Clinical trial NCT04223843
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim
Start date: 2020-01-08; Completion date: 2020-09-29
Enrollment: 213 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To demonstrate the efficacy of inhaled tiotropium + olodaterol via Respimat® on lung function in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD) with optimal and sub-optimal Peak Inspiratory Flow Rate (PIFR). Disease severity (moderate to severe) is based on the Global Initiative for Chronic Lung Disease (GOLD) guidelines (GOLD 2 - 3)

Detailed description:

Arms: arm 1: Tiotropium + Olodaterol Fixed Dose Combination (FDC) via Respimat arm 2: Matching placebo via Respimat
Interventions: intervention 1: Tiotropium + olodaterol intervention 2: Placebo
Intervention descriptions: intervention 1: Oral Inhalation intervention 2: Oral Inhalation

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Clinical Trial Protocol
TITLE PAGE
Document Number:
c27526629-04
EudraCT No.
2019-001719-21
BI Trial No.
1237-0095
BI Investigational
Medicinal Product
Tiotropium + olodaterol (fixed dose combination) Respimat® or 
matching placebo
Title
A randomized, double blind, placebo-controlled, multi-center, 
parallel group study to compare the efficacy of inhaled tiotropium
+ olodaterol, fixed dose combination (5µg/5µg) vs. placebo 
delivered by Respimat inhaler in patients with moderate to severe 
COPD, stratified by peak inspiratory flow rate [TRONARTO].
Lay Title
A study to test the combination of tiotropium and olodaterol using 
the Respimat® inhaler in people with chronic obstructive 
pulmonary disease (COPD) who have different abilities to inhale.
Clinical Phase
IV
Clinical Trial Leader
Phone:
Fax:
Coordinating 
Investigator
Phone:
Fax:
Status
Final Protocol (Revised Protocol based on Global Amendment 2)
Version and Date
Version: 3.0
Date: 28 January 2020
Page 1 of 73
Proprietary confidential information.
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
18 September 2019
Revision date
28 January 2020
BI trial number
1237-0095
Title of trial
A randomized, double blind, placebo-controlled, multi-center, parallel 
group study to compare the efficacy of inhaled tiotropium + 
olodaterol, fixed dose combination (5µg/5µg) vs. placebo delivered 
by Respimat inhaler in patients with moderate to severe COPD, 
stratified by peak inspiratory flow rate [TRONARTO].
Coordinating
Investigator
Phone:
Fax:
Trial site(s)
Multi-center, multi-national
Clinical phase
IV
Trial rationale
Despite evidence supporting the efficacy of tiotropium + olodaterol
Respimat® in a broad COPD population, data demonstrating the 
effectiveness of tiotropium + olodaterol Respimat® on pulmonary 
function in individuals stratified by optimal and sub-optimal peak 
inspiratory flow rate (PIFR) is lacking.
Trial objective
This study is designed to demonstrate the efficacy of inhaled 
tiotropium + olodaterol 5ug/5ug via Respimat® on lung function in 
patients with moderate to severe COPD with optimal and sub-optimal 
PIFR.
Trial endpoints
Primary endpoint:
Change from baseline in FEV1 AUC0-3h at week 4.
Key secondary endpoint:
Change from baseline in trough FEV1 at week 4.
Trial design
Randomized, double blind, multi-center, parallel group, placebo-
controlled trial stratified by PIFR optimal (≥60L/min) and sub-
optimal (<60L/min) group.
Total number of patients
randomized
Approximately 200
Number of patients on 
each treatment
100
Diagnosis
Patients diagnosed with moderate to severe COPD (GOLD 2 - 3), 
based on Global Initiative for Chronic Lung Disease guidelines.
Main inclusion and 
exclusion criteria
Inclusion Criteria:
1. Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial.


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2. Male or female patients, 40 years of age or older.
3. Diagnosis of chronic obstructive pulmonary disease and must 
meet the following spirometric criteria: patients with a post-
bronchodilator FEV1 >30% and <80% of predicted normal; and a 
post-bronchodilator FEV1/FVC <70%, at the screening visit.
4. Patients must be current or ex-smokers with a smoking history of 
more than 10 pack years (Appendix 10.2).
5. Patients should meet the PIFR criteria (optimal or sub-optimal) at 
the time of randomization depending on which strata is available 
for inclusion in the study.
6. Women of childbearing potential must be ready and able to use 
highly effective methods of birth control.
7. Patients must be able to perform, according to investigator’s 
judgment, all trial related procedures.
Exclusion Criteria
1. Patients with a significant disease other than COPD
2. Patients who have had a COPD exacerbation that required 
treatment with antibiotics, systemic steroids (oral or intravenous) 
or hospitalization in the last 6 weeks prior to visit 1.
3. Patients who experienced two or more moderate COPD 
exacerbations (exacerbation that required treatment with 
antibiotics and/or oral corticosteroids), or one or more 
exacerbation leading to hospitalization within a year prior to the 
screening visit (visit 1).
4. Patients with a history of asthma. 
5. Patients taking inhaled corticosteroids (including combinations, 
e.g. ICS/LABA) in the 6 months prior to screening
6. Patients being treated with oral corticosteroid medication due to 
reasons other than COPD exacerbation within 6 weeks prior to 
visit 1.
7. A history of myocardial infarction within 6 months of the 
screening visit
8. Hospitalization for heart failure within the past year.
9. Pregnant or nursing women.
Test products
Tiotropium + olodaterol Respimat® fixed dose combination or 
matching placebo delivered via Respimat® inhaler.
dose
5µg tiotropium + 5µg olodaterol daily
(2.5 μg /2.5 μg per actuation administered as 2 actuations once daily)
mode of 
administration
Oral inhalation (2 inhalations in the morning)
Duration of treatment
4 weeks
Statistical methods
The primary endpoint will be analysed using an ANCOVA model in 
PIFR optimal and sub-optimal groups seperately. The ANCOVA 
model will include the fixed, categorical effect of the treatment and 
the fixed continuous effect of baseline. The key secondary endpoint
will be analysed using restricted maximum likelihood (REML) based 


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mixed effects model repeated measures (MMRM) approach because 
data are available at an additional visit. The MMRM model will 
include the fixed, categorical effect of treatment at each visit, and the 
fixed continuous effect of baseline at each visit. The primary endpoint 
will be compared across treatment groups in PIFR subgroups (first 
optimal and then sub-optimal). Then the key secondary endpoint will 
be compared across treatment groups in the PIFR subgroups in the 
same order.The entire hierarchical hypothesis testing strategy for 
tiotropium + olodaterol FDC (5µg/5µg) versus placebo in PIFR 
subgroups will be protected at an overall two-sided 0.05 type I error 
rate.


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FLOW CHART
Trial Periods
Screening 
Treatment 
Follow-up
Visit
11
2
3
42
(EOT)
5
(Phone call)
Days
-3 to -14
1
15
29
50
Week
-2
0
2
4
7
Time window for visits
NA
NA
±2 days
±2 days
+ 7 days
Informed consent3
X
Demographics/baseline conditions
X
Medical history
X
Physical examination & vital signs4
X
X
X
Register patient in IRT5
X
X
X
Medication washout check6
X
X
X
Pulmonary function tests7
X
X
X
X
Plethysmography8
X
X
Laboratory tests (safety)9
X
X
X
eGFR10
X
Pregnancy test11
X
X
X
X
12 lead-ECG12
X
X
X
Review of in-/exclusion criteria
X
X
Dispense 
& 
paper patient diary
X
training14
X
X
X
PIFR measurements at clinic15
X
X
X
X
Dispense rescue medication16
X
X
X
Collect rescue medication
X
X
X
Training in the use of Respimat®17
X
X
Randomization18
X
Administration of trial medication in 
clinic
X
X
X
Dispense trial medication19
X
Collect trial medication
X
AEs/SAEs*****
X
X
X
X
X
Medication compliance check20
X
X
Concomitant therapy
X
X
X
X
X
Trial completion
X21
Footnotes:
1.
The interval between visits 1 and 2 (screening period) can be extended for up to 2 weeks for 
administrative reasons (section 6.2.1).
2.
All patients discontinued permanently during the treatment period, should complete EOT visit and the 
procedures associated with EOT visit.  Follow-up visit (via telephone) for discontinued patients should 
be scheduled 3 weeks after the last dose of trial medication.
3.
All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation 
in the trial, which includes medication washout and restrictions.  Medication washout is not required 
for screening visit in this study.  Patients participating in the optional body plethysmography procedure 
must sign a separate consent.
4.
Please refer to sections 5.2.1 and 5.2.2 for guidance on physical examination and vital signs.


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5.
Patient should be registered in IRT as an enrolled patient on the day of consent.  At visit 2, patient will 
be randomized and stratified via the IRT.  Please refer IRT user manual for details on other transactions 
with IRT.
6.
Medication washout criteria should be checked before initiating any visit procedures.  If patient does 
not meet medication washout requirements, visit should be rescheduled.
7.
Pulmonary function tests: visit 1 measurements are to determine patient eligibility.  Schedule for serial 
spirometry measurements at visits 2 and 4 are provided in the table below the footnotes.  At visit 3, 
only trough FEV1 measurements are done.  At visit 2, the PFTs should begin between 07: 00 a.m. and 
10:00 a.m.  At visits 3 and 4, PFTs should begin within ± 30 minutes of the time it started at visit 2.  
Pulmonary function tests must be completed before plethysmography in patients participating in the 
optional trial procedure.
8.
Plethysmography to be done only at selected sites on selected patients.  Sites should have their own 
body plethysmography equipment.  At the screening visit, an assessment will be completed to see if the 
patient can perform technically acceptable body plethysmography tests.
9.
Fasting is not required for safety labs.
10. eGFR will be derived from serum creatinine values, age, sex and race based on the CKD-EPIcr 
equation [R12-1392].
11. Women of child-bearing potential: serum pregnancy test is to be completed at visit 1.  Urine pregnancy 
test (dipstick) is to be completed at visits 2, 3, and 4 (see section 5.2.3)
12. If the interval between screening and randomization visits is less than one week, and the ECG 
recording obtained at the screening visit is normal, ECG will not be repeated at the randomization visit.
13.
must be dispensed at the screening visit along with the paper diary.  Patient must 
be trained on how the PIFR measurements will be performed and recorded in the diary
(see section 6.1).  At visits 2 and 3, the diary should be reviewed, and additional training provided to 
the patient if necessary.
14. Patients should be coached on how PIFR measurements are done and recorded in the patient’s diary.  
Patients should be reminded to bring the diary to all future clinic visits.
15. PIFR measurements using med/low and high resistance in the 
will be collected in 
the clinic at visits 2, 3, and 4.  Measurements made at the screening visit are for training purpose only.  
For more details, see section 6.1.
16. Rescue medication (salbutamol, also known as albuterol) must be dispensed at the screening visit.  
Patient should bring the inhaler back to the clinic at all future visits.  Investigator should ensure that 
patient has adequate supply of rescue medication until the next clinic visit.  Salbutamol will not be 
dispensed at EOT.  Supply of salbutamol will not be managed via IRT.
17. At the randomization visit, patient must receive adequate training on using the Respimat® device
(see section 6.2.2).  If necessary, patient must be trained again at visit 3. Study sites will have separate 
inhalers as training device.
18. PIFR measurement with med/low resistance will be used for stratification of optimal and sub-optimal 
groups.  Measurements will be made in triplicate and the highest value will be used for stratification.  
PIFR measurements made at the screening visit must not be used for stratification.
19. For unscheduled re-supply of study drug, refer to IRT user manual.
20. Please refer to section 4.3 for treatment compliance.
21. Follow-up visit will be completed by telephone.  Investigator will have the discretion to bring the 
patient to do an in-clinic follow-up visit if any safety issues are identified at EOT.
(*****) After the Follow-up visit (=individual patient’s end of the trial) the investigator should report 
only any cancers of new histology and exacerbations of existing cancer and trial treatment related 
SAEs of which the investigator may become aware of and only via the BI SAE form, please see section 
5.2.6.2.1.


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         Pulmonary Function Tests: Visits 2 and 4*
-10 
min
0
5   
min
15 
min
30 
min
1   
hour
2 
hours
3 
hours
-
-
-
±5 
min
±5 
min
±5 
min
±10 
min
±10 
min
Administer trial 
medication
X
Vital signs**
X
X
Pulmonary Functions 
Tests
(FEV1, FVC)
X
X
X
X
X
X
X
*At visit 3, PFTs done at 10 mins pre-dose (trough) only, including pre-dose vital signs
**Vital signs (when applicable) should be checked before the PFTs.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
1.2
DRUG PROFILE................................................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................16
1.4
BENEFIT - RISK ASSESSMENT.....................................................................17
1.4.1
Benefits.................................................................................................................17
1.4.2
Risks .....................................................................................................................17
1.4.3
Discussion.............................................................................................................18
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................19
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........19
2.1.1
Main objectives....................................................................................................19
2.1.2
Primary endpoints...............................................................................................19
2.1.3
Key secondary endpoints....................................................................................19
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
3.1
OVERALL TRIAL DESIGN.............................................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP...........................................................................................21
3.3
SELECTION OF TRIAL POPULATION .......................................................21
3.3.1
Main diagnosis for trial entry ............................................................................22
3.3.2
Inclusion criteria .................................................................................................22
3.3.3
Exclusion criteria ................................................................................................23
3.3.4
Withdrawal of patients from treatment or assessments..................................24
3.3.4.1
Discontinuation of trial treatment .........................................................................24
3.3.4.2
Withdrawal of consent to trial participation .........................................................25
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................25
4.
TREATMENTS...................................................................................................26
4.1
INVESTIGATIONAL TREATMENTS ...........................................................26
4.1.1
Identity of Investigational Medicinal Products................................................26
4.1.2
Selection of doses in the trial..............................................................................26
4.1.3
Method of assigning patients to treatment groups...........................................27
4.1.4
Drug assignment and administration of doses for each patient......................27


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4.1.5
Blinding and procedures for unblinding...........................................................28
4.1.5.1
Blinding.................................................................................................................28
4.1.5.2
Unblinding and breaking the code ........................................................................28
4.1.6
Packaging, labelling, and re-supply...................................................................28
4.1.7
Storage conditions...............................................................................................28
4.1.8
Drug accountability.............................................................................................29
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................29
4.2.1
Rescue medication...............................................................................................29
4.2.2
Emergency procedures .......................................................................................30
4.2.3
Restrictions ..........................................................................................................30
4.2.3.1
Restrictions regarding concomitant treatment ......................................................30
4.2.3.2
Restrictions on diet and life style..........................................................................33
4.2.3.3
Contraception requirements..................................................................................33
4.3
TREATMENT COMPLIANCE........................................................................34
5.
ASSESSMENTS..................................................................................................35
5.1
ASSESSMENT OF EFFICACY........................................................................35
5.1.1
Pulmonary function testing................................................................................35
5.1.2
Peak inspiratory flow rate measurements ........................................................35
5.2
ASSESSMENT OF SAFETY.............................................................................35
5.2.1
Physical examination ..........................................................................................36
5.2.2
Vital signs.............................................................................................................36
5.2.3
Safety laboratory parameters ............................................................................36
5.2.4
Electrocardiogram ..............................................................................................37
5.2.5
Other safety parameters.....................................................................................37
5.2.6
Assessment of adverse events.............................................................................37
5.2.6.1
Definitions of AEs ................................................................................................37
5.2.6.1.1
Adverse event........................................................................................................37
5.2.6.1.2
Serious adverse event............................................................................................38
5.2.6.1.3
AEs considered “Always Serious”........................................................................38
5.2.6.1.4
Adverse events of special interest.........................................................................38
5.2.6.1.5
Intensity (severity) of AEs....................................................................................38
5.2.6.1.6
Causal relationship of AEs....................................................................................39
5.2.6.2
Adverse event collection and reporting ................................................................39
5.2.6.2.1
AE Collection........................................................................................................39
5.2.6.2.2
AE reporting to the sponsor and timelines referring.............................................40
5.2.6.2.3
Pregnancy..............................................................................................................40
5.2.6.2.4
COPD Exacerbation..............................................................................................40
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................41
5.4
ASSESSMENT OF BIOMARKERS.................................................................41
5.5
BIOBANKING ....................................................................................................41
5.6
OTHER ASSESSMENTS...................................................................................41
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................42
6.
INVESTIGATIONAL PLAN.............................................................................44


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6.1
VISIT SCHEDULE.............................................................................................44
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................46
6.2.1
Screening period..................................................................................................46
6.2.2
Treatment period ................................................................................................47
6.2.3
Follow-up period and trial completion..............................................................48
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................49
7.1
STATISTICAL DESIGN - MODEL.................................................................49
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................49
7.3
PLANNED ANALYSES.....................................................................................50
7.3.1
Primary endpoint analyses.................................................................................50
7.3.2
Secondary endpoint analyses .............................................................................51
7.3.4
Safety analyses.....................................................................................................51
7.3.5
Interim Analyses .................................................................................................52
7.4
HANDLING OF MISSING DATA ...................................................................52
7.5
RANDOMIZATION...........................................................................................52
7.6
DETERMINATION OF SAMPLE SIZE .........................................................53
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........55
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................55
8.2
DATA QUALITY ASSURANCE ......................................................................56
8.3
RECORDS...........................................................................................................56
8.3.1
Source documents ...............................................................................................56
8.3.2
Direct access to source data and documents.....................................................57
8.3.3
Storage period of records ...................................................................................57
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................57
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........57
8.6
TRIAL MILESTONES.......................................................................................58
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................58
9.
REFERENCES....................................................................................................60
9.1
PUBLISHED REFERENCES............................................................................60
9.2
UNPUBLISHED REFERENCES......................................................................63
10.
APPENDICES.....................................................................................................64
10.1
BODY PLETHYSMOGRAPHY MEASUREMENT TECHNIQUE.............64
10.2
ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA...........65
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................66


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ABBREVIATIONS
AE
Adverse Event
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ATS
American Thoracic Society
AUC
Area under the Curve
BI
Boehringer Ingelheim
CKD-EPIcr
Chronic Kidney Disease Epidemiology Collaboration Equation
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRO
Contract Research Organization
DPI
Dry Powder Inhaler
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ECSC
European Coal and Steel Community
eDC
Electronic Data Capture
EELV
End-expiratory Lung Volume
eGFR
Estimated Glomerular Filtration Rate
EOT
End of Treatment
ERS
European Respiratory Society
ERV
Expiratory Reserve Volume
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDC
Fixed Dose Combination
FEV1
Forced Expiratory Volume in one second
FRC 
Functional Residual Capacity
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
IC
Inspiratory Capacity


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ICH
International Council on Harmonisation
ICS
Inhaled Corticosteroids 
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IVC
Inspiratory Vital Capacity
LABA
Long-Acting β2-agonist
LPLT
Last Patient Last Treatment
MDI
Metered Dose Inhalers
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed Model with Repeated Measurements
NA
Not Applicable
PFT
Pulmonary Function Test
PIFR
Peak Inspiratory Flow Rate
pMDI
Pressurized metered dose inhaler
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
RV
Residual Volume
SAE
Serious Adverse Event
SD
Standard Deviation
SGOT
Serum Glutamic Oxaloacetic Acid
SGPT
Serum Glutamic Pyruvic Transaminase
SGRQ
St. George's Respiratory Questionnaire
SMI
Soft Mist Inhaler
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TDI
Transition Dyspnea Index
TLC
Total Lung Capacity
TSAP
Trial Statistical Analysis Plan
USPI
United States Prescribing Information
WHO
World Health Organization


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WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
The complementary modes of action of tiotropium + olodaterol have previously been 
demonstrated in phase II clinical trials and during the Phase IIIa program that led to the 
registration of tiotropium + olodaterol combination in the European Union (EU), the United 
States and several other countries (P15-03349).
In the Phase III program the additional benefits of the tiotropium + olodaterol fixed dose 
combination (FDC) over its mono-components and placebo have been assessed on lung
function, quality of life (St. George's Respiratory Questionnaire -SGRQ), dyspnea (Transition 
Dyspnea Index-TDI), moderate and severe chronic obstructive pulmonary disease (COPD)
exacerbations and exercise endurance time (P15-03349).
Inhaled bronchodilators are a mainstay of therapy for COPD, bronchodilator therapy can be 
delivered via several modalities including dry powder inhalers (DPIs), soft mist inhalers 
(SMIs), nebulized solutions, and pressurized metered dose inhalers (pMDIs).  Drug delivery 
via inhalation devices is dependent on the inspiratory flow rate generated by the patient.  It is 
now widely recognised that a successful treatment outcome in COPD depends as much on the 
inhaler device as it does on the drug (P06-04748).
The majority of patients with COPD present with moderate to severe airflow obstruction at 
time of diagnosis.  In COPD patients expiratory airflow limitation is typically accompanied 
by decreased inspiratory capacity, hyperinflation and respiratory muscles impairment, which 
combined, result in reduced inspiratory flow rates, which could diminish lower airway 
deposition of the drug (P06-04750).
Achieving the correct inhalation flow from any inhalation device is critical in order for the 
patient to achieve therapeutic benefit from the inhaled drug. Patients with COPD may use 
sub-optimal inhalation flows as they may not have the energy generated by their inspired 
breath to achieve the effective inhalation flows that are required for some devices (R15-5362). 
However, inspiratory flow rates or the patient´s ability to perform the required inhalation 
maneuver are rarely checked in clinical practice before selecting an inhaler/treatment, 
increasing the risk of patients not receiving the full clinical benefits of the treatment 
prescribed.
The Respimat® Soft MistTM Inhaler actively delivers a metered dose of medication, with 
minimal inspiratory effort from the patient,  as a fine slow moving, long lasting mist, with a 
high fine particle fraction, resulting in a high lung deposition and lower oropharyngeal 
deposition (P12-01215, P05-10480, P06-10775). In vitro data has demonstrated that
Respimat® Soft MistTM delivers high lung deposition at low modelled flow rates and across 
disease severities, and requires only a very low inspiratory effort (P17-06338).
Dry powder inhalers have higher internal resistance than that of SMIs and pMDIs; as a result, 
the inspiratory force necessary to overcome the internal resistance of DPIs, to optimally 


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release the medication from the inhaler and deliver into the airways, is greater than what is 
required for pMDIs and SMIs. The 
.) 
has been introduced as a simple, low cost method of measuring an individual’s inspiratory 
flow rate.  It is generally accepted that a PIFR of 60 L/Min (optimal PIFR) is required for 
adequate drug delivery by a DPI with medium internal resistance.  In previous studies of 
small cohorts, approximately 30-50% of patients are unable to generate the targeted PIFR of 
60 L/Min as measured by
with medium or low resistance.  There is also 
evidence demonstrating that, at the time of discharge from an acute care hospital for 
treatment of a COPD-related hospitalization, one third of patients had a sub-optimal PIFR 
with medium or low resistance measured by 
.  It has been demonstrated 
that sub-optimal PIFR is a predictor of 90-day readmission for COPD, days to all-cause 
readmissions and days to COPD readmission. Multivariate analysis has demonstrated that 
age, gender, height, forced vital capacity (FVC) % predicted and inspiratory capacity (IC) % 
predicted are independent predictors of sub-optimal PIFR. This evidence highlights the 
importance of inspiratory flow rate in the effective delivery of inhaled therapies; yet, the 
evidence for the benefits provided by currently available inhaled treatments for COPD 
according to the inspiratory flow rates generated by patients, is scarce.  
1.2
DRUG PROFILE
Tiotropium + olodaterol combination
Tiotropium + olodaterol FDC is an aqueous solution of tiotropium + olodaterol contained in a 
cartridge. It is administered by using the Respimat® inhaler. One cartridge is used per 
inhaler, which is inserted into the device prior to first use.
In the pivotal studies (c01735218-03, c01735249-03), tiotropium + olodaterol FDC showed 
statistically significant improvements in Forced Expiratory Volume in first second (FEV1) 
Area under the curve (AUC0-3h) response and trough FEV1 response after 24 weeks compared 
to the mono-components and these improvements were maintained up to 52 weeks. 
Tiotropium + olodaterol FDC showed statistically significant improvements in health-related 
quality of life (SGRQ) and dyspnea experienced during everyday activities [Transition 
Dyspnea Index (TDI)] after 24 weeks compared to the mono-components. More patients 
treated with the combination had an improvement in SGRQ total score and TDI focal score 
which exceeded the Minimal Clinically Important Difference.
Treatment with tiotropium + olodaterol FDC also resulted in reductions in both daytime and 
night time rescue bronchodilator use compared to the mono-components. The
bronchodilatory profile of the combination was confirmed in a supportive 6-week study 
(c02093555-02), in which the mean FEV1 improvements over 24 hours were superior to the 
monocomponents, with improvements in FVC, inspiratory capacity (IC), and functional 
residual capacity (FRC), supporting the results for FEV1. 
Tiotropium + olodaterol FDC was shown to be safe and well tolerated over 1 year in a 
moderate to very severe COPD population. The overall incidence of adverse events (AEs), 
serious adverse events (SAEs), fatal AEs, frequencies for cardiac events and major adverse 


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cardiovascular event in the tiotropium + olodaterol FDC treatment group were similar to the 
mono-components. The nature and frequency of AEs in general was consistent with the 
disease under study. There were no results in the clinical development program suggesting 
the need for absolute contraindications for the combination product.
Based on these observations, marketing authorization for tiotropium + olodaterol (5μg /5μg) 
FDC (total daily dose) has been granted in US, Canada, Australia, in all European countries 
within the decentralized procedure as well as in a number of other countries worldwide.
For a more detailed description of the drug profile refer to the current Summary of Product 
Characteristics (SmPC) for Spiolto® or the United States Prescribing Information (USPI) for 
Stiolto® which are included in the Investigator Site File (ISF).
Boehringer Ingelheim’s Respimat® inhaler will be used for administration of study drug. The 
medication is provided as an aqueous solution in a cartridge, which is inserted into the device 
prior to first use. A propellant-free device, the Respimat® inhaler generates a soft mist which 
is released over a period of approximately 1.5 seconds. The fraction of fine particles 
accessible to the lungs and airways is very high compared with many metered dose aerosols 
or dry powder devices. The use of the Respimat® inhaler has been shown to be safe with 
regards to paradoxical bronchoconstriction during chronic use in patients with COPD 
(P05-08465). The Residual Effect Period (REP) of tiotropium + olodaterol FDC is 21 days.
Salbutamol used as rescue medication in this trial is a short-acting, selective beta2-adrenergic 
receptor agonist used in the treatment of asthma and COPD.  Salbutamol is a bronchodilator 
that opens up the airways affected by bronchoconstriction, therefore relieving the wheezing 
and shortness of breath.  Salbutamol can be used as a fast-acting rescue medication that 
provides quick relief..
1.3
RATIONALE FOR PERFORMING THE TRIAL
Despite evidence supporting the efficacy of tiotropium + olodaterol Respimat® (R19-2073) in 
a broad COPD population, data demonstrating the effectiveness of tiotropium + olodaterol 
Respimat® on pulmonary function (trough FEV1, FEV1 AUC) in individuals stratified by 
optimal and sub-optimal PIFR is lacking.  Spirometry data from the tiotropium + olodaterol 
clinical development program include mostly lung function and volumes from an expiratory 
maneuver, which does not allow to measure PIFR; when an inspiratory maneuver has been 
performed, it is performed against no resistance from the spirometer, which makes it not 
possible to measure the PIFR simulating the resistance of an inhaler.  Furthermore, since the 
measurement of PIFR is not routinely performed in daily clinical practice, the effectiveness 
of tiotropium + olodaterol Respimat® according to the patients´ PIFR from real world use has 
not been assessed.
Data from this study may facilitate the clinician´s decision when choosing a treatment and 
delivery system, as it could provide certainty that the treatment selected will be effectively 
delivered independently of the patient ability to generate sufficient energy through the 
inhalation effort.


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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Clinical trials conducted to date have shown tiotropium + olodaterol (5μg/5μg) fixed dose 
combination to be a safe, well tolerated and efficacious combination therapy according to 
treatment guidelines in a moderate to very severe COPD population.  The OTEMTO studies, 
demonstrated improvements in lung function with tiotropium + olodaterol over placebo and 
tiotropium after 12 weeks of treatment in patients with moderate to severe COPD 
(P15-08379), the population to be included in this study
1.4.2
Risks
Potential risks associated with administration of the combination of tiotropium + olodaterol 
include the listed (expected) adverse events for tiotropium / olodaterol (5μg/5μg) fixed dose 
combination as described in the USPI/EU SmPC.
Women of childbearing potential may be included in clinical trials for tiotropium + olodaterol
(5μg/5μg) fixed dose combination provided appropriate precautions are taken to minimize the 
probability of becoming pregnant.  These precautions include pregnancy testing and use of a 
highly effective method of birth control.  Continued testing and monitoring during the trial 
should be sufficient to ensure compliance with the measures not to become pregnant during 
the period of drug exposure.
A placebo group is included in the trial to provide an appropriate control for the assessment 
of the effects of the tiotropium + olodaterol FDC on lung function (FEV1) according to the 
inspiratory flow rate (PIFR) the patients can generate.  In order to minimize the risk for the 
study patients, a number of population and design measures have been put in place, namely:

The duration of the treatment period including placebo is limited to 4 weeks.

The population for this study excludes patients with very severe COPD and patients 
currently treated with inhaled corticosteroids (ICS).

Patients with a recent exacerbation (6 weeks prior to visit 1) or with a history of 
frequent exacerbations (two or more exacerbation requiring treatment with systemic 
glucocorticoids, antibiotics or both, or an exacerbation that required hospitalization 
within one year prior to visit 1) are also excluded.

The study does not include a long washout period.  In order to shorten the time of 
placebo treatment; patients will continue to receive their prescribed treatment until 
three days before randomization.

Patients will receive salbutamol as rescue medication.

Within the four-week treatment period, a study visit in the clinic has been added after 
two weeks of treatment as an opportunity for assessment of the patients’ condition by 
the investigators.
Boehringer Ingelheim will provide open-label salbutamol as rescue medication for all 
patients during the course of the trial.


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1.4.3
Discussion
Tiotropium + olodaterol FDC delivered via the Respimat® device was shown to be effective 
in improving lung function, quality of life and dyspnea as well as improve exercise tolerance.  
It has also shown to be safe and well tolerated over 1 year in a moderate to very severe 
COPD population; however, there is currently no clinical data available from randomized 
controlled trials or from real world studies to demonstrate whether COPD patients can benefit 
from tiotropium + olodaterol Respimat® independently of the inspiratory flow they can 
generate.  
Data from this study will provide this evidence and therefore help in the personalization of 
treatment selection for COPD patients.  Considering a placebo arm is included in the study, 
the treatment and follow-up period has been kept short, and includes a clinic visit after two 
weeks of treatment to assess the patients’ condition.  Further measures are in place to 
minimize the risk for the study population are the exclusion of the most severe COPD 
population, the population treated with inhaled corticosteroids, those patients with a very 
recent COPD exacerbation, or with a history of frequent COPD exacerbations and at risk of 
COPD exacerbations.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
This study is designed to demonstrate the efficacy of inhaled tiotropium + olodaterol 5µg/5µg 
via Respimat® on lung function in patients with moderate to severe COPD with optimal (≥60 
L/min) and a sub-optimal (<60 L/min) PIFR.  Disease severity (moderate to severe) is based 
on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines
(GOLD 2 – 3).
2.1.2
Primary endpoints
Change from baseline in FEV1 AUC0-3h after 4 weeks of treatment.
Analyses will be performed in PIFR optimal (≥60 L/min) group and PIFR sub-optimal 
(<60 L/min) group separately.
2.1.3
Key secondary endpoints
Change from baseline in trough FEV1 after 4 weeks of treatment
Analyses will be performed in PIFR optimal (≥60 L/min) group and PIFR sub-optimal 
(<60 L/min) group separately.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This trial is a randomized, double-blind, placebo-controlled, multicenter, parallel study 
designed to assess efficacy of tiotropium + olodaterol delivered by Respimat® on FEV1
AUC0-3h, and trough FEV1 in patients with moderate to severe COPD, stratified by optimal 
and sub-optimal PIFR.  The study will consist of a screening period of up to 2 weeks, a 
4-week randomized treatment period and a three week follow-up period.  An overview of the 
trial design is presented in Figure 3.1: 1.
Figure 3.1: 1 Trial Design
Approximately 200 patients will be randomized (1:1) to either the active arm (tiotropium + 
olodaterol, FDC) or the placebo arm. The randomization will be stratified by optimal 
(≥60 L/min) or sub-optimal (< 60 L/min) PIFR as measured with the 
set 
at med/low resistance. Each strata will be capped to a total of approximately 100 patients.  
An interactive response technology (IRT) will be used for randomization and stratification.
After signing informed consent and completing the screening visit, patients will enter a 
screening period of 3 to 14 days. During the screening period, patients will continue to 
receive their COPD maintenance treatment, except for the medication washout requirements 
required before the randomization visit (see Table 4.2.3.1: 1).  Patients will be randomized 
into the 4-week treatment period in which they will be randomly assigned to one of two 
treatments: tiotropium + olodaterol FDC or matching placebo.  The randomization visit (visit 
2) will be followed by a clinic visit in 2 weeks (visit 3) and end of treatment (EOT) visit (visit 
4) will be 4 weeks (28 days) after randomization.  A follow-up visit by telephone will be 
scheduled three weeks after the last dose of study medication.  Study procedures to be 
performed at each clinic visit are presented in the Flow Chart.  The timing of the pulmonary 
function tests with serial spirometry at baseline (visit 2) and at EOT (visit 4) is provided in
the table below the Flow Chart.
Patients will be washed out of COPD medications for approximately 72 hours before 
randomization.  Patients will be allowed to use salbutamol as rescue medication during this 


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washout period.  Once randomized, patients will receive either tiotropium + olodaterol FDC 
via Respimat® inhaler or matching placebo.  All patients will receive salbutamol for use as 
rescue medication, as needed, from screening visit until EOT.  At the conclusion of EOT 
visit, patients can resume taking their regular COPD medications.  At the EOT visit,
investigator should advise the patients on appropriate care during the follow-up period and 
after completion of the study.  During the follow-up period, patients will not receive study 
medication.  Rescue medication will not be dispensed at EOT visit for use during the follow-
up period.  Patients on ICS maintenance therapy (monotherapy or combination with 
bronchodilators) will not be eligible to participate in this study.
Body plethysmography measurements will be an optional trial procedure at visit 2 and will be 
done only at selected sites on selected patients.  Approximately 30 (15%) patients are 
expected to participate in this procedure.  Patients participating in this optional trial procedure 
will have to sign a separate informed consent. At the screening visit, an assessment will be 
completed to see if the patient can perform technically acceptable body plethymography 
measurements.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
Currently, data on the impact of PIFR on the effectiveness of treatments/inhalers available for 
COPD is not consistent or not available, and available data on existing treatments/inhalers 
cannot be extrapolated to the population of interest.  A comparison with placebo was 
considered the best approach to assess the effect of tiotropium + olodaterol FDC in this 
population.
There is no previous data or knowledge of the treatment effect of tiotropium + olodaterol on 
spirometric parameters in the two PIFR populations (< 60 L/min and ≥ 60 L/min). Therefore 
the trial will need to enroll a sufficient number of placebo patients in order to make an 
assessment of efficacy between treatment and placebo.  A 4-week treatment period is 
considered sufficient to evaluate the effects of tiotropium + olodaterol FDC in patients with 
COPD (P19-01878).
It is anticipated that with 200 patients randomized 1:1 in the trial and, a duration of 4 weeks,
there is adequate statistical power to detect an effect of the treatment vs placebo in each of 
the PIFR sub populations.
3.3
SELECTION OF TRIAL POPULATION
Recruitment of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites once a sufficient number of patients have been screened to randomize 200 patients.  
Approximately 40 study sites are expected to participate in this study.  Approximately 300 
patients are expected to be screened.  Patients in screening at the time when a decision is 
made to stop further screening will be allowed to continue and may be randomized in the 
study if eligible.


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A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrollment), the sponsor should be contacted immediately.  A 
decision on whether this patient will receive additional study medication and continue in the 
trial will be made in consultation with the sponsor.  The investigator must obtain documented 
approval from the sponsor to allow the wrongly enrolled patient to continue in the trial.
3.3.1
Main diagnosis for trial entry
Patients diagnosed with moderate to severe COPD (Stage 2 or 3) based on GOLD guidelines
(P19-00675).
Refer to section 8.3.1 (Source Documents) for the documentation requirements pertaining to 
the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
2. Male or female patients, 40 years of age or older.
3. All patients must have a diagnosis of COPD and must meet the following spirometric 
criteria: patients with a post-bronchodilator FEV1 >30% and <80% of predicted 
normal (ECSC, (R94-1408); and a post-bronchodilator FEV1/FVC <70%, at the 
screening visit.
4. Patients must be current or ex-smokers with a smoking history of more than 10 pack 
years (Appendix 10.2).
5. Patients should meet the PIFR criteria (optimal or sub-optimal) at the time of 
randomization depending on which strata is available for inclusion in the study.
6. Women of childbearing potential (WOCBP) must be ready and able to use highly 
effective methods of birth control per ICH M3 (R2) that result in a low failure rate of 
less than 1% per year when used consistently and correctly. A list of contraception 
methods meeting these criteria is provided in the patient information.
7. Patients are expected to be able to perform, according to investigator’s judgment, all 
trial related procedures including:
a.
Technically acceptable pulmonary function tests (spirometry)
b. Use of 
device to measure PIFR
c.
Inhale medication in a competent manner (in the opinion of the investigator) 
from the Respimat® device
d. Perform technically acceptable body plethysmography measurements.  This is 
applicable only to patients who will consent to the optional trial procedure at 
the selected sites.


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3.3.3
Exclusion criteria
1. Patients with a significant disease other than COPD; a significant disease defined as a 
disease which, in the opinion of the investigator, and referring to the warnings to be 
observed as quoted in the locally applicable SmPC or prescribing information, could 
(i) put the patient at risk because of participation in the trial, (ii) influence the results 
of the trial, or (iii) cause concern regarding the patient’s ability to participate in the 
trial.
2. Patients who have had a COPD exacerbation that required treatment with antibiotics, 
systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to 
screening visit or during the screening period.
3. Patients who experienced two or more moderate COPD exacerbations (exacerbation 
that required treatment with antibiotics and/or oral corticosteroids), or one or more 
exacerbation leading to hospitalization within a year prior to visit 1.
4. Patients with a history of asthma. For patients with allergic rhinitis or atopy, source 
documentation is required to verify that the patient does not have asthma.
5. Patients taking inhaled corticosteroids (including combinations, e.g. ICS/LABA) in 
the 6 months prior to screening visit.
6. Patients being treated with oral corticosteroid medication due to reasons other than 
COPD exacerbation within 6 weeks prior to the screening visit.
7. Patients who have completed a pulmonary rehabilitation program in the 6 weeks prior 
to screening visit or patients who are currently in a pulmonary rehabilitation program.
8. A history of myocardial infarction within 6 months of the screening visit.
9. Unstable or life-threatening cardiac arrhythmia.
10. Hospitalization for heart failure within 12 months of the screening visit.
11. Known active tuberculosis.
12. A malignancy for which patient has undergone resection, radiation therapy or 
chemotherapy within last five years (patients with treated basal cell carcinoma are 
allowed).
13. A history of cystic fibrosis.
14. Clinically evident bronchiectasis.
15. Patients who have taken an investigational drug within one month or 6 half-lives 
(whichever is greater) prior to screening visit.
16. Pregnant or nursing women.
17. Women of childbearing potential not using a method of birth control classified at least 
as “acceptable”.  Female patients will be considered to be of childbearing potential 
unless surgically sterilized by hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or post-menopausal (defined as no menses for 12 months without an 
alternative medical cause). Tubal ligation is not a method of permanent sterilization.
18. Patients who have previously been randomized in this study or currently 
enrolled in another investigational device or drug study.  Patients 
participating in an observational trial will not be excluded.
19. Patients who are unable to comply with medication restrictions prior to 
randomization, or who are expected to require treatment with a restricted 
medication during the trial (section 4.2.3.1).


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20. Patients with clinically relevant abnormal baseline haematology, blood chemistry.
21. Patients with creatinine >2x upper limit of normal or an estimated glomerular 
filtration rate (eGFR) determined below 50 ml/min/1.73 m2 (as derived from CKD-
EPIcr equation [R12-1392]).
22. Patients with a hypersensitivity or contraindication to tiotropium and/or olodaterol.
23. Patients with upper respiratory obstruction (i.e. vocal cord dysfunction).
24. A history of significant alcohol or drug abuse based on investigator judgment.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent for trial participation as a whole
(“withdrawal of consent”). Please see sections 3.3.4.1 and 3.3.4.2 below.
Every effort should be made to keep the patients in the trial, if possible on treatment.  
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrollment, as well as the
explanation of the procedures if the patient withdraws from the trial.  The decision to 
discontinue trial treatment or withdraw consent to trial participation, and the reason must be 
documented in the patient files and electronic case report forms (eCRF).  If applicable,
consider the requirements for adverse event collection and reporting (sections 5.2.6.2.1 and 
5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.

If a patient experiences a COPD exacerbation (moderate, or severe) during the treatment 
period, patient will be discontinued from the study (section 6.2.2).

The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment (section 4.2.3.1)

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).  In case of a temporary reason, trial 
treatment should be restarted if medically justified.
In terms of discontinuation of trial treatment, the following criteria must also be taken into 
account:

Trial treatment must be stopped immediately if a paradoxical bronchospasm or an allergic 
reaction of the immediate type occurs. 

If two or more eye symptoms (triggering or aggravation of narrow angle glaucoma, eye 
pain or discomfort, temporary blurred vision, eye halos or altered color perception 
associated with reddened eyes due to conjunctival congestion or corneal edema) occur, 
trial treatment should be discontinued and the patient should consult a specialist 
immediately. 
For safety reasons, the investigator may decide that the patient should discontinue trial 
treatment.


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If new efficacy/safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flow Chart and section 6.2.3. 
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, (section 3.3.4.1).
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrollment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk 
assessment that could significantly affect the continuation of the trial.
3. Deviations from Good Clinical Practice (GCP), the trial protocol, or the contract 
impairing the appropriate conduct of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
After screening, eligible patients will be randomly assigned to one of two treatment arms: 
tiotropium + olodaterol FDC or matching placebo, both delivered by a Respimat® inhaler.  
Patient will inhale two puffs from the Respimat® inhaler, once daily, in the morning
during the 4-week treatment period.
4.1.1
Identity of Investigational Medicinal Products
Table 4.1.1: 1
Test product 1
Substance:
Tiotropium + olodaterol fixed dose combination
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
2.5 µg / 2.5 µg per actuation 
Posology
2 inhalations once daily (a.m. dosing)
Route of administration:
Oral inhalation via Respimat® inhaler
Table 4.1.1: 2
Test product 2
Substance:
Matching placebo
Pharmaceutical formulation:
Inhalation solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
NA
Posology
2 inhalations once daily (a.m. dosing)
Route of administration:
Oral inhalation via Respimat® inhaler
4.1.2
Selection of doses in the trial
Tiotropium + olodaterol Respimat® 5µg/5µg once daily is an approved dose regimen for the 
treatment of COPD in many countries.  The clinical trials conducted during the Phase III 
program for tiotropium + olodaterol FDC 5µg/5µg have shown that this dose is a safe, well 
tolerated and efficacious combination therapy.


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4.1.3
Method of assigning patients to treatment groups
After the assessment of all inclusion and exclusion criteria, each eligible patient will be 
stratified based on PIFR (optimal vs. sub-optimal) and randomized to one of the two 
treatment arms: tiotropium + olodaterol FDC or matching placebo in a 1:1 ratio at visit 2 via
IRT using each strata. The PIFR will be measured with the 
set at 
med/low resistance.  PIFR measurements with med/low resistance will be done in triplicate 
the highest PIFR will be used for stratification.  Note that the medication number is different 
from the patient number (the latter is generated during screening via the IRT System).
4.1.4
Drug assignment and administration of doses for each patient
Dispensing trial medication
At visit 2 the IRT will assign two Respimat® kits (one for treatment and one as reserve).  At 
visit 3 the patient will bring in all treatment kits (including the reserve kits) that were 
dispensed at visit 2.  If the reserve kit dispensed at visit 2 was used by the patient, a new 
reserve kit can be dispensed at visit 3.  Each treatment kit will have a unique medication ID 
number.  Trial medication will be dispensed to the patient by the investigator or a qualified 
site staff at these visits.  The amount of trial medication dispensed will be recorded on the 
drug accountability forms.  Patients must return all Respimat® kits at visit 4 which is the end 
of treatment period
The reserve kits allow the patient the flexibility of not having to return to the clinic 
immediately to replace a lost or malfunctioning inhaler. In the event that a patient may need 
additional inhalers and cartridges due to rescheduled visits, inhaler loss or malfunction, these 
will be supplied on an ‘on demand’ basis. Dispensing of these extra inhalers will also be 
managed via the IRT.
At home, if the patient forgets to take the morning dose of trial medication, the patient can 
take the morning dose up until 12:00 midnight. After 12:00 midnight, the patient should skip 
the dose for that day and take the next dose the following morning.
Priming of the Respimat®Inhaler
Each newly assembled Respimat®Inhaler has to be primed.  Priming should not take place in 
the same room where the patient is inhaling trial medication.  The inhaler should be primed 
by actuating it until an aerosol is visible plus three additional actuations.  All priming 
actuations should be directed to the ground.
Once assembled, the shelf-life of the Respimat® Inhaler with trial medication 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.
Dispensing rescue medication
Salbutamol will be dispensed to all patients when they complete the screening visit, and are 
eligible to enter the screening period.  Patients will receive adequate supply of rescue 
medication until the end of treatment period.  Rescue medication will not be provided for the 
follow-up period.  Before using for the first time, one actuation should be released into the air 
to ensure the device is working.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators, and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomized treatment 
assignments until after database lock.  The access to the randomization code will be kept 
restricted until its release for analysis.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT.  It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise ensure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate eCRF page.
In case the automated unblinding option via the IRT system is malfunctioning, the IRT 
service provider can be contacted (24 hours a day coverage) and the treatment allocation can 
be obtained.  IRT support has direct access to the database and the treatment information can 
be manually obtained. Details about this process will be included in the ISF. 
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim (BI)
Pharmacovigilance group to access the randomization code for individual patients during trial
conduct.  The access to the code will only be given to authorized pharmacovigilance
representatives for processing in the pharmacovigilance database system and not be shared 
further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI.  They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice. Re-supply to the
sites will be managed via an IRT system, which will also monitor expiry dates of supplies 
available at the sites.  For details of packaging and the description of the label, refer to the 
ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation. If the storage conditions are found to 
be outside the specified range, the Clinical Research Associate (CRA), as provided in the list 
of contacts in the ISF, must be contacted immediately.
Further details are provided in the “storage conditions for trial medications” document and on 
the country-specific labels, a sample of which will be part of the ISF.


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Rescue medication (salbutamol) should be stored according to instructions in the local 
prescribing information.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB) / Ethics 
Committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of Food and Drug Administration (FDA) Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution center or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution center will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol, and reconcile all 
investigational medicinal products received from the sponsor. At the time of return to the 
sponsor or appointed Contract Research Organization (CRO), the investigator or designee 
must verify that all unused or partially used drug supplies have been returned by the clinical 
trial patient and that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Rescue medication
Administration of rescue medication can occur at any point during the trial as deemed 
necessary by the patient or the investigator.  Open label salbutamol (also known as albuterol) 
will be provided as rescue medication by the sponsor.  Only the salbutamol provided by the 
sponsor should be used during the screening and treatment periods.  Patient should return all 
rescue medication (used and unused) to the study site at visit 4.


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If the patient requires rescue medication during the pulmonary function testing, the 
pulmonary function tests (PFTs) will be discontinued. The medication used, route of 
administration, and 24-hour clock time will be recorded on the Rescue Medication eCRF 
page.  Patient can continue in the trial.
4.2.2
Emergency procedures
There are no emergency procedures to be followed.  Medications to control acute COPD 
exacerbations are allowed as medically necessary during the patient’s participation in the 
study.
4.2.3
Restrictions
4.2.3.1
Restrictions regarding concomitant treatment
Table 4.2.3.1: 1
Overview of permitted and restricted medication
Drug Class
Sub-class
Prior to 
study
Study Period
Screening 
Period
Treatment 
Period
Follow-up 
Period
Corticosteroids
Inhaled corticosteroids
Permitted1
NOT 
permitted
NOT 
permitted
Permitted
Oral corticosteroids
Permitted2
NOT 
permitted
NOT 
permitted
Permitted
Injected Corticosteroids –
local administration
(for treatment of e.g. bursitis)
Permitted
Permitted
Permitted
Permitted
β-adrenergics
Inhaled short-acting β-
adrenergics
Permitted
Rescue3
Rescue3
Permitted
Inhaled long-acting β-
adrenergics
(e.g. formoterol / salmeterol)
Permitted
Permitted4
NOT 
permitted 
Permitted
Anti-
cholinergics
Short-acting anticholinergics
(inhalation aerosol, nasal 
spray)
Permitted
Permitted3
NOT 
permitted
Permitted
Long-acting anticholinergics
(i.e. tiotropium, aclidinium,
glycopryonnium, 
umeclidinium, tiotropium +
olodaterol)
Permitted
Permitted4
NOT 
permitted
Permitted
Combinations
ICS/LABA
Permitted1
NOT 
permitted
NOT 
permitted
Permitted
ICS/SABA
Permitted1
NOT 
permitted
NOT 
permitted
Permitted


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Table 4.2.3.1: 1
Overview of permitted and restricted medications (cont.)
Drug Class
Sub-class
Prior to 
study
Study Period
Screening 
Period
Treatment 
Period
Follow-up 
Period
Combinations
short-acting anticholinergic/ 
SABA
Permitted
Permitted3
NOT 
permitted
Permitted
Long-acting 
anticholinergics/long-acting β-
adrenergics (e.g. 
glycopyrronium+indacaterol, 
umeclidinium+vilanterol)
Permitted
Permitted4
NOT 
permitted
Permitted
ICS, long-acting 
anticholinergics, long-acting 
β-adrenergics, (e.g. 
fluticasone+umeclidinium, 
vilanterol)
Permitted1
NOT 
permitted
NOT 
permitted
NOT 
permitted
Miscellaneous
Other investigational drugs
(1 month or 6 half-lives 
(whichever is greater) prior to 
V1)
Permitted
NOT 
permitted
NOT 
permitted
NOT 
permitted
Cromolyn sodium / 
nedocromil sodium
(if prescribed for non-asthma 
condition)
Permitted
Permitted
Permitted
Permitted
Antihistamines, 
antileukotrienes
(if prescribed for non-asthma 
condition)
Permitted
Permitted
Permitted
Permitted
Methylxanthines
(if prescribed for non-asthma 
condition)
Permitted
Permitted
Permitted
Permitted
Mucolytics
(not containing 
bronchodilators; stabilized 6 
wks. prior to V1)
Permitted
Permitted
Permitted
Permitted
Phosphodiesterase type 4 
(PDE-4) inhibitor (e.g. 
roflumilast)
Permitted5
NOT 
permitted
NOT 
permitted
NOT 
permitted
Biologics or other 
immunomodulators
(until 3 months or 6 half-lives, 
whichever is greater prior to 
visit1)
Permitted
NOT 
permitted
NOT 
permitted
NOT 
permitted
Footnotes for Table 4.2.3.1: 1
1.
Permitted until 6 months prior to visit 1
2.
Permitted until 6 weeks prior to visit 1


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3.
Refer to washout criteria before PFTs at visits 2, 3, and 4. Note: inhaled short-acting β–adrenergics, 
short-acting anticholinergics and combinations of these medications are permitted up to 8 hours prior to 
visit 2.
4.
Permitted until 72 hours prior to visit 2
5.
Permitted until 3 months prior to visit 1


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Medication restrictions for pulmonary function testing (Visits 2, 3, and 4)
•
Trial medication should not be taken at home on the morning of visits 3 and 4.
•
At least an 8-hour washout of rescue medication prior to visits 2, 3 and 4.  In this trial 
salbutamol is supplied as rescue medication by the sponsor or a designated vendor.
•
Medication washout restrictions for randomization visit (visit 2) can be found in 
Table 4.2.3.1: 1.
4.2.3.2
Restrictions on diet and life style
Restrictions prior to PFT visits:
•
Medication washout restrictions should be adhered to before the PFTs.
•
The patient should remain in the building where the pulmonary function testing is 
performed and should return to the laboratory at least ten minutes prior to the start of 
each test.
•
On pulmonary function test days during the treatment period, patients should refrain 
from strenuous activity for at least 12 hours prior to pulmonary function testing and 
throughout the testing period. Patients should also avoid cold temperatures, 
environmental smoke, dust or areas with strong odors (e.g. perfumes).
•
Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, and 
ice-cold beverages are not allowed for at least 2 hours prior to and during the 
pulmonary function testing at clinic visits.  Decaffeinated beverages are acceptable.
•
Smoking should be discouraged for the 12 hours prior to pulmonary function testing 
and throughout the test day and will not be permitted in the 30-minute period prior 
to spirometry.
4.2.3.3
Contraception requirements
WOCBP (for the definition refer to section 3.3.3) who is a trial participant will be required to 
use an acceptable method of birth control throughout the trial, and for a period of at least 21
days after last trial drug intake.
WOCBP who is a trial participant must use a highly effective method of birth control per ICH 
M3 (R2) that results in a low failure rate of less than 1% per year when used consistently and 
correctly if their sexual partner is a man able to father a child.

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal)

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion


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Or
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods, declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits 3 and 4. 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, it is possible to calculate the number of puffs
that should have been administered by the patient. The Respimat® Inhaler contains 60 
actuations (30 daily doses). The dose indicator shows approximately how much medication is 
left. The dose indicator scale is divided into 4 quarters. One quarter used accounts for 7 days 
of treatment (14 actuations). When the pointer enters the red area of the scale, there is 
approximately medication for 7 days (14 actuations left).  Once the dose indicator has 
reached the end of the red scale (i.e. all 30 daily doses have been used) the Respimat® inhaler 
is empty.  Patient compliance should be estimated using the dose indicator.
The acceptable medication compliance should have an overall value in the range 80% to 
120%. If the compliance is outside this range, patient needs to be re-trained.
Randomized patients should not be discontinued for lack of medication compliance without
prior discussion with the sponsor.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
This study is designed to demonstrate the efficacy of inhaled tiotropium + olodaterol 5µg/5µg 
via Respimat® on lung function in patients with moderate to severe COPD with optimal 
(≥60 L/min) and a sub-optimal (<60 L/min) PIFR.
5.1.1
Pulmonary function testing
 spirometers will be provided to sites for the on-site spirometry 
measurements.  The spirometers and their use, including daily calibration on test days, must 
meet American Thoracic Society (ATS) and European Respiratory Society (ERS) criteria
(P05-12782). Spirometry will be conducted with the patient in a seated position, and it is 
preferable that the same trained individual performs the PFTs for a given patient. The best of 
three efforts will be defined as the highest FEV1 and the highest FVC, each obtained on any 
of three blows meeting the ATS criteria (with a maximum of five attempts). The highest 
FEV1 and FVC will be selected regardless of whether they come from different spirometric 
maneuvers or from the same maneuver. The 24-hour clock time of the first maneuver for each 
PFT time point will be recorded. 
The clock time of the start and end of inhalation procedure of trial medication will be 
captured by the 
 spirometer.
At the screening visit, pulmonary function tests will be performed to determine patient 
eligibility (inclusion criteria 3, section 3.3.2). At visit 2, the PFTs should begin between 
07: 00 a.m. and 10:00 a.m.  At visits 3 and 4, PFTs should begin within ± 30 minutes of the 
time it started at visit 2.  At visits 2 and 4, PFTs will be measured up to 3 hours with serial 
spirometry (specified time points are provided in the Flow Chart).  At visit 3, only trough
FEV1 measurements are performed.
5.1.2
Peak inspiratory flow rate measurements
The 
 a hand held device to measure PIFR will be provided to each 
patient.  At the randomization visit the optimal and sub-optimal groups will be determined 
based on the PIFR measurements completed at the clinic at visit 2. PIFR values obtained 
from med/low resistance level will be used for stratifying the patients via IRT. Additional 
PIFR measurements will also be done in the clinic during visits 2, 3, and 4.  Measurements 
will be made in triplicate using med/low and high resistance and the highest value for each 
resistance setting will be recorded.  In addition, patients will use the
at 
home to collect the PIFR data and record the measurements in the patient diary.  Additional 
guidance on PIFR measurements in the clinic and at home are presented in section 6.1.
5.2
ASSESSMENT OF SAFETY
There are no safety endpoints in this trial.  Safety and tolerability will be assessed in a 
descriptive way based on:


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
Adverse events

Serious adverse events

Physical examination
5.2.1
Physical examination
A physical examination according to the local practice will be performed at the time points 
specified in the Flow Chart.  It includes at a minimum general appearance, neck, lungs, 
cardiovascular system, abdomen, extremities, and skin.  Measurement of height and body 
weight will be performed.  The results must be included in the source documents available at 
the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flowchart, prior to blood 
sampling.  This includes systolic and diastolic blood pressure and pulse rate (electronically or 
by palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must 
be included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety lab assessments will be performed by a central laboratory service provider.  For the 
sampling time points, see the Flow Chart.  All analyses will be performed by a central 
laboratory, and the reference ranges will be provided in the ISF.  Patients do not have to be 
fasted for the blood sampling for the safety laboratory. 
Hematology panel should include the following
Haemoglobin, haematocrit, red blood cell count, white blood cell count, including differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), total eosinophil count and
platelet count.
Blood chemistry should include the following
Alkaline phosphatase, Lactate Dehydrogenase (LDH), gamma-GT, SGOT, SGPT, glucose, 
calcium, inorganic phosphorus, uric acid, urea nitrogen, creatinine, total protein, potassium, 
sodium, chloride, total bilirubin, creatinine phosphokinase.
Urinalysis assessment to include
Specific gravity, pH, glucose, protein and occult blood.
A serum human chorionic gonadotrophin (HCG) pregnancy test will be performed on all 
females of child-bearing potential at the screening visit. A urine dip stick pregnancy test will 
be performed at the site for all clinic visits.  If the urine test is positive, a serum pregnancy 
test will be performed at the central lab.  If serum pregnancy test is positive, patient will be 
discontinued from the study.
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual. 


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The lab reports from central laboratory will be made available to the investigator.  It is the 
responsibility of the investigator to evaluate the laboratory reports. Clinically relevant 
abnormal findings as judged by the investigator will be reported as adverse events 
(section 5.2.6).
The central laboratory will transfer the results of the analysis to the sponsor.
5.2.4
Electrocardiogram
The 12-lead electrocardiogram (ECG) must be administered by a qualified technologist and 
results will be recorded as scheduled in the Flow Chart.  The investigator or a designee will 
evaluate whether the ECG is normal or abnormal and assess clinical relevance.  ECGs may be 
repeated for quality reasons.  Additional ECGs may be recorded for safety reasons. Dated and 
signed printouts of ECG with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.2.5
Other safety parameters
Not applicable for this trial.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the eCRF and BI SAE form 
(if applicable):
Worsening of the underlying disease or of other pre-existing conditions 
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF.


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5.2.6.1.2
Serious adverse event
A SAE is defined as any AE, which fulfils at least one of the following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalization or prolongation of existing hospitalization
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture (eDC)
system. A copy of the latest list of “Always Serious AEs” will be provided upon request. 
These events should always be reported as SAEs as described in section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Adverse events of special interest
No adverse events of special interest have been defined for this trial.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.


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5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative etiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a more 
likely explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial
(completion of follow-up period): 
all AEs (serious and non-serious).


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•
After the individual patient’s end of trial: the investigator does not need to actively 
monitor the patient for new AEs but should only report any occurrence of cancer and trial 
treatment related SAEs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form 
(section 5.2.6.2.2), but not on the eCRF.
5.2.6.2.2
AE reporting to the sponsor and timelines referring
The investigator must report SAEs and non-serious AEs which are relevant for the reported 
SAE on the BI SAE form via fax immediately (within 24 hours) to the sponsor’s unique entry 
point (country specific contact details will be provided in the ISF). The same timeline applies 
if follow-up information becomes available. In specific occasions, the investigator could 
inform the sponsor upfront via telephone. This does not replace the requirement to complete 
and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form for Studies to the sponsor.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B).  The ISF will contain the Pregnancy Monitoring Form for Studies
(Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Studies and not the SAE form is to be completed. If 
there is an SAE associated with the pregnancy an SAE form must be completed in addition.
5.2.6.2.4
COPD Exacerbation
For the purpose of this study, a COPD exacerbation is defined as a complex of lower 
respiratory events / symptoms (increase or new onset) related to the underlying COPD, with
duration of three days or more, requiring prescription of antibiotics and/or systemic steroids
and/or hospitalization:
A complex of lower respiratory events is defined as at least two of the following:

Shortness of breath

Sputum production (volume)

Change in sputum color


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
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:
Moderate:
patient receiving an exacerbation-related prescription of oral corticosteroids
and/ or antibiotic not requiring hospitalization.
Severe: 
COPD-related hospitalization
If a patient experiences a moderate, or severe COPD exacerbation, the patient will be 
discontinued from the study (section 6.2.2).
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable for this trial.
5.4
ASSESSMENT OF BIOMARKERS
Not applicable for this trial.
5.5
BIOBANKING
Not applicable in this trial.
5.6
OTHER ASSESSMENTS
Body Plethysmography
Patients participating in this optional trial procedure will have to sign a separate informed 
consent.  Relative lung volumes can be measured by spirometry.  The absolute volumes of air 
in the lung can be measured by body plethysmography, where the residual volume, functional 
residual capacity, and total lung capacity can be determined.
The site’s own equipment will be used for the body plethysmography measurements. The 
volume-constant body plethysmography devices and their use, including daily calibration, 
must meet ATS/ERS criteria [R08-1121; R98-1487].  Body plethysmography will be 
conducted with the patient in a seated position and it is preferable that the same trained 
individual performs the measurements for a given patient. The body plethysmography 
measurements for assessment of FRC, total lung capacity (TLC), Residual Volume (RV) and 
IC should be performed as linked maneuver (i.e. without the patient coming off the 
mouthpiece prior to the completion of the maneuver; refer to Appendix 10.1) and to the body 
plethysmography manual in the ISF.


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FRC is the sum of Expiratory Reserve Volume (ERV) and RV. This sum corresponds to the 
volume of gas present in the lung and airways at the average end-expiratory level. At least 
three technically acceptable FRC values should be obtained which agree within 5% (i.e. the 
difference between the highest and the lowest value divided by the mean is smaller or equal 
to 0.05).  If this repeatability is not accomplished, i.e. the observed deviation is larger, 
additional values should be obtained until the repeatability criterion is achieved or a 
maximum of six efforts have been performed.  If repeatability is not accomplished after the 
maximum of six efforts, no more efforts should be performed and mean FRC data will be 
regarded as acceptable, as long as they fulfill technical satisfactory quality criteria.  All 
acceptable efforts must be used for calculation of mean values of FRC (and ERV), and 
exclusion of tests for the sake of achieving repeatability is not permitted. The mean FRC 
value should be reported.  Linked to technically acceptable ERV and Inspiratory Vital 
Capacity (IVC) maneuver, mean FRC value is used for calculating the RV and TLC.
Please refer to Appendix 10.1 and to the body plethysmography manual in the ISF for further 
details in calculation of Residual Volume (RV), TLC and Inspiratory Capacity (IC).
The 24-hour clock time of the first maneuver for each body plethysmography measurement 
time-point will be recorded. Clock of 
 used is relevant for all visit 
activities and clock of body plethysmography system should be synchronized.
5.7
APPROPRIATENESS OF MEASUREMENTS
Spirometry
Pulmonary function tests are a validated and well established measurement tool for lung
function testing. Pulmonary function tests will be conducted at clinic visits using
standardized spirometry equipment. FEV1 is a standard measurement for the assessment of
lung function.
Peak inspiratory flow rate measurements
The
is a hand held device to measure PIFR.  It is commonly used in 
patients diagnosed with lung diseases like COPD and asthma.  Clinicians use this device to 
train the patients on the correct inspiratory technique to be used when inhaling the
medications from the device the patient will use to take the prescribed medication. 
is calibrated by the manufacturer to ensure accuracy.  Each patient will be 
provided an 
and a sufficient quantity of disposable mouthpieces for 
daily use.
Body Plethysmography
Pathology of COPD is not only characterized by progression in airflow limitation but also by 
progressive destruction of supporting tissues and elastin fibers of the lung. This results in 
progressive air trapping distally with increased RV, FRC and TLC and a decrease in IC.  
Hence, evaluation of static lung volumes (such as FRC, TLC, RV and IC) using body 


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plethysmography is a valuable tool for assessment of hyperinflation. This contributes to 
COPD symptoms like breathlessness and physical limitations while IC has the highest 
correlation with dyspnea (R11-4386; P03-10426).
Body plethysmography is technically more challenging than spirometry and requires a high
level of experience in performance. Prerequisite for study site participation in the body 
plethysmography procedures will be the availability of a volume-constant (i.e. pressure 
variable) body plethysmography device as measurements will be performed using their own 
equipment.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The trial consists of a screening period, a 4-week treatment period, followed by a 3-week
follow-up period.  The follow-up visit will be by telephone.  If visit 3 has to be rescheduled, 
visit 4 should follow the original visit date schedule.
Patients should make every attempt to complete the study.  Investigators should encourage 
patient treatment compliance and adherence to other protocol specific procedures.  Please 
refer to the Flow Chart for the trial procedures at each visit, and the time windows for the 
visits.  All deviations from the planned visit schedule will be documented.
If a patients does not meet medication washout criteria at visits 2, 3, or 4, the visit should be 
rescheduled.  The rescheduled visit should occur as soon as possible.  If visit 3 is 
rescheduled, the EOT visit (visit 4) should be scheduled on the originally planned date 
(28 days after the randomization visit).  If a patient missed visit 3, and rescheduling was not 
possible, visit 4 should be completed on the originally planned date.
At selected sites who have their own body plethysmography equipment, patients can 
participate in the body plethysmography procedures.  Patients should indicate their 
willingness to participate in this optional trial procedure by signing a separate informed 
consent.

All blood draws should be done after the ECG is completed.  

PIFR measurements should be completed before the PFTs performed with the 

Plethysmography measurements, in patients who signed a separate consent for the 
optional trial procedure should be completed after completing the PFTs with the 
If a patient experiences a COPD exacerbation (moderate or severe) during the screening 
period, patient will be screen failed.  If a patient experiences a COPD exacerbation (moderate 
or severe) during the treatment period, patient will be discontinued from the study.  The 
definition of a COPD exacerbation (for the purpose of this trial) can be found in Section 
5.2.6.2.4.
Using the 
All patients will be coached to use the 
and will receive instructions on 
how the PIFR measurements should be done at home, and how the PIFR values are entered in 
the paper diary. Below are the basic steps involved in the use of the 

Align the scale with the desired resistance level (med/low or high)

Attach a clean mouthpiece

Patient should exhale slowly and deeply

Seal lips around the mouthpiece, and instruct the patient to inhale hard and fast


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
Record the inspiratory flow from the position of the red cursor against the scale.

Reset, and repeat two more times.
Resetting the 

Hold the device vertically with the mouthpiece uppermost, so that the rounded end of 
the meter can be tapped against the other hand or a horizontal surface, such as a table.

A gentle tap will dislodge the magnetic resetting weight, which will return the red 
cursor to a start position. When this has happened, the meter must turn through 
180 degrees to return the magnetic weight to its resting position.
In-clinic measurement of PIFR using the 

Select the proper setting in the 

Perform PIFR in a seated position

Use maximum inspiratory effort, by first breathing out fully, and breathing in as hard 
and fast as possible.  Repeat the maneuver two more times, and record the highest 
value in the eCRF.

The highest PIFR value obtained with med/low setting is used for stratification in the 
IRT at the randomization visit (visit 2).

Repeat the procedure again to do the measurements in triplicate with high resistance, 
and record the highest value in eCRF.

PIFR measurements should be completed before PFTs are done in the 

If the patient experiences any discomfort during the measurements, short breaks 
should be allowed.

PIFR measurements done at the screening visit are for training purpose only and are 
not recorded in the eCRF.
Home measurement of PIFR: Using the
Patients will record their PIFR using the 
once a day in the evening.  
Patients should be coached on the proper use of the 
16 during the screening 
visit, before dispensing the device.  Patients should also be coached at future visits if the 
study site staff deems necessary.  The following steps should be followed when PIFR 
measurements are collected at home.

Select the “med/low” setting in the 

Perform PIFR in a seated position.

Use maximum inspiratory effort, by first breathing out fully, and breathing in as hard 
and fast as possible.  Repeat the maneuver two more times.  Record all three PIFR 
measurements in the patient diary.

If the patient experiences any discomfort during the measurements, short breaks are 
allowed.

Patient will bring the diary to the clinic for visits 2, 3, and 4.

The highest PIFR values obtained with the “med/low” setting on each day of the 
treatment period will be entered in the eCRF.


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
PIFR measurements done between the screening visit (visit 1) and randomization visit 
(visit 2) are for training purpose only and are not entered in the eCRF.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
To keep the number of screen failures as low as possible, patients should be very carefully 
selected for this trial. Therefore, investigators should make a preliminary check of major 
inclusion and exclusion criteria when considering patients for enrollment in the trial.
Patient numbers will be assigned in the IRT system and transferred to EDC, thereby creating 
the subject in EDC.  Details of any patient who is screened for the trial but is found to be 
ineligible must be entered in the enrollment log and documented in the eCRF.
No trial procedures should be performed until the patient has consented to take part in the 
trial.  Each patient will be assigned a unique patient number and enrollment will be recorded.
Baseline conditions, medical history, and eligibility criteria will be assessed at visit 1.  
Concomitant therapy and AE (if any) will be recorded.  At the conclusion of visit 1, patients 
should receive instructions on procedures to be followed during the screening period.
If the patient is expected to meet all the eligibility criteria, randomization visit (visit 2) will 
be scheduled.  Rescue medication (salbutamol) will be dispensed with instructions for use.
Patients will receive the 
to measure the PIFR at home during the 
screening period.  Patient will also receive a paper diary with instructions on how to record 
the PIFR obtained from the 
  Patients will complete the PIFR 
measurements each evening.  The PIFR measurements will be done in triplicate at the 
med/low resistance level.  Patients should be reminded that they can take breaks in between 
measurements, if needed.  Adequate training should be provided to the patients before they 
leave after the completion of the screening visit.  Patient will be asked to bring the device to 
each clinic visit.
PIFR measurements obtained at the screening visit must not be used for stratification at the 
randomization visit. PIFR value is not an eligibility criteria.  However, there is cap of 
approximately 100 patients in each strata (section 3.1).  Once the cap in a particular strata is 
reached, additional patients cannot be randomized in this strata.  Once a cap in a particular 
strata is reached, PIFR values at the screening visit will be used to determine eligibility for 
the study.  If the PIFR value obtained at the screening visit will make the patient eligible for 
the strata that is closed, patient will be screen failed at the screening visit.
Screening period may be extended by two weeks for administrative reasons after consultation 
with the Clinical Trial Manager.  Total screening period should not exceed 4 weeks 
(informed consent to randomization) unless written approval is obtained from the Clinical 
Trial Leader.  If screening period exceeds 4 weeks, the Investigator should review the 
laboratory reports from the screening visit (visit 1), and make a determination if any labs 


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specified in the protocol must be repeated before the randomization visit.  If deemed 
necessary, test samples should be drawn and sent to the central laboratory. 
Discontinuation during the screening period
If patients discontinue from the study during the screening period, no additional clinic visits 
are required, and they will be marked as screen failures.
If there is any indication during the screening period that the patient is not stable enough to 
complete the trial or that the patient will be non-compliant with the trial medication or 
restrictions, the patient should not be randomized, and should be screen failed.
Rescreening and retesting
Patients may be rescreened once with approval from the sponsor.  This includes patients who 
met all the inclusion criteria but were screen failed due to acute medical conditions that have 
since been resolved or those who were screen failed for administrative reasons (e.g., extended 
travel, life events).
If the investigator believes that an ineligible lab test result is the result of an error or
extenuating circumstance, then that lab test can be retested once without the patient having   
to be rescreened.
6.2.2
Treatment period
Patients who meet all the protocol criteria will be randomized at visit 2.  After randomization, 
patients will start the 4-week treatment period.  All visits during the treatment period should 
preferably be on the same day of the week.  Procedures to be completed at each visit can be 
found in the Flow Chart.
At the randomization visit (visit 2), patients will be adequately trained to use the Respimat®
inhaler.  Patients will inhale the study medication in the mornings.  Medication should be
taken approximately on the same time of the day during the 28-day treatment period.  Site 
should ensure patient has adequate supply of study medication at visit 3. Patients should be 
instructed not to take their dose of study medication at home on the day of visits 3 and 4.
Investigator should ensure that patient has adequate supply of rescue medication for the 
treatment period.  The intake of rescue medication (number of puffs) will not be collected.
PIFR measurements will be done at home (evenings) by the patient during the treatment 
period.  Measurements will be completed and readings will be recorded in the paper diary as 
described in Section 6.2.1.
At the beginning of each visit, the investigator and site personnel should ensure the 
well-being of the patient, and complete the following:
•
Any adverse events and changes in concomitant therapies will be recorded.


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•
Medication washout compliance and lifestyle restrictions will be verified.
•
Before dosing with trial medication site personnel should ensure that the patient knows 
how to inhale properly from the Respimat® Inhaler.
•
At the close of each visit during treatment period, the investigator and site personnel 
should ensure that the patient is provided with all instructions for the next visit.
•
Patient will be instructed at each visit to bring all rescue medication to the site.
•
Patient will be instructed to bring the study medication (both inhalers including the 
reserve) at visits 3 and 4.
Unscheduled clinic visits may be arranged if necessary and the procedures completed during 
the unscheduled visit will depend on the circumstances under which the visit was scheduled, 
and will be at the discretion of the investigator.
After completion of the treatment phase (visit 4), all patients will enter the 3-week follow-up 
period.
Discontinuation during the treatment period
If patients discontinue from the study during the treatment period for any reason, study drug 
should be stopped, and the patient will complete the EOT visit (visit 4), and the follow-up 
visit by telephone should be scheduled 3 weeks after the last dose of study drug.  The 
investigator may schedule the follow-up visit as a clinic visit if deemed necessary.
6.2.3
Follow-up period and trial completion
The three-week follow-up period ends with a visit by telephone.  Procedures to be completed 
at the follow-up visit can be found in the Flow Chart.  Patients will not do the PIFR 
measurements at home during the follow-up period.  Adverse events and concomitant 
therapies will be reviewed and recorded.  At the end of this follow-up visit, patient should be 
advised to continue with their regular COPD medication.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
Design
This is a randomized, double-blind, placebo-controlled , multicenter, parallel group, study 
designed to assess efficacy of tiotropium + olodaterol delivered by Respimat® on FEV1
AUC0-3h and trough FEV1 in patients with moderate to severe COPD and in the subgroups of 
patients with peak inspiratory flow rate less than and greater than or equal to 60 L/min.
Objective
The primary objective of the trial is to describe the efficacy of inhaled tiotropium + 
olodaterol via Respimat® on lung function in patients with moderate to severe COPD and in 
the subgroups of patients with optimal and a sub-optimal PIFR.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The following hypotheses will be tested in the study on the primary and key secondary 
endpoints. Each hypotheses will be tested in hierarchical order at 5% level of significance 
(two-sided) to protect the overall type I error at 5% (two-sided). The baseline value will be 
the measurement made prior to the first dosing at Visit 2.

H0-1: Mean FEV1 AUC0-3h change from baseline (tiotropium + olodaterol  via 
Respimat®) = Mean FEV1 AUC0-3h change from baseline (Placebo) in the optimal 
PIFR group at 4 weeks
vs.
H1-1: Mean FEV1 AUC0-3h change from baseline (tiotropium + olodaterol via 
Respimat®) ≠Mean FEV1 AUC0-3h change from baseline (Placebo) in the optimal 
PIFR group at 4 weeks.

H0-2: Mean FEV1 AUC0-3h change from baseline (tiotropium + olodaterol via 
Respimat®) = Mean FEV1 AUC0-3h change from baseline (Placebo) in the sub-optimal 
PIFR group at 4 weeks
vs.
H1-2: Mean FEV1 AUC0-3h change from baseline (tiotropium + olodaterol via 
Respimat®) ≠Mean FEV1 AUC0-3h change from baseline (Placebo) in the sub-optimal 
PIFR group at 4 weeks.

H0-3: Mean trough FEV1 change from baseline (tiotropium + olodaterol via 
Respimat®) = Mean trough FEV1 change from baseline (Placebo) in the optimal PIFR 
group at 4 weeks 


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vs.
H1-3: Mean trough FEV1 change from baseline (tiotropium + olodaterol  via 
Respimat®) ≠Mean trough FEV1 change from baseline (Placebo) in the optimal PIFR 
group at 4 weeks.

H0-4: Mean trough FEV1 change from baseline (tiotropium  + olodaterol via 
Respimat®) = Mean trough FEV1 change from baseline (Placebo) in the sub-optimal 
PIFR group at 4 weeks 
vs.
H1-4: Mean trough FEV1 change from baseline (tiotropium + olodaterol via 
Respimat®) ≠Mean trough FEV1 change from baseline (Placebo) in the sub-optimal 
PIFR group at 4 weeks.
Each of the tests will only be considered confirmatory if all previous tests are successful, 
i.e. the hypotheses tests were significant at 2-sided 5% level and the treatment effect favored 
tiotropium + olodaterol over placebo in each PIFR subgroup. 
7.3
PLANNED ANALYSES
The efficacy analysis will be performed in all randomized patients who were documented to 
have received any dose of trial medication and who have both baseline and any evaluable 
post-baseline measurement for at least one of the efficacy endpoints. This set will be called 
Full Analysis Set (FAS). The FAS definition will be fully specified or updated in the trial 
statistical analysis plan (TSAP).
For efficacy and safety analyses, patients will be analysed according to their planned 
treatment group.
7.3.1
Primary endpoint analyses
The primary endpoint will be analysed using an ANCOVA model including the fixed, 
categorical effect of treatment and the fixed continuous effect of baseline.
Significance tests will be based on adjusted means using a two-sided α = 0.05 (two-sided 
95% confidence intervals).
The primary analysis will be performed on the FAS within the optimal and sub-optimal PIFR 
groups, respectively. Patients will be analysed according to the PIFR stratum to which they 
belong (regardless of any misassignment to treatment based on identification of the wrong 
stratum), as such an error occurs before randomization and is therefore consistent with 
regulatory guidance.
To assess the homogeneity of the treatment effect on the primary endpoint across the levels 
of PIFR subgroups, the same ANCOVA model as in the primary analysis will be fitted in the 
overall population but replacing the treatment term by a treatment-by-PIFR subgroup term. A 


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descriptive p-value of treatment effect homogeneity at week 4 will be calculated. No overall 
treatment effect will be estimated from this model as it is not interpretable.
Similarly, the same ANCOVA model as in the primary analysis will be fitted in the overall 
population but replacing the treatment term by a treatment-by-continuous baseline PIFR term. 
A descriptive p-value of treatment effect homogeneity at week 4 will be calculated. No 
overall treatment effect will be estimated from this model as it is not interpretable.
The results of the analysis of the primary endpoints for tiotropium + olodaterol FDC within 
the optimal and sub-optimal PIFR groups will be presented in a forest plot and the treatment 
by PIFR subgroup interaction p-value will be provided. Sensitivity analysis will be performed 
by including additional covariates such as severity, gender and age in the model to adjust for 
potential differences in prognostic factors between sub-optimal and optimal PIFR subgroups.
7.3.2
Secondary endpoint analyses
The key secondary endpoint will be analysed using the restricted maximum likelihood 
(REML) based approach using a mixed model with repeated measurements (MMRM). The 
analysis will be performed on the FAS within the optimal and sub optimal PIFR groups, 
respectively.
The analysis will include the fixed, categorical effect of treatment at each visit and the fixed 
continuous effect of baseline at each visit. Visits will be treated as repeated measures with an 
unstructured covariance structure used to model the within-patient measurements.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Significance tests will be based on least-squares means using a 
two-sided α = 0.05 (two-sided 95% confidence intervals).
A selected set of analyses as that of the primary endpoint will be performed on the key 
secondary endpoint as well.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the REP, a period of 
21 days after the last dose of trial medication, will be assigned to the treatment period for 
evaluation. All randomized patients who have taken at least one dose of study drug (i.e., the 


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treated set) will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect 
period is defined as 21 days. Adverse events that start before first drug intake and deteriorate
under treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of MedDRA.
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.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarized. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Interim Analyses
An interim analysis is not planned in this clinical trial.
7.4
HANDLING OF MISSING DATA
Missing completely at random is assumed for the primary endpoint as very little missing data 
is expected and no imputation will be performed.The REML-based MMRM model described 
in section 7.3.2 will handle missing data due to early drop outs or missing data in between 
visits which are assumed to be missing at random. Additional details on the imputation of 
missing data will be specified in the TSAP prior to unblinding.
7.5
RANDOMIZATION
Approximately 200 patients will be randomized in blocks to double-blind treatment stratified 
by PIFR optimal and sub-optimal subgroups Approximately equal numbers of patients will be 
randomized to each treatment group (50 in tiotropium + olodaterol Respimat® and 50 in
placebo Respimat® for each PIFR subgroup). BI will arrange for the randomization and the 
packaging and labelling of trial medication. The randomization list will be generated using a 
validated system, which involves a pseudo-random number generator so that the resulting 
treatment will be both reproducible and non-predictable. The block size will be documented 
in the Clinical Trial Report. Access to the codes will be controlled and documented.


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7.6
DETERMINATION OF SAMPLE SIZE
From previous studies, an appropriate estimate of the standard deviation (SD) for change 
from baseline in FEV1 AUC0-3h (Δ FEV1 AUC0-3h ) and trough FEV1 (ΔTFEV1) is 210 mL 
(c02098902-03, c02037872-05). Based on an assumed treatment difference of 260 ml in 
Δ FEV1 AUC0-3h and 140 ml in ΔTFEV1 between tiotropium + olodaterol Respimat® and 
placebo Respimat®, two-sided alpha of 0.05 and SD of 210 ml, a total of 98 patients will 
provide 99% power within the optimal and sub-optimal PIFR subpopulations for FEV1. 
AUC0-3h and 90% power for trough FEV1.The results of power calculations are shown in 
Tables 7.6: 1 and 7.6: 2.  From previous studies (c02098902-03, c02037872-05), the 
discontinuation rate is assumed to be low within the first 2-4 weeks.
Therefore, a sample size of 200 patients overall with 1:1 randomization ratio and 100 within 
each subpopulation (100 in optimal PIFR and 100 in sub-optimal PIFR) will provide 
adequate power to detect a treatment difference of 260 ml for FEV1 AUC0-3h and to detect a 
treatment difference of 140 ml for trough FEV1.
Table 7.6: 1 
Sample size to achieve 90% power assuming two-sided alpha=0.05 and 
standard deviation of 210 ml 
Power
Difference in 
ΔTFEV1
SD
N Total
90%
120 ml
210 ml
132
90%
130 ml
210 ml
112
90%
140 ml
210 ml
98
90%
150 ml
210 ml
86
90%
160 ml
210 ml
76
Power
Difference in 
ΔFEV1 AUC0-3h
SD
N Total
90%
260 ml
210 ml
30
90%
280 ml
210 ml
26
90%
300 ml
210 ml
24


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Table 7.6: 2
Power for given sample size of 98 patients assuming a two-sided alpha=0.05 
and standard deviation of 210 ml
Difference in 
ΔTFEV1 
SD
N Total
Power
120 ml
210 ml
98
80%
130 ml
210 ml
98
86%
140 ml
210 ml
98
90%
Difference in 
ΔFEV1 AUC0-3h
SD
N Total
Power
260 ml
210 ml
98
>99%
280 ml
210 ml
98
>99%
300 ml
210 ml
98
>99%
Calculations were performed using SAS PROC POWER in SAS v9.4.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for GCP,
relevant BI Standard Operating Procedures (SOPs), the EU directive 2001/20/EC / EU 
regulation 536/2014.  Investigators and site staff must adhere to these principles. Deviation 
from the protocol, the principles of ICH GCP or applicable regulations as will be treated as 
protocol deviation.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / Independent Ethics Committee (IEC) and competent 
authority 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 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.  The patient must be given sufficient time to 
consider participation in the trial. The investigator or delegate obtains written consent of the 
patient’s own free will with the informed consent form after confirming that the patient
understands the contents. The investigator or 
 delegate must sign (or place a seal on) and 
date the informed consent form.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.  The consent and re-consenting 
process should be properly documented in the source documentation.


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks.  An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
Electronic CRFs for individual patients will be provided by the sponsor. See section 4.1.5.2
for rules about emergency code breaks. For drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “Attributable, Legible, Contemporaneous, Original, Accurate
(ALCOA) principles” and be attributable, legible, contemporaneous, original and accurate. 
Changes to the data should be traceable (audit trail).  Data reported on the eCRF must be 
consistent with the source data or the discrepancies must be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make every attempt to retrieve previous 
medical records.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the eCRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history


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
Adverse events and outcome events (onset date, mandatory), and end date (if available)

Serious adverse events (onset date (mandatory), and end date (if available)

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria.  The absence of 
records (either medical records or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits.  The 
investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review and 
regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor, and regulatory inspector 
(e.g. FDA). They may review all eCRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in section 8.3.1.
The sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: Personalized 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 at the site as a result of the 


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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.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely).  Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim. A Coordinating Investigator is responsible to 
coordinate investigators at the different sites participating in this trial. Tasks and 
responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
Investigators targeted for this study will include pulmonologists and general physicians who 
have access to the patient population.  Equipment for central spirometry will be provided by a 
vendor designated by the sponsor.  For sites participating in the body plethysmography 
procedures, will need to have their own equipment.


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BI has appointed a Clinical Trial Leader, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers, CRAs, and 
investigators of participating countries.
The organization of the trial in the participating countries will be performed by the respective 
local or regional BI-organization (Operating Unit) in accordance with applicable regulations 
and BI SOPs, or by a CRO with which the responsibilities and tasks will have been agreed 
and a written contract filed before initiation of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organize, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, and an IRT vendor will be used in this trial. Details will be 
provided in the IRT user manual and central laboratory manual.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Hodder R, Pavia D, Dewberry H, Alexander K, Iacono P, Ponitz H, 
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and COPD patients during chronic use of Respimat Soft Mist inhaler.
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Pitcairn G, Reader S, Pavia D, Newman S Deposition of corticosteroid 
aerosol in the human lung by Respimat Soft Mist inhaler compared to 
deposition by metered dose inhaler or by Turbuhaler dry powder 
inhaler. J Aerosol Med 18 (3), 264 - 272 (2005)
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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)
P06-04748
Newman SP Inhaler treatment options in COPD. Eur Respir Rev 14 
(96), 102 - 108 (2005)
P06-04750
Chapman KR, Voshaar TH, Virchow JC Inhalerchoice in primary 
practice. Eur Respir Rev 14 (96), 117 - 122 (2005)
P06-10775
Anderson P Use of Respimat Soft Mist inhaler in COPD patients.
Int J Chronic Obstruct Pulm Dis 1 (3), 251 - 259 (2006)
P12-01215
DalbyRN, Eicher J, Zierenberg B Development of Respimat Soft Mist 
Inhaler and its clinical utility in respiratory disorders. Med Devices 
Evid Res 4, 145 - 155 (2011)
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Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G, et 
al. Tiotropium + olodaterol fixed-dose combination versus mono-
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P15-08379
Singh D, Ferguson GT, Bolitschek J, Groenke L, Hallmann C, Bennett 
N, Abrahams R, Schmidt O, Bjermer L Tiotropium + olodaterol shows 
clinically meaningful improvements in quality of life.
Respir Med 109 (10), 1312 - 1319 (2015)
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Ciciliani AM, Langguth P, Wachtel H In vitro dose comparison of 
Respimat inhaler with dry powder inhalers for COPD maintenance 
therapy. Int J Chronic Obstruct Pulm Dis 12, 1565 - 1577 (2017)
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Global strategy for the diagnosis, management, and prevention of 
chronic obstructive pulmonary disease (2019 report).
https://goldcopd.org/gold-reports/ (access date: 17 January 2019) ; 
Global Initiative for Chronic Obstructive Lung Disease (GOLD) (2019)
P19-01878
Maltais F, Hamilton A, Voss F, Maleki-Yazdi MR Dose determination 
for a fixed-dose drug combination: a phase II randomized controlled 
trial for tiotropium/olodaterol versus tiotropium in patients with COPD.
Adv Ther 36 (4), 962 - 968 (2019)
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Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, 
Casaburi R, Crapo R, Enright P, Grinten CPM van der, Gustafsson P, 
Hankinson J, Jensen R, Johnson D, MacIntyre N, McKay R, Miller 
MR, Navajas D, Pellegrino R, Viegi G Standardisation of the 
measurement of lung volumes. Eur Respir J 26 (3), 511 - 522 (2005)
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Diaz O, Villafranca C, Ghezzo H, Borzone G, Leiva A, Milic-Emil J, 
Lisboa C Role of inspiratory capacity on exercise tolerance in COPD 
patients with and without tidal expiratory flow limitation at rest. Eur 
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Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI).  A new equation to 
estimate glomerular filtration rate.  Ann Intern Med 150 (9), 604 - 612 
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treatment of COPD. COPD Res Pract 1, 9 (2015)
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Stiolto Respimat (tiotropium bromide and olodaterol) inhalation spray, 
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Coates AL, Peslin R, Rodenstein D, Stocks J Measurement of lung 
volumes by plethysmography. Eur Respir J 10, 1415 - 1427 (1997)
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9.2
UNPUBLISHED REFERENCES
c01735218-03
A randomised, double-blind, parallel group study to assess the efficacy
and safety of 52 weeks of once daily treatment of orally inhaled 
tiotropium + olodaterol fixed dose combination (2.5 μg / 5 μg; 
5 μg /5 μg) (delivered by the Respimat® Inhaler) compared with the 
individual components (2.5 μg and 5 μg tiotropium, 5 μg olodaterol) 
(delivered by the Respimat® Inhaler) in patients with Chronic 
Obstructive Pulmonary Disease (COPD) [TOnado™ 1]. 1237.5 
Clinical Trial Report. 10 April 2014. Revised: 17 December 2014.
c01735249-03
A randomised, double-blind, parallel group study to assess the efficacy
and safety of 52 weeks of once daily treatment of orally inhaled 
tiotropium + olodaterol fixed dose combination (2.5 μg / 5 μg; 
5 μg /5 μg) (delivered by the Respimat® Inhaler) compared with the 
individual components (2.5 μg and 5 μg tiotropium, 5 μg olodaterol) 
(delivered by the Respimat® Inhaler) in patients with Chronic 
Obstructive Pulmonary Disease (COPD) [TOnado™ 2]. 1237.6 
Clinical Trial report. 10 April 2014. Revised: 18 December 2014
c02037872-05
A randomised, double-blind, placebo- and active-controlled parallel 
group study to assess the efficacy of 12 weeks of once daily treatment 
of two doses of orally inhaled tiotropium + olodaterol fixed dose 
combination (delivered by the Respimat® inhaler) in patients with 
moderate to severe Chronic Obstructive Pulmonary Disease (COPD) 
[OTEMTO™2] 1237.26 Clinical Trial Protocol 09 August 2013
c02093555-02
Randomised, double-blind, placebo-controlled, 6 treatment, 4 period,
incomplete cross-over trial to characterise the 24-hour lung function
profiles of tiotropium + olodaterol fixed dose combination (2.5/5 μg,
5/5 μg), tiotropium (2.5 μg, 5 μg) and olodaterol (5 μg) (oral
inhalation, delivered by the Respimat® Inhaler) after 6 weeks once
daily treatment in patients with Chronic Obstructive Pulmonary
Disease (COPD) [VIVACITOTM]. 1237.20 Clinical Trial Report      
04 April 2014
c02098902-03
Combined analysis of efficacy data obtained in the twin studies 1237.5
and 1237.6 - Randomised, double-blind, parallel group studies to assess
the efficacy and safety of 52 weeks of once daily treatment of orally
inhaled tiotropium + olodaterol fixed dose combination (2.5 j.tg / 5 lig; 
5 jig / 5 lig) (delivered by the Respimate Inhaler) compared with the
individual components (2.5 f.tg and 5 jig tiotropium, 5 lig olodaterol)
(delivered by the Respimat® Inhaler) in_ patients with Chronic 
Obstructive Pulmonary Disease (COPD) [TOnado T" 1 and 
TOnadoml 2]. 1237.5/1237.6 Clinical Trial Report. 09 April 2014. 
Revised: 19 December 2014 


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10.
APPENDICES
10.1
BODY PLETHYSMOGRAPHY MEASUREMENT TECHNIQUE
Detailed instructions on the procedures will be provided in a body plethysmography manual 
in the ISF.  The body plethysmography procedures will be performed in “linked” maneuver, 
i.e. without the patient coming off the mouthpiece prior to the completion of the maneuvers.

Quiet tidal volume breathing, ensuring stable End-expiratory Lung Volume (EELV), 
followed by

Shutter closing at EELV and panting with hands over cheeks, followed by

Opening of the shutter and return to quiet tidal breathing (ensuring stable EELVs, 
which are at the same position as those prior to shutter closing), followed by

An ERV maneuver, followed by a slow IVC maneuver.
Note:
The term “body plethysmography” is being used to specifically refer to body 
plethysmography system procedures that are performed with system´s door closed.
Spirometry (FEV1, FVC) will not be performed using the body plethysmography system, but 
rather with a stand-alone 
 spirometer supplied by a vendor designated by 
the sponsor.
Calculation of RV, TLC and IC:
Residual Volume (RV) is the volume of gas remaining in the lung at the end of a full 
expiration. The reported value for RV is the reported value for FRC minus the mean of 
technically acceptable ERV measurements, linked to technically acceptable FRC 
determinations (a maximum of six efforts).
Total Lung Capacity (TLC) is the volume of gas in the lung at the end of a full inspiration.  
The reported value of TLC is the reported value for RV plus the largest of the technically 
acceptable IVCs. A good quality IVC is thus required for the calculation of TLC. For IVC, 
the two best efforts (of at least three) MUST NOT differ by more than 150 mL. If 
repeatability is not achieved after three efforts, additional efforts up to a maximum of six 
need to be performed.
Inspiratory Capacity (IC) is the maximal volume which can be inspired from FRC. IC is 
calculated for each individual effort as the difference between IVC and ERV. At least three 
efforts must be performed, and the individual efforts must lie within ±6% of their mean. If 
repeatability is not achieved after three efforts, additional efforts of up to a maximum of six 
need to be performed.


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10.2
ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA
Smoking: calculation of number of pack years
Calculation of pack years based on number of cigarettes:
Pack years =    Number of cigarettes/day     x years of smoking
                                        20


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
05 December 2019
EudraCT number
EU number
2019-001719-21
BI Trial number
1237-0095
BI Investigational Medicinal 
Product(s)
Tiotropium + olodaterol Respimat®
Title of protocol
A randomized, double blind, placebo-controlled, 
multi-center, parallel group study to compare the 
efficacy of inhaled tiotropium + olodaterol, fixed 
dose combination (5µg/5µg) vs. placebo delivered 
by Respimat inhaler in patients with moderate to 
severe COPD, stratified by peak inspiratory flow 
rate [TRONARTO].
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Synopsis and Section 3.3.2 – Inclusion criteria 3. 
Description of change
In the Synopsis, Inclusion Criteria 3:  
Diagnosis of chronic obstructive pulmonary 
disease and must meet the following spirometric 
criteria: patients with a post-bronchodilator FEV1
> 30% and <80% of predicted normal; and a post-
bronchodilator FEV1/FVC <70%, at the screening 
visit.
Was changed to:
Diagnosis of chronic obstructive pulmonary 
disease and must meet the following spirometric 
criteria: patients with a post-bronchodilator FEV1 ≥ 
30% and <80% of predicted normal; and a post-
bronchodilator FEV1/FVC <70%, at the screening 
visit.
In section 3.3.2, Inclusion Criteria 3: All patients 
must have a diagnosis of COPD and must meet the 
following spirometric criteria: patients with a post-
bronchodilator FEV1 >30% and <80% of predicted 
normal (ECSC, [R94-1408]); and a post-


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bronchodilator FEV1/FVC <70%, at the screening 
visit.
Was changed to:
All patients must have a diagnosis of COPD and 
must meet the following spirometric criteria: 
patients with a post-bronchodilator FEV1 ≥30% 
and <80% of predicted normal (ECSC, [R94-
1408]); and a post-bronchodilator FEV1/FVC 
<70%, at the screening visit.
Rationale for change
Formatting issue corrected
Section to be changed
Flowchart: Footnote 1
Description of change
The interval between visits 1 and 2 (screening 
period can be extended up to 4 weeks (28 days) for 
administrative reasons (section 6.2.1).
Was changed to:
The interval between visits 1 and 2 (screening 
period can be extended up to 2 weeks for 
administrative reasons (section 6.2.1).
Rationale for change
Footnote 1 of the Flowchart was clarified to align 
with section 6.2.1.
Section to be changed
Flowchart: Footnote 14
Description of change
PIFR measurements using med/low resistance in 
the 
 will be collected in the 
clinic at visits 2, 3, and 4.  
Was changed to:
PIFR measurements using med/low and high 
resistance in the 
 will be 
collected in the clinic at visits 2, 3, and 4.  
Rationale for change
Footnote 14 of the Flowchart was clarified to align 
with section 6.1: In clinic measurement of PIFR 
using the 
Section to be changed
First footnote for Flowchart - Pulmonary Function 
Tests: Visits 2 and 4*
Description of change
*At visit 2, PFTs done at 10 min pre-dose only
Was changed to:
*At visit 3, PFTs done at 10 min pre-dose (trough) 


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only, including pre-dose vital signs
Rationale for change
Editorial change and clarification regarding the 
conduct of Visit 3 PFTs.
Section to be changed
Abbreviations
Description of change
The following abbreviation was removed: 
DILI – Drug Induced Liver Injury
Rationale for change
This abbreviation was removed as the term is no 
longer referenced in the protocol.
Section to be changed
Section 3.1
Description of change
Body plethysmography measurements will be an 
optional trial procedure in this study, and will be 
performed at selected sites at visit 2. 
Approximately 30 (15%) patients are expected to 
participate in this procedure. Patients participating 
in this optional trial procedure will have to sign a 
separate informed consent. 
Was changed to:
Body plethysmography measurements will be an 
optional trial procedure at visit 2 and will be done 
only at selected sites on selected 
patients.Approximately 30 (15%) patients are 
expected to participate in this procedure.  Patients 
participating in this optional trial procedure will 
have to sign a separate informed consent. At the 
screening visit, an assessment will be completed to 
see if the patient can perform technically 
acceptable body plethymography measurements.
Rationale for change
Clarification and alignment with Flowchart 
footnote 8
Section to be changed
Section 5.1.2
Description of change
PIFR measurements will also be done in the clinic 
during visits 3, and 4.  Measurements will be made 
in triplicate using med/low resistance and the 
highest value will be used. 
Was changed to:
Additional PIFR measurements will also be done 
in the clinic during visits 2, 3, and 4.  
Measurements will be made in triplicate using 
med/low and high resistance and the highest value 


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for each resistance setting will be recorded.
Rationale for change
Clarification and alignment with Section 6.1: In 
clinic measurement of PIFR using the 
 
Section to be changed
Section 5.2.3 
Description of change
The following content was removed:
In case the criteria for hepatic injury are fulfilled, a 
number of additional measures will be performed 
(section 5.2.6.1), and the drug induced liver injury 
(DILI) checklist provided in the ISF.  The amount 
of blood taken from the patient concerned will be 
increased due to this additional sampling. 
Rationale for change
As noted in Section 5.2.6.1.4, there are no adverse 
events of special interest.  This DILI content was 
included in error. 
Section to be changed
Section 6.1 – Home measurement of PIFR: Using 
the 
Description of change
The following content was removed:

Change the setting to “high” and complete 
three maneuvers as done with the “med/low” 
setting. Record all three PIFR measurements 
in the patient diary.
Rationale for change
Reduction in the complexity of patient procedures 
at home.
Section to be changed
Section 6.2.1
Description of change
Patients will complete the PIFR measurements 
each evening. The PIFR measurements will be 
done with two different resistance levels (med/low 
and high).  At each resistance levels, 
measurements will be done in triplicate.
Was changed to:
Patients will complete the PIFR measurements 
each evening.  The PIFR measurements will be 
done in triplicate at the med/low resistance level.  
Rationale for change
Reduction in the complexity of patient procedures 
at home.
Section to be changed
Section 6.2.2


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Description of change
Addition of the following content: 
Patients should be instructed not to take their dose 
of study medication at home on the day of visits 3 
and 4.
Rationale for change
Clarification and alignment with Section 4.2.3
11.2
GLOBAL AMENDMENT 2
Date of amendment
28 January 2020
EudraCT number
EU number
2019-001719-21
BI Trial number
1237-0095
BI Investigational Medicinal 
Product(s)
Tiotropium + olodaterol Respimat®
Title of protocol
A randomized, double blind, placebo-controlled, 
multi-center, parallel group study to compare the 
efficacy of inhaled tiotropium + olodaterol, fixed 
dose combination (5µg/5µg) vs. placebo 
delivered by Respimat inhaler in patients with 
moderate to severe COPD, stratified by peak 
inspiratory flow rate [TRONARTO].
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Abbreviations
Description of change
The following abbreviations were added:
CKD-EPIcr – Chronic Kidney Disease 
Epidemiology Collaboration Equation
eGFR – Estimated Glomerular Filtration Rate
Rationale for change
These abbreviations were added as terms are 
referenced in Section 3.3.3 Exclusion criteria 21 
and Flow Chart
Section to be changed
Section 3.3.3 – Exclusion criteria 1
Description of change
Patients with a significant disease other than 
COPD; a significant disease defined as a disease 
which, in the opinion of the investigator, could (i) 
put the patient at risk because of participation in 
the trial, (ii) influence the results of the trial, or 
(iii) cause concern regarding the patient’s ability 
to participate in the trial.
Was changed to:


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Patients with a significant disease other than 
COPD; a significant disease defined as a disease 
which, in the opinion of the investigator, and 
referring to the warnings to be observed as quoted 
in the locally applicable SmPC or prescribing 
information, could (i) put the patient at risk 
because of participation in the trial, (ii) influence 
the results of the trial, or (iii) cause concern 
regarding the patient’s ability to participate in the 
trial
Rationale for change
Provide additional guidance regarding Exclusion 
Criteria 1.
Section to be changed
Section 3.3.3 – Exclusion criteria 21
Description of change
Patients with creatinine >2x upper limit of normal
Was changed to:
Patients with creatinine >2x upper limit of normal 
or an estimated glomerular filtration rate (eGFR) 
determined below 50 ml/min/1.73 m2 (as derived 
from CKD-EPIcr equation [R12-1392])
Rationale for change
Additional parameter for assessment of renal 
function in Exclusion Criteria 21.
Section to be changed
Flow Chart and Footnote 10
Description of change
The following content was added to the Flow 
Chart:
eGFR
eGFR will be derived from serum creatinine 
values, age, sex and race based on the CKD-
EPIcr equation [R12-1392].
Rationale for change
Additional parameter for assessment of renal 
function in Exclusion Criteria 21.
Section to be changed
Section 3.3.4.1 – Discontinuation of trial 
treatment
Description of change
The following content was added: In terms of 
discontinuation of trial treatment, the following 
criteria must also be taken into account:

Trial treatment must be stopped immediately 
if a paradoxical bronchospasm or an allergic 
reaction of the immediate type occurs. 

If two or more eye symptoms (triggering or 


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aggravation of narrow angle glaucoma, eye 
pain or discomfort, temporary blurred vision, 
eye halos or altered color perception 
associated with reddened eyes due to 
conjunctival congestion or corneal edema) 
occur, trial treatment should be discontinued 
and the patient should consult a specialist 
immediately. 
For safety reasons, the investigator may decide 
that the patient should discontinue trial treatment.
Rationale for change
To specify more precise termination criteria for 
trial treatment.
Section to be changed
Table 4.2.3.1:1 – Overview of permitted and 
restricted medications
Description of change
Under Combinations the following content was 
added:
Sub-class
Prior to 
study
Study Period
Screening 
Period
Treatment 
Period
Follow-up
Period
ICS, long-acting 
anticholinergics, 
long-acting β-
adrenergics,  (e.g. 
fluticasone +
umeclidinium, 
vilanterol)
Permitted1
NOT 
permitted
NOT 
permitted
NOT
permitted
Footnotes for Table 4.2.3.1: 1
1.
Permitted until 6 months prior to visit 1


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Rationale for change
Clarification that all combination products 
containing inhaled corticosteroids are restricted 
medications and their use is not permitted 
within 6 months of study entry and during the 
screening, treatment and follow-up periods.
Section to be changed
9.1 Published References
Description of change
The following reference added:
R12-1392 - Levey AS, Stevens LA, Schmid 
CH, Zhang Y, Castro AF, Feldman HI, Kusek
JW, Eggers P, Lente F van, Greene T, Coresh J, 
Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI).  A new equation to 
estimate glomerular filtration rate.  Ann Intern 
Med 150 (9), 604 - 612 (2009)
Rationale for change
Reference required for eCFR equation
11.3
GLOBAL AMENDMENT 3
Date of amendment
EudraCT number
EU number
2019-001719-21
BI Trial number
1237-0095
BI Investigational Medicinal 
Product(s)
Tiotropium + olodaterol Respimat®
Title of protocol
A randomized, double blind, placebo-controlled, 
multi-center, parallel group study to compare the 
efficacy of inhaled tiotropium + olodaterol, fixed 
dose combination (5µg/5µg) vs. placebo delivered 
by Respimat inhaler in patients with moderate to 
severe COPD, stratified by peak inspiratory flow 
rate [TRONARTO].
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Description of change
Rationale for change

SAP_001.pdf: 
001-MCS-50-415_RD-01 (1.0) / Saved on: 03 Dec 2018
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c27526629-04
BI Trial No.:
1237-0095
Title:
A randomized, double blind, placebo-controlled, multi-center,
parallel group study to compare the efficacy of inhaled tiotropium
+ olodaterol, fixed dose combination (5μg/5μg) vs. placebo
delivered by Respimat® inhaler in patients with moderate to severe
COPD, stratified by peak inspiratory flow rate [TRONARTO®].
Including Protocol global amendment 3 [c27526629-04]
Investigational
Product(s):
Tiotropium + Olodaterol Respimat® fixed dose combination or
matching placebo delivered via Respimat® inhaler.
Responsible trial 
statistician(s):
Telephone:  
Date of statistical 
analysis plan:
29 SEP 2020 SIGNED
Version:
Final
Page 1 of 29
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................5
2.
LIST OF ABBREVIATIONS ..............................................................................6
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS(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 endpoint(s) ..........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENT(S)................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTERS .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINT(S) ................................................................................17
7.4.1
Primary analysis of the primary endpoint(s) ...................................................18
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoint(s)............................................................................................18
7.5
SECONDARY ENDPOINT(S) ..........................................................................21
7.5.1
Key secondary endpoint(s).................................................................................21
7.5.1.1
Primary analysis of the key secondary endpoint(s) ..............................................21
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key 
secondary endpoint(s) ...........................................................................................22
Homogeneity of treatment effect ..........................................................................................22
7.5.2
Other Miscellaneous endpoint(s).......................................................................23
7.7
EXTENT OF EXPOSURE.................................................................................23
7.8
SAFETY ANALYSIS..........................................................................................23
7.8.1
Adverse Events ....................................................................................................23
7.8.2
Laboratory data ..................................................................................................24


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7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24
8.
REFERENCES....................................................................................................26
10.
HISTORY TABLE..............................................................................................29


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LIST OF TABLES
Table 6.1: 1  Treatment and labels...........................................................................................11
Table 6.2: 1
Handling of iPDs..............................................................................................12
Table 10: 1
History table .....................................................................................................29


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ADS
Analysis Data Set
AE
Adverse event
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BRPM
Blinded report planning meeting
CD
Concomitant diagnosis
CML
Clinical Monitor Local
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CT
Concomitant treatment
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Data Base Lock
DH
Digital Health
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DRA
Drug Regulatory Affairs
eCRF
electronic Case Report Form
EoT
End of Text
EMEA
FAS
European Agency for the Evaluation of Medicinal Product
Full analysis set
FDC
Fixed Dose Combination
FEV1
Forced Expiratory Volume in One Second
FVC
Forced Vital Capacity
ICF
Informed Consent Form
ICH
International Conference on Harmonisation


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Term
Definition / description
(I)PD
(Important) Protocol Deviation
(I)PV
(Important) Protocol Violation
IVRS
Interactive Voice Response System
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed effects model repeated measures
MQRM
Medical Quality Review Meeting
PEF
Peak Expiratory Flow
PFT
PIFR
Pulmonary Function Test
Peak Inspiratory Flow Rate
PK
Pharmacokinetics
PPS
Per protocol set
PRN
Pro re nata (when necessary)
PSTAT
Project Statistician
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
REML
Restricted maximum likelihood
RS
Randomised set
SABA
Short-acting beta agonist
SAE
Serious Adverse Event
SAMA
Short-acting muscarinic antagonist
SD
Standard deviation
SMQ
Standardised MedDRA query
SOC
System organ class
TS
Treated set
TSAP
Trial statistical analysis plan
TTM
Termination of trial medication


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (1) , the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the protocol, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size.” Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
SAS® Version 9.4 or later will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Sensitivity analyses were added for primary and key secondary analyses in section 7.4.2 and 
7.5.1. The analysis of further endpoint includes MMRM analysis.
5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is change from baseline in FEV1 AUC0-3h after 4 weeks of treatment.
Analyses will be performed in PIFR optimal (≥60 L/min) group and PIFR sub-optimal 
(<60 L/min) group separately.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
The key secondary endpoint is change from baseline in trough FEV1 after 4 weeks of 
treatment.
Analyses will be performed in PIFR optimal (≥60 L/min) group and PIFR sub-optimal 
(<60 L/min) group separately.
5.2.2
Secondary endpoint(s)
There are no additional secondary endpoints in this trial.


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5.4
OTHER VARIABLE(S)
Safety
All adverse events (including those identified during the physical examination): Details can 
be found in section 7.8.1.
Treatment exposure/Time to discontinuation from study drug
Treatment exposure will be calculated as drug stop date minus drug start date plus 1. Time to 
discontinuation of study drug is defined as discontinuation date minus drug start date plus 1.
Treatment compliance
-
Percent compliance
-
Percent missing compliance information
Treatment compliance (80% to 120%) will be based on data recorded in the eCRF.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
As described in Section 4 of the CTP, the following treatments are planned to be investigated 
in this study:
Table Error! No text of specified style in document.: 1  Treatment and labels
Treatment
Label
Tiotropium + Olodaterol FDC (5 μg / 5 μg) inhalation solution
T+O 5/5
Matching Placebo inhalation solution
PBO
This trial is a randomized, double-blind, placebo-controlled, multicenter, parallel study 
designed to assess efficacy of tiotropium + olodaterol delivered by Respimat® on FEV1
AUC0-3h, and trough FEV1 in patients with moderate to severe COPD, stratified by optimal 
and sub-optimal PIFR.  The study will consist of a screening period of up to 2 weeks, a 
4-week randomized treatment period and a three week follow-up period. An overview of the 
trial design is presented in Figure 6.1: 1
Figure 6.1: 1
Trial Design
The residual effect period is defined as 21 days.
Approximately 200 patients will be randomized (1:1) to either the active arm (tiotropium + 
olodaterol, FDC) or the placebo arm.  The randomization will be stratified by optimal 
(≥60 L/min) or sub-optimal (< 60 L/min) PIFR as measured with the 
 set 


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at med/low resistance.  Each strata will be capped to a total of approximately 100 patients.  
An interactive response technology (IRT) will be used for randomization and stratification.
After signing informed consent and completing the screening visit, patients will enter a 
screening period of 3 to 14 days.  During the screening period, patients will continue to 
receive their COPD maintenance treatment, except for the medication washout requirements 
required before the randomization visit.  Patients will be randomized into the 4-week 
treatment period in which they will be randomly assigned to one of two treatments: 
tiotropium + olodaterol FDC or matching placebo.  The randomization visit (visit 2) will be 
followed by a clinic visit in 2 weeks (visit 3) and end of treatment (EOT) visit (visit 4) will be 
4 weeks (28 days) after randomization.  A follow-up visit by telephone will be scheduled 
three weeks after the last dose of study medication.
6.2
IMPORTANT PROTOCOL DEVIATIONS
A patient’s deviation (PD) from the trial protocol is considered “important” if it can be 
expected that the deviation had a distorting influence on the assessment of the treatment 
effect on the primary endpoint of the trial or could affect the patient’s safety or rights.
Table 6.2:1 gives the important PDs for this trial. The final decision with regard to important 
PVs and exclusion from the PPS will be made at the final review meeting. Some important 
PVs will be set automatically; others will need a decision at a Medical Quality Review 
Meeting (MQRM) team review of the manual PD log. 
The IQRMP addresses the risks of items related to COVID-19. The DV domain contains all 
iPD and relevant information regarding COVID-19. All iPD will be listed.
Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief 
Description
Requirement
Excluded from 
which analysis set
A1
Inclusion criteria not met
IN #2-7 (per protocol)
None
A2
Exclusion Criteria not met
EX #1-24 (per protocol)
None
B1
Informed consent not 
available/not done
IN #1. Verify that the subject has 
been properly consented and has 
signed re consent when applicable
All
B2
Informed consent too late
Verify that the subject has been 
properly consented and has signed re 
consent when applicable
None 
C1
Incorrect trial medication 
taken
Incorrect trial medication taken
None
C2
Randomization order not 
Verify correct dispensing of IMP by 
None


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followed and incorrect trial 
medication taken
comparing IRT records against IMP 
Accountability Log 
C3.2
Non-compliance with study 
medication as defined in 
protocol section 4.3 
Treatment Compliance
Serious non-compliance with study 
medication as defined in protocol 4.3 
Treatment Compliance
None
C4
Medication code broken 
inappropriately
Medication code broken 
inappropriately
None
D1
Improper medication washout 
at baseline visit or at primary 
endpoint visit 4.
Verify that patients have complied 
with medication washout 
requirements prior to PFT 
measurements during V2 (baseline), 
V3 and V4 (primary endpoint) 
(protocol table 4.2.3.1.1 and 
footnotes)
None
D2
Prohibited medication use 
during the study
Prohibited medication use during 
study as per protocol section 4.2.3.1.1
None
F3.1
PFT measurement at 3-hour 
time point performed more 
than 4  hours after dosing
At visit 2, the PFTs should begin 
between 07: 00 a.m. and 10:00 a.m.  
At visits 3 and 4, PFTs should begin 
within ± 30 minutes of the time it 
started at visit 2.
None
F3.2
PFT measurement at 3:00 
planned time performed 
earlier than 2 hours after 
dosing at primary endpoint 
visit(s)
At visit 2, the PFTs should begin 
between 07: 00 a.m. and 10:00 a.m.  
At visits 3 and 4, PFTs should begin 
within ± 30 minutes of the time it 
started at visit 2.
None
F4.1
Trial medication taken prior 
to pre-dose measurement at 
baseline visit
Verify that the visit has been 
rescheduled and the site has retrained 
the subject to dose only after the 
trough PFT measurement during V2.
None
F4.2
Trial medication taken prior 
to pre-dose measurement at 
primary endpoint visit(s)
Verify that the visit has been 
rescheduled and the site has retrained 
the subject to dose only after the 
trough PFT measurement during V4.
None
F4.4
Drug administration outside 
time window at 
randomization visit and 
primary endpoint visit.
Verify that the subject dosed 5 
minutes prior to the first PFT 
measurement during V2 and V4.  
None
Q1
Missed examinations; Non-
COVID-19 related
None


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Q2
Missed visit; Non-COVID-19 
related 
None
Q3
Drug shipment; Non-
COVID-19 related
None
…
…
…
6.3
SUBJECT SETS ANALYSED
The following subject sets are defined in this trial:

Randomized Set (RS): This patient set includes all patients who signed the informed 
consent form and were randomized, regardless whether the patient was treated with 
trial medication or not.

Treated Set (TS): All randomized patients who were dispensed trial medication and 
were documented to have taken any dose of trial medication.

Full Analysis Set (FAS): This patient set is nested within the TS and includes patients 
who had baseline and at least one post-baseline measurement for at least one  efficacy 
endpoint(either a baseline and post-baseline primary endpoint or a baseline and a 
post-baseline key secondary endpoint) The FAS will be used for the primary analyses 
of the primary efficacy endpoint and for all other efficacy endpoints.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
Treated 
set
FAS
RS
Primary and key secondary 
endpoints 
primary 
analysis
(other) Secondary and further 
endpoints 
X
Safety endpoints & treatment 
exposure
X
Demographic/baseline 
endpoints
Disposition
X
X


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6.5
POOLING OF CENTERS
This section is not applicable because center/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Every effort should be made to collect complete data for each time point on each test day.
The REML-based MMRM model described in Sections 7.4.1 and 7.5.1 will handle missing 
data due to early drop outs or missing data in between visits which are assumed to be missing 
at random.
Adjusted multiple imputation will be used to handle missing data in a sensitivity analysis. 
Details are described in Section 7.4.1 and 7.5.1.2.
FEV1 measurements
FEV1 measurements at individual time points that are flagged as unacceptable by the vendor 
will be set to missing prior to applying any missing data imputation rules. Missing FEV1
measurements at a given in-clinic visit will be imputed by the available data from the patient 
at that visit except for trough FEV1. Completely missing visits will not be imputed and will 
be handled through the MMRM statistical model expect for cases where a patient 
discontinues due to an AE indicative of worsening of COPD. For the case of discontinuing 
due to an AE indicative of worsening of COPD, completely missing visits, missing data 
points will be imputed with the worst observation observed before discontinuation.
Discontinuation due to an AE indicative of worsening of COPD will be determined as 
follows.

Check that the reason for discontinuation on the termination of trial medication is 
adverse event.

Get the AE flagged by the investigator as the primary reason for discontinuation of 
trial medication.

Check whether this AE belongs to the group of AEs identified as corresponding to 
either COPD exacerbation or lower respiratory disorders.  This will be based on the 
BI system in place for grouping MedDRA preferred terms into medical concepts 
(currently referred to as pharmacovigilance endpoints).
Additional details on the imputation of missing data for specific cases are provided below:


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
Any visit occurring more than one day after discontinuation of study medication which 
has non-missing data will not be used in the analysis. 

For patients taking a salbutamol (SABA) as rescue medication during Visit 2 and 4, any 
subsequent FEV1 measurements from the time of rescue use until time of rescue plus 8 
hours (e.g., 2:17 to 10:17) will be set to missing and imputed by the worst non-missing 
(either observed or imputed) observation for that visit strictly prior to the administration 
of the rescue medication (even if it is a pre-dose value, either observed or imputed). If 
there are FEV1 measurements after the 8-hour window they will be considered valid and 
not imputed provided that they are not in the 8-hour window for a subsequent rescue 
medication use. If rescue medication is taken at any on-treatment in-clinic visit and there 
is no rescue medication time given, data for the entire visit will be considered missing and 
it will be handled the same way as the case where all measurements after rescue use are 
set to missing. 
Missing safety data will not be imputed with the exception of missing AE dates which will be 
imputed according to BI standards (see Boehringer Ingelheim Data Management and 
Statistics Manual (DM&SM) “Handling of missing and incomplete AE dates.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value will be the measurement made prior to the first dosing at Visit 2. If there 
are more than one measurement of FEV1 available prior to randomization, the mean of the 
two pre-dose pulmonary function test measurements at Visit 2, prior to the administration of 
the first dose of the randomized treatment, is used as the baseline FEV1. Planned and actual 
study day will be included in the analysis data sets. These will both be calculated relative to 
the beginning of study as indicated in the following table (nominal visits). See Table 6.7:1. 
Time windows will not be used but rather planned visits.
Table 6.7:1 Planned and actual study days
Visit
Planned Study Day
Actual Study Day
2
1
1
3
15
Visit 3 date – Visit 2 date + 1
4
29
Visit 4 date – Visit 3 date + 1


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7.
PLANNED ANALYSIS
For End-of-Text (EoT) tables, the set of summary statistics for descriptive displays of 
continuous variables is: N / Mean / SD / Min / Median / Max. 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
The efficacy analysis will be performed in FAS.
For efficacy and safety analyses, patients will be analysed according to their planned 
treatment group.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. COPD background 
characteristics will be summarized.
Body plethysmography will be analyzed descriptively for visit 2.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. A table of number (%) of 
patients with concomitant diagnoses (CDs) by system organ class (SOC) and preferred term 
(PT) will be included along with a supporting listing. Concomitant diagnoses will be coded 
with the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) 
in effect at database lock.
Frequency tables (%) will be presented for medical history and COPD background 
characteristics. 
Pulmonary medication will be summarized as the number (%) of patients taking pulmonary 
medications within the last three months before visit 1 and during the treatment periods.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. Summary statistics will 
be given for percent compliance along with the number (%) of patients with compliance in 
the categories <80% or >120%, 80% - 120%.
7.4
PRIMARY ENDPOINT(S)
The primary endpoint is change from baseline in FEV1 AUC0-3h after 4 weeks of treatment.


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Analyses will be performed in PIFR optimal (≥60 L/min) group and PIFR sub-optimal 
(<60 L/min) group separately.
7.4.1
Primary analysis of the primary endpoint(s)
The primary endpoint will be analyzed using an ANCOVA model including the fixed, 
categorical effect of treatment and the fixed continuous effect of baseline. The data is 
collected at baseline (visit 2) and at visit 4.
Significance tests will be based on adjusted means using a two-sided α = 0.05 (two-sided 
95% confidence intervals).
The primary analysis will be performed on the FAS within the optimal and sub-optimal PIFR 
groups, respectively. Patients will be analyzed according to the PIFR stratum to which they 
belong (regardless of any miss-assignment to treatment based on identification of the wrong 
stratum), as such an error occurs before randomization and is therefore consistent with 
regulatory guidance.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Significance tests will be based on least-squares means using a 
two-sided α = 0.05 (two-sided 95% confidence intervals).
The following SAS code will be used for the analysis.
PROC MIXED DATA=alldat method=reml order=formatted; 
  CLASS trtp (ref=last); 
  MODEL chg = base trtp ; 
  LSMEANS trtp / cl diff om cov; 
RUN;
Here the endpoint is chg (change from baseline), baseline value of the endpoint is base and 
the treatment group is trtp. The data set alldat will be set to the optimal and sub-optimal PIFR 
subgroups, respectively. The data set should only include post baseline visits since change 
from baseline will be identical to zero for the baseline visit. 
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary
endpoint(s)
Sensitivity analysis
Additional models will include covariates such as severity (e.g. GOLD stage), gender and 
age. These models will be analyzed separately for each PIFR subgroup.
Missing data analysis
The ANCOVA primary analysis only accounts for missing observations under the MCAR 
(missing completely at random) assumption. The robustness of the primary analysis to the 


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MAR (missing at random) assumption will therefore be assessed by performing a multiple 
imputation (MI) sensitivity analysis with an extended covariate set. Data from Trough FEV1
will also be included in the imputation procedure as it is measured at both visits 3 and 4. It 
therefore may provide information about patient state prior to discontinuation that is not 
available directly for the primary endpoint and hence reduce any biases caused by missing 
data.
Missing data will be multiply imputed 100 times using the MCMC (Markov Chain Monte 
Carlo) method. The imputation will be performed separately for each combination of 
treatment and PIFR subgroup. Separate chains will be used for each imputation, with 1000 
burn-in iterations. Jeffrey’s prior will be used. The seed number will be set to 123795. The 
following variables will be included in the multiple imputation model: treatment (Tio+Olo vs 
placebo), continuous baseline FEV1, continuous age, gender (male or female) and disease 
severity (GOLD group 2 or 3), smoking (yes/no), previous exacerbation (yes/no), country 
(US, Germany), change from baseline Trough FEV1 at visit 3 and 4 and change from 
baseline FEV1 AUC0-3h at visit 4.
For each imputed complete data set, the primary endpoint will be analyzed at visit 4 using the 
primary ANCOVA analysis model. The 100 estimates and standard errors will then be 
combined using Rubin’s rules (16,17) to produce a single estimate with standard error, 
confidence interval and nominal p-value.
The following SAS code will be used for multiple imputation step.
PROC MI data=midat seed=123795 nimpute=100 out=miout;
    VAR var;
    MCMC chain=multiple nbiter=1000 prior=jeffreys;
    BY pifr trtp;
RUN;
Here the data set is midat, var are all the variables to be entered into model, trtp is the 
treatment group and pifr is the PIFR sub group. The data set midat must have one record per 
patient with all variables  for each visit arranged horizontally. The variable chg4 is the change 
from baseline for the endpoint of interest to be analyzed below.
An ANCOVA model will be used on the result of the imputations using the SAS code as 
follows.
PROC SORT data=miout;
  BY _imputation_ pifr;
RUN;
ODS OUTPUT diffs=mixdiff ;
ODS LISTING CLOSE;
PROC MIXED DATA=miout method=reml order=formatted; 


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  BY _imputation_ pifr;
  CLASS trtp (ref=last); 
  MODEL chg4 = trtp var / solution cl covb ddfm=KR s; 
  LSMEANS trtp / cl diff om cov; 
RUN;
ODS LISTING;
Finally the results of the 100 ANCOVA analyses will be combined using the SAS code 
below.
PROC SORT data=mixdiff ;
  BY pifr _imputation_;
RUN;
PROC MIANALYZE data=mixdiff;
   BY pifr;
   MODELEFFECTS estimate;
   STDERR stderr;
run;
Homogeneity of treatment effect
To assess the homogeneity of the treatment effect on the primary endpoint across the levels 
of PIFR subgroups, the same ANCOVA model as in the primary analysis will be fitted in the 
overall population but replacing the treatment term by a treatment-by-PIFR subgroup term. A 
descriptive p-value of treatment effect homogeneity at week 4 will be calculated. No overall 
treatment effect will be estimated from this model as it is not interpretable. The analysis will 
be done separately for population before and after COVID-19.
Similarly, the same ANCOVA model as in the primary analysis will be fitted in the overall 
population but replacing the treatment term by a treatment-by-continuous baseline PIFR term. 
A descriptive p-value of treatment effect homogeneity at week 4 will be calculated. No 
overall treatment effect will be estimated from this model as it is not interpretable. The 
analysis will be done separately for population before and after COVID-19. 
The results of the analysis of the primary endpoints for tiotropium + olodaterol FDC within 
the optimal and sub-optimal PIFR groups will be presented in a forest plot and the treatment 
by PIFR subgroup interaction p-value will be provided. Sensitivity analysis will be performed 
by including additional covariates such as severity, gender and age in the model to adjust for 
potential differences in prognostic factors between sub-optimal and optimal PIFR subgroups.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
The key secondary endpoint is change from baseline in trough FEV1 after 4 weeks of 
treatment.
Analyses will be performed in PIFR optimal (≥60 L/min) group and PIFR sub-optimal 
(<60 L/min) group separately. 
7.5.1.1
Primary analysis of the key secondary endpoint(s)
The key secondary endpoint will be analyzed using the restricted maximum likelihood 
(REML) based approach using a mixed model with repeated measurements (MMRM). The 
analysis will be performed on the FAS within the optimal and sub optimal PIFR groups, 
respectively. The data is collected at baseline (visit 2), visit 3 and visit 4.
The analysis will include the fixed, categorical effect of treatment at each visit and the fixed 
continuous effect of baseline at each visit. Visits will be treated as repeated measures with an 
unstructured covariance structure used to model the within-patient measurements.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Significance tests will be based on least-squares means using a 
two-sided α = 0.05 (two-sided 95% confidence intervals).
If a patient misses a visit, the missing data will not be imputed. The mixed effect model will
handle missing data based on a likelihood method under the “missing at random” assumption.
The following SAS code will be used for the analysis.
PROC MIXED DATA=alldat cl method=reml order=formatted; 
  CLASS usubjid trtp (ref=last) tptno; 
  MODEL chg = trtp*tptno base*tptno / ddfm=kr solution; 
  REPEATED tptno / subject=usubjid type=un r rcorr;
  LSMEANS tptno*trtp / pdiff=all om cl alpha=0.05 slice=tptno; 
RUN;
Here tptno is the planned analysis day number for each visit, the endpoint is chg, baseline 
value of the endpoint is base and the treatment group is trtp.
The data set alldat will be set to the optimal and sub-optimal PIFR subgroups, respectively.
The data set should only include post baseline visits since change from baseline will be 
identical to zero for the baseline visit. 
In the event of non-convergence, the following methods will be attempted (in order) to 
overcome it:


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1. Add the ‘singular=1e-10’ option in the model statement – This raises the threshold at 
which columns are declared linearly dependent (from typically 1e-12). 
2. Set ‘maxiter=100’ in the PROC MIXED statement – This increases the number of 
convergence iterations used from a default of 50. 
3. Set ‘scoring=4’ to specify use of the Fisher scoring algorithm in the first 4 iterations. 
4. Include the statement ‘performance nothread’ – this removes multi-threading from the
calculations. 
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key secondary 
endpoint(s)
Sensitivity analysis
Additional models will include covariates such as disease severity (e.g. GOLD stage), gender 
and age. These models will be analyzed separately for each PIFR subgroup.
Missing data analysis
A multiple imputation analysis will be performed on the key secondary endpoint similar to 
that of the primary endpoint described in section 7.4.2.
Homogeneity of treatment effect
To assess the homogeneity of the treatment effect on the key secondary endpoint across the 
levels of PIFR subgroups, the same MMRM model as in the key secondary analysis will be 
fitted in the overall population but replacing the treatment term by a treatment-by-PIFR 
subgroup term. A descriptive p-value of treatment effect homogeneity at week 4 will be 
calculated. No overall treatment effect will be estimated from this model as it is not 
interpretable. The analysis will be done separately for population before and after COVID-19. 
Similarly, the same MMRM model as in the key secondary analysis will be fitted in the 
overall population but replacing the treatment term by a treatment-by-continuous baseline 
PIFR term. A descriptive p-value of treatment effect homogeneity at week 4 will be 
calculated. No overall treatment effect will be estimated from this model as it is not 
interpretable. The analysis will be done separately for population before and after COVID-19. 
The results of the analysis of the key secondary endpoints for tiotropium + olodaterol FDC 
within the optimal and sub-optimal PIFR groups will be presented in a forest plot and the 
treatment by PIFR subgroup interaction p-value will be provided. Sensitivity analysis will be 
performed by including additional covariates such as severity, gender and age in the model to 
adjust for potential differences in prognostic factors between sub-optimal and optimal PIFR 
subgroups.


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7.5.2
Other Miscellaneous endpoint(s)
For the FVC data descriptive statistics at screening are planned for this section of the report.
The analyses will be done separately for each PIFR sub group. 
7.7
EXTENT OF EXPOSURE
Extent of exposure will be summarized using descriptive statistics for days of exposure as 
well as number (%) of patients whose total exposure falls in the categories of <2weeks and 2-
<4weeks and more than 4 weeks.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse Events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All
analyses of AEs will be based on the number of subjects with AEs and NOT on the number 
of AEs.
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:

All AE attributes are identical (LLT, intensity, action taken, therapy required, seriousness, 
reason for seriousness, relationship, outcome)

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 (13,14).


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The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till last drug 
intake + residual effect period (21 days) will be assigned to the randomized treatment. All 
adverse events occurring before first drug intake will be assigned to ‘screening’ and all 
adverse events occurring after the residual effect period will be assigned to ‘post-treatment’ 
(for listings only). Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent . For details on the treatment 
definition, see Section 6.1.
According to ICH E3 AEs classified  as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting.
An overall summary of adverse events will be presented. 
The frequency of subjects with adverse events will be summarized by treatment, primary 
system organ class and preferred term (mention MedDRA levels to be displayed in the 
tables). Separate tables will be provided for subjects with other significant adverse events 
according to ICH E3 and for subjects with serious adverse events.
The system organ classes will be sorted alphabetically, preferred terms will be sorted by 
frequency (within system organ class).
7.8.2
Laboratory data
Clinically relevant findings in laboratory data will be reported as AEs and will be analyzed as 
part of the AE analysis.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report. Clinically relevant 
findings in vital signs will be reported as AEs and will be analyzed as part of the AE analysis.
7.8.4
ECG
Abnormal findings in ECGs will be reported either as baseline conditions (if identified at the 
screening visit) or as AEs if judged clinically relevant by the investigator.
7.8.5
Others
Not applicable since there were no additional endpoints.


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8.
REFERENCES
1.
001-MCS-50-415_RD-02: “Project Analysis Dataset (PADS) Template (template) “, 
current version, Group “Biostatistics & Data Sciences”, IDEA for CON.
2.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
3.
001-MCS-50-415_RD-03: “Clinical Trial Analysis Decision Log (template) Decision 
Log”, current version, Group “Biostatistics & Data Sciences”, IDEA for CON.
4.
001-MCS-36-472: “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics”, current version, Group “Biostatistics & Data 
Sciences”, IDEA for CON.
5.
001-MCS-40-106_RD-03: “Clinical Trial Protocol general template for Phase I-IV”, 
current version, Group “Clinical Operations”, IDEA for CON.
6.
001-MCS-80-606: “Management of Non-Compliances”, current version, Group “Quality 
Medicine”, IDEA for CON.
7.
001-MCS-40-413: Identify and Manage Important Protocol Deviations (iPD)”, current 
version, Group “Clinical Operations”, IDEA for CON.
8.
001-MCS-40-135_RD-01: “Integrated Quality and Risk Management Plan”, current 
version, Group “Clinical Operations”, IDEA for CON.
9.
REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF 
THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, 
and repealing Directive 2001/20/EC, European Commission webpage.
10. 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, EMA webpage.
11. 001-MCS-80-606: “Handling of Non-Compliances in Clinical Development, Medicine 
and QRPE”, current version; IDEA for CON.
12. 001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON.
13. 001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
14. 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.
15. BI Statistical Position Paper- Standards for Inferential Analyses v1.1(April 2019)


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16. Rubin D.B. Inference and missing data. Biometrika 63, 581-592 (1976).
17. R12-2094 Little, R.J. & Rubin, D.B. Statistical Analysis with Missing Data, 2nd ed. New 
York: John Wiley & Sons (2002)


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
01-JUL -2020
None
This is the initial TSAP with necessary
information for trial conduct
Final
29-SEP-2020
None
This is the final TSAP 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32418241
1.0
8-01-tsap-core-initial
8-01-tsap-core-initial
Author-Trial Statistician
29 Sep 2020 23:16 CEST
Approval-Project Statistician
30 Sep 2020 00:19 CEST
Approval-Medical Writer
30 Sep 2020 10:16 CEST
Approval-Clinical Trial Leader
30 Sep 2020 14:38 CEST
Approval-Team Member Medicine
01 Oct 2020 10:32 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32418241
1.0