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

ABCD
Protocol for non-interventional studies based on existing data
TITLE PAGE
TITLE PAGE
Document Number: 
c30699487-01
BI Study No.:
1237-0094
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, Long-acting β2 Agonists and Long-acting 
Muscarinic Antagonists in COPD Patients
Title for lay people:
Comparative Effectiveness and Safety of Tiotropium and 
Olodaterol in comparison to Triple Therapy
Date of last version of 
protocol:
NA
EU PAS Register No:
Not applicable
Marketing 
authorization 
holder(s):
Author/Responsible 
Parties/BI contact 
person:
Authors/Responsible parties:
Tel.: 
Mobil: 
Fax: 
 
Email:
Country(-ies) of study:
United States
Status:
Protocol Final Version 1

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
EU-QPPV:
only applicable for PASS
Not applicable
Signature of 
EU-QPPV:
only applicable for PASS
Not applicable
Version: 1.0
Date : 12 Dec 2019
Page 1 of 57
Proprietary confidential information
© 2019 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

Boehringer Ingelheim                                                                                           Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ABSTRACT
Name of company:
ABCD
Boehringer Ingelheim
Name of product: Spiolto
Name of active ingredient:
Tiotropium bromide + Olodaterol
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
12 December 2019
1237-0094
1.0
NA
Proprietary confidential information
© 2019 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, Long-acting β2 Agonists and Long-
acting Muscarinic Antagonists in COPD Patients
Team member
Epidemiology:
and 
Project team:
(Principal Investigator)

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
ABCD
Boehringer Ingelheim
Name of product: Spiolto
Name of active ingredient:
Tiotropium bromide + Olodaterol
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
12 December 2019
1237-0094
1.0
NA
Proprietary confidential information
© 2019 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 involves multiple therapies, including long-acting β2 
agonists (LABA) (with and without inhaled corticosteroids (ICS) and long-
acting muscarinic antagonists (LAMA), with combinations of these drugs 
now formulated into single inhalers. 
There are recommendations to restrict triple therapy use further, to only 
patients who are likely to respond to ICS (such as those with asthma-COPD 
overlap or patients with high risk of exacerbations and elevated blood 
eosinophils [P15-08642, P07-11503, R19-3048]. There is an increasing body 
of evidence suggesting that ICS are particularly effective at reducing the
incidence of COPD exacerbations in patients only with a very high blood 
eosinophil concentration, but not in normal levels [P18-09975]. Hence there 
is a clear need for better evidence on specific patient populations upon which 
to base treatment recommendations.
This non-interventional study aims to assess the comparative effectiveness of 
combination Tiotropium and Olodaterol (Tio+Olo) (FDC) compared to 
combination LAMA/LABA and ICS (fixed or open), and to explore whether 
this varies across COPD sub populations defined by exacerbation risk. The 
intended audiences are payers and prescribers.  The results from the study 
will be published in the scientific literature.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
ABCD
Boehringer Ingelheim
Name of product: Spiolto
Name of active ingredient:
Tiotropium bromide + Olodaterol
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
12 December 2019
1237-0094
1.0
NA
Proprietary confidential information
© 2019 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 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 ICS/LABA/LAMA. All 
analyses will be repeated 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 (with exacerbation history defined as either 1+ 
hospitalization or 2+ exacerbations in emergency department or outpatients 
settings [R05-1384]), and (2) circulating eosinophils (cut-off B-Eos 300
cells/uL [P18-09975]) Both overall and among those without a history of 
exacerbation.
The primary objective is to compare the effectiveness of maintenance therapy 
initiation with the combination treatment Tiotropium and Olodaterol 
(Tio+Olo) compared with any LABA/LAMA/ICS combination in COPD as 
the time to the first COPD exacerbation. 
The secondary objective is to assess the association between maintenance 
therapy initiation with the combination treatment (Tio+Olo vs any 
LABA/LAMA/ICS combination in COPD and time to community acquired 
pneumonia.
Additionally, we will assess differences between Tio+Olo vs any 
LABA/LAMA/ICS in healthcare utilization and all-cause and COPD-specific
cost overall and by care setting.
Study design:
A incident new-user cohort design will be used, with confounding controlled 
via fine stratification and reweighting of time-conditional propensity scores

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
ABCD
Boehringer Ingelheim
Name of product: Spiolto
Name of active ingredient:
Tiotropium bromide + Olodaterol
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
12 December 2019
1237-0094
1.0
NA
Proprietary confidential information
© 2019 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
Population:
The cohort will consist of all patients in the HIRD with a diagnosis of COPD 
who received Tio+Olo or combination LABA/LAMA/ICS treatment from 1 
January 2013 until 31 March 2019 (or the most recent date available at the 
time of cohort extraction). To increase the likelihood of a diagnosis of COPD
and decrease the likelihood of including misdiagnosed asthma patients, we 
will only include patients 40 years of age or older on the index date and 
exclude all patients with a diagnosis of asthma within the year prior to the 
index date or lung cancer, interstitial lung disease, or lung transplantation at 
any time prior to the index date.   
Patients will have at least one year of medical history information prior to the 
cohort entry date to allow the identification of new use and the measurement 
of baseline covariates.  Patients will be followed until switching to the other 
treatment, other changes in therapy, discontinuation of COPD treatment, the 
end of the individual’s health plan eligibility, 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: 5,458
New users of LABA/LAMA/ICS: 42,361
With eosinophil result data: 
New users of Tio+Olo: 2,198
New users of LABA/LAMA/ICS: 15,712
Main criteria for 
inclusion:
- New users of Tio+Olo on the same date or of LABA, LAMA and ICS,
either as a fixed-dose combination (LABA/LAMA/ICS) or free combination
(LABA/ICS + LAMA, etc), on the same date between January 2013 and 
March 2019.
- Diagnosis of COPD prior to first maintenance inhaler and age ≥ 40 years at 
index date

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
ABCD
Boehringer Ingelheim
Name of product: Spiolto
Name of active ingredient:
Tiotropium bromide + Olodaterol
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
12 December 2019
1237-0094
1.0
NA
Proprietary confidential information
© 2019 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 (index date)
-Lung cancer, interstitial lung disease, or lung transplantation at any time 
prior to the index date
-Asthma diagnosis within one year prior to the index date
Comparison groups:
Initiating Tio+Olo compared to initiating LABA/LAMA/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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
ABSTRACT..............................................................................................................................3
TABLE OF CONTENTS ........................................................................................................8
1.
LIST OF ABBREVIATIONS AND TERMS....................................................10
2.
RESPONSIBLE PARTIES ................................................................................12
3.
AMENDMENTS AND UPDATES....................................................................12
4.
MILESTONES ....................................................................................................12
5.
RATIONALE AND BACKGROUND ..............................................................13
6.
RESEARCH QUESTIONS AND OBJECTIVES............................................14
7.
RESEARCH METHODS...................................................................................15
7.1
STUDY DESIGN.................................................................................................15
7.2
SETTING.............................................................................................................15
7.3
SUBJECTS ..........................................................................................................15
7.4
VARIABLES .......................................................................................................16
7.4.1
Exposures.............................................................................................................16
7.4.2
Outcome(s)...........................................................................................................16
7.4.2.1
Primary outcome(S)............................................................................................16
7.4.2.2
Secondary outcome(s).........................................................................................17
7.4.3
Covariates ............................................................................................................17
7.5
DATA SOURCES ...............................................................................................19
7.6
BIAS .....................................................................................................................19
7.7
STUDY SIZE.......................................................................................................20
7.8
DATA MANAGEMENT....................................................................................21
7.9
DATA ANALYSIS..............................................................................................22
7.9.1
Main analysis.......................................................................................................22
7.10
QUALITY CONTROL.......................................................................................24
7.11
LIMITATIONS OF THE RESEARCH METHODS ......................................25
7.12
OTHER ASPECTS .............................................................................................25
8.
PROTECTION OF HUMAN SUBJECTS .......................................................26
9.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS..................................................................27
10.
PLANS FOR DISSEMINATION AND COMMUNICATION OF STUDY 
RESULTS ............................................................................................................28
11.
REFERENCES....................................................................................................29
11.1
PUBLISHED REFERENCES............................................................................29
11.2
UNPUBLISHED REFERENCES......................................................................32

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
12.
FUNDING............................................................................................................33
13.
ANNEX ................................................................................................................34
ANNEX 1: LIST OF STAND-ALONE DOCUMENTS .....................................................34
ANNEX 2: ENCEPP CHECKLIST FOR STUDY PROTOCOLS...................................35
ANNEX 3:ADDITIONAL INFORMATION ......................................................................41
ANNEX 3.1: DEFINITION OF STUDY EXPOSURES.....................................................41
ANNEX 3.2: DEFINITIONS OF STUDY OUTCOMES...................................................42
ANNEX 3.3: DEFINITIONS OF STUDY COVARIATES................................................44
ANNEX 3.4:STATISTICAL CONSIDERATIONS............................................................57

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
LIST OF ABBREVIATIONS AND TERMS
AE
Adverse Event
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
EMA
European Medicines Agency
FDC
Fixed Dose Combination
GVP
Guideline on Good Pharmacovigilance Practices
HIPAA
Health Insurance Portability and Accountability Act
HIRD
HealthCore Integrated Research Database
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
PHI
Protected Health Information
PS
Propensity score
PSTAT
Project Statistician
PY
Person-years at risk
RR
Rate Ratio
TIO+OLO
Tiotropium+Olodaterol

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
TM Epi
Team Member Epidemiology
cells/µL
Microliter
US
United States
UTS
Up-to-standard

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.
RESPONSIBLE PARTIES
 (Principal Investigator)
Tel: 
3.
AMENDMENTS AND UPDATES
There are currently no amendments to the protocol.
4.
MILESTONES
Milestone
Planned date
Start of data collection: 
Data extraction and coding
August 1, 2019
End of data collection:
Not applicable. This study is an observational study based on 
existing data.
Study progress report(s) as 
referred in Article 
107 m(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)

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.
RATIONALE AND BACKGROUND
The treatment of COPD involves multiple therapies, including Long-acting β2 agonists
(LABA) (with and without inhaled corticosteroids (ICS) and long-acting muscarinic 
antagonists (LAMA), with combinations of these drugs now formulated into single inhalers.
Several trials compared a single-inhaler triple therapy with an ICS/LABA and a LAMA 
respectively and found greater benefit with triple FDC [P19-08111]. However, they represent 
a limited view of the patients who could potentially use these treatments so that a real-world 
study of patients who are representative of clinical practice is of interest.
There are recommendations to restrict triple therapy use further, to only patients who are 
likely to respond to ICS (such as those with asthma-COPD overlap or elevated blood 
eosinophils [P15-08642). There is an increasing body of evidence suggesting that ICS are
particularly effective at reducing the incidence of COPD exacerbations in patients only with a
very high blood eosinophil concentration, but not in normal levels [P18-09975]. Hence there 
is a clear need for better evidence on specific patient populations upon which to base 
treatment recommendations.
This non-interventional study aims to assess the comparative effectiveness of combination 
Tiotropium and Olodaterol (Tio+Olo) (FDC) compared to combination LAMA/LABA and 
ICS (fixed or open) This study will provide useful data on the relative benefits of different 
combinations in treating COPD patients The intended audiences are payers and prescribers.  
The results from the study will be published in the scientific literature.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.
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 ICS/LABA/LAMA. All analyses will be conducted for the total 
population, as well as in sub-groups of patients under (1) high- or low risk of exacerbation 
based on previous history of exacerbations in the year preceding cohort entry (cut-off: 0-1 vs 
2+ exacerbations [P07-11503], (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 objectives:
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/LAMA/ICS combination in COPD as the time to the first COPD 
exacerbation. 
Secondary objective:
The secondary objective is to assess the association between maintenance therapy initiation 
with the combination treatment (Tio+Olo vs any LABA/LAMA/ICS combination in COPD 
and time to community acquired pneumonia.
Exploratory objective:
To assess differences between Tio+Olo vs any LABA/LAMA/ICS in all-cause and COPD-
specific healthcare utilization and cost overall and by care setting.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.
RESEARCH METHODS
7.1
STUDY DESIGN
Population-based incident new-user cohort design.
7.2
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 7.5).
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).
7.3
SUBJECTS
The study cohort will be formed based on the following entry criteria.
Inclusion Criteria:
1. At least one prescription for Tio+Olo or a LABA/LAMA/ICS combination between
1 January 2013 and 31 March 2019.
a.
For Tio+Olo users, the first dispensing of Tio+Olo will be defined as the index 
date.
b. LABA/LAMA/ICS use can occur either in free or fixed combinations. 
The first date when all three medications are used based on either concurrent 
or overlapping dispensings in the pharmacy claims data will be defined as the 
index date.
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 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 ICS for the Tio+Olo group, discontinuation of 

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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.
7.4
VARIABLES
7.4.1
Exposures
The exposure measures are based on pharmacy dispensings of the study medications, namely 
Tio+Olo and LABA/LAMA/ICS combination therapy. As described in the data analysis 
section, the as-treated analysis, which is the main analysis, will consider continuing exposure 
of the initial treatment of Tio+Olo or LABA/LAMA/ICS within the treated groups defined by 
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 7.9.2). Codes used to identify study medications are included in Annex 3.1.
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, applies to Tio+Olo only)
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.
7.4.2
Outcome(s)
7.4.2.1
Primary outcome(S)
The primary outcome event for effectiveness is the first COPD exacerbation to occur after 
cohort entry.The event is defined as follows:

Severe exacerbation:
o
Hospitalization with a principal discharge diagnosis of COPD.

Moderate exacerbation:
o
An ED visit with a discharge diagnosis of COPD and/or
o
Dispensing of an antibiotic and an oral corticosteroid on the same day
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 with the 
prescription of an antibiotic and/or 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 

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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.
7.4.2.2
Secondary outcome(s)
The secondary outcome is the occurrence of the 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].
7.4.3
Covariates
Patient characteristics at baseline will be assessed for Tio+Olo and LABA/LAMA/ICS user 
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

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

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
o
LABA/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:
o
Short-acting beta-agonists
o
Anticholinergics
o
Methylxanthines
o
Muscarinic antagonists
o
Short-acting muscarinic antagonists

Use of antibiotics 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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Sub-populations will include patients with high or low circulating eosinophils (B-Eos 
300 cells/uL [P18-09975] 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. However, number of patients with baseline exacerbations and data available 
on B-Eos is very low (see section 7.7) and therefore analysis would not be meaningful and 
will not be performed.
7.5
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 
members across the United States (US). Member enrolment, 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] 
7.6
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 [R19-3031].
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.7
STUDY SIZE
Preliminary patient counts in the HIRD are shown here:
Tio+Olo
ICS/LABA/LAMA
N
%
N
%
New users
8,233
100.0
82,534
100.0
At least 12 months of 
pre-index eligibility
6,263
76.1
50,153
60.8
Age 40 +
6,126
97.8
48,267
96.2
At least 1 diagnosis of COPD
5,469
89.3
42,227
87.5
At least 1 eosinophil % result 
prior to the index date
2,207
40.4
15,699
37.2
Eosinophil result (N, % of 
those with a result)
0-2%
1,059
48.0
7,488
47.7
2-4%
745
33.8
5,136
32.7
4%+
403
18.3
3,075
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
9,516
27.3
≥300 cells/uL
481
10.5
3,481
10.0
Unknown
2,739
59.5
21,813
62.7
Eosinophil result, patients 
with high exacerbation history 
(1 + inpatient or 2 + outpatien
t events at baseline, N, %)
vents
<300 cells/uL
226
26.0
1,888
25.5
≥300 cells/uL
105
12.1
707
9.5
Unknown
537
61.9
4,822
65.0
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 and analyses 
that are stratified based on the presence of claims-based indicators of exacerbation are 
expected to have adequate power. Analyses limited to individuals with specific eosinophils 
will be more limited. Given low expected sample size, stratification by eosinophil analysis
within individuals with exacerbations at baseline will not be performed by Eosinophil 
categories.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8
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 
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.9
DATA ANALYSIS
7.9.1
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 ug/mL 

Circulating eosinophils: B-Eos 300 ug/mL+

History of exacerbation: 0 inpatient and 0-1 outpatient events & circulating 
eosinophils: B-Eos < 300 ug/mL

History of exacerbation: 0 inpatient and 0-1 outpatient events & circulating 
eosinophils: B-Eos 300 ug/mL +
We will first describe formation of the study cohort. Patient characteristics at baseline in 
patients treated with Tio+Olo and patients treated with LABA/LAMA/ICS will be described 
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.
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 
LABA-LAMA-ICS combination versus the Tio+Olo 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-LAMA-ICS use relative to Tio+Olo 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. This approach allows consideration of exposure as time-dependent, 
accounting for the changes in exposure during the follow-up.  In particular, this analysis 
excludes patients stopping one or more of the drugs prior to the index date.
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The analysis of the risk of pneumonia will also use a time-dependent Cox proportional hazard 
regression model with an as-treated approach, similar to that of the primary analysis. 
In addition, we will repeat the primary effectiveness analysis on the time to exacerbation 
separately for moderate and severe exacerbations.  
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.10
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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.
7.11
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 
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. 
7.12
OTHER ASPECTS
None

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
PLANS FOR DISSEMINATION AND COMMUNICATION OF
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
11.
REFERENCES
11.1
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 pulmonary disease. Int J COPD. 
2014;(9): 775-783
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.
P15-08642
Barjaktarevic 
IZ, 
Arredondo 
AF, 
Cooper 
CB. 
Positioning 
new 
pharmacotherapies for COPD. Int J Chron Obstruct Pulmon Dis. 
2015;10:1427-42. doi: 10.2147
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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.
P16-10095
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):60-6
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.
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.
R05-1384
Global Strategy for the Diagnosis, Management and Prevention of COPD, 
Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017.
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 SJ, 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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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. Clinicoeconomics Outcomes Res. 2014; 6, 349 – 356.
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): p. 249-257.
R19-3048
Miravitlles M, Anzueto A. Chronic Respiratory Infection in Patients with 
Chronic Obstructive Pulmonary Disease: What Is the Role of Antibiotics? Int 
J Mol Sci. 2017;18(7). pii: E1344. doi: 10.3390
P19-08111
Calverley, P.M.A., et al., Triple Therapy in COPD: What We Know and What 
We Don't. COPD: Journal of Chronic Obstructive Pulmonary Disease, 2017. 
14(6): p. 648-662.
R19-3031
Lash, T.L., et al., Good practices for quantitative bias analysis. Int J Epidemiol, 
2014. 43(6): p. 1969-85.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
11.2
UNPUBLISHED REFERENCES
None

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
12.
FUNDING
There are no additional sources of funding.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
13.
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

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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, Long-acting β2 agonists and long-acting muscarinic antagonists in COPD 
patients 
Study reference number:
205.526
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.
15
15
15
15
15
Comments:
Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1Does 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?
17
17
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?
17
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.

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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) 
18
3.2 Does the protocol specify the primary and 
secondary (if applicable) endpoint(s) to be 
investigated?
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)
25-27
Comments:
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1Is the source population described?
18, 22
4.2Is 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?
18
18
18
18, 22
18, 20-21
20
4.3 Does the protocol define how the study population 
will be sampled from the source population? (e.g. 
event or inclusion/exclusion criteria)  
18
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) 
19
5.2 Does the protocol discuss the validity of exposure 
measurement? (e.g. precision, accuracy, prospective 
ascertainment, exposure information recorded before 
19, 22

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
the outcome occurred, use of validation sub-study)
5.3 Is exposure classified according to time windows? 
(e.g. current user, former user, non-use)
19
5.4 Is exposure classified based on biological 
mechanism of 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? 
19-20
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)
19-20, 22
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)
20-21
7.2 Does the protocol address known effect modifiers? 
(e.g. collection of data on known effect modifiers, 
anticipated direction of effect)
22
Comments:

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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?
22
22
22
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.)
22
22
22
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)
22
22
22
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?
22-23
Comments:

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1
Does the plan include measurement of excess 
risks?
25-27
10.2
Is the choice of statistical techniques described? 
25-27
10.3
Are descriptive analyses included?
25
10.4
Are stratified analyses included?
25-27
10.5
Does the plan describe methods for adjusting for 
confounding?
25-27
10.6
Does the plan describe methods addressing 
effect modification?
25-27
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?
22
11.2 Does the protocol provide information on data 
storage? (e.g. software and IT environment, 
database maintenance and anti-fraud protection, 
archiving)
24
11.3 Are methods of quality assurance described?
24
11.4 Does the protocol describe possible quality issues 
related to the data source(s)?
24
11.5 Is there a system in place for independent review 
of study results? 
27
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)
22, 28
12.2 Does the protocol discuss study feasibility? (e.g. 
sample size, anticipated exposure, duration of
22-23

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
follow-up in a cohort study, patient recruitment)
12.3 Does the protocol address other limitations?
22, 28
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?
28-29
13.2
Has any outcome of an ethical review procedure 
been addressed?
13.3
Have data protection requirements been 
described?
24
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?
14
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?
29
Comments:
Name of the main author of the protocol: 
Date: 16 August 2019
Signature: ___________________________

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ANNEX 3:ADDITIONAL INFORMATION
Additional annexes may be included if necessary.
ANNEX 3.1: DEFINITION OF STUDY EXPOSURES
  
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
LABA/LAMA
Formoterol/glycopyrroni
um
44209902543220

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Medication
HCPCS
GPI
Indacaterol/glycopyrroni
um
44209902600110
Vilanterol/umeclidinium
4420990295X
Olodaterol/tiotropium
4420990292X
LABA-LAMA-ICS
Fluticasone 
furoate/umeclidinium/vil
anterol
44209903408020
ANNEX 3.2: DEFINITIONS OF STUDY OUTCOMES 
Condition
ICD9
ICD10
ICD9 
proc
ICD10 
proc
HCPCS
CPT
COPD
491
J41
491
J41.0
491.1
J41.1
491.2
J41.8
491.21
J42
491.22
J43
491.8
J43.0
491.9
J43.1
492
J43.2
492
J43.8
492.8
J43.9
496
J44
J44.0
J44.1
J44.9
Pneumonia
480
J10.00
480.1
J10.01
480.2
J10.08
480.3
J11.00

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
480.8
J11.08
480.9
J12.0
481
J12.1
482
J12.2
482.1
J12.3
482.2
J12.81
482.3
J12.89
482.31
J12.9
482.32
J13
482.39
J14
482.4
J15.0
482.41
J15.3
482.42
J15.4
482.49
J15.5
482.81
J15.6
482.82
J15.7
482.83
J15.8
482.84
J15.9
482.89
J16.0
482.9
J16.8
483
J17
483.1
J18.0
483.8
J18.1
484.1
J18.2
484.3
J18.8
484.5
J18.9
484.6
J69.0
484.7
J85.1
484.8
J95.4
485
J95.89
486
997.31

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
997.32
Medication
HCPCS
GPI
Prednisolone 
J2650, J7510, J7512 
22100040X
22109902201810
22100045X
ANNEX 3.3: DEFINITIONS OF STUDY COVARIATES
Complete list of ICD-9-CM, ICD-10, CPT, HCPCS, and GPI codes.
Medication
HCPCS
GPI
Short-acting beta-
agonists
Levalbuterol
J7617,J7607,J7612,
J7614,J7615
4420104510X
4420104550X
Albuterol
J7602, J7603, 
J7609-J7611,
J7613, J7616, 
J7620,
J7625, Q4093, 
Q4094
4420101000X
4420101010X
Terbutaline
J3105,J7680,J7681
442010602X
Isoproterenol
J7657
J7658
J7659
J7660
44201040X
Methylxanthines
Aminophylline
4430001000x
4430001010x
Theophylline (SR)
J2810
4430004000x   499100240X   
4499100220X
4499100242X   4499100250X   
44992203X
44993003X   44993204X   44999003X
44999602X   4499220310X   
4499960270X
4499220315X

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Medication
HCPCS
GPI
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
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

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Medication
HCPCS
GPI
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
J45
493
J45.2
493
J45.20
493.01
J45.21
493.02
J45.22
493.1
J45.3
493.1
J45.30
493.11
J45.31
493.12
J45.32
493.2
J45.4
493.2
J45.40
493.21
J45.41
493.22
J45.42
493.8
J45.5
493.81
J45.50
493.82
J45.51

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
493.9
J45.52
493.9
J45.9
493.91
J45.90
493.92
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
J84.842
J84.843
J84.848
Lung 
transplant
33.50
33.51
33.52
0BYC0Z0
S2060
S2061
00580
32850
-
32856
33935
33933
0BYC0Z1
0BYC0Z2
0BYD0Z0
0BYD0Z1

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
0BYD0Z2
0BYF0Z0
0BYF0Z1
0BYF0Z2
0BYG0Z0
0BYG0Z1
0BYG0Z2
0BYH0Z0
0BYH0Z1
0BYH0Z2
0BYJ0Z0
0BYJ0Z1
0BYJ0Z2
0BYK0Z0
0BYK0Z1
0BYK0Z2
0BYL0Z0
0BYL0Z1
0BYL0Z2
0BYM0Z0
0BYM0Z1
0BYM0Z2
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; 
I20.%-
I25.%%%
I47.%, 
I48.%%; 
I49.%%
I44.%%; 
I45.%%
I50.%%
I11.%; 
I13.%; 
O10.1%; 
O10.3%
37.7x–
37.8x, 
37.94–
37.99

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
443.xx
272.x
393-398; 
421.x; 
422.xx; 
746.0x-746.7
I70.%%%; 
I71.%%; 
I72.%; 
I73.%%
E78.%%
I05.%-
I09.%%; 
I33.%-I39; 
Q22.%, 
Q23.%
Diabetes
250
E10.10
250.01
E10.11
250.02
E10.21
250.03
E10.29
250.1
E10.311
250.11
E10.319
250.12
E10.36
250.13
E10.37X1
250.2
E10.37X2
250.21
E10.37X3
250.22
E10.37X9
250.23
E10.39
250.3
E10.40
250.31
E10.51
250.32
E10.618
250.33
E10.620
250.4
E10.621
250.41
E10.622
250.42
E10.628
250.43
E10.630
250.5
E10.638
250.51
E10.641
250.52
E10.649

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
250.53
E10.65
250.6
E10.69
250.61
E10.10
250.62
E10.11
250.63
E10.21
250.7
E10.29
250.71
E10.311
250.72
E10.319
250.73
E10.36
250.8
E10.37X1
250.81
E10.37X2
250.82
E10.37X3
250.83
E10.37X9
250.9
E10.39
250.91
E10.40
250.92
E10.51
250.93
E10.618
E10.620
E10.621
E10.622
E10.628
E10.630
E10.638
E10.641
E10.649
E10.65
E10.69
E10.10
E10.11
E10.21
Thyroid 
226, 240.0, 
D09.3, D34, 

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
disease
240.9, 241.0, 
241.1, 241.9, 
242*, 243, 
244*, 245*, 
246*, 790.94
D44.0,
E01.1,E01.2, 
E01.8, E02, 
E03*, E04*, 
E05*, E06*, 
E07*,
E01.0
E89.0
Renal failure
403
I12.0
403.01
I12.9
403.1
N18.1
403.11
N18.2
403.9
N18.3
403.91
N18.4
585.1
N18.5
585.2
N18.6
585.3
N18.9
585.4
N17.0
585.5
N17.1
585.6
N17.2
585.9
N17.8
586
N17.9
Autoimmune 
disease
135
D86.9
274.9
M10.9
275.49
E83.59
279.49
D89.89
283
D59.0
443
D59.1
448.9
I73.00
530.5
I73.01
555.9
I78.9
571.42
K22.4

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
571.6
K50.90
576.1
K75.4
579
K74.3
696
K74.4
696.1
K74.5
710
K83.0
710.1
K90.0
710.2
L40.50
710.3
L40.54
710.9
L40.59
711.9
L40.0
712.19
L40.1
714
L40.2
714.3
L40.8
715.09
M32.10
715.11
M34.0
715.12
M34.1
715.13
M34.2
715.14
M34.81
715.15
M34.82
715.17
M34.83
715.18
M34.89
715.96
M34.9
719.42
M35.00
719.44
M35.01
719.45
M35.02
719.47
M35.03
719.49
M35.04
720
M35.09
721.9
M33.90

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
725
M35.9
729.1
M00.9
729.5
M11.9
795.79
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

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
R76.11
R76.12
R76.8
R76.9
Obesity
278
E65
278.01
E66.01
278.02
E66.2
278.03
E66.3
278.1
E66.9
278.2
E67.0
278.3
E67.1
278.4
E67.3
278.8
E67.8
V85.30
Z68.30
V85.31
Z68.31
V85.32
Z68.32
V85.33
Z68.33
V85.34
Z68.34
V85.35
Z68.35
V85.36
Z68.36
V85.37
Z68.37
V85.38
Z68.38
V85.39
Z68.39
Alcohol use 
disorder
303
F10.159
94.46
HZ2ZZZ
Z
303.01
F10.180
94.53
HZ30ZZ
Z
303.02
F10.181
94.61
HZ31ZZ
Z
303.03
F10.188
94.62
HZ32ZZ
Z
303.9
F10.20
94.63
HZ33ZZ

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
Z
303.91
F10.21
94.67
HZ34ZZ
Z
303.92
F10.229
94.68
HZ35ZZ
Z
303.93
F10.259
94.69
HZ36ZZ
Z
F10.27
HZ37ZZ
Z
F10.280
HZ38ZZ
Z
F10.281
HZ39ZZ
Z
F10.288
HZ3BZZ
Z
F10.959
HZ40ZZ
Z
F10.980
HZ41ZZ
Z
F10.99
HZ42ZZ
Z
Z65.8
HZ43ZZ
Z
HZ44ZZ
Z
HZ45ZZ
Z
HZ46ZZ
Z
HZ47ZZ
Z
HZ48ZZ
Z
HZ49ZZ
Z
HZ4BZZ
Z

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
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
F17.219
Z71.6
C9801
C9802
G0375
G0376
G0436
G0437
G8453
G8455
G8456
G8692
G9276
G9458
G9497
G9642
G9792
G9906
G9908
S9075
S9453
G9902  
G9907  
G9909  
99406
99407
Cancer 
(excluding 
basal cell 
carcinoma)
140.xx –
195.xx
C00%-C76%,
200.xx –
208.xx
C81%-C96%
196.xx -
199.xx
C77%-C80%
EXCLUDIN
G:
EXCLUDIN
G:
173.01
C44.01
173.11
C44.111

Boehringer Ingelheim  
        Page 1 of 57
Protocol for non-interventional  studies based on existing data
BI Study Number 1237-0094
c30699487-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Condition
ICD9
ICD10
ICD9 
proc
ICD10 proc
HCPC
S
CPT
173.21
C44.1121
173.31
C44.119
173.41
C44.91
173.51
C44.311
173.61
C44.319
173.71
C44.310
173.81
C44.510
173.91
C44.511
C44.519
C44.41
C44.81
C44.211
C44.212
C44.219
C44.611
C44.612
C44.619
C44.711
C44.712
C44.719
ANNEX 3.4:STATISTICAL CONSIDERATIONS
See section 7.9

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c30699487
1.0
bi-se-laba-tt-final
Effectiveness and Safety of Maintenance Treatment with Combination of Tiotropium
and Olodaterol in comparison to Maintenance Treatment with a Combination of
Inhaled Corticosteroids, Long-acting β2 Agonists and Long-acting Muscarinic
Antagonists in COPD Patients
Approval-Other
17 Dec 2019 13:14 CET
Approval-
 Safety Evaluation
Therapeutic Area
18 Dec 2019 08:50 CET
Approval-
 of Global
Epidemiology
07 Jan 2020 20:03 CET
Approval-Team Member Medicine
16 Jan 2020 14:11 CET
Approval-Team Member Medicine
16 Jan 2020 15:26 CET

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c30699487
1.0