Characteristics and Treatment Patterns of Patients With Chronic Obstructive Pulmonary Disease (COPD), Initiating Tio+Olo or Other Maintenance Therapies in the US and the UK: A Retrospective Claims Database Study
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
 
Protocol for non-interventional studies based on existing data 
TITLE PAGE 
Document Number: 
document number 
BI Study Number: 
1237-0091  
BI Investigational 
Product(s): 
Sp(t)iolto® Respimat® 
Title: 
Characteristics and Treatment Patterns of Patients with Chronic 
Obstructive Pulmonary Disease (COPD), Initiating Tio+Olo or 
Other Maintenance Therapies in the US and the UK: A 
Retrospective Claims Database Study. 
Protocol version identifier: 1.0 
Date of last version of 
protocol: 
N/A 
PASS: 
No 
EU PAS register number: 
Study not registered 
Active substance: 
Olodaterol and Tiotropium Bromide (ATC R03AL06) 
Medicinal product: 
Product reference: 
N/A 
Procedure number: 
N/A 
Joint PASS: 
No 
Research question and 
objectives: 
The primary objectives of the study are to use US and UK data to 
describe the characteristics of COPD patients according to various 
demographic, lifestyle, clinical, and concomitant medication use at 
the following times: 
● Date of COPD claim confirming diagnosis. 
● Date of initiation of Tio+Olo or any other mono, dual, or triple 
combination of LAMA, LABA, or ICS as first maintenance 
therapy after May 21, 2015 or July 1, 2015. 
● Date of initiation of Tio+Olo or any other mono, dual, or triple 
combination of LAMA, LABA, or ICS as second maintenance 

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therapy after first maintenance therapy. 
 
The secondary objectives of the study are as follows: 
● To estimate the time between the following events among COPD 
patients, overall and stratified by maintenance therapy type: 
○ COPD claim confirming diagnosis and first 
maintenance therapy 
○ COPD claim confirming diagnosis and second 
maintenance therapy 
○ First and second maintenance therapy 
● To estimate the number of COPD exacerbations overall and 
stratified by maintenance therapy type during the year prior to the 
following: 
○ Date of first maintenance therapy. 
○ Date of second maintenance therapy. 
● To describe COPD patients at the time of COPD claim 
confirming diagnosis according to various demographic, lifestyle, 
clinical, and medication use, stratified by calendar year. 
● To describe the characteristics of COPD patients stratified by 
therapy category at the following times: 
○ Date of initiation of Tio+Olo or other maintenance 
therapies as first maintenance therapy. 
○ Date of initiation of Tio+Olo or other maintenance 
therapies as second maintenance therapy. 
To estimate the proportion of patients who used each combination of 
therapy class at first vs. second maintenance therapy. 
Country(-ies) of study: 
United States; United Kingdom 
Author: 
Tel: 
 
Email: 
 
Tel: 
Email:
Marketing authorisation 

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holder(s): 
MAH contact person: 
 
T: 
 
Email:
In case of PASS, add: 
<EU-QPPV:> 
N/A 
In case of PASS, add: 
<Signature of EU-QPPV:> 
N/A 
Date: 
22 Feb 2019 
Page 1 of 50 
Proprietary confidential information 
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. 
All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used 
without prior written permission 

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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
1. 
TABLE OF CONTENTS ................................................................................................... 4 
2. 
LIST OF ABBREVIATIONS ............................................................................................ 6 
3. 
RESPONSIBLE PARTIES ................................................................................................ 7 
4. 
ABSTRACT ....................................................................................................................... 8 
5. 
AMENDMENTS AND UPDATES ................................................................................. 16 
6. 
MILESTONES ................................................................................................................. 16 
7. 
RATIONALE AND BACKGROUND ............................................................................ 17 
8. 
RESEARCH QUESTION AND OBJECTIVES ............................................................. 18 
9. 
RESEARCH METHODS ................................................................................................ 19 
 
STUDY DESIGN .......................................................................................... 19 
 
SETTING ...................................................................................................... 19 
 
Definitions ..................................................................................................... 19 
 
Study population............................................................................................ 22 
9.2.2.1 
Primary Study Population ............................................................................ 25 
9.2.2.2 
Child Cohort for First Maintenance Therapy............................................... 26 
9.2.2.3 
Grandchild Cohort for Second Maintenance Therapy ................................. 27 
 
VARIABLES................................................................................................. 29 
 
Exposures ...................................................................................................... 29 
 
Outcomes ....................................................................................................... 32 
9.3.2.1 
Primary outcomes ........................................................................................ 32 
9.3.2.2 
Secondary outcomes .................................................................................... 33 
 
Covariates ...................................................................................................... 34 
 
DATA SOURCES ......................................................................................... 36 
 
STUDY SIZE ................................................................................................ 37 
 
DATA MANAGEMENT .............................................................................. 37 
 
DATA ANALYSIS ....................................................................................... 38 
 
Main analysis ................................................................................................. 38 

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9.7.1.1 
Descriptive Analysis .................................................................................... 39 
9.7.1.2 
Time to Initiation of Therapy ....................................................................... 40 
9.7.1.3 
Number of COPD Exacerbations ................................................................. 41 
 
QUALITY CONTROL ................................................................................. 45 
 
LIMITATIONS OF THE RESEARCH METHODS .................................... 45 
 
OTHER ASPECTS........................................................................................ 46 
 
SUBJECTS .................................................................................................... 46 
 
Cases .............................................................................................................. 46 
 
Controls ......................................................................................................... 47 
 
BIAS .............................................................................................................. 47 
10. 
PROTECTION OF HUMAN SUBJECTS .................................................................. 47 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ........................................................................................................................... 48 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS . 48 
13. 
REFERENCES ............................................................................................................ 48 
 
PUBLISHED REFERENCES ....................................................................... 48 
 

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LIST OF ABBREVIATIONS 
ACEi 
Angiotensin Converting Enzyme Inhibitor 
ACOS 
Asthma COPD Overlap Syndrome 
AIDS 
Acquired Immune Deficiency Syndrome 
BMI 
Body Mass Index 
CI 
Confidence Interval 
COPD 
Chronic Obstructive Pulmonary Disease 
CPRD 
Clinical Practice Research Datalink 
DPP-4 
Dipeptidyl peptidase-4 
EMR 
Electronic Medical Record 
ENCEPP 
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance 
FVC 
Forced Vital Capacity 
FEV 
Forced Expiratory Volume 
GLP-1 
Glucagon-like Peptide-1 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HIV 
Human Immunodeficiency Virus 
ICD 
International Classification of Diseases 
ICS 
Inhaled Corticosteroid 
IP 
Inpatient 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
LABA 
LAMA 
Long-Acting Beta-Agonists 
Long-Acting Muscarinic Antagonists 
NOA 
Non-obstructive Asthma 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
OP 
Outpatient 
PDE-4 
Phosphodiesterase-4 
SABA 
Short-acting Beta Agonist 
SAMA 
Short-acting Muscarinic Antagonist 
SD 
Standard Deviation 
SGLT2 
Sodium-glucose Cotransporter 2 
TIA 
Transient Ischemic Attack 

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RESPONSIBLE PARTIES 
 
T: 
 
Email :
 
 
 
Email : 
 
 
 
T : 
 
Email:
 
 
Tel : 
 
Email :
 

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ABSTRACT 
Name of company: 
 
 
Boehringer Ingelheim International GmbH 
Name of finished medicinal product:  
Name of active ingredient: 
Olodaterol and Tiotropium Bromide (ATC 
R03AL06) 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
22 February 2019 
1.0 
Title of study: 
Characteristics and Treatment Patterns of Patients with Chronic Obstructive 
Pulmonary Disease (COPD), Initiating Tiotropium+Olodaterol or Other 
Maintenance Therapies in the US and the UK: A Retrospective Claims 
Database Study 
Rationale and 
background: 
Chronic obstructive pulmonary disease (COPD) is a common disease 
characterized by airway obstruction confirmed by spirometry, often including 
small airway obstruction and emphysema. 
For patients who are diagnosed with COPD, maintenance treatments often 
include bronchodilators, primarily long-acting muscarinic antagonists 
(LAMA), long-acting beta agonists (LABA), and inhaled corticosteroids 
(ICS) alone or in combination with each other and corticosteroids. 
Sp(t)iolto® Respimat®, a LAMA+LABA combination, was approved in May 
21, 2015 in the US and July 1, 2015 in the EU (marketed as Stiolto in the US 
and Spiolto in the EU, referred to here as Tio+Olo).  
Selective prescribing according to patient characteristics, known as 
channeling, can lead to bias in comparative studies where drugs with similar 
therapeutic indications are prescribed to groups of patients with prognostic 
differences. Claimed advantages of a new drug may be distorted if they are 
channeled to patients with special pre-existing morbidity, with the 
consequence that disease states can be incorrectly attributed to use of the 
drug. Therefore, it is important to identify clinical and socio-demographic 
characteristics of patients who initiate each treatment as opposed to other 
available maintenance treatments in COPD patients.  
Research question 
and objectives: 
The primary objectives of the study are to use US and UK data to describe the 
characteristics of COPD patients according to various demographic, lifestyle, 
clinical, and medication use at the following times: 
● Date of COPD claim confirming diagnosis (at any time). 
● Date of initiation of Tio+Olo or other maintenance therapies as first 
maintenance therapy (after date of Spiolto launch). 
● Date of initiation of Tio+Olo or other maintenance therapies as 
second maintenance therapy (after date of Spiolto launch). 

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Name of company: 
 
 
Boehringer Ingelheim International GmbH 
Name of finished medicinal product:  
Name of active ingredient: 
Olodaterol and Tiotropium Bromide (ATC 
R03AL06) 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
22 February 2019 
1.0 
The secondary objectives of the study are as follows: 
● To estimate the time between the following events among COPD 
patients, overall and stratified by maintenance therapy type: 
○ COPD claim confirming diagnosis and first maintenance 
therapy. 
○ COPD claim confirming diagnosis and second maintenance 
therapy. 
○ First and second maintenance therapy in patients receiving 
second maintenance therapy. 
● To estimate the number of COPD exacerbations overall and stratified 
by maintenance therapy type during the year prior to the following: 
○ Date of first maintenance therapy. 
○ Date of second maintenance therapy. 
● To describe COPD patients at the time of COPD claim confirming 
diagnosis according to various demographic, lifestyle, clinical, and 
medication use, stratified by calendar year. 
● To describe the characteristics of COPD patients stratified by therapy 
category at the following times: 
○ Date of COPD claim confirming diagnosis. 
○ Date of initiation of Tio+Olo or other maintenance therapies as 
first maintenance therapy. 
○ Date of initiation of Tio+Olo or other maintenance therapies as 
second maintenance therapy. 
● To estimate the proportion of patients who used each combination of 
therapy class at first vs. second maintenance therapy 
Study design: 
Retrospective cohort study using previously collected administrative 
healthcare data.  
Population: 
COPD (“Parent”) Cohort: 
The study population for the analysis will consist of all patients with at least 
one medical claim with a diagnosis code of COPD identified (ICD-9-CM 
code 491.*, 492.*, 496.*, ICD-10-CM J41.*, J43.*, J44.*, or the appropriate 
READ codes) between date of first availability of Tio+Olo (launch date May 
21, 2015 in the United States and July 1, 2015 in the UK) and last date of 
available data (March 31, 2017 for MarketScan and June 6, 2018 for CPRD). 

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Name of company: 
 
 
Boehringer Ingelheim International GmbH 
Name of finished medicinal product:  
Name of active ingredient: 
Olodaterol and Tiotropium Bromide (ATC 
R03AL06) 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
22 February 2019 
1.0 
Patients will be required to be >= age 40 at cohort entry date and have at least 
12 months of enrolment in the health plan prior to COPD claim confirming 
diagnosis. Patients with previous use of any maintenance medication in the 12 
months before index will be excluded. 
Child Cohort: 
Among the COPD (“Parent”) cohort, includes all patients of the parent cohort 
who initiated first maintenance therapy with any combination of LAMA, 
LABA, or ICS after the date of Spiolto approval. 
Grandchild Cohort: 
Among the Child cohort, includes all patients of the Child cohort who 
initiated second maintenance therapy with any combination of LAMA, 
LABA, or ICS that is different from the first maintenance therapy. 
Variables: 
Therapy Classes 
● Mutually exclusive maintenance therapy categories: 
                  Monotherapy 
○ LAMA 
○ LABA 
○ ICS 
Dual Therapy 
○ Tio+Olo (LAMA + LABA) 
○ LAMA + LABA that is not Tio+Olo 
○ LAMA + ICS 
○ LABA + ICS 
Triple Therapy 
○ LAMA + LABA + ICS  
● First maintenance therapy is defined as first occurrence after Spiolto 
approval date. 
● Second maintenance therapy is defined as any subsequent 
maintenance therapy category that differs from the first maintenance 
therapy category. 
 
Outcome 
• 
Time between COPD claim confirming diagnosis and first 

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Name of company: 
 
 
Boehringer Ingelheim International GmbH 
Name of finished medicinal product:  
Name of active ingredient: 
Olodaterol and Tiotropium Bromide (ATC 
R03AL06) 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
22 February 2019 
1.0 
maintenance therapy. 
• 
Time between COPD claim confirming diagnosis and second 
maintenance therapy. 
• 
Time between first and second maintenance therapy. 
• 
Duration of first maintenance therapy. 
• 
Number of COPD exacerbations prior to index therapy. 
Covariates 
A series of baseline variables will be created as covariates. All variables will 
be assessed in the 365-day baseline period before COPD claim confirming 
diagnosis, except for comorbidities, which will be assessed from the start of 
all available data to the cohort entry date: 
Demographics 
● Age on cohort entry date 
● Sex 
● Region (MarketScan) 
● Practice Region (CPRD) 
 
Concomitant Medications in Previous 365 days 
● Corticosteroids 
● Short acting muscarinic antagonist (SAMA) 
● Short acting beta agonist (SABA) 
● NSAIDs 
● Antihistamines 
● Oral antibiotics 
● Diabetes mellitus medications 
● Insulin 
● Methotrexate 
● Statins 
● Antihypertensives 
● Anticoagulants 
● Anti-psychotic/anti-depressives/anxiolytic 
● Opioids 
● Oxygen therapy 
 

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Name of company: 
 
 
Boehringer Ingelheim International GmbH 
Name of finished medicinal product:  
Name of active ingredient: 
Olodaterol and Tiotropium Bromide (ATC 
R03AL06) 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
22 February 2019 
1.0 
Comorbidities Since Start of All Data 
● All-Cause Hospitalization (MarketScan only) 
● All-Cause Emergency Department Visits (MarketScan only) 
● Respiratory-related Hospitalization (MarketScan only) 
● Peripheral Vascular Disease 
● Cerebrovascular Disease 
● Myocardial Infarction 
● Cardiac Arrhythmia 
● Heart Failure 
● Angina Pectoris 
● Hypertension 
● Osteoporosis 
● Anxiety 
● Depression 
● Type 2 Diabetes 
● Upper respiratory tract infection  
● Lower respiratory tract infection 
● Pneumonia 
● Bronchiectasis 
● Asthma 
● Allergic Rhinitis 
● Chronic Sinusitis 
● Chronic Bronchitis 
● Lung Fibrosis 
● Exertional breathlessness 
● Impaired Cognitive Function/Dementia 
● Charlson Deyo Comorbidity Score 
● Cancer (any except non-melanoma skin cancer) 
● Lung Cancer 
● Lung Transplant 
● Rheumatologic Disease 
● Hepatic Failure/Injury 
● Hemiplegia or Paraplegia 
● Chronic Kidney Disease (CKD) without ESRD 
● End Stage Renal Disease (ESRD) 
● AIDS/HIV 

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Name of company: 
 
 
Boehringer Ingelheim International GmbH 
Name of finished medicinal product:  
Name of active ingredient: 
Olodaterol and Tiotropium Bromide (ATC 
R03AL06) 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
22 February 2019 
1.0 
● Peptic Ulcer Disease (PUD) 
● Gastroesophageal Reflux Disease (GERD) 
Lifestyle 
● Smoking-related Claim (MarketScan only) 
● Vaccination for Influenza or Pneumococcus 
● Body mass index (BMI) (last recorded) (CPRD only) 
● Smoking status (last recorded) (CPRD only) 
● Alcohol consumption (last recorded) (CPRD only) 
Other Variables of Interest 
● Calendar year of cohort entry date 
● FEV1/FVC (last recorded) (CPRD only) 
Data sources: 
MarketScan: a claims database that captures longitudinal, individual-level 
administrative claims data from the United States.  
CPRD: administrative database based on standardized electronic medical 
records (EMR) systems in primary care practices in the United Kingdom 
(UK). This database represents over 700 contributing general practices in the 
UK, and includes approximately 17.8 million patients. 
Study size: 
Among approximately 1,487,765 patients with COPD in MarketScan who 
did not use maintenance therapy before May 21, 2015, there were about 
1,269 with at least 1 claim for Stiolto Respimat in follow-up. 
 
Among approximately 98,537 patients with COPD in CPRD who did not 
use maintenance therapy before July 1, 2015, there are 332 with at least 1 
claim for Spiolto Respimat in follow-up.  

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Name of company: 
 
 
Boehringer Ingelheim International GmbH 
Name of finished medicinal product:  
Name of active ingredient: 
Olodaterol and Tiotropium Bromide (ATC 
R03AL06) 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
22 February 2019 
1.0 
Data analysis: 
Baseline Covariates 
• 
All covariates will be reported as mean (SD) and/or median (IQR) for 
continuous variables and counts and frequency (%) for categorical 
variables. 
• 
Descriptions of baseline variables will be done for all three cohorts at 
the cohort entry date. 
• 
For the parent cohort of COPD patients, will be further stratified by 
whether COPD claim confirming diagnosis took place before or after 
date of Spiolto approval. 
Maintenance Therapy Use  
• 
In the child and grandchild cohorts, absolute and relative frequencies 
of use for each therapy class will be reported on the date of initiation. 
Time between COPD claim confirming diagnosis and first maintenance 
therapy. 
• 
In the child cohort, will be reported as mean and median time to 
initiation. 
• 
Will be stratified by therapy class 
Time between COPD claim confirming diagnosis and second maintenance 
therapy. 
• 
In the grandchild cohort, will be reported as mean and median time to 
initiation. 
• 
Will be stratified by therapy class 
Time between first and second maintenance therapy. 
• 
In the grandchild cohort, will be reported as mean and median time to 
initiation. 
• 
Will be stratified by therapy class 
Number of COPD exacerbations 
• 
Will be reported in the baseline period for the child and grandchild 
cohorts as mean (SD) and median (IQR) for continuous variables and 
frequency (%) for categories (0, 1, 2, 3, 4, 5+) 
• 
Will be stratified by therapy class 

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Name of company: 
 
 
Boehringer Ingelheim International GmbH 
Name of finished medicinal product:  
Name of active ingredient: 
Olodaterol and Tiotropium Bromide (ATC 
R03AL06) 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
22 February 2019 
1.0 
Milestones: 
 
Sept 2018 
Descriptive - Kick-off meeting 
Dec 2018 
Draft Protocol development for Marketscan and CPRD implementation 
Feb 2019 
Revised Protocol for Marketscan and CPRD implementation 
April 2019 
Preliminary Result Table 
May 2019 
Revised Result Tables 
May 2019 
Final Result Tables, any final revisions, and Final Aetion Implementation Report 

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AMENDMENTS AND UPDATES 
Number 
Date 
Section of  
study 
protocol 
Amendment or 
update 
Reason 
<1> 
DD Month 
YYYY 
None 
None 
None 
 
 
MILESTONES 
Milestone 
Planned Date 
Start of data collection 
DD Month YYYY 
End of data collection 
DD Month YYYY 
<Study progress report 1> 
DD Month YYYY 
<Study progress report 2> 
DD Month YYYY 
<Study progress report n> 
DD Month YYYY 
<Interim report 1> 
DD Month YYYY 
<Interim report 2> 
DD Month YYYY 
<Interim report n> 
DD Month YYYY 
<Registration in the EU PAS 
register> 
DD Month YYYY 
Final report of study results: 
DD Month YYYY 

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RATIONALE AND BACKGROUND 
Chronic obstructive pulmonary disease (COPD) is a common disease characterized by airway 
obstruction confirmed by spirometry, often including small airway obstruction and 
emphysema (Barnes 2015). Patients may experience exacerbations, defined as acute onset, 
short but sustained worsening of patient’s condition beyond normal levels. Exacerbations 
often lead to hospitalization and/or change in medication, as they negatively impact long-
term health outcomes (Pavord 2016). Asthma COPD Overlap Syndrome (ACOS) is another 
complication that consists of concurrent COPD and asthma. Most studies have reported that 
patients with ACOS have worse prognosis than patients with only COPD in terms of more 
frequent and severe exacerbations, worsened symptoms, and decreased quality of life (Barnes 
2016). Scant information exists on appropriate therapy for ACOS, because these patients are 
often excluded from clinical trials of asthma or COPD (Barnes 2016). 
No known medications can reverse COPD, but use of rescue medications in the form of short 
acting muscarinic antagonists (SAMA), short acting beta agonists (SABA), and also regular 
maintenance treatments can help manage symptoms and improve quality of life. The Global 
Initiative for Chronic Obstructive Disease (GOLD 2017) recommends classifying patients for 
treatment based on assessment of existing symptoms and history of exacerbations. For 
patients who are diagnosed with COPD, maintenance treatments often include 
bronchodilators, primarily long-acting muscarinic antagonists (LAMA), long-acting beta 
agonists (LABA), and inhaled corticosteroids (ICS) alone or in combination with each other 
and corticosteroids. Sp(t)iolto® Respimat®, a LAMA+LABA combination, was approved in 
May 21, 2015 in the US and July 1, 2015 in the EU (marketed as Stiolto in the US and 
Spiolto in the EU, referred to here as Sp(t)iolto). Currently the product is sold in 46 countries, 
including the UK and most of the EU countries, US, Japan, Canada and several other 1st wave 
countries. Respimat is a device that aerates the Tio+Olo drug into a mist that may be more 
effective in reaching the lungs. Compared with LAMA or LABA alone, LAMA+LABA has 
demonstrated improved lung function, patient-reported outcomes, and quality of life 
measures in clinical trials (Calzetta 2017). Furthermore, the classic side effects of weight 
gain, osteoporosis, and community-acquired pneumonia associated with ICS use do not 
appear to be as severe for LAMA+LABA use (Tariq 2017). 
Selective prescribing according to patient characteristics, known as channeling, can lead to 
allocation bias in comparative studies, where drugs with similar therapeutic indications are 
prescribed to groups of patients with prognostic differences (Petri 1991). Claimed advantages 
of a new drug may be distorted if they are channeled to patients with special pre-existing 
morbidity, with the consequence that disease states can be incorrectly attributed to use of the 
drug. Therefore, it is important to identify clinical and socio-demographic characteristics of 
patients who initiate each treatment as opposed to other available maintenance treatments in 
COPD patients. 
This study will allow us to evaluate patient characteristics by first and second maintenance 
therapy and to identify factors potentially driving prescriptions to different patient 
populations in the US and UK. 

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RESEARCH QUESTION AND OBJECTIVES 
The primary objectives of the study are to use US and UK data to describe the characteristics 
of COPD patients according to various demographic, lifestyle, clinical, and medication use at 
the following times: 
• Date of COPD claim confirming diagnosis. 
• Date of initiation of Tio+Olo or other as first maintenance therapy, after Spiolto 
approval date. 
• Date of initiation of Tio+Olo or other as second maintenance therapy, after Spiolto 
approval date. 
 
The secondary objectives of the study are as follows: 
 
• To estimate the time between the following events among COPD patients, overall and 
stratified by maintenance therapy type: 
o COPD claim confirming diagnosis and first maintenance therapy. 
o COPD claim confirming diagnosis and second maintenance therapy. 
o First and second maintenance therapy. 
• To estimate the number of COPD exacerbations overall and stratified by maintenance 
therapy type during the year prior to the following: 
o Date of first maintenance therapy. 
o Date of second maintenance therapy. 
• To describe COPD patients at the time of COPD claim confirming diagnosis 
according to various demographic, lifestyle, clinical, and medication use, stratified by 
pre vs. post Spiolto approval. 
• To describe the characteristics of COPD patients stratified by therapy category at the 
following times: 
o Date of initiation of Tio+Olo or other maintenance therapies as first 
maintenance therapy. 
o Date of initiation of Tio+Olo or other maintenance therapies as second 
maintenance therapy. 
• To estimate the proportion of patients who used each combination of therapy class at 
first vs. second maintenance therapy. 

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RESEARCH METHODS 
 
STUDY DESIGN 
MarketScan: 
The proposed study is a non-interventional retrospective study based on existing data from 
the Truven Health MarketScan, a US claims database. Data from Jan 1, 2008 (earliest data 
available) to March 31, 2017 (latest data available) will be used to characterize COPD 
patients who initiated first and/or second maintenance treatment in three different cross 
sections: at COPD claim confirming diagnosis date, at date of first maintenance therapy, and 
at date of second maintenance therapy. Details of the study design are provided below. 
 
CPRD: 
The proposed study is a non-interventional retrospective study based on existing data from 
the CPRD, a UK-based administrative database. Data from November 21, 1987 (earliest data 
available) to June 30, 2018 (latest data available) will be used to characterize COPD patients 
who initiated first and/or second maintenance treatment in three different cross sections: at 
COPD claim confirming diagnosis date, at date of first maintenance therapy, and at date of 
second maintenance therapy. Details of the study design are provided below. 
 
 
SETTING 
 
Definitions 
Study Period: The period of time that includes the baseline, cohort entry date, and follow-up 
period for the study population. This period is the same for all patients. 
 
The study period will be from January 1, 2008 to March 31, 2017 in MarketScan and 
November 21, 1987 to June 30, 2018 in the CPRD, encompassing the date of earliest follow-
up availability to the date of the latest follow-up availability.  
 
Patient Selection Period: the period of time for which patients are eligible to enter the cohort. 
The earliest date of the patient selection period is January 1, 2009 for MarketScan and 
November 21, 1988 for CPRD, corresponding to 12 months after the date of first data 
availability to allow for a sufficient enrollment and washout period. 
 
Cohort Entry Date: Date of entry to the initial cohort of COPD patients. 
 
1st Treatment Index Date: Date of initiation of Tio+Olo or other as first maintenance therapy. 
 

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2nd Treatment Index Date: Date of initiation of Tio+Olo or other as second maintenance 
therapy. 
 
Baseline Period: The 365-day period prior to the cohort entry date or treatment index date 
used to assess concomitant medication use and lifestyle variables. The baseline period will 
vary between patients depending on these dates. 
 
Follow-Up Period: For patients who were diagnosed with COPD before May 21, 2015 
(MarketScan) or July 1, 2015 (CPRD), the follow-up period will be May 22, 2015 
(MarketScan) or July 2, 2015 (CPRD) to the earliest occurrence of death, disenrolment, or 
end of data. For patients diagnosed after those dates in their respective dataset, the follow-up 
period will be 1 day after their cohort entry date to the earliest occurrence of death, 
disenrolment, or end of data. Occurrence of first and second maintenance treatment will be 
assessed during this period. 
 
For entry into the study population, patients will be required to have 365 days of continuous 
enrolment with both medical and pharmacy coverage, as well as no occurrence of COPD in 
the previous 365 days. The follow-up period will be used for capturing first and second 
maintenance therapies. This is illustrated in Figure 1. 

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Figure 1a. Study timeline for MarketScan for the Primary Study Population (Parent Cohort)_ 
 
Figure 1b. Study timeline for CPRD for the Primary Study Population (Parent Cohort) 
 

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Study population 
The overall flow chart for the study population is depicted in Figure 2. 
Figure 2a. Flow chart of the study population in MarketScan. 
 

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Figure 2b. Flow chart of the study population in CPRD. 
 
 
Three cohorts will be used to address the study objectives: 1) a parent cohort of COPD 
patients with no previous maintenance medication use; 2) a child cohort of first maintenance 
therapy users; 3) a grandchild cohort of second maintenance therapy users. All analyses will 
include patients who are aged 40 years or older on the cohort entry date, and who have at 
least 365 days of continuous enrolment before these dates. For the parent cohort, patients who 
had maintenance medication use in the 365 days before index will be excluded (i.e. parent 
cohort will include only incident COPD cases).  

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Table 1 indicates the study periods for each of the three cohorts. 
Table 1a. Study Periods for each Cohort in MarketScan. 
Parent Cohort 
Child Cohort 
Grandchild Cohort 
MarketScan (US) 
Case Definition 
COPD (1 IP/OP ICD-9 
or  
1 IP/OP ICD-10 Code) 
First Maintenance 
Therapy (See 
Section 9.3.2.1 
) 
Second Maintenance 
Therapy (See Section 
9.3.2.1) 
Cohort Entry or 
Index Date 
Date of diagnosis 
Date of Initiation of  
First Maintenance 
Therapy 
Date of Initiation of  
Second Maintenance 
Therapy 
Study Period 
1 Jan 08 - 31 Mar 17 
1 Jan 08 - 31 Mar 17 
1 Jan 08 - 31 Mar 17 
Patient Selection 
Period 
1 Jan 09 - 31 Mar 17 
21 May 15 - 31 Mar 17 22 Jun 15 - 31 Mar 17 
Baseline Period 
365 days before Cohort 
Entry Date 
365 days before 
Treatment Index Date 
365 days before 
Treatment Date 
Comorbidity 
Assessment 
Period 
1 Jan 08 – Cohort Entry 
Date 
1 Jan 08 – Cohort Entry 
Date 
1 Jan 08 – Cohort Entry 
Date 
Follow-up Period 
Cohort Entry Date to 
Earliest Occurrence of 
Death, Disenrolment, or 
31 Mar 17 
Index Date to Earliest 
Occurrence of Death, 
Disenrolment, or 31 Mar 
17 
N/A 
 

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Table 1b. Study Periods for each Cohort in CPRD. 
CPRD (UK) 
Case Definition COPD (1 READ Code) 
First Maintenance 
Therapy (See 
Section 9.3.2.1) 
Second Maintenance 
Therapy (See Section 
9.3.2.1) 
Cohort Entry or 
Index Date 
Date of diagnosis date 
Date of Initiation of  
First Maintenance 
Therapy 
Date of Initiation of  
Second Maintenance 
Therapy 
Study Period 
21 Nov 87 - 30 Jun 18 21 Nov 87 - 31 Mar 17 
21 Nov 87 - 31 Mar 17 
Patient 
Selection Period 21 Nov 88 - 30 Jun 18 1 Jul 15 - 31 Mar 17 
2 Aug 15 - 31 Mar 17 
Baseline Period 365 days before Cohort 
Entry Date 
365 days before 
Treatment Index Date 
365 days before 
Treatment Index Date 
Comorbidity 
Assessment 
Period 
21 Nov 87 – Cohort 
Entry Date 
21 Nov 87 – Cohort Entry 
Date 
21 Nov 87 – Cohort Entry 
Date 
Follow-up 
Period 
Cohort Entry Date to 
Earliest Occurrence of 
Death, Disenrolment, 
or 30 Jun 18 
Index Date to Earliest 
Occurrence of Death, 
Disenrolment, or 30 Jun 
18 
N/A 
9.2.2.1 
Primary Study Population 
The study population will consist of patients diagnosed with COPD, defined as at least one 
inpatient or outpatient diagnosis of COPD (MarketScan: ICD-9 codes 491.*, 492.*, 496.* or 
ICD-10 codes J41.*, J43.*, J44.*; CPRD: READ codes “H3…00”, “H3…11”, “H30..00”, 
“H30..11”, “H30..12”, “H300.00”, “H301.00”, “H302.00”, “H30z.00”, “H31..00”, 
“H310.00”, “H310000”, “H310100”, “H310z00”, “H311.00”, “H311000”, “H311100”, 
“H311z00”, “H312.00”, “H312000”, “H312011”, “H312100”, “H312200”, “H312300”, 
“H312z00”, “H313.00”, “H31y.00”, “H31y000”, “H31y100”, “H31yz00”, “H31z.00”, 
“H32..00”, “H320.00”, “H320000”, “H320100”, “H320200”, “H320300”, “H320311”, 
“H320z00”, “H321.00”, “H322.00”, “H32y.00”, “H32y000”, “H32y100”, “H32y111”, 
“H32y200”, “H32yz00”, “H32yz11”, “H32z.00”, “H36..00”, “H37..00”, “H38..00”, 
“H39..00”, “H3A..00”, “H3B..00”, “H3y..00”, “H3y..11”, “H3y0.00”, “H3y1.00”, “H3z..00”, 
“H3z..11”, “14B3.12”, “Hyu3100”, “66Ye.00”, “66Yi.00”, “8H2R.00” (Mukherjee (2014)) 
identifiable in the database. The identification period of this primary cohort of COPD patients 
will be from date of earliest available data to date of latest available data.  

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As the objective is to study the first and second prescription for maintenance therapy, patients 
receiving maintenance treatment at study entry or up to 365 days prior to study entry will be 
excluded. In order to ensure that the first prescriptions are captured, at least 1 year of 
continuous data available prior to COPD claim confirming diagnosis will be required. All 
patients must also be age 40 years or more on the date of COPD claim confirming diagnosis. 
The study timelines for this primary study population are depicted in Figures 1 and 2. 
9.2.2.2 
Child Cohort for First Maintenance Therapy 
A child (i.e. nested) cohort will be created consisted solely of individuals who ever initiated 
first maintenance therapy. The parent cohort is the population of COPD patients described 
above. The date of initiation of first maintenance therapy will be set as the index date, and the 
365-day period before index will be used to provide descriptive analyses and number of 
COPD exacerbations. Importantly, the date of initiation of first maintenance therapy 
must occur on or after May 21, 2015 (MarketScan) or July 1, 2015 (CPRD), the Spiolto 
approval date. 
 
For entry into this child cohort, patients will be required to have 365 days of continuous 
insurance enrolment with both medical and pharmacy coverage prior to initiation of the 
maintenance therapy. Data in this baseline period will be used to provide descriptive statistics 
and number of COPD exacerbations. This is illustrated in Figure 3.  
Figure 3a. Study timeline for MarketScan for the Child Cohort (Initiation of First 
Maintenance Therapy as Index) 
 
 
 

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Figure 3b. Study timeline for CPRD for the Child Cohort (Initiation of First Maintenance 
Therapy as Index) 
 
 
9.2.2.3 
Grandchild Cohort for Second Maintenance Therapy 
A grandchild cohort will be created consisted solely of individuals who ever initiated second 
maintenance therapy. The grandchild cohort will be nested within the child cohort described 
above consisting of patients who ever initiated first maintenance therapy and had COPD 
diagnosis. The date of initiation of second maintenance therapy will be set as the index date, 
and the 365-day period before index will be used to provide descriptive analyses, number of 
COPD exacerbations, and proportion of patients who used each combination of therapy 
category at first vs. second maintenance. 
 
For entry into this child cohort, patients will be required to have 365 days of continuous 
insurance enrolment with both medical and pharmacy coverage. This is illustrated in Figure 
4. Note that the study period and patient identification periods are shifted forward by 31 days 
compared to the child cohort because the shortest possible time between initiation of first and 
initiation of second maintenance therapy is 31 days by definition (30 days of use of previous 
therapy + 1 day). 

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Figure 4a. Study timeline for MarketScan for the Grandchild Cohort (Initiation of Second 
Maintenance Therapy as Index) 
 
 
Figure 4b. Study timeline for CPRD for the Grandchild Cohort (Initiation of Second 
Maintenance Therapy as Index) 
 

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VARIABLES 
 
Exposures 
Specific drug class definitions are defined herein. A list of drug definitions, formulations, and 
brands is provided in Annex 5. 
 
Mutually exclusive maintenance therapy categories: 
Monotherapy 
• LAMA 
• LABA 
• ICS 
Dual Therapy 
• Tio+Olo (LAMA + LABA) 
• LAMA + LABA that is not Tio+Olo 
• LAMA + ICS 
• LABA + ICS 
• SAMA + SABA 
Triple Therapy 
• Tio+Olo + ICS 
• LAMA + LABA + ICS 
 
The two medication-related outcomes in this non-interventional study are as follows: 
1. First maintenance therapy is defined as first occurrence of any of the categories listed 
above after cohort entry date. 
2. Second maintenance therapy is defined as any subsequent maintenance therapy 
category that differs from the first maintenance therapy category. The earliest date of 
initiation of second maintenance therapy is 30 days after date of initiation of first 
maintenance therapy. 
 
Classification of individuals to different therapy categories will be based on the continuous 
use of a single drug (defined by the supply of the drug over the number of treatment days) for 
at least 30 days (monotherapy), a combination therapy for at least 30 days (dual therapy), an 
overlap of two different mono-formulations (e.g. LAMA overlapping with LABA) for at least 
30 days (dual therapy), or different combination formulations and mono-formulations 
together for at least 30 days (triple therapy). We will employ a 14-day allowable gap for 
continuous drug use to account for possible under-dosing of maintenance therapies 
(analogous to splitting pills) and skipping or forgetting to take doses. The specific definitions 
for therapy classification are detailed below. 

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Monotherapy is defined as at least 30 days of continuous drug use (with a 14-day allowable 
gap), without use of either of the other two drug classes during that 30-day period. For 
illustrations of three possible cases that would be classified as monotherapy, see Figure 5 
below. 
 
Figure 5. Three possible monotherapy scenarios. 
 
 
 
Dual therapy is defined as:  
• At least 30 days of overlap of continuous drug use of separate prescriptions for two 
drug classes, OR  
• At least 30 days of continuous drug use of a fixed-dose combination formulations. 
• In both cases, there is a 14-day allowable gap between individual drug fills. 
 
For illustrations of three possible cases that would be classified as dual therapy, see Figure 6 
below. 

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Figure 6. Three possible dual therapy scenarios. 
 
 
 
Triple therapy is defined as:  
• At least 30 days of overlap of continuous drug use of separate prescriptions for three 
drug classes, OR  
• At least 30 days of overlap of a dual fixed-dose combination formulations paired with 
a mono-formulation for the third drug class, OR 
• At least 30 days of continuous drug use of a triple fixed-dose combination 
formulations. 
• In all cases, there is a 14-day allowable gap between individual drug fills. 
 
For illustrations of three possible cases that would be classified as triple therapy, see Figure 7 
below. 

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Figure 7. Three possible triple therapy scenarios. 
 
 
 
 
Outcomes 
9.3.2.1 
Primary outcomes 
Patient characteristics, include various demographic, lifestyle, clinical, and medication 
characteristics will be reported at three points in time: 1) COPD claim confirming diagnosis 
date (Cohort Entry Date), overall and stratified by before or after Spiolto approval date; 2) 
Date of initiation of first maintenance therapy (1st Treatment Index Date), overall and 
stratified by therapy category; 3) Date of initiation of second maintenance therapy (2nd 
Treatment Index Date), overall and stratified by therapy category.  

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9.3.2.2 
Secondary outcomes 
We will also examine two clinical outcomes over follow-up among individuals among 
individuals who had first and/or second maintenance therapy: 
• Exacerbations in the year prior to the start of first maintenance therapy. 
• Exacerbations in the year prior to the start of second maintenance therapy (if 
available). 
 
For MarketScan, there are specific ICD-10 codes to identify exacerbations, but no ICD-9 
code. COPD exacerbations will be defined as any of the following:  
• An acute COPD exacerbation diagnosis (ICD-10 J44.0, J44.1); 
• A claim for an antibiotic or a corticosteroids on the same day or within 7 days 
following an outpatient COPD diagnosis; 
• An inpatient diagnosis of COPD in any position;  
• A hospitalization due to respiratory condition; 
• An emergency department visit with a COPD diagnosis in any position; 
• Lower respiratory tract infection diagnosis (ICD-9 466, ICD-10 J20.9, J21.0, J21.8, 
J22) (Rothnie 2016);  
 
For CPRD, COPD exacerbations will be defined as any of the following:  
• An acute COPD exacerbation diagnosis or respiratory failure (READ code 
“H312200”, “8BP8.00”, “H3y1.00”, “H590.00”, “H59..00”, “R2y1.00”, “R2y1z00”);  
• A lower respiratory tract infection diagnosis (READ code “H060.00”, “H060.11”, 
“H060300”, “H060500”, “H060w00”, “H060x00”, “H060z00”, “H062.00”, 
“H06z000”, “H06z011”, “H06z100”, “H06z112”, “H20..11”, “H20y.00”, “H20z.00”, 
“H22..00”, “H22..11”, “H22y.00”, “H22yz00”, “H22z.00”, “H23..11”, “H24..00”, 
“H24y.00”, “H24yz00”, “H24z.00”, “H25..00”, “H25..11”, “H26..00”, “H26..11”, 
“H260.00”, “H261.00”, “H2B..00”, “H2z..00”, “H30..11”, “H300.00”, “H301.00”, 
“H30z.00”, “H3y0.00”, “H540000”, “H540100”, “Hyu0800”, “Hyu0A00”, 
“Hyu0B00”, “Hyu0H00”, “Hyu1.00” );  
• Antibiotic or oral corticosteroids prescription on the same or within 7 days following 
a COPD diagnosis (Chalmers 2018). 
 
Exacerbations occurring within 14 days of one another will be considered a single event. 
 
The mean (SD) and median (IQR) number of COPD exacerbations will be reported. 
Categories of COPD exacerbations will also be reported as: 0, 1, 2, 3, 4, 5+ exacerbations. 

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Covariates 
Patient characteristics will be identified based on data recorded within one year prior to or on 
the index date (date of dispensing/initiation of the exposure), unless otherwise specified. If 
multiple measurements are made in the baseline period, then the most recent measurement 
prior to index date will be used.  
 
Demographics (Last Recorded Value) 
• Age on index date (Mean, Median, Categories: 40 – 54, 55 – 64, 65 – 74, 75 – 84, 
85+) 
• Sex 
• Region (MarketScan): Northeast, North Central, South, West, Unknown, Missing 
• Practice Region (CPRD): North East, North West, Yorkshire & The Humber, East 
Midlands, West Midlands, East of England, South West, South Central, London, 
South East Coast, Northern Ireland, Scotland, Wales, Missing 
 
Recent Concomitant Medications (365-day Baseline Period) 
• Corticosteroids 
• Short acting muscarinic antagonist (SAMA) 
• Short acting beta agonist (SABA) 
• NSAIDs 
• Antihistamines 
• Oral antibiotics 
• Diabetes mellitus medications 
• Insulin 
• Methotrexate 
• Statins 
• Antihypertensives 
• Anticoagulants 
• Anti-psychotic/anti-depressives/anxiolytic 
• Opioids 
• Oxygen therapy 
 
Comorbidities (All Available Data) 
• All-Cause Hospitalization 
• All-Cause Emergency Department Visits 
• Respiratory-related Hospitalization  

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• Cardiovascular Disease 
o Peripheral Vascular Disease 
o Cerebrovascular Disease 
o Myocardial Infarction 
o Cardiac Arrhythmia 
o Heart Failure 
o Angina Pectoris 
o Hypertension 
• Exertional breathlessness 
• Osteoporosis 
• Anxiety 
• Depression 
• Type 2 Diabetes 
o Diabetic Retinopathy/Nephropathy/Neuropathy 
• Upper/lower respiratory tract infection 
o Pneumonia 
• Bronchiectasis 
• Asthma 
• Allergic Rhinitis 
• Sinusitis 
• Chronic Bronchitis 
• Chronic Cough 
• Impaired Cognitive Function/Dementia 
• Gastroesophageal Reflux Disease (GERD) 
• Deyo Charlson Comorbidity Score 
• Cancer (any except non-melanoma skin cancer) 
o Lung Cancer 
• Lung Transplant 
• Rheumatic Disease (any kind) 
• Hepatic Failure/Injury 
• Hemiplegia or Paraplegia 
• Renal Disease 
○ Chronic Kidney Disease (CKD) 
○ Acute Renal Failure 
○ End Stage Renal Disease (ESRD) 
• AIDS/HIV 
• Peptic Ulcer Disease (PUD) 
• Lung Fibrosis 

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Lifestyle 
• Smoking-related Claim 
• Vaccination for Influenza or Pneumococcus 
• Body mass index (Categories: < 18.5, 18.5 - 24.9, 25.0 - 29.9, 30.0 - 34.9, 35+ kg/m2) 
(last recorded) (CPRD Only) 
• Smoking status (Categories: Never smoker, Past smoker, Current smoker, Unknown) 
(last recorded) (CPRD Only) 
• Alcohol consumption (last recorded) (Categories: Never drinker, Past drinker, Current 
drinker, Unknown) (CPRD Only) 
 
Other Variables of Interest 
• Calendar year of index date (Categories: 1987, …, 2018) 
• FEV1/FVC (last recorded) (CPRD Only) 
 
DATA SOURCES 
The proposed study will utilize data from two separate data sources: the Truven MarketScan 
data (US) and The Clinical Practice Research Datalink (CPRD) (UK).  
 
MarketScan 
The Truven MarketScan databases capture longitudinal, individual-level administrative 
claims data from the United States. The data available for study included three components of 
MarketScan: the Commercial Claims and Encounters (CCAE) Database, the Medicare 
Supplemental and Coordination of Benefits Database (MDCR), and the Medicaid Database. 
Patients in the databases are active employees, dependents, retirees, COBRA recipients, and 
Medicare or Medicaid enrollees. Data were drawn from large employers, health plans, and 
public organizations in the United States. The following tables of the MarketScan databases 
were available for analysis: Enrolment Detail, Inpatient Admissions, Inpatient Services, 
Outpatient Services, Outpatient Pharmaceutical Claims, and Long Term Care. These tables 
provide information on plan enrolment, healthcare utilization and expenditures, 
demographics, and integrated records for inpatient events, outpatient events, and pharmacy 
dispensings. Data were available from January 1, 2008 to March 31, 2017, and represent 
approximately 155.8 million patients. 
 
CPRD 
Clinical Practice Research Datalink (CPRD) is based on standardized electronic medical 
records (EMR) systems in primary care practices in the United Kingdom (UK). This database 
represents over 700 contributing general practices in the UK, and includes approximately 
17.8 million patients. The geographical distribution of the practices has been shown to be 
representative of the UK population, and age and sex distributions of patients in the databases 
are similar to those reported by the national population census (Walley 1997). Participating 
general practitioners have been trained to record medical information, including demographic 

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data, medical diagnoses, procedures, and deaths using a standardized form (Garcia Rodriguez 
1998). The EMR system records conditions, interventions and diagnostics using READ codes 
and medication prescribing is recorded using the British National Formulary (BNF). The 
EMR system records the prescribing of medications, including over-the-counter medications, 
but it does not verify whether patients fill the medications at the pharmacy. The system 
records laboratory test results and lifestyle measures like smoking, alcohol use, and body 
mass index with varying degrees of completeness. The database is limited to recordings by 
the primary care physician including the transferred notes from specialists and some 
information on hospitalization. Linkage to other datasets is possible, including the Hospital 
Episodes Statistics (HES), which is a data warehouse containing records of all patients 
admitted to NHS hospitals in England (Walley 1997). In the current study, event dates 
spanned from November 21, 1987 through June 30, 2018. 
 
STUDY SIZE 
Among approximately 1,487,765 patients with COPD in MarketScan who did not use 
maintenance therapy before May 21, 2015, there were about 1,269 with at least 1 claim for 
Stiolto Respimat in follow-up. 
Among approximately 98,537 patients with COPD in CPRD who did not use maintenance 
therapy before July 1, 2015, there are 332 with at least 1 claim for Spiolto Respimat in 
follow-up.  
 
DATA MANAGEMENT 
MarketScan 
The Truven Health MarketScan database is comprised of fully adjudicated and paid claims 
records of integrated longitudinal enrolment, inpatient, outpatient and drug data from 
multiple payers, that has been standardized and de-identified prior to use for the analysis. The 
statistical analysis will be conducted using the Aetion Evidence Platform. 
 
Drug Duration 
For MarketScan, unless otherwise noted, drug event duration was calculated from the “Days 
Supply” field, and in cases where this field was 0, the duration was assumed to be 1 day.  
 
Handling of Missing Data 
Missing data that occurs in covariates or descriptive variables will be classified as own 
category. In addition, a feasibility assessment before beginning the analyses will be done, and 
variables with >75 % missing values will be excluded from all analyses, other than baseline 
characteristics. If a variable is left with only one category other than missing, the variable 
will be excluded completely from all analyses. The percentage of patients with missing data 
for both categorical and continuous variables will be reported. 

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CPRD 
 
Drug Duration 
For CPRD, drug events' duration was calculated from the provided number of days field. In 
the case where this field was zero and a dosage identifier was present in the text field, the 
days supplied was determined from the quantity field and the numeric daily dose from the 
associated dosage metadata. In the case where this field was zero and no numeric daily dose 
could be determined, the default duration will be set to thirty days. 
 
Handling of Missing Data 
Missing data that occurs in covariates or descriptive variables will be classified as its own 
level. In addition, a feasibility assessment before beginning the analyses will be done, and 
variables with >75 % missing values will be excluded from all analyses, other than baseline 
characteristics. If a variable is left with only one level other than missing, the variable will be 
excluded completely from all analyses. 
 
For clinical variables (FEV1/FVC, BMI), distributions of observed values will be evaluated 
and clinically feasible ranges will be applied. Following implementation of reasonable 
ranges, a final assessment of outliers will be tested visually using histograms to understand 
the distribution of these variables. Any potential effects of skewed distributions will be 
presented in results and revised approaches will be considered where necessary. 
 
DATA ANALYSIS 
 
Main analysis 
For all analyses, variables will be reported as follows: 
• Continuous variables (e.g., age) will be presented as means (with standard deviation, 
SD) and/or medians (with interquartile range, IQR). 
• Categorical variables (e.g., sex) will be presented as absolute and relative frequencies. 
• All results will have two digits following the decimal point. 

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9.7.1.1 
Descriptive Analysis 
• Descriptive Analysis at Cohort Entry Date 
 
All variables specified in section 9.3.3 will be reported. For demographic and lifestyle 
variables, the value recorded on the cohort entry date will be reported, otherwise the most 
recent known value will be reported. Presence of concomitant medication use will be 
determined based whether they ever occurred within the 365-day baseline period preceding 
the cohort entry date. Presence of comorbidities will be determined based on whether they 
ever occurred within all data preceding cohort entry. In CPRD, BMI, alcohol use, smoking 
status, and FEV1/FVC will be reported based on the last recorded value. 
 
• Descriptive Analysis at First Maintenance Therapy 
 
The child cohort described in section 9.2.2.2 will be used for this analysis. 
All variables specified in section 9.3.3 will be reported. For demographic and lifestyle 
variables, the value recorded on the date of initiation of first maintenance therapy will be 
reported, otherwise the most recent known value will be reported. Presence of concomitant 
medication use will be determined based whether they ever occurred within the 365-day 
baseline period preceding the cohort entry date. Presence of comorbidities will be determined 
based on whether they ever occurred within all data preceding date of initiation of first 
maintenance therapy. In CPRD, BMI, alcohol use, smoking status, and FEV1/FVC will be 
reported based on the last recorded value. 
 
• Descriptive Analysis at Second Maintenance Therapy 
 
The grandchild cohort described in section 9.2.2.3 will be used for this analysis. 
All variables specified in section 9.3.3 will be reported. For demographic and lifestyle 
variables, the value recorded on the date of initiation of second maintenance therapy will be 
reported, otherwise the most recent known value will be reported. Presence of concomitant 
medication use will be determined based whether they ever occurred within the 365-day 
baseline period preceding the cohort entry date. Presence of comorbidities will be determined 
based on whether they ever occurred within all data preceding date of initiation of second 
maintenance therapy. In CPRD, BMI, alcohol use, smoking status, and FEV1/FVC will be 
reported based on the last recorded value. 

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• Treatment Patterns at First vs. Second Maintenance Therapy 
 
The grandchild cohort described in section 9.2.2.3 will be used for this analysis. 
A table will be constructed cross tabulating proportions of patients using a specific 
medication class at first maintenance vs. a specific medication class at second maintenance. 
We will present two proportions, a conditional and a marginal proportion: 1) For the 
conditional proportion, the numerator will be the number of patients who used that specific 
combination, and the denominator will include all patients who used the first maintenance 
drug for that combination. Using arbitrary values as an example, if the number of patients 
who switched from LABA → LAMA was 400 and the number of patients who used LABA 
as first maintenance therapy was 1000, then the conditional proportion would be: 400 / 1000 
= 0.4; 2) For the marginal proportion, the numerator will be the number of patients who used 
the specific combination, and the denominator will include all patients in the grandchild 
cohort. Using arbitrary values as an example, if the number of patients who switched from 
LABA → LAMA was 400 and all patients who used any second maintenance therapy was 
5,000, then the marginal proportion would be: 400 / 5000 = 0.08.  
Sankey plots will also be generated to visually illustrate the flow of patients from first to 
second maintenance therapy according to therapy category. 
9.7.1.2 
Time to Initiation of Therapy 
• Time Between Cohort Entry Date and First Maintenance Therapy 
 
Among patients with first maintenance therapy, the mean (SD) and median (IQR) time (days) 
between index date and first maintenance therapy will be reported in tabular form.  
 
• Time Between Cohort Entry Date and Second Maintenance Therapy 
 
Among patients with second maintenance therapy, the mean (SD) and median (IQR) time 
(days) between cohort entry date and second maintenance therapy will be reported in tabular 
form.  
 
• Time Between First and Second Maintenance Therapy 
 
Among patients with second maintenance therapy, the mean (SD) and median (IQR) time 
(days) between date of initiation of first to the date of initiation of second maintenance 
therapy will be reported in tabular form.  

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9.7.1.3 
Number of COPD Exacerbations 
• Number of COPD Exacerbations in the Year Before First Maintenance Therapy 
 
The child cohort described in section 9.2.2.2 will be used for this analysis. 
The mean (SD) and median number (IQR) of COPD exacerbations, defined in section 9.3.2.2, 
during the baseline period preceding the date of initiation of first maintenance therapy will be 
reported. For the mean, plots will be generated depicting the mean and SD (as error bars) 
number of COPD exacerbations. Categories of number of COPD exacerbations (0, 1, 2, 3, 4, 
5+) will also be reported as a percentage. 
 
• Number of COPD Exacerbations in the Year Before Second Maintenance Therapy 
 
The grandchild cohort described in section 9.2.2.3. will be used for this analysis. 
The mean (SD) and median number (IQR) of COPD exacerbations, defined in section 9.3.2.2, 
during the baseline period preceding the date of initiation of second maintenance therapy will 
be reported. Categories of number of COPD exacerbations (0, 1, 2, 3, 4, 5+) will also be 
reported as a percentage. 

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QUALITY CONTROL 
Aetion will build measures for cohort inclusion, outcomes and covariates. Some of the 
measure algorithms will be based on those collaboratively developed for another respiratory-
related protocol with clinical input from external pulmonology expert. When available, 
algorithms that have been validated in administrative databases will be used. When validated 
algorithms are not available, coding criteria will be based on clinical input and through 
searches of medical claim coding systems. 
 
All measures created, cohorts developed, statistical analyses implemented, and tables 
completed will undergo quality control review by at least 1 additional analyst or scientist 
under the supervision of the senior scientist. 
 
This protocol will be strictly followed in the study. All changes to this protocol will be 
documented in protocol amendments. 
 
The study protocol has been written following the Code of Conduct by the European Network 
of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) [R15-4870] that 
provides a set of rules and principles for post-authorisation studies with regard to the best 
practices and transparency, thereby promoting scientific independence of such studies. The 
study will be registered to the ENCePP’s E-register and the results will also be published on 
the same site. 
 
The study protocol also follows the key elements of the Guideline for Good 
Pharmacoepidemiology Practices (GPP) by International Society for Pharmacoepidemiology 
[R11-4318], and the recent draft Guidance for Industry and FDA Staff “Best Practices for 
Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic 
Healthcare Data Sets” [R15-4859]. 
 
Quality controls include checks for the validity and logical content of codes and checks for 
missing values and variables. In order to control for potential inconsistencies and errors, all 
variables will be tabulated. In addition, the distribution of each variable will be examined. 
Extreme observations with values larger than ± 3 standard deviations (SD) will be examined 
as potential outliers and consequently excluded from the dataset. 
 
LIMITATIONS OF THE RESEARCH METHODS 
MarketScan 
This study will be conducted using data from insurance claims and is subject to certain 
limitations. One limitation is that these are based on a large, non-random convenience 
sample, which may contain biases or lack generalizability to other populations. Data also 
come mostly from large employers, and although the database also includes a large amount of 
data from health plans, data from medium and small firms may be underrepresented. 

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Additionally, the MarketScan database also poses some limitations inherent to administrative 
claims data. Electronic outpatient pharmacy dispensing records are considered accurate 
because pharmacists fill prescriptions with little room for interpretation and are reimbursed 
by insurers on the basis of detailed, complete, and accurate claims submitted electronically 
(Stergachi 1988, Levy 2003). Pharmacy dispensing information is usually seen as the gold 
standard of drug exposure information compared to self-reported information (West 1995) or 
prescribing records in outpatient medical records (West 1994). However, drugs used during 
hospital stays are not recorded in this data source. Finally, while the EMR system records the 
prescribing of medications, including over-the-counter medications, it does not verify 
whether patients fill the medications at the pharmacy, and up to 50% of prescriptions are 
never filled (Fischer 2010). Further, these prescriptions do not ensure that medications were 
taken as prescribed, and any medications filled over-the-counter or provided as samples by 
the physician will not be observed in the claims data. Finally, patients are required not to 
have used any maintenance medications in the year before COPD claim confirming 
diagnosis, but use of these medications may have occurred beyond one year. 
 
CPRD 
This study will be conducted using data from electronic medical records, which is subject to 
certain limitations. While the electronic medical records from CPRD strive for high quality 
data, this relies upon correct entry of the data by health practitioners. Therefore, it is possible 
that there may be missing values where data has not been recorded, or values which have 
been recorded incorrectly. This may affect the data we have on patient demographics and 
comorbidities, and the factors we are interested in investigating which may influence the 
choice of therapy. 
Finally, prescription data is likely to be entered correctly as the electronic system requires 
that the data is input in order to generate a patient prescription. These prescriptions do not 
ensure that medications were taken as prescribed, and any medications filled over-the-counter 
or provided as samples by the physician will not be observed in the claims data. Finally, 
patients are required not to have used any maintenance medications in the year before COPD 
claim confirming diagnosis, but use of these medications may have occurred beyond one 
year. 
 
OTHER ASPECTS 
Not applicable. 
 
SUBJECTS 
 
Cases 
See Section 9.2.2. 

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Controls 
Not applicable. 
 
BIAS 
The population-based nature of the CPRD will avoid selection bias and ensure external 
validity. However, the validity of research based on any automated database depends on the 
quality and completeness of data recorded. The CPRD carries out a series of ongoing checks 
to ensure quality of the data; this comprises assessment of both patient data (age, gender, 
registration details and event dates) and the completeness, continuity and plausibility of 
electronic data recording in key areas at the practice level (for example, ensuring a minimum 
specified percentage of deaths have cause of death recorded, a minimum referral rate per 100 
patients, and a minimum number of prescriptions per patient per month) (Herrett 2015). 
Prescription data in the CPRD are known to be well documented as the prescriptions are 
automatically recorded in the database. The therapy file is therefore considered complete, 
except for prescriptions issued in secondary care and for drugs that are purchased over the 
counter (Herrett 2015). Validity of the diagnoses has been assessed in numerous validation 
studies. However, because this database is limited to general practice, specialist care and 
hospitalization events may not be captured. 
In principle, in the US when a patient goes to a pharmacy and gets a drug dispensed, the 
pharmacy bills the insurance carrier for the cost of that drug. Electronic outpatient pharmacy 
dispensing records are considered accurate because pharmacists fill prescriptions with little 
room for interpretation, and are reimbursed by insurers on the basis of detailed, complete, and 
accurate claims submitted electronically (Levy 2013, Stergachis 1988). Pharmacy dispensing 
information is usually seen as the gold standard of drug exposure information compared to 
self-reported information or prescribing records in outpatient medical records. Yet, the 
obvious limitation in these data is that drugs purchased out of pocket will not result in a 
pharmacy claim. 
To minimize misclassification of the recorded patient characteristics, previously validated 
algorithms or code lists will be used whenever available. Code lists will be reviewed by the 
qualified medical reviewers prior to implementation. Basic plausibility checks will be 
implemented for continuous variables (e.g. BMI, patient age etc.). 
 
PROTECTION OF HUMAN SUBJECTS 
The final study CPRD protocol will be submitted for approval to the Independent Scientific 
Advisory Committee (ISAC) (http://www.cprd.com/ISAC). 
 The CPRD has obtained ethical approval from a Multicentre Research Ethics Committee 
(MREC) for all observational research using CPRD data without patient involvement; 
however, ISAC may recommend that the MREC review the study documentation if any 
ethical issues arise.  

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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 in which the patient may be identified during data compilation, data 
reporting or data analysis. 
Based on current guidelines from the International Society for Pharmacoepidemiology [R11 
4318] and the EMA [R13-1970], non-interventional studies such as the one described in this 
protocol, conducted using health care records, do not require expedited reporting of suspected 
adverse events/reactions. Specifically, as stated in section VI.C.1.2.1 of Guideline on Good 
Pharmacovigilance Practices (GVP), Module VI – Management and Reporting of Adverse 
Reactions to Medicinal Products, for non-interventional study designs, which are based on 
use of secondary data, reporting of adverse reactions is not required. 
 
 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
The results of the study will primarily serve internal decision making for future studies on 
comparative effectiveness. These baseline results will be published as an abstract and/or 
manuscript. Conference and Journal to be decided. 
 
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