Comparison of Exacerbation Risk and Health Outcomes in Maintenance Treatment naïve Chronic Obstructive Pulmonary Disease (COPD) Patients Using Stiolto Versus Trelegy, a Real-World Study
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
ABCD 
 
 
 
 
 
 
Non-Interventional Study (NIS) Protocol 
 
Document Number: 
c38026921-01 
BI Study Number: 
1237-0121 
BI Investigational 
Product(s): 
Tiotropium bromide + Olodaterol 
Title: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy. 
Brief lay title: 
Outcomes in COPD patients using Stiolto Respimat vs. Trelegy 
Ellipta. 
Protocol version 
identifier: 
1.0 
Date of last version of 
protocol: 
10/25/2021 
PASS: 
No 
EU PAS register 
number: 
Study not registered 
Active substance: 
Tiotropium and Olodaterol 
Medicinal product: 
Stiolto® Respimat® 
Product reference: 
Not applicable 
Procedure number: 
Not applicable 
Marketing 
authorization holder(s): 
Not applicable 
Joint PASS: 
No 
Research question and 
objectives: 
Primary objective: 
• To characterize the COPD patient population who 
are maintenance treatment naïve and initiated Trelegy 
or Stiolto as the first line therapy. 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 2 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
• To compare the effectiveness of Stiolto 
(new treatment initiation) with Trelegy 
(new treatment initiation) for time to the first 
COPD exacerbation (moderate/severe) in COPD 
patients who are maintenance treatment naïve. 
 
• To compare COPD exacerbations following 
initiation of Stiolto (new treatment initiation) 
with initiation of Trelegy (new treatment 
initiation) 
Secondary objectives: 
• To compare the effectiveness of Stiolto 
(new treatment initiation) with Trelegy 
(new treatment initiation) for time to the first 
hospitalization of community acquired pneumonia in 
COPD patients who are maintenance treatment naïve. 
• To assess differences between Stiolto vs Trelegy in, 
“all-cause” and “COPD and/or pneumonia-related”, 
HCRU and HCRU cost (total population and sub-groups 
by care setting). 
Country(-ies) of study: 
United States 
Author: 
Address: 
 
Tel.: +
 
Marketing authorisation 
holder(s): 
Address: 
 
Tel.: +
 
In case of PASS, add: 
MAH contact person: 
Not applicable as it is not a PASS study 
In case of PASS, add: 
<EU-QPPV:> 
Not applicable as it is not a PASS study 
In case of PASS, add: 
<Signature of EU- 
QPPV:> 
Not applicable as it is not a PASS study 
Date: 
10/25/2021 
Page 1 of 47 
Proprietary confidential information 
© 2022 Boehringer Ingelheim Group of 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 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 3 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
TITLE PAGE 
1. TABLE OF CONTENTS 
TITLE PAGE ................................................................................................ 1 
1. 
TABLE OF CONTENTS ....................................................................................... 3 
2. 
LIST OF ABBREVIATIONS ................................................................................ 5 
3. 
RESPONSIBLE PARTIES .................................................................................... 6 
4. 
ABSTRACT ........................................................................................................... 7 
5. 
AMENDMENTS AND UPDATES ..................................................................... 15 
6. 
MILESTONES ..................................................................................................... 16 
7. 
RATIONALE AND BACKGROUND ................................................................ 16 
8. 
RESEARCH QUESTION AND OBJECTIVES ................................................. 18 
9. 
RESEARCH METHODS .................................................................................... 18 
9.1 
STUDY DESIGN… ....................................................................................... 18 
9.2 
SETTING ........................................................................................................ 20 
9.2.1 
Study sites ............................................................................................... 20 
9.2.2 
Study Population .................................................................................... 20 
9.2.3 
Study Visits ............................................................................................ 22 
9.2.4 
Study Discontinuation ............................................................................ 22 
9.3 
VARIABLES ................................................................................................. 22 
9.3.1 
Exposures ............................................................................................... 27 
9.3.2 
Outcomes ................................................................................................ 28 
9.3.2.1 
Primary Outcomes ........................................................................... 28 
9.3.2.2 
Secondary Outcome(s) .................................................................... 28 
9.3.3 
Covariates ............................................................................................... 29 
9.4 
DATA SOURCES ........................................................................................... 30 
9.5 
STUDY SIZE ................................................................................................. 31 
9.6 
DATA MANAGEMENT ................................................................................ 31 
9.7 
DATA ANALYSIS ......................................................................................... 32 
9.7.1 
Main analysis .......................................................................................... 32 
9.7.3 
Safety Analysis ........................................................................................ 34 
9.8 
QUALITY CONTROL .................................................................................. 34 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ..................................... 35 
 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 4 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
9.10 
OTHER ASPECTS ........................................................................................ 36 
10 
PROTECTION OF HUMAN SUBJECTS .......................................................... 36 
10.1 
 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT  ..................................................................................................... 36 
10.2 
STATEMENT OF CONFIDENTIALITY ...................................................... 36 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ....................................................................................................... 36 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
............................................................................................................................. 37 
13. 
REFERENCES .................................................................................................... 37 
13.1 PUBLISHED REFERENCES ........................................................................... 37 
13.2 UNPUBLISHED REFERENCES ..................................................................... 39 
APPENDIX 1: CODE LISTS ....................................................................................... 40 
APPENDIX 2: COPD-RELATED RESPIRATORY MEDICATIONS AND CLASSES40 
APPENDIX 3: COPD GUIDELINE-RECOMMEND ANTIBIOTIC MEDICATIONS42 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 44 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS............................... 44 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 44 
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES ................................... 44 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 5 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
 
2. LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special interest 
CA 
Competent Authority 
CCDS 
Company Core Data Sheet 
CI 
Confidence Interval 
CML 
Local Clinical Monitor 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
Clinical Trial Protocol 
eCRF 
Electronic Case Report Form 
ENCePP 
European Network of Centers for Pharmacoepidemiology and 
Pharmacovigilance 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEP 
Good Epidemiological Practice 
GPP 
Good Pharmacoepidemiology Practice 
GVP 
Good Pharmacovigilance Practices 
IB 
Investigator’s Brochure 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MAH 
Marketing Authorization Holder 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIS 
Non-Interventional Study 
PASS 
Post-Authorization Safety Study 
SAE 
Serious Adverse Event 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 6 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
 
 
 
 
3. RESPONSIBLE PARTIES 
NIS
: 
Address: 
 
Tel.: +
 
 
BI Team 
Address: 
 
Tel.: +
 
 
 Team: 
and
External Scientific Experts: 
and
 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 7 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
4. ABSTRACT 
 
 
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
25 October 2021 
Study 
number: 
1237.0121 
Version/Revision: 
1.0 
Version/Revision date: 
N/A 
Title of study: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy. 
Rationale and 
background: 
Chronic obstructive pulmonary disease (COPD) is a leading cause of 
morbidity and mortality throughout the world.1 COPD has risen to 
become the third leading cause of death in the United States (US). 2,3 
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 
2020 report and the American Thoracic Society 2020 report 
recommends dual bronchodilator therapy (DBT) with long-acting 
muscarinic antagonists (LAMAs) plus long-acting beta2-agonists 
(LABAs) for patients with COPD who have persistent symptoms 
and/or exacerbations on LAMA or LABA monotherapy. 4,5 
Consideration of escalation to triple therapy (TT; 
LAMA+LABA+inhaled corticosteroids [ICS]) is recommended in 
case of further exacerbation (≥2 moderate exacerbations or 1 severe 
exacerbation) and after assessing the risks/benefits. An important 
consideration is the trade-off between preventing exacerbations and 
the increased risk of pneumonia associated with addition of ICSs. 6 
There are recommendations to restrict TT use further, to only patients 
who are likely to respond to ICS (such as ≥2 moderate exacerbations 
or 1 severe exacerbation in the previous year, to those with asthma- 
COPD overlap or elevated blood eosinophils. 7 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 8 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
25 October 2021 
Study 
number: 
1237.0121 
Version/Revision: 
1.0 
Version/Revision date: 
N/A 
Title of study: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy. 
Rationale and 
background: 
Several trials compared a single-inhaler fixed dose combination 
(FDC) TT with an open combination of TT (ICS/LABA plus LAMA) 
respectively and found a small degree of greater benefit with FDC TT. 
8 Several Randomized Controlled Trials (RCTs) assessing the 
comparison of DBT LAMA-LABA to TT FDC of LAMA-LABA-ICS 
inhalers reported fewer exacerbations over one year with TT FDC. 
9,10,11 However, these findings are complicated by methodologic 
issues related to the withdrawal of maintenance treatment at 
randomization, inclusion of patients with history of asthma and 
around at least 40% -70% utilizing ICS before entering the clinical 
trials. 12, 13,14 TT is associated with 53% greater risk of pneumonia 
compared to DBT and is frequently used inappropriately, including 
overuse in certain COPD patients. 15,16,17,18,19 Approximately 13% - 
15% of maintenance treatment naïve patients are prescribed FDC TT 
as first line long-acting maintenance medication (Data on File) 
contradicting guideline recommendations and irrespective of the 
safety concerns. We believe a major reason of that practice pattern is 
just out of convenience as FDC TT are now available in the market. 
and certain pharmaceutical companies are encouraging early 
prescribing of triple therapy, including amongst primary care 
physicians. Any deviation in pharmacological management, 
particularly maintenance treatment initiation of COPD patients that is 
different from GOLD 2020 or ATS 2020 strategy document for the 
management of COPD may have both clinical and economic 
consequences. 20 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 9 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
25 October 2021 
Study 
number: 
1237.0121 
Version/Revision: 
1.0 
Version/Revision date: 
N/A 
Title of study: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy. 
Rationale and 
background: 
Given the high-cost side effect associated with long-term use of ICS 
and inconsistent evidence concerning whether there is a clinically 
relevant benefit of ICS combination therapy in terms of COPD disease 
control, it is important to assess differences between subsets of COPD 
patients in terms of the effectiveness and cost of FDC TT versus other 
non-ICS options, such as FDC DBT (e.g., Tiotropium+Olodaterol). 
In view of all the above findings which represent a limited view of the 
patients who could potentially use these FDC TT treatments we intend 
to conduct an observational study in a real-world clinical practice 
setting. There is a clear unmet need for better evidence on specific 
patient populations upon which to base FDC TT treatment 
recommendations. We propose to assess the effectiveness of Trelegy 
Ellipta, a FDC TT and compare it with Stiolto, a FDC DBT in patients 
who are maintenance treatment naïve and measure the incidence of 
COPD exacerbation, the incidence of community acquired 
pneumonia, health care resource utilization (HCRU) and associated 
HCRU costs. 
Trelegy Ellipta is a FDC of TT (Fluticasone Furoate + Umeclidinium 
+ Vilanterol, 100/62.5/25 mcg) approved by the FDA in September 
2017 for once-daily, maintenance treatment of COPD. Stiolto 
Respimat is a FDC of DBT (tiotropium bromide + olodaterol, 5/5 
mcg), approved by FDA in May 2015 for once-daily, maintenance 
treatment of COPD). 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 10 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
25 October 2021 
Study 
number: 
1237.0121 
Version/Revision: 
1.0 
Version/Revision date: 
N/A 
Title of study: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy. 
Research question 
and objectives: 
The goal of this study is to investigate the risk of COPD 
exacerbations, community acquired pneumonia, and health care 
utilization in maintenance treatment naïve patients treated as first line 
therapy with Fixed Dose Combination (FDC) of Tiotropium + 
Olodaterol (Stiolto, 5/5 mcg), in comparison to maintenance treatment 
naïve patients treated with first line therapy, FDC of Fluticasone 
Furoate + Umeclidinium + Vilanterol (Trelegy, 100/62.5/25 mcg). 
Primary objective: 
▪ To characterize the COPD patient population who are 
maintenance treatment naïve and initiated Trelegy or Stiolto as 
the first line therapy. 
▪ To compare the effectiveness of Stiolto (new treatment 
initiation) with Trelegy (new treatment initiation) for time to 
the first COPD exacerbation (moderate/severe) in COPD 
patients who are maintenance treatment naïve. 
 
▪ To compare COPD exacerbations following initiation of 
Stiolto (new treatment initiation) with initiation of Trelegy 
(new treatment initiation) 
 
Secondary objectives: 
▪ To compare the effectiveness of Stiolto (new treatment 
initiation) with Trelegy (new treatment initiation) for time to 
the first hospitalization of community acquired pneumonia 
in COPD patients who are maintenance treatment naïve 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 11 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
25 October 2021 
Study 
number: 
1237.0121 
Version/Revision: 
1.0 
Version/Revision date: 
N/A 
Title of study: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy. 
Study design 
This is a non-interventional study with existing data. It will be a 
retrospective, observational, non-interventional, new user design, real 
world study of Commercial Insurance and Medicare beneficiaries, 
using administrative claims data for the period of 15th September 
2016 through 31st March 2020. 
Patients initiating Stiolto, or Trelegy will be identified using 
pharmacy claims (
 database). The date of the first prescription 
claim (on or after 15th September 2017) will be defined as the index 
date. Patients will be required to have a diagnosis of COPD (ICD-9- 
CM: 491.xx, 492.xx, 496.xx; ICD-10-CM: J41-J44) on two separate 
medical claims. Patients 40 years or older will be included in the 
study. Patients will be required to have continuous enrolment for 12 
months prior to the index date. Patients will be excluded if they show 
any use of COPD maintenance medications (ICS, LABA or LAMA in 
any combination), during the baseline period of six months pre-index 
date. This will satisfy the criteria for being considered as treatment 
naive. Patients with two separate medical claims with a diagnosis of 
asthma, lung cancer, interstitial lung disease, or cystic fibrosis during 
the study period will be excluded. Using propensity score matching 
(PSM) technique, we will develop matched cohorts of patients 
between Stiolto initiators and Trelegy initiators. We will conduct 1:1 
matching using nearest neighbor matching approach. Exacerbation 
will be defined as a COPD hospitalization (severe exacerbation) or 
Emergency Department (ED) visit (severe exacerbation) with COPD, 
or use of approved respiratory antibiotics (e.g., Azithromycin) ± Oral 
CorticoSteroids (OCS) medications within ±7 days of the 
office/outpatient visit (moderate exacerbation) as the primary 
diagnosis. Multiple exacerbations occurring within 14 days of each 
other will be considered as a single exacerbation and will be per the 
higher severity. 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 12 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
25 October 2021 
Study 
number: 
1237.0121 
Version/Revision: 
1.0 
Version/Revision date: 
N/A 
Title of study: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy. 
Population: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy.Inclusion Criteria: 
1. ≥40 years of age as of the year of the index date 
2. At least one pharmacy claim for Stiolto Respimat or Trelegy 
Ellipta between 15 September 2017 and 31st March 2020. 
a. For Stiolto Respimat users, the first pharmacy claim of 
FDC of Tiotropium + Olodaterol (5/5 mcg) will be 
defined as the index date. 
b. For Trelegy Ellipta users, the first pharmacy claim of 
FDC of Fluticasone Furoate + Umeclidinium + 
Vilanterol (100/62.5/25 mcg), will be defined as the 
index date. 
3. Two medical claims (at least one claim on index date or before 
in the baseline period) with an ICD-9/10 diagnosis code(s) for 
COPD in any position during the study period (baseline ± post 
index date). 
4. At least one year of continuous medical and pharmacy health 
plan eligibility prior to the index date is required (to allow a 
baseline period for the covariates and characterizing the study 
population). 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 13 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
25 October 2021 
Study 
number: 
1237.0121 
Version/Revision: 
1.0 
Version/Revision date: 
N/A 
Title of study: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy. 
Population: 
Exclusion Criteria: 
1. To increase the likelihood of a true diagnosis of COPD, we 
will exclude all patients with two medical claims of asthma, 
cystic fibrosis, lung cancer, or interstitial lung disease in any 
position on separate dates of service during the study period. 
2. To restrict the cohort to first line maintenance therapy of 
Stiolto Respimat or first line maintenance therapy of Trelegy 
Ellipta we will exclude; patients on LAMA. monotherapy; 
LABA monotherapy; ICS monotherapy; free or FDC of 
ICS+LABA, LAMA+LABA, ICS+LABA+LAMA therapy 
within six months prior to index date. 
3. Pharmacy claims for multiple index medications on the index 
date. 
4. Pharmacy claims for non-index COPD maintenance 
medications on the index date. 
Variables: 
Moderate and Severe COPD exacerbation, Pneumonia (time to and 
counts), HCRU for COPD and Pneumonia; both related and 
attributable costs. 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 14 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
25 October 2021 
Study 
number: 
1237.0121 
Version/Revision: 
1.0 
Version/Revision date: 
N/A 
Title of study: 
Comparison of Exacerbation Risk and Health Outcomes in 
Maintenance Treatment Naïve COPD patients using Stiolto vs. 
Trelegy. 
Data sources: 
We will utilize medical and pharmacy claim records for COPD 
patients included in the 
 database (previously named 
 
 This database contains administrative insurance data and 
enrolment information derived from approximately 150 million 
commercially insured and Medicare lives. This longitudinal database 
allows documentation and analysis of the patient journey from 
diagnosis to intervention and follow-up. It is nationally representative 
covering 90% of US hospitals and compliant with current HIPAA 
(Health Insurance Portability and Accountability Act) regulations. 
Study size: 
~3000 patients in each cohort are sufficient for ≥80% power of 
Data analysis: 
Summary measures will include standard descriptive statistics (e.g., 
mean, standard deviation, median and range for continuous variables; 
counts and percentages for categorical variables). 
Milestones: 
Data collection will begin in Nov 2021, interim results will be 
available in Dec 2021, data collection will end in Dec 2021, and the 
final report will be completed and be made available in Jan 2022. 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 15 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
 
 
 
 
 
None 
5. AMENDMENTS AND UPDATES 
 
Number 
Date 
Section of 
study 
protocol 
Amendment or 
update 
Reason 
1 
2 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 16 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
6. MILESTONES 
 
 
Milestone 
Planned Date 
Start of data collection 
NOV 2021 
End of data collection 
DEC 2021 
<Registration in the EU 
PAS register> 
NOV 2021 
Final report of study results: 
FEB 2022 
 
 
7. 
RATIONALE AND BACKGROUND 
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality 
throughout the world.1 COPD has risen to become the third leading cause of death in the 
United States (US). 2,3 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 
2020 report and the American Thoracic Society 2020 report recommends dual bronchodilator 
therapy (DBT) with long-acting muscarinic antagonists (LAMAs) plus long-acting beta2- 
agonists (LABAs) for patients with COPD who have persistent symptoms and/or 
exacerbations on LAMA or LABA monotherapy. 4,5 Consideration of escalation to triple 
therapy (TT; LAMA+LABA+inhaled corticosteroids [ICS]) is recommended in case of 
further exacerbation (≥2 moderate exacerbations or 1 severe exacerbation) and after assessing 
the risks/benefits. An important consideration is the trade-off between preventing 
exacerbations and the increased risk of pneumonia associated with addition of ICSs. 6 There 
are recommendations to restrict TT use further, to only patients who are likely to respond to 
ICS (such as ≥2 moderate exacerbations or 1 severe exacerbation in the previous year, to 
those with asthma-COPD overlap or elevated blood eosinophils. 7 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 17 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
Several trials compared a single-inhaler fixed dose combination (FDC) TT with an open 
combination of TT (ICS/LABA plus LAMA) respectively and found a small degree of 
greater benefit with FDC TT. 8 Several Randomized Controlled Trials (RCTs) assessing the 
comparison of DBT LAMA-LABA to TT FDC of LAMA-LABA-ICS inhalers reported 
fewer exacerbations over one year with TT FDC. 9,10,11 However, these findings are 
complicated by methodologic issues related to the withdrawal of maintenance treatment at 
randomization, inclusion of patients with history of asthma and around at least 40% -70% 
utilizing ICS before entering the clinical trials. 12,13,14 TT is associated with 53% greater risk 
of pneumonia compared to DBT and is frequently used inappropriately, including overuse in 
certain COPD patients. 15,16,17,18,19 Approximately 13% -15% of maintenance treatment naïve 
patients are prescribed FDC TT as first line long-acting maintenance medication (Data on 
File) contradicting guideline recommendations and irrespective of the safety concerns. We 
believe a major reason of that practice pattern is just out of convenience as FDC TT are now 
available in the market. and certain pharmaceutical companies are encouraging early 
prescribing of triple therapy, including amongst primary care physicians. Any deviation in 
pharmacological management, particularly maintenance treatment initiation of COPD 
patients that is different from GOLD 2020 or ATS 2020 strategy document for the 
management of COPD may have both clinical and economic consequences.20 
 
Given the high-cost side effect associated with long-term use of ICS and inconsistent 
evidence concerning whether there is a clinically relevant benefit of ICS combination therapy 
in terms of COPD disease control, it is important to assess differences between subsets of 
COPD patients in terms of the effectiveness and cost of FDC TT versus other non-ICS 
options, such as FDC DBT (e.g., Tiotropium+Olodaterol). 
 
In view of all the above findings which represent a limited view of the patients who could 
potentially use these FDC TT treatments we intend to conduct an observational study in a 
real-world clinical practice setting. There is a clear unmet need for better evidence on specific 
patient populations upon which to base FDC TT treatment recommendations. We propose to 
assess the effectiveness of Trelegy Ellipta, a FDC TT and compare it with Stiolto, a FDC 
DBT in patients who are maintenance treatment naïve and measure the incidence of COPD 
exacerbation, the incidence of community acquired pneumonia, health care resource 
utilization (HCRU) and associated HCRU costs. 
 
Trelegy Ellipta is a FDC of TT (Fluticasone Furoate + Umeclidinium + Vilanterol, 
100/62.5/25 mcg) approved by the FDA in September 2017 for once-daily, maintenance 
treatment of COPD. Stiolto Respimat is a FDC of DBT (tiotropium bromide + olodaterol, 5/5 
mcg), approved by FDA in May 2015 for once-daily, maintenance treatment of COPD). 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 18 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
8. RESEARCH QUESTION AND OBJECTIVES 
The goal of this study is to investigate the risk of COPD exacerbations, community acquired 
pneumonia, and health care utilization in maintenance treatment naïve patients treated as first 
line therapy with Fixed Dose Combination (FDC) of Tiotropium + Olodaterol (Stiolto, 5/5 
mcg), in comparison to maintenance treatment naïve patients treated with first line therapy, 
FDC of Fluticasone Furoate + Umeclidinium + Vilanterol (Trelegy, 100/62.5/25 mcg). Primary 
and Secondary analyses will be conducted for the total population and
 
 
 
 
 
Primary objective: 
▪ To characterize the COPD patient population who are maintenance treatment naïve and 
initiated Trelegy or Stiolto as the first line therapy. 
 
▪ To compare the effectiveness of Stiolto (new treatment initiation) with Trelegy (new 
treatment initiation) for time to the first COPD exacerbation (moderate/severe) in 
COPD patients who are maintenance treatment naïve. 
 
▪ To compare COPD exacerbations following initiation of Stiolto (new treatment 
initiation) with initiation of Trelegy (new treatment initiation) 
 
Secondary objectives: 
▪ To compare the effectiveness of Stiolto (new treatment initiation) with Trelegy (new 
treatment initiation) for time to the first hospitalization of community acquired 
pneumonia in COPD patients who are maintenance treatment naïve. 
 
▪ To assess differences between Stiolto vs Trelegy in, “all-cause” and “COPD and/or 
pneumonia-related”, HCRU and HCRU cost (total population and sub-groups by care 
setting). 
 
9. 
RESEARCH METHODS 
9.1 
STUDY DESIGN 
 
This is a non-interventional study with existing data. It will be a retrospective, observational, 
non-interventional, new user design, real world study of Commercial Insurance and Medicare 
beneficiaries, using administrative claims data for the period of 15th September 2016 through 
31st March 2020. 
Patients initiating Stiolto, or Trelegy will be identified using pharmacy claims 
database). The date of the first prescription claim (on or after 15th September 2017) will be 
defined as the index date. Patients will be required to have a diagnosis of COPD (ICD-9-CM: 
491.xx, 492.xx, 496.xx; ICD-10-CM: J41-J44) on two separate medical claims. Patients 40 
years or older will be included in the study. Patients will be required to have continuous 
enrolment for 12 months prior to the index date. Patients will be excluded if they show any  
 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 19 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
use of COPD maintenance medications (ICS, LABA or LAMA in any combination), during 
the baseline period of six months pre-index date. This will satisfy the criteria for being 
considered as treatment naive. Patients with two separate medical claims with a diagnosis of 
asthma, lung cancer, interstitial lung disease, or cystic fibrosis during the study period will be 
excluded. Using propensity score matching (PSM) technique, we will develop matched 
cohorts of patients between Stiolto initiators and Trelegy initiators. We will conduct 1:1 
matching using nearest neighbour matching approach with a caliper of 0.2. Exacerbation will 
be defined as a COPD hospitalization (severe exacerbation) or Emergency Department (ED) 
visit (severe exacerbation) with COPD, or use of approved respiratory antibiotics (e.g., 
Azithromycin) ± Oral CorticoSteroids (OCS) medications within ±7 days of the 
office/outpatient visit (moderate exacerbation) as the primary diagnosis. Multiple 
exacerbations occurring within 14 days of each other will be considered as a single 
exacerbation and will be per the higher severity. A schematic of the study design is presented 
below in Figure 1. 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 20 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
Figure 1 
Study Design 
 
 
 
Patients will be followed the index date to record time to first incidence of exacerbations, 
record time to first incident case of pneumonia, and HCRU. The analysis will be, “on 
treatment”, analysis. Patients will be followed from the index date until the earliest of the first 
occurrence of outcome event, switch in index treatment (Stiolto or Trelegy), discontinuation 
of index treatment (Stiolto or Trelegy), the end of the study period, the end of continuous 
health plan eligibility, or (for main analyses) one year after index date. Hazard ratios and 
their 95% CI from proportional hazards models will be used to assess differences in the risk 
of COPD exacerbation and pneumonia. 
 
 
 
 
 
 
 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 21 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
 
9.2 
SETTING 
 
We will utilize medical and pharmacy claim records for COPD patients included in the 
 database (previously named 
). This database contains administrative 
insurance data and enrolment information derived from approximately 150 million 
commercially insured and Medicare lives. This longitudinal database allows documentation 
and analysis of the patient journey from diagnosis to intervention and follow-up. It is 
nationally representative covering 90% of US hospitals and compliant with current HIPAA 
(Health Insurance Portability and Accountability Act) regulations. 
 
9.2.1 
Study sites 
 
There are no specific trial sites in this study. We will utilize medical and pharmacy claim 
records for COPD patients included in the 
 database (previously named 
 
 This database contains administrative insurance data and enrolment information 
derived from approximately 150 million commercially insured and Medicare lives. This 
longitudinal database allows documentation and analysis of the patient journey from 
diagnosis to intervention and follow-up. It is nationally representative covering 90% of US 
hospitals and compliant with current HIPAA (Health Insurance Portability and 
Accountability Act) regulations. 
. 
 
9.2.2 
Study Population 
 
Patients initiating Stiolto, or Trelegy will be identified using pharmacy claims (
 
database). The date of the first prescription claim (on or after 15th September 2017) will be 
defined as the index date. Patients will be required to have a diagnosis of COPD (ICD-9-CM: 
491.xx, 492.xx, 496.xx; ICD-10-CM: J41-J44) on two separate medical claims. Patients 40 
years or older will be included in the study. Patients will be required to have continuous 
enrolment for 12 months prior to the index date. Patients will be excluded if they show any 
use of COPD maintenance medications (ICS, LABA or LAMA in any combination), during 
the baseline period of six months pre-index date. This will satisfy the criteria for being 
considered as treatment naive. Patients with two separate medical claims with a diagnosis of 
asthma, lung cancer, interstitial lung disease, or cystic fibrosis during the study period will be 
excluded. Using propensity score matching (PSM) technique, we will develop matched 
cohorts of patients between Stiolto initiators and Trelegy initiators. We will conduct 1:1 
matching using nearest neighbour matching approach with a caliper of 0.2. Exacerbation will 
be defined as a COPD hospitalization (severe exacerbation) or Emergency Department (ED) 
visit (severe exacerbation) with COPD, or use of approved respiratory antibiotics (e.g., 
Azithromycin) ± Oral CorticoSteroids (OCS) medications within ±7 days of the 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 22 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
office/outpatient visit (moderate exacerbation) as the primary diagnosis. Multiple 
exacerbations occurring within 14 days of each other will be considered as a single 
exacerbation and will be per the higher severity. 
 
Patients will be followed after the index date to record time to first incidence of 
exacerbations, record time to first incident case of pneumonia, and HCRU. The analysis will 
be, “on treatment”, analysis. Patients will be followed from the index date until the earliest of 
the first occurrence of outcome event, switch in index treatment (Stiolto or Trelegy), 
discontinuation of index treatment (Stiolto or Trelegy), the end of the study period, the end of 
continuous health plan eligibility, or (for main analyses) one year after index date. Hazard 
ratios and their 95% CI from proportional hazards models will be used to assess differences 
in the risk of COPD exacerbation and pneumonia. 
 
 
 
 
 
 
 
Inclusion Criteria: 
▪ ≥40 years of age as of the year of the index date 
▪ At least one pharmacy claim for Stiolto Respimat or Trelegy Ellipta between 15 
September 2017 and 31st March 2020. 
o For Stiolto Respimat users, the first pharmacy claim of FDC of Tiotropium + 
Olodaterol (5/5 mcg) will be defined as the index date. 
o For Trelegy Ellipta users, the first pharmacy claim of FDC of Fluticasone 
Furoate + Umeclidinium + Vilanterol (100/62.5/25 mcg), will be defined as 
the index date. 
▪ Two medical claims (at least one claim on index date or before in the baseline period) 
with an ICD-9/10 diagnosis code(s) for COPD in any position during the study period 
(baseline ± post index date). 
▪ At least one year of continuous medical and pharmacy health plan eligibility prior to 
the index date is required (to allow a baseline period for the covariates and 
characterizing the study population). 
 
 
Exclusion Criteria: 
▪ To increase the likelihood of a true diagnosis of COPD, we will exclude all patients 
with two medical claims of asthma, cystic fibrosis, lung cancer, or interstitial lung 
disease in any position on separate dates of service during the study period. 
▪ To restrict the cohort to first line maintenance therapy of Stiolto Respimat or first line 
maintenance therapy of Trelegy Ellipta we will exclude; patients on LAMA. 
monotherapy; LABA monotherapy; ICS monotherapy; free or FDC of ICS+LABA, 
LAMA+LABA, ICS+LABA+LAMA therapy within six months prior to index date. 
▪ Pharmacy claims for multiple index medications on the index date. 
▪ Pharmacy claims for non-index COPD maintenance medications on the index date. 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 23 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
9.2.3 Study Visits 
 
9.2.4 Study Discontinuation 
 
Boehringer Ingelheim reserves the right to discontinue the study overall or at any time for the 
following reasons: 
 
1. In the overall population, Stiolto initiators from September 2017 – March 2020 will be 
matched using Propensity Score Matching (PSM) with Trelegy initiators from September 
2017 – March 2020 on a prespecified list of covariates listed in section 10.2.2. to ensure 
that the two cohorts are well balanced (i.e., standardized difference ≤10%) across all 
characteristics. However, for any baseline characteristics with significant differences 
(Standardized differences (SD) greater than 0.10 (10%)) after PSM matching, these 
characteristics will be included as covariates in the regression models, or we will develop 
interaction terms to match on or discontinue the study if major channeling (SD>10%) is 
observed. 
 
2. Violation of Good Pharmacoepidemiology Practice (GPP), the study protocol, or the 
contract by a research collaborator, disturbing the appropriate conduct of the study 
 
 
The research collaborator will be reimbursed for reasonable expenses incurred in case of 
study termination (except in case of the second reason). 
 
9.3 
VARIABLES 
 
The definitions for exacerbations are as below. 
 
▪ A severe exacerbation will be defined as follows: 
o An inpatient admission or an ER visit with a COPD diagnosis code in the 
primary position; or 
o An inpatient admission or an ER visit with a diagnosis code for acute 
respiratory failure in the primary position and a COPD diagnosis code in any 
position; or 
o An inpatient admission or an ER visit with a diagnosis code for acute 
respiratory failure in the primary position + an inpatient admission or an ER 
visit within ±7 days with a COPD diagnosis code in any position. 
▪ A moderate exacerbation will be defined as follows: 
o An ambulatory (office or outpatient) visits with a COPD diagnosis code in any 
position + a pharmacy claim for an oral corticosteroid (OCS) prescription 
within ±7 days of the office/outpatient visit; or 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 24 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
o An office or outpatient visit with a COPD diagnosis code in any position + a 
pharmacy claim for respiratory antibiotic prescription within ±7 days of the 
office/outpatient visit; or 
o An office or outpatient visit with a COPD diagnosis code in any position + a 
pharmacy claim for an OCS + a pharmacy claim for respiratory antibiotic 
prescription within ±7 days of the office/outpatient visit. 
 
▪ Pneumonia diagnosis: Binary indicators will be created to identify patients with a 
diagnosis of 1) pneumonia (Appendix 1). The time to first pneumonia diagnosis, 
and time to first pneumonia, during follow-up will also be captured. 
▪ Pneumonia-related hospitalization: Binary indicators will be created to identify 
patients with an acute hospitalization with diagnosis of 1) pneumonia in any 
position (Appendix 1) The time to first pneumonia-related hospitalization during 
follow-up will also be captured. 
▪ COPD exacerbation and/or pneumonia diagnosis: Binary indicators will be 
created to identify patients with each of the following composite outcomes: severe 
COPD exacerbation or an acute hospitalization with a diagnosis of pneumonia in 
any position, severe COPD exacerbation or a hospitalization with a diagnosis of 
pneumonia in any position, any COPD exacerbation or pneumonia diagnosis in 
any position, and any COPD exacerbation or pneumonia diagnosis in any position. 
Time to event variables will be created for each composite outcome during the 
follow-up period. 
 
The following outcomes will be measured in the baseline and follow-up periods. The baseline 
period will include claims occurring on the index date, except for the index medication 
claims, which will be included in the follow-up period. 
 
▪ All-cause health care resource utilization: Indicator variables and counts of physician 
office visits, hospital outpatient visits, ED visits, “other” (non-inpatient) visits, inpatient 
stays, and pharmacy claims will be created. Other medical visits are a residual category 
that includes, but is not limited to, services rendered at independent laboratories, 
assisted living facilities, and by home health providers. An indicator variable will be 
created to identify inpatient stays with an acute stay during the inpatient admission. The 
length of inpatient stays will also be captured. The time to first inpatient stay, the time 
to first inpatient stay with an acute stay, and the time to first ED visit during follow-up 
will be captured. 
▪ COPD and/or pneumonia-related health care resource utilization: This utilization will 
be calculated analogously to all-cause utilization, but restricted to medical claims with 
a diagnosis for COPD and/or pneumonia, in any position (Appendix 1) and pharmacy 
claims for a COPD-related treatment (Appendix 2), including COPD-guideline 
recommended antibiotics (Appendix 3). 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 25 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
▪ COPD-related health care resource utilization: This utilization will be calculated 
analogously to all-cause utilization, but restricted to medical claims with a diagnosis 
for COPD in any position (Appendix 1) and pharmacy claims for a COPD-related 
treatment (Appendix 2), including COPD-guideline recommended antibiotics 
(Appendix 3) 
▪ Pneumonia-related health care resource utilization: This utilization will be calculated 
analogously to all-cause utilization but restricted to medical claims with a diagnosis for 
pneumonia in any position (Appendix 1). 
▪ COPD or pneumonia-attributable health care resource utilization: This utilization will 
be calculated analogously to all-cause utilization, but restricted to medical claims with 
a diagnosis for COPD or pneumonia in the primary position or a diagnosis for acute 
respiratory failure in the primary position and a diagnosis for COPD or pneumonia in a 
non-primary position (Appendix 1) and pharmacy claims for a COPD-related treatment 
(Appendix 2), including COPD-guideline recommended antibiotics (Appendix 3) 
▪ All-cause health care costs (insurer + patient paid amounts): Health care costs will be 
computed from the payer and patient perspective together. This is the actual amount 
paid to the provider by the health plan plus the patient co-pay and/or coinsurance 
amounts, rather than an estimated cost. Total costs will be calculated and presented as 
the combined pharmacy costs and medical costs. Medical costs will be presented and 
will include sub-categories of physician office costs, hospital outpatient costs, 
emergency services costs, inpatient costs, and other costs. 
o Costs will be adjusted to 2019 dollars using the medical care component of the 
Consumer Price Index (CPI) to reflect inflation between the date of the claim 
and 2019.22 The final report will include additional columns with the latest 
available 2020 mid-year CPI adjustment applied to costs for scaling the results 
as needed. 22 
o Costs from other payers may be important, particularly for studies involving 
older patients dually eligible for commercial and Medicare coverage. In 
consultation with 
 this study will NOT incorporate the amounts estimated 
to be paid by other payers for a total paid or allowable amount. 23 
▪ COPD and/or pneumonia-related health care costs (insurer + patient paid amounts): 
These costs will be calculated analogously to the all-cause costs, but restricted to 
medical 
claims 
with 
a 
diagnosis 
for 
COPD, 
pneumonia, 
or 
acute 
bronchitis/bronchiolitis in any position (Appendix 1) and pharmacy claims for a COPD- 
related treatment (Appendix 2), including COPD-guideline recommended antibiotics 
(Appendix 3). 
▪ COPD-related health care costs (insurer + patient paid amounts): These costs will be 
calculated analogously to the all-cause costs, but restricted to medical claims with a 
diagnosis for COPD in any position (Appendix 1) and pharmacy claims for a COPD- 
related treatment (Appendix 2), including COPD-guideline recommended antibiotics 
(Appendix 3). 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 26 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
▪ Pneumonia-related health care costs (insurer + patient paid amounts): These costs will 
be calculated analogously to the all-cause costs but restricted to medical claims with a 
diagnosis for pneumonia in any position (Appendix 1). 
▪ COPD or pneumonia-attributable health care costs (insurer + patient paid amounts): 
These costs will be calculated analogously to the all-cause costs, but restricted to 
medical claims with a diagnosis for COPD or pneumonia in the primary position or a 
diagnosis for acute respiratory failure in the primary position and a diagnosis for COPD 
or pneumonia in a non-primary position (Appendix 1) or pharmacy claims for a COPD- 
related treatment (Appendix 2), including COPD-guideline recommended antibiotics 
(Appendix 3). 
 
 
Clinical characteristics will be measured in the baseline period. The baseline period will 
include claims occurring on the index date, except for the index medication claims, which 
will be included in the follow-up period. 
▪ Quan-Charlson comorbidity score: A comorbidity score will be calculated based on the 
presence of diagnosis codes (in any position) on medical claims in the baseline period. 
24,25,26 The score is calculated based on a weighted sum of 12 comorbid conditions. The 
score represents the cumulative likelihood of one-year mortality and serves as a proxy 
for comorbidity burden. The Quan-Charlson comorbidity score also will be categorized 
into the following groups: zero, one, two, three, four, and five or more. 
▪ Oxygen therapy: Evidence of oxygen use will be captured in the baseline period based 
on diagnosis (ICD-9, ICD-10), procedure (HCPCS, CPT, ICD-9) and revenue codes for 
oxygen therapy (Appendix 1). 
▪ Baseline respiratory medication utilization: Indicator variables for respiratory 
medication classes and selected individual respiratory medications will be based on 
both pharmacy and medical claims (nebulizer treatments may appear in medical 
claims). Medication classes will include: LAMAs (alone; overall and separately), 
LABAs (alone), ICS (alone), ICS/LABA single inhaler combination medications, 
SAMAs (alone), SABAs (alone), SAMA/SABA single inhaler combination 
medications, any rescue (SAMA alone, SABA alone, or SAMA/SABA single inhaler 
combination medications), methylxanthines, phosphodiesterase-4 (PDE-4) inhibitors 
and oral corticosteroids (OCS). Baseline medication use variables will exclude claims 
which make up the index therapy assignment. Number of fills by class will also be 
captured. Indicator variables will be created to identify patients who are naïve to long- 
acting bronchodilators (free or fixed dose LAMAs or LABAs) and to long-acting 
bronchodilators plus inhaled corticosteroids (free or fixed dose LAMAs, LABAs, and 
ICSs) at index. 
▪ Index provider specialty: The specialty of the provider on the index prescription fill will 
be captured. If no provider specialty is recorded on the index prescription fill, the 
provider specialty from the most recent COPD-related visit on or prior to the index date 
will be captured. An indicator variable will identify if the provider specialty was 
determined from the index pharmacy claim. Provider specialty will be classified as one 
of the following: pulmonology, primary care [family practice, general practice, and 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 27 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
geriatrics], internal medicine, allied health professional, cardiology, other specialty, and 
unknown specialty. If claims for more than one provider occur on the date used to 
classify the provider’s specialty, the hierarchy of categories listed above will be used to 
pick a single provider specialty. 
▪ Pulmonology visits within 30 days of index date: An indicator variable will be created 
to identify patients with a pulmonologist visit within 30 days prior to and excluding the 
index date. 
▪ Spirometry testing: If available, indicator and count variables will be created to identify 
patients with lung function testing (Appendix 1). A count of spirometry tests during the 
baseline period will be created. Multiple spirometry tests within a 30-day period will 
be counted as one test. 
Patient characteristics will be measured as of the index date, or the first available claim after 
the index date with valid values for each of the characteristics. It may be necessary to modify 
or remove some variables or analytic table templates to preclude identification of individual 
patients and protect proprietary health plan information. 
▪ Index year: The year of the patient’s index date will be identified. 
▪ Seasonality: The month of the patient’s index date will be identified and classified as 
fall (September, October, November), winter (December, January, February), spring 
(March, April, May), or summer (June, July, August). 
▪ Age: Age will be defined as of the index year 
▪ Age groups: Patients will be assigned to one of the following age groups: 40-44, 45-49, 
50-54, 55-59, 60-64, 65-69, 70-74, 75-79 and 80+ 
▪ Gender: Gender will be captured from enrolment data; patients with undefined gender 
will be removed from the study sample 
▪ Race/ethnicity: Race/ethnicity information will be captured if available in the 
 
database, no further linking with any additional consumer sociodemographic data will 
be attempted, but if data is available it will be categorized as follows: White, African 
American/Black, Asian, Hispanic, or unknown (unknown includes missing). This 
variable depends on the availability of data and will be missing for some or all patients. 
▪ Insurance type: Whether the patient was covered under a commercial or Medicare 
Advantage health plan will be captured 
▪ Plan type: Plan type will be categorized as Exclusive Provider Organization (EPO), 
Health Maintenance Organization (HMO), Point of Service (POS), Preferred Provider 
Organization (PPO), Individual and Other 
▪ Geographic region: The US region in which the study patient is enrolled in a health plan 
will be determined and reported and states will be categorized into five geographic 
regions in accordance with the US Census Bureau’s region designations; the four health 
plan regions are presented in the table 1 below. Patients categorized into “other” will 
be excluded from the study. 

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
Page 28 of 47 
 
 
 
 
 
Table 1 
Health Plan Regions 
 
Region 
State 
Northeast 
CT, MA, ME, NH, RI, VT, NJ, NY, PA 
Midwest 
IL, IN, MI, OH, WI, IA, KS, MN, MO, ND, NE, SD 
South 
DC, DE, FL, GA, MD, NC, SC, VA, WV, AL, KY, MS, TN, 
AR, LA, OK, TX 
West 
AZ, CO, ID, MT, NM, NV, UT, WY, AK, CA, HI, OR, WA
 
 
9.3.1 
 Exposures 
 
Patients will be assigned to one of the following mutually exclusive study cohorts based on 
the index pharmacy claim: Stiolto Respimat or Trelegy Ellipta. Exposure measures will be 
based on pharmacy dispensing of the two medications under study, namely Stiolto Respimat 
or Trelegy Ellipta, over a follow-up period, beginning the index date and lasting up to one 
year from index date. Discontinuation for index medication will be defined as a gap in index 
medication of ≥45 days (sensitivity analysis with ≥30 days can be included) following the 
runout of days’ supply (discontinuation date = runout prior to the gap in therapy). Switch in 
index medication will be defined as a pharmacy fill for ≥30 consecutive days of a non-index 
maintenance medication (switch date = first date of the new treatment regimen). Switch 
includes any other change in use of index medication by active ingredient, inclusive of a 
change to a different combination therapy (ICS/LABA FDC, different LAMA/LABA or 
LAMA/LABA/ICS FDC) change from a FDC to a free form combination therapy with mono 
LAMA plus mono LABA, or mono ICS plus mono LABA, or mono LAMA plus mono 
LABA plus mono ICS or a change to a monotherapy. 
 
Individuals in the study cohort will be followed from the index date until the earliest of the 
date of a switch in treatment, addition of an ICS for the Stiolto Respimat group, 
discontinuation of the index COPD maintenance treatment, the end of the study period, or the 
end of continuous health plan eligibility. Main analyses will be further limited to the first 12 
months after index date, with sensitivity analyses considering all available data. 
 
All patients will be required to be continuously enrolled in the health plan for a minimum of 
12 months. The 12 months prior to and including the index date (index date – 364 through 
index date) will be used to assess baseline characteristics. The period starting the day after the 
index date, up to a maximum of 12 months duration (index date +1 through index date +365) 
will be used to assess exacerbation, pneumonia, HCRU and cost outcomes. Patients will be 
censored at the earliest of the following: discontinuation of the index medication (Stiolto or 
Trelegy), switch to a non-index medication, disenrollment from the health plan, 12-months 
following the index date, or the end of the study period. 

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
Page 29 of 47 
 
 
 
 
 
 
9.3.2 
Outcomes 
 
 
9.3.2.1 
Primary Outcomes 
 
 
The primary outcome event for effectiveness is time to first COPD exacerbation after cohort 
entry. The event is defined as follows: 
 
▪ Severe exacerbation: 
o Hospitalization with a principal discharge diagnosis of COPD and/or 
o An emergency department (ED) visit with a discharge diagnosis of COPD 
o An inpatient admission or an ER visit with a diagnosis code for acute 
respiratory failure in the primary position and a COPD diagnosis code in any 
position 
 
▪ Moderate exacerbation: 
o An antibiotic for a respiratory condition dispensed ± an OCS 
 
Time to the first COPD exacerbation will be measured from index date until the occurrence 
of a hospitalization for COPD (severe exacerbation) or ED visit for COPD (severe 
exacerbation) or prescription of an antibiotic ± an OCS on the same day (moderate 
exacerbation). Severe and moderate exacerbations were considered as a composite for main 
analyses. Sensitivity analyses will include stratification by exacerbation severity. 
 
Exacerbations will be categorized as moderate or severe and a count of any (severe or 
moderate), severe, and moderate will be provided.  
 
9.3.2.2  
Secondary Outcome(s) 
 
The secondary outcome is time to first hospitalization for community-acquired pneumonia 
(serious pneumonia). Pneumonia was defined using ICD-9-CM diagnoses 481.x-486.x; 
487.0, 507.x, 507.0, 507.1, 507.8, 510.0, 510.9, 511.0, 513.0, 514.x, 517.1, 519.8, 530.84, 
and ICD-10 diagnosis codes J10.0; J11.0; J12-J18; J22; J69; J85.0; J85.1; J86. This 
definition has been previously used in COPD. 27,28 
• COPD and/or pneumonia related HCRU (including acute inpatient stays and their 
length of stay, emergency department visits, ambulatory [Physician office visits, 
hospital outpatient visits], and other medical visits) 
• COPD-related HCRU 
• Pneumonia-related HCRU 
• COPD-attributable HCRU 
• All-cause HCRU 

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
Page 30 of 47 
 
 
 
 
HCRU is defined as total inpatient, emergency department, and outpatient care episodes. 
Estimates will be presented both overall and for COPD and/or pneumonia-related care, 
defined as claims where a diagnosis of COPD or pneumonia is present. Medications used, 
defined as total number of distinct medication subclasses dispensed (e.g., 4-digit level of the 
Generic Product Identifier) and total number of dispensing for medications per year. COPD- 
related medication utilization included all COPD medications, OCS, and guideline- 
recommended antibiotics 
 
Annual HCRU costs (including costs paid by the patient, health plan, and any third party via 
coordination of benefits) will be then calculated as total costs, medical costs, pharmacy costs, 
ambulatory costs, ED costs, inpatient costs, and other costs. Costs were defined as related to 
COPD if the claim has a diagnosis for COPD in any position or is a pharmacy claim for a 
medication used to treat COPD. The sum of all costs from all care settings and pharmacy 
dispensing will be assessed overall, for COPD and/or pneumonia-related care. 
 
9.3.3 Covariates 
 
Patient characteristics at baseline will be assessed for Stiolto and Trelegy users overall and 
stratified by history of exacerbation. 
 
The covariates included in the Propensity Score Matching (PSM) will include all the below 
covariates including the ones defined during the 12-month pre-index baseline period and 
chronic comorbid conditions. 
• Gender 
• Age group (years, categorical and a continuous variable) 
• Calendar year of cohort entry 
• Region 
• Insurance type (e.g., Commercial, Medicare) 
• Season of index date (winter, spring, summer, fall) 
 
Additional characteristics that will be defined during the 12-month pre-index baseline period: 
• Previous acute COPD exacerbation (measured both overall and in the 30 days prior to 
cohort entry), categorized as 0, 1, or ≥2. 
o All exacerbations (Moderate+Severe) 
o Hospitalizations (Severe) 
• Use of other respiratory drugs in the 12-month pre-index period: 
o Short-acting beta-agonists 
o Short-acting Anticholinergics 
o Methylxanthines 
o LAMA 
o LABA 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 31 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
o ICS 
o ICS/LABA 
• Use of antibiotics commonly prescribed for a respiratory condition (e.g., 
azithromycin) 
• Use of OCS 
• Oxygen Use 
• Pulmonary Rehabilitation 
 
Chronic comorbidities were defined using diagnoses identified during all available data prior 
to the index date, and included 
• Quan-Charlson Comorbidity Index score/individual comorbidities 
• Cardiovascular disease 
• Diabetes 
• Renal failure 
• GERD 
• Arthritis 
• Osteoporosis 
• Cancer (excluding basal cell carcinoma) 
• Baseline pneumonia diagnosis 
• Baseline acute bronchitis diagnosis 
• Diagnosis of dyspnea during baseline identified using ICD 9 786.0x and ICD 10 
R06.0x 
• Diagnosis of obesity during baseline identified using ICD 9 278.xx and ICD 10 
E66.xx 
• Diagnosis of alcohol dependence during baseline identified using ICD 9 303.xx, 
305.0x and ICD 10 F10.xx 
• Smoking dependence during baseline identified using ICD 9 305.1 and ICD 10 
F17.xx 
• Tobacco use or cessation counselling* 
 
*We anticipate limited capture of lifestyle variables known to be risk factors and potential 
confounders, including obesity, smoking status, and excessive alcohol consumption. 
 
 
 
 
 
 
9.4 
DATA SOURCES 
 
We will utilize medical and pharmacy claim records for COPD patients included in the 
 database (previously named 
).

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
Page 32 of 47 
 
 
 
9.5 
STUDY SIZE 
 
Considering the study design being non-interventional study with existing data, retrospective, 
new user design and treatments being: Stiolto Respimat (active treatment) vs. Trelegy Ellipta 
(comparator), primary endpoint of time to first exacerbation (moderate/severe) and COPD 
population being maintenance treatment naïve, we didn’t find any such study that exactly 
matches these criteria in literature. 
 
We looked at two retrospective, observational, non-interventional studies in the literature. 
Suissa et al published in Chest (CHEST 2020; 157(4):846-855) a real-world study of COPD 
treatment, the triple combination of LAMA, LABA, and ICS inhalers and compared its 
effectiveness to combining LAMA and LABA inhalers in preventing COPD exacerbations.23 
Suissa et al had a sample size of ~2000 patients on LAMA and LABA.23 They reported that 
the adjusted hazard ratio (HR) of a COPD exacerbation associated with LAMA-LABA-ICS 
initiation compared with LAMA-LABA initiation was 0.97 (95% CI, 0.87-1.08). For patients 
with blood eosinophil counts > 6%, the HR was 0.66 (95% CI, 0.46- 0.94). For patients with 
two or more prior exacerbations, it was 0.83 (95% CI, 0.70-0.98). 29 The incidence of severe 
pneumonia requiring hospitalization was increased with LAMA-LABA-ICS initiation (HR, 
1.46; 95% CI, 1.03-2.06). 29 The second study, by Palli et al compared health plan-paid costs, 
COPD exacerbations, and pneumonia diagnoses among patients newly treated with a LAMA 
+ LABA regimen composed of tiotropium (TIO) + olodaterol (OLO) in a fixed-dose 
combination inhaler (TIO + OLO) or TT in a U.S. Medicare Advantage Part D insured 
population.24 This study was published in Journal of Managed Care & Specialty 
Pharmacy 2020 26:10, 1363-1374 and had a sample size of ~1500 patients on Stiolto.30 Palli 
et al reported longer time to first severe COPD exacerbation (P = 0.020) and first pneumonia 
diagnosis (P = 0.002) for TIO + OLO versus TT and a lower percentage of TIO + OLO 
patients experiencing these events (severe COPD exacerbation: 9.0% vs. 16.1%; pneumonia: 
14.5% vs. 19.3%).30 
 
Feasibility Assessment: Using 
 database we identified 15,538 and 35,686 patients who 
initiated first line treatment with Stiolto or Trelegy, respectively, between 15th September 
2017 and 31st March 2020. These patients had 12-months of baseline with both medical and 
pharmacy coverage. After applying the inclusion/ exclusion criteria the sample size is 
reduced to 3996 patients in the Stiolto group and 5121 in the Trelegy group and post PSM 
our final sample size is 3018 in each group, which gives sufficient power when compared to 
earlier studies (Suissa et al (~2000 patients with LAMA-LABA) and Palli et (~1500 patients 
per cohort) as mentioned above). Based on these two studies from the literature and the 
feasibility numbers for the current study we are confident that we will have enough patients 
to ensure ≥80% power. 
 
 

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
Page 33 of 47 
 
 
 
 
9.6 
DATA MANAGEMENT 
 
All established security and confidentiality procedures will be observed by BI and/or 
 personnel who are assigned appropriate access to the data. Enrolment 
data, medical claims, and prescription claims will be accessed from the administrative 
claims’ dataset. The analyses will be performed on limited data sets that are void of 
 
member protected health information and all results were shared in aggregate form 
only. 
 
9.7 
DATA ANALYSIS 
 
Summary measures will include standard descriptive statistics (e.g., mean, standard 
deviation, median and range for continuous variables; counts and percentages for categorical 
variables). However, for any baseline characteristics with significant differences 
(Standardized differences (SD) greater than 0.10 (10%)) after PSM matching, these 
characteristics will be included as covariates in the regression models, or we will develop 
interaction terms to match on or discontinue the study if major channeling (SD>10%) is 
observed. Basically, a two-step approach: The first step will be to characterize the patients 
after PS matching to see whether balance can be achieved (based on SD) and at least 2000 
patients from the Stiolto cohort can be matched with at least 2000 patients in the Trelegy 
cohort before proceeding to the second step of doing the comparative analysis. Sensitivity 
analyses may be performed on a select set of covariates considered to be prognostic factors. 
In the event of study discontinuation, partial results (all analysis leading up to and including 
PSM) will be provided in a final report. 
 
A Cox proportional hazards models will be used on the time to first COPD exacerbation with 
treatment as a covariate. Comparisons will be made between treatment cohorts using HR and 
will be presented with associated 95% CI. To account for variable lengths of follow-up 
observation time, population annualized results will be provided (annualized costs [e.g., Sum 
of total costs/Sum of total follow-up patient years for each cohort]). The annualized cost may 
be modelled as dependent variable in a Generalized Linear Model with treatment cohort as a 
covariate and the follow-up patient years as an offset for each cohort. 
Comparisons will be made between treatment cohorts and will be presented with associated 
95% CI. Additionally, descriptive techniques that account for the length of observation time 
measure will be used appropriately. Per patient per month calculations will not be performed 
because of bias concerns. Appropriate tests comparing the Stiolto cohort and the Trelegy 
cohort (e.g., standardized differences, McNamara’s tests, paired t-tests, sign tests) will be 
used based on the distribution of the measure. Patients not matched will be excluded from the 
post-match analysis. 
 
9.7.1 
Main analysis 
 
Analyses will be presented comparing Stiolto vs Trelegy overall after PSM matching and 
stratified as follows if the sample size allows (at least 15% in each strata): 
• Low history of exacerbation: 0 inpatient (i.e., severe exacerbations) and 0-1 outpatient 
events (i.e., moderate exacerbations) 

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
Page 34 of 47 
 
 
 
 
• High history of exacerbation: ≥1 inpatient (i.e., severe exacerbations) or ≥2 outpatient 
events (includes ED) 
 
We will describe the formation of the study cohort. Patient characteristics at baseline in 
patients treated with Stiolto and patients treated with Trelegy will be assessed separately 
using standard descriptive statistics. 
 
Propensity scores including both pre-specified and data-derived variables will be then 
calculated. Balance of patient characteristics between the cohorts will be described before 
and after propensity score application and compared using standardized differences. For each 
Stiolto patient, a Trelegy patient with the closest available propensity score will be selected. 
Nearest neighbor matching method with a caliper of 0.2 will be utilized. Standardized 
differences greater than 0.10 (10%) will be taken to indicate imbalance, and these variables 
will also be included in outcome models, categorized as appropriate. 
 
For the analysis of the primary objective, a Cox proportional hazard regression model will be 
used to perform an as-treated analysis that assesses the effect of first line maintenance 
medication with Stiolto versus the first line maintenance medication with Trelegy on the time 
to first COPD exacerbation. This estimates the HR of a COPD exacerbation associated with 
Stiolto use relative to Trelegy use, along with 95% CI. Based on the days’ supply post index 
date, allowing a grace period of 45 days following the end of days’ supply to account for 
intermittent use. 
 
Stratified analyses will be using the same approach as the main analysis. Calculation of 
propensity scores will be repeated within the subset of the cohort with available results to 
create weighted populations suitable for these stratified analyses. 
 
The analysis of the secondary objective related to the risk of pneumonia will also be assessed 
using Cox proportional hazard regression models with an as-treated approach, like that of the 
primary analysis. 
 
In terms of HCRU, we will be presenting continuous and categorical variables using standard 
descriptive statistics to describe total visits and total costs related to inpatient, outpatient, and 
emergency care as well as distinct medications used, and pharmacy costs. Utilization and 
costs will be stratified to facilitate comparison between Stiolto and Trelegy and presented by 
individual setting and cost will also be presented as a composite. All-cause and COPD and/or 
pneumonia specific cost and utilization characteristics will be described separately. 
 

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
Page 35 of 47 
 
 
 
 
 
 
 
 
 
 
 
 
9.7.3 
Safety Analysis 
 
Data is anonymized and extracted, analyzed, validated, and reported in aggregate. There is no 
potential that any employee of BI or agent working on behalf of BI will access individual 
patient data where adverse events is identified during data compilation, data reporting or data 
analysis. 
 

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
Page 36 of 47 
 
 
 
 
9.8 
QUALITY CONTROL 
 
All programming will be quality controlled by two-step code checking by
 
. All results generated will be reviewed internally by two co-investigators 
separately prior to finalization. 
 
 develops study approaches of sound scientific design that meet 
clinically stringent review. Researchers develop detailed protocols that include 
definitions, codes, analyses, and table shells. The coding strategy is then reviewed by 
a clinical team member for validity and relevance to ensure potential outlying issues 
are identified and addressed. The protocol further provides 
 and 
 an 
opportunity to solidify research questions and address any potential gaps in 
information 
 incorporates meticulous quality assurance checks during data set 
construction to generate the most accurate data set. Our analysts perform record-level 
verification of all data elements, double-program certain portions of the data set, 
program data edit checks, visually review raw claims data against the constructed data 
elements and review the analysis to assess the validity of results. 
Results will be verified by the 
 and BI research team assigned to the 
study. 
 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 37 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
9.9 
LIMITATIONS OF THE RESEARCH METHODS 
 
As with all studies utilizing claims data, there are certain limitations that should be 
noted. The presence of a claim for a filled prescription or prescription absent a claim 
does not indicate that the medication was consumed or that it was taken as prescribed. 
Medications filled over the counter or provided as samples by the physician will not 
be observed in the claims data. Patients with commercial health insurance may be 
different from those with non-commercial or without (commercial) health insurance, 
and hence study results may not be generalizable to the overall population. Population 
aged 65 years and older might be underrepresented, which may affect external 
validity in the case of Medicare, Medicare Advantage or Medicaid patients. 
Socioeconomic data is not available. Smoking status information during the study 
period is not available in this data source. Since unmatched patients will be excluded, 
the results may not be generalizable to all patients. Some study measures and 
outcomes will include missing data and hence reduce the sample size. 
This real-world evidence study lacks controls available with RCTs. Patient 
misclassification, missing data, objective and reliable measurement of patient 
outcomes, and lack of detailed information regarding subjects’ clinical history or 
clinical status during the study timeframe may undermine the accuracy of our study 
results. In the absence of randomization, confounding by indication could be an issue. 
Controlling via PSM should limit this bias but can control only for measured 
covariates and may produce estimates that are impacted by residual confounding. This 
is of particular importance in the case of lifestyle factors that are less critical to 
insurance billing and thus poorly captured in claims data. 
There is the possibility of information bias due to misclassification of the outcomes or 
exposure or missing data as prescriptions dispensed by a pharmacy but not taken by 
patients could lead to misclassification of exposure. Pharmacy dispensing data does 
bring us one step closer to patient use than physician prescribing given that the patient 
has taken the effort to obtain the medication as instructed, however, information such 
as indication can only be inferred based on diagnostic patterns. 
Finally, we cannot exclude the possibility of unmeasured differences in exacerbation 
risk across exposure groups. Data on several relevant confounders (e.g., Body mass 
index, smoking habits, symptom scores), as well as data from spirometry on lung 
function will not be available for analysis. Although certain bias analysis can be 
planned but they are limited by the strength of the assumptions they rely on. An 
impact of residual confounding caused by these unmeasured factors cannot be ruled 
out. Further, we cannot exclude the possibility that patients may have gone on to 
develop outcomes later beyond the study period. We will conduct bias analysis as 
appropriate to address these concerns. 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 38 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
9.10 
OTHER ASPECTS 
 
Not applicable. 
 
10 PROTECTION OF HUMAN SUBJECTS 
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, Guidelines for Good Pharmacoepidemiology Practice (GPP), and the 
relevant BI Standard Operating Procedures (SOPs). 
 
The rights of the investigator and of the sponsor about publication of the results of this study 
are described in the investigator contract. As a rule, no study results should be published prior 
to finalization of the study report. 
 
 
10.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
 
This NIS is a retrospective database analysis of existing data and is IRB exempt as there is no 
patient informed consent required for the study. 
 
 
10.2 
STATEMENT OF CONFIDENTIALITY 
 
No patient’s identity or medical records will be disclosed for the purposes of this study 
except in compliance with applicable law. 
 
11. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
Data is anonymized and extracted, analyzed, validated, and reported in aggregate. There is 
no potential that any employee of BI or agent working on behalf of BI will access individual 
patient data where adverse events is identified during data compilation, data reporting or 
data analysis. 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 39 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
 
The rights of the investigator and of the sponsor regarding publication of the results of this 
study are described in the investigator contract. As a rule, no study results should be 
published prior to finalization of the study report. 
 
13. REFERENCES 
13.1 PUBLISHED REFERENCES 
 
1. Rabe KF, Hurd S, Anzueto A et al. Global strategy for the diagnosis, management, 
and prevention of chronic obstructive pulmonary disease: GOLD executive 
summary. Am J Respir Crit Care Med 2007;176(6):532-555. (P07-11503) 
2. Lopez AD, Shibuya K, Rao C et al. Chronic obstructive pulmonary disease: current 
burden and future projections. Eur Respir J 2006;27(2):397-412. (R13-1383) 
3. Guidelines for Good Pharmacoepidemiology Practices (GPP) (revision 2: April 
2007). http://www.pharmacoepi.org/resources/guidelines_08027.cfm; Bethesda: 
International Society for Pharmacoepidemiology (ISPE) (2007) (R11-4318) 
4. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020: 
https://goldcopd.org/wp-content/uploads/2020/03/GOLD-2020-POCKET-GUIDE- 
ver1.0_FINAL-WMV.pdf (P20-00875) 
5. Nici L, Mammen MJ, Charbek E, Alexander PE, Au DH Boyd, CM, et al, 
American Thoracic Society Assembly on Clinical Problems. Pharmacologic 
management of chronic obstructive pulmonary disease: an official American 
Thoracic Society clinic practice guideline. Am J Respir Crit Care Med 
2020;201(9):e56-e69. (R21-1059) 
6. Ernst P, Saad N, Suissa S. Inhaled corticosteroids in COPD: the clinical evidence. 
Eur Respir J. 2015;45(2):525-537. (P21-10741) 
7. Barjaktarevic IZ, Arredondo AF, Cooper CB. Positioning new pharmacotherapies 
for COPD. Int J Chronic Obstruct Pulm Dis 2015;10(1): 1427-1442 (P15-08642) 
8. Calverley PMA, Magnussen H, Miravitlles M, Wedzicha JA. Triple therapy in 
COPD: what we know and what we don't. COPD J Chronic Obstruct Pulm Dis 
2017;14(6):648-662 (P19-08111) 
9. Papi A, Vestbo J, Fabbri L, et al. Extrafine inhaled triple therapy versus dual 
bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a 
double-blind, parallel group, randomised controlled trial. Lancet. 
2018;391(10125):1076-1084 (R18-0514) 
10. Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus 
dual therapy in patients with COPD. N Engl J Med. 2018;378(18): 1671-1680. 
(R18-1532) 
11. Rabe K, Martinez F, Ferguson G et al, Triple Inhaled Therapy at Two 
Glucocorticoid Doses in Moderate-to-Very-Severe COPD. N Engl J Med 2020; 
383:35-48 (P20-06028) 
12. Suissa S, Drazen JM. Making sense of triple inhaled therapy for COPD. N Engl J 
Med. 2018;378(18):1723-1724. (R18-1531) 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Page 40 of 47 
 
 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
13. Suissa S, Ariel A. Triple therapy trials in COPD: a precision medicine opportunity. 
Eur Respir J. 2018;52(6):1801848. (R21-3908) 
14. Wedzicha JA, Banerji D, Kostikas K. Single-inhaler triple versus dual therapy in 
patients with COPD. N Engl J Med. 2018;379(6):590-593 (P18-07556) 
15. Yawn BP, Li Y, Tian H, Zhang J, Arcona S, Kahler KH. Inhaled corticosteroid use 
in patients with chronic obstructive pulmonary disease and the risk of pneumonia: 
a retrospective claims data analysis. Int J Chron Obstruct Pulmon Dis. 2013;8:295- 
304.(P13-14557) 
16. Zheng et al 2018 Zheng Y, Zhu J, Liu Y, et al. Triple therapy in the management of 
chronic obstructive pulmonary disease: systematic review and meta-analysis. BMJ. 
2018;363:k4388. (P21-10740) 
17. Cazzola, M., Rogliani, P. & Matera, M.G. Escalation and De-escalation of Therapy 
in COPD: Myths, Realities and Perspectives. Drugs 75, 1575–1585 (2015). (P21- 
10739) 
18. Bruselle G, Price D et al. The inevitable drift to triple therapy in COPD: an 
analysis of prescribing pathways in the UK. Int J Chron Obstruct Pulmon Dis. 
2015; 10: 2207–2217 (P17-01773) 
19. Hurst J, Dilleen M, Morris K et al. Factors influencing treatment escalation from 
long-acting muscarinic antagonist monotherapy to triple therapy in patients with 
COPD: a retrospective THIN-database analysis. Int J Chron Obstruct Pulmon Dis. 
2018; 13: 781–792 (P18-02649) 
20. Palli SR, Zhou S, Shaikh A, Willey VJ. Effect of compliance with GOLD 
treatment recommendations on COPD health care resource utilization, cost, and 
exacerbations among patients with COPD on maintenance therapy. J Managed 
Care Spec Pharm 2021;27(5):625-637. (R21-2227) 
21. Pauwels RA, et al. Global initiative for chronic obstructive lung disease: pocket 
guide to COPD diagnosis, management, and prevention: a guide for health care 
professionals (updated July 2004). Workshop on COPD of the National Heart, 
Lung, and Blood Institute and the World Health Organization, Apr 1998. 
www.goldcopd.com/pg2004clean.pdf: 2004 (R05-1384) 
22. U.S. Bureau of Labor Statistics databases, tables & calculators by subject: CPI for 
all urban consumers (CPI-U). http://data.bls.gov/cgi-bin/surveymost?cu (access 
date: 30 November 2021) ; Washington: U.S. Bureau of Labor Statistics; 2021 
(R21-4317) 
23. Frytak JR, Henk HJ, Zhao Y, Bowman L, Flynn JA, Nelson M. Health service 
utilization among Alzheimer's disease patients: evidence from managed care. 
Alzheimers Dement 2008;4(5):361-367. (P21-11033) 
24. Bayliss EA, Ellis JL, Shoup JA, Zeng C, McQuillan DB, Steiner JF. Association of 
patient-centered outcomes with patient-reported and JCD-9-based morbidity 
measures. Ann Fam Med 2012;10(2):126-133. (R21-4087) 
25. Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and 
validating the Charlson comorbidity index and score for risk adjustment in hospital 
discharge abstracts using data from 6 countries Am J Epidemiol 2011;173(6):676- 
682 (R20-2288) 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 41 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
  
 
 
 
26.  Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC Saunders LD, 
Beck CA, Feasby TE, Ghali WA. Coding algorithms for defining comorbidities in 
ICD-9-CM and ICD-10 administrative data. Med Care 2005;43(11):1130-1139 
(R14-4775) 
27. Ernst P, Gonzalez AV Brassard P, Suissa S. Inhaled corticosteroid use in chronic 
obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J 
Respir Crit Care Med 2007; 176(2): 162-166 (P07-09514) 
28. Suissa S, Dellaniello S, Ernst P. Long-acting bronchodilator initiation in COPD 
and the risk of adverse cardiopulmonary events: a population-based comparative 
safety study. Chest, Accepted Manuscript, Published online August 25, 2016, doi: 
10.2016/j. chest 2016. 08. 001; 2017 p. 60-67 (P16-10095) 
29. Suissa et al. Comparative Effects of LAMA-LABA-ICS vs LAMA-LABA for 
COPD Cohort Study in Real-World Clinical Practice. CHEST 2020; 157(4):846- 
855 (P21-01220) 
30. Palli et al. Differences in Real-World Health and Economic Outcomes Among 
Patients with COPD Treated with Combination Tiotropium/Olodaterol Versus 
Triple Therapy. Journal of Managed Care & Specialty 
Pharmacy 2020 26:10, 1363-1374 (P20-06571) 
 
 
 
13.2 UNPUBLISHED REFERENCES 
 
NA 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 42 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
  
 
 
 
 
 
APPENDIX 1: CODE LISTS 
 
 
Code 
Code Type 
Description 
518.81 
ICD-9 Dx 
Acute respiratory failure 
518.82 
ICD-9 Dx 
Other pulmonary insufficiency, not elsewhere classified 
518.84 
ICD-9 Dx 
Acute and chronic respiratory failure 
799.1 
ICD-9 Dx 
Respiratory arrest 
J9600 
ICD-10 Dx 
Acute respiratory failure, unspecified whether with hypoxia or 
hypercapnia 
J9601 
ICD-10 Dx 
Acute respiratory failure with hypoxia 
J9602 
ICD-10 Dx 
Acute respiratory failure with hypercapnia 
J80 
ICD-10 Dx 
Acute respiratory distress syndrome 
J9620 
ICD-10 Dx 
Acute and chronic respiratory failure, unspecified whether with 
hypoxia or hypercapnia 
J9621 
ICD-10 Dx 
Acute and chronic respiratory failure with hypoxia 
J9622 
ICD-10 Dx 
Acute and chronic respiratory failure with hypercapnia 
R092 
ICD-10 Dx 
Respiratory arrest 
 
 
 
APPENDIX 2: COPD-RELATED RESPIRATORY MEDICATIONS AND 
CLASSES 
 
Drug Class 
Subclass 
Medication 
Maintenance 
medications 
Inhaled long-acting anti- 
muscarinic 
agents (LAMA) 
aclidinium 
glycopyrrolate 
revefenacin 
tiotropium 
umeclidinium 
arformoterol 
Long-acting β-agonists 
(LABA) 
formoterol 
indacaterol 
olodaterol 
salmeterol 
beclomethasone 
budesonide (both inhaler and nebulizer) 
ciclensonide 
Inhaled corticosteroids (ICS) flunisolide 
fluticasone 
mometasone 
triamcinolone 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 43 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
  
 
 
 
Drug Class 
Subclass 
Medication 
Inhaled LAMA/LABA 
combination 
aclidinium/formoterol 
glycopyrrolate/formoterol 
indacaterol/glycopyrrolate 
tiotropium/olodaterol 
umeclidinium/vilanterol 
Inhaled ICS/LABA 
combination 
budesonide/formoterol 
fluticasone/salmeterol 
fluticasone/vilanterol 
mometasone/formoterol 
Inhaled ICS/LABA/LAMA 
combination 
Budesonide/glycopyrrolate/formoterol 
fumarate1 
Fluticasone/umeclidinium/vilanterol 
Methylxanthines 
(intravenous, oral) 
aminophylline 
dyphylline 
theophylline 
PDE-4 inhibitor (oral) 
roflumilast 
Rescue 
medications 
Short-acting β-agonists 
(SABA) (inhalation, oral) 
albuterol 
bitolterol 
isoetharine 
isoproterenol 
levalbuterol 
metaproterenol 
pirbuterol 
Short-acting anti-muscarinic 
Agents (SAMA) (inhalation) ipratropium 
SAMA/SABA (inhalation) 
ipratropium/albuterol 
Oral corticosteroids (OCS)2 
betamethasone 
dexamethasone 
hydrocortisone 
methylprednisolone 
prednisolone 
prednisone 
1This medication was FDA approved for maintenance treatment of COPD on 24 July 2020, which is outside of the study 
time period, and will not be included in this study. 
2Including tablets, oral solutions, elixirs, etc. Injectable corticosteroid medications will not be included. 

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
Page 44 of 47 
c38026921-01 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
 
APPENDIX 3: COPD GUIDELINE-RECOMMEND ANTIBIOTIC 
MEDICATIONS 
 
Drug Category 
Drug Class 
Medication 
COPD Guideline- 
recommended Antibiotics1 
Cephalosporins 
cefaclor 
cefdinir 
cefditoren 
cefepime 
cefpodoxime 
cefprozil 
ceftibuten 
ceftriaxone 
cefuroxime 
Macrolides 
azithromycin 
clarithromycin 
Penicillins 
amoxicillin 
amoxicillin/potassium 
piperacillin/tazobactam 
Quinolones 
levofloxacin 
moxifloxacin 
Sulfonamide 
combinations 
sulfamethoxazole/trimethoprim 
Tetracyclines 
doxycycline 
1The American Thoracic Society (2017) and Global Initiative for Chronic Obstructive Lung Disease (2020) 
guidelines recommend that antibiotics for acute exacerbation of chronic bronchitis be selected based on local 
sensitivity patterns. For more specific recommendations, The Sanford Guide to Antimicrobial Therapy (2020) was 
referenced. 
 
 
COPD Exacerbation Definition 
• Exacerbation Hierarchy: Exacerbation events will be classified as severe or moderate 
according to the highest severity contributing event. 
• Exacerbation Episodes: Exacerbations occurring within 14 days of each other will be 
considered a single exacerbation episode and will be classified according to the highest 
severity contributing event. 
• Episode Length: The start date of the exacerbation episode will be the service date of 
the first event (medical encounter or pharmacy fill for an OCS or antibiotic). The end 
date of the exacerbation episode will be defined as the last observed exacerbation event 
date (or discharge date if an inpatient event) + 14 days. 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
Page 45 of 47 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
• Single Event Episode 
• In a single event episode, the exacerbation begins with the earliest occurrence of these 
events: COPD exacerbation defined inpatient admission, ER visit, ambulatory visit, or 
corticosteroid or antibiotic dispensing as defined in Section 9.3.2.1. In a single event 
episode, the exacerbation ends 14 days from the start of the event, hospital discharge, 
or following the OCS or antibiotic dispensing, whichever is later. 
• Episode Start date = service date of a qualifying event (inpatient admission, ED visit, 
ambulatory visit, or OCS or antibiotic dispensing). 
o If the qualifying event is a hospitalization, the start date is the admission date. 
o If the qualifying event is an ED visit, the start date is the service date. 
o If the qualifying event is an ambulatory visit or an OCS or antibiotic dispensing, 
the start date is the earliest of the associated medical visit or medication 
dispensing date. 
Episode End Date 
o If the qualifying event is a hospitalization: discharge date + 14 days 
o If the qualifying event is an ER visit: start date + 14 days 
o If the qualifying event is an ambulatory visit or an OCS or antibiotic dispensing: 
Fthe latest of the medical visit or medication dispensing + 14 days 
• If the Episode End Date is after the end of follow-up, then set an additional flag 
CENSORED=1. 
• NOTE: Under this definition, it is possible for the runout of a medication to exceed the 
End Date. 
• MULTIPLE EVENT EPISODES 
• If another qualifying event occurs before the episode End Date, then the episode is 
extended. The date of the second event is used to reset the End Date per the definition 
above, using information from this second event. The process continues until a 14-day 
period with no exacerbation qualifying events occur. The End Date is set (as defined 
above). 
• Episode Length: (End date – Start date) + 1 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
Page 46 of 47 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
NA 
 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
NA 
 
ANNEX 3. ADDITIONAL INFORMATION 
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES 
The NIS Protocol must be sent for review to the following individuals prior to approval. 
 
Reviewer 
NIS involving BI 
product(s) 
NIS not involving BI product(s) 
Global NIS 
Local NIS 
NIS Lead 
X 
X 
X 
Global TM Epi 
X 
X 
X 
Global TMM / TMMA / TM Market 
Access 
X 
X 
Global Project Statistician 
X 
X 
Global TM RA 
X 
Global PVWG Chair 
X 
GPV SC 
X 
X 
X 
Global CTIS representative 
X 
Local Medical Director 
X (if local study) 
X 
Local Head MAcc / HEOR Director 
X (if local study) 
X 
Global TA Head Epi* 
X 
X 
Global TA Head Clinical 
Development / Medical Affairs / 
Market Access* 
X 
X 
Global TA Head PV RM* 
X 
RWE CoE 
X 
X 
PSTAT / PSTAT-MA 
(for NISnd only) 
X 
X 
X 
NIS DM 
X 
X 
X 
Local Head MA/Clinical 
Development 
X (does not apply to 
NISed without chart 
abstraction) 
* After review by Global TM for function 

Boehringer Ingelheim 
Non-Interventional Study (NIS) Protocol 
BI Study Number 1237-0121 
c38026921-01 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
 
Page 47 of 47 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
Study Title: Comparison of Exacerbation Risk and Health Outcomes in Maintenance 
Treatment Naïve COPD patients using Stiolto vs. Trelegy. 
 
Study Number: 1237.0121 Protocol Version:1.0