Randomized Pragmatic Clinical Trial in a Community-Based Setting Comparing STIOLTO® RESPIMAT® vs. ICS-LABA Plus LAMA in Patients With COPD
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

 
PROTOCOL No: 1237-0064 – Boehringer Ingelheim COPD Study 
 
 
 
 
 
 
 
 
 
 
Randomized Pragmatic Clinical Trial in a Community-Based Setting 
Comparing STIOLTO® RESPIMAT® vs. ICS-LABA plus LAMA in Patients 
with COPD 
The AIRWISE Study: Assessment In a Real World setting of the effect of Inhaled 
Steroid-based triple therapy versus the combination of tiotropium and olodaterol on 
reducing COPD Exacerbations 
 
 
Protocol No.  1237-0064 
 
 
 
 
 
Fax: 
 
 
 
May 9, 2018 
Version 2.0 
 
 
 
 
 
 
This document and its contents are the property of Boehringer Ingelheim 
and are confidential.  Unauthorized copying or use is prohibited. 
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Protocol No. 1237-0064 
 
Version 2.0 May 9, 2018 
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Study Physician Agreement: 
I have read the protocol “Randomized Pragmatic Clinical Trial in a Community-Based Setting 
Comparing STIOLTO® RESPIMAT® vs. ICS-LABA plus LAMA in Patients with COPD” and 
agree to ensure that all staff members involved in the conduct of this study are informed of their 
obligations in meeting the commitments in accordance with it. 
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or 
supervise the described pragmatic trial. 
 
Signature:    
 
 
 
 
 
 
Date:  
 
 
 
Print Name:   
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
STUDY APPROVALS ......................................................................................................... 2 
STUDY PHYSICIAN AGREEMENT .................................................................................. 3 
TABLE OF CONTENTS ..................................................................................................... 4 
SYNOPSIS ........................................................................................................................... 7 
LIST OF ABBREVIATIONS ............................................................................................. 11 
1 
INTRODUCTION ...................................................................................................... 13 
1.1 
Background and Rationale .................................................................................................................................. 13 
2 
STUDY OBJECTIVES ............................................................................................... 15 
2.1 
Primary Objectives ................................................................................................................................................ 15 
2.1.1 
Primary Objective Definitions .......................................................................................................................................... 15 
2.2 
Secondary Objectives ............................................................................................................................................ 15 
3 
STUDY ENDPOINTS ................................................................................................. 16 
4 
STUDY DESIGN ........................................................................................................ 17 
4.1 
Overview .................................................................................................................................................................... 17 
4.2 
Practice and Participant Selection ................................................................................................................... 17 
4.2.1 
Physician Practice Eligibility ............................................................................................................................................ 17 
4.2.2 
Participant Recruitment and Eligibility ....................................................................................................................... 18 
4.2.3 
Participant Inclusion Criteria ........................................................................................................................................... 18 
4.2.4 
Participant Exclusion Criteria .......................................................................................................................................... 18 
4.2.5 
Participant Enrollment ........................................................................................................................................................ 19 
4.2.6 
Patient Randomization ........................................................................................................................................................ 19 
FIGURE 1: SCHEMATIC OF STUDY DESIGN ............................................................... 20 
5 
STUDY PROCEDURES ............................................................................................. 21 
5.1 
Enrollment Procedures ........................................................................................................................................ 21 
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5.2 
Baseline Visit ............................................................................................................................................................ 21 
5.2.1 
Participant Characteristics ................................................................................................................................................ 21 
5.2.2 
Treatments ............................................................................................................................................................................... 21 
5.3 
PROs............................................................................................................................................................................. 21 
5.3.1 
COPD Assessment Test TM (CAT) ..................................................................................................................................... 22 
5.4 
Study Period ............................................................................................................................................................. 22 
5.5 
Final Visit/EOS ......................................................................................................................................................... 22 
 
 
5.7 
Withdrawals ............................................................................................................................................................. 23 
5.7.1 
Physician Practices ............................................................................................................................................................... 23 
5.7.2 
Participants .............................................................................................................................................................................. 23 
6 
STATISTICAL METHODS ....................................................................................... 23 
6.1 
Analysis Overview .................................................................................................................................................. 23 
6.2 
Study Populations................................................................................................................................................... 24 
6.2.1 
Analysis Populations ............................................................................................................................................................ 24 
6.2.2 
Safety Population ................................................................................................................................................................... 24 
6.3 
Sample Size Determination ................................................................................................................................. 25 
6.3.1 
Power and Sample Size for Primary Objective ......................................................................................................... 25 
6.3.2 
Randomization and Blinding ............................................................................................................................................ 25 
6.3.3 
Interim Analysis ..................................................................................................................................................................... 25 
6.4 
Effectiveness Analysis ........................................................................................................................................... 25 
6.5 
Patient Reported Outcome (PRO) Analysis................................................................................................... 26 
6.6 
Safety Analysis ......................................................................................................................................................... 26 
 
 
 
 
 
 
 
6.8 
Missing Data ............................................................................................................................................................. 29 
7 
AE REPORTING ....................................................................................................... 29 
7.1 
AEs ................................................................................................................................................................................ 30 
7.2 
SAEs.............................................................................................................................................................................. 31 
7.2.1 
Reporting Period of SAEs ................................................................................................................................................... 31 
7.3 
Pregnancy .................................................................................................................................................................. 32 
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8 
DATA COLLECTION ............................................................................................... 32 
8.1 
Data Sources ............................................................................................................................................................. 32 
8.2 
eCRFs/EDC ................................................................................................................................................................. 33 
8.3 
Database Development ........................................................................................................................................ 33 
8.4 
Data Quality Assurance ........................................................................................................................................ 33 
9 
STUDY MANAGEMENT .......................................................................................... 34 
9.1 
Regulatory and Ethical Consideration ............................................................................................................ 34 
9.1.1 
IRB/Independent Ethics Committee (IEC) ................................................................................................................. 34 
9.1.2 
Informed Consent .................................................................................................................................................................. 34 
9.2 
Dropouts .................................................................................................................................................................... 35 
9.3 
Record Retention and Access ............................................................................................................................. 35 
10 PUBLICATION OF STUDY RESULTS .................................................................... 35 
TABLE 1: TIME AND EVENTS SCHEDULE .................................................................. 36 
TABLE 2: SAMPLE SIZE CALCULATIONS .................................................................. 37 
APPENDIX A: COPD ASSESSMENT TESTTM (CAT) ..................................................... 38 
SUMMARY OF AMENDMENTS AND UPDATES .......................................................... 39 
 
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SYNOPSIS 
 
Title: Randomized Pragmatic Clinical Trial in a Community-Based Setting Comparing STIOLTO® 
RESPIMAT® vs. ICS-LABA plus LAMA in Patients with COPD 
Study Name/Brief Title: Assessment In a Real World setting of the effect of Inhaled Steroid-based triple 
therapy versus the combination of tiotropium and olodaterol on reducing chronic obstructive pulmonary 
disease (COPD) Exacerbations [AIRWISE] 
Sponsor: Boehringer Ingelheim 
Treatment: Stiolto® Respimat® 
Active Ingredient: Tiotropium bromide & olodaterol 
Comparator Product: Inhaled Corticosteroid plus Long-acting beta agonists combination plus Long-acting 
muscarinic antagonists (ICS plus LABA plus LAMA)  (Triple Therapy) 
Protocol No.:  1237-0064 
Study Physicians:  Approximately 400 physicians who actively manage adult patients in the target 
indication, chronic obstructive pulmonary disease (COPD).   
Country: United States (US) 
Patients: Adults (40 years of age or older) with COPD who are currently on long-acting muscarinic 
antagonist (LAMA) or long-acting beta agonist (LABA) or inhaled corticosteroid (ICS)/LABA maintenance 
therapy, and whose treatment is not controlled on the current medication regimen as determined by the 
physician. 
Anticipated enrollment for this study is approximately 3200 patients, with approximately 1600 patients 
enrolled in each group. Patients will be randomized to either Stiolto Respimat or ICS plus LABA plus 
LAMA (triple therapy) made up of the combination of any approved drugs that their physician chooses. 
Study Objectives: The objectives of this study are as follows: 
1.) The primary objective of this pragmatic study is to compare the time to first moderate or severe 
COPD exacerbation in patients, not controlled on their current therapy, randomized to Stiolto 
Respimat versus triple therapy over 12 months of treatment. 
2.) The secondary objectives of this study are: 
a. To compare the annual rate of moderate or severe COPD exacerbations for patients on 
Stiolto Respimat with patients on triple therapy. 
b. To compare the time to first severe COPD exacerbation in both treatment arms.  
c. To compare the annual rate of severe COPD exacerbations in both treatment arms. 
d. To compare the proportion of patients with moderate or severe COPD exacerbations in both 
treatment arms. 
 
 
 
 
 
 
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Study Endpoints: 
Primary endpoint: time to first moderate or severe chronic obstructive pulmonary disease (COPD) 
exacerbation over 12 months of treatment 
 
Secondary endpoints: 
• 
Annual rate of moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations 
• 
Time to first severe chronic obstructive pulmonary disease (COPD) exacerbation over the 12 
month observation period 
• 
Annual rate of severe chronic obstructive pulmonary disease (COPD) exacerbations 
• 
Proportion of patients with moderate or severe chronic obstructive pulmonary disease (COPD) 
exacerbations over the 12 month observation period 
 
 
 
 
 
 
 
 
Study Design:  This is a pragmatic randomized open label active controlled parallel group design trial 
conducted in a real-world, community-based practice setting for a fixed duration of 12 months of treatment.  
All participating patients will already be on LAMA, LABA or ICS/LABA for COPD, but will have been 
determined by their physician to not be controlled on their current therapy.  Patients enrolled in the study 
will be randomized to either Stiolto Respimat or ICS plus LABA plus LAMA (triple therapy) and provided 
with a prescription for the assigned treatment.   
Inclusion and exclusion criteria are minimally restrictive and there are few study-specific evaluations.  Study 
physicians will follow and treat patients according to their routine clinical practice and judgment.  Clinical 
and healthcare claims data will be collected from study patients for 12 months.  
 
 
 
 
It is anticipated that patients who are being treated for COPD will, as part of usual care, likely undergo 
medical evaluation at regular intervals over the course of the study.  Physicians will collect study data during 
patient office visits and other patient contact (e-mail, phone, contact with another treating physician, receipt 
of records) that occur as part of standard clinical practice over the course of the study.  However, the only 
required study visits are a baseline visit and a final end of study (EOS) visit at 12 months.   
Patient Selection: 
Inclusion Criteria:   
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study: 
Priority will be given to patients actively enrolled in an 
 affiliated health plan. 
• 
COPD diagnosis as defined by the study physician 
• 
Currently on one of the following maintenance therapies: 
o LAMA monotherapy  
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o LABA monotherapy  
o ICS/LABA (Fixed Dose Combination (FDC)) 
• 
Physician determination that patient is not controlled on current pharmacotherapy  
• 
Adult patient 40 years of age or older at time of study enrollment 
• 
Willingness and ability to understand and provide documented Informed Consent Form (ICF) and 
Health Insurance Portability and Accountability Act (HIPAA) Authorization Form prior to 
commencement of any study required assessments, either directly or through Legally Authorized 
Representative. 
Exclusion Criteria: 
Patients presenting with any of the following exclusion criteria will not be eligible for enrollment into the 
study: 
• 
Currently on LAMA/LABA (free or FDC) or triple therapy (ICS plus LABA plus LAMA) 
• 
Contraindication to any study medications (LAMA, LABA or ICS) 
• 
Documented diagnosis of current asthma 
• 
Pregnant or nursing women 
 
Study Procedures: 
• 
Study physicians will identify eligible patients for participation. 
• 
Study physicians will obtain written informed consent and patients will be randomized to either 
Stiolto Respimat or triple therapy upon enrollment. 
• 
Study physicians will collect demographic, clinical and COPD history data on electronic Case 
Report Forms (eCRFs) at baseline. 
• 
A complete blood count (CBC) including differential white cell count will be drawn at baseline. In 
the event that a CBC is not available at baseline, laboratory results within 12 months of baseline will 
be accepted. 
• 
The COPD Assessment TestTM (CAT) symptom score will be assessed at baseline. 
• 
Study physicians will collect patient data (exacerbations, targeted medication changes, selected 
adverse events (AEs) (AEs leading to study treatment discontinuation, dose modification, or trial 
withdrawal)) during any patient office visits or other patient contact during the 12 months the 
patient is on study and enter it via an electronic data capture (EDC) system. Any Serious Adverse 
Events (SAEs), including COPD exacerbation SAEs, will be collected via paper system. 
• 
Clinical data collection at the EOS visit at 12 months will include exacerbations, targeted 
medication changes, selected AEs and any SAEs. 
• 
 
 
 
 
 
Study Duration:  Patients will be on study and followed for 12 months by the physician to collect clinical 
data. 
 
Patient Reported Outcomes (PROs):  The CAT will be administered at baseline to provide a simple and 
reliable measure of health status in COPD and assist patients and their physicians in quantifying the impact 
of COPD on the patient’s health at baseline.   
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Effectiveness Analysis:  The primary effectiveness analysis will assess time to first moderate or severe 
COPD exacerbation (as prospectively collected in the eCRF) of Stiolto Respimat compared to triple therapy.  
A Cox proportional hazards model will be used to compare treatments.   
Secondary/Sensitivity Analyses:  As a secondary effectiveness objective, the annual rate of moderate or 
severe exacerbations will also be calculated and compared between treatment groups.  Other secondary 
analyses include evaluation of severe COPD exacerbations for time to first exacerbation and annual rate, 
proportion of patients with moderate or severe COPD exacerbations, sensitivity analyses relating to 
exacerbation definition and source data, and sensitivity analyses relating to generalizability of the study 
population.   
 
 
 
 
 
Safety:  All SAEs reported by the patients during the study period are required to be documented on the 
appropriate SAE reporting form.  Selected AEs, e.g. AEs leading to study treatment discontinuation, dose 
modification, or trial withdrawal, will be collected on the eCRF during the study. During extraction of data 
from the claims database, any identified SAEs will be reported if not already collected on SAE form. 
 
 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation or 
Special Term 
Definition  
AE 
Adverse Event 
AIRWISE 
Assessment In a Real World setting of the effect of Inhaled 
Steroid-based triple therapy versus the combination of 
tiotropium and olodaterol on reducing COPD Exacerbations 
CAT 
COPD Assessment Test 
CBC 
Complete Blood Count 
eCCGs 
Electronic Case Report Form Completion Guidelines 
CDM 
Clinical Data Manager 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
COPD 
Chronic Obstructive Pulmonary Disease 
eCRF 
Electronic Case Report Form 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
ER 
Emergency Room 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
FEV1 
Forced Expiratory Volume in One Second 
FVC 
Forced Vital Capacity 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HCRU 
Healthcare Resource Utilization 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
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Abbreviation or 
Special Term 
Definition  
HR 
Hazard Ratio 
ICD-10 
International Classification of Disease, 10th Revision 
ICF 
Informed Consent Form 
ICS 
Inhaled Corticosteroid 
ID 
Identifier 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent to Treat 
LABA 
Long-Acting Beta Agonist 
LAMA 
Long-Acting Muscarinic Antagonist 
MedDRA 
Medical Dictionary for Regulatory Activities 
PP 
Per Protocol 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
PV 
Pharmacovigilance 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SM 
Service Mark 
SMQ 
Standardized Medical Queries 
SOC 
System Organ Class 
T2DM 
Type 2 Diabetes Mellitus 
TM 
Trademark 
US 
United States 
WISDOM 
Withdrawal of Inhaled Steroids during Optimized 
Bronchodilator Management 
 
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1 
INTRODUCTION 
1.1 
Background and Rationale 
Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by 
progressive airflow limitation and airway inflammation leading to a gradual loss in lung 
function.1  COPD is one of the most prevalent chronic diseases and the third leading cause of 
deaths in the United States (US) in 2011.2  However, a majority of the patients (>50%) with low 
pulmonary function are unaware of their COPD condition.3  This under diagnosis poses 
challenges in community clinical practice, resulting in inappropriate patient management. 
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends classifying 
patients for treatment based on assessment of existing symptoms, severity of airflow limitation, 
and history of exacerbations.4  Airflow obstruction is measured by spirometry, which is 
considered as the gold standard for accurate and repeatable measurement of lung function.  The 
presence of post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital 
capacity (FVC) <0.70 confirms the presence of persistent airflow limitation and hence COPD 
diagnosis.  However, spirometry is significantly underutilized by primary care physicians to 
confirm the diagnosis of COPD.5   
For patients who are diagnosed with COPD, treatments include maintenance medication with 
mono- and combination bronchodilator therapies.  Treatment with both a long-acting muscarinic 
antagonist (LAMA) and a long-acting beta agonist (LABA) has been recommended in patients 
whose COPD is not sufficiently controlled with mono- bronchodilator therapy.  Clinical trials 
examining combination treatment with LAMA and LABA have shown long term improvements 
in lung function, symptom scores, and exacerbations in patients with moderate to very severe 
COPD.6,7  Further, the convenience of fixed dose combination (FDC) products might provide an 
improved patient-centered approach that enhances patient acceptance and adherence to dual 
                                                        
 
1 Dewar M, Curry W. Chronic Obstructive Pulmonary Disease: Diagnostic Considerations. Am Fam Physician. 
2006 Feb 15;73(4):669-676. 
2 Hoyert DL, Xu JQ. Deaths: preliminary data for 2011. Natl Vital Stat Rep. 2012; 61(6):1-65. Hyattsville, MD: 
National Center for Health Statistics. 2012 
3 Center for Disease Control and Prevention. What is COPD? Available at http://www.cdc.gov/copd/index.htm. 
Accessed on January 20, 2015. 
4 Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) 2017. Available from: http://goldcopd.org. Accessed on March 4, 2017. 
5 Mapel DW, Dalal AA, Johnson P, et al. A clinical study of COPD severity assessment by primary care physicians 
and their patients compared to spirometry. Am J Med. 2015. doi: 10.1016/j.amjmed.2014.12.018. 
6 Vogelmeier C, Kardos P, Harari S, et al. Formoterol mono- and combination therapy with tiotropium in patients 
with COPD:  a 6 month study. Respir Med. 2008;102:1511-1520. 
7 Tashkin DP, Pearle J, Iezzoni D, et al. Formoterol and tiotropium compared with tiotropium alone for treatment of 
COPD. COPD. 2009;6:17-25. 
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bronchodilator therapy and reduces copay burden to the patient.  Stiolto® Respimat® is an FDC 
containing tiotropium (a LAMA) and olodaterol (a LABA) that was approved by the Food and 
Drug Administration (FDA) in May of 2015.  Multiple randomized controlled trials have 
demonstrated that the Stiolto Respimat is superior to either monotherapy. 
GOLD 2017 does not recommend the use of triple combination therapy (LABA/inhaled 
corticosteroid (ICS) + LAMA) except potentially in a subset of patients in group D (high risk for 
exacerbation/high symptom scores).  On the other hand, long-acting bronchodilators, including 
the combination of LAMA and LABA, are recommended as options in groups B (low risk for 
exacerbation/high symptoms scores), C (high risk for exacerbation/low symptoms scores) and D. 
However, multiple observational analyses of real-world data, including the preparatory analyses 
performed by 
 in the 
 population, continue to show a high proportion of 
COPD patients being prescribed ICS-containing regimens, including triple therapy.  The 
magnitude of ICS prescribing seems to be contrary to the recommendations provided by GOLD 
2017, and provides the impetus to perform the proposed study. 
While the benefits of ICS therapy are well documented across a broad spectrum of patients with 
asthma, their benefits in the COPD population appear to be more targeted to select patient 
phenotypes.  Specifically, the benefit appears to be most robust in patients with severe COPD 
with a history of frequent exacerbations or with an inflammatory/allergic component to their 
disease.  In addition, ICS therapy is associated with localized symptoms such as voice hoarseness 
and thrush, as well as systemic diseases such as upper respiratory tract infections and 
osteoporosis. 
The Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM)8 
trial explored the impact of withdrawing ICS in patients concurrently receiving LAMA/LABA 
combination therapy.  In this randomized, double-blind, non-inferiority designed study the risk 
of moderate or severe exacerbations was similar between those who had their ICS withdrawn 
versus those who continued.  A logical follow-up research question from the WISDOM study is 
to assess patients who are not controlled on their current therapy of ICS-LABA, LABA alone or 
LAMA alone, to see if change in therapy to LAMA/LABA FDC therapy is similar in effect to 
triple therapy.  Studying the question in a manner that assesses patients as therapy is “stepped-
up” is reflective of usual clinical practice and would provide valuable and relevant real-world 
evidence to both practicing clinicians and health care payers.  In addition, the GOLD 2017 
update specifically states that “more evidence is needed to draw conclusions on the benefits of 
triple therapy LABA/LAMA/ICS compared to LABA/LAMA.”  To this end, the proposed study, 
AIRWISE: Assessment In a Real World setting of the effect of Inhaled Steroid-based triple 
                                                        
 
8 Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of Inhaled Glucocorticoids and Exacerbations of 
COPD. N Engl J Med. 2014;317:1285-94. 
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therapy versus the combination of tiotropium and olodaterol on reducing COPD Exacerbations, 
is a non-inferiority trial of community-based COPD patients randomized to either Stiolto 
Respimat or triple therapy following a physician decision to escalate therapy.  The decision to 
escalate therapy will be at the discretion of the treating physician.  Patients will be treated 
according to routine clinical practice and followed for clinical (exacerbations, etc.) 
 
 
 
2 
STUDY OBJECTIVES   
2.1 
Primary Objectives 
The primary objective of this pragmatic study is to compare the time to first moderate or severe 
COPD exacerbation in patients, not controlled on their current therapy, randomized to Stiolto 
Respimat versus triple therapy over 12 months of treatment. 
2.1.1 
Primary Objective Definitions 
For the purpose of this study, a COPD exacerbation is defined as a complex of lower respiratory 
events/symptoms (increase or new onset) related to the underlying COPD, with duration of three 
days or more, requiring a prescription of antibiotics and/or systemic steroids and/or 
hospitalization. 
A complex of lower respiratory events/symptoms is defined as at least two of the following: 
• Shortness of breath 
• Sputum production (volume) 
• Change in sputum color 
• 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: Exacerbation requiring receipt of an exacerbation-related prescription of oral 
corticosteroids and/or antibiotic, but not requiring hospitalization 
Severe: Exacerbation requiring COPD-related hospitalization 
For hospitalizations associated with COPD exacerbation, the information collected should 
include the start date of all COPD-related hospitalizations, as well as the discharge date from the 
hospital or equivalent. 
2.2 
Secondary Objectives 
The secondary objectives of this study include: 
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1) To compare the annual rate of moderate or severe COPD exacerbations for patients on 
Stiolto Respimat with patients on triple therapy. 
2) To compare the time to first severe COPD exacerbation in both treatment arms.  
3) To compare the annual rate of severe COPD exacerbations in both treatment arms. 
4) To compare the proportion of patients with moderate or severe COPD exacerbations in 
both treatment arms. 
3 
STUDY ENDPOINTS 
The primary endpoint of this study is time to first moderate or severe chronic obstructive 
pulmonary disease (COPD) exacerbation over 12 months of treatment. 
Secondary endpoints include: 
• Annual rate of moderate or severe chronic obstructive pulmonary disease (COPD) 
exacerbations 
• Time to first severe chronic obstructive pulmonary disease  (COPD) exacerbation 
over the 12 month observation period 
• Annual rate of severe chronic obstructive pulmonary disease  (COPD) exacerbations 
• Proportion of patients with moderate or severe chronic obstructive pulmonary disease 
(COPD) exacerbations over the 12 month observation period 
 
 
 
 
 
 
 
 
 
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4 
STUDY DESIGN 
4.1 
Overview 
This is a pragmatic non-inferiority trial conducted in a real-world, community-based practice 
setting for a fixed duration of 12 months of treatment.  All participating patients will already be 
on LAMA, LABA or ICS/LABA for COPD, but will have been determined by their physician to 
not be controlled on their current therapy.  No definition of ‘controlled’ will be offered by the 
trial protocol in order to allow physicians to make real-world autonomous decisions.  Patients 
enrolled in the study will be randomized to either Stiolto Respimat or ICS plus LABA plus 
LAMA (triple therapy) and provided with a prescription for the assigned treatment.  Study 
treatments will be open-label. 
In keeping with the study objective to evaluate Stiolto Respimat in a real-world setting, this 
study is naturalistic in design.  Inclusion and exclusion criteria are minimally restrictive and 
there are few study-specific evaluations.  Study physicians will follow and treat patients 
according to their routine clinical practice and judgment.  Patients who enroll in the study agree 
to the release of health information and to answer questions about their health during the course 
of the study.  Clinical and healthcare claims data will be collected from study patients for 
approximately 12 months.  
 
 
 
 
 
 
 
 
 
Consistent with the naturalistic design, this study does not have a rigid visit schedule.  It is 
anticipated that patients who are being treated for COPD will, as part of usual care, likely 
undergo medical evaluation at regular intervals.  Physicians will collect study data during patient 
office visits and other patient contact (e-mail, phone, contact with another treating physician, 
receipt of records) that occur as part of standard clinical practice over the course of the study.  
The only required study visits are a baseline visit and a final end of study (EOS) visit at 12 
months post enrollment. 
4.2 
Practice and Participant Selection 
4.2.1 Physician Practice Eligibility 
Enrollment of approximately 400 physician sites with an adequate COPD population in the US is 
anticipated. 
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4.2.2 Participant Recruitment and Eligibility 
Eligible participants include active COPD patients whose physicians determine that their COPD 
is not controlled on their current therapy (LAMA or LABA monotherapy or ICS/LABA).  
Patient recruitment and eligibility study procedures reflect the study’s goal of evaluating Stiolto 
Respimat in a real-world setting.  As such, patients will be recruited from the physician’s patient 
population in a manner that is representative of the real-world population who are currently 
receiving care within their practice. 
The determination that the patient is not controlled on their current therapy, and therefore 
eligible for the study, is at the discretion of the physician.  Once an eligible patient is enrolled, 
they will be randomized in sequence. 
It is anticipated that participants will be recruited from patients who are actively enrolled in an 
 of 
 or 
 health plan (hence forth referred to as 
 health plans).  To 
meet enrollment goals recruitment will allow non-
 patients within enrolled physician 
practices, which may include Medicare/Medicaid patients.  
 
 
4.2.3 Participant Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
Priority will be given to patients actively enrolled in an 
 affiliated health plan. 
• COPD diagnosis as defined by the study physician 
• Currently on one of the following maintenance therapies: 
o LAMA monotherapy  
o LABA monotherapy  
o ICS/LABA (FDC) 
• Physician determination that patient is not controlled on current pharmacotherapy  
• Adult patient 40 years of age or older at time of study enrollment 
• Willingness and ability to understand and provide documented Informed Consent Form 
(ICF) and Health Insurance Portability and Accountability Act (HIPAA) Authorization 
Form prior to commencement of any study required assessments, either directly or 
through Legally Authorized Representative. 
4.2.4 Participant Exclusion Criteria 
Patients presenting with any of the following exclusion criteria will not be eligible for enrollment 
into the study: 
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• Currently on LAMA/LABA (free or FDC) or triple therapy (ICS plus LABA plus LAMA) 
• Contraindication to any study medications (LAMA, LABA or ICS) 
• Documented diagnosis of current asthma 
• Pregnant or nursing women 
Women of childbearing potential are not restricted in this trial, however it is expected that the 
investigator will assess the risks and benefits of the assigned treatment as per the product label(s) 
and discuss this with any women of childbearing potential prior to providing the patient with the 
prescription for the assigned treatment. 
4.2.5 Participant Enrollment 
Anticipated enrollment for this study is approximately 3200 patients, with approximately 1600 
patients enrolled in each group. 
4.2.6 Patient Randomization 
Enrolled study patients will be randomized to either Stiolto Respimat or triple therapy in a 1:1 
ratio.  Once the study physician has determined patient eligibility and has enrolled them into the 
study in the Electronic Data Capture (EDC) system, the physician will receive the randomization 
assignment (Stiolto Respimat or triple therapy) for that patient.   
Patient eligibility and randomization is depicted in the study schematic (Figure 1). 
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Figure 1: Schematic of Study Design 
Prior to  
Enrollment 
 
 
 
 
 
Enrollment 
 
 
 
 
 
 
 
 
 
Visit 1 
Time Point  
(Baseline Visit) 
 
 
 
 
 
Regular Care 
(On Study) 
 
 
 
 
 
 
 
 
End of Study 
(12 Month 
Visit) 
 
 
 
 
 
The only required study visits are Baseline and EOS at 12 months.  Data will be collected at 
routine clinical visits and other patient contact in between Baseline and EOS if available per 
standard clinical practice.  See Table 1 for additional detail. 
Screening Procedures 
• 
Identify eligible patients  
• 
Screen potential participants by inclusion and exclusion criteria  
• 
Obtain informed consent 
• 
Document inclusion/exclusion criteria   
Baseline Assessments  
Document:  
• 
Demographics 
• 
COPD history including exacerbations, pre-specified comorbid conditions, 
targeted medications, and reason for therapy escalation 
• 
Smoking status, blood eosinophil results  
• 
COPD Assessment Test (CAT) responses  
Randomize 3200 Participants Total 
Triple Therapy  
1600 participants 
Stiolto Respimat 
1600 participants 
On Study Follow-Up Assessments  
Patients seen according to routine clinical practice and physician judgment. Document:  
• 
Moderate to severe exacerbations, AE leading to discontinuation or dose 
modification of study treatment, or trial withdrawal, and SAEs  
• 
Treatment changes, select medication changes, changes to study medication  
 
Final Assessments 
Document:  
• 
Moderate to severe exacerbations, AE leading to discontinuation or dose 
modification of study treatment, or trial withdrawal, SAEs  
• 
Treatment changes, select medication changes, changes to study medication  
 
 
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5 
STUDY PROCEDURES 
5.1 
Enrollment Procedures 
Once potential physician sites have been identified, physicians who agree to participate in the 
study will be enrolled.  Following Institutional Review Board (IRB) approval of a site and study 
training, sites will begin patient enrollment.  The physician will make the decision regarding the 
patient’s suitability for the study, and in order to maintain the real-world nature of the study, 
patients will be approached for potential enrollment into the study during routine office visits or 
other patient contact as part of their standard care.   
5.2 
Baseline Visit 
Eligible patients interested in participating will provide written informed consent and be 
randomized to either Stiolto Respimat or triple therapy at their baseline visit.  Data collection at 
baseline will include inclusion/exclusion criteria as well as the data outlined in the sections 
below.  A blood sample will be drawn at the baseline visit for a complete blood count (CBC) 
including differential white cell count.  In the event that a CBC is not available at baseline, 
laboratory results within 12 months of baseline will be accepted. 
5.2.1 Participant Characteristics 
Study physicians or trained site personnel will collect patient characteristics at each office visit 
as summarized in Table 1, either directly from the patient or abstracted from the patient’s chart, 
and enter them into the electronic Case Report Form (eCRF).  Baseline assessments will include 
demographic data, baseline clinical data (selected pre-specified comorbid conditions, CBC 
including a required baseline blood eosinophil count, and smoking status) as well as COPD and 
exacerbation history. 
5.2.2 Treatments 
Upon enrollment, patients will be randomized to receive either Stiolto Respimat or triple therapy.  
Treatment details will be recorded in the eCRF. 
5.3 
PROs 
Symptomatology will be assessed at baseline via the COPD Assessment TestTM (CAT) to enable 
classification of patients by the 2017 GOLD A-D criteria in conjunction with exacerbation 
history data.  Patients will complete the CAT and site study personnel will enter the completed 
forms into the eCRFs. 
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5.3.1 COPD Assessment Test TM (CAT) 
The CAT is a short (8-item), simple, patient-completed questionnaire that measures the impact of 
COPD on a patient’s well-being and daily life.9  Patients rate the following items on a 6-point (0-
5) scale, where higher scores indicate worse symptoms: Cough, Phlegm, Chest Tightness,
Breathlessness, Activities at Home, Confidence Leaving Home, Sleep and Energy.  Scores from 
individual items are summed, yielding CAT scores ranging from 0-40, with higher scores 
indicating worse COPD-related health status. 
The CAT instrument is attached in Appendix A. 
5.4 
Study Period 
Patients will be followed from baseline to EOS at 12 months.  
 
 
 Patients will be followed for the full 12 months 
regardless of study treatment changes or discontinuation during the study period.  Only if a 
patient withdraws consent will data collection be discontinued. 
Consistent with the naturalistic design, this study does not have a rigid visit schedule.  Patients 
will be followed for 12 months according to their treating physician’s routine clinical practice 
and judgment.  On-study data collection during routine clinical visits or other contacts with 
patient, such as by phone or e-mail, contact with another treating physician, or receipt of records, 
will include exacerbations, COPD targeted concomitant medications, changes to study treatment, 
adverse events (AEs) leading to study treatment discontinuation, dose modification, or trial 
withdrawal and any Serious Adverse Events (SAEs).  It is anticipated that patients who are being 
treated for COPD will undergo medical evaluation at regular intervals; however, the only 
required study visits are baseline and EOS at 12 months. 
The study is anticipated to take 36 months from commencement of enrollment through data 
analysis and reporting. 
5.5 
Final Visit/EOS 
The EOS visit will be 12 months after baseline.  Data collection at EOS will include 
exacerbations, COPD concomitant medications, changes to study treatment, AEs leading to study 
treatment discontinuation or dose modification, or trial withdrawal, and any SAEs.  Post-study 
treatment is at the discretion of the physician. 
The study visit schedule is summarized in Table 1. 
9 Jones PW, Harding G, Berry P, et al. Development and first validation of the COPD Assessment Test. Eur Respir 
J. 2009;34:648-654. 
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5.7 
Withdrawals 
5.7.1 Physician Practices 
Boehringer Ingelheim and/or the IRB reserve the right to terminate the study or participation of 
the study physicians at any time.  In such cases, data collection will end.  After the collected data 
is received, the participating study physicians will be compensated as contractually agreed. 
5.7.2 Participants 
Discontinuation will be based upon physician clinical determination and/or by patient decision.  
Participation in this study is voluntary, and all patients are free to terminate their participation at 
any time.  In the event of early termination of study participation, details regarding the 
discontinuation will be recorded.  Patients will be followed for the full 12 months regardless of 
treatment changes or discontinuation during the study period.  Only if a patient withdraws 
consent will data collection be discontinued.  The study physician will record the reason for 
withdrawal and continue follow-up with the patient for any unresolved SAEs. 
 
6 
STATISTICAL METHODS 
6.1 
Analysis Overview 
This is a randomized, open-label, parallel-group, non-inferiority design pragmatic study, with a 
fixed duration of 12 months.  Patients are randomized to Stiolto Respimat or triple therapy.  The 
primary endpoint is the time to first moderate or severe COPD exacerbation. 
Null hypothesis for non-inferiority 
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The null hypothesis of this non-inferiority trial is that the hazard ratio (HR) of time to first 
moderate or severe COPD exacerbations in the Stiolto Respimat arm compared to the triple 
therapy arm is larger than 1.2.  The non-inferiority margin of 20% was based on practical 
considerations and kept consistent with the margin used in the WISDOM study.10  
H0: HR(Stiolto Respimat/Triple Therapy) >= 1.2 
versus 
H1: HR(Stiolto Respimat/Triple Therapy) < 1.2 
This will be addressed by comparing the upper bound of the 95% two-sided confidence interval 
for the HR with the non-inferiority margin of 1.2. 
6.2 
Study Populations 
The following populations will be defined for analysis and reporting. 
6.2.1 Analysis Populations 
6.2.1.1 Intent to Treat (ITT) Population 
The ITT population will include all randomized patients allocated to their original randomized 
treatment group, even if they switched or discontinued study treatment. 
6.2.1.2 Per Protocol (PP) Population 
No per-protocol set is defined and no analysis is planned.  A sensitivity analysis using on-
treatment exacerbations is described in Section 6.4. 
 
 
 
 
 
 
 
6.2.2 Safety Population 
The safety population will include all randomized patients who received a prescription of any 
study treatment (Stiolto Respimat or triple therapy).  
                                                        
 
10 Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of Inhaled Glucocorticoids and Exacerbations of 
COPD. N Engl J Med. 2014;317:1285-94. 
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6.3 
Sample Size Determination  
6.3.1 Power and Sample Size for Primary Objective 
Table 2 presents several scenarios considered for sample size.  The sample size for this study is 
3200 patients, with 1600 in each treatment group.  This sample size was calculated using 
Addplan 6.1 software based on a non-inferiority test for survival analysis (with Schoenfeld’s 
formula for calculating the number of events), under the following assumptions: 
• Expected HR of moderate or severe COPD exacerbations of 1.0 between Stiolto 
Respimat and triple therapy 
• 20% non-inferiority margin, with HR boundary of 1.20 
• 42.5% of patients in the triple therapy arm have at least one moderate or severe COPD 
exacerbation in 12 months 
• 90% power 
• One-sided Type I error rate of 0.025 
• Randomization ratio 1:1 between treatment arms 
• Fixed trial duration with 12 month follow up 
• 15% drop-out rate during 12 months in both treatment arms 
6.3.2 Randomization and Blinding 
A 
 statistician independent from the study will create the randomization schedule to 
be loaded into the EDC system.  Randomization will be validated by an independent statistician 
for the 3200 sample size plus 25% overrun.  Patients will be randomized in equal ratio to the two 
treatment arms and blocked randomization will be used.  The block size will be documented in 
the study report. 
This is an open-label randomized phase 4 trial, which is designed and conducted as a pragmatic 
trial, i.e. as a study in a real-world setting with minimal inclusion/exclusion criteria and few 
study-specific visits and procedures.  Blinding for this open-label pragmatic trial is not feasible; 
however selection bias will be eliminated via concealed treatment allocation through the EDC 
system.  The database for this pragmatic trial will not be blinded.  
6.3.3 Interim Analysis 
There is no interim analysis planned for this trial. 
6.4 
Effectiveness Analysis 
The effectiveness analysis will address the primary objective of this study: to determine whether 
Stiolto Respimat is non-inferior to triple therapy as measured by time to first moderate or severe 
exacerbation.  For the primary endpoint, COPD exacerbation defined as moderate or severe as 
collected in the eCRF will be used.   
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The primary analysis for the primary endpoint will be performed using the ITT population. 
Patients will be analyzed using the treatment arm to which they are randomized to, even if they 
switched or discontinued study treatment.  Patients will be censored at the time of last contact or 
death, if they did not experience a moderate or severe COPD exacerbation before.  The 
exacerbation data from eCRF will be used for the primary analysis.  
For the primary endpoint, i.e. time to first moderate or severe COPD exacerbation, the Cox 
proportional hazards model with baseline ICS prior use as a covariate will be used to estimate the 
HR and the two-sided 95% Wald confidence interval.  
 
 
 
 
 
The primary endpoint will also be analyzed for moderate or severe COPD exacerbations from 
different data sources: (1) claims data only and (2) integrated eCRF/claims data.  
The details of all analyses will be fully described in the Statistical Analysis Plan (SAP). 
6.5 
Patient Reported Outcome (PRO) Analysis 
The impact of COPD on patients’ health and quality of life will be assessed at baseline via the 
CAT.  PRO analysis will be descriptive in nature and will not involve any statistical testing.  
Rather, summary statistics will be used to describe patient perceived health status impairment 
associated with COPD at baseline, as well as potentially as an explanatory variable in any 
multivariate analyses or in subgroup analyses. 
6.6 
Safety Analysis 
Collection of AEs in the study eCRF will be limited to AEs leading to study treatment 
discontinuation or dose modification, or trial withdrawal.  All SAEs will be reported by the 
investigator via a dedicated SAE report form directly to Boehringer Ingelheim Global 
Pharmacovigilance as described in section 7.2.  As hospitalization SAEs are reflected in claims 
records, a patient-level review comparing hospitalization claims entries with reported SAEs for 
each respective patient will take place after completion of the 12-month visit in order to identify 
any hospitalizations of which the investigator was potentially unaware.  The investigator will 
receive information of any SAE identified through this process and report it using the standard 
SAE reporting process (See section 7.2).    
SAE data for analysis will be drawn from the Boehringer Ingelheim Safety Database. 
Analysis of non-serious AEs (leading to study treatment discontinuation or dose modification, or 
trial withdrawal) will be performed on the study database, as these are entered in the eCRF only.  
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Safety analyses will be descriptive in nature.  No hypothesis testing is planned prospectively. 
AEs will be coded using the current version of the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary at the time of reporting, and recoded to the MedDRA version 
current at the time of database integration.  Summary tables and listings will be produced to 
compare the incidence of AEs across treatment groups, by Preferred Term (PT)/System Organ 
Class (SOC) and also by medical concept (MedDRA Standardized Medical Queries (SMQ) or 
custom Boehringer Ingelheim searches termed Pharmacovigilance (PV) endpoints).  All AEs 
with an onset after the first dose of trial medication and up to 21 days after the last dose of trial 
medication will be assigned to the on-treatment period.  Other AEs will be assigned either to the 
screening period, post-treatment period or the post-study period as appropriate. 
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6.8 
Missing Data 
Missing data for exacerbation endpoints will not be imputed. 
 
7 
AE REPORTING  
The study physician is responsible for monitoring the safety of participating patients.  All SAEs 
reported by the patients during the study period are required to be documented on the appropriate 
SAE reporting form.  Selected AEs, e.g. AEs leading to study treatment discontinuation, dose 
modification, or trial withdrawal, will also be collected on the eCRF during the study.  SAEs 
identified in patient-level review of hospitalization data extracted from claims will be notified to 
the investigators and then reported by these on the SAE reporting form (cf. section 6.6). 
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7.1 
AEs 
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. 
Only selected non-serious AEs will be collected in eCRF: events leading to study treatment 
discontinuation, dose modification, or trial withdrawal. 
Causal relationship of AEs 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history. 
Arguments that may suggest a reasonable 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. preexisting 
or concomitant diseases, or co-medications). 
• The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome). 
• An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished). 
 
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
• No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned). 
• Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). 
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
• Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
• Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
 
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7.2 
SAEs 
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 
• Requires prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity, or 
• Is a congenital anomaly or birth defect, or 
• Is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgment which may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions.  
AEs considered “Always Serious” 
In accordance with the European Medicines Agency (EMA) initiative on Important Medical 
Events, Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always 
be considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.  The investigators will be notified of any AE that is entered in the eCRF that meets 
criteria as an Important Medical Event per Always Serious List.  The investigator will promptly 
complete the SAE form with all available information about the AE(s) and report to the 
sponsor’s unique entry point as described in the Investigator Site File (ISF) immediately (within 
24 hours). 
All SAEs will be reported via Boehringer Ingelheim SAE reporting forms to the Global 
Pharmacovigilance Database.  If patient-level review of claims versus site entries reveals any 
hospitalization SAE in claims not already captured by the investigator, the investigator will be 
contacted providing information and asking for completion of an SAE form with those details 
known to him/her.  
7.2.1 Reporting Period of SAEs 
AEs and SAEs will be reported from the time a patient signs consent until the final visit at 12 
months or until the patient discontinues the trial.  After the patient completes or discontinues the 
trial, the investigator does not need to actively monitor the patient for AEs but should only report 
related SAEs of which the investigator may become aware of by any means of contact with the 
patient, e.g. phone call. 
SAE reporting procedure will follow usual Boehringer Ingelheim forms and processes and will 
be further described in the ISF.  The investigator must report SAEs on a Boehringer Ingelheim 
SAE form via the fax form immediately (within 24 hours of investigator’s awareness of the 
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event) as described in the ISF.  The same timeline applies if follow up information becomes 
available.   
Healthcare Claims Database SAE reporting process 
If patient level review of claims database versus site entries at‘12+3 month mark’ (3 months after 
the 12 month follow-up visit) reveals any hospitalization in claims database that is not already 
captured by the investigator as an SAE, the investigator will be contacted with this information. 
The investigator will promptly complete the SAE form with all available information about the 
patient’s hospitalization and report to the sponsor’s unique entry point as described in the ISF 
immediately (within 24 hours). 
Information required 
For each AE, the Investigator should provide the information requested on the appropriate eCRF 
pages (if applicable) and Boehringer Ingelheim SAE Report form. The Investigator should 
determine the causal relationship to the trial medication. 
The following should also be recorded as S(AE) in the eCRF and SAE form (if applicable): 
• Worsening of pre-existing conditions,  
• Changes in vital signs, electrocardiograms (ECGs), physical examinations, and laboratory 
test results, if they are judged clinically relevant by the Investigator.  
If such abnormalities already pre-exist prior to trial inclusion they will be considered as baseline 
conditions. 
7.3 
 Pregnancy 
Once a female subject has been enrolled into the trial, after having taken study medication, the 
investigator must report immediately any drug exposure during pregnancy.  Drug exposure 
during pregnancy has to be reported immediately (within 24 hours or next business day, 
whichever is shorter, of the pregnancy becoming known to the investigator) to the defined 
unique entry point for SAE forms by means of Pregnancy Monitoring Form A (pregnancy 
monitoring forms and contact details will be provided in the ISF). 
The outcome of the pregnancy associated with the drug exposure must be followed up and 
reported by means of Pregnancy Monitoring Form B.   
In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical Trials and not the 
SAE form is to be completed. 
 
8 
DATA COLLECTION 
8.1 
Data Sources 
Data sources include demographic and clinical data collected prospectively by study sites, 
patient-completed PRO data and administrative claims data from patients on 
 health 
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plans (
 and targeted non-
 health plans.  In order to maintain patient 
confidentiality, each patient will be assigned a unique patient study ID upon enrollment to use in 
place of patient name or any other identifying information (e.g., medical record number).  
Clinical study data, PROs and claims-derived variables will be integrated into one analysis 
dataset via this confidential patient ID. 
The study physician has the ultimate responsibility for the collection and reporting of all clinical 
and patient data through the eCRFs as well as ensuring that they are accurate and complete. 
8.2 
eCRFs/EDC 
All clinical study data will be collected at the physician office and entered into eCRF by trained 
site study personnel through a fully validated, 21 CFR 11 and HIPAA compliant EDC system.  
Patients will complete PRO questionnaires (i.e., CAT) by paper and pen and the site study 
personnel will enter the completed forms into the EDC system. 
All study personnel involved in data entry will be trained on patient confidentiality and the EDC 
system prior to beginning data entry.  Site users will be provided eCRF Completion Guidelines 
(eCCGs) to assist with study data collection and entry.  Study personnel will access the EDC 
system through a secure study website. 
8.3 
Database Development 
All prospectively collected study data will reside in a 21 CFR 11 and HIPAA compliant secure 
database, developed and managed by 
 EDC vendor.  Patient-level study data will be 
downloaded from the EDC system to secure 
 servers for linkage to claims derived 
variables via a unique patient ID. 
A Clinical Data Manager (CDM) will manage the study database and act as the system 
administrator, creating and maintaining users and database access privileges.  Standard user-type 
privileges will be configured and implemented to ensure privacy and security compliance policy 
requirements.  Patient confidentiality will be strictly maintained. 
A Data Management Plan (DMP) will be developed at the beginning of the study to describe all 
functions, processes and specifications for collection, cleaning and validation of study data from 
study start up to database lock.   
8.4 
Data Quality Assurance 
The DMP will describe structures, processes, policies and procedures employed to ascertain the 
quality of the data and to ensure against errors in data entry, transfer or transformation accuracy 
throughout the study.  Data quality oversight will involve a multi-tiered process that includes 
electronic edit check specifications, manual checks, self-evident corrections, listing reviews and 
electronic data transfer agreement summaries.  Electronic edit checks will be programmed to 
show discrepancies online at the time of data entry, giving the operator the option to confirm 
acceptance of the discrepant data or change the data.  Manual review and listing reviews will be 
run as outlined in the DMP, either at predetermined intervals or as necessary.  The CDM will 
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open queries to resolve any discrepancies either within the database or directly with study 
personnel.  All changes to existing data will be fully tracked, maintaining an audit trail report of 
every transaction. 
 
9 
STUDY MANAGEMENT 
9.1 
Regulatory and Ethical Consideration 
All study activities will be conducted in accordance with regulatory guidelines for real-world, 
pragmatic research.  Study personnel at physician sites will be provided training on the study 
protocol, the ICF, data collection and data entry to ensure both the protection of potential study 
patients as well as the scientific integrity of the study.  A hybrid approach of both remote and 
onsite monitoring will be employed. 
9.1.1 IRB/Independent Ethics Committee (IEC) 
The study physician will have prospective approval of the study protocol, ICF and any patient 
information or recruiting materials, if applicable, prior to commencement of any study activities. 
In the case of a protocol amendment, the study physician must sign the revised protocol and 
submit the amendment to the IRB/IEC for review and approval prior to implementation of any 
changes specified in the protocol amendment.  All changes in research activity and all 
unanticipated problems involving risk to human patients or others must be reported promptly to 
the IRB/IEC. 
The study physician will obtain continued review of the study at intervals not to exceed one year 
or otherwise specified by the IRB/IEC. 
9.1.2 Informed Consent 
An ICF fully describing the purpose, procedures and potential risks and benefits of the study will 
be developed and approved by the IRB/IEC prior to study initiation.  The study physician must 
ensure that each study patient is fully informed of the study and authorizes release of health 
information prior to study enrollment.  The study physician, or study personnel designated by the 
study physician, will obtain written informed consent from each patient prior to initiation of any 
study-related procedures.  Each patient will be given a copy of the signed ICF.  The study 
physician will retain the original signed ICF for each patient. 
The IRB/IEC must prospectively approve the ICF and any changes to the ICF during the course 
of the study before use.  If a protocol amendment alters the study design or increases the 
potential risk to the patient, the ICF must be revised and submitted to the IRB/IEC for review 
and approval prior to implementation.  The revised ICF must then be used to obtain consent from 
new patients entering the study.  The revised ICF must also be used to obtain consent from 
currently enrolled patients if they are affected by the amendment. 
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9.2 
Dropouts 
Patient participation is strictly voluntary and patients may refuse to participate or withdraw from 
the study at any time and for any reason.  As such, patients may voluntarily withdraw prior to 
completing the final visit.  In such cases, the study physician will document the specific reason 
for the incomplete information (e.g., withdrawal of consent, lost to follow-up) on the eCRF.  The 
physician should continue follow-up with the patient for any unresolved SAEs. 
9.3 
Record Retention and Access 
This study may be subject to audits or evaluations by regulatory authorities or Boehringer 
Ingelheim (or its designee).  To enable such evaluations and/or audits, the study physician must 
agree to maintain and allow reasonable access to required patient and study records.  The study 
physician agrees to keep the identity of all participating patients (sufficient information to link 
records, e.g., hospital records), all original signed ICFs, SAE Forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (e.g., letters, meeting minutes, telephone calls, reports).  The study physician 
should retain records according to local regulations, or as specified in the Clinical Study 
Agreement, whichever is longer. 
 
10 
PUBLICATION OF STUDY RESULTS 
All information related to this study is considered confidential information belonging to 
Boehringer Ingelheim and 
  A final study report will be generated following 
completion of data collection and analysis.  Results and findings will be submitted to 
conferences and for publication in peer-reviewed scientific journals. 
 
 
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Protocol No. 1237-0064 
 
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Table 1: Time and Events Schedule 
 
Study Visits 
Assessment or Procedure 
Baseline 
On Study 
Follow-Up1 
EOS 
12 Months 
Written Informed Consent 
X 
 
 
Eligibility Criteria 
X 
 
 
Randomization 
X 
 
 
Demographics 
X 
 
 
Selected pre-specified comorbid 
conditions 
X 
 
 
CBC (Baseline Blood 
Eosinophil Count Required)2 
X 
 
 
Smoking Status 
X 
 
 
COPD Diagnosis Date  
X 
 
 
COPD Exacerbation History 
(number and severity of 
exacerbations in last year) 
X 
 
 
Pre-Study COPD Therapy 
X 
 
 
Reason for therapy escalation 
X 
 
 
COPD Concomitant 
Medications  
X 
X 
X 
CATTM 
X 
 
 
Study Treatment 
X 
X 
X 
COPD Exacerbations 
 
X 
X 
Selected AEs3 
 
X 
X 
SAEs3 
 
X 
X 
1The only required study visits are Baseline and EOS.  Data will be collected at routine clinical 
visits and other patient contact in between Baseline and EOS if available per standard clinical 
practice. 
2In the event that a CBC is not available at baseline, laboratory results within 12 months of 
baseline will be accepted. 
3All SAEs and selected AEs will be collected from Baseline through EOS or early termination of 
study participation.  Selected AEs are AEs leading to study treatment discontinuation, dose 
modification or trial withdrawal. 
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Protocol No. 1237-0064 
 
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Table 2: Sample size calculations (with number of events) under different assumptions for 
p1, HR and power, 20% non-inferiority margin, one-sided alpha 0.025 and 15% drop-out 
rate during 12 months. 
Scenario 
P1 (proportion 
of patients with 
>=1 moderate 
/severe COPD 
exacerbation 
during 12 
months in 
Triple Therapy 
arm) 
P2 (proportion 
of patients 
with >=1 
moderate/ 
severe COPD 
exacerbation 
during 12 
months in 
Stiolto arm) 
Expected HR 
of moderate/ 
severe COPD 
exacerbations 
between 
Stiolto and 
Triple 
Therapy 
Power 
Number of 
events 
(moderate/ 
severe COPD 
exacerbations) 
Sample 
size 
(total) 
1 
40% 
39.07% 
0.97 
95% 
1147 
3120 
2 
42.5% 
42.5% 
1 
90% 
1264 
3200 
3 
45% 
46% 
1.03 
80% 
1358 
3204 
These sample size calculations were completed using Addplan 6.1 software based on a non-
inferiority test for survival analysis. 
 
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APPENDIX A: COPD Assessment TestTM (CAT) 
 
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Protocol No. 1237-0064 
 
Version 2.0 May 9, 2018 
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 Summary of Amendments and Updates 
 
Summary of Changes 
1237-0064 Protocol Version 2.0, dated 09May2018 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
Global Change 
 
May 9, 2018June 7, 2017 
 
Version 12.0 
 
Updated protocol date and 
version. 
2 
Study Approvals, 
page 2 
Sponsor Approval: 
 
Name:
 
 
Title:  
 of 
Clinical Development & 
Medical 
Affairs, Primary Care - 
RespiratoryCOPD & 
Asthma 
 
 
Updated sponsor Principal 
Investigator for study 
approval signature. 
3 
Synopsis Study 
Procedures, page 9 
 
• A complete blood count 
(CBC) including differential 
white cell count will be 
drawn at baseline. In the 
event that a CBC is not 
available at baseline, 
laboratory results within 12 
months of baseline will be 
accepted. 
 
Added language to relax the 
timing required for a baseline 
CBC. This change increases 
the flexibility of study 
requirements and is 
consistent with the pragmatic 
design. 
4 
Section 4 Study 
Design 
4.2.2 Participant 
Recruitment and 
Eligibility, page 
17-18 
To maintain the real-world 
nature of the study, patients will 
be recruited for enrollment 
when they interact with their 
physician as part of their 
standard care. 
 
Removed sentence to allow 
additional patient outreach at 
study sites to increase study 
enrollment. 
5 
Section 4 Study 
Design 
To enhance enrollment at trial 
initiation, up to 500 non-
 
Deleted sentences to remove 
any restriction from 
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Protocol No. 1237-0064 
 
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4.2.2 Participant 
Recruitment and 
Eligibility, page 18 
patients will be allowed to 
enroll, following which 
enrollment will be restricted to 
 patients only if 
possible.  In such event that 
additional non-
 patients 
are needed to complete 
enrollment, the decision to re-
open enrollment to non-
 
patients will be made jointly 
between 
 and 
Boehringer Ingelheim. 
 
enrollment of non-
 
patients to increase study 
enrollment. 
6 
Figure 1: 
Schematic of 
Study Design, 
page 20 
• Identify Eeligible 
patients interacts with 
physician in course of 
normal care 
Modified sentence to allow 
additional patient outreach at 
study sites to increase study 
enrollment, consistent with 
change #4 in 4.2.2 above 
 
7 
Section 5 Study 
Procedures 
5.2 Baseline Visit, 
page 21 
A blood sample will be drawn 
at the baseline visit for a 
complete blood count (CBC) 
including differential white cell 
count.  In the event that a CBC 
is not available at baseline, 
laboratory results within 12 
months of baseline will be 
accepted. 
 
Added language to relax the 
timing required for a baseline 
CBC. This change increases 
the flexibility of study 
requirements and is 
consistent with the pragmatic 
design. 
8 
Table 1: Time and 
Events Schedule, 
page 36 
 
CBC (Baseline Blood 
Eosinophil Count Required)2 
 
2In the event that a CBC is not 
available at baseline, laboratory 
results within 12 months of 
baseline will be accepted. 
 
Added footnote to relax the 
timing required for a baseline 
CBC. This change increases 
the flexibility of study 
requirements and is 
consistent with the pragmatic 
design, and consistent with 
changes #3 and #7 in Study 
Procedures above. 
 
9 
Table 1: Time and 
Events Schedule, 
page 36 
 
Selected AEs23 
SAEs23 
 
23All SAEs and selected AEs 
will be collected from Baseline 
through EOS or early 
termination of study 
Updated footnote numbering 
to accommodate addition of 
footnote in change #8. 
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Protocol No. 1237-0064 
 
Version 2.0 May 9, 2018 
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41 
 
participation.  Selected AEs are 
AEs leading to study treatment 
discontinuation, dose 
modification or trial 
withdrawal. 
 
 
 
Doc. No.: c23740530-01

 
 
 
 
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