Comparative Effectiveness of Combination Therapies in COPD
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
 
TITLE PAGE 
Protocol for observational studies based on existing data 
TITLE PAGE 
Document Number:  
<Document Number> 
BI Study No.: 
0205-0538 
BI Investigational 
Product(s): 
Tiotropium bromide 
Title: 
Comparative effectiveness of combination therapies in COPD 
Title for lay people: 
Comparative effectiveness of combination therapies in COPD 
Date of last version of 
protocol: 
19 May 2017 
EU PAS Register No: 
only applicable for PASS 
tbd 
 
 
Marketing 
authorization holder(s): 
Boehringer Ingelheim GmbH 
Binger Straße 173 
55216 Ingelheim am Rhein 
Germany 
Author/Responsible 
Parties/BI contact 
person: 
Authors/Responsible parties: 
 
Tel:
 
 
Fax:
 
BI contact person:  
Tel.:
Fax:
E-mail:
Country(-ies) of study: 
United Kingdom 
Status: 
Final protocol 
 
 
EU-QPPV: 
only applicable for PASS 
 
 
Signature of EU-QPPV: 
only applicable for PASS 
[The signature of the EU-QPPV is provided electronically.] 

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Version and Date: 
Version 1.1, May 19, 2017 
Page 1 of 35 
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PROTOCOL ABSTRACT 
Name of company: 
 
ABCD 
Boehringer Ingelheim  
Name of product:  
Spiriva 
 
Name of active ingredient: 
Tiotropium bromide 
 
 
 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
19 May 2017 
0205-0538 
1.1 
Version 1.1, May 19, 
2017 
Proprietary confidential information 
© 2017 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 
Title of study: 
Comparative effectiveness of combination therapies in COPD 
Team member 
Epidemiology: 
 
Project team: 
 
(Principal investigator) 
Rationale and 
background: 
The treatment of COPD increasingly involves multiple therapies, including long-
acting bronchodilators (LAMAs and LABAs) and inhaled corticosteroids (ICS), with 
combinations of these drugs now formulated into single inhalers. The use of ICS has 
increased disproportionately with respect to COPD treatment guidelines and may be 
inappropriate in a subset of these users [P15-12888; P16-12287]. New evidence 
suggests that patients can be safely weaned off ICS, including the WISDOM trial that 
observed no difference in the risk of moderate or severe exacerbations between 
patients who discontinued ICS and those who continued receiving ICS [P14-13477]. 
Moreover, discontinuation of ICS has been associated with a reduction in the risk of 
pneumonia [P15-13167]. While most trials of the combination treatments have been 
conducted against the respective mono components or placebo, very few head-to-head 
trials versus other combinations have been performed to date. For example, the recent 
FLAME randomized trial reported that patients receiving the LABA-LAMA 
combination had fewer exacerbations than those receiving the LABA-ICS 
combination over a one-year follow-up period [P16-05628]. Also, the ENERGITO 
trial reported significant improvements in lung function with a LAMA/LABA 
combination versus LABA/ICS in GOLD 2-3 patients after 6 weeks of treatment 
[P16-01440]. These trials, however, represent a limited view of the patients who 
could potentially use these treatments, with many exclusion criteria based on for 
example stage of disease, lung function and exacerbation history, as well as 
exclusions of many patients during the screening and run-in periods.  Thus, a real-
world study of patients who are representative of clinical practice is of interest. 
As many of these drugs have been in use in separate inhalers for many years, an 
observational study of their comparative effectiveness is feasible and would provide 
useful data on the relative benefits of these different combinations in the treatment of 
COPD. The intended audience is the scientific community, patients, payers and 
prescribers.  The results from the study will be published in the scientific literature. 

Boehringer Ingelheim  
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Protocol for observational studies based on existing data 
0205-0538 
 
 
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
Name of company: 
 
ABCD 
Boehringer Ingelheim  
Name of product:  
Spiriva 
 
Name of active ingredient: 
Tiotropium bromide 
 
 
 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
19 May 2017 
0205-0538 
1.1 
Version 1.1, May 19, 
2017 
Proprietary confidential information 
© 2017 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 
Research question and 
objectives: 
Primary: To assess the effectiveness of maintenance treatment of COPD with the 
combination of the LAMA tiotropium with a LABA compared with the combination 
of a LABA with ICS on the time to COPD exacerbation. 
Secondary: To compare the effectiveness on the rate of exacerbation and the safety on 
the incidence of community acquired pneumonia for LABA and tiotropium with 
LABA and ICS. 
Study design: 
A prevalent new-user cohort design will be used, with time-conditional propensity 
scores to match the two comparison groups. 
Population: 
The base cohort will consist of all patients with a diagnosis of COPD who received at 
least one prescription for a long-acting bronchodilator, either LABA or the LAMA 
tiotropium, or for an inhaled corticosteroid from 1 January 2002 until 31 December 
2015. To increase the likelihood of a diagnosis of COPD, we only include patients 55 
years of age or older on the date of this initial prescription and exclude all patients 
with a prior diagnosis of asthma.    
The primary study cohort will first be defined as the members of the base cohort with 
their first concurrent prescriptions of a LABA and tiotropium on the same date. 
Patients initiating a LABA and tiotropium will not include users of a LABA+ICS 
fixed dose combined inhaler.  
Patients receiving for the first time a LABA and tiotropium on the same day will be 
propensity score and time matched with members of the base cohort who initiate 
treatment with LABA and ICS on the same day, either as a fixed-dose combination 
or free combination.   
Subjects will need to have at least one year of medical history information prior to 
the date of combined treatment initiation (cohort entry date) to allow the 
identification of new use and the measurement of baseline covariates. Subjects will 
be followed for up to one year from the date of combined treatment initiation, or until 
switching to the other treatment, the date of death, 31 December 2016, or the end of 
coverage in the practice, whichever occurs first. 
Study data source: 
 
United Kingdom’s Clinical Practice Research Datalink (CPRD) linked with the 
Hospital Episodes Statistics (HES) database 
Expected study size: 
New users of LABA and tiotropium : 3,000 
New users of LABA and ICS: 3,000 
Main criteria for 
inclusion: 
- New users of long-acting bronchodilators, LABA and tiotropium on the same date or 
of LABA and ICS, either as a fixed-dose combination or free combination, on the 
same date between January 2002 and December 2015. 
- Diagnosis of COPD and age ≥ 55 years  

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Protocol for observational studies based on existing data 
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
Name of company: 
 
ABCD 
Boehringer Ingelheim  
Name of product:  
Spiriva 
 
Name of active ingredient: 
Tiotropium bromide 
 
 
 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
19 May 2017 
0205-0538 
1.1 
Version 1.1, May 19, 
2017 
Proprietary confidential information 
© 2017 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 
Main criteria for 
exclusion: 
-Less than one year of medical history information prior to the date of combined 
treatment initiation (cohort entry) 
-Asthma diagnosis 
Comparison groups: 
Initiating LABA and tiotropium compared to initiating LABA and ICS therapy 
Expected duration of 
exposure: 
One year for the primary and secondary analyses 
 

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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
PROTOCOL ABSTRACT ...................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................ 6 
LIST OF TABLES ................................................................................................................... 8 
LIST OF FIGURES ................................................................................................................. 9 
1. 
LIST OF ABBREVIATIONS AND TERMS  ---.............................................. 10 
2. 
RESPONSIBLE PARTIES ................................................................................ 11 
3. 
AMENDMENTS AND UPDATES .................................................................... 12 
4. 
MILESTONES .................................................................................................... 13 
5. 
RATIONALE AND BACKGROUND .............................................................. 14 
6. 
RESEARCH QUESTIONS AND OBJECTIVES ............................................ 15 
7. 
RESEARCH METHODS ................................................................................... 16 
7.1 
STUDY DESIGN ................................................................................................. 16 
7.2 
SETTING ............................................................................................................. 16 
7.3 
SUBJECTS .......................................................................................................... 16 
7.4 
VARIABLES ....................................................................................................... 17 
7.4.1 
EXPOSURES ....................................................................................................... 17 
7.4.2 
OUTCOME(S) ..................................................................................................... 17 
7.4.2.1 
PRIMARY OUTCOME(S) ................................................................................... 17 
7.4.2.2 
SECONDARY OUTCOME(S)............................................................................. 18 
................................................................................. 18 
7.4.3 
COVARIATES .................................................................................................... 18 
7.5 
DATA SOURCES ............................................................................................... 19 
7.6 
BIAS ..................................................................................................................... 19 
7.7 
STUDY SIZE ....................................................................................................... 19 
7.8 
DATA MANAGEMENT .................................................................................... 20 
7.9 
DATA ANALYSIS .............................................................................................. 20 
7.9.1 
MAIN ANALYSIS .............................................................................................. 20 
................................................................................... 21 
7.10 
QUALITY CONTROL ....................................................................................... 22 
7.11 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 22 
7.12 
OTHER ASPECTS ............................................................................................. 22 
8. 
PROTECTION OF HUMAN SUBJECTS ....................................................... 23 
9. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS .................................................................. 24 
10. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS ............................................................................................................ 25 
11. 
REFERENCES .................................................................................................... 26 

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11.1 
PUBLISHED REFERENCES ............................................................................ 26 
11.2 
UNPUBLISHED REFERENCES ...................................................................... 27 
12. 
FUNDING ............................................................................................................ 27 
13. 
ANNEX ................................................................................................................ 28 
ANNEX 1: LIST OF STAND-ALONE DOCUMENTS ..................................................... 28 
ANNEX 2: ENCEPP CHECKLIST FOR STUDY PROTOCOLS ................................... 29 
ANNEX 3: ADDITIONAL INFORMATION ..................................................................... 35 
ANNEX 3.1: DEFINITION OF STUDY EXPOSURES ..................................................... 35 
ANNEX 3.2: DEFINITIONS OF STUDY OUTCOMES ................................................... 35 
ANNEX 3.3: DEFINITIONS OF STUDY COVARIATES ................................................ 35 
ANNEX 3.4: STATISTICAL CONSIDERATIONS ........................................................... 35 
 
 
 
 
 
 

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LIST OF TABLES  
 
There are not tables included in the document 
 

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LIST OF FIGURES 
 
There are not figures included in the document 
 
 

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1. 
LIST OF ABBREVIATIONS AND TERMS  ---   
AE 
Adverse Event 
BI 
Boehringer Ingelheim 
CI 
Confidence Interval 
COPD 
Chronic obstructive pulmonary disease 
CPRD 
Clinical Practice Research Datalink 
ICS 
Inhaled corticosteroids 
IR 
Incidence Rate 
LABA 
Long-acting beta2-agonist 
N 
Number 
PS 
Propensity score 
PSTAT 
Project Statistician 
PY 
Person-years at risk 
RR 
Rate Ratio 
TM Epi 
Team Member Epidemiology 
UTS 
Up-to-standard 
 
 

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2. 
RESPONSIBLE PARTIES 
 (principal investigator) 
Tel:
 
 
Fax:
 

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3. 
AMENDMENTS AND UPDATES 
There are currently no amendments to the protocol.  
 
 

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4. 
MILESTONES 
 
Milestone 
Planned date 
Start of data collection: 
Data extraction and 
coding 
June 1, 2017 
End of data collection: 
Not applicable. This study is an observational study based on 
existing data.  
Study progress report(s) 
as referred in Article 
107m(5) of Directive 
2001/83/EC: 
tbd 
Interim report(s) of study 
results: 
Preliminary results: 30 December 2017 
 
Registration in the EU 
PAS register 
tbd 
Final report of study 
results: 
May 2018 
 
 
 
 
 

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5. 
RATIONALE AND BACKGROUND 
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality 
throughout the world [P07-11503].  It has recently risen to become the third leading cause of 
death in the US [R13-1383; minion et al. 2010].  Long-acting bronchodilator medications, that 
include long-acting beta2-agonists (LABAs) and the long-acting muscarinic antagonists 
(LAMAs) such as the anticholinergic tiotropium, have become central maintenance therapy 
to the management of COPD, with inhaled corticosteroids (ICS) added with increasing 
severity[P07-11503].   
 
As a result, the treatment of COPD increasingly involves using several of these drugs, with 
some of their combinations now formulated into single inhalers. The use of ICS has, 
however, increased disproportionately with respect to COPD treatment guidelines and may 
be inappropriate in a subset of patients, with new evidence suggesting that patients can be 
safely weaned off ICS.[ P15-12888; P16-12287] Indeed, the large WISDOM trial observed 
no difference in the risk of moderate or severe exacerbations between patients who 
discontinued ICS and those who continued receiving ICS, while the OPTIMO study also 
observed no deterioration of lung function, symptoms, and exacerbation rate after withdrawal 
[P14-13477; P14-13078]. Moreover, discontinuation of ICS has been associated with a 
reduction in the risk of pneumonia [P15-13167].  While most trials of the combination 
treatments have been conducted against the respective mono components or placebo, few 
head-to-head trials versus other combinations have been performed to date. For example, the 
recent FLAME randomized trial reported that patients receiving the LABA-LAMA 
combination had fewer exacerbations than those receiving the LABA-ICS combination over 
a one-year follow-up period [P16-05628]. Similarly, the ENERGITO trial reported 
significant improvements in lung function with a LABA/LAMA combination versus 
LABA/ICS in GOLD 2-3 patients after 6 weeks of treatment [P16-01440].  
 
These trials, however, were limited by the fact that a majority of the patients were already 
using these treatments that they had to discontinue and enter a run-in period before 
randomisation, which does not emulate the clinical setting. Moreover, the trials represent a 
limited view of the patients who could potentially use these treatments, with several 
exclusion criteria involving for example stage of disease, lung function and exacerbation 
history, in addition to the exclusions of many patients during the screening and run-in 
periods.  Thus, a real-world study of patients who are representative of clinical practice is of 
interest. Finally, assessing the effectiveness in terms of COPD exacerbations should be 
balanced against the safety of ICS with respect to pneumonia in the context of real-world 
clinical practice.   
 
 
 
 
 

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6. 
RESEARCH QUESTIONS AND OBJECTIVES 
The primary objective of this study is to assess the effectiveness of maintenance treatment of 
COPD with the combination of a LABA and the LAMA tiotropium (LABA-TIO) compared 
with the combination of a LABA and an ICS (LABA-ICS) on the time to COPD 
exacerbation.  More specifically, the patients who initiate treatment with a combination of a 
LABA and tiotropium at the same time, or who are on a LABA (no ICS) and who add 
tiotropium, or who are on tiotropium and add a LABA (no ICS), will be compared with 
similar patients who receive a LABA and an ICS on the time to first COPD exacerbation.  
 
The secondary objective is to assess the comparative effectiveness on the rate of exacerbation 
and the comparative safety on the incidence of community acquired pneumonia.   
 
 
 
 

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7. 
RESEARCH METHODS 
7.1 
STUDY DESIGN 
Population-based propensity score-matched new-user cohort study.  
7.2 
SETTING 
The study will be conducted in a general practice setting, within the United Kingdom’s 
Clinical Practice Research Datalink (CPRD; details in Section 7.5). It will be restricted to the 
practices which can be linked to the Hospital Episodes Statistics (HES) database. The 
maximal observation period will be from January 1995 until December 2016.  
7.3 
SUBJECTS 
The base cohort will consist of all patients with a diagnosis of COPD from 1 January 1995 
until 31 December 2015 who subsequently received at least one prescription for a long-acting 
bronchodilator, either LABA or tiotropium, or for an inhaled corticosteroid, alone or in 
combination, from 1 January 2002 until 31 December 2015.  The time span for the study was 
selected to ensure that LABAs and tiotropium were concurrently available, in view of the 
differing dates of market entry for LABAs (1990s) and tiotropium (2002).  To increase the 
likelihood of a diagnosis of COPD, we will exclude all patients less than 55 years of age on 
the date of their initial prescription for these drugs during this time period and exclude all 
patients with a previous diagnosis of asthma. Because the definition of some outcomes under 
study involve hospitalization, the base cohort will be restricted to the practices which can be 
linked to the Hospital Episodes Statistics (HES) database (please refer to section 7.5).  
 
Study Cohort 
The study cohort will be formed from the base cohort using an incident new-user cohort 
design with time-conditional propensity scores [P17-04653].  We will thus identify from the 
base cohort all subjects who, during follow-up, received for the first time prescriptions for a 
LABA and a tiotropium on the same day, but no inhaled corticosteroid. This can occur as the 
first time they received a long-acting bronchodilator, with both a LABA and tiotropium as 
initial treatment, or with initial treatment with a single long-acting bronchodilator followed 
by the addition of the other long-acting bronchodilator.  We will then identify from the base 
cohort all subjects who, during follow-up, received for the first time prescriptions for a 
LABA and an ICS on the same day, as two different prescriptions or in a single inhaler, but 
no tiotropium. Here again, this can occur as the first time they received a LABA and ICS as 
initial treatment, or with initial treatment with a LABA followed by the addition of ICS or 
vice versa. Cohort entry will be taken as the first date that LABA and tiotropium or LABA 
and ICS prescriptions are given simultaneously.  All subjects will require at least one year of 
up-to-standard (UTS) medical history prior to study cohort entry to allow a baseline period 
for the covariates and identification of new use. New use will thus be defined as the first 
simultaneous prescriptions for LABA and tiotropium or for LABA and ICS, preceded by 
prescriptions for only one of the two drug classes or none in the baseline year. 
 
To form the study cohort, we will identify, for each subject initiating LABA and tiotropium 
(LABA-TIO) treatment, a matched LABA-ICS comparator subject using a time-conditional 

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propensity score-matched approach. The potential comparator subjects will be selected from 
the base cohort by forming time-based exposure sets defined by the calendar year of entry 
into the base cohort for the LABA-TIO and LABA-ICS simultaneous prescription users. To 
allow matching on the propensity of treatment choice, we will compute high-dimensional 
time-conditional propensity scores (TCPS) by identifying all available data (e.g., diagnoses, 
procedures, medications) in the one-year period prior to the date of cohort entry for each 
time-based exposure set using Cox proportional hazards regression. Then, for each LABA-
TIO exposed subject, and starting chronologically with the first one, we will identify a 
matched comparator subject from the members of the subject’s time-based exposure set. We 
will first match subjects on sex, previous components of the study treatment (LABA only, 
TIO only, ICS alone, none of these) and the presence of an acute COPD exacerbation in the 
year before cohort entry. The matched reference subject will then be selected as the one with 
the closest time-conditional propensity score in the matched set, after trimming within each 
exposure set, and allowing a maximum difference in scores of 0.05 for a match. In the 
absence of a tight propensity score match, we will take the closest and the analysis will be 
complemented by an adjustment for the propensity score.   
 
After matching, the subjects in the study cohort will be followed up for up to one year from 
cohort entry (the date of the matched set), with follow-up ending at the earliest of the date of 
a switch or addition of either an ICS for the LABA-TIO group or of tiotropium to the LABA-
ICS group, death, one year after cohort entry, December 31, 2016, or the end of coverage in 
the practice, whichever occurs first. 
 
7.4 
VARIABLES 
7.4.1 
EXPOSURES 
The exposure measures are based on the prescription of the two long-acting bronchodilators 
under study, namely LABAs and tiotropium, as well as ICS. As described in the data analysis 
section, the as-treated analysis, which is the main analysis, will consider exposure as current 
use of LABA-TIO or LABA-ICS within the treated groups defined as within the 60-day 
period after the prescriptions’ dispensing dates.  
 
7.4.2 
OUTCOME(S) 
7.4.2.1 
PRIMARY OUTCOME(S) 
The primary outcome event is the first COPD exacerbation to occur after cohort entry.  The 
event is defined as a hospitalization for COPD (severe exacerbation) or the prescription of an 
oral corticosteroid, namely prednisolone (moderate exacerbation). 

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7.4.2.2 
SECONDARY OUTCOME(S) 
The first secondary outcome is the rate of COPD exacerbations over the one-year follow-up.  
This outcome will be based on the number of hospitalizations and on the number of courses 
of treatment with an oral corticosteroid. A gap of at least 30 days between treatment courses 
will be required to consider the exacerbations as separate events. The second secondary 
outcome is the occurrence of the first hospitalization for community-acquired pneumonia 
(serious pneumonia). Pneumonia will be defined from the following ICD10 codes: J10.0; 
J11.0; J12-J18; J22; J69; J85.0; J85.1; J86.  This definition has been used successfully in 
COPD [P07-09514; P16-10095].     
7.4.3 
COVARIATES 
Sex, previous treatment and previous acute COPD exacerbation, as well as calendar year of 
cohort entry, are all matching factors and will thus inherently be accounted for.  
 
Although we will use the high-dimensional approach to identify variables entering the time-
conditional propensity score, some key covariates will be highlighted. First, we will identify 
key lifestyle variables available in the CPRD, known to be risk factors and potential 
confounders, including the body mass index (BMI), smoking status and excessive alcohol 
consumption. Missing data for smoking status and BMI will be entered as an additional 
category in the model. We will also explore the possibility of obtaining blood eosinophils 
measured in the year prior to cohort entry and will use this information only if complete. 
 
Second, the occurrence of the study outcomes prior to cohort entry will be identified during 
the one-year baseline period and adjusted for in the analysis if found to be imbalanced 
between treatment groups after propensity score matching. In particular, COPD exacerbations 
occurring in the 30 days prior to the study cohort entry date, a marker of COPD exacerbation 
risk, will be identified separately from those occurring previously during the baseline year.  
In addition, the severe exacerbations requiring hospitalizations will be counted, while the 
moderate exacerbations will be identified from counts of prescriptions for oral 
corticosteroids. 
  
Third, use of other respiratory drugs during the baseline period will be included as a measure 
of COPD severity. Thus, the number of prescriptions for short-acting beta-agonists, 
anticholinergics, methylxanthines and muscarinic antagonists used during the year prior to 
cohort entry will be identified. As well, the number of prescriptions for antibiotics for a 
respiratory condition will be counted. In addition, we will count the number of prescriptions 
for the study drugs used during the baseline period.  These will be combined into a single 
variable because of the study design which inherently selects patients into the two study 
groups according to their prior LABA, TIO or ICS use.  Finally, for each of the cohorts, 
baseline co-morbidity will be measured using diagnoses and prescriptions for various 
conditions observed often in patients with COPD, namely cardiovascular disease, diabetes, 
thyroid disease, renal failure, autoimmune disease and cancer, all in the year prior to cohort 
entry.   

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7.5 
DATA SOURCES  
The Clinical Practice Research Datalink (CPRD) will be used for this study. It includes 
computerized medical records of more than 12 million patients from more than 650 general 
practices in the United Kingdom. General practitioners, using standardized recording of 
medical information, record data on the patient’s demographic characteristics, symptoms, 
history, medical diagnoses, and drug prescriptions, as well as details of referrals to specialists 
and hospitals. The completeness and validity of the recorded information on diagnoses, coded 
using READ codes, and drug exposures, coded using a coding system with a direct mapping 
to the NHS dictionary of medicines and devices, are checked on an ongoing basis by staff of 
the CPRD and have been shown in several studies [R11-2162; R16-2198]. In addition, the 
CPRD can be linked by unique identifier to the Hospital Episodes Statistics (HES) database 
which provides extensive information on all hospitalizations, coded using ICD-10 codes, 
including data on length of stay, ward types, as well as extensive disease and procedure 
coding, based on OPCS4 (Office of Population Censuses and Surveys Classification of 
Interventions and Procedures) codes.  The linkage between the CPRD and the HES databases 
applies to over half of the practices contributing to the CPRD.  The database has been used 
for the study of numerous diseases, including studies of COPD [R16-2197; P16-10095].   
7.6 
BIAS 
Several potential biases inherent to any observational study need to be considered. First, 
confounding by indication could be an issue. Matching subjects initiating LABA-TIO with 
subjects initiating LABA-ICS on several marker of disease, including prior COPD 
exacerbations, previous treatment and on the propensity score should limit this potential bias 
since matched subjects will have comparable probability of using either combination. In 
addition to matching on the propensity score, sex, prior exacerbation, prior treatment and 
calendar time, several variables such as general severity of COPD, comorbidity and 
concomitant drug use will be in the propensity score and adjusted for in the outcome model.  
Second, there is the possibility of information bias due to misclassification of the outcomes or 
exposure. CPRD contains prescriptions written by the GP rather than filled or taken by 
patients. This could be a source of misclassification of exposure. Another source of 
information bias due that we will investigate is immeasurable time bias due to the presence of 
hospitalizations during follow-up, particularly during the current exposure window, where 
GP prescriptions are not available, so that exposure is not measurable. Finally, the linkage to 
HES data to identify hospitalization for COPD exacerbation and for community-acquired 
pneumonia should reduce the potential for misclassification of outcomes.  
7.7 
STUDY SIZE 
In our previous study of the cardiovascular effects of long-acting bronchodilators, there were 
around 230,000 users of LABA or TIO between 2002 and 2012 in the CPRD, which should 
include around 140,000 who come from HES-linked practices [P16-10095]. From these, we 
expect around 4,000 who received a LABA and tiotropium on the same day, where the 
LABA is not combined with an inhaled corticosteroid in a single inhaler. The number of 
users of LABA-ICS is over 100,000, providing a large pool for matching purposes. Thus, 
after matching and trimming, we expect the study to include a minimum of 3,000 patients per 
arm, a conservative estimate.  Using recent data from the FLAME trial [P16-05628], we 
expect that the cumulative incidence of a first COPD exacerbation, moderate or severe, 

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during the one-year follow-up is expected to be 50%.  These sample sizes will permit to 
detect a 15% reduction in the risk of a first exacerbation (hazard ratio 0.85) with 99% power 
and a 10% reduction (hazard ratio 0.90) with 97% power. For the severe exacerbations, we 
expect the one-year cumulative incidence to be around 15%, which will permit to detect a 
20% reduction in the risk of a first severe exacerbation (hazard ratio 0.80) with 92% power.   
7.8 
DATA MANAGEMENT 
All data related to this study will be stored on secured and encrypted database servers of the 
Data Management Unit Datacentre, located in the Centre for Clinical Epidemiology, Lady 
Davis Institute for Medical Research of the Jewish General Hospital, Montreal.  The Centre 
for Clinical Epidemiology is equipped with an electronic access card system which is limited 
to the research staff and students of the Centre. The DMU Datacentre has a unique electronic 
access card system which is limited to specific personnel only. The building is under 24/7 
video surveillance and regular scheduled round trips by security guards are done. The DMU 
Datacentre is monitored and managed for data access, data integrity and backup. The DMU 
Datacentre uses proven technology to safeguard its data, including Cisco ASA firewalls, 
IDS/IPS, antivirus, anti-spyware, hard drive encrypted, user access tracking, backup of all 
data. Copies of backed up files are kept in a safe outside of the institution.  
 
All statistical analyses for the study will be conducted using SAS, Version 9.4 (SAS institute, 
Inc., Cary, NC) and R (R Foundation for Statistical Computing, Vienna, Austria; 
http://www.R-project.org/). All programs written by the statistical programmer, coding of 
variables, outputs and protocol amendments are stored in the servers. Access to the files 
related to a study is password-protected on the server and accessible only to the study 
statisticians. For ethical and scientific reasons, data and documentation are kept for five years 
following the publication date. 
 
7.9 
DATA ANALYSIS 
7.9.1 
MAIN ANALYSIS 
For the base cohort, patient characteristics at baseline will be described using standard 
descriptive statistics. The unmatched study cohort, which will also address the tertiary 
objective, will be used to provide and compare baseline patient characteristics between the 
two groups. These comparisons will also be provided for the matched cohort.   
 
For the analysis of the primary objective, the matched cohort will be used to estimate the 
crude 1-year cumulative incidence of severe and moderate COPD exacerbations for the two 
combination treatment groups. The main comparative analysis will also be based on the 
matched cohort and a time-dependent Cox proportional hazard regression model to perform 
an as-treated analysis that assesses the effect of current use of LABA-TIO combination 
versus the LABA-ICS combination on the risk of a first COPD exacerbation. It will provide 
an estimate of the hazard ratio (HR) of a COPD exacerbation associated with LABA-TIO use 
relative to LABA-ICS use, along with 95% confidence intervals (CI). Current use will be 
defined as a prescription dispensed within the 60-day period of the date defined by the risk 
set of the Cox model. This approach allows consideration of exposure as time-dependent, 
accounting for the changes in exposure during the follow-up.  In particular, this analysis 

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censors patients stopping one or both of the drugs prior to the index date. Besides the 
matching inherent in the design, the Cox proportional hazard regression model will be 
adjusted for additional confounders.  This model will include patient characteristics found to 
be different after matching on propensity scores, as well as the decile of propensity score. 
Body mass index (BMI) is expected to be the only variable with missing data in the CPRD, 
though infrequently (less than 4% of subjects in our previous studies in COPD).  Patients 
with missing BMI will be classified as a separate category. 
 
The analysis of the secondary objective related to the rate of exacerbation will be based on 
the negative binomial regression models, which corresponds to a Poisson regression model 
adjusted for between-subject variation in exacerbations, with the same approach to covariate 
adjustment as the primary analysis. A 30-day gap between events will be used to distinguish 
between one continuous exacerbation and two separate events.  The analysis of the secondary 
objective related to the risk of pneumonia will use a time-dependent Cox proportional hazard 
regression model with an as-treated approach, similar to that of the primary analysis.  
 

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7.10 
QUALITY CONTROL 
All data will be stored in the servers of the McGill Pharmacoepidemiology Research Unit 
located within the Center for Clinical Epidemiology.  In accordance with the CPRD 
regulations, these data are secure within the Center which is protected by an electronic 
keypad entry system.  All data will be kept for a period of five years after publication of the 
paper from this study.  Documentation on the data selection, definitions and programs will be 
available in the Center for inspection. 
 
Our McGill Pharmacoepidemiology Research Unit is quite familiar with the CPRD and has 
published over 100 scientific articles using this database since 2005. 
7.11 
LIMITATIONS OF THE RESEARCH METHODS 
Several potential biases inherent to any observational study need to be considered. Because 
this is primarily a study of effectiveness, confounding by indication is among the most 
important potential sources of bias in the absence of randomisation. However, matching the 
two groups on prior COPD exacerbations, prior treatments and on the propensity score should 
limit this potential bias. The possibility of information bias due to misclassification of the 
outcomes or exposure is present. Indeed, the CPRD includes prescriptions written by the GP 
rather than filled or taken by patients, which could be a source of misclassification of 
exposure and the outcome of a moderate exacerbation defined by prescriptions. With respect 
to the other outcome definitions, the linkage to HES data to identify hospitalization for 
COPD exacerbation and for community-acquired pneumonia should also reduce the potential 
for misclassification of outcomes.  
 
7.12 
OTHER ASPECTS  
None 

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8. 
PROTECTION OF HUMAN SUBJECTS 
 
This study is based on existing data collected in general practices and does not require patient 
informed consent. All data used for this study are anonymized. 
 
Approval of the study protocol will be obtained from the Independent Scientiﬁc Advisory 
Committee (ISAC) for the U.K. Medicines and Healthcare Products Regulatory Agency 
before coding, extraction, and processing of CPRD data. Ethics approval for this study will 
be obtained from the Research Ethics Committee of the Jewish General Hospital, Montreal, 
Canada. 
 

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9. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
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. 

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10. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
We plan to publish the study in a peer-reviewed medical journal. 
Authorship and publication will follow the corresponding BI SOP 001-MCS-00-002 and 
guidelines of good scientific practice. 

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11. 
REFERENCES 
 
11.1 
PUBLISHED REFERENCES 
P07-11503 
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. 
R13-1383 
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. 
R13-4036 
Minino AM, Xu J, Kochanek KD. Deaths: Preliminary data for 2008. National Vital 
Statistics Reports NCHS 2010;59(2). 
P15-12888 
Suissa S, Rossi A. Weaning from inhaled corticosteroids in COPD: the evidence. Eur 
Respir J 2015;46(5):1232-1235. 
P16-12287 
Yawn BP, Suissa S, Rossi A. Appropriate use of inhaled corticosteroids in COPD: 
the candidates for safe withdrawal. NPJ Prim Care Respir Med 2016;26:16068. 
P14-13477 
Magnussen H, Disse B, Rodriguez-Roisin R et al. Withdrawal of inhaled 
glucocorticoids and exacerbations of COPD. N Engl J Med 2014;371(14):1285-1294. 
P14-13078 
Rossi A, Guerriero M, Corrado A. Withdrawal of inhaled corticosteroids can be safe 
in COPD patients at low risk of exacerbation: a real-life study on the appropriateness 
of treatment in moderate COPD patients (OPTIMO). Respir Res 2014;15:77. 
P15-13167 
Suissa S, Coulombe J, Ernst P. Discontinuation of Inhaled Corticosteroids in COPD 
and the Risk Reduction of Pneumonia. Chest 2015;148(5):1177-1183. 
P16-05628 
Wedzicha JA, Banerji D, Chapman KR et al. Indacaterol-Glycopyrronium versus 
Salmeterol-Fluticasone for COPD. N Engl J Med 2016;374(23):2222-2234. 
P16-01440 
Beeh KM, Derom E, Echave-Sustaeta J et al. The lung function profile of once-daily 
tiotropium and olodaterol via Respimat((R)) is superior to that of twice-daily 
salmeterol and fluticasone propionate via Accuhaler((R)) (ENERGITO((R)) study). 
Int J Chron Obstruct Pulmon Dis 2016;11:193-205. 
P17-04653 
Suissa S, Moodie EE, Dell'Aniello S. Prevalent new-user cohort designs for 
comparative drug effect studies by time-conditional propensity scores. 
Pharmacoepidemiol Drug Saf 2017;26(4):459-468. 
P07-09514 
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. 
R11-2162 
Jick SS, Kaye JA, Vasilakis-Scaramozza C et al. Validity of the general practice 
research database. Pharmacotherapy 2003;23(5):686-689. 
R16-2198 
Lawrenson R, Williams T, Farmer R. Clinical information for research; the use of 
general practice databases. J Public Health Med 1999;21(3):299-304. 
R16-2197 
Quint JK, Mullerova H, DiSantostefano RL et al. Validation of chronic obstructive 
pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-
GOLD). BMJ Open 2014;4(7):e005540. 
P16-10095 
Suissa S, Dellaniello S, Ernst P. Long-acting bronchodilator initiation in COPD and 
the risk of adverse cardio-pulmonary events: A population-based comparative safety 
study. Chest 2017; 151(1):60-67 
 

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11.2 
UNPUBLISHED REFERENCES 
none 
 
 
 
 
 
 
12. 
FUNDING 
There are no additional sources of funding.  

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13. 
ANNEX 
ANNEX 1: LIST OF STAND-ALONE DOCUMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ANNEX 2: ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
ENCePP Checklist for Study Protocols (Revision 2, amended) 
Adopted by the ENCePP Steering Group on 14/01/2013 
 
Study title: 
Combined bronchodilators in chronic obstructive pulmonary disease and the risk of adverse cardio-
pulmonary events: A population-based observational study 
 
 
 
 
Section 1: Milestones 
 
Yes 
No 
N/A 
Page 
Number(s) 
1.1 Does the protocol specify timelines for  
1.1.1 Start of data collection1 
1.1.2 End of data collection2 
1.1.3 Study progress report(s)  
1.1.4 Interim progress report(s) 
1.1.5 Registration in the EU PAS register 
1.1.6 Final report of study results. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 
16 
13 
13 
      
13 
Comments: 
      
 
Section 2: Research question 
 
Yes 
No 
N/A 
Page 
Number(s) 
2.1 Does the formulation of the research question and 
objectives clearly explain:  
 
2.1.1 Why the study is conducted? (e.g. to address an 
important public health concern, a risk identified in the risk 
management plan, an emerging safety issue) 
 
2.1.2 The objective(s) of the study? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 
 
15 
 
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised) 
 
2.1.4 Which formal hypothesis(-es) is (are) to be 
tested?  
 
2.1.5 If applicable, that there is no a priori 
hypothesis? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 
 
15 
 
      
Comments: 
      
 
 
                                                 
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts. 
2 Date from which the analytical dataset is completely available. 

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Section 3: Study design 
 
Yes 
No 
N/A 
Page 
Number(s) 
3.1 Is the study design described? (e.g. cohort, case-
control, randomised controlled trial, new or alternative design)  
 
 
 
16 
3.2 Does the protocol specify the primary and 
secondary (if applicable) endpoint(s) to be 
investigated? 
 
 
 
17-18 
3.3 Does the protocol describe the measure(s) of 
effect? (e.g. relative risk, odds ratio, deaths per 1000 
person-years, absolute risk, excess risk, incidence rate ratio, 
hazard ratio, number needed to harm (NNH) per year) 
 
 
 
20 
Comments: 
      
 
Section 4: Source and study populations 
 
Yes 
No 
N/A 
Page 
Number(s) 
4.1 Is the source population described? 
 
 
 
16 
4.2 Is the planned study population defined in terms 
of: 
4.2.1 Study time period? 
4.2.2 Age and sex? 
4.2.3 Country of origin? 
4.2.4 Disease/indication?  
4.2.5 Co-morbidity? 
4.2.6 Seasonality? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 
16 
16 
16 
      
      
4.3 Does the protocol define how the study population 
will be sampled from the source population? (e.g. 
event or inclusion/exclusion criteria)   
 
 
 
 
 
 
 
16 
Comments: 
      
 
Section 5: Exposure definition and measurement 
 
Yes 
No 
N/A 
Page 
Number(s) 
5.1 Does the protocol describe how exposure is 
defined and measured? (e.g. operational details for 
defining and categorising exposure)  
 
 
 
 
 
 
 
17 
5.2 Does the protocol discuss the validity of exposure 
measurement? (e.g. precision, accuracy, prospective 
ascertainment, exposure information recorded before the 
outcome occurred, use of validation sub-study) 
 
 
 
 
 
 
 
19 
5.3 Is exposure classified according to time windows? 
(e.g. current user, former user, non-use) 
 
 
 
 
 
 
 
17 
5.4 Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug? 
 
 
 
 
 
 
 
      

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Section 5: Exposure definition and measurement 
 
Yes 
No 
N/A 
Page 
Number(s) 
5.5 Does the protocol specify whether a dose-
dependent or duration-dependent response is 
measured? 
 
 
 
20 
Comments: 
      
 
Section 6: Endpoint definition and measurement 
 
Yes 
No 
N/A 
Page 
Number(s) 
6.1 Does the protocol describe how the endpoints are 
defined and measured?  
 
 
 
 
 
 
 
17-18 
6.2 Does the protocol discuss the validity of endpoint 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or 
retrospective ascertainment, use of validation sub-study) 
 
 
 
 
 
 
 
19 
Comments: 
      
 
Section 7: Confounders and effect modifiers 
 
Yes 
No 
N/A 
Page 
Number(s) 
7.1 Does the protocol address known confounders? 
(e.g. collection of data on known confounders, methods of 
controlling for known confounders) 
 
 
 
 
 
 
 
18 
7.2 Does the protocol address known effect modifiers? 
(e.g. collection of data on known effect modifiers, anticipated 
direction of effect) 
 
 
 
 
 
 
 
21 
Comments: 
      
 
Section 8: Data sources 
Yes 
No 
N/A 
Page 
Number(s) 
8.1 Does the protocol describe the data source(s) 
used in the study for the ascertainment of: 
8.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)  
8.1.2 Endpoints? (e.g. clinical records, laboratory markers 
or values, claims data, self-report, patient interview including 
scales and questionnaires, vital statistics, etc.) 
8.1.3 Covariates?  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 
 
19 
 
19 
8.2 Does the protocol describe the information 
available from the data source(s) on: 
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily dosage,  
prescriber)  
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, 
severity measures related to event)  
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 
 
19 
 
19 

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Section 8: Data sources 
Yes 
No 
N/A 
Page 
Number(s) 
8.3 Is a coding system described for: 
8.3.1 Diseases? (e.g. International Classification of 
Diseases (ICD)-10) 
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory 
Activities (MedDRA) for adverse events) 
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 
 
19 
 
19 
8.4 Is the linkage method between data sources 
described? (e.g. based on a unique identifier or other)  
 
 
 
 
 
 
 
19 
Comments: 
      
 
Section 9: Study size and power 
 
Yes 
No 
N/A 
Page 
Number(s) 
9.1 Is sample size and/or statistical power calculated?  
 
 
 
19-20 
Comments: 
      
 
Section 10: Analysis plan 
 
Yes 
No 
N/A 
Page 
Number(s) 
10.1 Does the plan include measurement of excess 
risks? 
 
 
 
20-21 
10.2 Is the choice of statistical techniques described?  
 
 
 
20-21 
10.3 Are descriptive analyses included? 
 
 
 
20-21 
10.4 Are stratified analyses included? 
 
 
 
21 
10.5 Does the plan describe methods for adjusting for 
confounding? 
 
 
 
 
 
 
 
20-21 
10.6 Does the plan describe methods addressing 
effect modification? 
 
 
 
 
 
 
 
21 
Comments: 
      
 
Section 11: Data management and quality 
control 
 
Yes 
No 
N/A 
Page 
Number(s) 
11.1 Is information provided on the management of 
missing data? 
 
 
 
21 
11.2 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving) 
 
 
 
22 
11.3 Are methods of quality assurance described? 
 
 
 
22 

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Section 11: Data management and quality 
control 
 
Yes 
No 
N/A 
Page 
Number(s) 
11.4  Does the protocol describe possible quality 
issues related to the data source(s)? 
 
 
 
22 
11.5 Is there a system in place for independent 
review of study results?  
 
 
 
25 
Comments: 
      
 
Section 12: Limitations 
 
Yes 
No 
N/A 
Page 
Number(s) 
12.1 Does the protocol discuss: 
12.1.1 Selection biases? 
12.1.2 Information biases? 
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods) 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
19-22 
12.2 Does the protocol discuss study feasibility? (e.g. 
sample size, anticipated exposure, duration of follow-up in a 
cohort study, patient recruitment) 
 
 
 
19 
12.3 Does the protocol address other limitations?  
 
 
 
19-22 
Comments: 
      
 
Section 13: Ethical issues 
 
Yes 
No 
N/A 
Page 
Number(s) 
13.1 Have requirements of Ethics 
Committee/Institutional Review Board approval 
been described? 
 
 
 
23 
13.2 Has any outcome of an ethical review procedure 
been addressed? 
 
 
 
      
13.3 Have data protection requirements been 
described? 
 
 
 
23 
Comments: 
      
 
Section 14: Amendments and deviations 
 
Yes 
No 
N/A 
Page 
Number(s) 
14.1 Does the protocol include a section to document 
future amendments and deviations?  
 
 
 
12 
Comments: 
      
 
 
 

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Section 15: Plans for communication of study 
results 
 
Yes 
No 
N/A 
Page 
Number(s) 
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?  
 
 
 
      
15.2 Are plans described for disseminating study 
results externally, including publication? 
 
 
 
25 
 
Comments: 
      
 
Name of the main author of the protocol: 
 
Date: 23/02/2017 
 
Signature: ___________________________ 
 
 
 

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ANNEX 3: ADDITIONAL INFORMATION 
Additional annexes may be included if necessary. 
ANNEX 3.1: DEFINITION OF STUDY EXPOSURES 
See section 7.4.1.  Complete list of drug codes will be finalized and supplied to BI in the 
course of the study 
ANNEX 3.2: DEFINITIONS OF STUDY OUTCOMES  
See section 7.4.2.  Complete list of READ and ICD-10 codes will be finalized and supplied to 
BI in the course of the study 
ANNEX 3.3: DEFINITIONS OF STUDY COVARIATES 
See section 7.4.3.  Complete list of READ and drug codes will be finalized and supplied to BI 
in the course of the study 
 
ANNEX 3.4: STATISTICAL CONSIDERATIONS 
See section 7.9.