Effectiveness and Safety of Maintenance Treatment With Combination of Tiotropium and Olodaterol in Comparison to Maintenance Treatment With a Combination of Inhaled Corticosteroids and Long-acting β2 Agonists in COPD Patients
Conditions: COPD
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0) 
TITLE PAGE 
Protocol for observational studies based on existing data 
TITLE PAGE 
Document Number: 
c31403012-01 
BI Study No.: 
1237-0093 
BI Investigational 
Product(s): 
Tiotropium bromide + Olodaterol 
Title: 
Effectiveness and Safety of Maintenance Treatment with Combination 
of Tiotropium and Olodaterol in Comparison to Maintenance 
Treatment with a Combination of Inhaled Corticosteroids and Long-
acting β2 agonists in COPD patients 
Title for lay people: 
Comparative Effectiveness and Safety of Tiotropium and Olodaterol in 
Comparison to LABA/ICS 
Date of last version of 
protocol: 
NA 
PASS: 
No 
EU PAS Register No: 
only applicable for PASS EUPAS31932 
Active substance: 
Tiotropium and Olodaterol 
Medicinal product: 
Spiolto® Respimat® 
Product reference: 
N/A 
Procedure number: 
N/A 
Joint PASS: 
No 
Marketing 
authorization holder(s): 
Author/Responsible 
Parties/BI contact 
person: 
Tel.:
 
Mobil: 
 
Email: 
 
MAH contact person: 
Tel.: 
 
Mobil: 
 
Email: 
 

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Protocol for observational studies based on existing data 
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001-MCS-90-124_RD-01 (4.0) 
Country(-ies) of study: United States 
Status: 
Protocol Final Version 1 
EU-QPPV: 
only applicable for PASS 
Not applicable 
Signature of EU-QPPV: 
only applicable for PASS 
Not applicable 
Version and Date: 
1.0, 19th February 2020 
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Protocol for observational studies based on existing data 
BI Study Number 1237-0093 
c31403012-01 
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-124_RD-01 (4.0) 
TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................... 1 
TABLE OF CONTENTS.................................................................................................. 3 
1.
PROTOCOL ABSTRACT.............................................................................. 5
2.
LIST OF ABBREVIATIONS AND TERMS ................................................ 10
3.
RESPONSIBLE PARTIES ........................................................................... 11
4.
AMENDMENTS AND UPDATES ............................................................... 11
5.
MILESTONES.............................................................................................. 11
6.
RATIONALE AND BACKGROUND .......................................................... 11
7.
RESEARCH QUESTIONS AND OBJECTIVES ......................................... 12
8.
RESEARCH METHODS ............................................................................. 13
8.1 
STUDY DESIGN .......................................................................................... 13 
8.2 
SETTING...................................................................................................... 13 
8.3 
PATIENTS.................................................................................................... 13 
8.4 
VARIABLES ................................................................................................ 14 
8.4.1 
Exposures...................................................................................................... 14 
8.4.2 
Outcome(s) .................................................................................................... 14 
8.4.2.1 
Primary outcome(s) .........................................................................................14 
8.4.2.2 
Secondary outcome(s)......................................................................................15 
 
 
8.4.4 
Covariates...................................................................................................... 16 
8.5 
DATA SOURCES ......................................................................................... 17 
8.6 
BIAS.............................................................................................................. 18 
8.7 
STUDY SIZE ................................................................................................ 18 
8.8 
DATA MANAGEMENT .............................................................................. 19 
8.9 
DATA ANALYSIS ........................................................................................ 20 
8.9.1 
Main analysis ................................................................................................ 20 
 
 
8.10 
QUALITY CONTROL ................................................................................. 23 
8.11 
LIMITATIONS OF THE RESEARCH METHODS.................................... 23 
8.12 
OTHER ASPECTS ....................................................................................... 24 
9.
PROTECTION OF HUMAN SUBJECTS.................................................... 24
10.
MANAGEMENT AND REPORTING OF ADVERSE
EVENTS/ADVERSE REACTIONS ............................................................. 25 
11.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS ..................................................................................................... 25 
12.
REFERENCES ............................................................................................. 26
12.1 
PUBLISHED REFERENCES....................................................................... 26 

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001-MCS-90-124_RD-01 (4.0) 
12.2 
UNPUBLISHED REFERENCES ................................................................. 28 
13.
FUNDING ..................................................................................................... 29
14.
ANNEX ......................................................................................................... 30
ANNEX 1: LIST OF STAND-ALONE DOCUMENTS.................................................. 30 
ANNEX 2: ENCEPP CHECKLIST FOR STUDY PROTOCOLS................................. 31 
ANNEX 3: ADDITIONAL INFORMATION................................................................. 37 
ANNEX 3.1: DEFINITION OF STUDY EXPOSURES ................................................. 37 
ANNEX 3.2: DEFINITIONS OF STUDY OUTCOMES................................................ 38 
ANNEX 3.3: DEFINITIONS OF STUDY COVARIATES ............................................ 40 
ANNEX 3.4: STATISTICAL CONSIDERATIONS....................................................... 53 

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Protocol for observational studies based on existing data 
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001-MCS-90-124_RD-01 (4.0) 
1.
PROTOCOL ABSTRACT
Name of company: 
ABCD
Boehringer Ingelheim 
Name of product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision 
date: 
19 February 2020 
1237-0093 
1.0 
NA 
Proprietary confidential information 
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
Title of study: 
Effectiveness and Safety of Maintenance Treatment with Combination of 
Tiotropium and Olodaterol in Comparison to Maintenance Treatment with a 
Combination of Inhaled Corticosteroids and Long-acting β2 agonists in 
COPD patients 
Team member 
Epidemiology: 
Project team: 
(Principal Investigator) 

Boehringer Ingelheim  
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Protocol for observational studies based on existing data 
BI Study Number 1237-0093 
c31403012-01 
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-124_RD-01 (4.0) 
Name of company: 
ABCD
Boehringer Ingelheim 
Name of product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision 
date: 
19 February 2020 
1237-0093 
1.0 
NA 
Proprietary confidential information 
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
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 appropriate only 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]. 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. The ENERGITO study showed significant 
improvements in lung function with the LAMA/LABA FDC Tio+Olo versus 
LABA/ICS. Although, a recent population-based observational study showed no 
difference in exacerbation risk for COPD patients with B-Eosinophils below 4% if 
treated either with LAMA or LABA/ICS [P18-09975], this data have yet to be 
confirmed in population based studies in real world conditions. Given high-cost 
adverse events associated with long-term use of ICS and inconsistent evidence 
concerning whether there is a clinically relevant benefit of ICS combination 
therapy in terms of disease control, it is important to assess differences between 
subsets of COPD patients in terms of the effectiveness and cost of LABA/ICS 
combination therapies versus other non-ICS options, such as 
Tiotropium+Olodaterol (Tio+Olo). 
The proposed study will investigate the comparative effectiveness of Tiotropium 
and Olodaterol (Tio+Olo) vs any LABA /ICS combination in COPD, describe 
differences in healthcare utilization, and compare cost effectiveness. Whether 
associations with time to exacerbation, community acquired pneumonia, 
escalation to triple therapy, and adverse outcome are modified by exacerbation 
risk (measured based on individual history and eosinophil levels) will also be 
assessed.   
The intended audience is the scientific community, patients, payers and 
prescribers.  The results from the study will be published in the scientific 
literature. 

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Protocol for observational studies based on existing data 
BI Study Number 1237-0093 
c31403012-01 
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
001-MCS-90-124_RD-01 (4.0) 
Name of company: 
ABCD
Boehringer Ingelheim 
Name of product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision 
date: 
19 February 2020 
1237-0093 
1.0 
NA 
Proprietary confidential information 
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
Research question and 
objectives: 
The primary objective is to compare the effectiveness of maintenance therapy 
initiation with the combination treatment Tiotropium and Olodaterol 
(Olo+Tio) compared with LABA/ICS combination in COPD as the time to the 
first COPD exacerbation.  
Secondary objectives are to compare patients treated with Tio+Olo and 
patients treated with LABA/ ICS combination: (1) Time to community 
acquired pneumonia, (2) time to escalation to triple therapy (3) time to an 
adverse outcome including exacerbation, escalation to triple therapy, or 
pneumonia, and (4) healthcare utilization outcomes and an analysis of all-
cause and COPD-specific cost overall and by care setting. 
Additionally, the study will investigate the effect modification of circulating 
eosinophil levels and exacerbation history on the safety and effectiveness of 
Tio+Olo compared with any LABA/ICS. Analyses will be repeated in sub-
groups of patients under high or low risk of exacerbation based on previous 
history of exacerbations in the year preceding cohort entry (with exacerbation 
history defined as either 1+ hospitalization or 2+ exacerbations in emergency 
department or outpatients settings [R05-1384]), as well as based on circulating 
eosinophils (cut-off: B-Eos 300cells/uL [P18-09975]) overall and among 
those without a history of exacerbation. 
Study design: 
A incident new-user cohort design will be used, with confounding controlled 
via fine stratification and reweighting of time-conditional propensity scores 

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Protocol for observational studies based on existing data 
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001-MCS-90-124_RD-01 (4.0) 
Name of company: 
ABCD
Boehringer Ingelheim 
Name of product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision 
date: 
19 February 2020 
1237-0093 
1.0 
NA 
Proprietary confidential information 
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
Population: 
The cohort will include all patients with a diagnosis of COPD who received 
at least one dispensing of a long-acting bronchodilator, Tio+Olo, LABA or 
for an inhaled corticosteroid from 1 January 2013 until 31 March 2019 (or the 
most recent date available at the time of cohort extraction). Only fixed-dose 
combinations products will be included in the main analyses. To increase the 
likelihood of a diagnosis of COPD, we only include patients 40 years of age 
or older at initiation of study treatment (i.e., the index date) and exclude all 
patients with a diagnosis of asthma within the baseline year or lung cancer, 
interstitial lung disease, or lung transplantation at any time prior to the index 
date.  
Patients will need to have at least one year of medical and pharmacy health 
plan eligibility prior to the date of Tio+Olo or LABA/ICS initiation (index 
date) to allow the identification of new use and the measurement of baseline 
covariates. Patients will be followed until switching to the other treatment, 
the end of the individual’s health plan eligibility, escalation of therapy, 
discontinuation of COPD treatment, or the end of the study period, whichever
occurs first. Main analyses will be limited to the first year following the index 
date. 
Additional restriction to individuals who have laboratory test result data 
showing eosinophil levels will occur for relevant sensitivity analyses. 
Study data source: 
The HealthCore Integrated Research DatabaseSM (HIRD) 
Expected study size: 
Overall: 
New users of Tio+Olo: 5,469 
New users of LABA/ICS: 53,432 
With eosinophil result data:  
New users of Tio+Olo: 2,207 
New users of LABA/ICS: 19,407 

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Protocol for observational studies based on existing data 
BI Study Number 1237-0093 
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001-MCS-90-124_RD-01 (4.0) 
Name of company: 
ABCD
Boehringer Ingelheim 
Name of product: 
Stiolto/Spiolto 
Name of active ingredient: 
Tiotropium bromide + Olodaterol 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision 
date: 
19 February 2020 
1237-0093 
1.0 
NA 
Proprietary confidential information 
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
Main criteria for 
inclusion: 
- New users of Tio+Olo or LABA/ICS in a fixed dose combination between 
January 2013 and March 2019. 
- Diagnosis of COPD and age ≥ 40 years  
Main criteria for 
exclusion: 
-Less than one year of medical history information prior to the index date 
-Asthma diagnosis within one year prior to the index date 
-Lung cancer, interstitial lung disease, or lung transplantation at any time 
prior to the index date 
-Use of triple therapy (LABA/LAMA/ICS) prior to the index date 
Comparison groups: Initiating Tio+Olo compared to initiating LABA/ICS therapy 
Expected duration of 
exposure: 
Analyses will be limited to one year following the index date for the primary 
and secondary analyses. Sensitivity analyses will use all available exposure 
data. 

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2.
LIST OF ABBREVIATIONS AND TERMS
BI 
Boehringer Ingelheim 
BMI 
Body Mass Index 
CI 
Confidence Interval 
COPD 
Chronic Obstructive Pulmonary Disease 
CPRD 
Clinical Practice Research Datalink 
DSAs 
Data Sharing Agreements 
ED 
Emergency Department 
FDC 
Fixed Dose Combination 
FTCO 
First Treatment Carry-On Analysis 
HIPAA 
Health Insurance Portability and Accountability Act 
HIRD 
HealthCore Integrated Research Database 
HR 
Hazard Ratio 
ICD-9 
International Classification of Disease, Version 9 
ICD-10 
International Classification of Disease, Version 10 
ICS 
Inhaled Corticosteroids 
IR 
Incidence Rate 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
LABA 
Long-acting Beta2-agonist 
LAMA 
Long-acting Muscarinic Antagonists 
N 
Number 
NDI 
National Death Index 
PHI 
Protected Health Information 
PS 
Propensity Score 
RR 
Rate Ratio 
SOPs 
Standard Operating Procedures 
cells/µL 
Microliter 
US 
United States 

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3.
RESPONSIBLE PARTIES
(Principal Investigator) 
Tel: 
 
4.
AMENDMENTS AND UPDATES
There are currently no amendments to the protocol. 
5.
MILESTONES
Milestone 
Planned date 
Start of data collection: Data extraction and 
coding 
August 1, 2019 
End of data collection: 
March 31, 2019* 
Study progress report(s) as referred in Article 
107m(5) of Directive 2001/83/EC: 
Not applicable 
Interim report(s) of study results: 
Not applicable 
Registration in the EU PAS register 
Not applicable 
Final report of study results: 
April 2020 (Preliminary results: 19 
December 2019) 
* This is an observational study based on existing data collected in the form of administrative claims. The date listed reflects
the expected end of data availability at the start of analysis. 
6.
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]. 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].  
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. Optimal treatment choice appears to be 
influenced by a variety of factors including exacerbation risk. Although the use of ICS has 
increased disproportionately with respect to COPD treatment guidelines, it may be 
appropriate only in a subset of these users [P15-12888; P16-12287]. 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-

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up period. In the WISDOM trial, in patients on triple therapy the risk of moderate or severe 
exacerbations was similar among those who discontinued and those who continued ICS. The 
ENERGITO study showed significant improvements in lung function with the LAMA/LABA 
FDC Tio+Olo versus LABA/ICS. Further, pneumonia associated with long-term ICS use 
increases the risk of hospitalization, and is associated with substantial increases in cost [P07-
09514; R18-2874]. 
Although, a recent population-based observational study showed no difference in 
exacerbation risk for COPD patients with B-Eosinophils below 300 cells/uL) if treated either 
with LAMA or LABA/ICS [P18-09975], this data have yet to be confirmed in population 
based studies in real world conditions. Given high-cost adverse events associated with long-
term use of ICS and inconsistent evidence concerning whether there is a clinically relevant 
benefit of ICS combination therapy in terms of disease control, it is important to assess 
differences between subsets of COPD patients in terms of the effectiveness and cost of 
LABA/ICS combination therapies versus other non-ICS options, such as 
Tiotropium+Olodaterol (Tio+Olo).  
The proposed study will investigate the comparative effectiveness of Tio+Olo vs any LABA 
/ICS combination in COPD, describe differences in healthcare utilization, and compare cost 
effectiveness. Whether associations with time to exacerbation, community acquired 
pneumonia, escalation to triple therapy, and adverse outcome are modified by exacerbation 
risk (measured based on individual history and eosinophil levels) will also be assessed. 
7.
RESEARCH QUESTIONS AND OBJECTIVES
The goal of this study is to investigate the risk of COPD exacerbations, community acquired 
pneumonia, and health care utilization in patients treated with Tio+Olo in comparison to 
patients treated with LABA/ICS combination therapy. All analyses will be conducted for the 
total population, as well as in sub-groups of patients under high- or low risk of exacerbation 
based on (1) previous history of exacerbations in the year preceding cohort entry (cut-off: 0-1 
vs 2+ exacerbations [R05-1384], (2) circulating eosinophils (cut-off B-Eos 300 cells/uL 
[P18-09975]), and (3) as an exploratory analysis, a combination of exacerbation history and 
circulating eosinophils. 
Primary objective:  
The primary objective is to compare the effectiveness of new use of maintenance therapy 
initiation with the combination treatment Tiotropium and Olodaterol (Tio+Olo) compared 
with new use of LABA/ICS combination in COPD as the time to the first COPD 
exacerbation.  
Secondary objectives: 
Secondary objectives are to compare patients treated with Tio+Olo and patients treated with 
LABA/ICS combination therapy with respect to: 
Time to first community acquired pneumonia,  
Time to escalation to triple therapy, and 

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Time to an adverse outcome including exacerbation, pneumonia, or escalation to triple 
therapy 
Exploratory objective: 
To assess differences between Tio+Olo vs any LABA/ICS combination in all-cause and 
COPD-specific healthcare utilization and cost overall and by care setting 
8.
RESEARCH METHODS
8.1 
STUDY DESIGN
Population-based propensity score-matched new-user cohort study. 
8.2 
SETTING 
The study will be conducted using administrative healthcare claims and laboratory result data 
captured in the HealthCore Integrated Research Database (HIRD; details in Section 8.5). The 
observation period will be from January 2013 until the most recent date available at the time 
that the cohort is extracted (estimated March 2019).  
8.3 
PATIENTS 
The study cohort will be formed based on the following entry criteria. 
Inclusion Criteria: 
1. At least one prescription for Tio+Olo combined inhaler or a LABA/ICS combined
inhaler between 1 January 2013 and 31 March 2019. 
a) The first dispensing of either Tio+Olo or LABA/ICS combined inhaler will be
defined as the index date. 
b) For the main analyses, only fixed dose combination (FDC) inhalers will be
included. Sensitivity analyses will also accept free combinations of 
LABA/ICS.  
2. At least one diagnosis of COPD at any time prior to the index date.
3. At least one year of continuous medical and pharmacy health plan eligibility prior to
the index date will be required to allow a baseline period for the covariates and
identification of new use of the study drugs.
Exclusion Criteria: 
1.
To increase the likelihood of a true diagnosis of COPD, we will exclude:
a) All patients less than 40 years of age on the index date, and
b) All patients with a diagnosis of asthma in the year prior to the index date
2.
To limit the population to those without severe lung compromise outside of
COPD, we will exclude individuals with lung cancer, interstitial lung disease, or
lung transplant identified at any time prior to the index date
3.
To restrict the cohort to new users of Tio+Olo or LABA/ICS, we will exclude any
individual with use of either Tio+Olo, LABA/ICS, or LABA/LAMA/ICS

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combination therapy in free or fixed form for at least one year prior to the index 
date. 
Outpatient laboratory data is available for a subset of patients. Some analyses will be further 
restricted to the subset of the population with at least one laboratory result showing 
circulating eosinophil levels within six months before the index date. 
Individuals in the study cohort will be followed from the index date until the earliest of the 
date of a switch in treatment, addition of either an ICS for the Tio+Olo group or of LAMA to 
the LABA/ICS group, discontinuation of COPD treatment, the end of the study period, or the 
end of continuous health plan eligibility. Main analyses will be further limited to the first year 
after cohort entry, with sensitivity analyses considering all available data. 
8.4 
VARIABLES 
8.4.1 
Exposures 
The exposure measures are based on pharmacy dispensings of the two long-acting 
bronchodilators under study, namely fixed-dose combination of Tio+Olo and a fixed-dose 
combination of LABA and ICS, over one year of follow-up. As described in the data analysis 
section, the as-treated analysis, which is the main analysis, will consider exposure as current 
use of Tio+Olo or LABA/ICS within the treated groups defined as within the days supply 
recorded at the time of pharmacy dispensing, allowing for a gap between dispensings of up to 
15 days. This gap is allowed in consideration of plausible delays in obtaining medication 
refills and continued use beyond the days supplied where medication has been missed due to 
imperfect adherence, and will be varied in sensitivity analyses (see Section 8.9.2). The 
treatment segment ends at the earliest of the following events: 
1. Fifteen days after the end of the observed days supply for the medication
received on the index date without a subsequent dispensing of COPD 
medication (i.e., discontinuation) 
2. Initiation of triple therapy (i.e., addition of ICS to Tio+Olo or a LAMA to
LABA/ICS (i.e., treatment escalation) 
3. Any other change in use of study medication by active ingredient, inclusive of
a change to a different combination therapy, change from a fixed form to a 
free form combination therapy, or a change from combination therapy to 
monotherapy (i.e., switch) 
Changes in dose for medications started on the index date will not impact the end of the 
treatment segment. Codes used to identify study medications are included in Annex 3.1. 
8.4.2 
Outcome(s) 
8.4.2.1 
Primary outcome(s) 
The primary outcome event for effectiveness is time to first COPD exacerbation after cohort 
entry. The event is defined as follows: 
•
Severe exacerbation:

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o
Hospitalization with a principal discharge diagnosis of COPD.
•
Moderate exacerbation:
o
An ED visit with a discharge diagnosis of COPD, and/or
o
An antibiotic for a respiratory condition dispensed the same day as an oral 
corticosteroid
Time to the first COPD exacerbation will be measured from cohort entry until the occurrence 
of a hospitalization for COPD (severe exacerbation) or ED visit for COPD or prescription of 
an antibiotic and an oral corticosteroid on the same day (moderate exacerbation). Severe and 
moderate exacerbations will be considered as a composite for main analyses. Sensitivity 
analyses will stratify by exacerbation severity.  
Although there is precedent for defining moderate exacerbation based on use of antibiotics 
for a respiratory infection without requiring concomitant oral corticosteroids, we have chosen 
a more restrictive definition of exacerbation. Because diagnoses listed on outpatient claims 
often correspond to a patient’s past medical history in addition to acute problems, we expect 
limited ability to capture the indication for which antibiotics are prescribed. As such, 
including antibiotics alone as a case definition for exacerbation would introduce potentially 
substantial misclassification of outcome where antibiotics were truly given for non-
respiratory infections. Given that our analyses will yield estimates on a ratio measure, non-
differentially reduced sensitivity is a less important threat to validity than reduction of 
outcome specificity, which produces an expectation of bias towards the null hypothesis. In 
order to test our assumptions that the sensitivity of our outcome definition is not differential 
between the Tio+Olo and LABA/ICS groups, we would produce counts of patients with 
antibiotics alone during follow-up, and determine whether the proportion of potential 
exacerbations that we excluded through this design decision is comparable across groups. 
8.4.2.2 
Secondary outcome(s) 
The first secondary outcome is time to first hospitalization for community-acquired 
pneumonia (serious pneumonia). Pneumonia will be defined using ICD-9-CM diagnoses 
481.x-486.x; 487.0, 507.x, 507.0, 507.1, 507.8, 510.0, 510.9, 511.0, 513.0, 514.x, 517.1, 
519.8, 530.84, and ICD-10 diagnosis codes J10.0; J11.0; J12-J18; J22; J69; J85.0; J85.1; J86. 
This definition has been used successfully in COPD [P07-09514; P16-10095].  
The second secondary outcome is time to a pharmacy dispensing indicating escalation to 
triple therapy, (i.e., addition of ICS to Tio+Olo or a LAMA to LABA/ICS). 
The third secondary outcome is time to an adverse outcome including exacerbation, 
hospitalization for pneumonia, and escalation to triple therapy, defined as time from cohort 
entry until the earliest primary or secondary outcome as defined above (See Section 8.4.2.1, 
8.4.2.2). 

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8.4.4 
Covariates 
Patient characteristics at baseline will be assessed for Tio+Olo and LABA/ICS users overall 
and stratified by history of exacerbation, circulating eosinophils, subgroups defined by both 
exacerbation and eosinophil levels.  
We will identify and describe the following demographic characteristics as of the index date: 
•
Sex
•
Age (years, as both a categorical and a continuous variable)
•
Calendar year of cohort entry
•
Season of index date (winter, spring, summer, fall)
•
US census region of residence
•
Insurance type (e.g., Commercial, Medicare)
Additional characteristics will be defined during the 12-month pre-index baseline period: 
•
Number of previous COPD treatments
•
Specific previous COPD treatments
o
LAMA monotherapy
o
LABA monotherapy
o
ICS monotherapy
o
LAMA/ICS combination therapy
•
Previous acute COPD exacerbation (measured both overall and in the 30 days prior to
cohort entry), categorized as 0, 1, or 2+.
o
All exacerbations (Moderate+Severe)
o
ED visits or dispensings of inhaled corticosteroids/antibiotics (Moderate)
o
Hospitalizations (Severe)
•
Use of other respiratory drugs in the 12-month pre-index period::

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o Short-acting beta-agonists 
o Anticholinergics 
o Methylxanthines 
o Muscarinic antagonists 
o Short-acting muscarinic antagonists  
• Use of antibiotics commonly prescribed for a respiratory condition (e.g., 
azithromycin) 
 
Chronic comorbidities will be defined using diagnoses identified during all available data 
prior to the index date, and will include: 
• Cardiovascular disease 
• Charlson comorbidity index  
• Diabetes 
• Thyroid disease 
• Renal failure 
• Autoimmune disease 
• Pneumonia 
• Obesity* 
• Alcohol use disorder* 
• Tobacco use or cessation counselling* 
• Cancer (excluding basal cell carcinoma)  
 
*We anticipate limited capture of lifestyle variables known to be risk factors and potential 
confounders, including obesity, smoking status and excessive alcohol consumption. Although 
we will describe them as identified in the HIRD, bias analyses to examine the extent to which 
residual confounding may impact results are also planned.  
Additionally to the covariates defined above, we will use the high-dimensional approach to 
identify variables entering a time-conditional propensity score.  
 
Sub-populations with high or low risk of exacerbations will be defined as based on 
circulating eosinophils (cut-off of B-Eos 300 cells/uL) as identified based on the laboratory 
result value that is closest but prior to the index date (within 6 months). Additional 
stratification will include previous history of exacerbations in the year preceding cohort entry 
(with exacerbation history defined as either 1+ hospitalization or 2+ exacerbations in 
emergency department or outpatients settings), and among those without a history of 
exacerbation at baseline, based on circulating eosinophil results as noted above. We will not 
present results stratified by circulating eosinophil levels among those with baseline 
exacerbations due to low counts observed when assessing study feasibility (see Section 8.7). 
 
8.5 
DATA SOURCES  
This study will be conducted using the HIRD, a large administrative healthcare database 
maintained by HealthCore for use in health outcomes and pharmacoepidemiologic research. 
The HIRD includes longitudinal medical and pharmacy claims data from health plan 

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members across the United States (US). Member enrollment, medical care (professional and 
facility claims), outpatient prescription drug use, outpatient laboratory test result data, and 
health care utilization may be tracked for health plan members in the database dating back to 
January 2006, and with diagnoses recorded in International Classification of Disease, Version 
10 (ICD-10) since October, 2015. Laboratory result data are additionally available for those 
tests that have been performed using two large, national reference laboratories (Quest and 
LabCorp) [R14-4278]. The database has been used for the study of numerous diseases, 
including studies of COPD [R19-2324; R19-2321; R19-2323; R19-2322; P15-11025; P14-
12233].  
8.6 
BIAS 
Several potential biases are inherent to any observational study in the HIRD. In the absence 
of randomization, confounding by indication could be an issue. Controlling by propensity 
score should limit this bias, but can control only for measured covariates and may produce 
estimates that are impacted by residual confounding. This is of particular importance in the 
case of lifestyle factors that are less critical to insurance billing and thus poorly captured in 
claims data. Quantitative bias analyses can formally describe the extent to which these issues 
are present, but bias analysis parameters are informed by literature and clinical expert 
opinion. As such, the accuracy of bias corrected analyses is limited by the accuracy of the 
assumptions that inform them. 
 
Second, there is the possibility of information bias due to misclassification of the outcomes or 
exposure or missing data, especially, differential missingness of some data (e.g. eosinophils, 
which may only be measured in sicker patients). The prescriptions dispensed by a pharmacy 
but not taken by patients could lead to misclassification of exposure. Pharmacy dispensing 
data does bring us one step closer to patient use than physician prescribing given that the 
patient has taken the effort to obtain the medication as instructed, however, information such 
as indication can only be inferred based on diagnostic patterns.  
8.7 
STUDY SIZE 
Preliminary counts of FDC Tio+Olo and ICS/LABA users in the HIRD are shown here: 
  
Tio+Olo 
ICS/LABA  
  
N 
% 
N 
% 
New users 
8,233 
100.0 
341,352 
100.0 
At least 12 months of pre-index 
eligibility 
6,263 
76.1 
187,093 
54.8 
Age 40+ 
6,126 
97.8 
136,310 
72.9 
At least 1 diagnosis of COPD 
5,469 
89.3 
53,432 
39.2 
At least 1 eosinophil % result prior to 
the index date 
2,207 
40.4 
19,407 
36.3 
Eosinophil result (N, % of those with 
a result) 
  
  
 
  
0-2% 
1,059 
48.0 
8,907 
45.9 
2-4% 
745 
33.8 
6,698 
34.5 

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4%+ 
403 
18.3 
3,802 
19.6 
Eosinophil result, patients with low 
exacerbation history(0 inpatient and 
0-1 outpatient events at baseline, N, 
%) 
 
 
 
 
<300 cells/uL 
1,381 
30.0 
12,351 
27.1 
≥300 cells/uL  
481 
10.5 
4,437 
9.7 
Unknown 
2,739 
59.5 
28,733 
63.1 
Eosinophil result, patients with high 
exacerbation history (1+ inpatient or 
2+ outpatient events at baseline, N, 
%) 
 
 
 
 
<300 cells/uL 
226 
26.0 
1,820 
23.0 
≥300 cells/uL  
105 
12.1 
670 
8.5 
Unknown 
537 
61.9 
5,421 
68.5 
 
In a recent analysis of the risk of exacerbations based on Clinical Practice Research Datalink 
(CPRD), a total of 2,000 patients per cohort detected a 15% difference in risk of a first 
exacerbation (hazard ratio 0.85) with over 90% power. As such, overall analyses are expected 
to have adequate power. Analyses that are stratified based on the presence of claims-based 
indicators of exacerbation and/or limited to individuals with specific eosinophils levels will 
be more limited. Given low expected sample size, stratification by eosinophil results within 
individuals with exacerbations at baseline will not be performed. 
8.8 
DATA MANAGEMENT 
All statistical analysis for the study will be conducted using SAS version 9.4 or higher (SAS 
Institute, Cary, NC). All sensitive data pertaining to the study will be stored on secured 
servers with access only permitted by approved study team members. 
 
A number of Information Security policies are enforced, audited, and in place at HealthCore, 
including complex password requirements and encryption systems. Security mechanisms and 
policies are in place HealthCore's facilities are standard corporate office space. Office space 
is segregated and managed by monitored electronic access. HealthCore areas which contain 
project and study-related documents are only access by HealthCore associates or contract 
personnel. All non-HealthCore associates must be accompanied by an associate at all times in 
order to enter these areas. All study related files are kept in locked cabinets and work areas. 
There are no visible labels or client listings viewable by any visitor or passerby. All 
passwords and user authentication mechanisms are forced changed at regular intervals and 
there is automatic locking of workstations after a short period of time (< 15 minutes). 
 
Data Center space is permitted on an as required basis and monitored by electronic access. 
HealthCore maintains a cumulative record that indicates, for any point in time, the names of 
authorized personnel, their titles, and a description of their access privileges to the Data 
Center. Data access is restricted, monitored, logged, and audited. HealthCore’s computer 

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networks have been designed to separate patient or physician identified data from de-
identified or masked data. Network security, firewalls, and password permissions control 
which HealthCore personnel have access to patient or physician identifiers. Unless the study 
protocol calls for patient or physician authorization or a waiver of authorization as granted by 
an IRB, no research analyst will have access to patient or physician identifiers within 
HealthCore’s computer systems. All research analysis databases have been de-identified. 
HealthCore’s Data Center is also physically secured by a controlled access facility, with only 
authorized personnel having access to network servers, tape libraries and other media that 
contains patient identifiers. 
 
Research analysis files used by HealthCore do not contain patient or physician identifiers 
unless necessary to perform such research; if such is the case, access will be made after 
receipt of the patient’s or physician’s authorization or IRB waiver of such authorization has 
been granted. It is also HealthCore policy to provide for secure storage of study materials, 
including data, reports, and other files after the study is completed, with a destroy date 
assigned based on study requirements. HealthCore reviews data requirements for each study 
to assure that only the minimum of patient or physician information is obtained to answer the 
research question(s). For those studies where direct patient identifiers are needed for 
additional data collection such as medical chart abstracts, access to information will be 
limited to the greatest possible extent within the research team. Both structural and 
contractual safeguards reinforce policies to minimize the risk of breaching patient or 
physician privacy. The structural safeguards include a clearly defined data flow process. This 
process minimizes the risk of individual identifiers being improperly used or disclosed. The 
contractual safeguards include contractual binding to confidentiality of individuals involved 
in the research.  
8.9 
DATA ANALYSIS 
8.9.1 
Main analysis 
All analyses will be presented for each group (Tio+Olo vs LABA/LAMA/ICS) overall and 
stratified as follows: 
• History of exacerbation: 0 inpatient and 0-1 outpatient events 
• History of exacerbation: 1+ inpatient or 2+ outpatient events 
• Circulating eosinophils: B-Eos <300 cells/µL 
• Circulating eosinophils: B-Eos 300 cells/µL+  
• History of exacerbation: 0 inpatient and 0-1 outpatient events & circulating 
eosinophils: B-Eos <300 cells/uL  
• History of exacerbation: 0 inpatient and 0-1 outpatient events & circulating 
eosinophils: B-Eos 300 cells/uL+  
 
We will first describe formation of the study cohort. Patient characteristics at baseline in 
patients treated with Tio+Olo and patients treated with LABA/ICS will be described 
separately using standard descriptive statistics. Because eosinophil levels may vary based on 
exacerbation, we will also provide a count and percentage of the number of individuals 
whose eosinophil results were recorded within 30 days of an exacerbation event.  

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High-dimensional propensity scores including both pre-specified and data-derived variables 
will then be calculated. We will use fine stratification and reweighting of the exposure 
propensity score to control for measured covariates [R19-3030]. Balance of patient 
characteristics between the cohorts will be described before and after propensity score 
application and compared using standardized differences (in the crude population and the 
reweighted pseudo-population). Standardized differences greater than 0.10 (10%) will be 
taken to indicate imbalance and further refinement approaches will be applied.  
 
For the analysis of the primary objective, a Cox proportional hazard regression model will be 
used to perform an as-treated analysis that assesses the effect of current use of Tio+Olo 
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 
Tio+Olo use relative to LABA/ICS use, along with 95% confidence intervals (CI). Current 
use will be defined based on the days supply during the period of overlap, allowing a grace 
period of 15 days following the end of days supply to account for intermittent use.  
 
Stratified analyses will use the same approach. Because not all individuals will have available 
laboratory result data available, fine stratification and reweighting by propensity score will be 
repeated within the subset of the cohort with available results to create weighted populations 
suitable for these stratified analyses. Potential effect modification by B-Eosinophils and/or 
exacerbation history will be studied by comparing models with and without interaction terms 
and through qualitative consideration of differences in stratum-specific estimates.  
 
The analysis of the secondary objectives related to the risk of pneumonia, treatment 
escalation, and an adverse outcome will use a Cox proportional hazard regression model with 
an as-treated approach, similar to that of the primary analysis.  
 
In terms of healthcare utilization, we will present continuous and categorical variables using 
standard descriptive statistics to describe total visits and total costs related to inpatient, 
outpatient, office visit, and emergency care as well as total pharmacy dispensings, distinct 
medications used, and pharmacy costs. Utilization and costs will be stratified to facilitate 
comparison between Tio+Olo and LABA/ICS, and presented by individual setting and as a 
composite. All-cause and COPD-specific data will be shown.  
 

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8.10 
QUALITY CONTROL 
HealthCore operates observational research studies with the goal that the services provided to 
our clients are of high quality. To support this imperative we believe it is critical 1) to have 
dedicated training and quality resources and 2) that all talking points and major processes to 
be implemented with the study be approved by Boehringer Ingelheim in advance.  
 
HealthCore’s quality control program is centralized within the Regulatory Compliance 
Office. The Regulatory Compliance Office Manager is responsible for quality control and 
reports directly to the Vice President of Operations of HealthCore on all quality matters. 
HealthCore’s quality system is organized around the Quality Manual, the quality checks 
within the project life cycle, and Standard Operating Procedures (SOPs). HealthCore has 
procedures for retention of protected health information (PHI) and project data. The study 
will be tracked at various levels to help ensure that all aspects including project delivery, 
infrastructure, quality processes, resource management, and financial issues are addressed. To 
help ensure the highest level of quality on every project, HealthCore has established several 
layers of quality assurance throughout the project lifecycle.  
 
Role Based Control Checks: Each member of the team is responsible to perform thorough 
quality control checks on their work. In addition, the PI and Research Project Manager are 
also accountable for quality of all deliverables.  
 
Quality Check Points: Centralized “checkpoints” have been implemented during the data 
management cycle to help ensure accurate translation of programming requests. 
 
Quality Assurance Standards: Standard review procedures have been developed and are 
applied throughout the project lifecycle. 
 
Automation: HealthCore has developed standard definitions of many variables and disease 
states and developed programs to apply these standards as needed on projects. These 
standards help ensure consistency, repeatability and accuracy for each project. 
 
8.11 
LIMITATIONS OF THE RESEARCH METHODS 
Several potential biases are inherent to any observational study in the HIRD. In the absence 
of randomization, confounding by indication could be an issue. Controlling for propensity to 
add the second treatment should limit this bias, but can control only for measured covariates 

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and may produce estimates that are impacted by residual confounding. This is of particular 
importance in the case of lifestyle factors that are less critical to insurance billing and thus 
poorly captured in claims data. Quantitative bias analyses can formally describe the extent to 
which these issues are present, but bias analysis parameters are informed by literature and 
clinical expert opinion. As such, the accuracy of bias corrected analyses is limited by the 
accuracy of the assumptions that inform them.  
 
Second, there is the possibility of information bias due to misclassification of the outcomes or 
exposure or missing data, especially, differential missingness of some data (e.g. eosinophils, 
which may only be measured in sicker patients). The prescriptions dispensed by a pharmacy 
but not taken by patients could lead to misclassification of exposure. Pharmacy dispensing 
data does bring us one step closer to patient use than physician prescribing given that the 
patient has taken the effort to obtain the medication as instructed, however, information such 
as indication can only be inferred based on diagnostic patterns.  
 
8.12 
OTHER ASPECTS  
None 
9. 
PROTECTION OF HUMAN SUBJECTS 
HealthCore maintains Data Sharing Agreements (DSAs) and Business Associate Agreements 
with covered entities that provide protected health information (PHI) incorporated into the 
HealthCore Integrated Research Database (HIRD). HealthCore’s access, use, and disclosure 
of PHI are in compliance with the Health Insurance Portability and Accountability Act 
(HIPAA) Privacy Rule [45 CFR Part 160 and Subparts A and E of Part 164]. HealthCore 
does not access, use, or disclose PHI other than as permitted by HIPAA and its Business 
Associate Agreements. When using PHI for research, this typically means we will use PHI to 
create limited data sets for research, or when that is not feasible we may obtain a specific 
waiver of the HIPAA authorization requirements from an Institutional Review Board (IRB). 
HealthCore also takes into consideration other federal and state laws and regulations that 
might limit use of certain types of data more than HIPAA, including those laws related to 
identifiable records related to substance abuse and human immunodeficiency virus. 
The current study is designed as an analysis based on medical and pharmacy claims data from 
a large insured population in the United States (US). There is no active enrollment or active 
follow-up of study subjects, and no data will be collected directly from individuals.  
At no time during the conduct of this study will HealthCore provide patient or provider 
identifying information to Boehringer Ingelheim All data and/or results will be in an 
aggregated and de-identified format. Data variables with values ≤10 will be reported only as 
“≤10.” Boehringer Ingelheim will not attempt to re-identify any results provided for the 
study.  

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10. 
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. 
 
11. 
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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12. 
REFERENCES 
12.1 
PUBLISHED REFERENCES 
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. 
 
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. 
 
P14-12233 
Kern DM, Williams SA, Tunceli O, Wessman C, Zhou S, Pethick N, Elhefni 
H, Trudo F. A US database study characterizing patients initiating a 
budesonide-fomoterol combination versus tiotropium bromide as initial 
maintenance therapy for chronic obstructive 
 
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. 
 
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. 
 
P15-11025 
Trudo F, Kern DM, Davis JR. Comparative effectiveness of 
budesonide/formoterol combination and tiotropium bromide among COPD 
patients new to these controller treatments. Int J Chron Obstruct Pulmon Dis. 
2015;10:2055–2066. 
 
P15-12888 
Suissa S, Rossi A. Weaning from inhaled corticosteroids in COPD: the 
evidence. Eur Respir J 2015;46(5):1232-1235. 
 
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. 
 
P16-01440 
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. 
 
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. 

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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 
 
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. 
 
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. 
 
P18-09975 
Suissa, S, Dell'Aniello S, Ernst P. Comparative effectiveness of LABA-ICS 
versus LAMA as initial treatment in COPD targeted by blood eosinophils: a 
population-based cohort study. Lancet Respir Med, 2018. 6(11): p. 855-862. 
 
R05-1384 
Global Strategy for the Diagnosis, Management and Prevention of COPD, 
Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. 
 
R11-4318 
Guidelines for Good Pharmacoepidemiology Practices (GPP) (revision 2: 
April 2007). http://www.pharmacoepi.org/resources/guidelines_08027.cfm 
(access date: 13 September 2011) ; Bethesda: International Society for 
Pharmacoepidemiology (ISPE) (2007) 
 
R11-2162 
Jick SS, Kaye JA, Vasilakis-Scaramozza C et al. Validity of the general 
practice research database. Pharmacotherapy 2003;23(5):686-689. 
 
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. 
 
R13-1970 
European Medicines Agency (EMA), Heads of Medicines Agencies (HMA) 
Guideline on good pharmacovigilance practices (GVP): module VI - 
management and reporting of adverse reactions to medicinal products (22 June 
2012, EMA/873138/2011). 
 
R13-4036 
Minino AM, Xu J, Kochanek KD. Deaths: Preliminary data for 2008. National 
Vital Statistics Reports NCHS 2010;59(2). 
 
R14-4278 
Schneeweiss S, Rassen JA, Glynn RJ, Myers J, Daniel GW, Singer J, Solomon 
DH, Kim SY, Rothman KJ, Liu J, Avorn J Supplementing claims data with 
outpatient laboratory test results to improve confounding adjustment in 
effectiveness studies of lipid-lowering treatments. BMC Med Res Methodol. 
2012; 12, 180. 
 

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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. 
 
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. 
 
R18-2874 
Lin J, Li Y, Tian H, Goodman MJ, Gabriel S, Nazareth T, et al. Costs and 
health care resource utilization among chronic obstructive pulmonary disease 
patients with newly acquired pneumonia. 
 
R19-2321 
Stephenson JJ, Wertz D, Gu T, Patel J, Dalal AA. Clinical and economic 
burden of dyspnea and other chronic obstructive pulmonary disease symptoms 
in a managed care setting. Int J COPD, 2017; 12: 1947-1959. 
 
R19-2322 
Ke X, Marvel J, Yu T-C, Wertz D, Geremakis C, Wang L, Stephenson JJ, 
Mannino DM. Impact of lung function on exacerbations, health care 
utilization, and costs among patients with COPD. Int J COPD, 2016; 11:1689-
1703. 
 
R19-2323 
Johannes CB, McQuay LJ, Midkiff KD, Calingaert B, Andrews EA, Tennis P, 
Brown JS, Camargo CA, Disantostefano R, Rothman KJ, Sturmer T, Lanes S, 
Davis KJ. The feasibility of using multiple databases to study rare outcomes: 
the potential effect of long-acting beta agonists with inhaled corticosteroid 
therapy on asthma mortality. Pharmacoepidemiology and Drug Safety 
2017;26(4):446-458. 
 
R19-2324 
Wallace A, Kaila S, Bayer V, Shaikh A, Shinde MU, Willey V, Napier M, and 
Singer J. Health Care Resource Utilization and Exacerbation Rates in Patients 
with COPD Stratified by Disease Severity in a Commercially Insured 
Population. Journal of Managed Care & Specialty Pharmacy 2019 25:2, 205-
217 
 
R19-3030 
Desai, R.J., et al., A Propensity-score-based Fine Stratification Approach for 
Confounding Adjustment When Exposure Is Infrequent. Epidemiology, 2017. 
28(2): 249-257. 
 
R19-3031 
Lash, T.L., et al., Good practices for quantitative bias analysis. Int J 
Epidemiol, 2014. 43(6): p. 1969-85. 
12.2 
UNPUBLISHED REFERENCES 
None 

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13. 
FUNDING 
There are no additional sources of funding.  

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14. 
ANNEX 
ANNEX 1: LIST OF STAND-ALONE DOCUMENTS 
Documents listed in Annex 1 can be maintained separately from the study protocol. They 
should be clearly identifiable and provided on request. Write “None” if there is no document 
or list documents in a table as indicated below. 
 
Number 
Document 
reference number Date 
Title 
1 
None 
None 
None 
 

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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: 
Safety and Effectiveness of Maintenance Treatment with Combination of Tiotropium and Olodaterol 
in Comparison to Maintenance Treatment with a Combination of Inhaled Corticosteroids and Long-
acting β2 Agonists in COPD Patients 
Study reference number: 
1237-0093 
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. 
13 
13 
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? 
15 
15 
2.1.3 The target population? (i.e. population or subgroup 
to whom the study results are intended to be generalized) 
2.1.4 Which formal hypothesis(-es) is (are) to be tested? 
2.1.5 If applicable, that there is no a priori hypothesis? 
15 
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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Comments: 
      
 
Section 3: Study design 
 
Yes 
No 
N/A 
Page 
Number(s) 
3.1 Is the study design described? (e.g. cohort, case-control, 
randomized controlled trial, new or alternative design)  
 
 
 
16 
3.2 Does the protocol specify the primary and secondary (if 
applicable) endpoint(s) to be investigated? 
 
 
 
16 
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) 
 
 
 
25-26 
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 
16 
19 
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 
categorizing 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) 
 
 
 
 
 
 
 
17, 20-21 
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 
 
 
 
 
 
 
 
      

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Section 5: Exposure definition and measurement 
 
Yes 
No 
N/A 
Page 
Number(s) 
action and taking into account the pharmacokinetics and 
pharmacodynamics of the drug? 
5.5 Does the protocol specify whether a dose-dependent or 
duration-dependent response is measured? 
 
 
 
 
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) 
 
 
 
 
 
 
 
18, 20-21 
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) 
 
 
 
 
 
 
 
19-20 
7.2 Does the protocol address known effect modifiers? (e.g. 
collection of data on known effect modifiers, anticipated 
direction of effect) 
 
 
 
 
 
 
 
20 
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?  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 
 
20 
 
20 
8.2 Does the protocol describe the information available 
from the data source(s) on: 
 
 
 
 
 
 
 
 
 
 
 
 

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Section 8: Data sources 
Yes 
No 
N/A 
Page 
Number(s) 
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.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 
 
20 
 
20 
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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 
 
20 
 
20 
8.4 Is the linkage method between data sources 
described? (e.g. based on a unique identifier or other)  
 
 
 
 
 
 
 
 
Comments: 
      
 
Section 9: Study size and power 
 
Yes 
No 
N/A 
Page 
Number(s) 
9.1 Is sample size and/or statistical power calculated?  
 
 
 
21-22 
Comments: 
      
 
Section 10: Analysis plan 
 
Yes 
No 
N/A 
Page 
Number(s) 
10.1 
Does the plan include measurement of excess risks? 
 
 
 
23-26 
10.2 
Is the choice of statistical techniques described?  
 
 
 
23-26 
10.3 
Are descriptive analyses included? 
 
 
 
23 
10.4 
Are stratified analyses included? 
 
 
 
23-26 
10.5 Does the plan describe methods for adjusting for 
confounding? 
 
 
 
 
 
 
 
23-26 
10.6 Does the plan describe methods addressing effect 
modification? 
 
 
 
 
 
 
 
23-26 
Comments: 
      
 

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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? 
 
 
 
22-23 
11.2 Does the protocol provide information on data storage? 
(e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving) 
 
 
 
22-23 
11.3 Are methods of quality assurance described? 
 
 
 
26 
11.4  Does the protocol describe possible quality issues 
related to the data source(s)? 
 
 
 
22-23 
11.5 Is there a system in place for independent review of 
study results?  
 
 
 
26 
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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
20-21, 27 
12.2 Does the protocol discuss study feasibility? (e.g. sample 
size, anticipated exposure, duration of follow-up in a 
cohort study, patient recruitment) 
 
 
 
21-22 
12.3 Does the protocol address other limitations?  
 
 
 
20-21, 27 
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? 
 
 
 
28 
13.2 Has any outcome of an ethical review procedure been 
addressed? 
 
 
 
      
13.3 Have data protection requirements been described? 
 
 
 
22 
Comments: 
      
 

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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: 
      
 
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? 
 
 
 
30 
 
Comments: 
      
 
Name of the main author of the protocol: 
 
Date: DDMMYYYY 
 
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 8.4.1.  Complete list of drug codes will be added to this document after review 
and approval. 
Medication 
HCPCS 
GPI 
LABA (single) 
 
 
Indacaterol 
 
44201042X 
Salmeterol 
 
4420105810X 
Formoterol 
J7605, J7606,  
J7640, Q4099 
44201027X   44201012102520 
Olodaterol 
 
44201052X 
LAMA (single) 
 
 
Tiotropium 
 
44100080X 
Aclidinium 
 
44100007X 
Glycopyrronium 
J7642, J7643 
44100020X 
Umeclidinium 
 
44100090X 
Revefenacin 
 
44100075002020 
ICS (single) 
 
4440X 
4220X 
Fluticasone 
J7641 
44400033X 
Budesonide 
 
J7626, J7627, 
J7633, J7634 
44400015X 
Beclomethasone 
J7622 
42200010x 
44400010x 
Mometasone 
 
42200045101820 
44400036X 
Flunisolide 
J7641 
44400030X 
Ciclesonide 
 
4440001700x 
Dexamethasone 
 
4440002010x 
Triamcinolone 
J7683, J7684 
4440004020x 

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LABA/LAMA 
 
 
Formoterol/glycopyrroni
um 
 
44209902543220 
Indacaterol/glycopyrroni
um 
 
44209902600110 
Vilanterol/umeclidinium 
 
4420990295X 
Olodaterol/tiotropium 
 
4420990292X 
LABA-ICS 
 
 
Fluticasone 
furoate/salmeterol 
 
4420990270X 
Fluticasone 
furoate/vilanterol 
 
4420990275X 
Mometasone/formoterol 
 
4420990290X 
Budesonide/formoterol 
 
4420990241X 
 
ANNEX 3.2: DEFINITIONS OF STUDY OUTCOMES  
See section 8.4.2.  Complete list of codes will be added to this document after review and 
approval. 
Condition 
ICD9 
ICD10 
ICD9 
proc 
ICD10 
proc 
HCPCS CPT 
COPD 
491 
491 
491.1 
491.2 
491.21 
491.22 
491.8 
491.9 
492 
492 
492.8 
496 
 
J41 
J41.0 
J41.1 
J41.8 
J42 
J43 
J43.0 
J43.1 
J43.2 
J43.8 
J43.9 
J44 
J44.0 
 
 
 
 

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J44.1 
J44.9 
Pneumonia  
480 
480.1 
480.2 
480.3 
480.8 
480.9 
481 
482 
482.1 
482.2 
482.3 
482.31 
482.32 
482.39 
482.4 
482.41 
482.42 
482.49 
482.81 
482.82 
482.83 
482.84 
482.89 
482.9 
483 
483.1 
483.8 
484.1 
484.3 
484.5 
J10.00 
J10.01 
J10.08 
J11.00 
J11.08 
J12.0 
J12.1 
J12.2 
J12.3 
J12.81 
J12.89 
J12.9 
J13 
J14 
J15.0 
J15.1 
J15.20 
J15.211 
J15.212 
J15.29 
J15.3 
J15.4 
J15.5 
J15.6 
J15.7 
J15.8 
J15.9 
J16.0 
J16.8 
J17 
 
 
 
 

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484.6 
484.7 
484.8 
485 
486 
997.31 
997.32 
 
J18.0 
J18.1 
J18.2 
J18.8 
J18.9 
J69.0 
J85.1 
J95.4 
J95.89 
 
Medication 
HCPCS 
GPI 
Prednisolone  
J2650, J7510, 
J7512  
22100040X 
22109902201810 
22100045X 
 
ANNEX 3.3: DEFINITIONS OF STUDY COVARIATES 
See section 8.4.3.Complete list of codes will be added to this document after review and 
approval. 
 
Medication 
HCPCS 
GPI 
Short-acting beta-
agonists 
 
 
Levalbuterol 
J7617J7607J7612, 
J7614,J7615 
4420104510X 
4420104550X 
Albuterol 
J7602, J7603, 
J7609-J7611, 
J7613, J7616, 
J7620, 
J7625, Q4093, 
Q4094 
4420101000X 
4420101010X 
 
Terbutaline 
J3105J7680,J7681 
442010602X 
 
Isoproterenol 
J7657 
J7658 
J7659 
44201040X 

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J7660 
Methylxanthines 
 
 
Aminophylline 
 
4430001000x 
4430001010x 
Theophylline (SR) 
J2810 
4430004000x   499100240X   
4499100220X 
4499100242X   4499100250X   
44992203X 
44993003X   44993204X   44999003X 
44999602X   4499220310X   
4499960270X 
4499220315X 
SAMA (Short-acting 
muscarinic antagonists) 
 
 
Ipratropium bromide 
J7644, J7655 
4230X 44100030X 
Antibiotics for a 
respiratory condition 
 
 
Aamikacin 
J0278  
07000010x 
Amoxicillin/potassium 
clavulanate 
 
0199000220x 
Amoxicillin  
01200010x 
Ampicillin 
J0290  
01200020x 
Ampicillin-sulbactam 
J0295 
0199000225x 
Azithromycin 
J0456 
03400010x 
Aztreonam 
S0073  
16000005x 
Cefaclor 
02200040x 
Cefdinir 
02300040x 
Cefepime 
J0692 
02400040x 
Cefixime  
02300060x 
Cefotaxime  
J0698  
02300075x 
Cefpodoxime 
02300065x 
Cefprozil 
02200062x 
Ceftazidime 
J0713, J0714 
02300080x 
Ceftriaxone 
J0696 
02300090x 

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Cefuroxime 
J0697 
02200065x 
Ciprofloxacin 
J0744 
05000020x 
Clarithromycin 
03500010x 
Doxycycline 
04000020x 
Ertapenem 
J1335  
16150030x 
Erythromycin 
J1364  
0310x 
Gemifloxacin 
05000083x 
Imipenem 
J0743  
16159902x 
Levofloxacin 
J1956  
05000034x 
Linezolid 
J2020  
16230040x 
Meropenem  
J2185  
16150050x 
Moxifloxacin 
J2280  
05000037x 
Penicillin G benzathine 
J0561, J0558 
01990002x, 01100020x 
Penicillin VK 
01100040x 
Piperacillin 
S0081  
01400040x 
Piperacillin-tazobactam 
J2543 
019900027x 
Procaine penicillin 
J0558, J2510 
Ticarcillin 
01400050x 
Ticarcillin-clavulanate 
S0040 
019900023x 
Trimethoprim-
sulfamethoxazole 
S0039 
169900023x 
 Vancomycin 
J3370 
16000060102x 
 
Condition 
ICD9 
ICD10 
ICD9 
proc 
ICD10 
proc 
HCPC
S 
CPT 
Asthma 
493 
493 
493 
493.01 
493.02 
493.1 
493.1 
J45 
J45.2 
J45.20 
J45.21 
J45.22 
J45.3 
J45.30 
 
 
 
 

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493.11 
493.12 
493.2 
493.2 
493.21 
493.22 
493.8 
493.81 
493.82 
493.9 
493.9 
493.91 
493.92 
 
J45.31 
J45.32 
J45.4 
J45.40 
J45.41 
J45.42 
J45.5 
J45.50 
J45.51 
J45.52 
J45.9 
J45.90 
J45.901 
J45.902 
J45.909 
J45.99 
J45.990 
J45.991 
J45.998 
 
Lung cancer 
162 
231.2 
197.0 
176.4 
235.7 
V10.11 
C33 
C34.00 
C34.10 
C34.2 
C34.30 
C34.80 
C34.90 
C46.50 
C78.00 
D02.20 
D38.1 
Z85.118 
 
 
 
 
Interstitial 
lung disease 
516.6* 
516.34 
J84.115 
J84.83 
J84.841 
 
 
 
 

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J84.842 
J84.843 
J84.848 
Lung 
transplant 
 
 
33.50 
33.51 
33.52 
0BYC0Z
0 
0BYC0Z
1 
0BYC0Z
2 
0BYD0Z
0 
0BYD0Z
1 
0BYD0Z
2 
0BYF0Z0 
0BYF0Z1 
0BYF0Z2 
0BYG0Z
0 
0BYG0Z
1 
0BYG0Z
2 
0BYH0Z
0 
0BYH0Z
1 
0BYH0Z
2 
0BYJ0Z0 
0BYJ0Z1 
0BYJ0Z2 
0BYK0Z
0 
0BYK0Z
1 
0BYK0Z
2 
0BYL0Z
0 
0BYL0Z
1 
0BYL0Z
2 
S2060 
S2061 
 
00580 
32850
-
32856 
33935 
33933 

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0BYM0Z
0 
0BYM0Z
1 
0BYM0Z
2 
Cardiovascul
ar disease 
410.xx-
414.xx 
427.xx; 
785.0; 785.1 
426.xx 
428.xx 
401.xx–
405.xx 
440.xx; 
441.xx; 
442.xx; 
443.xx 
272.x 
393-398; 
421.x; 
422.xx; 
746.0x-
746.7 
I20.%-I25.%%% 
I47.%, I48.%%; 
I49.%% 
I44.%%; I45.%% 
I50.%% 
I11.%; I13.%; 
O10.1%; O10.3% 
I70.%%%; 
I71.%%; I72.%; 
I73.%% 
E78.%% 
I05.%-I09.%%; 
I33.%-I39; 
Q22.%, Q23.% 
37.7x–
37.8x, 
37.94–
37.99 
 
 
 
Diabetes  
250 
250.01 
250.02 
250.03 
250.1 
250.11 
250.12 
250.13 
250.2 
250.21 
250.22 
250.23 
250.3 
250.31 
E10.10 
E10.11 
E10.21 
E10.29 
E10.311 
E10.319 
E10.36 
E10.37X1 
E10.37X2 
E10.37X3 
E10.37X9 
E10.39 
E10.40 
E10.51 
 
 
 
 

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001-MCS-90-124_RD-01 (4.0) 
 
250.32 
250.33 
250.4 
250.41 
250.42 
250.43 
250.5 
250.51 
250.52 
250.53 
250.6 
250.61 
250.62 
250.63 
250.7 
250.71 
250.72 
250.73 
250.8 
250.81 
250.82 
250.83 
250.9 
250.91 
250.92 
250.93 
 
E10.618 
E10.620 
E10.621 
E10.622 
E10.628 
E10.630 
E10.638 
E10.641 
E10.649 
E10.65 
E10.69 
E10.8 
E10.9 
E11.00 
E11.01 
E11.10 
E11.11 
E11.21 
E11.29 
E11.311 
E11.319 
E11.36 
E11.39 
E11.40 
E11.51 
E11.618 
E11.620 
E11.621 
E11.622 
E11.628 
E11.630 
E11.638 

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001-MCS-90-124_RD-01 (4.0) 
 
E11.641 
E11.649 
E11.65 
E11.69 
E11.8 
E11.9 
E13.10 
Thyroid 
disease 
226, 240.0, 
240.9, 
241.0, 
241.1, 
241.9, 242*, 
243, 244*, 
245*, 246*, 
790.94 
D09.3, D34, 
D44.0, 
E01.1,E01.2, 
E01.8, E02, E03*, 
E04*, E05*, 
E06*, E07*, 
E01.0 
E89.0 
 
 
 
 
Renal failure 
403 
403.01 
403.1 
403.11 
403.9 
403.91 
585.1 
585.2 
585.3 
585.4 
585.5 
585.6 
585.9 
586 
584.5 
584.6 
584.7 
584.8 
I12.0 
I12.9 
N18.1 
N18.2 
N18.3 
N18.4 
N18.5 
N18.6 
N18.9 
N17.0 
N17.1 
N17.2 
N17.8 
N17.9 
 
 
 
 
 

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001-MCS-90-124_RD-01 (4.0) 
 
584.9 
Autoimmune 
disease 
135 
274.9 
275.49 
279.49 
283 
443 
448.9 
530.5 
555.9 
571.42 
571.6 
576.1 
579 
696 
696.1 
710 
710.1 
710.2 
710.3 
710.9 
711.9 
712.19 
714 
714.3 
715.09 
715.11 
715.12 
715.13 
715.14 
715.15 
715.17 
D86.9 
M10.9 
E83.59 
D89.89 
D59.0 
D59.1 
I73.00 
I73.01 
I78.9 
K22.4 
K50.90 
K75.4 
K74.3 
K74.4 
K74.5 
K83.0 
K90.0 
L40.50 
L40.54 
L40.59 
L40.0 
L40.1 
L40.2 
L40.8 
M32.10 
M34.0 
M34.1 
M34.2 
M34.81 
M34.82 
M34.83 
 
 
 
 

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001-MCS-90-124_RD-01 (4.0) 
 
715.18 
715.96 
719.42 
719.44 
719.45 
719.47 
719.49 
720 
721.9 
725 
729.1 
729.5 
795.79 
 
M34.89 
M34.9 
M35.00 
M35.01 
M35.02 
M35.03 
M35.04 
M35.09 
M33.90 
M35.9 
M00.9 
M11.9 
M06.9 
M08.00 
M15.0 
M19.019 
M19.029 
M19.039 
M19.049 
M16.0 
M16.10 
M16.11 
M16.12 
M19.079 
M19.91 
M17.9 
M25.529 
M79.643 
M79.646 
M25.559 
M25.579 
M25.50 
M45.9 
M47.819 
M35.3 
M60.9 
M79.1 
M79.609 
R76.0 
R76.11 
R76.12 
R76.8 
R76.9 
 

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001-MCS-90-124_RD-01 (4.0) 
 
Obesity  
278 
278.01 
278.02 
278.03 
278.1 
278.2 
278.3 
278.4 
278.8 
V85.30 
V85.31 
V85.32 
V85.33 
V85.34 
V85.35 
V85.36 
V85.37 
V85.38 
V85.39 
V85.41 
V85.42 
V85.43 
V85.44 
V85.45 
E65 
E66.01 
E66.2 
E66.3 
E66.9 
E67.0 
E67.1 
E67.3 
E67.8 
Z68.30 
Z68.31 
Z68.32 
Z68.33 
Z68.34 
Z68.35 
Z68.36 
Z68.37 
Z68.38 
Z68.39 
Z68.41 
Z68.42 
Z68.43 
Z68.44 
Z68.45 
 
 
 
 
Alcohol use 
disorder 
303 
303.01 
303.02 
303.03 
303.9 
303.91 
303.92 
303.93 
 
F10.159 
F10.180 
F10.181 
F10.188 
F10.20 
F10.21 
F10.229 
F10.259 
94.46 
94.53 
94.61 
94.62 
94.63 
94.67 
94.68 
94.69 
 
HZ2ZZZ
Z 
HZ30ZZ
Z 
HZ31ZZ
Z 
HZ32ZZ
Z 
HZ33ZZ
Z 
HZ34ZZ
 
 

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001-MCS-90-124_RD-01 (4.0) 
 
F10.27 
F10.280 
F10.281 
F10.288 
F10.959 
F10.980 
F10.99 
Z65.8 
 
Z 
HZ35ZZ
Z 
HZ36ZZ
Z 
HZ37ZZ
Z 
HZ38ZZ
Z 
HZ39ZZ
Z 
HZ3BZZ
Z 
HZ40ZZ
Z 
HZ41ZZ
Z 
HZ42ZZ
Z 
HZ43ZZ
Z 
HZ44ZZ
Z 
HZ45ZZ
Z 
HZ46ZZ
Z 
HZ47ZZ
Z 
HZ48ZZ
Z 
HZ49ZZ
Z 
HZ4BZZ
Z 
HZ93ZZ
Z 
HZ96ZZ
Z 
 
Tobacco use 
or cessation 
counselling 
305.1* 
649.0* 
989.84 
V15.82 
Z72.0 
F17.21 
F17.210 
F17.211 
F17.218 
 
 
C9801 
C9802 
G0375 
G0376 
G0436 
99406 
99407 

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001-MCS-90-124_RD-01 (4.0) 
 
F17.219 
Z71.6 
G0437 
G8453 
G8455 
G8456 
G8692 
G9276 
G9458 
G9497 
G9642 
G9792 
G9906 
G9908 
S9075 
S9453 
G9902   
G9907   
G9909   
Cancer 
(excluding 
basal cell 
carcinoma) 
140.xx – 
195.xx 
200.xx – 
208.xx 
196.xx - 
199.xx 
EXCLUDIN
G: 
173.01 
173.11 
173.21 
173.31 
173.41 
173.51 
173.61 
173.71 
173.81 
173.91 
 
C00%-C76%, 
C81%-C96% 
C77%-
C80%EXCLUDIN
G: 
C44.01 
C44.111 
C44.1121 
C44.119 
C44.91 
C44.311 
C44.319 
C44.310 
C44.510 
C44.511 
C44.519 
C44.41 
C44.81 
C44.211 
C44.212 
C44.219 
C44.611 
C44.612 
 
 
 
 

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001-MCS-90-124_RD-01 (4.0) 
 
C44.619 
C44.711 
C44.712 
C44.719 
 
ANNEX 3.4: STATISTICAL CONSIDERATIONS 
See section 8.9.  
 

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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bi-se-laba-combination-final
Effectiveness and Safety of Maintenance Treatment with Combination of Tiotropium
and Olodaterol in Comparison to Maintenance Treatment with a Combination of
Inhaled Corticosteroids and Long-acting β2 agonists in COPD patients
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19 Feb 2020 10:55 CET
Approval-
 of Global
Epidemiology
19 Feb 2020 11:29 CET
Approval-
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Therapeutic Area
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Approval-Team Member Medicine
02 Mar 2020 09:18 CET
Approval-Team Member Medicine
02 Mar 2020 09:48 CET

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