Cohort Study of Cardiovascular Events in Patients With Chronic Obstructive Pulmonary Disease Initiating Olodaterol or Other Long-acting beta2-agonists
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Protocol for observational studies based on existing data
Document Number:
c02330001-03
BI Study Number:
1222.54
BI Investigational
Product(s):
Olodaterol
Title:
Cohort study of cardiovascular events in patients with chronic 
obstructive pulmonary disease initiating olodaterol or other long-
acting beta2-agonists
Protocol version 
identifier:
3.0
Date of last version of 
protocol:
14 Oct 2014
PASS:
Yes
EU PASS register 
number:
Study not registered
Active substance:
Olodaterol
Medicinal product:
Striverdi, Respimat
Product reference:
BI 1744
Procedure number:
Not applicable
Marketing 
authorisation holder(s):
Joint PASS:
No
Date:
28 October 2016
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Additional Information
Research question and 
objectives:

Examine the risk of selected cardiac arrhythmias in patients 
with chronic obstructive pulmonary disease (COPD) 
exposed to olodaterol compared with the risk in patients 
exposed to other long-acting beta2-agonists (LABAs)

Examine the risk of acute myocardial infarction (AMI) and 
other serious ischaemic heart disease events, including 
unstable angina, in patients with COPD exposed to 
olodaterol compared with the risk in patients exposed to 
other LABAs

Secondarily, examine the mortality risk in patients with 
COPD exposed to olodaterol compared with the risk in 
patients initiating other LABAs
Country(-ies) of study:
Denmark 
Author:
Marketing 
authorisation holder(s):
MAH contact person:
 
EU-QPPV:
Signature of EU-QPPV:
The signature of the EU-QPPV is provided electronically

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1.
TABLE OF CONTENT
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENT......................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 12
6.
MILESTONES..................................................................................................... 15
7.
RATIONALE AND BACKGROUND................................................................ 16
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 17
9.
RESEARCH METHODS .................................................................................... 18
9.1
STUDY DESIGN............................................................................................ 18
9.2
SETTING........................................................................................................ 18
9.3
VARIABLES .................................................................................................. 20
9.3.1
Exposures ................................................................................................ 20
9.3.1.1
Definition of new use...........................................................................20
9.3.1.2
Follow-up.............................................................................................20
9.3.1.2.1
Exposure definition................................................................................. 21
9.3.2
Outcomes................................................................................................. 22
9.3.2.1
Primary outcomes ................................................................................22
9.3.2.1.1
Case ascertainment ................................................................................. 22
9.3.2.1.2
Review of automated longitudinal health profiles.................................. 23
9.3.2.2
Secondary outcomes ............................................................................23
9.3.3
Covariates................................................................................................ 23
9.3.3.1
Medical characteristics at baseline.......................................................24
9.3.3.1.1
Severity of COPD................................................................................... 24
9.3.3.1.2
Definition of COPD Severity.................................................................. 25
9.3.3.2
Other Characteristics............................................................................28
9.4
DATA SOURCE............................................................................................. 28
9.4.1
Denmark.................................................................................................. 29
9.4.2
Planned data source summary................................................................. 29
9.5
STUDY SIZE.................................................................................................. 30
9.6
DATA MANAGEMENT................................................................................ 32

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9.7
DATA ANALYSIS......................................................................................... 33
9.7.1
Main analysis........................................................................................... 33
9.7.1.1
Description of cohort characteristics ...................................................33
9.7.1.2
Characteristics of follow-up.................................................................34
9.7.1.3
Safety endpoints...................................................................................34
9.8
QUALITY CONTROL................................................................................... 36
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 36
9.10
OTHER ASPECTS ......................................................................................... 37
9.10.1
Study size limitations .............................................................................. 37
9.10.2
Study standards ....................................................................................... 37
9.10.3
Bias and confounding.............................................................................. 38
9.11
SUBJECTS...................................................................................................... 38
9.11.1
Identification of COPD ........................................................................... 38
9.11.2
Study cohorts........................................................................................... 39
9.11.3
Inclusion criteria...................................................................................... 40
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 41
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 42
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 43
13.
REFERENCES .................................................................................................... 44
13.1
PUBLISHED REFERENCES......................................................................... 44
13.2
UNPUBLISHED REFERENCES................................................................... 49
Annex 1.
List of stand-alone documents................................................................ 50
Annex 2.
ENCePP checklist for study protocols.................................................... 51
Annex 3.
Evaluation of COPD severity in automated health databases................. 59
Annex 4.
ATC codes for selected respiratory medications.................................... 61
Annex 5.
Codes for comorbidities and other medications ..................................... 63
Annex 6.
Data source descriptions from feasibility report, 1 November 2013...... 67

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2.
LIST OF ABBREVIATIONS
AMI
Acute Myocardial Infarction
ATC 
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
CAT
COPD Assessment Test
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
CPRD
Clinical Practice Research Datalink
DAMD
Danish General Practice Database
EMA
European Medicines Agency
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
FEV1
Forced Expiratory Volume in 1 Second
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GP
General Practitioner or General Practice
ICD
International Classification of Diseases
ICD-10
International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision
ICD-9
International Classification of Diseases, 9th Revision
ICPC
International Classification of Primary Care
ICS
Inhaled Glucocorticosteroid
IRD
Incidence Rate Difference
IRR
Incidence Rate Ratio
LABA
Long-Acting Beta2-Agonist
LAMA
Long-Acting Muscarinic Antagonist
mMRC
Modified British Medical Research Council Questionnaire
NCSP
Nordic Medico-Statistical Committee Classification of Surgical 
Procedures
PASS
Post-Authorisation Safety Study
PHARMO
Institute for Drug Outcomes Research (the Netherlands); also short for the 
PHARMO Database Network 
PHARMO-GP
a data subset of PHARMO Database Network with information from GPs
PPV
Positive Predictive Value

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PRO
Patient-Reported Outcome
SABA
Short-Acting Beta2-Agonist
SAMA
Short-Acting Muscarinic Antagonist
SD
Standard Deviation
WHO
World Health Organization

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3.
RESPONSIBLE PARTIES
The following individual is the author of this protocol:
The following individuals have collaborated with the author and with the study sponsor on 
protocol development.
 formerly of
, currently retired

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Striverdi, Respimat
Name of active ingredient:
Olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
13 Feb 2014
1222.54
3.0
28 October 2016
Title of study:
Cohort study of cardiovascular events in patients with chronic 
obstructive pulmonary disease initiating olodaterol or other long-
acting beta2-agonists
Rationale and 
background:
Inhaled long-acting beta2-agonist (LABA) drugs are used in 
chronic obstructive pulmonary disease (COPD) to relieve 
bronchial constriction and associated symptoms. At present, 
formoterol, salmeterol, and indacaterol are the three major 
LABAs approved for COPD treatment.
The clinical long-term safety experience of the LABA olodaterol 
is based on four phase 3 randomised, placebo-controlled, 
parallel-group studies, two of which included formoterol as an 
active comparator in addition to placebo. No imbalances were 
detected in this study pool with regard to any cardiovascular 
effect during the 48-week study period. Nevertheless, cardiac 
arrhythmia and myocardial ischaemia are acknowledged class 
effects of LABAs and have been included as potential risks in 
the risk management plan for olodaterol.
Within the Decentralised Procedure for Striverdi Respimat, the 
health authorities of the European Union/European Economic 
Area Member States requested that a post-authorisation safety 
study (PASS) to gather additional data on safety in long-term use 
of olodaterol be included in the risk management plan 
framework. The results of this study will provide insight into the 
absolute and relative frequency of cardiac arrhythmias and 
myocardial ischaemia events of interest in comparison to 
alternative LABA therapies for COPD.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Striverdi, Respimat
Name of active ingredient:
Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
13 Feb 2014
1222.54
3.0
28 October 2016
Research 
question and 
objectives:
Primary objectives:

Examine the risk of selected cardiac arrhythmias in 
patients with chronic obstructive pulmonary disease 
(COPD) exposed to olodaterol compared with the risk in 
patients exposed to other long-acting beta2-agonists
(LABAs)

Examine the risk of acute myocardial infarction (AMI) and 
other serious ischaemic heart disease events, including 
unstable angina, in patients with COPD exposed to 
olodaterol compared with the risk in patients exposed to 
other LABAs
Secondary objective:

Examine the risk of overall mortality in patients with 
COPD exposed to olodaterol compared with the risk in 
patients exposed to other LABAs
Study design:
This will be an observational cohort study of patients diagnosed 
with COPD aged 40 years or older and initiating olodaterol or an 
alternative LABA indicated for use in COPD.
Population:
The study population will consist of patients with COPD (disease 
cohort) aged 40 years or older in Denmark, a country where 
olodaterol, either alone or in a fixed combination with 
tiotropium, is available and where a large proportion of the 
population is included in health care databases used for 
pharmacoepidemiologic research. Patients will be new users of 
olodaterol or any other LABA, with no dispensing of any LABA 
in the 6 months before the first prescription of olodaterol or 
LABA during the study period (index date) and at least 1 year of 
enrolment in the electronic database.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Striverdi, Respimat
Name of active ingredient:
Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
13 Feb 2014
1222.54
3.0
28 October 2016
Variables:
Primary outcomes in new users

Incidence of atrial fibrillation or flutter during new use

Incidence of hospitalisation for ventricular tachycardia, 
including ventricular fibrillation/flutter and cardiac arrest

Incidence of supraventricular tachycardia (other than atrial 
fibrillation/flutter)

Incidence of hospitalisation for acute myocardial infarction

Incidence of hospitalisation for serious acute coronary 
heart disease, including unstable angina
Exposures of interest are (1) new use of olodaterol and (2) new 
use of any other LABA.
Covariables of interest are severity of COPD and a history of any 
the following conditions prior to the index date: comorbidities 
such as cardiovascular disease, hypertension, diabetes, 
hyperlipidemia, high body mass index, smoking, chronic kidney 
disease, liver disease, osteoporosis, pneumonia, and cancer.
Data sources:
The study will be conducted by using data on drug prescriptions
and disease occurrence routinely collected on an ongoing basis 
for large, population-based automated health care databases in 
Denmark.
Study size:
To achieve an 80% probability of detecting a true risk ratio of 
2.5 (3.0 for ventricular tachycardia), assuming a minimum ratio 
of 4:1 unexposed (any other LABA) to exposed (olodaterol) 
subjects, a two-sided alpha level of 0.05, and a range of expected 
incidence rates of each study endpoint, the minimum number of 
olodaterol-exposed person-years ranges from 100 person-years
for all-cause mortality to 8,380 person-years for ventricular 
tachycardia.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Striverdi, Respimat
Name of active ingredient:
Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
13 Feb 2014
1222.54
3.0
28 October 2016
Data analysis:
The incidence rate ratio (IRR) and incidence rate difference 
(IRD) for each event of interest in the olodaterol-exposed group 
relative to that in the comparator group will be derived. The 
effects of demographics and specified baseline characteristics 
will be assessed, and adjusted IRR will be calculated by 
adjusting for each covariate one at a time. A fitted propensity 
score model will be used to estimate a propensity score for each 
patient, and the IRRs for each event of interest will be stratified 
by propensity score deciles. For each endpoint, IRR and IRD 
will be stratified by propensity score deciles, and the overall 
adjusted IRR and IRD and associated 95% confidence intervals 
will be derived by weighting each stratum by the prevalence 
among the olodaterol cohort. 
Milestones:
 
 
 

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5.
AMENDMENTS AND UPDATES
Version 3.0 includes clarifications to the milestone table, available databases within 
Denmark, and clarification that another country may be added in the future.

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Number
Date
Section of 
Study 
Protocol
Amendment or Update
Reason
1
 
6
Update of milestones 
Delay in finalisation of 
protocol to respond to 
regulatory authority 
review
2
 
9.3.3
9.7.1.1
9.7.1.3
Clarification of handling 
of missing data 
Response to regulatory 
review 
3
 
9.5
Clarification of expected 
study statistical precision 
for outcome effect 
measures
Response to regulatory 
review 
4
 
9.5
9.10
Specification that data 
from Sweden will be 
added in the event that the 
exposed cohort in 
Denmark is too small 
Response to regulatory 
review
5
9.1, 9.3, 
9.11, and 
across the 
protocol
Clarified study 
medications
Clarified that olodaterol 
includes olodaterol 
monotherapy and fixed-
dose combinations
6
3
Updated list
Previous lead author has 
retired; added investigator 
from Denmark
7
6
Updated milestones
Clarified start and end of 
data collection, as applied 
to the analysis of 
secondary databases, and 
timing for progress
reports
8
9.1
Clarified study period
To differentiate from 
study milestones, 
clarified study period and 
look-back period

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9
9.3.3
Updated COPD severity 
definition
To better align with 
COPD guidelines 
10
9.4.1
Deleted Danish General 
Practice Database 
(DAMD) as a data source
No longer available for 
research 
11
9.5
Removed the naming of 
Sweden and replaced with 
“other country”; added 
update on the number of 
users in Denmark
Uptake in Sweden is 
lower than expected; a 
specific other country 
will be identified if 
needed
Provided number of users 
of olodaterol (olodaterol
was not available in 
Denmark at the time of 
the previous protocol)
12
9.7.1
Clarified that two 
propensity score models, 
one for each “type of 
COPD treatment 
initiated” (with or without 
LAMA) will be 
performed or an 
interaction term will be 
included
To take into account 
differences between 
patients initiating LABA 
alone versus those 
initiating LABA/LAMA 
13

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6.
MILESTONES

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7.
RATIONALE AND BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a serious chronic disease that affects 
millions of people worldwide. [P13-02399] [P12-14293] COPD typically involves persistent 
limitation of airflow, a progressive course, and chronically enhanced inflammatory response 
of the airways to airborne particulates and gases. [P13-02399]
Worldwide, the estimated number of patients with COPD is 63.6 million, and in 2004, the 
European region had approximately 11.3 million patients with prevalent, symptomatic 
COPD. [R09-2531] The prevalence of COPD increases with increasing age. In a meta-
analysis of 67 publications, the pooled prevalence among people aged younger than 40 years 
(n = 9 studies) was approximately 3.1 per 100; pooled prevalence among people aged 65 
years or older (n=11 studies) was 14.2 per 100.[R06-4117] The health, societal, and 
economic burdens of COPD are predicted to increase in the next several decades because of 
continuing exposure to tobacco smoke and other risk factors and because of the increasing 
older populations in many countries. [P13-02399]
The major types of comorbidities in patients with COPD are cardiovascular disease, 
osteoporosis, anxiety and depression, lung cancer, serious infections, metabolic syndrome, 
and diabetes. [P13-02399] The incidence of cardiovascular outcomes in patients with COPD 
is about two times greater than in individuals without COPD. [R09-0579] [R07-2623]
Inhaled long-acting beta2-agonist (LABA) drugs are used in COPD to relieve bronchial 
constriction and associated symptoms. At present, formoterol, salmeterol, and indacaterol are 
the three major LABAs approved for COPD treatment.
The clinical long-term safety experience of the LABA olodaterol is based on four phase 3 
randomised, placebo-controlled, parallel-group studies, two of which included formoterol as 
an active comparator in addition to placebo. No imbalances were detected in this study pool 
with regard to any cardiovascular effect during the 48-week study period. Nevertheless, 
cardiac arrhythmia and myocardial ischaemia are acknowledged class effects of LABAs
[P12-09395] [P12-09396] and have been included as potential risks in the risk management
plan for olodaterol.
Within the Decentralised Procedure for Striverdi Respimat, the health authorities of the 
European Union/European Economic Area Member States requested that a post-authorisation 
safety study (PASS) to gather additional data on safety in long-term use of olodaterol be 
included in the risk management plan framework. The results of this study will provide 
insight into the absolute and relative frequency of cardiac arrhythmias and myocardial 
ischaemia events of interest in comparison to alternative LABA therapies for COPD. The 
country of implementation of this study is Denmark.

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8.
RESEARCH QUESTION AND OBJECTIVES
This study aims to quantify the frequency of selected adverse cardiovascular conditions 
among users of olodaterol compared with users of other LABAs. Study objectives are as 
follows:
Primary objective:
●
Examine the risk of selected cardiac arrhythmias in patients with COPD newly 
exposed to olodaterol compared with the risk in patients newly exposed to any other 
LABA
●
Examine the risk of acute myocardial infarction (AMI) and other serious acute 
ischaemic heart disease events, including unstable angina, in patients with COPD 
newly exposed to olodaterol compared with the risk in patients newly exposed to any 
other LABA
Secondary objective:
●
Examine the risk of overall mortality in patients with COPD newly exposed to 
olodaterol compared with the risk in patients newly exposed to any other LABA

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This will be an observational cohort study of patients diagnosed with COPD aged 40 years or 
older and initiating olodaterol either alone or in free- or fixed-dose combination with a 
LAMA or an alternative LABA alone or in a free- or fixed-dose combination with a LAMA 
indicated for use in COPD. The study period will start at the time of olodaterol launch in 
Denmark (March 2014) and will end in Q1 2019 (i.e., the last date with data available for the 
data cut for the final report in Q1 2020), due to a 1-year time lag in the availability of data in
the data source.
The study will be conducted using existing population-based health care databases in 
Denmark. A cohort study will be conducted so that the incidence of each of the events of 
interest among olodaterol initiators can be estimated. The age is limited to individuals aged 
40 years and older to maximise the likelihood that all subjects in each exposure group are 
receiving LABA for treatment of COPD. [R06-4117] Any olodaterol initiator with a COPD 
diagnosis at any time after 1994 and the first prescription of olodaterol or indacaterol will be 
included. Similarly, individuals in the comparator cohort must have a record of a COPD 
diagnosis. If the sizes of each exposure cohort permits, stratification on presence or absence 
of a diagnosis of asthma will be implemented. To establish that members of each exposure 
cohort are new users, each study subject must have at least 12 months of enrolment in the 
database prior to the index date.
It is not atypical for new users of a new medication, before starting the medication, to be at 
higher risk of the events of interest than individuals with the same disease and taking 
medications traditionally available. To address this issue, the study requires that all olodaterol 
users and users of the comparator LABAs have no previous use of any LABA in the 6 
months preceding study medication initiation. The protocol synopsis specified a definition of 
no recent other LABA use measured during the12 months before new use of a study LABA. 
However, to maximise study size, the definition of no recent other LABA use now requires 
absence of other study LABA use during the 6 months before the index date. Also, 6 months 
is sufficient time that no adverse impact from earlier LABA use will remain.
In addition, this study will control for severity of COPD and presence of other cardiovascular 
disease risk factors, as much as such factors can be ascertained from the entire available 
medical history in the data source since converting to ICD-10 in 1994 (see Section 9.3.3,
Covariates). Propensity scores will be developed, and propensity score categories (deciles if 
study size allows) will be used for stratification of incidence rate ratios and incidence rate 
differences and derivation of the overall adjusted incidence rate ratio and adjusted incidence 
rate difference (see Section 9.7).
9.2
SETTING
The database selection criteria were the following:

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●
There is published research experience on the use of the data to study drug safety 
questions and on the validity of the outcomes identified via hospital discharge codes
●
The database contains the earliest and largest available number of olodaterol initiators 
at the time of study implementation
●
The database must permit identification of the following information:
●Dates and discharge diagnoses for hospitalisations for arrhythmias and ischaemic 
cardiac events
●Severity of COPD defined by patterns of use of LABA, antibiotic use for respiratory 
infection, oxygen therapy, nebuliser therapy, hospitalisation for COPD, diagnosis of 
pneumonia, use of systemic corticosteroids, and diagnosis of emphysema, information 
that is frequently recorded in prescription and hospital records
●The database must have a reliable recording of outpatient dispensings or prescriptions
●The database must have completed data collection for at least 12 months before the 
index prescription
The national health registers of Denmark, covering 100% of the population in Denmark, are 
expected to yield the largest study size. Key data features of this database are summarised in 
Table 1. A detailed description of the study database is provided in Section 9.4.
Table 1
Selected characteristics of the study data source
Type of Data 
National Registers, Denmark
Hospital inpatient discharge diagnoses 
Yes
Hospital inpatient procedures
Yes
Hospital/clinic outpatient diagnoses
Yes
General practitioner diagnoses
No
Pharmacy-dispensed medications
Yes
Prescribed medications
No
New users will be characterised by past medical history and use of medications (Table 2). 
Diagnoses are coded using the International Statistical Classification of Diseases and 
Related Health Problems, 10th Revision (ICD-10). Procedures are coded using ICD-10 codes. 
The Anatomical Therapeutic Chemical (ATC) classification is used to code dispensed 
medications.

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Table 2
Types of diagnoses, procedures, and medication codes in the National 
Registers of Denmark
Type of Code 
Coding System Used
Diagnoses 
ICD-10 (since 1994)
Procedures 
NCSP, version 1.16:2012
Medications 
ATC 
ATC = Anatomical Therapeutic Chemical; ICD-10 = International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision; NCSP = Nordic Medico-Statistical Committee Classification of Surgical Procedures.
9.3
VARIABLES
9.3.1
Exposures
Olodaterol became available in Denmark in March 2014, and olodaterol/tiotropium became 
available in July 2015. Members of each exposure cohort will be identified from available 
outpatient pharmacy dispensing files.
9.3.1.1
Definition of new use
A new user will be defined as a patient with a diagnosis of COPD who receives a first 
dispensing for a study LABA during the study period and no prescriptions for any LABA in 
the 6 months prior to the first dispensing for LABA during the study period. The LABA 
initiated at cohort entry will be referred to as the index LABA. To meet the objectives, the 
study will assess the incidence ratio for each endpoint of interest among new users of 
olodaterol compared with the incidence among new users of the alternative LABAs combined 
as a comparator group.
Potential confounding by use of concomitant dispensing of inhaled steroids or other 
respiratory medications (listed in Annex 4) will be addressed in the analysis.
9.3.1.2
Follow-up
Patients will be followed from the first dispensing for the index LABA after the patient has 
fulfilled all other eligibility criteria (Figure 1). Follow-up will continue until the earliest of 
the following possible termination dates:
●
Disenrolment from the database
●
14 days after estimated discontinuation of the last dispensing for the index LABA 
(e.g., after switching or stopping index LABA use)
●
Addition of a second LABA
●
Death
●
End of study period, the date of the latest available data from the data source

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LABA = long-acting beta2-agonist; Rx = prescription.
a. Outcome event or other end-of-follow-up criteria: disenrolment from the database, addition of a second LABA, death, or 
end of study period (date of the latest available data from the data source).
b. End of exposure is 14 days after estimated discontinuation of the last dispensing for the index LABA. Duration of 
exposure will depend on the number of days supplied.
Figure 1
Diagram of study follow-up
9.3.1.2.1
Exposure definition
Exposure data will be assessed from recorded dispensings for each of the study LABAs.
Exposure will be classified by the subjects’ index LABA, which could be in a free- or fixed-
dose combination with a LAMA, at the time of their first prescription for that LABA (e.g., 
new user of olodaterol). For each person, duration of exposure to olodaterol or comparator 
LABA will be defined as starting on the dispensing date and ending 14 days after the end of
days’ supply or defined daily doses recorded on each prescription. Additional days are added 
to the duration of the dispensing to estimate actual use that may not adhere to 
recommendations and to capture events in individuals who switch because of early symptoms 
of the outcome of interest. Definitions may be slightly modified if otherwise indicated in the 
data.
Total patient-years of time at risk from current use of each medication of interest will be 
calculated as the sum of days supplied plus 14 days for consecutive prescriptions. Only the 
first episode of consecutive use will be considered. Calculations of consecutive use will allow 
for a maximum gap of 14 days between the estimated end of use of one prescription and the 
dispensing date of the following prescription. Overlapping time at risk from consecutive 
prescriptions of the study medications will be concatenated, with the overlapping time 
counted only once. For individuals switching at the end of study LABA use, there will be no 
adjustment for the newly started LABA. Switching at the end of study exposure will be 
characterised in the descriptive analysis.
Sensitivity analyses will explore the impact of using 30-day and 60-day extensions of the 
time windows for duration of exposed follow-up (instead of 14 days). Provided there is 
sufficient sample size, two additional sensitivity analyses will explore subgroup analyses of 
different regimens: (1) study LABAs initiated as monotherapy and (2) LABAs initiated in
free- or fixed-dose combinations with LAMAs.

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To capture other exposures during the 14-day extension, medical and recent prescription 
history at the time of event for each type of outcome will be described.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
Cardiac arrhythmias and myocardial ischaemia have been identified in the Olodaterol Risk 
Management Plan as potential risks of olodaterol use.
The primary outcomes are as follows:
●
Incidence of atrial fibrillation or flutter during new use
●
Incidence of hospitalisation for ventricular tachycardia, including ventricular 
fibrillation/flutter and cardiac arrest during new use
●
Incidence of supraventricular tachycardia (other than atrial fibrillation/flutter) during 
new use
●
Incidence of hospitalisation for acute myocardial infarction during new use
●
Incidence of hospitalisation for serious acute coronary heart disease, including 
unstable angina, during new use
Incidence rate ratio and incidence rate difference for each of the five listed outcome 
categories among new users of olodaterol (either in free- or fixed-dose combination with 
tiotropium or other LAMAs) will be assessed relative to the incidence among new users of 
other LABAs (either in free- or fixed-dose combination with tiotropium or other LAMAs). 
Non-serious events, such as angina, electrocardiographic signs of ischaemia without 
immediate clinical consequence, or non-serious arrhythmia, may frequently not receive 
medical attention and are not always detectable in the database. Such events have not been 
validated and therefore will not be assessed.
9.3.2.1.1
Case ascertainment
Potential cases of the outcomes listed above will be ascertained during the follow-up period 
for each study subject by using validated diagnostic code algorithms to identify the outcomes 
in the automated data. Linkage to hospital discharge diagnoses listed in national hospital files 
to identify relevant hospitalisations for arrhythmias and also to outpatient hospital diagnoses 
will be conducted as appropriate and available. (See Annex 5 for relevant ICD-10 codes.)
Studies validating cardiovascular outcomes have been published for Denmark. Using data 
from one region of Denmark, the PPV of atrial fibrillation or flutter among users of non-
steroidal anti-inflammatory drugs was 90%.[P11-08175] Studies have reported the validity of 
myocardial infarction in the Danish National Patient Registry. For acute myocardial 
infarction, the PPV was 82% to 94%. [R14-0355] R14-0358]
Validated in other population-based data sources in other countries, algorithms to identify 
AMI including out-of-hospital coronary heart disease deaths can be used according to the 
availability of data. [P09-14662] [P04-09631] [R11-4316] [P10-05107] [P09-14650] The 

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PPV for AMI diagnosis was reported to be about 93% (95% confidence interval [CI], 90%-
96%) in a United Kingdom database of GP records. [R11-2266] In addition, other published 
algorithms used in other databases for atrial fibrillation, [R10-0756] [R13-1398] ventricular 
arrhythmia, [R13-1391] and serious coronary heart disease including revascularisation 
procedures and unstable angina [P10-05107] [R13-1397] may be useful.
9.3.2.1.2
Review of automated longitudinal health profiles
Where feasible, a random sample of up to 100 patient profiles (the chronological electronic 
listings of the diagnoses, procedures, and medications [but no free text]) will be reviewed by 
a clinician blinded to the exposures of interest. This is an important step to assure that coding 
algorithms identify individuals who have disease natural history consistent with the events of 
interest.
9.3.2.2
Secondary outcomes
Cardiac arrhythmia and myocardial ischaemia, in severe conditions, can contribute to 
mortality in a vulnerable COPD population. Therefore, the secondary outcome of interest for 
this study is mortality from all causes.
In Denmark, the fact and date of death are obtained for research studies through linkage to 
the national death files. The Danish Civil Registration System includes the fact and date of 
death, but not the cause of death. [R16-2604] The Danish Registry of Causes of Death 
includes all records of deaths in Denmark since 1943. The record lists the name, personal 
identification (the unique CPR number assigned to all Danish citizens and other residents of 
Denmark since 1968), and information from the death certificate, including birthplace, date, 
and place of death and classification of the underlying and contributory causes of death.
9.3.3
Covariates
All covariables will be ascertained on or before the index date. The look-back observation 
period to define covariables of interest will be specified for each variable in the statistical 
analysis plan, e.g., ever before for most comorbidities. In general, in database analyses, the 
absence of information such as an outpatient diagnosis is classified as the absence of the 
condition. All subjects without a dispensing for a medication will be considered unexposed, 
and all subjects without a diagnosis will be considered as not having the condition. Age on 
the index date and patient sex are readily available. Information on lifestyle factors can be 
obtained only from the general practitioner outpatient database, which is no longer available.

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9.3.3.1
Medical characteristics at baseline
9.3.3.1.1
Severity of COPD
Guidelines of the Global Initiative for Obstructive Lung Disease (GOLD) recommend 
evaluating the severity of COPD and its impact on the health of patients by the combination 
of the (1) current level of symptoms, (2) severity of the spirometric abnormality, and (3) risk 
of exacerbations. [P13-02399] The presence of comorbidities also influences the severity of 
COPD, which is a predictor of morbidity and mortality. According to these parameters, 
severity of COPD is classified into four severity groups as illustrated in Figure 2.
Risk
GOLD 
classification of 
airflow 
limitation
4
3
C
D
≥2 without 
hospitalisation 
or > 1 
hospitalisation
Risk
Exacerbation 
history
2
A
B
≤ 1 without 
hospitalisation 
and no 
hospitali-
sations
1
mMRC 0-1
CAT < 10
mMRC ≥ 2
CAT ≥ 10
COPD Severity Categories
Severity 
Category
Characteristics
Spirometric 
Classification
Exacerbations 
per Year
mMRC
CAT
A
Low risk, fewer 
symptoms
GOLD 1-2
(mild-
moderate)
≤ 1 without 
hospitalisation 
and no 
hospitalisations
0-1
< 10
B
Low risk, more 
symptoms
≥ 2
≥ 10
C
High risk, fewer 
symptoms
GOLD 3-4
(severe-very 
severe)
≥ 2 without 
hospitalisation 
or ≥ 1 
hospitalisation
0-1
< 10
D
High risk, more 
symptoms
≥ 2
≥ 10
CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Obstructive 
Lung Disease; mMRC = Modified British Medical Research Council questionnaire.
Source: Adapted from GOLD, 2016. [P16-00121]
Figure 2
Association between symptoms, spirometric classification, and future 
risk of exacerbations according to the Global Initiative for 
Obstructive Lung Disease
Some of the parameters to evaluate the severity of COPD are not available or are partially
recorded in automated health databases. These include the level of symptoms of COPD and 

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the results from spirometric tests. Therefore, severity of COPD in studies conducted in health 
databases is usually evaluated by other parameters that serve as proxies of severity.
[P07-09136] [R13-1392] [P09-04948] [R08-1492] [P11-13226]
A summary of the evaluation of severity of COPD in health database studies is presented in 
Annex Table 3:1. In a study conducted in the General Practice Research Database (GPRD) 
(forerunner to the current Clinical Practice Research Datalink [CPRD]) in the United 
Kingdom, the definition of severity was based on the intensity of use of bronchodilators and 
the use of oxygen therapy or nebulised therapy. [R08-1492] A modification of this definition 
of severity was used in a study conducted in the Integrated Primary Care Information Project 
database in the Netherlands. [P11-13226] The definition used in that study included 
hospitalisations for COPD, the use of antibiotics for the treatment of respiratory tract 
infections, and the use of systemic glucocorticosteroids for the treatment of COPD 
exacerbations. The classification of severity based on these factors had a PPV of 82% when 
compared to results from spirometry. In a study conducted in the Saskatchewan Health 
databases in Canada, determinants of COPD severity were the presence of emphysema, use 
of nebuliser therapy, use of oxygen therapy, use of inhaled and/or systemic 
glucocorticosteroids, intensity of bronchodilator use, pneumonia, and prior COPD 
exacerbation. [P07-09136] These factors were associated with increased cardiovascular 
morbidity and mortality.
9.3.3.1.2
Definition of COPD Severity
Severity of COPD will be evaluated among new users of olodaterol and other LABAs that 
have a recorded diagnosis of COPD before the index date. Severity of COPD will be 
evaluated at the index date by a modified version of the algorithm developed by Verhamme 
and colleagues [P11-13226] and taking into account the updated GOLD recommendations 
[P16-00121] (see Table 3).

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Table 3
Definition criteria of COPD severity
Severity of 
COPD
Definition
Mild
Fewer than two dispensings of the same COPD drug class with a 
maximum interval of 6 months in the 12 months before the index date
Moderate
Regular treatment defined as having at least two dispensings of the 
same COPD drug class with a maximum interval of 6 months in the 
12 months before the index date1,2
Severe
Occurrence of at least one of the following events in the 12 months
before the index date:

Hospitalisation for COPD2

Recorded diagnosis of pneumonia2

Second course of antibiotics for respiratory tract infections2

Second course of systemic corticosteroids for the treatment of 
COPD exacerbation2

Two diagnoses of COPD exacerbation without hospitalisation
Very severe
Occurrence of at least one of the following events in the 12 months
before the index date unless other time period is specified:

Dispensed oxygen therapy1,2

Dispensed nebuliser therapy1,2

Diagnosis of emphysema at any time before the index date2
COPD = Chronic Obstructive Pulmonary Disease.
Sources: modified from Verhamme et al. [P11-13226]; Soriano et al. [R08-1492]; Curkendall et al.; [P07-09136] and 
GOLD, 2016 [P16-00121].
1
Severity criteria also included in definition from Soriano et al. [R08-1492]
2
Severity criteria also included in definition from Curkendall et al. [P07-09136]
Indicators of severity presented in Table 3 will be mutually exclusive, and patients that fulfil 
criteria for more than one category will be classified as being in the most severe category. 
The operational definition of severity is as follows:
●
Same class of “COPD drugs”: the following drug classes will be considered (see):
Annex 4
●
Bronchodilators: inhaled short-acting muscarinic antagonists (SAMAs), inhaled 
long-acting muscarinic antagonists (LAMAs), inhaled short-acting beta2-agonists 
(SABAs), inhaled long-acting beta2-agonists (LABAs), and fixed combinations
of SABA and SAMA
●
Inhaled glucocorticosteroids (ICS): ICS alone, fixed combinations of SABA and 
ICS, fixed combinations of LABA and ICS
●
Systemic (oral) glucocorticosteroids
●
Systemic beta2-agonists

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●
Xanthines
●
Roflumilast
●
Hospitalisation for COPD
●
Primary or secondary hospital discharge diagnosis for COPD
●
ICD-10 codes J40-J44
●
Recorded diagnosis of pneumonia
●
Primary or secondary hospital discharge diagnosis or outpatient hospital clinic 
diagnosis for pneumonia
●
ICD-10 codes J09-J18
●
Second course of antibiotics for respiratory tract infection
●
A single course of antibiotic treatment involving multiple dispensings is defined 
as that involving consecutive dispensings of antibiotics with fewer than 7 days 
between the end of days of supply of one dispensing and the date of the next 
dispensing
●
ATC codes for antibiotics: J01 (antibacterials for systemic use)
●
Second course of systemic glucocorticosteroids for the treatment of COPD 
exacerbation
●
A single course of systemic corticosteroids involving multiple dispensings is 
defined as that involving consecutive dispensings with fewer than 7 days between 
the end of days of supply of one dispensing and the date of the next dispensing.
●
ATC codes for systemic glucocorticosteroids: H02AB
●
Two diagnoses of COPD exacerbation without hospitalisation
●
Outpatient hospital clinic diagnosis of COPD exacerbation
●
ICD-10 codes: J44.1
●
Oxygen therapy. ATC code: V03AN01; NCSP code: BGXA5
●
Nebuliser therapy. To be identified in each database using national drug codes or 
NCSP code: BGXA10
●
Emphysema
●
Primary or secondary hospital inpatient discharge diagnosis or outpatient hospital 
clinic diagnosis of emphysema at any time before the index date
●
ICD-10 code: J43
●
Other characteristics include the following:
●
Asthma (from outpatient hospital clinic and inpatient diagnoses)
●
History of COPD, chronic bronchitis, or emphysema (from outpatient hospital 
clinic and inpatient diagnoses)

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9.3.3.2
Other Characteristics
The following indicators of general comorbidity and cardiovascular disease or risk factors for 
cardiovascular disease at any time in the past or on the day of cohort entry will be utilised.
●
Comorbidities will be ascertained from hospital discharge diagnoses, when available 
(see Annex 5 for codes). Outpatient dispensings may also be used to identify relevant 
treatments for conditions of interest, as follows:
●
Coronary heart disease, including myocardial infarction, angina, and 
revascularisation procedures
●
Atrial fibrillation, other supraventricular arrhythmias, and ventricular arrhythmias
●
Heart failure
●
Stroke and transient ischaemic attack
●
Hypertension
●
Diabetes
●
Hyper- or dyslipidaemia
●
Chronic kidney disease
●
Liver disease
●
Osteoporosis
●
Pneumonia (see Section 9.3.3.1.2 for codes)
●
Cancer diagnosis
●
History of medications dispensed in the 12 months before or on the index date will be 
identified from the pharmacy dispensing history (see Annex 5 for codes):
●
Cardiovascular drugs: antihypertensives, antiarrhythmics, nitrates, other
●
Lipid-lowering medications
●
Blood glucose–lowering medications
●
Anticoagulants and antiplatelet agents
●
Antibiotics
●
Antineoplastic agents
9.4
DATA SOURCE
The study will be conducted by using data on drug prescriptions and disease occurrence 
routinely collected on an ongoing basis for large, population-based automated health care 
databases in Denmark. New users will be characterised in terms of past medical history and 
use of medications. An overview of the information on diagnoses and procedures is shown in 
Table 4, Section 9.4.2.

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9.4.1
Denmark
The Danish health care system provides universal coverage to all Danish residents 
(5.6 million inhabitants). Health care coverage includes visits to general practitioners (GPs) 
and specialists, hospital admissions, and outpatient visits. The costs of medicines are partially 
covered by the Danish health system. The centralised Civil Registration System in Denmark 
allows for personal identification of each person in the entire Danish population and for the 
possibility of linkage to all Danish registries (all registries contain civil registration numbers), 
such as the Danish National Registry of Patients, Danish National Health Services 
Prescription Database, and the Danish Registry of Causes of Death. Data collected in these 
registries are available for research purposes.
For 1980-2008, the National Registry of Patients counted 236,494 patients with a first 
hospital contact for COPD. [R12-3324] From the National Health Service, for persons aged 
45 to 84 years, the prevalence of COPD was estimated at 12%, using a sample of 299,000 
residents of two counties. [R12-3265]
9.4.2
Planned data source summary
Table 4 shows the characteristics of the planned data source in Denmark where olodaterol use 
may be sufficient to address the study questions.
Table 4
Overview of planned data source, contingent upon approval
Data Element
National Registers, Denmark 
Database type
National health record and prescription databases linked 
through the unique civil personal registration number
Database population
Denmark
Country population1
5,602,628
Approximate proportion of 
the country’s population 
covered by the database
100%
Representativeness of 
patients and practices
Complete, given that the total country population is 
included
Linkage
Unique patient-specific identifiers
Data on medications
Pharmacy-dispensed prescriptions
Dose
Formulation strength
Duration
Based on prescriptions
Drug dictionary codes/ 
therapeutic classification
ATC 

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Table 4 (cont'd)
Overview of planned data source, contingent upon approval
Data Element
National Registers, Denmark 
Number of indacaterol 
prescriptions2 (approximate)
47,400 (years 2010-2011)
Clinical indication 
Not recorded per se but may be surmised based on proxies 
(i.e., prescribed medication, hospital discharge diagnosis, 
and outpatient diagnosis history)
Outpatient diagnosis
From hospital outpatient specialty clinics 
Hospital diagnosis
Yes, ICD-10
Procedure codes
Yes, NCSP version 1.16:2012
Pulmonary function testing 
From hospital clinics and also from primary care when 
recorded
Information on death
Fact and date in the Civil Registration System, and 
underlying cause of death available in National Death 
Register
Access to medical records
No
Lifestyle risk factors
No, only some if recorded among inpatients (body mass 
index, and alcohol only from diagnosis codes, smoking not 
available, and socioeconomic status proxies not available)
Data availability
Since 1994
Updates
Annual
Approximate time lag 
1 year
Data transfer
Not permitted; requires collaboration with Danish 
investigator3
Approval process
Danish Data Protection Agency approval required
ATC = Anatomical Therapeutic Chemical; ICD-10 = International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision; Nordic Medico-Statistical Committee Classification of Surgical Procedures.
1
Eurostat. 2013. Available at: 
epp.eurostat.ec.europa.eu/tgm/table.do?tab=table&init=1&language=en&pcode=tps00001&plugin=1. Accessed 
January 28, 2014.
2
Indacaterol was selected as an example of a LABA indicated only for COPD.
3
Collaboration of local investigator has not been obtained and is contingent upon staffing availability.
9.5
STUDY SIZE
Table 5 shows for the situation where the IRR for the events of interest for olodaterol use 
compared with other LABAs is 1 and the number of person-years of olodaterol use necessary 
to obtain a probability of 0.80 that the upper bound of the 95% confidence interval of the IRR 
is below 1.5, 2.0, 2.5, and 3.0. If all olodaterol initiators in the Denmark data source are 
eligible for the study, the study size could be sufficient by calendar year 2019 or 2020 to 

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demonstrate an IRR less than 3.0 for AMI and atrial fibrillation and less than 1.5 for all-cause 
mortality if the true IRR for olodaterol compared with other LABAs is 1.0. As three or more 
other LABAs are already available in these countries, a relatively low use of olodaterol is 
expected. As per Section 9.1, the study is proposed for a 5-year duration. For each study 
outcome, the IRR will be calculated if the number of exposed person-years is sufficient for 
the upper bound of the 95% confidence interval around the IRR to be approximately 2.5; for 
ventricular tachycardia, including ventricular fibrillation/flutter and cardiac arrest, the IRR 
will be calculated if the number of exposed person-years is sufficient for the upper bound of 
the 95% confidence interval is approximately 3.If the number of olodaterol users in Denmark 
is insufficient to meet these statistical goals, another country (e.g., Netherlands) will be added 
as an additional study population, and combined estimates will be generated, if appropriate. If 
total olodaterol use is lower than expected or analyses from Denmark and the other country
cannot be pooled, analyses will be restricted to descriptive analyses only.

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Table 5
Number of exposed person-years necessary to have a probability of 
0.80 that the upper bound of the 95% confidence interval of the IRR 
is below the specified value, assuming IRR in the population is 1.0
Safety endpoint
Rate per 1,000 
person-years in 
unexposed persons 
with COPD
Upper bound of 95% CI of IRR for 
olodaterol versus comparator
1.5
2
2.5
3
AMI
6.31
9,890
3,390
1,940
1,350
9.52
6,230
2,130
1,220
850
Atrial fibrillation
5.92
10,060
3,450
1,970
1,370
2.53
23,820
8,150
4,670
3,250
Ventricular tachy-
cardia, ventricular 
fibrillation, or 
cardiac arrest
0.972
61,470
21,040
12,040
8,380
Other arrhythmias
2.962,4
20,110
6,880
3,940
2,740
All-cause mortality
106.585
510
180
100
70
AMI = acute myocardial infarction; CI = confidence interval; COPD = chronic obstructive pulmonary disease; 
CPRD = Clinical Practice Research Datalink; IRR = incidence rate ratio; LABA = long-acting beta2-agonist.
Note: Calculations are for a 1:4 olodaterol:comparator person-year ratio and population incidence rate ratio = 1.0. This table 
was prepared with the use of Episheet—spreadsheets for the analysis of epidemiologic data. [R13-1396]
1
García-Rodríguez et al. [R12-3322]; CPRD, United Kingdom; new diagnosis of an outcome during the study period in 
general practitioner medical records and hospital summaries.
2
Sidney et al. [R07-2623]; Kaiser Permanente, United States; primary hospital discharge diagnoses.
3
Ruigómez et al. [R10-0421]; CPRD, chronic atrial fibrillation in COPD, aged 40-89 years; estimated by multiplying 
incidence in the general population (1.7 per 1,000 person-years) by the relative risk of atrial fibrillation associated with 
chronic respiratory disease (1.5).
4
Other arrhythmias included paroxysmal supraventricular arrhythmias, cardiac dysrhythmias, and premature beats.
5
Curkendall et al. [R09-0579]; Saskatchewan Health, Canada; incidence of primary hospital discharge diagnoses or 
underlying cause of death.
Data from 2014 became available during the second quarter of 2015. Based on feasibility 
data for Denmark, there were over 600 unique users of olodaterol in 2014. Actual counts of 
patients using olodaterol in 2015 are not yet available, but will be monitored and reported in 
the study progress reports. In addition, the entire pool of patients with COPD in Denmark can 
be approximated. During a recent 4-year period (2005-2008), 38,527 individuals in Denmark 
received hospital care (outpatient or inpatient) for COPD for the first time, or approximately 
9,630 per year. [R12-3324]
9.6
DATA MANAGEMENT
Routine procedures include checking electronic files, maintaining security and data 
confidentiality, following analysis plans, and performing quality-control checks of all 

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programs. The database research partner will maintain any patient-identifying information 
securely onsite according to internal standard operating procedures.
The research institution conducting analysis of data from the data source has been reviewed 
and qualified by the 
 Office of Quality Assurance. The research team 
will follow its own established procedures. All summary tables of results, and no individual 
patient identifiers, will be provided to 
, who will develop the report.
 
 will follow quality-control procedures regarding transfer of data.
Security processes will be in place to ensure the safety of all systems and data. Every effort 
will be made to ensure that data are kept secure so that they cannot be accessed by anyone 
except select study staff.
Appropriate data storage and archiving procedures will be followed standard procedures will 
be in place at each location handling the data to restore files in the event of a hardware or 
software failure.
The extent of missing data will be evaluated and described. Imputation methods may be used 
to estimate key missing values such as dosage of exposure of interest, smoking status, or 
body mass index.
For requests to access to data for audit purposes, only aggregated data from the research 
centre will be available. The audit trail will consist of a detailed description of the methods to 
extract and process the electronic health records or claims data, as applicable. Access to raw 
data at the database research centre will require the data requestor to obtain a licence or apply 
for approval at a research committee and to fulfil the conditions required under the 
governance rules of the database research centre. The research team will follow its
established data management procedures for handling patient-specific data. A data
management plan specific to the contracted research centre will be included in the statistical 
analysis plan, a separate document not yet developed.
9.7
DATA ANALYSIS
9.7.1
Main analysis
Descriptive analyses by exposure category, overall and stratified by pre-defined strata, will be 
provided. Categorical variables will be summarised with counts and percentages. Continuous 
variables will be summarised with univariate statistics (e.g., mean, standard deviation, 95% 
confidence intervals).
9.7.1.1
Description of cohort characteristics
All covariables will be ascertained on or before the index date. Age on the index date and 
patient sex are readily available. When presenting results stratified on a single variable, 
subjects missing the variable will be reported as a separate category.
●
Reasons for exclusion among all identified olodaterol initiators and among the “other
LABA” initiators will be summarised.

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●
Demographic and medical characteristics (e.g., medical history) at the index date will 
be summarised by cohort and stratified also by COPD severity, stratified by history of 
outcome of interest.
●
Prior medications dispensed before the index date and concomitant medications 
dispensed on index date will be summarised by cohort.
9.7.1.2
Characteristics of follow-up
To assess the potential for differential loss-to-follow-up, the distribution of patient-specific 
person-time at risk will be visually evaluated and compared by exposure group. Reasons for 
terminating follow-up, e.g. occurrence of event of interest, end of exposure, death, or end of 
study period, will also be described.
9.7.1.3
Safety endpoints
Incidence rates for each event of interest will be calculated for each cohort as follows:
Incidence rate (IRE) = (total number of patients in the olodaterol cohort experiencing 
an event of interest for the first time during the given time period) / (total time at risk 
from current use of olodaterol during the given period)
Incidence rate (IRC) = (total number of patients in the comparator cohort experiencing 
an event of interest for the first time during the given time period) / (total time at risk 
from current use of comparator LABAs during the given period)
The incidence rate ratio (IRR) for each event of interest in the olodaterol-exposed group 
relative to that in the comparator group will be derived as follows:
Incidence rate ratio = IRE/ IRC, where IRE represents the incidence rate from the 
olodaterol cohort and IRC represents the incidence rate from the matched comparator 
cohort.
The IRRs will be calculated and 95% confidence intervals will be derived. Incidence 
differences and their 95% confidence intervals will also be derived.
The effects of demographics and selected baseline characteristics will be assessed. Adjusted 
IRR will be calculated by adjusting for each covariate one at a time. The following factors 
will be considered as potential confounders:
●
Age at the index date
●
Sex
●
Calendar year of the index date
●
Use of specific comedications (e.g., ICS, LAMA) at or before the index date
●
History of cardiovascular events of interest (number of strata to be evaluated may be 
constrained by number of events) at or before the index date
●
Baseline severity of COPD, measured within 12 months before the index date

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●
Diagnosis code for COPD only versus diagnosis codes for both COPD and asthma
●
Individual cardiovascular risk factors listed in Section 9.3.3.2, such as hypertension, 
diabetes, hyperlipidaemia.
Additional strata may be defined as needed.
The IRR will be calculated by stratifying on and adjusting for each potential confounder one 
at a time. A change of less than 10% in the adjusted IRR compared with the crude IRR will 
serve as an indicator that confounding for that variable is of negligible importance in the data. 
Variables associated with a change in the IRR greater than 10% will be included in the 
propensity score model.
A fitted propensity score model will be used to estimate a propensity score for each patient. If 
enough patients are exposed among (1) initiators of olodaterol or other LABA alone and 
(2) initiators of olodaterol or LABA in combination with a LAMA (in free- or fixed-dose 
combination) (≥1,000), two propensity score models will be fitted, one for each group. If the 
numbers are not adequate, then a variable indicating presence or absence of background 
LAMA, together with its interaction terms with clinically relevant covariables, will be 
included in one propensity score model as an adjustment variable. [R16-4007, P12-08895]
The IRRs for each event of interest will be stratified by propensity score deciles. Adjusted 
IRRs will be calculated across propensity score deciles, overall and by background treatment,
with or without LAMA subgroups. [R10-1239] The propensity scores will be generated using 
the factors shown to be associated with confounding in the data. For modelling (i.e., when 
computing exposure propensity scores), variables with a significant amount of missing data 
(e.g., > 10%) may be imputed.
The distributions of propensity scores in olodaterol and in comparator patients will be 
examined. Patients with extreme or non-overlapping propensity scores (i.e., ranges in the 
upper or lower tails of the propensity score distribution within which only patients taking 
olodaterol or patients taking comparator LABAs fall) will be excluded. This allows for the 
removal of patients for whom there are no comparable patients in the other cohort.
Person-time and endpoint counts for each cohort will be stratified into deciles of propensity 
scores defined by the distribution of propensity scores for the olodaterol cohort. To check that 
the covariables are balanced within each propensity score decile, the distribution of each 
variable within each propensity score decile will be compared visually between the cohorts to 
evaluate whether there are clinically relevant differences.
For each endpoint, IRR and incidence rate difference (IRD) will be stratified by propensity 
score deciles, and the overall adjusted IRR and IRD and associated 95% CIs will be derived 
by weighting each stratum by the prevalence among the olodaterol cohort.

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9.8
QUALITY CONTROL
At the coordinating centre, an independent Office of Quality Assurance performs audits and 
assessments that involve various aspects of its projects, including but not limited to 
documentation of education and training, data entry, data transfer, and approval by the RTI 
International institutional review board, of which 
 is a research unit. 
Such audits at
 will be conducted by the Office of Quality Assurance 
according to established criteria in standard operating procedures and other applicable 
procedures. The database research centres will follow its own quality and audit trail 
procedures. The quality and audit trails may be different from that of the coordinating centre.
Data management and analysis will be conducted in at each participating research centre. 
Standard operating procedures specific to each research centre will be used to guide the 
conduct of the study. These procedures include internal quality audits and the opportunity for 
external audits, rules for secure and confidential data storage, methods to maintain and 
archive project documents, quality-control procedures for programming, standards for writing 
analysis plans, and requirements for senior scientific review.
 will follow quality-control procedures for report generation, including
senior review by an expert other than the author.
9.9
LIMITATIONS OF THE RESEARCH METHODS
Existing population-based data are very useful for evaluating research questions about real-
world clinical practice because of the diversity of patients and medical practices represented 
therein. However, the results must be interpreted with caution because of the following 
known limitations of such data sources:
●
The length of medical history in some databases will be limited, and earlier medical 
events or drug exposures may be unknown. This may especially be true for data 
sources that have become available for research in the recent past.
●
The study’s ability to enrol large enough numbers of patients using LABAs and to 
follow them for an adequate number of person-years will depend on uptake of 

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olodaterol in each country and on health insurance reimbursement decisions for this 
medication.
●
For severity of COPD, ideally FEV1 (forced expiratory volume in 1 second) would be 
used to classify all individuals by application of standard criteria; however, it is 
anticipated that most databases will not capture this information. Other variables, such 
as information on hospitalisations for COPD or use of oxygen, may be available.
●
The candidate data sources planned for this study reliably contain information on 
outpatient dispensings, but actual exposure may be misclassified for individuals who 
do not use their medication as prescribed.
●
When outpatient diagnoses are absent, such comorbidities may also be assessed with 
medication use. Using this approach may result in underestimation if patients are 
untreated or overestimation if the indicator medication is used for multiple 
indications.
●
Internal and external validity of some cardiovascular endpoints might be of concern. 
For arrhythmias, using hospitalisation discharge codes will underestimate the 
occurrence of these events because only the more severe arrhythmias will be captured. 
Although events diagnosed at hospital outpatient clinics will be included for these 
endpoints, a proportion of events diagnosed in the primary care sector will be missed 
if these data are not available to be used. Given that out-of-hospital events are not 
included, 20% to 30% of AMI outcomes may be missed. This could result in biased 
IRR estimates if olodaterol were to change the severity of such outcomes.
9.10
OTHER ASPECTS
9.10.1
Study size limitations
The ability to accrue a sufficient study size for patients treated with newly approved 
olodaterol depends upon the accrual rate of new use of olodaterol in Denmark. In the 2018
progress report analysis (second progress report), the uptake and rate of increase of olodaterol 
use, including free- and fixed-dose combination with a LAMA, will be evaluated. In the 
event that uptake is slower than anticipated, another country, such as the Netherlands, will be 
added as an additional study population, and a meta-analysis will be conducted in the final 
analysis if appropriate. If total use is lower than expected or analyses from Denmark and 
from the other country cannot be pooled, analyses will be restricted to descriptive analyses 
only.
9.10.2
Study standards
The study will be conducted in accordance with the International Society for 
Pharmacoepidemiology [R11-4318] Guidelines for Good Pharmacoepidemiology Practices 
(GPP) and in accordance with the European Network of Centres for Pharmacoepidemiology 
and Pharmacovigilance (ENCePP) Guide on Methodological Standards in 
Pharmacoepidemiology. [R13-5419] The ENCePP Checklist for Study Protocols [R13-5419]
will be completed, and the study will be registered in the EU PAS register, [R14-0354] as 
well as in ClinicalTrials.gov.

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The study is a PASS and will comply with the definition of the non-interventional 
(observational) study provided in the 2012 European Medicines Agency (EMA) Guideline on 
Good Pharmacovigilance Practice (GVP): Module VIII – Post-Authorisation Safety Studies.
[R16-4611] The study will comply with the nature of non-interventional (observational) 
studies referred to in the ICH (International Conference on Harmonisation) harmonised 
tripartite guideline Pharmacovigilance Planning E2E. [R11-2259]
9.10.3
Bias and confounding
The most likely source of bias is confounding by indication, e.g., severity of COPD. Because 
olodaterol will be new to the market, it is likely that early in its availability, olodaterol will be 
prescribed to individuals who have tried other treatments for COPD. This study design 
attempts to remove such confounding by limiting the study to individuals who are not 
switching to a study treatment (olodaterol vs. other LABA) but are naïve to the class, 
according to the available pharmacy dispensing history. However, this approach may not 
fully address the channelling bias, will reduce the study size, and will require a longer period 
of time to accrue initiators of olodaterol naïve to LABA use.
To address the issue of confounding by indication and by other factors in the 
non-interventional setting, stratification of incidence rate ratios by propensity score 
(representing the tendency to receive olodaterol) and subsequent derivation of the overall 
adjusted incidence rate ratio will be implemented, provided that the market uptake of 
olodaterol in Denmark is large enough to meet the required study size. The ability to control 
for such differences is dependent upon having data on the key factors that differentiate users 
of the study medications from each other.
9.11
SUBJECTS
The study population will consist of patients with COPD (disease cohort) aged 40 years or 
older in a country where olodaterol is available and where a large proportion of the 
population is included in health care databases for pharmacoepidemiologic research. The 
study will be conducted by using the national population-based registers in Denmark.
Study subjects will be identified as individuals with an outpatient dispensing for olodaterol, 
or an alternative LABA, in free- or fixed-dose combination with another LAMA, during the 
study period and no recent LABA use in the last 6 months. The study period will start at the 
time that olodaterol is available in Denmark, and the study period will end at the latest date of 
available research data in the data source. All available patient-specific data covering time 
before study cohort entry (minimally, outpatient dispensings, and hospital diagnoses) will be 
used for identification of patient characteristics at the time of cohort entry, i.e., the study 
index date.
9.11.1
Identification of COPD
Patients diagnosed with COPD will be identified by compatible outpatient and inpatient 
diagnostic codes for COPD (i.e., ICD-10 codes for COPD, chronic bronchitis, and 
emphysema). Hospital discharge diagnoses of COPD have been shown to have a positive 
predictive value (PPV) of 92%.[R14-0359]

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9.11.2
Study cohorts
Two exposure cohorts of patients with diagnosed COPD will be identified and followed via 
available medical histories in the data source (Figure 3):
●
The cohort of new users of olodaterol, i.e., anyone with a dispensing for olodaterol
(including either in free- or fixed-dose combination with a LAMA).
●
The comparator cohort of new users of indacaterol, salmeterol, or formoterol 
(including either in free- or fixed-dose combinations with a LAMA).
Individuals selected for the comparator cohort will be frequency-matched to the cohort of 
olodaterol initiators by 5-year age category, sex, and calendar year of first dispensing of study 
LABA. The number of comparator patients selected will be from 1 to 5 times the number of 
olodaterol patients. The date of the first dispensing of study LABA is defined as the index 
date. Patients with COPD switching LABA at the study index date, indicated by use of 
another LABA within the previous 6 months, will not be included in either study cohort. The 
rationale for this exclusion is to maximise similarity of COPD disease between the two 
exposure cohorts and to remove potential lingering effects of a recently used other LABA. If 
the drug utilisation study demonstrates that this approach would exclude 25% or more 
initiators of olodaterol from the study, an alternative approach to balancing exposure groups 
may be developed and applied; if used, the alternative approach will be described in the 
report. Use of oral beta2-agonists will not be included as study medications of interest.
Individuals will be randomly selected for the comparator cohort from each stratum of 
qualifying individuals in the same 5-year age category, sex, and calendar year of index 
dispensing as an olodaterol initiator.

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LABA = long-acting beta2-agonist.
The comparator LABAs are indacaterol, salmeterol, and formoterol in single-agent formulations.
Figure 3
Selection of study cohorts
9.11.3
Inclusion criteria
Patients in both exposure cohorts will be required to meet the following criteria:
●
Have been diagnosed with COPD
●
Be aged 40 years or older (to minimise the likelihood of including individuals who 
have asthma only)
●
Be a new user of olodaterol or a new user of indacaterol, salmeterol, or formoterol 
(not in fixed-dose combination with an inhaled corticosteroid) and have no dispensing 
of any LABA in the 6 months before the index date
●
Have at least 1 year of enrolment in the electronic database before their first LABA 
dispensing (defined as the index LABA)
●
Have data on sex (i.e., sex must be known)

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10.
PROTECTION OF HUMAN SUBJECTS
Institutional review board approval and/or any other required reviews of the study protocol 
by specific committees will be obtained in accord with applicable national and local 
regulations.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Based on current guidelines from the International Society for Pharmacoepidemiology
[R11-4318] and the EMA Guideline on Good Pharmacovigilance Practices (GVP),
[R13-1970] non-interventional studies such as the one described in this protocol conducted 
using or electronic health care records do not require expedited reporting of suspected 
adverse events/reactions. Based on the data planned for this study, no suspected adverse 
events/reactions are expected.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The study protocol, study status, and report(s) will be included in regulatory communications 
in line with the risk management plan, Periodic Benefit-Risk Evaluation Report, and other 
regulatory milestones and requirements.
Study results will be published following the International Committee of Medical Journal 
Editors recommendations, [R13-5418] and communication in appropriate scientific venues 
(e.g., International Society for Pharmacoepidemiology) will be considered.
When reporting results of this study, the appropriate STROBE (Strengthening the Reporting 
of Observational Studies in Epidemiology) checklist [R11-4902] will be followed.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
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de Abajo FJ, Rodriguez LA. Risk of ventricular arrhythmias 
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Eisner MD, Omachi TA, Katz PP, Yelin EH, Iribarren C, Blanc 
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medications and the risk of cardiac arrhythmias. Epidemiology. 
2005 May;16(3):360-6.
R13-1970
EMA. Guideline on good pharmacovigilance practices (GVP). 
Module VI – Management and reporting of adverse reactions to 
medicinal products. European Medicines Agency; 22 June 2012. 
Available at: website: 
emea.europa.eu/docs/en_GB/document_library/Scientific_guidelin
e/2012/06/WC500129135.pdf. Accessed 8 January 2014.
R13-5415
Danish Quality Unit of General Practice. Danish General Practice 
Database (DAMD). 2014. Available at: website: dak-
e.dk/flx/english/dak_e_it/danish_general_practice_database_damd/
. Accessed 31 January 2014.
R13-5418
ICMJE. Recommendations for the conduct, reporting, editing, and 
publication of scholarly work in medical journals. International 
Committee of Medical Journal Editors; August 2013. Available at: 
website: icmje.org/urm_main.html. Accessed 28 October 2013.

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R13-5419
ENCePP. Guide on methodological standards in 
pharmacoepidemiology (revision 2). EMA/95098/2010 Rev.2. 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance; 18 June 2013. Available at: website: 
encepp.eu/standards_and_guidances/methodologicalGuide.shtml. 
Accessed 8 January 2014.
R13-5420
ENCePP. ENCePP checklist for study protocols (revision 2). 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance; 14 January 2013. Available at: website: 
encepp.eu/standards_and_guidances/checkListProtocols.shtml. 
Accessed 8 January 2014.
R14-0354
ENCePP. EU PAS Register. European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance; 7 January 2014. 
Available at: website: 
encepp.eu/encepp_studies/indexRegister.shtml. Accessed 8 
January 2014.
R14-0355
Joensen AM, Jensen MK, Overvad K, Dethlefsen C, Schmidt E, 
Rasmussen L, et al. Predictive values of acute coronary syndrome 
discharge diagnoses differed in the Danish National Patient 
Registry. J Clin Epidemiol. 2009 Feb;62(2):188-94.
R14-0358
Madsen M, Davidsen M, Rasmussen S, Abildstrom SZ, Osler M. 
The validity of the diagnosis of acute myocardial infarction in 
routine statistics: a comparison of mortality and hospital discharge 
data with the Danish MONICA registry. J Clin Epidemiol. 2003 
Feb;56(2):124-30.
R14-0359
Thomsen RW, Lange P, Hellquist B, Frausing E, Bartels PD, Krog 
BR, et al. Validity and underrecording of diagnosis of COPD in the 
Danish National Patient Registry. Respir Med. 2011 
Jul;105(7):1063-8.
R16-2604
Schmidt M, Pedersen L, Sørensen HT. The Danish Civil 
Registration System as a tool in epidemiology. Eur J Epidemiol. 
2014 Aug;29(8):541-9.
R16-4007
Girman CJ, Gokhale M, Kou TD, Brodovicz KG, Wyss R, Sturmer 
T. Assessing the impact of propensity score estimation and 
implementation on covariate balance and confounding control 
within and across important subgroups in comparative 
effectiveness research. Med Care. 2014 Mar;52(3):280-7.
R16-4611
EMA. Guideline on good pharmacovigilance practices (GVP). 
Module VIII – Post-authorisation safety studies (Rev 2). European 
Medicines Agency; 04 August 2016. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientifi
c_guideline/2012/06/WC500129137.pdf. Accessed 06 August 
2016.

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13.2
UNPUBLISHED REFERENCES
None

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None.

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMA/540136/2009
ENCePP Checklist for Study Protocols (Revision 3)
Adopted by the ENCePP Steering Group on 01/07/2016
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP
to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP 
Guide on Methodological Standards in Pharmacoepidemiology, which reviews and gives direct 
electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply 
to a particular study (for example, in the case of an innovative study design). In this case, the 
answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section 
should be used to explain why. The “Comments” field can also be used to elaborate on a “No” 
answer.
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). The Checklist is a supporting document and does not replace the 
format of the protocol for PASS as recommended in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP).
European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance

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Study title:
Cohort study of cardiovascular events in patients with chronic obstructive pulmonary 
disease initiating olodaterol or other long-acting beta2-agonists
Study reference number:
BI Study Number: 1222.54
Section 1: Milestones
Yes
No
N/
A
Section 
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection1
6
1.1.2 End of data collection2
6
1.1.3 Study progress report(s)
6
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
6
1.1.6 Final report of study results
6
Comments:
Section 2: Research question
Yes
No
N/
A
Section 
Number
2.1
Does the formulation of the research question 
and objectives clearly explain: 
8
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)
8
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
8
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
8
                                                
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
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design) 
9.1
3.2
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9.1
3.3
Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk)
9.1
3.4
Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm 
(NNH) per year)
9.1, 9.7
3.5
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
9.1, 9.7
Comments:
Section 4: Source and study populations
Yes
No
N/
A
Section 
Number
4.1
Is the source population described?
9.4, 9.11
4.2
Is the planned study population defined in 
terms of:
4.2.1 Study time period?
9.1, 9.11
4.2.2 Age and sex?
9.11
4.2.3 Country of origin?
9.4, 9.11
4.2.4 Disease/indication?
9.11
4.2.5 Duration of follow-up?
9.3.1.2
4.3
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
9.11
Comments:

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Section 5: Exposure definition and 
measurement
Yes
No
N/
A
Section 
Number
5.1
Does the protocol describe how the study 
exposure is defined and measured? 
(e.g. operational details for defining and categorising 
exposure, measurement of dose and duration of drug 
exposure)
9.3.1
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, 
use of validation sub-study)
9.3.1
5.3
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
9.3.1
5.4
Is exposure classified based on biological 
mechanism of action and taking into account 
the pharmacokinetics and pharmacodynamics 
of the drug?
9.3.1
Comments:
Section 6: Outcome definition and 
measurement
Yes
No
N/
A
Section 
Number
6.1
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3.2
6.2
Does the protocol describe how the outcomes 
are defined and measured? 
9.3.2
6.3
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, prospective 
or retrospective ascertainment, use of validation sub-
study)
9.3.2
6.4
Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services 
utilisation, burden of disease, disease management)
9.3.2
Comments:
Section 7: Bias
Yes
No
N/
A
Section 
Number
7.1
Does the protocol describe how confounding 
will be addressed in the study?
9.10.3
7.1.1. Does the protocol address confounding 
by indication if applicable?
9.10.3
7.2
Does the protocol address:
9.10.3

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Section 7: Bias
Yes
No
N/
A
Section 
Number
7.2.1. Selection biases (e.g. healthy user bias)
9.10.3
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias)
9.10.3
7.3
Does the protocol address the validity of the 
study covariates?
9.10.3
Comments:
Section 8: Effect modification
Yes
No
N/
A
Section 
Number
8.1
Does the protocol address effect modifiers?
(e.g. collection of data on known effect modifiers, sub-
group analyses, anticipated direction of effect) 
9.7.2.1, 
9.10.3
Comments:
Sensitivity analyses will exclude individuals with history of the outcomes.
Section 9: Data sources
Yes
No
N/
A
Section 
Number
9.1
Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-
face interview)
9.4
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
9.4
9.1.3 Covariates?
9.4
9.2
Does the protocol describe the information 
available from the data source(s) on:
9.4
9.2.1 Exposure? (e.g. date of dispensing, drug 
quantity, dose, number of days of supply prescription, 
daily dosage, prescriber)
9.4
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.4
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle)
9.4
9.3
Is a coding system described for: 
9.4
9.3.1 Exposure? (e.g. WHO Drug Dictionary, 
Anatomical Therapeutic Chemical (ATC) Classification 
System)
9.4
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
9.4

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Section 9: Data sources
Yes
No
N/
A
Section 
Number
Activities (MedDRA))
9.3.3 Covariates?
9.4
9.4
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)
9.4
Comments:
Section 10: Analysis plan
Yes
No
N/
A
Section 
Number
10.1 Is the choice of statistical techniques 
described? 
9.7.1
10.2 Are descriptive analyses included?
9.7.1
10.3 Are stratified analyses included?
9.7.1
10.4 Does the plan describe methods for adjusting 
for confounding?
9.7.1
10.5 Does the plan describe methods for handling 
missing data?
9.7.1
10.6 Is sample size and/or statistical power 
estimated?
9.5
Comments:
Section 11: Data management and quality 
control
Yes
No
N/
A
Section 
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
9.6
11.2 Are methods of quality assurance described?
9.8
11.3 Is there a system in place for independent 
review of study results? 
Comments:
This is a protocol that will be implemented by a research institution that is qualified 
and has available staffing at the time of study initiation, i.e. after EMA review, 
olodaterol is launched. At that time the specifics of data management, quality control, 
and data security can be specified. To date no advisory board is planned.

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Section 12: Limitations
Yes
No
N/
A
Section 
Number
12.1 Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
9.10.3
12.1.2 Information bias?
9.10.3
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such 
biases, validation sub-study, use of validation and 
external data, analytical methods)
9.10.3
12.2 Does the protocol discuss study feasibility? 
(e.g. study size, anticipated exposure, duration of follow-
up in a cohort study, patient recruitment)
9.10.1
Comments:
Section 13: Ethical issues
Yes
No
N/
A
Section 
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?
10
13.2 Has any outcome of an ethical review 
procedure been addressed?
13.3 Have data protection requirements been 
described?
9.10.2, 10
Comments:
Section 14: Amendments and deviations
Yes
No
N/
A
Section 
Number
14.1 Does the protocol include a section to 
document amendments and deviations? 
5
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/
A
Section 
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)? 
12
15.2 Are plans described for disseminating study 
results externally, including publication?
12

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Comments:
Name of the main author of the protocol:
Date: 28/October/2016
Signature: 

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ANNEX 3. EVALUATION OF COPD SEVERITY IN AUTOMATED
HEALTH DATABASES
Annex Table 3:1
Published definitions of COPD severity in studies conducted in 
automated health databases
Reference, Severity 
Criteria
COPD Severity
Mild
Moderate
Severe
Integrated Primary Care Information Project, Netherlands [P11-13226]
With spirometry data, 
used GOLD criteria
[P13-02399]
Without spirometry, used 
methods of Curkendall,
[P07-09136] Eisner,
[R13-1392] and Soriano 
[R08-1492]
At initial COPD 
symptoms
At least two 
prescriptions of 
bronchodilators of the 
same drug class with a 
maximum interval of 6 
months in 1 year
Severe:

Hospitalisation for 
COPD, or

Third course of 
antibiotics for 
respiratory infection 
in 1 year, or

Second course of 
systemic 
corticosteroids for 
COPD exacerbation in
1 year
Very severe:

Oxygen therapy, or

Scheduled for lung 
transplant
Saskatchewan Health, Canada [R09-0579]
Case-control study to 
find severity marker 
variables, using the 
following data:

Pre-existing 
chronic 
conditions

Recent acute 
conditions

Recent high use 
of bronchodilators
Specific components of 
the above are detailed in 
the article’s appendix 
Patients ranked into 
quintiles by 
likelihood of COPD 
hospitalisation, from 
conditional logistic 
regression model
Factors in previous 180 days 
associated with severe 
COPD:

Emphysema

Recent nebuliser use

Home oxygen therapy

Corticosteroid use

Frequent 
bronchodilator use

Pneumonia

Previous COPD 
exacerbation

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Annex Table 3:1 (cont’d)
Published definitions of COPD severity in studies conducted in 
automated health databases
Reference, Severity 
Criteria
COPD Severity
Mild
Moderate
Severe
General Practice Research Database,1 United Kingdom [R08-1492]
Severity based on only 
drug data
At first diagnosis of 
COPD
At least two 
prescriptions of the 
same COPD drug 
within 6 months, using 
data on inhaled or oral 
bronchodilators, 
xanthines, cromones, 
steroids, or 
combinations

Oxygen therapy, or

Nebuliser therapy
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease.
1
This database is now known as Clinical Practice Research Datalink (CPRD).

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ANNEX 4. ATC CODES FOR SELECTED RESPIRATORY 
MEDICATIONS
Annex Table 4:1 
Inhaled selective beta2-adrenoreceptor agonists, anticholinergics, and 
glucocorticosteroids
ATC Code 
Name
Defined Daily Dose Units (Administration Route)
Inhaled short-acting beta2-agonists
R03AC02
Salbutamol 
0.8 mg (aerosol, powder)
0.10 mg (solution)
R03AC03
Terbutaline
2 mg (aerosol, powder)
20 mg (solution)
R03AC04
Fenoterol
0.6 mg (aerosol, powder)
4 mg (solution)
R03AC05
Rimiterol
1.6 mg (aerosol)
R03AC06
Hexoprenaline
1.5 mg (aerosol)
R03AC07
Isoetarine
NA
R03AC08
Pirbuterol
1.2 mg (aerosol)
R03AC09
Tretoquinol
NA
R03AC10
Carbuterol
NA
R03AC11
Tulobuterol
1.6 mg (aerosol)
R03AC14
Clenbuterol
NA
R03AC15
Reproterol
NA
R03AC16
Procaterol
60 mcg (aerosol)
R03AC17
Bitolterol
NA
Inhaled long-acting beta2-agonists
R03AC12
Salmeterol
0.1 mg (aerosol, powder)
R03AC13
Formoterol
24 mcg (aerosol, powder)
R03AC18
Indacaterol
0.15 mg (inhal. powder)
R03AC19
Olodaterol
5mcg (inhal. solution)
Inhaled short-acting muscarinic antagonists
R03BB01
Ipratropium bromide
0.12 mg (aerosol, powder)
0.3 mg (solution)
R03BB02
Oxitropium bromide
0.6 mg (aerosol)
4 mg (solution)

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Annex Table 4:1 (cont’d)
Inhaled selective beta2-adrenoreceptor agonists, 
anticholinergics, and glucocorticosteroids
ATC Code 
Name
Defined Daily Dose Units (Administration Route)
Inhaled long-acting muscarinic antagonists
R03BB04
Tiotropium bromide
18 mcg (aerosol)
5 mcg (solution)
R03BB05
Aclidinium bromide
0.644 mg
R03BB06
Glycopyrronium bromide
44 mcg
R03BB07
Umeclidinium bromide
55 mcg (inhal. powder)
R03BB54
Tiotropium bromide, 
combinations
Inhaled glucocorticosteroids 
R03BA01
Beclometasone
0.8 mg (aerosol, powder)
1.5 mg (solution)
R03BA02
Budesonide
0.8 mg (aerosol, powder)
1.5 mg (solution)
R03BA03
Flunisolide
1 mg (aerosol)
R03BA04
Betamethasone
NA
R03BA05
Fluticasone
0.6 mg (aerosol, powder)
1.5 mg (solution)
R03BA06
Triamcinolone
NA
R03BA07
Mometasone
0.4 mg (powder)
R03BA08
Ciclesonide
0.16 mg (aerosol)
R03BA09
Fluticasone furoate
NA
ATC = Anatomical Therapeutic Chemical; NA = not yet available in the online ATC/DDD Index.
Source: WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2013. Updated 20 December 2012. 
Available at: website: whocc.no/atc_ddd_index/. Accessed 21 January 2013.
.

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ANNEX 5. CODES FOR COMORBIDITIES AND OTHER 
MEDICATIONS
Annex Table 5:1
Comorbidity
Disease Description
ICD-10 Code
Cardiovascular diseases 
I00-I99
Ischaemic heart disease
I20-I25 or coronary reperfusion surgery and 
procedures
Angina pectoris
I20
Acute myocardial infarction
I21
Other acute or subacute ischaemic heart disease 
I22-I24
Chronic ischaemic heart disease
I25
Coronary reperfusion surgery and procedures 
List of codes to be developed according to 
each database dictionary
Arrhythmias
I47-I49
Paroxysmal tachycardia
I47
Ventricular tachycardia
I47.0, I47.2
Supraventricular tachycardia and unspecified
I47.1, I47.9
Atrial fibrillation and flutter
I48
Other cardiac arrhythmias
I49
Ventricular fibrillation and flutter
I49.0
Other cardiac arrhythmias 
I49.1-I49.9
Conduction disorders
I44-I45
Cardiac arrest
I46
Heart failure
I50
Cerebrovascular disease
I60-I69, G45
Cerebral haemorrhage (subarachnoid, intracerebral, other 
non-traumatic)
I60-I62
Cerebral infarction and stroke 
I63, I64, G46.5
Transient ischaemic attack
G45
Other cerebrovascular disease and sequelae of 
cerebrovascular disease 
I65-I69
Hypertension and hypertensive heart disease
I10-I15

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Annex Table 5: 1 (cont’d)
Comorbidity
Disease Description
ICD-10 Code
Diseases of arteries, arterioles, and capillaries 
I70-I79 and peripheral arterial 
revascularisation procedures
Peripheral arterial revascularisation procedures 
List of codes to be developed according to 
each database dictionary
Other form of heart diseases
I00-I09, I30-I43, I80-I99
Hyperlipidaemia
E78
Diabetes mellitus
E10-E14
Renal disease
N00-N39
Chronic kidney disease
N18
Other renal disorders
N00-N17, N19, N25-N39
Anaemias
D50-D64
Nutritional anaemias
D50-D53
Iron deficiency anaemias 
D50
Other anaemias
D55-D64
Peptic ulcer disease
K25-K28
Liver disease
K70-K77
Osteoporosis
M80-M82
Rheumatoid arthritis and other inflammatory 
arthropathies
M05-M14
Systemic connective tissue diseases
M30-M36
Malignancy
C00-C97
Depressive disorders
F32-F33
Pregnancy (at the index date)
O00-O48
ICD-10 = International Statistical Classification of Diseases and Related Health Problems, 10th Revision.

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Annex Table 5:2
Anatomical Therapeutic Chemical codes for comedications
Medication Description
ATC Code
Respiratory medications
Inhaled short-acting muscarinic antagonists (SAMAs)
See Annex Table 4:1 for ATC codes 
Inhaled long-acting muscarinic antagonists (LAMAs)
See Annex Table 4:1 for ATC codes 
Inhaled short-acting beta2-agonists (SABAs)
See Annex Table 4:1 for ATC codes 
Inhaled long-acting beta2-agonists (LABAs)
See Annex Table 4:1 for ATC codes 
Inhaled glucocorticosteroids (ICS)
See Annex Table 4:1 for ATC codes 
Fixed combinations of SABA and SAMA
ATC codes not available1
Fixed combinations of SABA and ICS
ATC codes not available1
Fixed combinations of LABA and ICS
ATC codes not available1
Systemic glucocorticosteroids
H02AB
Systemic beta2-agonists
R03CC
Xanthines and adrenergics
R03DA, R03DB
Roflumilast
R03DX07 
Nasal glucocorticosteroids
R01AD
Omalizumab
R03DX05 
Leukotriene receptor antagonists
R03DC
Cromoglicic acid
R03BC01 
Nedocromil
R03BC03
Oxygen therapy
V03AN01 or NCSP code: BGXA05
Nebuliser therapy
NCSP code: BGXA10
Cardiovascular medications
All codes listed below in section 
Cardiovascular medications
Cardiac glycosides and antiarrhythmics, Class I and III
C01A, C01B 
Vasodilators used in cardiac diseases
C01D
Cardiac stimulants and other cardiac preparations
C01E, C01C
Diuretics
C03
Peripheral vasodilators
C04
Vasoprotectives
C05
Beta blocking agents
C07
Calcium channel blockers
C08
Antihypertensives
C02

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Annex Table 5:2 (cont’d)
Anatomical Therapeutic Chemical codes for comedications
Medication Description
ATC Code
Agents acting on the renin-angiotensin system
C09
Angiotensin-converting-enzyme inhibitors
C09A, C09B
Angiotensin II receptor antagonists
C09C, C09D
Renin-inhibitors
C09X
Lipid-modifying agents
C10
HMG CoA reductase inhibitors (statins)
C10AA
Other lipid-modifying agents
C10AB, C10AC, C10AD, C10AX, 
HMG CoA reductase inhibitors (statins), other 
combinations with acetylsalicylic acid
C10BX
Antithrombotic agents
B01
Platelet aggregation inhibitors
B01AC
Systemic antibacterials
J01
Iron preparations
B03A
Proton pump inhibitors
A02BC
Drugs used in diabetes 
A10
Insulins
A10A
Blood glucose–lowering drugs
A10B, A10X
Drugs for musculoskeletal system
M01A, N02BA, M01B, M01C
Anti-inflammatory and antirheumatic products, non-
steroids (non-steroidal anti-inflammatory drugs)
M01A
Acetylsalicylic acid (other analgesics and antipyretics)
N02BA
Other antirheumatic agents: Anti-
inflammatory/antirheumatic agents in combination, 
specific antirheumatic agents
M01B-M01C
Antidepressants
N06A
Selective serotonin reuptake inhibitors
N06AB
Antineoplastic agents
L01
Immunosuppressants
L04
Antivirals for systemic use
J05
Hormone-replacement therapy: Estrogens, 
progestogens, progestogens and estrogens in 
combination
G03C, G03D, G03F
Drugs used in nicotine dependence
N07BA 
ATC = Anatomical Therapeutic Chemical.
1
The national drug code of each database country will be used to identify medications without an individual ATC code.

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ANNEX 6. DATA SOURCE DESCRIPTIONS FROM FEASIBILITY 
REPORT, 1 NOVEMBER 2013
NATIONAL REGISTRY OF PATIENTS, DENMARK
Database Characteristics
The Danish health care system provides universal coverage to all Danish residents 
(5.5 million inhabitants). Health care coverage includes visits to general practitioners (GPs) 
and specialists, hospital admissions, and outpatient visits. The costs of medicines are partially 
covered by the Danish health system. The centralised Civil Registration System in Denmark 
allows for personal identification of each person in the entire Danish population and for the 
possibility of linkage to all Danish registries containing civil registration numbers, such as the 
Danish National Registry of Patients (individual hospitalised or attending outpatient hospital 
clinics), Danish National Prescription Database (for outpatient prescriptions), the Prescription 
Databases of the Central Denmark Region, and the Danish Registry of Causes of Death. Data 
collected in these registries are available for research purposes. [R13-5415]
For 1980-2008, The National Registry of Patients counted 236,494 patients with a first 
hospital contact for COPD. [R12-3324] From the National Health Service, for persons aged 
45 to 84 years, the prevalence of COPD standardised to the Danish population was estimated 
at 9%, using a sample of 299,000 residents of two counties. [R12-3265] In general, ICD
(International Classification of Diseases) diagnoses codes for COPD have shown a good 
positive predictive value (PPV). In the Danish National Registers, the PPV for the hospital 
discharge diagnosis of COPD was 92%. [R14-0359]
The conduct of research with the Danish National Registry of Patients requires collaboration 
with a local Danish university or investigator affiliated with a research institute to access the 
data and ethics committee notification or approval to handle data.

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Selected Published Research on Cardiovascular Outcomes
P11-08175
Schmidt M, Christiansen CF, Mehnert F, Rothman KJ, Sørensen HT. Non-
steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: 
population based case-control study. BMJ. 2011 Jul 4;343:d3450.
P13-04200
Larsen TB, Rasmussen LH, Skjøth F, Due KM, Callréus T, Rosenzweig M, 
et al. Efficacy and safety of dabigatran etexilate and warfarin in "real-world" 
patients with atrial fibrillation: a prospective nationwide cohort study. J Am 
Coll Cardiol. 2013 Jun 4;61(22):2264-73. 
P14-01137
Coloma PM, Valkhoff VE, Mazzaglia G, Nielsson MS, Pedersen L, 
Molokhia M, et al. Identification of acute myocardial infarction from 
electronic healthcare records using different disease coding systems: a 
validation study in three European countries. BMJ Open. 2013 Jun 20;3(6).
R14-0355
Joensen AM, Jensen MK, Overvad K, Dethlefsen C, Schmidt E, Rasmussen 
L, et al. Predictive values of acute coronary syndrome discharge diagnoses 
differed in the Danish National Patient Registry. J Clin Epidemiol. 2009 
Feb;62(2):188-94. 
R14-0358
Madsen M, Davidsen M, Rasmussen S, Abildstrom SZ, Osler M. The 
validity of the diagnosis of acute myocardial infarction in routine statistics: a 
comparison of mortality and hospital discharge data with the Danish 
MONICA registry. J Clin Epidemiol. 2003 Feb;56(2):124-30. 
R14-0393
Kristensen SL, Ahlehoff O, Lindhardsen J, Erichsen R, Jensen GV, Torp-
Pedersen C, et al. Disease activity in inflammatory bowel disease is 
associated with increased risk of myocardial infarction, stroke and 
cardiovascular death--a Danish nationwide cohort study. PLoS One. 
2013;8(2):e56944.
R14-0394
Høgh A, Lindholt JS, Nielsen H, Jensen LP, Johnsen SP. Beta-blocker use 
and clinical outcomes after primary vascular surgery: a nationwide 
propensity score-matched study Eur J Vasc Endovasc Surg. 2013 
Jul;46(1):93-102.
R14-0427
Krarup LH, Boysen G, Janjua H, Prescott E, Truelsen T. Validity of stroke 
diagnoses in a National Register of Patients. Neuroepidemiology. 
2007;28(3):150-4. 

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Strengths and Limitations
●
The Danish national personal identification number allows linkages of several 
different registries, including a cause-of-death registry. Therefore, sudden cardiac 
death occurring in the community can be identified.
●
Linkage to hospital diagnoses will result in reliable ascertainment of hospitalised 
acute myocardial infarction (AMI) events. Use of both hospital discharge diagnoses 
and hospital outpatient diagnoses can provide a reliable but incomplete ascertainment 
of potential arrhythmia events.
●
The prescription registry covers dispensings of reimbursed prescriptions.
●
There is an extensive track record of research in general epidemiology and 
pharmacoepidemiology, including indications and endpoints relevant to this PASS.
●
Overall, uptake of new medications in Nordic countries tends to be slow.