visit interval (Visit 1-2) may be extended beyond 7 days for administrative reasons (1 additional week) or to 
allow for recovery from respiratory infections (4 weeks after recovery from the infection).
**
Clinic visits: every 3 months from visit 2
***
Phone calls: between clinic visits, every 6 weeks
****
Conclusion of patient participation also needs to be completed if the patient withdraws prematurely following 
randomisation.
1.
Informed Consent: all patients must sign an informed consent consistent with ICH-GCP guidelines prior to any study 
related activities which includes medication washout and restrictions. A preliminary check of in-/exclusion criteria with 
a particular focus on COPD exacerbation status within the previous year is recommended to avoid unnecessary study
procedures in non-eligible patients.
2.
FEV1/FVC: historical data from spirometry measurements within the past 3 months either at the site or at a referral site 
will be used. Spirometry results for COPD severity staging need to be in the patient file on site prior to randomisation.
For patients participating in the spirometry sub-study, historical data will not be used for inclusion.
3.
Medication restriction review: Refer to Table 4.2.2.1: 1 (Permitted Medications and Medication Restrictions)
4.
Visit 6/EoT procedures are to be completed by all patients at the time of study drug discontinuation. For patients who 
discontinue early, the Visit 6/EoT visit should be performed instead of the scheduled trial visit at time of 
discontinuation. Please complete directly Visit6/EoT eCRF pages.
6.
Physical examination, vital signs and laboratory results: to be performed only if relevant findings at Visit 6 (or last 
treatment visit in case of premature discontinuation). Please refer to section 5.2.3.1 (Laboratory tests) and section 
5.2.3.2 (Physical examination)
7.
For prematurely discontinued patients: Vital status and COPD exacerbation status collection: Please refer to section 
3.3.4.1
8.
Rescue medication: to be dispensed to all patients. Please refer to section 4.2.1.1
9.
Laboratory testing: fasted condition is not required
10. Inhalation device trainings: please refer to section 4.1.4.3
10a: visit1, training session with the Respimat® inhaler training medication (placebo)
10b: visit 2, training session with the new assigned Respimat® treatment box
10c: visits 3, 4 and 5. Observance of the inhalation procedure from the new assigned Respimat® treatment box
11. If applicable. Serum pregnancy test at Visits 1 and 6 or EoT and urine dipstick pregnancy test at Visits 2, 3, 4, 5 and 
follow-up.
13. Vital status collection has to be collected in all patients having discontinued prematurely:

BEFORE Visit 4: 2 collection time points at the originally predicted visit 4 and follow-up visit

AFTER Visit 4: 1 collection time point at the originally predicted follow-up visit
14. COPD exacerbation status collection: has to be collected in all patients having discontinued prematurely. 
Collection frequency repeated every 6 weeks at the originally predicted clinic visits and telephone contacts.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
FLOW CHART SPIROMETRY SUB-STUDY...............................................7
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................15
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 17
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................17
2.2
TRIAL OBJECTIVES.......................................................................................17
2.3
BENEFIT - RISK ASSESSMENT ...................................................................17
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 19
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................19
3.1.1
Administrative structure of the trial...................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................22
3.3
SELECTION OF TRIAL POPULATION ......................................................22
3.3.1
Main diagnosis for study entry............................................................22
3.3.2
Inclusion criteria...................................................................................23
3.3.3 Exclusion criteria ..................................................................................24
3.3.4
Removal of patients from therapy or assessments.............................25
3.3.4.1
Removal of individual patients................................................25
3.3.4.2 Discontinuation of the trial by the sponsor ................................26
4.
TREATMENTS........................................................................................ 28
4.1
TREATMENTS TO BE ADMINISTERED....................................................28
4.1.1
Identity of BI investigational product and comparator product......28
4.1.2
Method of assigning patients to treatment groups ............................28
4.1.3
Selection of doses in the trial................................................................29
4.1.4
Drug assignment and administration of doses for each patient .......29
4.1.4.1 Priming of the Respimat® inhaler ............................................30
4.1.4.2 Study medication administration .............................................30


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4.1.4.3 Inhaler devices training............................................................31
4.1.4.4 Respimat® malfunctioning.......................................................32
4.1.5
Blinding and procedures for unblinding ............................................32
4.1.5.1
Blinding....................................................................................32
4.1.5.2
Procedures for emergency unblinding .....................................32
4.1.6
Packaging, labelling and re-supply .....................................................32
4.1.7
Storage conditions.................................................................................33
4.1.8
Drug accountability ..............................................................................34
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................35
4.2.1.1 Rescue medication ...................................................................35
4.2.1.2 Emergency procedures.............................................................36
4.2.1.3 Additional treatments...............................................................36
4.2.2
Restrictions............................................................................................36
4.2.2.1
Restrictions regarding concomitant treatment .........................36
4.2.2.2
Restrictions on diet and life style............................................40
4.3
TREATMENT COMPLIANCE.......................................................................40
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 42
5.1
EFFICACY.........................................................................................................42
5.1.1
Endpoints of efficacy.............................................................................42
5.1.2
Assessment of efficacy...........................................................................43
5.1.2.1 Definition of moderate and severe COPD exacerbations ........43
5.1.2.2 Assessment of moderate and severe COPD exacerbations......44
5.1.2.3 Assessment all-cause mortality................................................45
5.2 
SAFETY..............................................................................................................45
5.2.1
Endpoints of safety................................................................................45
5.2.2
Assessment of adverse events...............................................................45
5.2.2.1
Definitions of adverse events...................................................45
5.2.2.2
Adverse event and serious adverse event reporting.................47
5.2.2.3 Vital status collection...............................................................48
5.2.3
Assessment of other safety parameters...............................................48
5.2.3.1 Laboratory tests........................................................................49
5.2.3.2 Physical examination ...............................................................50
5.2.3.3 Electrocardiograms ..................................................................50
5.3 
OTHER...............................................................................................................50
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................50
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................53


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5.6
BIOMARKER....................................................................................................53
5.7
PHARMACODYNAMICS................................................................................53
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....53
6.
INVESTIGATIONAL PLAN.................................................................. 54
6.1
VISIT SCHEDULE............................................................................................54
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................55
6.2.1
Screening period....................................................................................55
6.2.2
Treatment periods.................................................................................58
6.2.2.1
Randomisation Visit 2 (Day 1) ................................................58
6.2.2.2
Clinic visits (Visits 3, 4 and 5).................................................60
6.2.2.3
Telephone contacts between clinic visits................................61
6.2.3
End of treatment ...................................................................................62
6.2.3.1
Visit 6/EoT...............................................................................62
6.2.3.2 Premature discontinuation .......................................................63
6.2.4
Follow-up visit.......................................................................................64
6.2.5
Trial completion....................................................................................65
7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE......................................................................................... 66
7.1
STATISTICAL DESIGN - MODEL................................................................66
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................66
7.3
PLANNED ANALYSES....................................................................................66
7.3.1
Primary analyses...................................................................................66
7.3.2
Secondary analyses ...............................................................................67
7.3.3
Safety analyses.......................................................................................67
7.3.4
Interim analyses ....................................................................................68
...................................................................................68
7.3.6
Pharmacokinetic analyses ....................................................................68
7.3.7
Pharmacodynamic analyses.................................................................68
7.3.8
Pharmacogenomic analyses..................................................................68
7.4
HANDLING OF MISSING DATA ..................................................................68
7.5
RANDOMISATION ..........................................................................................69
7.6
DETERMINATION OF SAMPLE SIZE ........................................................69
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 71
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................71
8.2
DATA QUALITY ASSURANCE .....................................................................72
8.3
RECORDS..........................................................................................................73


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8.3.1
Source documents .................................................................................73
8.3.2
Direct access to source data and documents.......................................73
8.3.3 Storage of records .................................................................................74
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................74
8.4.1
Listedness...............................................................................................74
8.4.2
Expedited reporting to health authorities and IECs/IRBs................74
8.5
STATEMENT OF CONFIDENTIALITY.......................................................74
8.6
COMPLETION OF TRIAL..............................................................................75
8.7
PROTOCOL VIOLATIONS ............................................................................75
8.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................75
9.
REFERENCES......................................................................................... 76
9.1
PUBLISHED REFERENCES...........................................................................76
9.2
UNPUBLISHED REFERENCES.....................................................................79
10. APPENDICES .......................................................................................... 80
10.1 THE RESPIMAT INHALER ...........................................................................80
10.2
RETURN OF INHALERS/CARTRIDGES ....................................................85
10.5 ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA..........93
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 95


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ABBREVIATIONS
AE
AESI
a.m.
ATS
Adverse Event
Adverse Event of Special Interest
Ante meridien
American Thoracic Society
AUC
Area under the curve
BAC
benzalkonium chloride
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
ECG
Electrocardiogram
ECSC
European Coal and Steel Community
eCRF
Electronic Case Report Form
EDC
EDTA
EoT
ERS
EU
Electronic Data Capture
Ethylenediaminetetraacetic acid
End of Treatment
European Respiratory Society
European Union
EudraCT
European Clinical Trials Database
FAS
FDC
FEV1
FVC
FRC
Full Analysis Set
Fixed Dose Combination
Forced expiratory volume in one second
Forced vital capacity
Functional residual capacity
GCP
GOLD
Good Clinical Practice
Global Initiative for Chronic Obstructive Lung Disease
IB
IC
ICS
Investigator’s Brochure
Inspiratory capacity
Inhaled corticosteroids
IEC
IMP
Independent Ethics Committee
Investigational Medicinal Product
IRB
Institutional Review Board
ISF
IRT
Investigator Site File
Interactive Response Technology
LABA
LAMA
Long-acting 2-agonist
Long acting muscarinic antagonist
MAC
Mortality Adjudication Committee
MACE
MCID
Major adverse cardiovascular event
Minimal clinically important difference
MedDRA
Medical Dictionary for Drug Regulatory Activities


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MDI
Metered Dose Inhaler
OPU
Operative Unit
p.o.
per os (oral)
PEFR
PFT
PRO
Peak expiratory flow rate
Pulmonary function testing
Patient-Reported Outcome
q.d.
RDC
quaque die (once a day)
Remote Data Capture
SAE
Serious Adverse Event
SPC
SGRQ
SOC
Summary of Product Characteristics
St. George's Respiratory Questionnaire
System Organ Class
SPC
Summary of Product Characteristics
TCM
TDI
Trial Clinical Monitor
Transition Dyspnea Index
TDMAP
Trial Data Management and Analysis Plan
TMF
Trial Master File
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
US
w.o
Trial Statistical Analysis Plan
United States
Wash-out


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs), are the 
cornerstone of maintenance therapy for patients with moderate to very severe chronic 
obstructive pulmonary disease (COPD) whose symptoms are not adequately controlled by 
short-acting bronchodilators alone [P13-05794, P14-01052].
An option recommended by GOLD for patients not adequately controlled on a single long-
acting bronchodilator is to combine a LAMA with a long-acting β2-agonist (LABA) [P14-
01052].This has prompted the development of combining LAMA+LABA as fixed-dose 
combinations (FDCs) [P13-05794]. The rationale for combining bronchodilators with 
different mechanisms is based on the notion of additive relaxation of airway smooth muscle 
by direct inhibition of cholinergic activity and functional antagonism of bronchoconstriction 
through β2-adrenergic pathways, with the expectation of an increase in the degree of 
bronchodilation for equivalent or lesser side effects. Several recent studies have provided 
evidence in support of this increased bronchodilatory effect when LABAs are added to 
LAMAs.
When beta-agonists and muscarinic antagonists with similar or equivalent posologies are 
combined, the opportunity exists for offering a simpler and more convenient administration 
regimen with the development of fixed combinations within the same inhaler device. 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®: salbutamol+ipratropium bromide; [P94-1346]). The development of the novel 
once daily (quaque die (q.d.) )long-acting β2-agonist olodaterol now offers the opportunity 
for a once daily fixed dose combination including the well-established long-acting muscarinic 
antagonist tiotropium.
Olodaterol is a highly selective and nearly full β2 agonist [P10-07776, P11-07720] that 
provides 24-h bronchodilation in patients with COPD [P13-11467, P13-14112, P13-11346, 
P13-11345] Olodaterol is also associated with symptomatic benefit [P13-11341] and 
enhanced exercise capacity [P13-14109]. 
 
 
The complementary modes of action of tiotropium and olodaterol have previously been 
demonstrated in animal models, phase II clinical trials [P10-09337, P14-12073, P10-14042, 
P13-02357] and during the Phase IIIa programme, which has recently be finalised. 
 
 
 
In the Phase III programme the additional benefits of the tiotropium + olodaterol FDC over 
its mono-components has been assessed on lung function, quality of Life (St. George's 
Respiratory Questionnaire -SGRQ), dyspnea (Transition Dyspnea Index-TDI) and exercise 
endurance time. Another clinically important potential benefit of the tiotropium + olodaterol 
FDC over the mono components has so far not thoroughly been investigated, which is the 


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impact on exacerbations of COPD. Exacerbation related parameters have been included into 
the pivotal studies as a further endpoint, to inform the planning of this dedicated exacerbation 
studies. While the studied showed a consistent numerical trend for a reduction in 
exacerbations for the tiotropium + olodaterol FDC over tiotropium, the magnitude of this 
effect varied considerably in magnitude, depending on the study (1237.5 vs. 1237.6), patient 
sub-set (treated set vs. patients with an exacerbation history) and the exacerbation related 
outcome (time to first exacerbation vs. annual rate), as this can be expected in a non-powered 
study. 
1.2
DRUG PROFILE
Tiotropium
Tiotropium is an established once-daily (QD) LAMA that improves the main functional and 
patient-orientated outcomes of COPD [P08-12524, P10-08261, P13-04267, P11-07562, P11-
03885, P13-11053].  Tiotropium has also been demonstrated to moderate disease progression, 
even in the early stages of COPD (e.g. patients not receiving maintenance therapy [P10-
02376] or those with Global initiative for chronic Obstructive Lung Disease [P14-01052] 2 
disease [P09-11278]).
Tiotropium in the dry powder inhaler HandiHaler has been approved in 
 
countries worldwide. An alternative aqueous formulation for use in the Respimat
inhaler 
(tiotropium 5μg q.d.) is approved in
 countries worldwide including EU and
Japan
. Further information 
about tiotropium can be found in the respective Summary of Product Characteristics (SPC)
for the product.
Tiotropium + olodaterol fixed dose combination
Tiotropium + olodaterol FDC is an aqueous solution of tiotropium and olodaterol contained 
in a cartridge. It is administered by using the RESPIMAT inhaler. The same device is used 
for tiotropium (approved in the EU and 
 other countries worldwide), olodaterol 
(approved in the EU and several other countries worldwide) and Combivent® (approved in 
the US). One cartridge is used per inhaler, which is inserted into the device prior to first use. 
In pivotal clinical trials and for the intended marketed product, the clinical dose consists of 
two actuations once daily. The RESPIMAT inhaler uses mechanical energy to create a soft 
mist which is released over a period of approximately 1.5 seconds.
In the pivotal studies (1237.5/.6), tiotropium + olodaterol FDC showed statistically 
significant improvements in FEV1 Area under the curve (AUC0-3h) response and trough 
Forced expiratory volume in one second (FEV1) response after 24 weeks compared to the 
mono-components and these improvements were maintained up to 52 weeks. The 
bronchodilatory profile of the combination was confirmed in a supportive 6-week study
(1237.20), in which the mean FEV1 improvements over 24 hours were superior to the mono-
components, with improvements in forced vital capacity (FVC), inspiratory capacity (IC), 
functional residual capacity (FRC), morning peak expiratory flow rate (PEFR) and evening 
PEFR supporting the results for FEV1.


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Tiotropium + olodaterol FDC showed statistically significant improvements in health-related 
quality of life (SGRQ) and dyspnoea experienced during everyday activities (TDI) after 24 
weeks compared to the mono-components. More patients treated with the combination had an 
improvement in SGRQ total score and TDI greater than the Minimal clinically important 
difference (MCID).
Treatment with tiotropium + olodaterol FDC resulted in reductions in both daytime and night 
time rescue bronchodilator use compared to the mono-components and patients treated 
perceived a greater improvement in their respiratory condition, as measured by a Patient´s 
Global Rating scale.
Tiotropium + olodaterol FDC was shown to be safe and well tolerated over 1 year in a 
moderate to very severe COPD population. The overall incidences of adverse events (AEs), 
serious adverse event (SAEs), fatal AEs, frequencies for cardiac events and Major adverse 
cardiovascular event (MACE) in the tiotropium + olodaterol FDC treatment group were 
similar to the mono-components. The nature and frequency of AEs in general was consistent 
with the disease under study. There were no results in the clinical development program 
suggesting the need for absolute contraindications for the combination product.
In conclusion, the clinical trials conducted to date have shown tiotropium + olodaterol FDC 
to be a safe, well tolerated and efficacious combination therapy according to treatment 
guidelines in a moderate to very severe COPD patient population that included patients with 
concomitant cardiovascular diseases.  The observed incremental bronchodilator response for 
the combination compared to the individual components translated into benefits that were 
meaningful to the patient, with improvements in several patient centred outcomes. For further 
information please refer the Investigators Brochure for the Tio+Olo FDC [c01735808].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
According to the GOLD guidelines, exacerbations are important events in the course of 
COPD as they have major impact on the patient`s quality of life and cause an increase in 
symptoms and a deterioration of lung function that may take several weeks to recover from. 
Moreover an exacerbation will accelerate the decline of lung function and is associated with 
significant mortality, especially if a hospitalisation is needed. It is without doubt, that 
exacerbations are associated with significant socioeconomic costs [P14-01052]
The benefits of tiotropium + olodaterol (5/5 μg) FDC that have been studied in the Phase III 
program include improvements in lung function, quality of life, dyspnea and exercise 
endurance time, but the benefit on exacerbations has not formally been assessed.
2.2
TRIAL OBJECTIVES
The aim of this study is to demonstrate that once daily treatment with tiotropium 5 µg + 
olodaterol 5 µg fixed dose combination will reduce the number of exacerbations over 
tiotropium 5 µg monotherapy. 
A secondary aim of the study is an assessment of a potential impact of tiotropium 5 µg + 
olodaterol 5 µg FDC on hospitalisation associated with exacerbations and survival, as 
compared to tiotropium 5 µg monotherapy. The latter will be included as secondary 
endpoints.
See section 5 for details concerning endpoints.
2.3
BENEFIT - RISK ASSESSMENT
The potential benefits of a treatment with tiotropium and tiotropium + olodaterol (5/5 μg)
FDC from the Respimat have been described above. Tiotropium is a well-established
maintenance treatment for patients with COPD across all severities. 
The clinical trials conducted to date have shown tiotropium + olodaterol (5/5 μg) FDC to be a 
safe, well tolerated and efficacious combination therapy according to treatment guidelines in 
a moderate to very severe COPD patient population (including patients with concomitant
cardiovascular diseases). The observed incremental bronchodilator response for the 
combination compared to the individual components translated into benefits that were 
meaningful to the patient, with improvements in several patient centred outcomes. Potential 
risks associated with administration of tiotropium include the listed (expected) adverse events 
for tiotropium monoproduct ([U92-0551]).
Potential risks associated with administration of the combination of tiotropium and olodaterol 
include the listed (expected) adverse events for tiotropium + olodaterol (5/5 μg) FDC.


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Women of childbearing potential may be included in clinical trials for tiotropium + olodaterol
(5/5 μg) FDC provided appropriate precautions are taken to minimize the risk of pregnancy. 
These precautions include pregnancy testing and use of a highly effective method of birth 
control.  Continued testing and monitoring during the trial should be sufficient to ensure 
compliance with the measures not to become pregnant during the period of drug exposure 
(which may exceed the length of study until the follow-up visit at 21 days after 
discontinuation of study medication) [R05-0370].
The trial design requires that patients will be randomized at Visit 2 (1:1) to one of the 
following treatments:
i.
Tiotropium + olodaterol FDC (2.5 µg / 2.5 µg per actuation) inhalation solution 
ii.
Tiotropium (2.5 µg / per actuation) inhalation solution (control group)
There is no placebo comparator in this trial.
Patients taking commercial tiotropium with/without LABAs will take their maintenance 
treatment up to the day prior to the randomization visit (visit 2).
Patients receiving inhaled corticosteroids before enrolment will continue their treatment (or 
the inhaled corticosteroids component alone if taken as a fixed combination with 
bronchodilator) at the same equivalent dose and regimen during the study. The only 
medications that are excluded during the treatment period are anticholinergic and long-acting 
β-adrenergic other than the study drugs.
The proposed medication restriction scheme is considered ethically acceptable given the 
availability of rescue SABA and permitted use of other maintenance medications in 
conjunction with close clinical monitoring for exacerbation symptoms.
During the whole course of the trial Boehringer Ingelheim will provide open-label 
salbutamol/albuterol HFA MDI to be used as rescue medication for all patients after they 
have signed their informed Consent.
Safety will be monitored (as described in Section 5.2) at site visits and at each telephone
contact alike. Patients will be contacted by site staff and asked for COPD exacerbation status, 
adverse events and change in concomitant therapy.
The study will be conducted under the guidance of a Steering Committee (SC).
An adjudicated analysis of all deaths will be also performed by an independent Mortality 
Adjudication Committee (MAC) in a blinded manner.
In conclusion, the proposed assessment of a potential added benefit of olodaterol to the 
known effects in reducing exacerbations shown with tiotropium alone is an important medical 
and health economic question. Therefore the potential benefits for patients outweigh potential 
risks and justify clinical development of tiotropium + olodaterol (5/5 μg) FDC. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a randomised, double-blind, active-controlled parallel group, phase IIIb study to 
evaluate the effect of 52 weeks of once daily treatment of orally inhaled tiotropium + 
olodaterol (5/5 μg) fixed dose combination compared with tiotropium on Chronic Obstructive 
Pulmonary Disease (COPD) exacerbation in patients with severe to very severe COPD and 
with one or more moderate to severe COPD exacerbation during the previous 12 months. 
The study is multinational and involves more than 50 participating countries.
The trial consists of three consecutive study periods including the screening, the treatment 
and follow-up periods. An overview of the trial design is shown in Figure 3.1:1.
Figure 3.1:1 Study Design
Having obtained the signed informed consent, the patient will be entered in a maximum 7-
day screening period to confirm the patient’s eligibility. At Visit 2 after a successful review 
of the inclusion and exclusion criteria, the patient will be randomly allocated in equal ratio to 
receive once daily study treatment (Refer to section 4.1.2) and will then enter the 52-week 
treatment phase. The randomised treatment period consists of five 3-monthly clinic visits and 
in the interim a telephone contact will be scheduled every 6 weeks (Refer to Flow chart).
The planned on-treatment period will begin with the administration of the first dose of trial 
medication and until the completion of visit 6/EoT.


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The patient’s trial participation will be concluded with the follow-up visit 21 days after 
V6/EoT.
For visit details please refer to section 6.2.
Patients who prematurely discontinue from their treatment period will be followed for vital 
status and COPD exacerbation status via phone calls until their predicted normal exit date 
from the trial (i.e. 52 weeks after taking the first dose of randomised treatment + 21 days). 
Please refer to section 3.3.4.1 and section 6.2.4.
Adverse events and moderate to severe COPD exacerbation events will be documented 
throughout the trial, i.e. starting with informed consent and ending 21 days after last 
administration of trial medication.
3.1.1
Administrative structure of the trial
Sponsor: Boehringer Ingelheim, as trial sponsor, will provide funding and trial materials, 
including study medication.  The sponsor has appointed a Trial Clinical Monitor (TCM), 
responsible for coordinating the activities required in order to manage the trial in accordance 
with applicable regulations and internal Standard Operating Procedures (SOPs), directing the 
clinical trial team in the preparation, conduct, and reporting of the trial, order the materials as 
needed for the trial, ensures appropriate training and information of local clinical monitor 
(CML), Clinical Research Associates (CRAs), and investigators of participating country.
Data Management and Statistical evaluation will be done by BI according to BI SOPs. For 
these activities, a Trial Data Manager and a Trial Statistician have been appointed.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs.
A list of responsible persons and relevant local information (as protocol reference if 
applicable) are in the investigator site file (ISF) and the trial master file (TMF) document.
Co-ordinating Investigator: the coordinating investigator is selected based on 
 expertise in 
this therapeutic area and reputation for being a leader in 
 field.
 will review the trial 
protocol, any subsequent amendments to the protocol and the Clinical Trial Report (CTR). 
 will provide 
 signature on the final protocol signature page and amendments and will 
provide 
 signature on the CTR indicating that, to the best of Co-ordinator’s knowledge, the 
final CTR accurately describes the conduct and results of the Trial.
Targeted group of Investigators: all physicians/qualified sites with access to the requested 
patient population and the facilities required to conduct the study assessments. The sites have 
to be able to perform electrocardiogram (ECG) and to conduct the procedure of blood 
sampling for clinical haematology and biochemistry. Patients will be treated on an outpatient 
basis. Recruitment is competitive. However, it is anticipated that each site will enrol an 
average of 10-12 patients. Beyond this commitment, sites will be able to include more 
patients after discussion and agreement with the TCM.


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Mortality Adjudication Committee (MAC): an independent mortality adjudication committee 
will be established for the blinded adjudication of all fatal cases in the trial.
A MAC Charter, under which the principles of the study design can be carried out, will 
govern their activities. The charter will provide detailed definitions of each endpoint and the 
processes by which adjudication will occur, including how blinding will be preserved.
Centralized laboratory: The sample transport logistics (from site to sponsor) and blood 
analysis will be the responsibility of the central laboratory. The central laboratory will 
provide sampling, urine dip stick pregnancy test and shipment materials.
ECG: A standard 12-lead electrocardiogram will be performed on all patients at the screening 
visit using the site´s own equipment.
Pulmonary function testing: historical spirometry data from measurements within the past 3
months either at the site or at a referral site may be used for inclusion into the trial. No 
spirometry equipment needs to be available at the site. Should for practical reason, the 
pulmonary function testing (PFT) be performed at the trial site, the spirometers and their use, 
including daily calibration, must meet ATS/ ERS criteria (P05-12782).
IRT: an Interactive Response Technology (IRT) system will be used for randomisation in this 
trial and for allocation of trial medication to patients throughout the treatment period. The 
ability to unblind will be available to the investigator via IRT.
Patient’s reminder card: all patients will be provided with a paper diary to serve as a reminder 
to support the structured COPD questionnaire clinic and telephone interview.
Trial documentation: all trial relevant documentation will be stored by Boehringer Ingelheim 
in the clinical trial master file (TMF). Trial relevant documentation for the trial sites will be 
filed in the Investigator Site File (ISF) at the investigator sites.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
A randomised, double-blind trial design with parallel treatment groups is a well-established 
design to compare beneficial effects of once-daily tiotropium+olodaterol FDC and tiotropium
on moderate to severe COPD exacerbations. Tiotropium has shown in numerous studies that 
it reduces the risk for a COPD exacerbation. Therefore tiotropium is the logical choice as 
active comparator for this trial. 
End of study is defined as last patient out. This will be after the last patient has received their 
last dose of study drug and completed the follow-up visit 21 days thereafter. 
The control group
The control group comprises the same type of COPD patients who are randomly allocated to 
receive tiotropium 5 µg Respimat®.
3.3
SELECTION OF TRIAL POPULATION
It is widely accepted that a COPD exacerbation increases the risk of the occurrence of future 
COPD exacerbations and that the frequency of exacerbations increases with progression of
COPD. The trial will recruit patients with severe lung function impairment and a history 
occurrence of moderate to severe treated COPD exacerbations, as these patients are known to 
have greater likelihood of having a re-occurrence of COPD exacerbation. The eligibility 
criteria employed in the study will allow enriching the patient population by ensuring the 
recruitment of patients prone to exacerbations.
This trial will be conducted worldwide and the distribution of patients between the countries 
will be dependent on the access to suitable patients as well as the operational feasibility of 
performing the trial in the country. It is anticipated that each site will enrol an average of 10 
to 12 patients.
An estimated total of 7800 patients randomised will be necessary to assess the primary 
endpoint “Annualised rate of moderate to severe COPD exacerbation during the treatment 
period”. Between Visit 1 and Visit 2, a low screen failure rate of 5% is foreseen due to the 
short screening period and, therefore, a lower likelihood for the enrolled patient to experience 
a new COPD exacerbation before the randomisation visit.
A log of all patients included 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 study entry
Outpatients with a history of COPD with severe to very severe pulmonary impairment 
(according to GOLD guideline) and having a documented history of at least one treated 
exacerbation in the previous 12 months are eligible for inclusion. All patients must fulfil all 


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of the inclusion criteria (Section 3.3.2) and do not present with any of the exclusion criteria
(Section 3.3.3).
3.3.2
Inclusion criteria
1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to 
participation in the trial, which includes medication washout and restrictions.
2. Male or female patients, 40 years of age or older.
3. All patients must have a diagnosis of COPD [P11-05865] and must meet the following 
spirometric criteria: stable airway obstruction with a documented post-bronchodilator 
FEV1< 60% 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).
Historical spirometry data within the past 3 months either at the site or at a referral site 
may be used or PFT measurement may be taken at the investigational site (See Appendix 
10.5 spirometry documentation).
4. Patients with a documented history (please refer to section 8.3.1) of at least one moderate 
to severe COPD exacerbation in the previous 12 months requiring treatment with 
systemic corticosteroids and/or antibiotics and/or related hospitalization.
5. Investigator should also ascertain that the patient is symptomatically stable as defined by:
no evidence of COPD exacerbation requiring use of either antibiotics and/or steroids 
4 weeks prior to visit 1,
no evidence of change in their usual COPD medication 4 weeks prior to visit 1.
6. Patients must be current or ex-smokers with a smoking history of more than 10 pack 
years. (See Appendix 10.5 calculation of number of pack years).
7. Patients must be able to perform all trial related procedures at the investigator discretion 
including:
technically acceptable and eligible pulmonary function test (if performed at site)
vital status follow-up in case of discontinuation until the predicted exit date (i.e.: 52 
weeks from first intake of randomised treatment + 21 days). 


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COPD exacerbation interview every 6 weeks in case of premature discontinuation 
until the predicted exit date (i.e.: 52 weeks from first intake of randomised treatment 
+ 21 days). 
8. Patients must be able to inhale medication in a competent manner from the Respimat®
inhaler (Appendix 10.1), and from a metered dose inhaler (MDI) in the opinion of the 
investigator.
3.3.3 
Exclusion criteria
1.
Patients with a significant disease other than COPD; a significant disease is defined as a
disease which, in the opinion of the investigator, may:
put the patient at risk because of participation in the study
influence the results of the study
cause concern regarding the patient’s ability to participate in the study.
2.
Patients with a, in the opinion of the investigator, clinically relevant abnormal baseline 
haematology, blood chemistry or creatinine > x2 ULN will be excluded regardless of 
clinical condition. (A repeat laboratory evaluation can be conducted if deemed necessary 
by the investigator.)
3.
Patients with a current documented diagnosis of asthma. For patients with allergic rhinitis 
or atopy, source documentation is required to verify that the patient does not have asthma
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 history of myocardial infarction within 6 months of screening visit (Visit 1).
6. Life-threatening cardiac arrhythmia, as judged by the Investigator.
7. Known active tuberculosis.
8. Any malignancy unless free of disease for at least 5 years (patients with treated basal cell 
carcinoma or squamous cell skin cancers are allowed).
9. A history of cystic fibrosis.
10. Clinically relevant bronchiectasis, as judged by the Investigator
11. Patients with severe emphysema requiring endobronchial interventions within 6 months 
prior to screening
12. A history of significant alcohol or drug abuse, as judged by the Investigator.


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13. 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).
14. Patients being treated with oral or patch β-adrenergics.
15. Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than 
4 weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone 
per day or 20 mg every other day.
16. Patients being treated with antibiotics for any reason (not limited to exacerbation 
infection) within 4 weeks of screening visit.
17. Patients being treated with PDE4 inhibitors within 3 months of screening visit (e.g. 
roflumilast) should not be enrolled and PDE4 inhibitors should not be withdrawn for the 
purpose of enrolling in this study.
18. Patients who have taken an investigational drug within one month or six half-lives
(whichever is greater) or in case the investigational drug (sub) class is listed within the 
wash-out period specified in table 4.2.2.1:1 prior to screening visit (Visit 1).
19. Patients with known hypersensitivity to β-adrenergic and/or anticholinergics drugs, BAC, 
EDTA, or any other component of the RESPIMAT inhalation solution.
20. Pregnant or nursing women.
21. Women of childbearing potential not using a highly effective method of birth control*. 
Female patients will be considered to be of childbearing potential unless surgically 
sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two 
years.
22. Patients who have previously been randomized in this study or are currently participating 
in another study.
23. Patients who are unable to comply with pulmonary medication restrictions prior to 
randomization.
* *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.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient will be withdrawn from the trial if any of the following criteria apply:


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
The patient withdraws consent, without the need to justify the decision.

The patient is no longer able to participate for medical reasons (e.g. pregnancy,
surgery, adverse events, or other diseases. 

Administrative reasons (protocol violations, persistent non-compliance).
No patient should be discontinued from the trial for a protocol violation before discussion 
with the clinical monitor. To be considered complete, a patient must complete all treatment 
visits (including telephone contacts) as specified in the flow chart.
Withdrawal from the screening phase
As long as a patient has not been assigned to a study treatment at Visit 2 (by IRT), the patient 
is not considered to belong to the treatment phase.  Prior to the randomisation, reasons for 
withdrawal can be connected with the criteria described in the section 3.3.4.1 or related to 
eligibility criteria (please refer to section 3.3.2 and 3.3.3).The data of patients who withdraw 
prior to randomisation will be entered in the trial database and will be listed.
Withdrawal from the treatment phase
If the patient has prematurely stopped taking the investigational product during the treatment 
phase, the withdrawn patient will be followed-up for vital status and COPD exacerbation 
status until the end of the planned treatment period of 52 weeks + 21 days. The objective is to 
collect information on vital status (dead or alive) and COPD exacerbation status in the time 
interval between the patients' withdrawal date from the treatment period and their predicted 
exit date. Please refer to section 6.2.3.2.
Please note
1. A patient should not be withdrawn from the trial because he/she experiences a COPD 
exacerbation during the treatment period.
2. If during the treatment period, the trial medication is for any reason (e;g. 
hospitalisation stay) interrupted more than 14 consecutive days, a discussion with the 
clinical monitor is required to re-assess the patient’s participation in the study.
Refer to Section 6.2.3 for procedures to be followed for patients prematurely terminating the 
trial.
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:

Failure to meet expected enrolment goals overall or at a particular trial site,

Emergence of any efficacy/safety information that could significantly affect 
continuation of  the trial 

Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing 
the appropriate conduct of the trial.


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
The investigator / the trial site will be reimbursed for reasonable expenses incurred in 
case of trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The study medication below will be supplied by Boehringer Ingelheim Pharma GmbH & 
Co.KG.
Patients will be randomized (1:1) to one of the following treatments:

Tiotropium + olodaterol FDC (2.5 µg / 2.5 µg per actuation) inhalation solution

Tiotropium (2.5 µg / per actuation) inhalation solution.
The patients inhale two puffs from the Respimat® inhaler, once a day, in the morning.
4.1.1
Identity of BI investigational product and comparator product
Substance (INN):
Tiotropium plus olodaterol fixed dose combination
Pharmaceutical form:
Inhalation solution
Unit strength:
2.5 µg / 2.5 µg per actuation
Total daily dose
5 µg / 5 µg q.d.
Route of administration: 
Oral inhalation via Respimat® inhaler (A5)
Dosage regimen:
2 inhalations once daily (a.m. dosing)
Substance (INN):
Tiotropium
Pharmaceutical form:
Inhalation solution
Unit strength:
2.5 µg per actuation
Total daily dose
5 µg q.d.
Route of administration: 
Oral inhalation via Respimat® inhaler (A5)
Dosage regimen:
2 inhalations once daily (a.m. dosing)
4.1.2
Method of assigning patients to treatment groups
When a patient is qualified for entry into the randomised treatment period, treatment 
assignment will be by means of a third-party phone/web-based randomisation on Visit 2. This 
will involve the use of an Interactive Response Technology (IRT) system which will 
implement a randomisation scheme generated using a validated randomisation software by 
Boehringer Ingelheim.
Refer to Section 4.1.6 for details on packaging and labelling.
Note that the Respimat® treatment box number assigned to the patient by the IRT is different 
from the study patient number assigned by the Remote Data capture (RDC) system upon 
signing informed consent.
Details on the IRT system are provided in the ISF.


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4.1.3
Selection of doses in the trial
The clinical trials conducted during the Phase III programme for tiotropium + olodaterol FDC
5/5 µg have shown that this dose is a safe, well tolerated and efficacious combination 
therapy. The observed incremental bronchodilator response for the combination compared to 
the individual components translated into benefits that were meaningful to the patient, with
improvements in several patient centred outcomes. An additional dose of tiotropium + 
olodaterol FDC has been studied during the Phase III programme, consisting of 2.5 µg 
tiotropium and 5 µg olodaterol. In the pivotal trials, a consistent difference in favour of 
tiotropium + olodaterol FDC 5/5 μg compared to tiotropium + olodaterol FDC 2.5/5 μg was 
demonstrated over the 52 week treatment period across various measures of lung function 
and patient-reported outcomes. 
Tiotropium + olodaterol FDC 5/5 μg demonstrated 
statistically significant and clinically relevant benefit over the individual components in all 
primary and secondary endpoints. On the other hand, the lung function improvement for 
tiotropium + olodaterol FDC 2.5/5 μg was more modest and a statistically significant benefit 
was not demonstrated in the pre-specified symptomatic primary endpoint, SGRQ total score.
Based on these observation, the tiotropium + olodaterol FDC 5/5 µg has been submitted for 
regulatory approval and is therefore considered to be the most appropriate dose to be studied 
in this trial.
Tiotropium 5µg (2.5 µg / per actuation) inhalation solution Respimat® has been approved in
more than 80 countries worldwide including Europe and Japan as an antimuscarinic 
bronchodilator with a once daily posology
. 
Therefore the marketed dose of tiotropium Respimat is deemed an adequate comparator for 
the study. 
4.1.4
Drug assignment and administration of doses for each patient
Trial medication will be dispensed to the patient by the investigator/pharmacist. At Visit 2 
eligible patients will be randomized to one of two double-blinded treatment arms (1:1 ratio) 
by the IRT. At subsequent clinic visits (every 3 months), the IRT will assign Respimat®
treatment boxes to each patient and each Respimat® treatment box will have a unique number 
with 6 digits. 
One of these Respimat® treatment boxes is a reserve Respimat® inhaler. This reserve kit 
allows the patient the flexibility of not having to return to the clinic immediately to replace a 
lost or malfunctioning Respimat® inhaler. In the event that a patient may need additional 
extra Respimat® inhalers and cartridges due to rescheduled visits, inhaler loss or malfunction, 
these will be supplied on an ‘on demand’ basis. Dispensing of these extra Respimat® inhalers 
will also be managed via the IRT.
Site personnel will enter all medication numbers dispensed to each patient in the Medication 
Record page of the electronic case report form (eCRF). 


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4.1.4.1 Priming of the Respimat® inhaler
Each newly assembled Respimat® inhaler has to be primed when appropriate. The Respimat®
inhaler should be primed by actuating it until an aerosol is visible plus three additional 
actuations. All priming actuations should be directed to the ground. 
Once assembled, the shelf-life of the Respimat® inhaler with study medication or training
medication (placebo) is 3 months. Therefore it is important to ALWAYS enter the date of the 
cartridge insertion on the medication label of the Respimat® inhaler immediately after the 
cartridge is inserted.
For detailed priming instructions please refer to the Respimat® inhaler handling instructions 
in Appendix 10.1
4.1.4.2 Study medication administration
For the patient’s sake of convenience regarding the trial drug administration, the clinic visit 
must be scheduled in the morning. During the treatment phase the patient will be instructed to 
withhold the morning dose of the trial medication in current use prior to come to visits 3, 4 
and 5 to avoid overdosing. 
The last administration of the study medication will be taken at visit 6 (EoT) from the
Respimat® inhaler that is in current use since no new Respimat® treatment box will be 
assigned.
Study medication administration at clinic visits
Dispensation and Respimat® inhaler assembling
Trial medication will be dispensed at visits 2, 3, 4 and 5. Patients will receive 3 new 
Respimat® treatment boxes + 1 Respimat® inhaler reserve. If the reserve kit is unused and 
intact, the IRT will not dispense a replacement reserve kit. During the clinic visit only one 
new Respimat® inhaler should be primed (= cartridge inserted and primed) under the 
oversight of the site staff. The other Respimat® inhalers should NOT be assembled prior to 
leaving the clinic. 
Drug administration
At each clinic visit, oral inhalation of two puffs of the study medication from the new 
assigned Respimat® inhaler will be self-administered by the patient under the direct 
supervision of the investigating physician or deputy. The investigator or qualified study 
personnel will observe the inhalation procedure. For training session please refer to section 
4.1.4.3.


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Respimat® inhalers return
At visits 3, 4, 5 and 6 all used and unused Respimat® will be returned to the clinic by the 
patient. If the reserve kit is unused and intact, the IRT will not dispense a replacement reserve 
kit.
For rescue medication dispensation, please refer to section 4.2.1
Study medication administration at home
Each morning, oral inhalation of two puffs on the study medication from the assigned 
Respimat® inhaler will be self-administered by the patient. Patients should be encouraged to 
take their study medication at approximately the same time in the morning (morning dose 
window until noon). If a patient misses the daily dose he/she should take the next dose the 
day after. The patient must assemble and prime the Respimat® inhaler at home once the 
current used Respimat® inhaler is empty and the device is locked.
The patient will be asked to record any missed dose of study medication in a patient’s 
reminder card.
4.1.4.3 Inhaler devices training 
SPECIAL CONSIDERATION: 
Most severe to very severe COPD patients are currently using different inhalation 
medications at the same time. This may cause technical challenges and affect their treatment 
adherence. Throughout the course of the study treatment period, the correct usage of their 
inhalation medications should be regularly re-instructed (ideally at each clinic visit) based on 
the package insert. 
Respimat®
Training on the use of the Respimat® inhaler will first be provided to the site staff who will 
subsequently train the patients. 

At visit 1: the first patient’s training session will be performed with the intention to
familiarise the patient with the Respimat® inhaler training medication (placebo). Detailed 
written instructions for the use of the Respimat® inhaler will also be given. (See Appendix 
10.1).

At visit 2: after the randomization, the second patient’s training session will be performed 
from the new assigned Respimat® inhaler. Instructions on how to assemble and prime the 
Respimat® inhaler at home should also be instructed.

Subsequent clinic visits: observance of the inhalation procedure. The correct inhalation 
technique should be reinforced in case of inadequate use of Respimat® inhaler. It is also 


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important to remind the patient on how to assemble and prime the Respimat® inhaler at 
home.
Rescue medication
Before using for the first time the Salbutamol (albuterol*) HFA MDI inhalation aerosol, one 
actuation should be released into the air to make sure the device is working. The patient’s 
inhaler technique should be reviewed and corrected if needed at each clinic visit.
4.1.4.4
Respimat® malfunctioning
Any Respimat® inhaler that has been reported as malfunctioning by a patient or investigator 
will be returned to Boehringer Ingelheim for investigation. See the ISF for specific
instructions and for details regarding drug accountability requirements.
Details of the procedure for the return of malfunctioning inhalers are provided in Appendix 
10.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators and everyone involved in analysing or with an interest in this double-
blind study will remain blinded with regard to the randomised treatment assignments until 
after database lock.
Boehringer Ingelheim will generate and store the randomisation schedule, and prepare and 
code the medication in a blinded fashion. Trial supplies will be assigned to the patients via 
IRT.
Refer to Section 4.1.5.2 for rules of breaking the code in emergency situations.
4.1.5.2
Procedures for emergency unblinding
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 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, 
rescue medication and Respimat® inhaler training kits. Expiry date will be pre-printed on the 
trial supplies labels.


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Open-label supplies= Non Investigational Medicinal Product (NIMP)

Training Respimat® inhaler, placebo cartridges and disposable mouthpieces for training 
purposes. A training device may be used for more than one training session. The training 
Respimat® can be used until 3 months after first insertion of the cartridge or until the 
device is empty.  The date of the cartridge insertion should be entered on the medication 
label of the Respimat® immediately after the cartridge is inserted. A new mouthpiece 
should be used for each patient.
Respimat® inhaler and disposable mouthpieces for training purposes will be provided by 
IRT along with the initial supply order.

Salbutamol (albuterol*) HFA MDI inhalation aerosol (100 µg per actuation) for use as 
rescue medication during screening, treatment and follow-up periods. The rescue 
medication will be provided by BI and purchased locally.

Salbutamol (albuterol*) HFA MDI inhalation aerosol (100 µg per actuation) will also be 
used for qualifying PFT at Visit 1 (+4/*,5%(*6 +-A?+(-=69. 
* NOTE: Albuterol sulphate is the official generic name in the US and salbutamol sulphate is 
the WHO recommended generic name.
Blinded study medication= Investigational Medicinal Product (IMP)

Packaging: the Respimat® treatment box will contain one Respimat® inhaler plus one 
drug-filled cartridge and contains sufficient medication for 30 days of treatment. The 
Respimat® inhaler will lock after 60 actuations have been administered and will no longer 
actuate any medication. 

Labelling: individual Respimat® treatment box will have a three-part tear-off label. One 
part of each tear-off label should be attached to the drug accountability form which will 
be part of the ISF, and one part will remain on the box (an extra part is available as well).
The investigator or designee should fill out the following information:
o
date of cartridge insertion should be entered at time of cartridge insertion on the 
cover page of the cartridge booklet
o
Investigator’s name should be entered at time of dispense on the cover page of the 
booklet on the Respimat® treatment box.
For details of the packaging and the description of the label, refer to the ISF.
#%?+-44'6 
Each site will receive a first supply at or after the initiation visit and will be resupplied upon
demand by IRT.
4.1.7
Storage conditions
All clinical trial supplies must be stored in a locked, secure cabinet and must be kept in their 
original packaging under the recommended storage conditions and may only be dispensed to 
trial subjects according to protocol. A temperature log must be maintained to assure that the 
drug supplies are stored at the correct temperature.


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The Respimat® inhaler and cartridges should be stored as indicated on the country specific 
booklet page. A temperature log must be maintained at the site to make certain that the drug 
supplies are stored at the correct temperature. If the storage conditions are found to be outside 
the specified range, immediately contact the local clinical monitor. 
Further details are provided in the IB and on the country-specific labels, a sample of which 
will be part of the ISF.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

approval of the study protocol by the IRB / ethics committee,

availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,

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 or immediately imminent 
signing of the clinical trial protocol, in exceptional cases, medication could already be 
sent to the site, before its activation via IRT.

if applicable: availability of the proof of a medical licence for the principal 
investigator, 

for USA availability of the Form 1572.
The investigator / pharmacist / investigational drug storage manager must maintain records 
of:

the product’s delivery to the trial site, 

the inventory at the site, 

the use by each patient, 

the return to the sponsor or alternative disposition of used/unused trial medication. 

the adequate documentation that the patients were provided the doses specified by the 
CTP

the reconciliation of all investigational products received from the sponsor
At the time of return to the sponsor, the investigator and/or pharmacist and/or investigational 
drug storage manager must verify that all drug supplies used/ unused or partially used have 
been returned by the clinical trial patient and that no remaining supplies are in the 
investigator’s possession.
The investigator/pharmacist will record on the drug accountability forms the following 
information.
Respimat® inhaler:
dates (dispense and return), 
dispenser’s initials,


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batch/serial numbers, 
expiry dates, 
the unique Respimat® treatment box number assigned by IRT,
trial patient number assigned by the RDC system.
See Section 4.1.2. It is important to enter the date of priming on the medication label of the 
Respimat®.  
Rescue medication:
One NIMP accountability form will be provided for salbutamol to the trial site. This record
will include:

dates (dispense and return)

dispenser’s initials

quantities,

batch/serial numbers,

expiry date,

the trial patient number assigned by the RDC system.
The patient will be asked to return all used/unused rescue medication inhalers at each clinic 
visit. Source data documentation and full drug accountability in regard to dispensed and 
returned medication to investigational site and to patients are required. Only used inhalers 
will be replaced at each clinic visit. For further details, please refer to section 4.2.1 (Rescue 
medication).
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
4.2.1.1 Rescue medication
Patients could use the open-label salbutamol /albuterol* inhalation aerosol (HFA-MDI) for 
p.r.n use as needed for symptom relief. Administration of rescue medication can occur at any 
point during the trial as deemed necessary by the patient or the investigator. 
Rescue medication will be issued to all patients at the screening visit (Visit 1) and can be 
dispensed at any time during the study until the follow-up Visit. It is important to provide 
sufficient rescue medication inhalers to cover the period between 2 clinic visits (3 months). 
Rescue medication training and testing: please refer to section 4.1.4.3
Rescue medication supply: please refer to section 4.1.6
Rescue medication accountability: please refer to section 4.1.8


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4.2.1.2 Emergency procedures
There are no special emergency procedures to be followed.
4.2.1.3 Additional treatments
In the case of COPD exacerbations, investigators are allowed to prescribe whatever COPD 
medication they deem appropriate for the patient.
The use of antibiotics is not restricted and may be prescribed as medically necessary for
exacerbations and / or infections. 
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.
The COPD maintenance therapy including
long-acting 
anticholinergic, inhaled corticosteroids and long-acting β-adrenergic drugs given either alone
or in combination should be discussed at Visit 1 in order to adapt optimal treatment 
management in tune with the Table 4.2.2.1:1 (Permitted Medications and Medication 
Restrictions). 
Patients receiving corticosteroids at baseline (inhaled corticosteroid component alone if taken 
as fixed combination with a bronchodilator) will continue treatment at the same dose or 
equivalent dose and regiment during their treatment period. If the patient withdraws from the 
treatment period, the dual ICS/LABA could be resumed.
Please refer to Section 3.3.4.1 (Removal of individual patients).
ICS mono-product adjustment is allowed during COPD exacerbation and should be linked to 
the reported exacerbation event.


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Table 4.2.2.1: 1 Permitted Medications and Medication Restrictions
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment Period
Follow up Period
Corticosteroids
Inhaled corticosteroids (iCS)
(stabilized 4wks prior to V1)
Permitted3
Permitted3
Permitted3
Permitted3
Oral corticosteroids
[≤10 mg prednisone per day or ≤20 mg prednisone every 
other day (or equivalent); stabilized 4 wks prior to V1]
Permitted
Permitted
Permitted
Permitted
Injected corticosteroids 
local administration (e.g. bursitis) 
Permitted
Permitted
Permitted
Permitted
Nasal corticosteroid  sprays
Permitted3
Permitted3
Permitted3
Permitted3
β-adrenergics
Inhaled short-acting β-adrenergics (SABA)
Permitted
Rescue medication
(as supplied) only 1
Rescue medication
(as supplied) only1
Rescue medication
(as supplied) only1
Inhaled long-acting β-adrenergics (bid)
(LABA)
(e.g. formoterol / salmeterol)
Permitted
Permitted5
NOT permitted
Permitted
Inhaled long-acting β-adrenergics (qd)
(e.g: indacaterol, vilanterol)
Permitted
Permitted5
Study medication
ONLY permitted
Permitted
Oral and patch beta-adrenergics
NOT permitted2
NOT permitted
Permitted
Beta blockers
(stabilized 6 wks prior to V1)
Permitted
Permitted 
Permitted 
Permitted 
Anticholinergics
Short-acting anticholinergics
(e.g: inhalation aerosol, nasal spray)
Permitted
Permitted5
NOT permitted
Permitted
Long-acting anticholinergics (bid/qd)
(e.g: commercial tiotropium, umeclidinium aclidinium, 
glycopyrronium)
Permitted
Permitted5
Study medication
ONLY permitted
Permitted


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Table 4.2.2.1: 1 Permitted Medications and Medication Restrictions (cont’d)
Drug Class
Sub-class
Prior to study
Study Period
Screening Period
Treatment Period
Follow up Period
Combinations
iCS/LABA (bid/qd)
Switch to iCS mono-product at the same dose or equivalent dose 
and regiment during their treatment period.
(e.g.fluticasone/vilanterol)
Permitted
Permitted5+6
NOT permitted
Permitted
iCS/SABA
Switch to iCS mono-product at the same dose or equivalent dose 
and regiment during their treatment period.
Permitted
Permitted5+6
NOT permitted
Permitted
Inhaled long-acting anticholinergics/ LABA
(e.g.glycopyrronium+indacaterol, umeclidinium+vilanterol)
Permitted
Permitted5+6
NOT permitted
Permitted
Short-acting anticholinergic/ SABA
Permitted
Permitted5
NOT permitted
Permitted
Antibiotics
For respiratory infections
The use of antibiotics is not restricted and may be prescribed as 
medically necessary for COPD exacerbation episodes and / or 
infections.
NOT permitted2
Permitted
(except antibiotics for prevention of exacerbation of COPD)
Any other infections
NOT permitted2
Permitted
Permitted
Permitted
Miscellaneous
Other investigational drugs 
(*see exclusion criterion #18)
NOT permitted2
NOT permitted
Cromolyn sodium / nedocromil sodium3
Permitted
Permitted
Permitted
Permitted
Antihistamines (including nasal route), 
antileukotrienes3
Permitted
Permitted
Permitted
Permitted
Methylxanthines3
Permitted
Permitted
Permitted
Permitted
Mucolytics not containing bronchodilators
(stabilized 4 weeks prior to V1)
Permitted
Permitted
Permitted
Permitted
Mucolytics  containing bronchodilators
NOT permitted2
NOT permitted
PDE-4 inhibitor (e.g: Roflumilast)
NOT permitted4
NOT permitted
1.
Use rescue medication delivered at Visit 1 (or Visit 0 for patients involved in the sub-study)
2.
Not permitted within 4 weeks prior to screening visit (w.o. 4 wks prior to V1)
3.
Permitted if prescribed for non-asthma condition
4.
Patients who were using roflumilast in the past may be included if their last use was a minimum of 3 months prior to Visit 1. In the event a patient with prior use of roflumilast is enrolled, past 
medical records are required to support and document why and when roflumilast was stopped.
5.
Treatment(s) should be discontinued at the latest the day before Visit 2 without wash-out requirement.
6.
Last dose of ICS/LABA combination product at the latest the day before Visit 2 and first dose of mono-ICS the day of Visit 2.


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4.2.2.2
Restrictions on diet and life style
Not applicable to this trial.
4.3
TREATMENT COMPLIANCE
Each patient will be trained in the correct use of the Respimat® inhaler using the training 
Respimat® inhaler with inserted placebo cartridge. Please refer to section 4.1.4.3.
Patients will be asked to return inhalation aerosols and devices (used and unused) to the study 
site. The trial medication adherence should be reviewed by the investigator and reported in 
the eCRF. 
Estimating Compliance to trial medication
Knowing the time interval between clinic visits should provide the estimate of the number of 
puffs that should have been administered by the patient three or four Respimat® inhalers used 
during that period of time.
The Respimat® inhaler contains 60 actuations (30 daily doses). The dose indicator shows 
approximately how much medication is left.  When the pointer enters the red area of the 
scale, there is, approximately, medication for 7 days (14 actuations) left.  
The dose indicator scale is divided into 4 quarters. One-quarter used accounts for 7 days of 
treatment (14 actuations).
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. Over a period of 3 months that is to say between 2 
clinic visits, patient should return 3 Respimat® inhalers empty (the dose indicator has reached 
the end of the red scale). The acceptable medication compliance should have an overall value 


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in the range from 80% to 100%. If the compliance is less than 80% the patient needs to be re-
trained. Please refer to section 4.1.4.3.
Randomised patients should not be discontinued for a lack of compliance without prior 
discussion with the local clinical monitor.
Figure 4.3:1 Respimat® inhaler dose indicator


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY 
In this study, it is important to note that lung function measurements are not used as criteria 
for treatment effectiveness. The primary efficacy endpoint is based on the annual rate of 
moderate/severe COPD exacerbations during a fixed-treatment period of 52 weeks.
5.1.1
Endpoints of efficacy
Primary endpoint

Annualised rate of moderate to severe COPD exacerbation during the treatment period
(within 1 day* after the last drug administration date).
Key secondary endpoint

Time to first moderate to severe COPD exacerbation during the treatment period
(within 1 day* after the last drug administration date).
Secondary endpoints 

Annualised rate of exacerbation leading to hospitalisation during the treatment period 
(within 1 day* after the last drug administration date).

Time to first COPD exacerbations leading to hospitalisation during the treatment 
period (within 1 day* after the last drug administration date).

Time to all-cause mortality (within 1 day* after the last drug administration date).


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5.1.2
Assessment of efficacy
5.1.2.1 Definition of moderate and severe 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 a prescription of antibiotics and / or systemic 
steroids and/or hospitalisation.
A complex of lower respiratory events / symptoms is defined as at least two of the following:

Shortness of breath

Sputum production (volume)

Change in sputum colour

Cough

Wheezing

Chest tightness
“Onset of exacerbation” will be defined by the onset of first recorded symptom. The “end of 
exacerbation” will be decided by the investigator based on clinical judgment.
Exacerbations will be classified as follows:
Mild: 
a new prescription of maintenance bronchodilator only
Moderate: 
patient receiving an exacerbation-related prescription of oral corticosteroids 
and/ or antibiotic not requiring hospitalisation.
Severe: 
COPD-related hospitalisation including emergency room visit*
To consider hospitalisation associated with COPD exacerbation, the information collected 
should include the start date of all COPD-related hospitalisations as well as the discharge date 
from the hospital or equivalent


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*Visit in emergency is defined as: an unscheduled emergency room visit resulting in
prescription of oral corticosteroids and/ or antibiotic.
Only the investigator-diagnosed COPD exacerbation fitting the above criteria of moderate to
severe COPD exacerbation will be used for the analysis of the annualized moderate to severe 
exacerbation rate as the primary endpoint. 
5.1.2.2 Assessment of moderate and severe COPD exacerbations
Information regarding exacerbations will be collected by the physicians during the visits and 
will be recorded in the eCRF. During all telephone calls and clinic visits, the same questions
regarding exacerbation will be addressed for collecting exacerbation-related details and then 
recorded in the eCRF.
At every clinical visit, the investigator will be asked to review (not to collect) the patient’s 
reminder card and all telephone calls since the last clinical visit to ensure that all 
exacerbations have been recorded and that the exacerbations meet the definition of study 
exacerbation.
The investigator (or deputy) will record the COPD exacerbation information the length of 
time the patient is treated with the trial medication but also for patients who will discontinue 
early. 
For all patients (completed/discontinued) the COPD exacerbation collection time of interest
will be the planned 52-week + 21 days starting from visit 2.
If patients are hospitalised, the study site will be responsible for collecting and reviewing 
pertinent medical records so that an informed judgment can be made as to the primary cause 
for admission.
Patient’s reminder card
The patient’s reminder card will be used to note changes in symptoms, missed dose 
medication or utilisation of health care services between visits and serve as a reminder for the 
patients. The patient reminder cards will not be collected by the site and remains the 
exclusive property of the patient. The patient will complete reminder cards entries daily from 
Visit 2 until the follow-up visit. 
In case of withdrawal from the treatment phase, discontinued patients are encouraged to 
complete their reminder cards in order to be able to answer questions on their COPD 
exacerbation status.


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5.1.2.3
Assessment all-cause mortality
Death from any cause includes cardiovascular death, non-cardiovascular-death and 
undetermined cause of death, as classified by adjudication.
For all patients 
(completed/discontinued) vital status collection time of interest will be the planned 52-week 
+ 21 days starting from visit 2.
Further details on death classification will be specified in the mortality adjudication charter.
5.2 
SAFETY
5.2.1
Endpoints of safety
Adverse events, serious adverse events and fatal adverse events 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, 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 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Cancers of new histology or exacerbations of existing cancer are considered serious adverse 
events. 
Vital status and COPD exacerbation status from patients who prematurely discontinue 
treatment will be collected.
ADDITIONAL INFORMATION FOR JAPAN:
The following events will be handled as “deemed serious for any other reason”. An AE which 
possibly leads to disability will be reported as an SAE. Every new occurrence of cancer will 
be reported as a SAE regardless of the duration between discontinuation of the drug and the 
occurrence of the cancer.


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Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which 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 adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms. 
ADDITIONAL INFORMATION FOR JAPAN:
The reason for the decision on causal relationship needs to be provided in the eCRF.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the 
AE. 
If a SAE is reported from a still blinded trial, the causal relationship must be provided by the 
investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. 
any active comparator).
The Investigator (or designee) will enter these events (even if they meet the criteria of an 
SAE) in the corresponding pages in the eCRF within 24 hours of awareness, as well as 
providing any defined supporting documentation This will be provided by the Sponsor to the 
AC, as defined in the charter.
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF.
Changes in vital signs, physical examination, and laboratory test results
Changes in vital signs, physical examination and laboratory test results will be recorded as an 
(S)AE in the eCRF , if they are judged clinically relevant by the investigator.
Protocol-specified adverse events of special interest (AESIs)
There are no protocol-specified adverse events of special interest (AESIs) in this trial.


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5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the follow-up period until 21 days
after the last administration of trial medication) will be collected, documented and reported to 
the sponsor by the investigator on the appropriate eCRFs / SAE reporting forms. Reporting 
will be done according to the specific definitions and instructions detailed in the ‘Adverse 
Event Reporting’ section of the Investigator Site File. 
For each adverse event, the investigator will provide:

Onset date

End date

Intensity

Treatment required

Outcome

Seriousness*

Action taken with the investigational drug. 

Causal relationship: SAEs and non-serious AEs must include a causal relationship 
assessment of the investigational drug made by the investigator as defined in 
section 5.2.2.1. 
The investigator must report the following events via telephone/fax using the SAE form 
immediately (within 24 hours or the next business day, whichever is shorter) to the sponsor: 
SAEs and non-serious AEs relevant to the reported SAE.
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. SAEs and non-serious AEs must include a causal relationship assessment made by 
the investigator.
Always serious adverse events 
BI has set up a list of AEs which are defined to be always serious. The list of these adverse 
events can be found via the RDC-system. In order to support the investigator with the 
identification of these “always serious adverse events”, if a non serious AE is identified to be 
serious per BI definition, a query will be raised. The investigator must verify the description 
and seriousness* of the event.  If the event description is correct, the item “serious” needs to 
be ticked and an SAE has to be reported in expedited fashion following the same procedure 
as above.
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. 
ADDITIONAL INFORMATION FOR JAPAN: this information must be also reported 
immediately to the head of the trial site.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File). This 
immediate report is required irrespective of whether the investigational product has been 


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administered or not and irrespective of causal relationship. It also applies if new information 
to existing SAEs or protocol-specified adverse events becomes available. 
AE and SAE reporting including the Follow-up period
The investigator also has the responsibility to report all serious and non-serious AEs 
occurring within the 21 days (+ 7 days of agreed time window) residual effect period. Any 
AEs reported to the sponsor during this period must be documented in the safety database.
All events with an onset after the first dose of trial medication up to a period of 21 days (+ 7 
days) after the last dose of trial medication will be assigned to the treatment period for 
evaluation.
AE and SAE reporting after the follow-up period
The Investigator does not need to actively monitor patients for AEs once the clinical trial has
ended. However, if the Investigator becomes aware of an SAE that occurred after the patient
has completed the clinical trial (including the follow-up period), the Investigator should 
report it to the sponsor if the Investigator considers it relevant to BI investigational product.
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours or next business day 
whichever is shorter) to the defined unique entry point for SAE forms of the respective BI 
OPU (country-specific contact details will be provided in the Investigator Site File). The 
study medication must be interrupted without delay (i.e.; as soon as pregnancy is known).
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical 
Trials and not the SAE form is to be completed. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
5.2.2.3
Vital status collection
The vital status collection will only concern patients having prematurely withdrawn BEFORE 
their predicted trial exit date. For the period of interest and frequency of survival information, 
please refer to section 3.3.4.1. The vital status information does not require a patient visit. If 
no information can be collected after at least 3 attempted (documented) phone calls and at 
least one registered letter, the patient will be regarded as lost to follow-up.
5.2.3
Assessment of other safety parameters
The safety endpoints will also evaluate vital signs, routine laboratory evaluations and 
physical examination.


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5.2.3.1 Laboratory tests
Clinical laboratory testing will be conducted on all patients at Visits 1 and 6/EoT. The fasted 
condition is not required. The laboratory tests at Visit 1 will be considered as the baseline 
measurements and the results of the Visit 1 tests have to be assessed by the investigator or 
designee prior to randomisation, to ensure no exclusion criteria are met.
Follow-up clinical laboratory testing must be performed at the follow-up visit if there are any 
clinically significant findings at the last study treatment visit (for completed patient = visit 6). 
It is the responsibility of the investigator to evaluate changes in laboratory value and 
reporting of adverse event should be followed according to the definition outlines in section 
5.2.2.2.
Hematology

Hemoglobin, 

Hematocrit

Erythrocyte count

Total and differential leucocyte count eosinophil count and 

Platelet count.
Serum chemistry 

Alkaline phosphatase (ALP)

LDH

Gamma-glutamyltranspeptidase (GGT) 

Alanin aminotransferase (ALT) or SGOT 

Aspartate aminotransferase (AST) or SGPT 

Glucose

Calcium

Inorganic phosphorus

Uric acid

Urea nitrogen

Creatinine

Protein (total)

Potassium

Sodium

Chloride

Total bilirubin

Creatinine phosphokinase.
Pregnancy Testing
A serum human chorionic gonadotrophin (HCG) test will be performed on all females of 
child-bearing potential at Visits 1 and 6 (or last study treatment visit in case of premature 
withdrawal). A urine dip stick pregnancy test will be performed at clinic visit (please refer to 
the flow chart).


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5.2.3.2
Physical examination
A complete, head-to-toe physical examination will be completed on all patients at Visits 1 
and 6 (or last study treatment visit in case of premature withdrawal).
All abnormal findings at Visit 1 will be recorded in the patients’ source documents and on the 
Medical History eCRF, if applicable. New abnormal findings or worsening of baseline 
conditions/medical history detected at Visit 6 will be re-assessed at follow-up visit and 
recorded as adverse events on the appropriate eCRF page.
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5.2.3.3
Electrocardiograms
A 12-lead ECG will be recorded at Visit 1 to evaluate the patient's eligibility. All abnormal 
findings at Visit 1 will be recorded in the patients’ source documents and on the Medical 
History eCRF, if applicable.
5.3 
OTHER
Other endpoints are defined in section 5.1.1
5.4
APPROPRIATENESS OF MEASUREMENTS
The occurrence of COPD exacerbations will be investigated at every clinic visits. The
exacerbation-related information will be reviewed and collected by the investigator during
the clinic visits and recorded in the eCRF. Only the investigator-diagnosed COPD
exacerbations that fit the criteria of moderate to severe COPD exacerbation definition section
5.1.2 will be used for the analysis of the exacerbation rate as primary endpoint. 


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Concomitant Therapies
All concomitant therapies taken within the 3 months preceding Visit 1 and throughout the 
study will be recorded in the subjects’ source documents and entered on the Concomitant 
Therapy eCRF, if applicable.
Cardiovascular risk-factor
Information on the cardiovascular (CV) risk-factors will be collected on all patients at the 
screening visit (Visit 1). The reported terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology.


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Pulmonary Function Testing
IF HISTORICAL DATA IS NOT AVAILABLE: the qualifying pulmonary function tests are
to be conducted at the investigational site. Subsequently, patients must have completed
spirometry at or within 3 months of the screening visit that meet the post-bronchodilator 
criterion listed in Section 3.3.2 for inclusion into the trial. Measurements of FEV1 and FVC 
will be performed using calibrated electronic spirometers at the investigational site or a 
referral site. Spirometers and their use, including daily calibration, must meet American 
Thoracic Society (ATS)/ European Respiratory Society (ERS) criteria (P05-12782).  
Spirometry will be conducted with the patient in a seated position. The test will be conducted 
in triplicate. The highest FEV1 and FVC from an acceptable maneuver will be recorded 
regardless of whether they come from different spirometric maneuvers or from the same 
maneuver ( preferably with a maximum of five attempts).


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable to this trial.
5.6
BIOMARKER
Not applicable to this trial.
5.7
PHARMACODYNAMICS
Not applicable to this trial.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
Not applicable to this trial.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. Some flexibility 
is allowed in scheduling the visits according to visit time windows as specified in the Flow 
Chart. If any visit has to be rescheduled, subsequent visits should follow the original visit 
date schedule (calculated from Visit 2). The trial medication kits contain sufficient 
medication to allow for these time windows. All deviations from the planned visit schedule 
will be documented.
The screening period should be restricted as much as possible to avoid any exacerbation 
episode during this period. For a patient in stable condition screening procedures should be 
completed within 7 days (between visit 1 and visit 2). The qualifying PFT and safety 
laboratory report must be available to confirm the eligibility at least on the day of 
randomization (Visit 2).
However, the screening period (between Visit 1 and Visit 2) may be extended by an 
additional 1 week for administrative reasons.
In case of respiratory tract infections or exacerbation during the screening period: visit 2 can 
be postponed 4 weeks following the recovery from the infection or exacerbation (based on 
the last dose of systemic corticosteroids and/or antibiotics). The complete procedures and 
observations of Visit 1 are to be repeated to ensure the complete review of the In/Ex criteria 
at Visit 2.
Rescheduling visits after Visit 2
If rescheduling of clinic visits after the randomisation is necessary, the total daily dose of the 
study medication needs to be maintained and the use of the reserve trial medication is 
recommended to continue the treatment without any interruption.
Any rescheduling of visits should be discussed with your monitor.


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
A preliminary check of in-/exclusion criteria with a particular focus on COPD exacerbation 
within the previous year is recommended to avoid unnecessary study procedures in non-
eligible patients.
A complete overview of assessments to be performed at each visit is provided in the trial 
Flow Chart. 
 
 
6.2.1
Screening period
Informed consent will be obtained prior to patient participation in the trial, which includes 
any medication washout procedures or restrictions. The study requirements, including the 
procedure for the follow-up of prematurely withdrawn patients must be fully explained to the 
patient and written informed consent obtained prior to initiating any study-related evaluation.
Patients will be assigned a study patient number by the Remote Data capture (RDC) system
once consent is signed. The site should also register the patient as a screened patient in IRT.
Eligibility will be assessed at the initial screening visit and confirmed at the randomisation 
visit (Visit 2). Patients who fail to complete all of the testing procedures will not be re-
enrolled at a later date.


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Screening Visit 1
Procedures and observations
Informed 
Consent
To be obtained prior to patient participation in the trial.
Demographics
Sex, race, date of birth, height, weight, trial indication with the 
duration of COPD will be recorded.
Cardiovascular 
risk-factor
Assessment
Physical 
examination
A complete head-to-toe physical examination including measurements 
of systolic and diastolic blood pressure and pulse rate. Refer to section 
5.2.3.2
(Sub-study)Vital signs must be taken immediately prior to the 
qualifying PFT
Concomitant 
diagnosis
Information for current conditions and conditions for which therapy is 
given. Any new clinically relevant findings (for instance after the ECG 
assessment or physical examination) should be reported (excluding 
trial indication).


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Qualifying * 
FEV1 and FVC 
*Based on historical data. A standard spirometry testing can be 
performed if no historical spirometry measurements within the last 3 
months are available at site. 
 
 
Haematology, 
serum chemistry
laboratory tests
To be submitted to the central laboratory.
(Fasted condition is not required).
Pregnancy test
Serum pregnancy test is to be conducted in all female patients of child 
bearing potential.
Smoking status
To be recorded
12-lead ECG
Performed locally.
Medication 
restriction 
Medication restriction outlined in Section 4.2.2 will be reviewed with 
the patient. 
In-/exclusion 
criteria
To be reviewed
Screening call 
(IRT)
Please refer to the IRT manual
Inhalation 
device trainings 
Training sessions on:
the use of rescue medication (salbutamol/albuterol)
the use of the Respimat® inhaler training medication (placebo)
Please refer to section 4.1.4.3 Inhaler devices training
Rescue 
medication 
Rescue medication will be issued to all patients. Please refer to section 
4.2.1.
Provide sufficient rescue medication inhalers to cover the period 
between 2 clinic visits. The patient should be instructed to return all 
used/unused rescue medication inhalers at each clinic visit.
Trial patient’s 
card
A trial identification card should be given.
Adverse events
To be checked
Concomitant 
medication
Medication used by the patient for the previous 3 months will be 
recorded in the source document on the Concomitant Therapies eCRF, 
if applicable.
Appointment
The qualifying PFT and safety laboratory report must be available to 
confirm the eligibility at least on the day of randomization (V2).
 
 


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6.2.2
Treatment periods
Patients who were already randomised in the study are not allowed to re-enter in case of 
premature discontinuation.
6.2.2.1 Randomisation Visit 2 (Day 1)
Procedures and observations
Pregnancy test
Urine pregnancy test is to be conducted in all female patients of child 
bearing potential prior to randomization.
Medication 
restriction 
review
Medication restriction outlined in Section 4.2.2 will be reviewed with 
the patient.
COPD 
exacerbation 
interview
Please refer to the section 5.1.2.2
Review of in-
/exclusion 
criteria
Conclusion of screening including the review of laboratory results to 
determine eligibility.
Randomisation 
call  
Please refer to the IRT manual
Assignment
of 
trial drugs
Allocate the appropriate medication kit using IRT.
Dispense 
trial 
drug
Three new Respimat® treatment boxes + 1 Respimat® inhaler reserve 
are assigned. Enter the date of priming on the medication label of the 
Respimat®. Record medication kit numbers in the eCRF.


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Trial drug: 
training and first 
intake 
The patient’s training session occurs after the randomization. The patient 
will self-administer the trial drug (from the new assigned Respimat®
inhaler) under the oversight of the site staff. Give instructions on how to 
assemble and prime the Respimat® inhaler at home.
Rescue 
medication 
Provide sufficient rescue medication inhalers to cover the period 
between 2 clinic visits. 
Patient’s 
reminder card
Patients will have the reminder card explained and will be provided with 
a copy. Refer to 5.1.2.2.
Patients will be instructed to bring the reminder card to the study site on 
the next scheduled visit (not to be collected by the site).
Adverse events
All adverse events experienced since the previous visit will be reviewed 
and documented.
Concomitant 
medication
Any changes in concomitant medications since the last visit will be 
reviewed and documented
Appointments
Patients will be instructed to bring all issued trial medication
(used/unused) and the rescue medication (used/unused) to the study site 
on the next scheduled clinic visit (Visit 3).
G.)%=-'%I

a phone appointment 6 weeks later

 

next clinic visit 3 months after the Visit 2


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6.2.2.2 Clinic visits (Visits 3, 4 and 5)
Procedures and observations
Pregnancy test 
Urine pregnancy test
COPD 
exacerbation 
interview

Patient’s reminder card (filled in by the patient) should be reviewed 
with the investigator.

Telephone call(s) information since the last clinic visit should be 
reviewed.
Please refer to the section 5.1.2.2
Patient’s 
reminder card
Patients will be provided with a new card.
Assignment of 
trial drugs
Allocate the appropriate medication kits using IRT.
Dispense trial 
drug
Three new Respimat® treatment boxes + 1 Respimat® inhaler reserve are 
assigned. Enter the date of priming on the medication label of the 
Respimat®. Record medication kit numbers in the eCRF.
Administration 
of trial drug 
The patient will self-administer the trial drug (from the new assigned 
Respimat® inhaler) under the oversight of the site staff.
Inhalation 
observance
Observance of the inhalation procedure. Give instructions on how to 
assemble and prime the Respimat® inhaler at home.
Rescue 
medication 
Provide sufficient rescue medication inhalers to cover the period 
between 2 clinic visits. 
Collect trial 
drugs
All trial medications are to be collected. Compliance to be checked.
Please refer to section 4.3 Treatment compliance.
Adverse events
All adverse events experienced since the previous visit will be reviewed 
and documented.


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Concomitant 
medication
Any changes in concomitant medications since the last visit will be 
reviewed and documented
Appointments
Patients will be instructed to bring all issued trial medication
(used/unused) and the rescue medication (used/unused) to the study site 
on the next scheduled clinic visit. 
Schedule:

J 4),0% &44,/0(5%0( K ;%%<+ '&(%* 

 
 

L%C( .'/0/. 2/+/(8 5,0()+ '&(%*
@ 
6.2.2.3 Telephone contacts between clinic visits
Study sites will follow up patients and collect information by telephone interviews every 6-
week (± 7 days). A patient’s reminder card will be provided to assist their memory recall in 
terms of respiratory symptoms, COPD exacerbations, hospitalisation or interim health care 
visits, concomitant therapy.
At each telephone contact, the investigator or deputy will review with the patient any related 
COPD exacerbation information (new occurrence of exacerbation, respiratory symptoms, 
COPD exacerbation-related hospitalisation etc…) and will record it in the eCRF. If patients 
are hospitalised, the study site will be responsible for collecting and reviewing pertinent 
medical records so that an informed judgment can be made as to the primary cause for 
admission.
Relevant sources of information may include hospital records, telephone or written 
correspondence with primary physicians, discharge summaries, and death certificates.
Emphasis will be placed on the first diagnosis listed in the discharge summary in determining 
the primary cause for the hospital admission. In case of hospitalisation, patients will be 
encouraged to inform the study site prior to their regularly scheduled telephone interviews.
Details of all exacerbations will be captured in the source notes.


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6.2.3
End of treatment 
6.2.3.1 Visit 6/EoT
At the conclusion of the 52-week treatment period, the following information will be 
collected for all patients (these visit procedures also apply for a patient who is discontinuing 
trial medication before the end of the trial).
Procedures and observations
Physical 
examination
Physical examination including measurements of systolic and diastolic 
blood pressure and pulse rate. 
Haematology, 
serum chemistry
laboratory tests
To be submitted to the central laboratory. 
(Fasted condition is not required).
Smoking status
To be reported.
COPD 
exacerbation 
interview

Patient’s reminder card (filled in by the patient) should be reviewed 
with the investigator

Telephone call(s) information since the last clinic visit should be 
reviewed.
Please refer to the section 5.1.2.2
Patient’s 
reminder card
Patients will be provided with a new card.
Last trial drug 
administration 
The last administration of the study medication from the Respimat®
inhaler that is in current use since no new Respimat® treatment box will 
be assigned.
Collect trial 
drug
All trial medications are to be collected. Compliance to be checked. 
Please refer to section 4.3 (Treatment compliance).
Rescue 
medication 
Rescue medication will be issued to all patients to cover the period until 
the follow-up Visit. 
Adverse events
All adverse events experienced since the previous visit will be reviewed 
and documented.


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Concomitant 
medication
Any changes in concomitant medications since the last visit will be 
reviewed and documented
Appointment
Patients will be instructed to bring all issued rescue medication 
(used/unused) at the follow-up visit.
G.)%=-'%I >,'',;
?-4 2/+/( MN =&6+ &>(%* 
O/+/( K@
Trial drug 
termination call 
Please refer to the IRT manual
6.2.3.2
Premature discontinuation
The Visit 6/EoT visit should be performed instead of the scheduled trial visit at time of 
premature discontinuation (Please refer to section 6.2.3.1). Afterwards, the initiation of the 
survival and exacerbation information collection will be initiated.
The need for follow-up information (vital status and COPD exacerbation) should have been
explained to patients prior to their participation in the trial and will be part of the written 
informed consent.
COPD exacerbation status collection
The collection of the COPD exacerbation status will be repeated every 6 weeks at the 
originally predicted clinic visits and telephone contacts until the predicted Visit 6.
Exacerbation contact information will be reported on the “COPD exacerbation check” eCRF. 
Exacerbation-related details will likewise recorded as an (S)AE and recorded in the COPD 
event eCRF, if applicable. In order to be able to provide COPD information, patients are 
strongly encouraged to use and complete the patient’s reminder card until the completion of 
the collection period.
Starting from the premise that COPD exacerbation and vital status collection should be 
timely aligned with the originally planned clinic visits and telephone contact. If the patient is 
not reachable during this period a second attempt is to be planned later (reason documented
i.e: hospitalization, holiday, family events….).


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Vital status collection
Depending on the time of the patient’s withdrawal, the survival status collection will be 
scheduled as following:
o
BEFORE Visit 4: 2 collection time points at the originally predicted visit 4 (26 
weeks from Visit 2) and follow-up visit (52 weeks + 21 days from Visit 2)
o
AFTER Visit 4: 1 collection time point at the originally predicted follow-up 
visit (52 weeks + 21 days from Visit 2).
The time interval of interest will be defined from the date of the Termination of Trial 
Medication (TTM) until their predicted follow-up visit.
If death occurs, the investigator will review the circumstances, including the relevant medical
records to ascertain the most likely primary cause. Vital status information will be collected
in accordance with national ethical and regulatory guidelines.
6.2.4
Follow-up visit
At the completion of the Visit 6 the follow-up visit should be performed in any case as 
described in the flow chart.
A patient who is withdrawn from therapy should complete the follow-up visit 21 days later 
last treatment study visit (including the EOT assessments). Please refer to section 6.2.3.2.
Physical 
examination
To be re-assessed ONLY in case of relevant findings at Visit 6 or at the 
last study treatment visit (in case of premature discontinuation)
Laboratory tests  
To be re-assessed ONLY in case of relevant findings at Visit 6 or at the 
last study treatment visit (in case of premature discontinuation)
Pregnancy test 
Urine pregnancy test
COPD 
exacerbation 
interview

Patient’s reminder card (filled in by the patient) should be 
reviewed with the investigator

Telephone call(s) information since the last clinic visit should be 
reviewed.
Please refer to the section 5.1.2.2
Rescue 
medication
To be collected
Adverse events
All adverse events experienced since the previous visit will be 
reviewed and documented.
Trial Completion 


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6.2.5
Trial completion
For completed patient
The “Trial completion” definition takes into consideration the trial drug termination date (i.e., 
visit 6) completed 21 days later by the follow-up visit.
Trial completion page has to be filled-in when the patient has terminated the follow-up visit.
For discontinued patient
The “Trial completion” definition takes into consideration the premature trial drug 
termination date (i.e., prior to visit 6) completed 21 days later by the follow-up visit.
Trial completion page has to be filled-in when the patient has terminated the follow-up visit.
Please refer to section 6.2.3.2.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomised, double-blind, active-controlled parallel group, phase IIIb study. The 
primary objective of this study is to evaluate the effect of once daily treatment of tiotropium 5 
μg + olodaterol 5 μg FDC delivered by the Respimat® inhaler on COPD exacerbation as 
compared with 5 μg tiotropium delivered by the Respimat® inhaler in patients with severe to 
very severe COPD. Each patient will stay in the trial for 52 weeks and will be followed up 
for COPD exacerbation if dropped out earlier. Vital status will be collected over the entire 
study period (52 weeks + 21 days follow-up).
7.2
NULL AND ALTERNATIVE HYPOTHESES
The effect of tiotropium + olodaterol FDC on COPD exacerbation will be assessed by testing 
the rate ratio for annual rate of moderate/severe COPD exacerbation and hazard ratio for  
moderate/severe COPD exacerbation between T+O FDC and Tio 5 in the following 
hypothesis testing hierarchy:
9. H10: the annualised rate of moderate to severe COPD exacerbation is equal between T+O 
5/5 and Tio 5
vs.
H11: the annualised rate of moderate to severe COPD exacerbation is different 
between T+O 5/5 and Tio 5.
10. H20: the survival distribution for the onset of the first moderate to severe COPD 
exacerbation is equal for T+O 5/5 and Tio 5
vs.
H21: the survival distribution for the onset of the first moderate to severe COPD 
exacerbation is different for T+O 5/5 and Tio 5
This hypothesis testing strategy ensures that the overall type I error is protected at two-sided 
0.01 level.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The primary analysis includes all randomised patients who are documented to have received 
any dose of study medication, i.e., the primary analysis is performed using the treated set.
The primary endpoint, i.e., annualised rate of moderate to severe COPD exacerbation will be 
analysed using a negative binomial model including the fixed, categorical effect of treatment 


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as well as the logarithm of the treatment exposure as an offset. In all analyses of annualised 
rate of event, the length of the event will be subtracted from the extent of exposure or the 
length of the observation period because one cannot expect to have another event during an 
event. Moderate to severe COPD exacerbations occurring within 1 day (i.e.: 24 hours) after 
the last drug administration date are included in the primary analysis.
7.3.2
Secondary analyses
For the key secondary endpoint, i.e., time to the onset of the first moderate to severe COPD 
exacerbation, as well as other time to event endpoints (see Section 5.1.1), a Cox’s 
proportional hazard model will be used to estimate the hazard ratio and the corresponding 
99% confidence intervals, while log-rank test will be used to obtain the p-value for testing the 
survival curves. For other annualised rate of event endpoints (see Section 5.1.1), the same 
negative binomial model as specified for the primary endpoint will be used.
For all efficacy analyses including time to all-cause mortality the treated set (on-treatment + 1 
day) will be used. 
 
 
 
 
 
 
7.3.3
Safety analyses
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned 
prospectively.
Adverse events will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA) coding dictionary. Standard BI summary tables and listings 
will be produced to compare the incidence of adverse events across treatment groups. All 
adverse events with an onset after the first dose of trial medication and up to 21 days after the 
last dose of trial medication will be assigned to the on-treatment period. Other adverse events 


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will be assigned either to the screening period, post-treatment period or the post-study period 
as appropriate.
Changes from baseline in vital signs and laboratory value will be summarised by treatment 
group and compared descriptively.
7.3.4
Interim analyses
No interim analysis is planned for this trial.
7.3.6
Pharmacokinetic analyses
No pharmacokinetic analyses are planned for this trial.
7.3.7
Pharmacodynamic analyses
No pharmacodynamic analyses are planned for this trial.
7.3.8
Pharmacogenomic analyses
No pharmacogenomic analyses are planned for this trial.
7.4
HANDLING OF MISSING DATA
Since patients are followed up for exacerbations and vital status and the CAT questionnaire is 
an exploratory endpoint, missing data will not be imputed. Missing safety data will not be 
imputed with the exception of missing AE dates which will be imputed according to BI 
standards.


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Randomly missing data (not due to worsening of disease or use of rescue medication) after 
inhalation for which there are data from that visit both before and after inhalations will be 
linearly interpolated. Randomly missing data with no subsequent non-missing values for that 
visit will be imputed using the last observation carried forward (LOCF) techniques prior to 
calculating AUC.
7.5
RANDOMISATION
Patients will be randomised in equal ratio to one of the two treatment groups in this trial and 
blocked randomisation will be used. Boehringer Ingelheim will generate the randomisation 
scheme and will prepare and code the medications to maintain the double-blind.
In order to maintain flexibility for drug supply, each individual medication kit will have a 
separate identification number. Assignment of medications at the clinic visits will be 
accomplished through the use of IRT. Each patient will be assigned a single randomisation 
number indicating the randomised treatment the patient will be on throughout the trial. BI 
will provide the randomisation and medication kit number lists to the IRT and the sites will 
access the IRT to obtain the randomisation number and medication kit numbers to be 
dispensed to the patient.
7.6
DETERMINATION OF SAMPLE SIZE
Based on a recent publication on the SPARK study (Wedzicha, et al, Lancet, 2013) and data 
from a previous BI study 
, the rate ratio and hazard ratio of moderate to severe 
COPD exacerbation between T+O  FDCs and Tio 5 are assumed to be 0.88.
Assuming an annualised rate of moderate to severe COPD exacerbation for Tio 5 to be 0.85, 
a 12-month fixed study duration, two-sided type I error rate of 0.01 and 90% power, the 
sample size depends on the dispersion parameter for the negative binomial distribution. Table 
7.6: 1 gives the sample size estimations for a range of the dispersion parameters. In addition, 
assuming a 15% loss of information in patient-years, the estimated power corresponding to 
the sample size is also provided in the last column in Table 7.6: 1 below.


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Table 7.6: 1
Sample size estimations for annualised rate of moderate to severe 
COPD exacerbation under different dispersion parameters with 2-
sided type I error rate of 0.01, 90% power, annual rate of 0.85 in Tio 
5 and rate ratio = 0.88
Annual 
Rate in 
Tio 5 
(r1)
Annual 
Rate in 
T+O 
FDC 
(r2)
r2/r1
Dispersion 
Parameter
N per 
arm
Average 
exposure 
(months)
Total 
exposure 
adjusted for 
15% loss of 
information 
(patient –
years)
Power 
(after 
adjusting 
15% loss of 
information 
in patient-
years)
0.85
0.748
0.88
0.625 
(SPARK)
3427
12
2913
85.8%
0.85
0.748
0.88
0.7
3563
12
3029
86.0%
0.85
0.748
0.88
0.8
3745
12
3184
86.2%
0.85
0.748
0.88
0.9
3927
12
3338
86.4%
The above calculation is based on the formulas in Zhu and Lakkis [P14-09564] and was
calculated using the validated software package R. A sample size of 3900 patients per arm 
will give a power between 90% to 94% under different dispersion parameters to detect a rate 
ratio of 0.88 between T+O FDC and Tio 5 in the annualised rate of moderate to severe COPD 
exacerbation assuming the annual rate in Tio 5 is 0.85 and two-sided type I error rate of 0.01. 
After adjusting for a 15% loss of information in patient-years and the same assumptions as 
above, a sample size of 3900 patients per arm will give a power between 86.1% to 90.6% 
Assuming the proportion of patients who had at least one moderate to severe COPD 
exacerbation within 1 year in the Tio 5 arm is 0.65, a hazard ratio between T+O FDC and Tio 
5 of 0.88, a two-sided type I error rate of 0.01 and power of 90%, the estimated sample size 
for time to the first moderate/severe COPD exacerbation is 2915 patients per arm (using 
nQuery Advisor 7.0). A sample size of 3900 patients per arm will give a power of 97% using 
the same assumptions.
A sample size of 3900 patients per arm or 7800 patients in total is selected for this trial 
because it provides acceptable power to detect a 12% reduction in annualised rate of 
moderate to severe COPD exacerbation of T+O FDC as compared with Tio 5 using a two-
sided type I error rate of 0.01, under a reasonable range of dispersion parameters of the 
negative binomial distribution and assuming the annual rate in Tio 5 is 0.85. This sample size 
also gives sufficient power to detect a 12% reduction in the hazard rate of moderate to severe 
COPD exacerbation of T+O FDC as compared to Tio 5 at a two-sided type I error rate of 0.01 
and assuming the proportion of patients who had at least one moderate/severe COPD 
exacerbation after 1 year in the Tio 5 arm is 0.65.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches
of the protocol/ICH GCP.
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 general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
ADDITIONAL INFORMATION FOR JAPAN:
For Japan and the Japanese GCP regulations (Ministry of Health and Welfare Ordinance 
No.28, March 27, 1997).
The rights of the investigator/trial site and of the sponsor with regard to publication of the 
results of this trial are described in the investigator/trial site’s contract.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / 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.
Informed consent procedure and Vital Status information collection
In order to successfully maintain the safety objectives of this trial, it is necessary that each 
patient’s COPD exacerbation follow-up and vital status be maintained until the predicted 


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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
patient’s exit date (i.e. 52 weeks (+ 1 week) +21 days after taking the first dose of 
randomized treatment). For this reason the informed consent includes a COPD exacerbation 
collection and vital status statements. All patients will agree to be followed for COPD 
exacerbation and vital status as a part of the informed consent procedure. Hence, patients who 
withdraw prematurely from study treatment will still be periodically contacted 
(approximately every 6 months contact) to determine survival status and every 6 weeks to 
collect COPD exacerbation status.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.
The investigator must give a full explanation to trial patients by using the patient information 
form, which is prepared avoiding the use of technical terms and expressions. The patient is 
given sufficient time to consider participation in the trial. The investigator obtains written 
consent of the patient’s own free will with the informed consent form after confirming that 
the patient understands the contents. The investigator must sign (or place a seal on) and date 
the informed consent form.
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs
(or places a seal on) and dates the informed consent.
8.2
DATA QUALITY ASSURANCE
The trial will be conducted according to the principles of Good Clinical Practice (GCP) and 
the company standard operating procedures (SOPs). The following steps will be taken to 
ensure accurate, consistent, complete, and reliable data:
∀
Investigator meetings 
∀
Training sessions including training material and training records 
∀
Centralised evaluations (central laboratory)
∀
On-site monitoring and extent of source data verification
∀
Risk Based Monitoring strategy
∀
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
∀
Coding (mention the dictionaries and thesauruses used, e.g. MedDRA)
∀
Data management procedures: “The data management procedures to ensure the quality of 
the data are described in detail in the trial data management and analysis plan (TDMAP) 
available in the TMF.”
∀
Mortality adjudication committee (refer to Section 3.1)


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
Steps to maintain the blind (refer to Section 4.1.5.1)
8.3
RECORDS
Electronic Case Report Forms (eCRFs) for individual patients will be provided by the 
sponsor via remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. 
For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
The patient’s reminder card will not be collected by the site.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all eCRFs, and written informed 
consents. An adaptive approach to clinical trial monitoring that directs monitoring focus and 
activities to the evolving areas of greatest risk which have the most potential to impact 
subject safety and data quality will be utilised. The accuracy of the data will be verified by 
reviewing the documents described in Section 8.3.1.


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8.3.3 
Storage of records
ADDITIONAL INFORMATION FOR JAPAN:
Trial site(s):
The trial site(s) must retain the source documents and essential documents for a period 
defined by the Japanese GCP regulation and in the trial site’s contract with the sponsor.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs. 
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For the 5 μg tiotropium inhalation solution this is the current version of the Investigator’s 
Brochure [U92-0551]. For the Fixed Dose Combination of tiotropium and olodaterol this is 
the current version of the Investigator’s Brochure [c01735808]. For the non-investigational 
medicinal product salbutamol/albuterol, the reference document is the US-PI (Proair HFA).
The current versions of these reference documents are to be provided in the ISF. No AEs are 
classified as listed for matching placebo (for training purposes only), study design, or 
invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities for EU>, i.e. the CA.


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8.6
COMPLETION OF TRIAL
ADDITIONAL INFORMATION FOR JAPAN:
When the trial is completed, the principal investigator should inform the head of the trial site 
of the completion in writing, and the head of the trial site should promptly inform the IRB 
and sponsor of the completion in writing.
ADDITIONAL INFORMATION FOR EU MEMBER STATES 
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient/patient out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.
8.7
PROTOCOL VIOLATIONS
ADDITIONAL INFORMATION FOR JAPAN:
“The investigator should document any deviation from the protocol regardless of their 
reasons. Only when the protocol was not followed in order to avoid an immediate hazard to 
trial subjects or for other medically compelling reason, the principal investigator should 
prepare and submit the records explaining the reasons thereof to the sponsor, and retain a 
copy of the records.”
8.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
ADDITIONAL INFORMATION FOR JAPAN
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R05-0370
CH harmonised tripartite guideline: maintenance of the ICH guideline on non-
clinical safety studies for the conduct of human clinical trials for 
pharmaceuticals M3(M) (recommended for adoption at step 4 of the ICH 
process on 16 July 1997 and amended on 9 November 2000 by the ICH 
Steering Committee).
Int Conf on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
R10-5669
ICH harmonised tripartite guideline: maintenance of the ICH guideline on 
non-clinical safety studies for the conduct of human clinical trials for 
pharmaceuticals M3(R2) (Current step 4 version, 11 June 2009)
R94-1408
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC
Lung volumes and forced ventilatory flows. Report Working Party 
Standardization of Lung Function Tests, European Community for Steel and 
Coal. Official Statement of the European Respiratory Society. 
Eur Respir J 6 (Suppl 16), 5 - 40 (1993)
P14-12073
Bouyssou T, Casarosa P, Pieper M, Schnapp A, Gantner F. Synergistic 
bronchoprotective activity of the long-acting beta 2-agonist olodaterol with 
tiotropium (long-acting M3 antagonist) and ciclesonide (inhaled steroid) on 
the ovalbumin-induced bronchoconstriction in anaesthetized guinea pigs. ERJ 
September 1, 2011 vol. 38 no. Suppl 55 3451
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo 
R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson DC, 
MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, 
Wanger J
Standardisation of spirometry.
Eur Respir J 26 (2), 319 - 338 (2005)
P08-12524
Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M, 
UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic 
obstructive pulmonary disease. N Engl J Med 359 (15), 1543 - 1554 (2008)


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P09-11278
Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP, UPLIFT 
Investigators. Effect of tiotropium on outcomes in patients with moderate 
chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup 
analysis of a randomised controlled trial. Lancet, (2009)
P10-02376
Troosters T, Celli B, Lystig T, Kesten S, Mehra S, Tashkin DP, Decramer M, 
UPLIFT Investigators. Tiotropium as a first maintenance drug in COPD: 
secondary analysis of the UPLIFT trial. Eur Respir J 36 (1), 65 - 73 (2010)
P10-07776
Bouyssou T, Casarosa P, Naline E, Pestel S, Konetzki I, Devillier P, Schnapp 
A. Pharmacological characterization of olodaterol, a novel inhaled beta2-
adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical 
models. J Pharmacol Exp Ther 334 (1), 53 - 62 (2010)
P10-08261
Bateman ED, Tashkin D, Siafakas N, Dahl R, Towse L, Massey D, Pavia D, 
Zhong NS. A one-year trial of tiotropium Respimat plus usual therapy in 
COPD patients. Respir Med 104, 1460 - 1472 (2010)
P10-09337
Bouyssou T, Schnapp A, Casarosa P, Pieper MP. Addition of the new once-
daily LABA BI 1744 to tiotropium results in superior bronchoprotection in 
pre-clinical models. ATS 2010, 106th Int Conf of the American Thoracic 
Society (ATS), New Orleans, 14 - 19 May 2010. Am J Respir Crit Care Med 
181, A4445, Abstr (2010)
P10-14042
Maltais F, Beck E, Webster D, Maleki-Yazdi MR, Seibt JV, Arnoux A, 
Hamilton A. Four weeks once daily treatment with tiotropium + olodaterol (BI 
1744) fixed dose combination compared with tiotropium in COPD patients.
20th Ann Cong of the European Respiratory Society (ERS), Barcelona, 18 - 22 
Sep 2010. Eur Respir J 36 (Suppl 54), 1014S, Abstr 5557 (2010)
P11-03885
Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Moelken MPMH, 
Beeh KM, Rabe KF, Fabbri LM, POET-COPD Investigators. Tiotropium 
versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 
364 (12), 1093 - 1103 (2011)
P11-05865
Global Initiative for Chronic Obstructive Lung Disease (GOLD)
Global strategy for the diagnosis, management, and prevention of chronic 
obstructive pulmonary disease: updated 2010.
http://www.goldcopd.com/ (access date: 12 May 2011) (2010)
P11-07562
Yohannes AM, Willgoss TG, Vestbo J. Tiotropium for treatment of stable 
COPD: a meta-analysis of clinically relevant outcomes. Respir Care 56 (4), 
477 - 487 (2011)
P11-07720
Casarosa P, Kollak I, Kiechle T, Ostermann A, Schnapp A, Kiesling R, Pieper 
M, Sieger P, Gantner F. Functional and biochemical rationales for the 24-
hour-long duration of action of olodaterol. J Pharmacol Exp Ther 337 (3), 600 
- 609 (2011)


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P13-02357
Aalbers R, Maleki-Yazdi MR, Hamilton A, Waitere-Wijker S, Pivovarova A, 
Schmidt O, Bjermer L. Dose-finding study for tiotropium and olodaterol when 
administered in combination via the Respimat inhaler in patients with COPD.
22nd Ann Cong of the European Respiratory Society (ERS), Vienna, 1 - 5 Sep 
2012. Eur Respir J 40 (Suppl 56), 525S - 526S, Abstr P2882 (2012)
P13-04267
Cooper CB, Celli BR, Jardim JR, Wise RA, Legg D, Guo J, Kesten S. 
Treadmill endurance during 2-year treatment with tiotropium in patients with 
COPD: a randomized trial. Chest 144 (2), 490 - 497 (2013)
P13-05794
Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the 
management of chronic obstructive pulmonary disease. Respir Res (Lond) 14, 
49 (2013)
P13-11053
Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, Dusser D, Joseph 
E, Kattenbeck S, Koenen-Bergmann M, Pledger G, Calverley P, TIOSPIR 
Investigators. Tiotropium Respimat inhaler and the risk of death in COPD. N 
Engl J Med 369 (16), 1491 - 1501 (2013)
P13-11341
Koch A, Paggiaro P, Hamilton A, Hart L, Korducki L, Salvo MC de, 
Pizzichini E. Symptomatic benefit of olodaterol QD delivered via Respimat vs 
placebo and formoterol BID in patients with COPD: combined analysis from 
two 48-week studies. 23rd Ann Cong of the European Respiratory Society 
(ERS), Barcelona, 7 - 11 Sep 2013
P13-11345
Koch A, Pizzichini E, Hamilton A, Hart L, Korducki L, Salvo MC de, 
Paggiaro P. Lung function efficacy of olodaterol QD delivered via Respimat 
vs placebo and formoterol BID in patients with COPD: two 48-week studies.
23rd Ann Cong of the European Respiratory Society (ERS), Barcelona, 7 - 11 
Sep 2013
P13-11346
Ferguson G, Feldman G, Hofbauer P, Hamilton A, Allen L, Korducki L, Sachs 
P. Lung function efficacy of olodaterol QD delivered via Respimat in COPD 
patients: results from two 48-week studies. 23rd Ann Cong of the European 
Respiratory Society (ERS), Barcelona, 7 - 11 Sep 2013
P13-11467
Lange P, Aumann JL, Derom E, Hamilton A, Tetzlaff K, Ting N, Noord JA 
van. The 24-h FEV1 time profile of olodaterol QD delivered via Respimat in 
COPD: results from two 6-week studies. 23rd Ann Cong of the European 
Respiratory Society (ERS), Barcelona, 7 - 11 Sep 2013
P13-14109
Maltais F, Kirsten AM, Hamilton A, Sousa D de, Wang F, Decramer M. 
Evaluation of the effects of olodaterol on exercise endurance in patients with 


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COPD: results from two 6-week studies. Chest 2013, 79th Ann Mtg of the 
American College of Chest Physicians, Chicago, 26 - 31 Oct 2013. Chest 144 
(4) (Suppl), 748A, Abstr (2013)
P13-14112
Feldman G, Bernstein JA, Hamilton A, Nivens C, LaForce C. The 24-hour 
FEV1 time profile of olodaterol once daily (QD) via Respimat and formoterol 
twice daily (BID) via Aerolizer in patients with COPD: results from two 6-
week studies. Chest 2013, 79th Ann Mtg of the American College of Chest 
Physicians, Chicago, 26 - 31 Oct 2013. Chest 144 (4) (Suppl), 749A, Abstr 
(2013)
P14-01052
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease (updated 2014). 
http://www.goldcopd.org/uploads/users/files/GOLD_Report_2014.pdf (access 
date: 22 January 2014) ; Global Initiative for Chronic Obstructive Lung 
Disease (GOLD) (2014)
P14-09564
Zhu H and Lakkis H Sample size calculation for comparing two negative 
binomial rates. Statistics in Medicine 33, 376-384 (2014)
P94-1346
Bone R, et al. 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)
9.2
UNPUBLISHED REFERENCES
U04-0202
. Investigator´s brochure - BI 1744 CL. 
Version 9, 23 August 2012
U92-0551
. Investigator's Brochure: Tiotropium Bromide,
Ba 679 BR. Version 20, 23 September 2013
c01735808
. Investigator’s brochure- BI 1744 and tiotropium - 1237.P1 -
Version 7, review 2014


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


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


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


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


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What if...
What if...
Reason
What to do
I can’t turn the base easily.
a) The RESPIMAT® inhaler is 
already prepared and ready 
to use. 
b) The RESPIMAT® inhaler is 
locked after 60 puffs (30 
doses).
a) The RESPIMAT® inhaler 
can be used as it is.
b) Prepare and use your new  
RESPIMAT® inhaler.
I can’t press the dose release 
button.
The clear base has not been 
turned.
Turn the clear base until it 
clicks. (half a turn)
The clear base springs back 
after I have turned it.
The clear base was not turned 
far enough.
Prepare the RESPIMAT®
inhaler for use by turning the 
clear base until it clicks. (half a 
turn)
I can turn the clear base past the 
point where it clicks.
Either the dose release button 
has been pressed, or the clear 
base has been turned too far.
With the grey cap closed, turn 
the base until it clicks. (half a 
turn) 
How to care for your inhaler
Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, 
at least once a week.
Any minor discoloration in the mouthpiece does not affect the performance of your RESPIMAT®
inhaler.
  
If necessary, wipe the outside of your RESPIMAT® inhaler with a damp cloth.
Further information
The RESPIMAT® inhaler must not be disassembled after inserting the cartridge and replacing the 
clear base.
Do not touch the piercing element inside the base.
Keep out of the reach and sight of children.
Do not freeze.
Boehringer Ingelheim Pharma GmbH & Co. KG
D - 55216 Ingelheim, Germany
  0123 HI-Master-Version-06-tiotropium+olodaterol-combination-Respimat-20140516


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10.2
RETURN OF INHALERS/CARTRIDGES
Return of Malfunctioning RESPIMAT Inhalers
Respimat® inhalers, with the used cartridge in situ, that appeared to malfunction, will be 
returned to 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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10.5 
ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA
Calculation of predicted normal values according to ECSC
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
Post-bronchodilator
FEV1< 60% of predicted normal (ECSC) and 
post-
bronchodilator FEV1/FVC <70% of predicted normal (ECSC): documentation
Patients may not be randomised to the study without the availability of spirometry data at 
the actual study site.
Historical data
To be performed within the past 3 months either at the site or at a referral site will be 
used. 
A referral letter and signed copies of the measurement printouts must be provided to the 
trial site for source data verification. However, any referral documentation does not result 
in the need to open “satellite sites”.
In case several qualifying spirometry measurements are available, the most recent one 
should be referred to as long as it was not performed during an exacerbation. 
OR
PFT measurement at investigational site:
Patient must be able to perform a post-dose pulmonary function test after the 
administration of 400 μg salbutamol/albuterol (preferred) for qualification.
OR: testing with either 200 μg salbutamol/albuterol or a combination of 
salbutamol/albuterol with ipratropium bromide (2 to 4 actuations) is acceptable.
The spirometers and their use, including daily calibration, must meet American Thoracic 
Society (ATS)/ European Respiratory Society (ERS) criteria.


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Calculation of number of pack years
Pack years =
Number of cigarettes/day
x years of smoking
20


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is a revised protocol.
Number of global amendment
1.0
Date of CTP revision
15 July 2015
EudraCT number
2014-002275-28
BI Trial number
1237.19
BI Investigational Products
-
Tiotropium + olodaterol fixed dose combination 
inhalation solution Respimat® 
-
Tiotropium 5 μg inhalation solution Respimat®
Title of protocol
A randomised, double-blind, active-controlled parallel 
group study to evaluate the effect of 52 weeks of once 
daily treatment of orally inhaled tiotropium + 
olodaterol fixed dose combination compared with 
tiotropium on Chronic Obstructive Pulmonary Disease 
(COPD) exacerbation in patients with severe to very 
severe COPD. [DYNAGITO]
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1
2
3
4
5
6
7
8
9
Synopsis, flowcharts (including footnotes)
Abbreviations
Section 3.1 Overall trial design and plan
Section 3.1.1 Administrative structure of the trial
Section 3.3 Selection of trial population
Section 3.3.2 Inclusion criteria
Section 3.3.3 Exclusion criteria
Section 4.1.4.2 Study medication administration
Section 4.1.6  Packaging, labelling and re-supply


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Number of global amendment
1.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Section 4.2.1.1 Rescue medication
Section 4.2.2.1 Restrictions regarding 
concomitant medication
Table 4.2.2.1 Permitted medications and 
medications restrictions (including footnotes)
Section 4.2.2.2 Restrictions on diet and life style
Section 5.1.1 Endpoints of efficacy
Section 5.1.2.2 Assessment of moderate to severe 
COPD exacerbation
Section 5.1.3.1 Laboratory test
Section 5.1.3.2 Physical examination
Section 5.4 Appropriateness of measurements
Section 6.1 Visit schedule
Section 6.2 Details of trial procedures at selected 
visits
Section 6.2.1 Screening period
Section 6.2  Treatment periods
Section 6.2.2.1 randomisation Visit 2  
Section 6.2.2.2 Clinic visits ( Visits 3, 4 and 5)
Section 6.2.2.3 telephone contacts between clinic 
visits
Section 6.2.2.2 Visit 6/EoT
Section 6.2.3.2 Premature discontinuation
Section 6.2.4 Follow-up visit
Section 7.3.5 Other analyses
Section 7.4 Handling of missing data
Section 7.6 Determination of sample size
Section 8.2 Data Quality assurance
10.5 Additional information regarding in/ex 
criteria
Description of change
Administrative changes, corrections and added 
clarifications
Main flow chart
(Time points for Vital status and COPD exacerbation 
collection time points re-specified, 
 
) 
, pregnancy test re-specified. The 
IRT trial completion call was removed.
Abbreviations- update
Section 3.3 Selection of trial population 
(enrolment average per site increased 10-12 patients)
Section 3.3.3 Exclusion criteria
(Ex #2: urinalysis removed. Possibility to repeat the lab 
test)
(Ex # 15-16: medication restrictions and wash-out revised 
for oral CS, antibiotics)
Table 4.2.2.1 Permitted medications and 
medications restrictions (including footnotes)


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Number of global amendment
1.0
Clarification on use of respiratory medicine including 
information related to antibiotics use not limited to COPD 
exacerbation)
Section 4.2.2.2 Restrictions on diet and life style
Section 5.1.2.2 Assessment of moderate to severe 
COPD exacerbation
(The patient’s reminded card will collect the missed dose 
medication)
Section 5.1.3.1 Laboratory test
Section 5.1.3.2 Physical examination
Section 5.4 Appropriateness of measurements
(The CAT questionnaire should be collected before the 
SGRQ)
Section 6.1 Visit schedule
(The screening period between V1 and V2 can be 
expanded by an additional 1 week)
Section 6.2.2.2 Visit 6/EoT
(Clarification on procedures carried out for completed 
patients and prematurely discontinued patients)
Section 6.2.3.2 Premature discontinuation
Clarification on timing of procedures
Section 6.2.4 Follow-up visit
(Urine pregnancy testing added to be consistent with the 
section 5.2.3.1 laboratory tests)


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Number of global amendment
1.0


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02247259
3.0
clinical-trial-protocol
A randomised, double-blind, active-controlled parallel group study to evaluate the
effect of 52 weeks of once daily treatment of orally inhaled tiotropium + olodaterol
fixed dose combination compared with tiotropium on Chronic Obstructive
Pulmonary Disease (COPD) exacerbation in patients with severe to very severe
COPD. [DYNAGITO]
Author-Clinical Monitor
16 Jul 2015 16:03 CEST
Verification-Paper Signature
Completion
16 Jul 2015 16:09 CEST
Approval-Therapeutic Area 
16 Jul 2015 16:48 CEST
Approval-Team Member Medical
Affairs
16 Jul 2015 17:12 CEST
Approval-Biostatistics
16 Jul 2015 17:49 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02247259
3.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c05079948-01
BI Trial No.:
1237.19
Title:
A randomised, double-blind, active-controlled parallel group study 
to evaluate the effect of 52 weeks of once daily treatment of orally 
inhaled tiotropium + olodaterol fixed dose combination compared 
with tiotropium on Chronic Obstructive Pulmonary Disease 
(COPD) exacerbation in patients with severe to very severe COPD. 
[DYNAGITO]  Including Protocol Amendment 01   1237.19-
protocol-amendment-01 [c02247259-03]
Investigational
Product(s):
Tiotropium + olodaterol fixed dose combination inhalation solution-
RESPIMAT®
Responsible trial 
statistician(s):
 
Phone:
Fax: 
Date of statistical 
analysis plan:
15 NOV 2016 SIGNED
Version:
Final 
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINT(S).......................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
.........................................................9
.......................................................10
.......................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
PATIENT SETS ANALYZED...........................................................................14
...................................................................................................14
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
6.8
CALCULATION OF TIME TO EVENT.........................................................17
6.9
CALCULATION OF ANNUALIZED RATE..................................................19
7.
PLANNED ANALYSIS......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINT .....................................................................................20
7.5
SECONDARY ENDPOINTS.............................................................................22
7.5.1
Key secondary endpoint .....................................................................................22
7.5.2
Secondary endpoints...........................................................................................23
....................................................23
....................................................24
7.7
EXTENT OF EXPOSURE.................................................................................25
7.8
SAFETY ANALYSIS..........................................................................................25
7.8.1
Adverse events.....................................................................................................25
7.8.2
Mortality ..............................................................................................................26
7.8.3
Laboratory data ..................................................................................................26
7.8.4
Vital signs.............................................................................................................27
7.8.5
ECG......................................................................................................................27
......................................................27
8.
REFERENCES....................................................................................................28


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9.
ADDITIONAL SECTIONS ...............................................................................29
9.1
DETAILED DESCRIPTION OF ENDPOINT: COPD EXACERBATION.29
10.
HISTORY TABLE..............................................................................................31


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LIST OF TABLES
Table 6.1: 1
Treatments and their labels ..............................................................................11
Table 6.1: 2 
Analyses performed within each period...........................................................12
Table 6.2: 1
Important protocol violations...........................................................................13
Table 10: 1
History table .....................................................................................................31


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
ANCOVA
Analysis of Covariance
AUC
Area under the curve
BI
Boehringer Ingelheim
BMI
Body Mass Index
BRPM
Blinded report planning meeting
COPD
Chronic Obstructive Pulmonary Disease
CI
Confidence interval
CML
Clinical Monitor Local
CRA
Clinical Research Associate
CT
Concomitant Therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database lock
EC
Exclusion Criterion
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOT
End of treatment
EoT
End-of-text
FDC
Fixed dose combination
FEV1
Forced expiratory volume in one second
FVC
Forced vital capacity
GCP
Good clinical practice
GOLD
Global Initiative on Chronic Obstructive Lung Disease
H
Hypothesis
IC
Inclusion Criterion
ICF
Informed Consent form
ICH
International Conference on Harmonisation
ICS
Inhaled Corticosteroids
(I)PV
(Important) Protocol violation


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Term
Definition / description
IRT
Interactive Response Technology
LABA
Long Acting Beta Agonists
LOCF
Last observation carried forward
LLT
Lowest level term
Max
Maximum
MI
Myocardial Infarction
Min
Minimum
MMRM
Mixed Model for Repeated Measures
MQRM
Medical Quality Review Meeting
N
Number
NYHA
New York Heart Association
PFT
Pulmonary Function Test
PH
Proportional Hazards
PT
Preferred term
PV
Protocol violation
REML
Restricted maximum likelihood
RR
Rate ratio
RS
Randomized Set
S
Survival distribution
SAS®
Statistical Analysis Software®
SD
Standard deviation
SOC
System organ class
T+O
Tiotropium bromide and Olodaterol 
TIA
Transient Ischemic Attack
Tio
Tiotropium bromide
TS
Treated Set
TSAP
Trial statistical analysis plan
UN(1)
Banded Main Diagonal 
AE
Adverse event


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3.
INTRODUCTION
As per 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 TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint will be used as defined in the revised CTP, Section 5.1.1: 

Annualized rate of moderate to severe COPD exacerbations during the actual 
treatment period.
The actual treatment period is defined as the interval from first in-take of study medication 
until 1 day after last in-take of study medication (see section 6.1).
The definition of a moderate to severe COPD exacerbation is given in Section 5.1.2 of the 
revised CTP.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
The key secondary endpoint in this study is defined in the revised CTP, Section 5.1.:

Time to first moderate to severe COPD exacerbation during the actual treatment 
period.
5.2.2
Secondary endpoints
Secondary endpoints are defined in the revised CTP, Section 5.1. They are:

Annualized rate of exacerbation leading to hospitalization during the actual treatment 
period.

Time to first COPD exacerbation leading to hospitalization during the actual 
treatment period.

Time to all-cause mortality occurring during the actual treatment period.
All deaths are adjudicated by a blinded and independent adjudication panel to determine the 
primary cause of death.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
As described in Section 4 of the revised CTP, patients will be randomized in equal allocation 
to one of two treatment groups delivered by the Respimat® inhaler: 

Tiotropium + olodaterol fixed dose combination (FDC) (5µg / 5µg) inhalation 
solution once daily

Tiotropium (5 µg) inhalation solution once daily.
Table 6.1: 1
Treatments and their labels
Treatment 
Short label 
Tiotropium + olodaterol FDC (5 μg / 5 μg) inhalation solution
T+O 5/5
Tiotropium (5 μg) inhalation solution
Tio 5
The trial consists of a 360 days of treatment followed by a 21 day residual effect period.
For analysis purposes the following periods are defined:

Planned study period
The planned study period is defined as 360 days of treatment + 21 days of follow up 
after the administration of the first dose of trial medication according to the CTP flow 
chart. 

Planned treatment period
The planned treatment phase is defined as 360 days of treatment + 1 day for wash-out
according to the CTP flow chart.

Actual treatment period
The actual treatment period is defined as the interval from first in-take of study 
medication until 1 day after last in-take of study medication.

On-treatment period
The on-treatment period is defined as the interval from first in-take of study 
medication until 21 days after last in-take of study medication.
Patients that discontinue early will be monitored for exacerbations and vital status until they 
have reached the end of their planned study period.


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Table 6.1:2 
Analyses performed within each period
Periods
Types of Analyses to be 
performed
Actual treatment 
period
(Treatment +1 day 
wash-out)
Planned 
treatment period 
(includes 1 day 
wash-out)
Planned study 
period
(includes residual 
effect period of 21 
days)
On-treatment  
period
(includes residual 
effect period of 21 
days after last drug 
intake)
Primary Exacerbation analysis

Sensitivity primary 
exacerbation analysis

Key secondary exacerbation 
analysis

AE safety analysis

Patients will be analyzed according to the treatment group of the first treatment received. 
Potential treatment switcher scenarios caused by treatment misallocation will be discussed at 
the Blinded Report Planning Meeting (BRPM). After database lock (DBL) patients who fall 
into these discussed scenarios will be analyzed according to meeting decisions. 
For the main safety analysis, data occurring during the on-treatment period (as described 
above) will be assigned to the respective treatment. Adverse events (AEs) occurring before 
first drug intake will be assigned to ‘screening’. AEs occurring after the 21 day residual effect 
period will be assigned to the follow-up period (not to any of the treatment arms).
6.2
IMPORTANT PROTOCOL VIOLATIONS
A patient’s deviation from the trial protocol is considered “important” if it can be expected 
that the deviation had a distorting influence on the assessment of the treatment effect on the 
primary endpoint of the trial or could affect the patient’s safety/rights. 
If the Interactive Response Technology (IRT)-assigned randomized medication is not 
available at the site at the first visit, a forced randomization will occur, and the IRT will 
assign a treatment that is available at the site. That patient will be assigned within the IRT 
system to receive that same treatment for the remainder of the trial. Forced randomizations 


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are part of the study plan and are not classified as important protocol violations. The number 
of forced randomizations will be closely monitored and described in the clinical trial report.
Table 6.2: 1
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded from
Automatic
/Manual
A
Entrance criteria not met
A1
Inclusion criteria not met
IC 3, 4, 5, 7, 8, 2, 6, 
None
Automatic
and 
manual
A2
Exclusion criteria not 
met
EC 3, 7, 9, 10, 11, 13, 
14, 15, 17, 23, 5, 6, 1, 4, 
8, 2, 12, 16, 18, 19, 20, 
21, 22
Excluded from TS: 
EC 22
Excluded from none:
EC 1-21, 23 
Automatic 
B
Informed consent
B1
Informed consent to study 
not available/not done*
All
Manual
B2
Informed consent too 
late**
None
Manual
C
Trial medication and randomization
C1
Incorrect trial medication 
taken
None
Manual
C2
Randomization order not 
followed 
Date of first trial drug 
intake prior to
randomization date
None
Automatic
C3***
Serious non-compliance 
with study medication as 
reported in monitoring 
report
Decision at 
BRPM/MQRM.
None
Manual
C4
Medication code broken 
inappropriately
None
Manual
D
Concomitant medication
 
 
D2
Prohibited medication use 
during study
Refer to Table 4.2.2.1: 1 
in revised CTP. 
None
Manual
Z
Other
Z1
Serious Good Clinical 
Practice (GCP) non-
compliance
Manual PVs reported by 
CML/CRA or in the 
GEM system. 
None
Manual
Z2
Other PV affecting 
efficacy and possibly 
safety
None
Manual
* Informed consent date missing; no signature on ICF.
** Applies to all informed consents. Date of informed consent was after the date of any study-related procedure. 
*** “Serious non-compliance with study medication” is defined by compliance >=200% (twice the dose or 
more).
Note: The following IPVs are not programmed and should therefore be identified at site level 
on the manual PV log: B1, B2, C1, C3, C4, D1, D2, Z1, and Z2.


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6.3
PATIENT SETS ANALYZED
Randomized set (RS)
This patient set includes all patients that were assigned a randomization number within the 
IRT system.
Treated set (TS)
This patient set includes all randomized patients who were documented to have taken at least 
one dose of study medication.
The treated set will be used in all planned analyses
 
 
No per-protocol set is defined and no analysis is planned.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Exacerbations and vital status data 
Patients will be followed up for exacerbation and vital status. Missing data for these 
endpoints will not be imputed. For each time to event analysis, patients who do not have a 
particular outcome will be censored (for details see section 7.5.2).
AE data
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates” (2). 


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The study’s treatment period is planned to have a duration of 360 days and includes 5 clinic 
visits, conducted every 3 months, interspersed with a telephone contact call 6 weeks between 
clinic visits. Twenty-one (21) days after the end-of-treatment (EOT) visit a follow-up visit 
will be performed.
Time windows will not be used. Variables that are collected at clinic visits will be analyzed 
by planned visit (e.g. for trough FEV1 in the sub-study). Exacerbation and time-to-event 
analyses are collected in real-time.
With regard to all efficacy assessments, the term “baseline” refers to the last observation 
obtained at visit 2.
For all other data, including relevant medical history, concomitant therapies, AEs, lab values, 
and vital signs, visit 1 will be classed as “baseline”.   
6.8
CALCULATION OF TIME TO EVENT
The calculation of the time-to-event and the time that patients without an event were in the 
study (at risk) is described here. 
Day 1
The date of first administration of treatment is the reference for all time-related analyses.
Date of event
In the exacerbation analyses, where a patient can have multiple events, the onset date of the 
first event will be used. 
For death, the adverse event end date reported on the eCRF will be used as the final date of 
death.
Last known date alive
The date of last known day alive is determined as the latest date among: the final vital status 
date (defined as the assessment date if alive, or date last known alive if ‘unknown’), the date 
of first dose of study medication, the date of last drug administration, all the visit dates 
(including phone contact dates in which the patient was reached and follow-up contact dates) 
and start or stop dates of events reported on the adverse event forms. 
If a patient dies, the date of death is the last date known alive.


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Survival time calculations:
A. Actual treatment event analysis: Events (death or exacerbation) are counted in the actual 
treatment time to event analysis whenever they occur between the first dose of 
randomized treatment and one day after treatment discontinuation (i.e. during the actual
treatment period) (see section 6.1).
Patients with no event observed during the actual treatment period will be censored at 
date of last dose of randomized study drug administration (i.e. treatment discontinuation) 
+1 day.
Time at risk: 

Patients with event counted: (<date of event> – <date of first drug administration> 
+1).

Patients without event counted: (<date of last dose of study drug> – <date of first drug 
administration > +1) + 1 day wash-out


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6.9
CALCULATION OF ANNUALIZED RATE
In all analyses of annualized* rate of event, the length of the event will be subtracted from the 
extent of exposure or the length of the observation period because an additional event cannot 
occur during an event.
For the on-treatment analysis total exposure is calculated as follows:
	 	
   
 = ∑all patients%exposure
365
	-
./ 
 	0 . =
∑number of events
∑all patients%exposure −∑duration of events
7.
PLANNED ANALYSIS
For End-of-Text (EoT) tables, the set of summary statistics for descriptive statistics of 
continuous variables displays is: N / Mean / SD / Min / Median / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category ‘missing’ will be displayed only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics by treatment group (and total) for the treated set are planned for 
this section of the report.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases and medication are collected by checkbox and will be summarized by 
treatment using descriptive statistics. For medical history, displays will be created for each: 
past, ongoing or recurring events as recorded at baseline. The following concomitant diseases 
and medications will be included:

Medical history [N (%)] (Metabolic disorders [diabetes mellitus, hyper-/dyslipidaemia], 
psychiatric disorders [anxiety, depression], renal and urinary disorders [prostatic disorder, 
urinary retention, urinary tract infection, renal impairment (renal failure)], cancer [treated 
basal cell carcinoma, squamous cell skin cancer], cardiac arrhythmia [supraventricular 
tachyarrhythmia, atrial fibrillation/flutter, ventricular tachyarrhythmia, palpitations, 
bradyarrhythmia, QT prolongation], cerebrovascular disorders/stroke [haemorrhagic 
cerebrovascular conditions, ischaemic cerebrovascular conditions, transient 
cerebrovascular event (TIA)], other cardiovascular disease [hypertension, hypotension, 
aneurysm, syncope, myocardial infarction (MI), other ischaemic heart disease (non-
infarction, angina pectoris), cardiac arrest, cardiac failure class (New York Heart
Association (NYHA) failure classification)], including number of COPD exacerbations or 
worsening episodes in the last year that were treated with steroids or antibiotics, number 
of COPD exacerbations in the last year that were associated with hospitalization, CAT

Concomitant therapy (CT) at baseline [N,(%)]
o
Pulmonary classes (as specified on case report form)
o
Cardiac classes (as specified on case report form)
o
Metabolic disease, psychiatric disease (as specified on case report form)

CT during treatment period [N (%)], if indicated to have been used for one day during 
randomized treatment period (Visit 2 through termination of trial medication will be 
summarized together. A separate display will be generated summarizing from the end of 
treatment until the 21 day follow-up visit.)
7.3
TREATMENT COMPLIANCE
Treatment compliance will only be assessed whether or not it is in the recommended range of 
between 80% and 100%. Compliance % is based on doses used during the maximum possible 
treatment period.
7.4
PRIMARY ENDPOINT
Primary Analysis
As stated in section 7.3.1 in the revised CTP: “The annualized rate of moderate to severe 
COPD exacerbation will be analyzed using a negative binomial model including the fixed, 
category effect of treatment as well as the logarithm of the treatment exposure as an offset. 
[…] Moderate to severe COPD exacerbations occurring within 1 day (24 hours) after the last 
drug administration date, are included in the primary analysis”.


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See section 6.9 for calculation of observed rate.
Annualized rates of moderate to severe COPD exacerbations will be tested for equivalence
between the two treatment groups T+O 5/5 and Tio 5. The hypothesis (H) test is:
H10: RR = 1 
vs.
H11: RR ≠ 1,
where 88 =
9(;<=)
9(;?@) and λTio is the annualized rate for the patients in the Tio 5 group and λT+O
is the annualized rate for the patients in the T+O 5/5 group and RR is the rate ratio between 
the two groups.
The hypothesis test will be evaluated using a two-sided α=0.01. Ninety-nine (99)% 
confidence intervals will be obtained. Type III sums of squares will be produced.
The following SAS® code for the negative binomial model will be used:
proc genmod data=exac_negbin;
    
class trt;
model evtnum=trt/noint dist=negbin  link=log offset=logdurs type3  
alpha=0.01;
    
lsmeans trt/cl diff exp alpha=0.01;
    run;
where TRT=treatment group and LOGDURS=log(exposure) as described in section 6.9. The 
OFFSET=LOGDURS is used to account for different exposure, or observation periods per 
subject.
The primary analysis will be an actual treatment analysis performed on the treated set (TS) 
(see section 6.3). The exacerbation events will be only counted in this analysis if they 
occurred during the actual treatment period (see section 6.1).


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Section 9.1 details additional rules applied to the analysis of the primary endpoint.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Time to first moderate to severe COPD exacerbation is the key secondary endpoint and will 
be assessed sequentially after the testing of the primary hypothesis (section 7.4), thereby 
protecting the overall type I error (at the 2-sided 0.01 level). 
As stated in the revised CTP (section 7.2), the hypotheses for this test of equivalence between 
T+O and Tio, are: 
H20: ST+O = STio
vs.
H21: ST+O ≠STio
where S = survival distribution.
The key secondary analysis will be performed on the TS and will include events that have 
occurred during the actual treatment period. 
A Cox proportional hazards model will be used to estimate the hazard ratio and the 
corresponding 99% CI, while log-rank test statistics will be used to obtain the p-value for 
testing the survival curves. Accompanying plots of cumulative hazard over time by treatment 
will also be presented.
The SAS® code for the Cox proportional hazards model is as follows:
proc phreg data=exac_surv;
    
class trt (ref=’control’);
model time*event(1)=trt / RL; *ADEXAC spec:0 is “not censored”, 1 is
“censored”;
hazardratio trt / diff=ref cl=wald alpha=0.01;
ods output hazardratios=hazard;
run;
Patients who discontinue medication early (i.e. prior to the planned end of the treatment 
period, see section 6.1) will be censored at the time they discontinue medication + 1 day.
The proportional hazards assumption will be checked prior to running the analysis. This will 
be done by conducting a Cox PH test for proportionality and examining the log(-log) versus 
log(survival time) plot.
The SAS® code for the Cox proportional hazards test for proportionality is as follows:
proc phreg data=testProp;
        class trt(ref='control’);
        model time*event(1) = trt ttreat/ RL;
        id ptno;


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        ttreat=trt*log(time);
        proportionality_test: test ttreat;
run;
7.5.2
Secondary endpoints
Secondary endpoints are:

Annualized rate of COPD exacerbations leading to hospitalization during the actual 
treatment period.

Time to first COPD exacerbation leading to hospitalization during the actual 
treatment period.

Time to all-cause mortality occurring during the actual treatment period
Annualized rate endpoints will be analyzed using a negative binomial model, as described in 
section 7.4. Time to event endpoints will be analyzed using a Cox model as described in 
section 7.5.1. 


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7.7
EXTENT OF EXPOSURE
Extent of exposure to trial medication within the study will be displayed by treatment for the 
TS. Treatment exposure will be calculated as drug stop date - drug start date + 1 day. Both 
descriptive statistics and categorization by exposure intervals (e.g. <=90 days, 91-180 days, 
181-270 days, 271-360 days, >=361 days) will be used.
The extent of observation time will be summarized similarly. The time intervals will be 
similar except for an additional category to account for the full follow-up period (i.e. 360 –
381 days and >=382 days).
7.8 SAFETY ANALYSIS
All safety analyses will be performed on the TS. Adverse events (AE) were actively collected 
during the on-treatment phase, which for AEs includes the time period from first dose of 
study drug until the last dose of study drug + 21 days (see section 6.1).
AEs that were voluntarily reported during the vital status and exacerbation follow-up period 
for early discontinuations will be listed within the study report in a separate table.
7.8.1
Adverse events
Unless otherwise specified, the analyses of AE will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and NOT on the number of AEs.
For the analysis, multiple AE occurrence data on the eCRF will be collapsed into an AE 
provided that all of the following applies:
•
All AE attributes are identical (lowest level term (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 (2), (3).
The analysis of AE will be based on the concept of treatment-emergent adverse events. That 
means that all AE occurring between first drug intake through last drug intake + residual 
effect period will be assigned to the randomised treatment. All AE occurring before first drug 
intake will be assigned to ‘screening’ and all AE occurring after the residual effect period 
will be assigned to ‘follow-up’ (for listings only). For details on the treatment definition, see 
section 6.1.
According to ICH E3 (4), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant AE 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 (MQRM).


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An overall summary of AE will be presented.
The frequency of patients with AE will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for patients with other 
significant AE according to ICH E3 (4) as well as for patients with serious AE and for 
patients with AEs leading to death.
The SOCs will be sorted alphabetically and PTs will be sorted by frequency (within SOC).
7.8.2
Mortality
All deaths are adjudicated by a blinded and independent adjudication panel to determine the 
primary cause of death. For each death, the cause as determined by both investigator and
adjudication will be listed. Frequency tables summarizing AEs leading to death will be 
displaying adjudicated causes of death.
Fatal AE SOC shifts (if applicable) from investigator determined SOC to adjudicator 
determined SOC will be displayed.
7.8.3
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (5). Appendix 16.1.9.2 and Appendix 16.2 displays to be included are as follows 
(table/listing numbers refer to the standard lab table/listing types). 
End-of-text

Frequency of patients [N (%)] with transitions relative to reference range 
(TCTCCHG)

Frequency of patients [N (%)] with possible clinically significant abnormalities 
(TPCSAF)

Descriptive statistics for baseline, last value on treatment, and difference from 
baseline (normalized values) (TDSTATBE)

Hy’s Law figure (HYLAW)
Appendix 16.1.9.2

Descriptive statistics for normalized values

Descriptive statistics for baseline, last value on treatment, and difference from 
baseline (normalized values) (TDSTATBE)
Appendix 16.2

Criteria for clinically significant abnormalities based on normalized laboratory values 
(Listing CRITPCSA – “normalized”)

Laboratory values (normalized values) by functional group, sorted by centre, 
treatment, and patient  (Listing LBNGRP)

Investigator comments for original values (Listing COMMENTS)

Peak values of ALT/Bilirubin in relation to their upper limit of the reference range 
(PEAKLIST)


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7.8.4
Vital signs
Only descriptive statistics and change from baseline are planned for this section of the report.
7.8.5
ECG
Only baseline data (screening) were collected. Abnormal findings will be summarized within 
the medical history display.


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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-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
3
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
4
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version
5
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.


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9.
ADDITIONAL SECTIONS
9.1
DETAILED DESCRIPTION OF ENDPOINT: COPD EXACERBATION
Detailed definition of an exacerbation is provided in the revised CTP section 5.1.2.1. The 
following additional rules will be applied in the analysis:
Collapsing rules
The revised CTP states that the end date of a COPD exacerbation is decided by the 
investigator. If, however a second exacerbation occurs within 7 days of the determined end 
date of a previous exacerbation, these two events will be collapsed and counted as one in the 
analysis with an onset date as the date of the beginning of the first event.
Severity rules:
•
If a milder event is collapsed with one that is more severe, the collapsed event will be 
classified according to the more severe event.
Fatal COPD exacerbation event
As defined in the revised CTP, an exacerbation will meet the definition if, among other 
factors listed, the duration is of three days or more. However, in cases where the primary 
cause of death has been determined by the investigator to be due to a COPD exacerbation, but 
the duration until death was less than 3 days, the COPD exacerbation event will be counted 
within the COPD exacerbation analysis as a severe exacerbation.
Analysis of COPD exacerbation leading to hospitalization
Only COPD exacerbations that have been marked on the eCRF as being associated with 
“admission to hospital” will be included in this analysis.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
15-Nov-16
None
This is the final TSAP without any 
modification