Real-world Treatment of Newly Diagnosed COPD Patients: A Retrospective German Claims Data Analysis
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0)
TITLE PAGE
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
c30035684-01
BI Study Number:
1237-0092
BI Investigational
Product(s):
Not applicable
Title:
Real-world treatment of newly diagnosed COPD patients: A 
retrospective German claims data analysis
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
16 October 2019
PASS:
No
EU PAS register 
number:
Not applicable
Active substance:
ATC code group R03
Medicinal product:
Not applicable
Product reference:
Not applicable
Procedure number:
Not applicable
Joint PASS:
No
Research question and 
objectives:
A. Description of the real-life drug treatment of patients with 
incident COPD, including description of treatment 
sequence/escalation in the first 12/24/36 months after 
incident diagnosis
B. Comparison of initial drug treatment of incident COPD 
patients with two versions of German treatment 
guidelines (2012/2018)
C. Description of exacerbation frequency (severe 
exacerbations associated with an inpatient hospitalization) 
of incident COPD patients in the first 12/24/36 months 
after incident diagnosis

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D. Description of health-care resource use (HCRU; including 
use of oxygen therapy) and direct treatment cost of 
incident COPD patients in the first 12/24/36 months after 
incident diagnosis 
Country(-ies) of study:
Germany
Author:
Marketing authorisation 
holder(s):
MAH contact person:
In case of PASS, add:
<EU-QPPV:>
Not applicable
In case of PASS, add:
<Signature of EU-
QPPV:>
Not applicable
Date:
16 October 2019
Page 1 of 58
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 15
6.
MILESTONES..................................................................................................... 16
7.
RATIONALE AND BACKGROUND................................................................ 17
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 19
9.
RESEARCH METHODS .................................................................................... 20
9.1
STUDY DESIGN............................................................................................ 20
9.2
SETTING........................................................................................................ 22
9.3
VARIABLES .................................................................................................. 24
9.3.1
Exposures ................................................................................................ 24
9.3.2
Outcomes................................................................................................. 25
9.3.2.1
Primary outcomes..................................................................................25
9.3.2.2
Secondary outcomes..............................................................................30
9.3.3
Covariates................................................................................................ 36
9.4
DATA SOURCES........................................................................................... 36
9.5
STUDY SIZE.................................................................................................. 36
9.6
DATA MANAGEMENT................................................................................ 36
9.7
DATA ANALYSIS......................................................................................... 37
9.7.1
Main analysis........................................................................................... 37
9.8
QUALITY CONTROL................................................................................... 40
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 40
9.10
OTHER ASPECTS ......................................................................................... 40
9.11
SUBJECTS...................................................................................................... 40
9.11.1
Cases........................................................................................................ 41
9.11.2
Controls................................................................................................... 41
9.12
BIAS................................................................................................................ 41
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 42

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10.1
PRINCIPLES OF GOOD RESEARCH PRACTICE ..................................... 42
10.2
PATIENT INFORMATION AND CONSENT.............................................. 42
10.3
INDEPENDENT ETHICS COMMITTEE (IEC)........................................... 42
10.4
CONFIDENTIALITY..................................................................................... 42
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 43
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 44
13.
REFERENCES .................................................................................................... 45
13.1
PUBLISHED REFERENCES......................................................................... 45
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 47
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 48
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 55

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001-MCS-90-124_RD-01 (4.0)
2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ATC
Anatomical Therapeutic Chemical / Defined Daily Dose Classification
BI
Boehringer Ingelheim
BMI
Body-Mass-Index
CAT
COPD Assessment Test
CCI
Charlson Comorbidity Index
CI
Confidence Interval
COPD
Chronic obstructive pulmonary disease
CRO
Clinical Research Organization
DALYs
Disability-Adjusted Life Years
DDD
Defined Daily Dose
DMP
diseases management program
EBM
Einheitlicher Bewertungsmaßstab
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
EU PAS 
(register)
European Union electronic Register of Post-Authorisation Studies
FEV(1)
Forced expiratory volume (in 1 second)
GLM
Generalized Linear Model
GOLD
Global initiative for chronic obstructive lung disease
GONr
Gebührenordnungs-Nr.
GP
General Practitioners
GPP
Good Pharmacoepidemiology practices
GVP
Good pharmacovigilance practices
HCRU
Health care resource use
HRQoL
Health-related quality of life
IC
Informed Consent
ICD
International Statistical Classification of Diseases and Related Health 
Problems
ICH-GCP
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
ISPE
International Society for Pharmacoepidemiology 
ISPOR
International Society for Pharmacoeconomics and Outcomes Research
KM
Kaplan-Meier
LABA
Long-acting beta agonist
LAMA
Long-acting muscarinic antagonist
LOCF
Last observation carried forward

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LTOT
Long-Term Oxygen Therapy
MedDRA
Medical Dictionary for Drug Regulatory Activities
mMRC
Modified Medical Research Council
NIS
Non-interventional study
OPS
Operationen- und Prozedurenschlüssel
PASS
Post-authorisation safety study 
PhRMA
Pharmaceutical Research and Manufacturers Association
PY
Patient year
PZN
Pharmazentralnummer
QALYs
Quality added life years
SABA
Short-acting beta antagonist
SAMA
Short-acting muscarinic antagonist
SD
Standard Deviation
SI
Study Investigator
WHO
World-Health Organization

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3.
RESPONSIBLE PARTIES
Function
Name
Affiliation
Project  Manager
Medical Project Member
TCM
Study Coordinator GPV
Scientific advisor
Scientific advisor
Scientific advisor
Scientific Lead
Main Project Management
Claims Data Management
Study investigators / Study 
sites 
NA
NA

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
COPD medication of any type
Name of active ingredient:
COPD medication of any type, 
ATC code R03
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
16 Oct 2019
1237-0092
1.0
Not applicable
Title of study:
Real-world treatment of newly diagnosed COPD patients: 
A retrospective German claims data analysis
Rationale and 
background:
In terms of COPD drug therapy, the current German COPD guideline 
(S2) [1, 2] recommends a treatment escalation procedure. For incident 
COPD patients (for the sake of simplicity, newly diagnosed and so far 
treatment naïve COPD patients will be referred to as “incident COPD 
patients” in the following), the German guideline recommends the 
following:

No treatment (low symptom burden)

SABA or SAMA 

LABA or LAMA or LABA+LAMA.
All other treatments, particularly combination treatments including 
ICS1, are only recommended as escalation therapy. 
Currently, knowledge on real world treatment of incident COPD 
patients in Germany is sparse, in particular regarding the frequency of 
different drug therapy prescriptions and the frequency of early therapy 
escalation including ICS.
This study aims to address this issue by reporting treatment of incident 
COPD patients in the real world. COPD and treatment associated 
outcomes, especially severe exacerbations (leading to hospitalization), 
health-care resource use, and early use of oxygen therapy, will be 
explored. In addition, real-world treatment of incident COPD patients 
will be compared to German guidelines, using current 2018 guidelines 
and 2012 guidelines as framework in two scenario calculations.
                                                
1 ICS is recommended by the guideline for COPD patients with an asthmatic component. Based on 
inclusion/exclusion criteria as applied in this study, these patients will be excluded from analysis.

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
COPD medication of any type
Name of active ingredient:
COPD medication of any type, 
ATC code R03
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
16 Oct 2019
1237-0092
1.0
Not applicable
Research question 
and objectives:
A.
Description of the real-life drug treatment of patients with 
incident COPD, including description of treatment 
sequence/escalation in the first 12/24/36 months after incident 
diagnosis
B.
Comparison of initial drug treatment of incident COPD patients 
with two versions of German treatment guidelines (2012/2018)
C.
Description of exacerbation frequency (severe exacerbations 
associated with an inpatient hospitalization) of incident COPD 
patients in the first 12/24/36 months after incident diagnosis
D.
Description of health-care resource use (HCRU; including use 
of oxygen therapy) and direct treatment cost of incident COPD 
patients in the first 12/24/36 months after incident diagnosis 
Study design:
A retrospective analysis will be done based on a claims dataset 
delivered by a German sickness fund (so far, a cooperation with 
 (approximately 3.2 million insured persons) is planned; a 
second sickness fund might be included as well). The dataset will 
cover the period 01/01/2013-30/06/20182, and will only include 
patients who were continuously insured within the sickness fund 
between the entire period (death is the only exception)3. In selected 
analyses, incident COPD patients will be observed for an exact follow-
up period of 12 months (in subgroup analyses: 24 and 36 months); 
censoring of patients will only be done in case a patient died during the 
respective follow-up period. 
 
 
                                                
2 If more data will be available until time of analysis start, further quarters (from 2018) will be included into the 
analysis. The Steering Board of the study will discuss whether it is meaningful to include additional date from 
2010/2011/2012 taking into account that a ministry approval would be necessary in that case.
3 Continuous insurance is necessary, to not accidently include patients twice in case they left the sickness fund 
intermediately and went back later on and are included within the dataset with two different pseudo numbers.    

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BI Study Number 1237-0092
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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
COPD medication of any type
Name of active ingredient:
COPD medication of any type, 
ATC code R03
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
16 Oct 2019
1237-0092
1.0
Not applicable
Population:
The following inclusion criteria apply:

All patients who were continuously insured by the sickness fund 
for the entire period (01/01/2013-30/06/2018) or, in case a patient 
deceased after index date, for the time until death4

A patient will be included as an incident COPD patient if either a 
hospital documented at least one COPD diagnosis (ICD-10 J 44.-) 
or a specialist (pneumologist) documented at least 2 confirmed 
COPD diagnoses (above ICD-10 code) in two different quarters; 
the first of the above diagnoses is defined as index diagnosis; 
inclusion period is defined as lasting from 01/01/2014 until 
30/06/20175

Patients should not have received any COPD diagnosis (ICD-10 
J44.-) or any COPD-associated medication (Suppl. Table 26) in the 
12 months pre-index period

Patient should have, at date of incident COPD diagnosis (index 
date), an age of at least 40 years
In the planned analyses, different subpopulations with regard to 
follow-up time and availability of disease management program 
(DMP) data will be defined.
                                                
4 Patients censored due to their death will be included as well including reporting of their baseline 
characteristics.
5 Please note: Based on all patients with at least one confirmed outpatient or inpatient COPD diagnosis (from 
specialists, GPs and/or hospitals), an attrition chart will show how many patients are subsequently excluded 
because of the applied inclusion/exclusion criteria.
6 Prescription of systemic/oral corticosteroids (SCS/oral) will not be considered as exclusion criteria

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
COPD medication of any type
Name of active ingredient:
COPD medication of any type, 
ATC code R03
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
16 Oct 2019
1237-0092
1.0
Not applicable
Variables:
Baseline characteristics (referring either to index date = date of 
incident (first) diagnosis of COPD, or to 12 months pre-index period)

Age

Gender

Concomitant diseases /comorbidity level
o
Most frequently observed 10 diseases, based on 
recorded ICD-10 codes up to 3rd level
o
Charlson Comorbidity Index (CCI)
o
Percentage of patients with at least one confirmed 
inpatient or two confirmed outpatient diagnoses in two 
different quarters of the following diseases:

Asthma 

Bronchiectasis

Bronchial carcinoma

Diabetes mellitus

Congestive heart failure

Moderate to severe kidney disease

Myocardial infarction

Hypertension

Peripheral vascular disease

Cerebrovascular event or transient ischemic 
attack

Hemiplegia

Dementia

Sleep apnoea

Osteoporosis
o
Percentage of patients with at least one confirmed 
inpatient or two confirmed outpatient diagnoses in two 
different quarters of the following respiratory diseases:

ICD-10 codes J0-J99 (Top-5 diseases)

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
COPD medication of any type
Name of active ingredient:
COPD medication of any type, 
ATC code R03
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
16 Oct 2019
1237-0092
1.0
Not applicable

Previous drug treatment in the pre-index period, based on 
appropriate ATC group level
o
Percentage of patients who received specific treatments 
(most common 10 treatments as observable for above 
samples) with at least two prescriptions in the pre-index 
period.
Documentation referring to the 12 months follow-up after index date 
(for patient subgroups: 24 months/36 months follow-up, or complete 
follow-up period)

For patients with available data resulting from a disease 
management program (DMP)
o
Weight [kg] (reported MIN, MAX and MEAN during 
follow-up period)
o
Height [cm]
o
Blood pressure (reported MIN, MAX and MEAN 
during follow-up period)
o
Non-drug treatment recommendations
o
Exacerbations (number and severity)
o
FEV1 (reported MIN, MAX and MEAN during follow-
up period)
o
Smoking status if applicable

Drug treatment with long-acting bronchodilators (incl. separate 
reporting for respective agent classes beta-agonists, 
anticholinergics, methylxanthines) 

Drug treatment with short-acting agents

Drug treatment with anti-inflammatory drugs (ICS, PDE-4, 
macrolides)

Top-10 prescribed non-COPD drug therapies (based on ATC 
codes on appropriate level)

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
COPD medication of any type
Name of active ingredient:
COPD medication of any type, 
ATC code R03
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
16 Oct 2019
1237-0092
1.0
Not applicable

Antibiotics for systemic use (based on ATC J02AA)

Antibiotics in combination with corticosteroids (based on ATC 
D07C) 

Systemic/oral corticosteroids (SCS/OCS; based on ATC
R01AD02; D07AA01; D10AA02; H02AB04)

All-cause hospitalizations
o
Among them: hospitalizations with COPD as main 
diagnosis (ICD-10 J44.-)

Among them: hospitalizations with a COPD exacerbation as 
main diagnosis (ICD-10 J44.1)

Exacerbations as documented by outpatient pneumologists 
(ICD-10 J44.1)

GP visits and pneumologists’ visits and visits to other 
specialists

Prescription of COPD-associated aids
o
Oxygen therapy

Date of death, if patient died during follow-up period (for 
censoring and time to event analyses).
Data sources:
This retrospective study is an analysis of an anonymized claims dataset 
provided by the
 and potentially a second sickness fund 
(approval still pending).
Study size:
Based on an initial feasibility assessment done by 
 N>40,000
incident COPD patients meeting above inclusion/exclusion criteria can 
be expected. 

Among them, about 26,000 (~65%) received at least one 
prescription of a long-acting bronchodilator in the 12 months 
follow-up period

Percentage of incident patients with at least one DMP 
documentation (providing more detailed information for 
additional analysis) is about 30%. Among the DMP patients, 
about 4,000 incident patients can be expected with at least one 
prescription of a long-acting bronchodilator in the 12 months 
follow-up period. It needs to be evaluated during the study 
whether the DMP data can be used for study purposes, which 
would require a start of DMP documentation early after the 
incident COPD diagnosis.

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Protocol for non-interventional studies based on existing data
BI Study Number 1237-0092
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Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
COPD medication of any type
Name of active ingredient:
COPD medication of any type, 
ATC code R03
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
16 Oct 2019
1237-0092
1.0
Not applicable
Data analysis:

Descriptive statistics will mainly be applied in this study. For 
categorical (including dichotomous) variables, frequencies, 
percentages and 95% confidence intervals (CIs) will be 
reported, along with corresponding sample sizes. Continuous 
variables will be summarized using mean, standard deviation, 
median, ranges and 95% CIs along with corresponding sample 
sizes. 

Statistical comparisons of socio-demographic and clinical 
characteristics will be conducted between different patient 
groups, e.g. patients with different comorbidity profile or 
therapy. Comparisons will be done based on appropriate tests, 
e.g. Chi-square tests, Fisher’s exact tests, t-tests or a suitable 
non-parametric tests.

Time to event analyses will be done based on a Kaplan Meier 
(KM) methodology; comparisons between groups will be done 
using Log Rank tests.
Milestones:

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5.
AMENDMENTS AND UPDATES
None

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6.
MILESTONES
Milestone
Planned Date
Draft of study protocol
First Steering Board 
Meeting
Final study protocol & 
approval by
Start of data collection
(Start of data access/ data 
validation)
End of data collection
(End of data analyisis)
Final report of study results
(Final Steering Board 
Meeting)
Finalization of publication 
drafts

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7.
RATIONALE AND BACKGROUND
In terms of chronic obstructive pulmonary disease (COPD) drug therapy, the current German 
COPD guideline (S2) [1] recommends a treatment escalation procedure (Figure 1). For 
incident COPD patients (for the sake of simplicity, newly diagnosed and so far treatment 
naïve COPD patients will be referred to as “incident COPD patients” in the following), the 
guideline recommends the following:

No treatment (low symptom burden) or

Short-acting beta antagonist (SABA) or short-acting muscarinic antagonist (SAMA) 
or 

Long-acting beta agonist (LABA) or long-acting muscarinic antagonist (LAMA) or 
LABA+LAMA.
All other treatments, particularly combination treatments including inhaled corticosteroids 
(ICS), are only recommended as escalation therapy. However, despite the increasing evidence 
(e.g. WISDOM study [3], FLAME study [4]), there might exist the view that early use of ICS 
in the treatment of COPD might be advisable, and might be prescribed in a substantial 
percentage of COPD-incident patients.
Treatment recommendations with regard to COPD stages, according 
Figure 1
to German 2018 S2 guideline [1]

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Currently, knowledge on real world treatment of incident COPD patients in Germany is 
sparse, in particular regarding the frequency of different drug therapy prescriptions and the 
frequency of early therapy escalation including ICS. With the current analyses, we aim to 
emphasize the central role of LAMA/LABA therapy in COPD and importance of treatment 
guideline adherence. 
This study aims to address the question of guideline adherence by reporting treatment of 
incident COPD patients as well as description of COPD-associated outcomes, especially 
severe exacerbations leading to hospitalization. In addition, real-world treatment of incident 
COPD patients will be compared to German guidelines, using current 2018 guidelines and 
2012 guidelines as framework in two scenario calculations. The results of this study could 
serve as basis for the tailored development of managed care projects together with payers.  

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8.
RESEARCH QUESTION AND OBJECTIVES
The main research questions of this study can be summarized as follows:
PRIMARY

Description of the real-life drug treatment of patients with incident COPD, including 
description of treatment sequence/escalation in the first 12/24/36 months after 
incident diagnosis
SECONDARY

Comparison of initial drug treatment of incident COPD patients with two versions of 
German treatment guidelines (2012/2018)

Description of exacerbation frequency (severe exacerbations associated with an 
inpatient hospitalization) of incident COPD patients in the first 12/24/36 months after 
incident diagnosis

Description of health-care resource use (HCRU; including use of long-term oxygen 
therapy (LTOT)) and direct treatment cost of incident COPD patients in the first 
12/24/36 months after incident diagnosis

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
A retrospective analysis will be done based on a claims dataset delivered by two German
sickness funds (so far, a cooperation with
 is planned, second sickness fund needs 
to be named yet). The dataset will cover the period 01/01/2013-30/06/20187. In selected 
analyses, incident COPD patients will be observed for an exact follow-up period of 12 
months (in subgroup analyses: 24 and 36 months); censoring of patients will only be done in 
case a patient died during the respective follow-up period. 
 
 
The data will be analyzed for a pre-index period (12 months before index diagnosis) and for a 
follow-up period of 12 months after index date. In subgroup analyses, longer follow-ups (24 
and 36 months, and full observation time (up to 54 months8)), are used. Death after index 
diagnosis during the follow-up is the only accepted exception from this rule. For a subsample 
of patients, disease management program (DMP) data might be available. These provide
disease specifics such as forced expiratory volume in 1 second (FEV1) values, specifics of 
prescribed therapy, and exacerbation frequency and severity.
The dataset contains available information on the sociodemographic characteristics of the 
patients, their treatment with prescription aids and medications, their outpatient and inpatient 
treatment, and COPD-specific clinical parameters for the patients who participated in a 
disease management program (DMP). A first overview of data generally available in claims 
data of a German sickness fund is given in Table 1. The study-specific data set (required data 
according to approved study protocol) needs to be approved by the respective sickness funds, 
based on the study objectives and the respective methodology as outlined in this protocol.
                                                
7 If more data will be available until time of analysis start, further quarters (from 2018) will be included into the 
analysis.
8 If more data will be available until time of analysis start, further quarters (from 2018) will be included into the 
analysis.

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Data generally available in the claims data set
Table 1
Sociodemo-
graphic 
characteristics
Inpatient care
Outpatient care
Outpatient medication 
(prescriptions only)
Other data
Age
Data about initial 
diagnoses 
including day of 
admission
All physicians‘ visits 
including type of 
physician (esp. GPs 
and specialists in 
different specialist 
groups)
Type of medication 
(medication number – in 
Germany: PZN), ATC 
code, number of packs, 
dates of prescription and 
of dispensing pharmacy
Costs for outpatient 
devices/other supportive 
measures
Outpatient surgeries
Gender
All documented 
diagnoses/ 
procedures
Documentation of 
diagnoses/ measures 
(EBM, GONr, OPS)
Prescribing physician
Other services paid by the 
insurance, e.g. salary co-
payments etc. and Costs of 
other diagnostic/ 
therapeutic measures
Type of 
insurance
Length of stay in 
days
Description of 
”safety” of 
diagnoses
Medication-specific data 
(DDD, other 
information)
Outpatient/in-patient long-
term care data
Partly: 
Socioecono
mic status
Costs including 
specific DRG
Dates (physician 
visits; all diagnostic/ 
therapeutic 
measures)
Costs; indirectly by 
calculation: patients’ co-
payments
Days absent from work
Mortality
Data about 
inpatient/ 
outpatient 
rehabilitation 
clinic stays/other 
follow-up 
measures
Costs of outpatient 
care based on 
activity points 
documented by 
doctors
Partly DMP data: FEV1, 
need for COPD 
medication, exacerbations 
(Suppl. Table 1)
For the claims data analysis, 
 will involve its university-affiliated partner, 
 
 has a 
longstanding experience in claims data analyses.
 will close a contract with the 
cooperating sickness funds. This includes a detailed and mutually agreed list defining data 
extraction inclusion/exclusion criteria as well as all variables and formats to be used. 
Moreover, the contract outlines which data protection measures need to be implemented by 
 The sickness funds will participate in the Steering Board of the study as well as being 
a co-author of all future publications of study results. The general model of cooperation is 
shown in Figure 2.

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General study organization
Figure 2
In a first meeting of the Steering board, the study protocol draft will be discussed and, finally, 
be approved. After the approval of the steering board, the protocol will be submitted to the 
cooperating sickness funds and BI for final approval. 
9.2
SETTING
An anonymized dataset from the cooperating sickness funds, which includes all patients with 
at least one COPD diagnosis, who were insured by this sickness funds for the entire period 
(01/01/2013 - 30/06/2018) will be available.
A patient will be confirmed as being COPD-incident if specialists documented at least two 
confirmed outpatient COPD diagnoses (ICD J44.-) and/or at least one inpatient COPD 
diagnosis (ICD J44.-), without such diagnoses in the previous 12 months and without any 
COPD prescription in the previous 12 months (Suppl. Table 2).  
Specific inclusion criteria can be described as follows:

All patients should have been covered by the sickness fund for the entire period 
(01/01/2013-30/06/2018) or, in case a patient deceased after index date, for the time 
until death

A patient will be included as an incident COPD patient if either a hospital 
documented at least one COPD diagnosis (ICD-10 J44.-) or a specialist 
(pneumologist) documented at least two confirmed COPD diagnoses (above ICD-10 
code) in two different quarters; the first of the above diagnoses is defined as index 
diagnosis; inclusion period is defined as lasting from 01/01/2014 until 30/06/2017 

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
Patients should not have received any COPD diagnosis (ICD-10 J44.-) or any COPD-
associated medication (Suppl. Table 2)9 in the 12 months pre-index period

Patient should have, at date of incident COPD diagnosis (index date), an age of at 
least 40 years
Patients who received at least one confirmed inpatient asthma diagnosis or two confirmed 
outpatient diagnoses of asthma (ICD-10: J45.-) by pneumologists after the incident COPD 
diagnosis (index diagnosis) will be separately observed.
Based on these inclusion/exclusion criteria, the following data sets will be analyzed 
(Figure 3)10:

COPD-FULL DATA: All incident COPD patients with a follow-up of up to 54 
months

COPD-12: All incident COPD patients with a follow-up11 of 12 months since index 
date

COPD-24: All incident COPD patients with a follow-up of 24 months since index 
date

COPD-36: All incident COPD patients with a follow-up of 36 months since index 
date

COPD DMP-FULL DATA: All incident COPD patients with available DMP data (at 
least one entry during 3 months after index date12) and a follow-up of up to 54 
months.

COPD DMP-12: All incident COPD patients with available DMP data (at least one 
entry during 3 months after index date) and a follow-up of 12 months since index date

COPD DMP-24: All incident COPD patients with available DMP data (at least one 
entry during 3 months after index date) and a follow-up of 24 months since index date

COPD DMP-36: All incident COPD patients with available DMP data (at least one 
entry during 3 months after index date) and a follow-up of 36 months since index 
date.
                                                
9 Prescription of systemic/oral corticosteroids (SCS/OCS) will not be considered as exclusion criteria
10 Please note that this samples will not include patients with at least one confirmed inpatient or two confirmed 
outpatient diagnoses of asthma (ICD-10: J45.-) by pneumologists after the incident COPD diagnosis (index 
diagnosis) during the follow-up period. Those patients will be described separately. 
11 Time since patient-individual index date until 30/06/2018; patients who died within this period will not be 
excluded from the analysis
12 So far it is unknown how many patients were included in the DMP directly after incident diagnosis and for 
how many patients an entry in the first months after diagnosis will be available. Thus, depending on the pattern 
that will be observed in the data, the restriction „at least one entry during the 3 months after index date“ might 
be extended to „at least one entry during the 6/12 months after index date“.

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Baseline period, inclusion period, follow-up period for different study 
Figure 3
samples
(note: for time to event analyses, COPD-full data sample (with full follow-up times) 
will be applied). DMP: disease management program (refers to the subsample of 
patients who participate in the COPD DMP and thus provide more detailed data)
9.3
VARIABLES
9.3.1
Exposures
For all above samples, baseline characteristics will be described. These refer either to index 
date (= date of incident (first) diagnosis of COPD) or to the 12-month pre-index period:

Age

Gender

Concomitant diseases /comorbidity level
o
10 most frequently documented diseases, based on recorded ICD-10 codes up 
to 3rd level
o
Charlson Comorbidity Index (CCI, see Suppl. Table 3)
o
Percentage of patients with at least one confirmed inpatient or two confirmed 
outpatient diagnoses in two different quarters of the following diseases:

Asthma (J45.)

Bronchiectasis (J47.)

Bronchial carcinoma (C34.)

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
Diabetes mellitus (E10.-E14.)

Congestive heart failure (I11., I50.)

Kidney disease (N17.-N19.)

Myocardial infarction (I21., I22.)

Hypertension (I10.-I15.)

Peripheral vascular disease (I73., I74., I77.)

Cerebrovascular event or transient ischemic attack (I60.-I69., G45.)

Hemiplegia (G81.)

Dementia (F00.-F03.)

Sleep apnoea (G47.3)

Osteoporosis (M80., M81.)
o
Percentage of patients with at least one confirmed inpatient or two confirmed 
outpatient diagnoses in two different quarters of the following respiratory 
diseases: ICD-10 codes J0-J99 (Top-5 diseases as observable for sample 
COPD-12 and COPD-FULL SAMPLE will be reported)
o
Previous drug treatment in the pre-index period, based on appropriate ATC 
group level

Percentage of patients who received specific treatments (most common 
10 treatments as observable for above samples) with at least two 
prescriptions in the pre-index period
9.3.2
Outcomes 
9.3.2.1
Primary outcomes
The primary objective of this study is to describe the real-life drug treatment of patients with 
incident COPD, including description of treatment sequence/escalation in the first 12/24/36 
months after incident diagnosis. This analysis will be based on the following samples:

COPD-12: All incident COPD patients with a follow-up of 12 months since index 
date (analysis will be done for the first 12 months of observation)

COPD-24: All incident COPD patients with a follow-up of 24 months since index 
date (analysis will be done for the first 24 months of observation)

COPD-36: All incident COPD patients with a follow-up of 36 months since index 
date (analysis will be done for the first 36 months of observation)

COPD FULL DATA: All incident COPD patients. (analysis will be done for the full 
observation period)

COPD DMP-12: All incident COPD patients with available DMP data (at least one 
entry after index date) and a follow-up of 12 months since index date (analysis will be 
done for the first 12 months of observation)

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In this analysis, baseline treatment as well as treatment cascades including mean duration of 
treatment in the pre-defined follow-up periods will be assessed. Results will be reported as 
follows:

Mean number of different agents an observed patient received (per patient year)13

List of most frequently prescribed agents (based on Suppl. Table 2) including 
percentage of patients who received these agents

Longitudinal analysis of treatment patterns/cascades with long-acting bronchodilators 
and ICS, as described in Table 2. Here, proportion of observed patients whose 
treatment can be described by the pre-defined treatment patterns will be assessed. 
Description of treatment patterns/cascades (template for reported 
Table 2
outcomes)14,15
(please note: below table might not show all theoretically possible treatment patterns. 
In the analysis, based on observed treatment patterns, all treatment pattern 
combinations that were observed in >5% of the patient population will be reported)
Therapy 
pattern after 
index date
1st line
2nd line
3rd line
4th 
line
N (%) 
of 
patients
Mono, no 
switch 
during 
follow-up 
period
LAMA
-
-
-
…
LABA
-
-
-
…
ICS
-
-
-
…
Mono, with 
switch 
LAMA
LABA
-
-
…
LAMA
ICS
-
-
…
LABA
LAMA
LABA
ICS
ICS
LABA
ICS
LAMA
                                                
13 Even if this study is based on fixed follow-up periods, death of some patients during the follow-up period 
might lead to shorter follow-up periods than 12, 24, or 36 months in some patients. That is why above numbers 
will be reported per observed patient year.
14 Analyses will be done for all three defined follow-up periods (12 months, 24 months, 36 months). For major 
treatment patterns, characteristics of respective patients will be described.
15 Switching between different drugs of the same drug class (LAMA,LABA,ICS) will not be taken into account 
for this analysis.

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Description of treatment patterns/cascades (template for reported
Table 2 (cont'd)
outcomes)
(please note: below table might not show all theoretically possible treatment   
patterns. In the analysis, based on observed treatment patterns, all treatment pattern 
combinations that were observed in >5% of the patient population will be reported)
Therapy 
pattern after 
index date
1st line
2nd line
3rd line
4th 
line
N (%) 
of 
patients
Mono, with 
switch to 
dual therapy
LAMA
LAMA+LABA
LAMA+ICS
LABA+ICS
-
-
…
LABA
LAMA+LABA
LAMA+ICS
LABA+ ICS
-
Mono, with 
switch to dual 
therapy and 
subsequent
switch to 
another dual 
therapy
LAMA
LAMA+LABA
LAMA+ICS
LABA+ICS
LAMA+ICS
LAMA+LABA
LABA+ICS
LABA
LABA+LAMA
LABA+ ICS
LAMA+ICS
LABA+ICS
LABA+LAMA
LAMA+ICS
Mono, with 
switch to 
dual therapy 
and 
subsequent 
triple 
therapy
LAMA
LAMA+LABA
LAMA+ICS
LAMA+LABA+ICS
LAMA+LABA+ICS
-
…
LABA
LAMA+LABA
LABA+ ICS
LAMA+LABA+ICS
LAMA+LABA+ICS
-
Mono, with 
switch to 
triple 
therapy
LAMA
LAMA+LABA+ICS
LABA
LAMA+LABA+ICS

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Description of treatment patterns/cascades (template for reported 
Table 2 (cont'd)
outcomes)
(please note: below table might not show all theoretically possible treatment 
patterns. In the analysis, based on observed treatment patterns, all treatment pattern 
combinations that were observed in >5% of the patient population will be reported)
Therapy 
pattern after 
index date
1st line
2nd line
3rd line
4th 
line
N (%) 
of 
patients
Dual 
therapy, no 
switch 
during 
follow-up 
period
LAMA+LABA
-
-
-
…
LABA+ICS
LAMA+ICS
-
-
-
Dual therapy 
with switch to 
another dual 
therapy
LAMA+LABA
LAMA+ICS
LABA+ICS
LAMA+ICS
LAMA+LABA
LABA+ICS
LABA+ICS
LAMA+LABA
LAMA+ICS
Dual therapy 
with switch 
to triple 
therapy
LAMA+LABA
LAMA+ICS
LABA +ICS
LAMA+LABA+ 
ICS
LAMA+LABA+ 
ICS
LAMA+LABA+ 
ICS
-
Triple 
therapy, no 
switch 
during 
follow-up 
period
LAMA+LABA+ICS

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Description of treatment patterns/cascades (template for reported 
Table 2 (cont'd)
outcomes)
(please note: below table might not show all theoretically possible treatment 
patterns. In the analysis, based on observed treatment patterns, all treatment pattern 
combinations that were observed in >5% of the patient population will be reported)
Therapy 
pattern after 
index date
1st line
2nd line
3rd line
4th 
line
N (%) 
of 
patients
Triple 
therapy, de-
escalation 
during 
follow-up
LAMA+LABA+ICS
LAMA+LABA
LAMA+ICS
LABA+ICS
LAMA+LABA
…
Dual 
therapy, any 
downgrading 
during 
follow-up
LABA+ICS
LABA+ICS
LAMA+ICS
LAMA+ICS
LABA+LAMA
LABA+LAMA
LABA
ICS
LAMA
ICS
LABA
LAMA
Others
For the most common Top-5 treatment cascades, duration of treatment of each line of therapy 
as well as characteristics of patients that could be assigned to the specific cascades will be 
reported.
Please note that a specific combination therapy will be assumed to have been prescribed if 
there was a prescription of a respective combination agent. In case separate agents were 
prescribed, two scenarios are applied: (1) A combination treatment is assumed to have been 
prescribed if the respective agents were prescribed at the same day or (2) a combination 
treatment is assumed to have been prescribed if the respective agents were prescribed within 
a 21 days window and a similar prescription behavior was repeated at least one additional 
time (example – assumed LABA+LAMA combination: LABA prescription day 1, 
LAMA day 10, LABA day 91, LAMA day 96). Coverage calculation (days covered by a 
respective treatment pattern) will be based on the defined daily dosage (DDD) of each 
prescription. 
An agent will be considered as discontinued if a supply gap of at least 60 days (sensit ivity 
analysis: 15/30/90 days) is observed. 
In 
an 
additional 
Kaplan 
Meier 
analysis, 
time 
to 
start 
of 
a 
dual 
therapy 
(LAMA+LABA/LABA+ICS/LAMA+ICS) and time to start of a triple therapy 
(LAMA+LABA+ICS) will be assessed (days from incident diagnosis until first day of triple 

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therapy). This analysis will be based on the COPD full data sample, i.e. no fixed follow-up 
period but patient-specific follow-up periods (until end of observational period or until 
censoring or until date of event, whatever comes first) will be applied. 
9.3.2.2
Secondary outcomes
First Secondary
Comparison of initial drug treatment with treatment guidelines
Comparison of real-world treatment of patients with guidelines will be done based on two 
samples: COPD-12 and COPD DMP-12. Assessment will generally be done for two time 
points:

For all patients at index date (+ 4 weeks)

For patients who received a triple combination (LABA+LAMA+ICS) at first day of 
triple therapy prescription.
Prescription patterns will be compared with German treatment guideline recommendations. 
Here, the 2018 S2 guideline [1] will be used (sensitivity analysis: 2012 guideline, which is an 
updated version of the 2006 guideline [2]). Obviously, as patients are only observed until mid 
of 2018, it cannot be expected that they were treated in line with the 2018 S2 guideline. 
However, this analysis describes potential needs to adapt the current treatment of the patients 
in the future, and is as such important for preparation of later initiatives to optimize the 
treatment of the patients.
Based on claims data only, assessment of the severity of the COPD disease for COPD 
patients is hardly possible. The reason is that neither FEV1 data nor symptoms’ data as 
measured by the COPD assessment test (CAT) or the Modified Medical Research Council 
(mMRC) are available in a claims dataset. So, for the comparison of the real-world treatment 
with 2018/2012 guideline recommendations, based on sample COPD-12, the following 
analyses will be done:

COPD-12, at index date
o
Based on the inclusion criteria, an incident COPD patient did not experience 
any exacerbation in the previous 12 months, as no such diagnosis was 
documented. So, the initial treatment with long-acting bronchodilators should 
generally not include use of ICS (both guidelines). Moreover, based on the 
2012 guideline, a therapy with long-acting bronchodilators should start with 
either a LAMA or a LABA, but not with a combination of them. 

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So, 
based 
on 
these 
criteria, 
the 
following 
percentages 
will 
be 
reported:
Percentage of patients not treated in line with 2018 guideline

Therapy 
at 
index 
date 
includes 
ICS
Percentage of patients not treated in line with 2012 guideline

Therapy at index date includes ICS or a LABA/LAMA 
combination or triple therapy of LABA+LAMA+ICS16

COPD-12, at first date of an observed LABA+LAMA+ICS combination, which is not 
the index date
o
According to both guidelines mentioned above, a triple combination treatment 
LABA+LAMA+ICS should only be prescribed if a patient experienced at least 
two exacerbations or one severe exacerbation requiring an inpatient treatment 
in the history of the disease. Based on this, the following percentage will be 
reported:

Percentage of patients not treated in line with the 2012/2018 guideline

Only 1 or less confirmed outpatient diagnoses and no inpatient 
diagnosis of a COPD exacerbation (ICD-10 J44.1) before date 
of prescription of a triple therapy.

COPD-12, for the whole follow-up period (12 months)
o
A treatment intensification (mono to dual therapy, mono to triple or dual to 
triple therapy) should generally be accompanied by a thorough application of 
recommended diagnostic measures, according to the 2012/2018 guidelines. 
For these, typically, general practitioners (GPs) do not have the necessary 
infrastructure. Based on this, the following percentage will be reported:

Percentage of patients who received a treatment intensification without 
any previous visit of a pneumologist or hospital (same quarter or 
previous quarter)
Sensitivity analysis
In a first sensitivity analysis, those of above patients will be included for whom at least one 
ICD-10 COPD code that provides information up to the 5th level is documented: These 
subcodes include information about FEV1 level. For patients for whom such a subcode is 
available, in this analysis, disease severity will be defined based on this information, which is
mainly important when applying the 2012 guideline. 
                                                
16 Of those patients starting with triple therapy of LABA+LAMA+ICS at time of incident COPD diagnosis, 
physician visits (separately of cardiologists, pneumologists) and measures of lung function (DMP-dataset only) 
before or at index date will be reported. Time since last physician visits to a cardiologist or a pneumologist will 
be reported too. 

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In a second sensitivity analysis, the sample COPD DMP-12 will be analyzed. In the DMP 
data set, additional documentation about exacerbation history and FEV1 is available. Based 
on these data, the following analyses are planned:

COPD DMP-12, at index date: no additional analysis, as DMP data will not be 
available for the pre-index period

COPD DMP-12, at first date of an observed LABA+LAMA+ICS combination, which 
is not the index date; patients for whom at least one DMP entry before date of 
prescription of above combination will be included
o
According to both above guidelines, a triple combination treatment 
LABA+LAMA+ICS should only be prescribed if a patient experienced at least 
2 exacerbations or one severe exacerbation requiring an inpatient treatment in 
the history of the disease. In addition, the 2012 guideline also recommended 
such a treatment in case a FEV1<50% could be observed. Based on this, the 
following percentages will be reported:

Percentage of patients not treated in line with the 2018 guideline

Only one or no confirmed outpatient diagnosis and no inpatient 
diagnosis of a COPD exacerbation (ICD-10 J44.1) before date 
of prescription of a triple therapy.

Percentage of patients not treated in line with the 2012 guideline

Only one or no confirmed outpatient diagnosis and no inpatient 
diagnosis of a COPD exacerbation (ICD-10 J44.1) and only one 
or no  outpatient diagnosis and no inpatient exacerbation 
diagnoses as documented in the DMP dataset and no 
documented FEV1 value <50%.
Second Secondary
Description of exacerbation frequency
For all samples (COPD-12, COPD-24, COPD 36, COPD DMP-12, COPD DMP-24, COPD 
DMP-36, COPD-FULL DATA), exacerbation frequency in the pre-defined follow-up periods 
(12 months, 24 months, 36 months, patient-individual follow-up times) will be described. 
Because of the higher diagnosis validity, in the main analysis only severe exacerbations 
leading to an inpatient hospitalization (COPD exacerbation documented as main diagnosis: 
ICD-10 J44.1) will be considered. Moreover, in a separate analysis proxies will be used to 
estimate non-severe exacerbations. Therefore prescriptions of SCS/OCS either separately or 
in combination with antibiotics, will be considered as proxy for the treatment of a non-severe 
exacerbation (without an inpatient hospitalization). Exacerbation frequency (once for severe 
and once for non-severe exacerbations) will be reported as percentage of patients having 
experienced at least 1 exacerbation, exactly 1 exacerbation, exactly 2 exacerbations, exactly 3 
exacerbations, and >3 exacerbations, and as mean number of exacerbations per observed 
patient-year. 
 
  

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Third Secondary
Description of health care resource use and direct treatment cost
Health care resource use (HCRU) and direct cost will be reported as described in Table 3, 
based on the perspective of a German sickness fund and based on prices of the respective 
years as reported in the claims data base. HCRU and cost will be reported for the following 
samples in separate analyses: COPD-12, COPD-24, and COPD-36.
Generally, HCRU/cost will be reported per observed patient year. HCRU and cost will be 
compared between the following patient groups:

Patients participating in a DMP versus those who did not participate

Patients having received early (first 3 months after index date) a triple combination 
therapy (LABA+LAMA+ICS) versus those who did not.
In a separate analysis based on COPD-36 sample, cost during the first year after incident 
COPD diagnosis will be compared with costs in the second and third year after incident 
diagnosis. 
HCRU and direct healthcare cost definition
Table 3
Item
HCRU
Cost
COPD medication
Nb. of prescriptions for medications as 
reported in Suppl. Table 2, per agent type
Nb. of prescribed DDDs for medications as 
reported in Suppl. Table 2, per agent type
Drug cost (based on list 
prices) for medications as 
reported in Suppl. Table 2.
Other medications
Nb. of non COPD-medications, defined as 
at least 2 prescriptions of an agent (on third 
level of ATC groups)
Antibiotics for systemic use (ATC J02AA) 
and antibiotics in combination with 
corticosteroids (ATC D07C) 
Drug cost of prescribed 
non-COPD medications
Outpatient treatment
Nb. of GP visits
Nb. of pneumologist visits
Nb. of other outpatient specialist visits
Cost of outpatient visits as 
defined in the HCRU 
column, based on the proxy 
of “treatment points”
Hospitalizations
Nb. of hospitalizations with a COPD-
exacerbation (J44.1) including mean 
duration of stay in days
Nb. of hospitalizations with any COPD 
diagnosis as main diagnosis (J44.-) 
including mean duration of stay
Other non-COPD hospitalizations including 
mean duration of stay in days
Time to first all-cause hospitalization
Cost for hospitalizations as 
defined in the HCRU 
column
Long-Term Oxygen 
Therapy (LTOT)17
Number of patients who received LTOT
Mean/median time from incident COPD 
diagnosis until start of LTOT for those 
patients
Cost for LTOT
                                                
17 J96.1, Z99.0, Z99.1, Z99.8, Z99.9, Z46.8, Z46.9 (ICD-10-GM-2018); 8-712.1, 8-713.0, 8-716 (OPS 2016)

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9.3.3
Covariates
9.4
DATA SOURCES
An analysis based on anonymous claims data provided by two cooperating German sickness 
funds (planned: 
+ one additional sickness fund) covering the years 2013 - 2017 
will be conducted. German claims data are a valid and often used source for health-economic 
analyses [5, 6, 7, 8, 9, 10, 11]. Validity of recording and coding can be evaluated as high in 
these databases. This is especially the case for any inpatient and prescription data because 
these data are directly relevant for reimbursement of hospitals/pharmacies by sickness funds. 
One of the main strengths of a claims data analysis are the use of an unselected large patient 
sample. This allows us to define cohorts, which are adequately powered to address the issues 
we are exploring. 
For the claims data analysis, 
 will involve its university-affiliated partner, the 
 will close a contract with the cooperating sickness fund. This includes a 
detailed and mutually agreed list of a data extraction manual defining inclusion/exclusion 
criteria as well as all variables and formats to be used. Moreover, it outlines which data 
protection measures need to be implemented by 
 The sickness funds will participate in 
the Steering Board of the study as well as being a co-author of all future publications of study 
results.
For a subsample of patients, disease management program (DMP) data might be available. 
These provide disease specifics such as FEV1 values, specifics of prescribed therapy, and 
exacerbation frequency and severity. Respective subsamples with availability of DMP data 
have been defined.
9.5
STUDY SIZE
Based on an initial feasibility assessment/previous study done by 
based on the 
dataset only, N>40,000 incident COPD patients meeting above inclusion/excl
 
criteria can be expected. Among them, about 26,000 (~65%) received at least one 
prescription of a long-acting bronchodilator in the 12 months follow-up period. Percentage of 
incident patients with at least one DMP documentation (providing more detailed information 
for additional analysis) is about 30%.
9.6
DATA MANAGEMENT
 will be responsible for data management, including quality checking of the data. 
Especially, the confidentiality of records that could identify patients within the database must 
be protected, respecting the privacy and confidentiality rules in accordance with the 
applicable regulatory requirement(s). Confidentiality is ensured by pseudonymizing of the 
dataset. A data protection plan will be in place ensuring that no data will be transferred to 
third parties and that access to data will be granted only to the core project team. Please note 
that no data but only aggregated study results will be transferred to the steering board of thi s 
study. The data protection plan is based on applicable German law; it is available on request 

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(in German language). Initial data processing will be undertaken using Microsoft SQL Server 
2014 later statistical analyses will be done using SPSS version 20, MS-Excel version 2016, 
and STATA version 14.1. 
9.7
DATA ANALYSIS
9.7.1
Main analysis
Generally, for all analyses specific samples will be used; these have been defined further 
above. Mainly, descriptive statistics will be applied in this study. Descriptive analysis of the 
data will be performed using summary statistics for continuous and categorical data. 
Continuous data will be described by the number of non-missing values, median, mean, 
range, standard deviation and 95% confidence intervals (CIs). Frequency tables will be 
generated for categorical data. Selected continuous variables will be categorized in a 
clinically meaningful way.
For rates/frequencies related to time periods, that might vary between the patients (e.g. 
shorter follow-up period due to death), respective numbers will be reported per patient-year 
(PY).
Furthermore, time-to-event analyses (Kaplan-Meier curves) will be conducted whenever 
applicable and appropriate. Especially, for the 
 KM curves will 
be evaluated. 
Comparisons for categorical variables will be conducted using either Chi-square tests or 
Fisher’s exact test (when the values in any of the cells of a contingency table are below 5). 
For continuous variables, statistical comparisons will be conducted using t-test or a suitable 
non-parametric test (for variables with skewed distribution). 
 
The main analyses planned are summarized in Table 5. 
Overview of main planned analyses
Table 4
Endpoint/study 
objective
Time period
Main reporting/analyses
PRIMARY: 
Description of 
drug treatment 
of incident 
COPD patients
Different 
follow-up 
periods 
since index 
date
Descriptive statistics (categorical 
variables: frequencies/percentages; 
continuous variables: mean, SD, 
median, ranges and 95% CIs)
Comparisons for categorical 
variables: either Chi-square tests 
or Fisher’s exact test;
Comparison for continuous 
variables: t-test or a suitable 
non-parametric test
Analysis of time to escalation 
therapy (therapy including ICS) 
using KM methodology

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Overview of main planned analyses
Table 4 (cont'd)
FIRST 
SECONDARY: 
Comparison of 
drug treatment with 
2012/18 guidelines
12-
month 
follow-
up since 
index 
date
Reporting of frequency tables 
regarding proportion of patients 
treated in line with guidelines, using 
different criteria as outlined above
Comparisons of patients treated 
in line/not in line with guidelines
Comparisons for categorical 
variables: either Chi-square tests 
or Fisher’s exact test;
Comparison for continuous 
variables: t-test or a suitable 
non-parametric test
Multivariable logistic regression 
to assess independent factors 
associated with treatment 
according to guidelines
SECOND 
SECONDARY: 
Description of 
exacerbation 
frequency
Different 
follow-
up 
periods 
since 
index 
date
Exacerbations as measured by 
inpatient encounters associated with 
respective ICD-10 code and, in 
additional analysis, based on DMP 
samples only, based on inpatient ICD-
10 codes plus DMP documentation:
Number patients with at least one, at 
least two, >2 exacerbations per PY
Time to first exacerbation since index 
date
Comparison of patients 
with/without an exacerbation in 
different follow-up periods
Comparisons for categorical 
variables: either Chi-square tests 
or Fisher’s exact test;
Comparison for continuous 
variables: t-test or a suitable 
non-parametric test
Analysis of time to exacerbation 
using KM methodology
THIRD 
SECONDARY: 
Description of 
HCRU and direct 
cost
Different 
follow-
up 
periods 
based on 
index 
date
HCRU/Cost:
Descriptive statistics for continuous 
variables whereas the numbers will be 
reported on the basis of PY
Comparisons for categorical 
variables: either Chi-square tests 
or Fisher’s exact test;
Comparison for continuous 
variables: t-test or a suitable 
non-parametric test

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Overview of main planned analyses
Table 4 (cont'd)

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9.8
QUALITY CONTROL
The study data management will adhere to pre-defined process guidelines which mainly 
consist of the following elements:

Internal staff engaged in this study will be trained; training will be documented.

A data validation based on a 100% computer-assisted checking of variables/values 
(MIN, MAX, MEAN, MEDIAN, cross-checking of variables etc.) will be done after 
data delivery.
Study design and study conduct will be in line with legal and regulatory requirements, as well 
as with scientific purpose, value and rigor and follow generally accepted research practices 
such as Good Pharmacoepidemiology Practices (GPP) issued by the International Society for 
Pharmacoepidemiology (ISPE), the International Society for Pharmacoeconomics and 
Outcomes Research (ISPOR) guidelines, Pharmaceutical Research and Manufacturers 
Association (PhRMA) guidelines and similar rules.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The main limitation of this claims data analysis is the limited availability of clinical 
information (clinical parameters, prescribed dosages, reasons for prescribing specific agents 
etc.). Information available in claims data is limited to parameters, which are generally 
relevant for reimbursement purposes. Clinical parameters will be only available for patients 
who participate in a DMP, whereas the validity and frequency of these documentations as 
well as the time of first documentation for incident COPD patients need to be checked. For a 
substantial part of the patients, these data might not be valid/available.
In addition to that, the available claims dataset will be a regional dataset, which probably 
covers only the regions of 
. 
9.10
OTHER ASPECTS
Not applicable
9.11
SUBJECTS
In this claims data analysis, patient selection takes place according to pre-defined inclusion 
criteria as outlined above. The overall sample of COPD-incident patients will be divided into 
subgroups, according to minimum follow-up periods and availability of DMP data. The 
assumptions/criteria for the assignment of each patient to the respective subgroups was 
described above.

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9.11.1
Cases
Not applicable
9.11.2
Controls
Not applicable
9.12
BIAS
By nature of the dataset, there does not exist any study site/patient selection bias. As 
 insures selection of persons from
 only, a regional bias might exist
due to the fact that only two specific regions of Germany will be covered. Further only 
patients continuously insured over the study period within the 
 will be included in 
the analysis, as this restriction is necessary for not considering patients multiple times. Thus, 
a potential selection bias is possible and the extent of the resulting effects will be estimated 
by describing the patients who were not continuously insures. Moreover, patients insured by 
the cooperating sickness funds may not be representative of the German COPD patients in 
terms of patient demographics. However, it is planned to involve another sickness fund in this 
study and thus, to cover another region of Germany. Furthermore, due to uniform treatment 
rules treatment of patients will not significantly differ from other regions.

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10.
PROTECTION OF HUMAN SUBJECTS
In this study, anonymous data only will be analyzed. Patient/physician names will remain 
anonymous at any time. All data will be collected and processed with adequate precautions to 
ensure confidentially and compliance with applicable data privacy protection laws and 
regulations.
10.1
PRINCIPLES OF GOOD RESEARCH PRACTICE
The guidelines of Good Clinical Practice developed by the International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH-GCP 
guidelines) will be followed whenever applicable for this cross-sectional patients’ survey.
10.2
PATIENT INFORMATION AND CONSENT
Generally, no informed consent (IC) is needed for this claims data analysis. 
10.3
INDEPENDENT ETHICS COMMITTEE (IEC)
The study protocol will be approved by a Scientific Committee, consisting of external 
experts, the cooperating sickness funds, BI, and 
. Due to the anonymous 
nature of the data, no ethical approval is needed.
10.4
CONFIDENTIALITY
BI as well as all investigators ensure adherence to applicable data privacy protection 
regulation. Data are transferred in encoded / anonymous form only. The entire documentation 
made available to BI does not contain any data, which, on its own account or in conjunction 
with other freely available data, can be used to re-identify natural persons. The investigators 
are obligated to ensure that no documents contain such data. 
All records identifying the subject will be kept confidential and will not be made publicly 
available. Study findings stored on a computer will be stored in accordance with local data 
protection laws.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Not applicable based on secondary use of data without any potential that any employee of BI 
or agent working on behalf of BI will access individually identifiable patient data.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
As part of the policy of German sickness funds, the results of this study need to be published. 
The members of the Steering Board will be authors of those publications. The publication 
strategy includes one full-text manuscript published in a peer-reviewed journal and (optional) 
one conference abstract/poster presented at a medical congress. Current guidelines and 
recommendation on good publication practice will be followed (e.g. GPP2 Guidelines [12], 
STROBE [13]).

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1] Vogelmeier C, Buhl R, Burghuber O, Criée S, Ewig S, Godnic-Cvar J, Harti S, Herth F, 
Kardos P, Kenn K, Nowak D, Rabe KF, Studnicka M, Watz H, Welte T, Windisch W, 
Worth H. S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit chronisch 
obstruktiver Bronchitis und Lungenemphysem (COPD), Deutsche Gesellschaft für 
Pneumologie und Beatmungsmedizin e.V., Deutsche Atemwegslige e.V., 2018. 
https://www.awmf.org/uploads/tx_szleitlinien/020-006l_S2k_COPD_chronisch-
obstruktive-Lungenerkrankung_2018-01.pdf (P19-01450)
[2] Abholz HH, Gillissen A, Magnussen H, Schultz K, Ukena D, Worth H. Nationale 
VersorgungsLeitlinie COPD (Langfassung): Version 1.9. basierend auf der Fassung vom 
Februar 2006, Bundesärztekammer, Kassenärztliche Vereinigung, Arbeitsgemeinschaft 
der Wissenschaftlichen Medizinischen Fachgesellschaften, 2012. 
https://www.leitlinien.de/mdb/downloads/nvl/copd/archiv/copd-vers1.9-lang.pdf 
(P19-09122)
[3] Magnussen H, Disse B, Rodriguez-Roisin R, Kirsten A, Watz H, Tetzlaff K, Towse L, 
Finnigan H, Dahl R, Decramer M, Chanez P, Wouters EFM, Calverley PMA. 
Withdrawal of inhaled glucocorticoids and exacerbations of COPD. 
N Engl J Med 2014;371:1285–1294 (P14-13477)
[4] Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel 
R, Patalano F, Vogelmeier CF. Indacaterol-Glycopyrronium versus Salmeterol-
Fluticasone for COPD. N Engl J Med 2016;374:2222–2234 (P16-05628)
[5] Koltermann KC, Schlotmann A, Schröder H, Willich SN, Reinhold T. Economic burden 
of deep infiltrating endometriosis of the bowel and the bladder in Germany: The 
statutory health insurance perspective. Z Evid Fortbild Qual Gesundhwes 2016;118-
119:24–30 (R19-3303)
[6] Schädlich PK, Schmidt-Lucke C, Huppertz E, Lehmacher W, Nixdorff U, Stellbrink C, 
Brecht JG. Economic evaluation of enoxaparin for anticoagulation in early cardioversion 
of persisting nonvalvular atrial fibrillation: A statutory health insurance perspective from 
Germany. Am J Cardiovasc Drugs 2007;7:199–217 (R19-3305)
[7] Krischak G, Tepohl L, Dannenmaier J, Hartschuh U, Auer R, Kaluscha R.  
Gesundheitsökonomische Effekte der Rehabilitation bei chronischem Rückenschmerz –
Eine Beobachtungsstudie mittels kombinierten Sekundärdaten einer gesetzlichen 
Krankenkasse und der Deutschen Rentenversicherung. Rehabilitation (Stuttg) DOI: 
10.1055/a-0668-4235 (R19-3304)
[8] Gansen FM. Health economic evaluations based on routine data in Germany: A 
systematic review. BMC Health Serv Res 2018;18:268 (R19-3300)

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[9] Hoffmann F. Review on use of German health insurance medication claims data for 
epidemiological research. Pharmacoepidemiol Drug Saf 2009;18:349–356 (R19-3302)
[10] Schubert I, Köster I, Küpper-Nybelen J, Ihle P. Versorgungsforschung mit GKV-
Routinedaten. Nutzungsmöglichkeiten versichertenbezogener Krankenkassendaten für 
Fragestellungen der Versorgungsforschung. Bundesgesundheitsblatt 
Gesundheitsforschung Gesundheitsschutz 2008;51:1095–1105 (R19-3306)
[11] Andersohn F, Garbe E. Pharmakoepidemiologische Forschung mit Routinedaten des 
Gesundheitswesens. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 
2008;51:1135–1144 (R19-3297)
[12] Graf C, Battisti WP, Bridges D, Bruce-Winkler V, Conaty JM, Ellison JM, Field EA, 
Gurr JA, Marx M-E, Patel M, Sanes-Miller C, Yarker YE. Research Methods & 
Reporting. Good publication practice for communicating company sponsored medical 
research: the GPP2 guidelines. BMJ 2009;339:b4330 (R19-3301)
[13] Elm E von, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP.
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 
statement: guidelines for reporting observational studies. Lancet 370;1453-1457  
(R13-2485)

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS

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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 include d 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).
Study title: Real-world treatment of newly diagnosed COPD patients: A retrospective 
German claims data analysis 
Study reference number: xxxxxx
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance

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Section 1: Milestones
Yes
No
N/A
Section 
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection23
6
1.1.2 End of data collection24
6
1.1.3 Study progress report(s)
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
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)
7
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)
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
8
2.1.5 If applicable, that there is no a priori
hypothesis?
8
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?
9.3
3.3
Does the protocol specify measures of
occurrence? (e.g. incidence rate, absolute risk)
9.7
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)
9.7
                                                
23 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.
24 Date from which the analytical dataset is completely available.

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Section 3: Study design
Yes
No
N/
A
Section 
Number
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)
Comments:
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.2
4.2
Is the planned study population defined in terms 
of:
9.2
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication?
4.2.5 Duration of follow-up?
4.3
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
9.2
Comments:
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)
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)
5.3
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
5.4
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
Comments:
This retrospective study is an anonymous data analysis, which is based on prescription 
data only with regard to drug exposure. So specific exposure measurement will not be 
done.

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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
6.2
Does the protocol describe how the outcomes 
are defined and measured? 
9.3
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
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
Comments:
Section 7: Bias
Yes
No
N/
A
Section 
Number
7.1
Does the protocol describe how confounding will 
be addressed in the study?
9.7
7.1.1. Does the protocol address confounding by 
indication if applicable?
7.2
Does the protocol address:
7.2.1. Selection biases (e.g. healthy user bias)
9.11
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias)
9.11
7.3
Does the protocol address the validity of the 
study covariates?
9.7
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
Comments:
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:
9.4
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview)
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)

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Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1.3 Covariates?
9.2
Does the protocol describe the information 
available from the data source(s) on:
9.3
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose, number of days of supply prescription, daily 
dosage, prescriber)
9.2.2 Outcomes? (e.g. date of occurrence, multiple
event, severity measures related to event)
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle)
9.3
Is a coding system described for: 
9.3
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.3 Covariates?
9.4
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)
Comments:
Section 10: Analysis plan
Yes
No
N/
A
Section 
Number
10.1 Is the choice of statistical techniques described? 
9.7
10.2 Are descriptive analyses included?
9.7
10.3 Are stratified analyses included?
10.4 Does the plan describe methods for adjusting for 
confounding?
9.7
10.5 Does the plan describe methods for handling 
missing data?
9.7.2
10.6 Is sample size and/or statistical power 
estimated?
9.7
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? 
9.6
Comments:

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001-MCS-90-124_RD-01 (4.0)
Section 12: Limitations
Yes
No
N/
A
Section 
Number
12.1 Does the protocol discuss the impact on the 
study results of:
9.11/ 9.9
12.1.1 Selection bias?
12.1.2 Information bias?
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)
12.2 Does the protocol discuss study feasibility? 
(e.g. study size, anticipated exposure, duration of follow-up 
in a cohort study, patient recruitment)
9.5
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?
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
Comments:
Name of the main author of the 
protocol:
Date: 
Signature: 

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ANNEX 3. ADDITIONAL INFORMATION
Supplemental Table 1: Variables available for DMP patients
DMP-key
Type
Meaning (German)
Meaning (English)
BETA2.LANG.BEDARF
Boolean1
Bedarf einer kurzfristigen 
langwirksamen Beta-2-
Sympathomimetikatherapie
Need for a short therapy with long-acting beta-2-
sympathomimetics
BETA2.LANG.DAUER
Boolean1
Bedarf einer dauerhaften 
langwirksamen Beta-2-
Sympathomimetikatherapie
Need for a long-lived therapy with long-acting beta-
2-sympathomimetics
BETA2_LANG.KEINE
Boolean1
Keine Langwirksame Beta-2-
Sympathomimetikatherapie 
indiziert
No therapy with long-acting beta-2-
sympathomimetics indicated
BETA2_LANG.KI
Boolean1
Langwirksame Beta-2-
Sympathomimetikatherapie 
kontraindiziert
Long-acting beta-2-sympathomimetics 
contraindicated
ANTI_LANG.BEDARF
Boolean1
Bedarf einer kurzfristigen 
langwirksamen 
Anticholinergikatherapie
Need for a short therapy with long-acting 
anticholinergics
ANTI_LANG.DAUER
Boolean1
Bedarf einer dauerhaften 
langwirksamen 
Anticholinergikatherapie
Need for a long-lived therapy with long-acting 
anticholinergics
ANTI_LANG.KEINE
Boolean1
Keine langwirksame 
Anticholinergikatherapie indiziert
No anticholinergics indicated
ANTI_LANG.KI
Boolean1
Langwirksame 
Anticholinergikatherapie 
kontraindiziert
Anticholinergics contraindicated
COP.STATIONAER
Integer2
Stationäre notfallmäßige 
Behandlungen wegen COPD seit 
der letzten Dokumentation 
(Anzahl)
Emergency inpatient hospitalizations due to COPD 
since last documentation
COP_EINWEISUNG.JA
Integer2
COPD-bezogene Über- bzw. 
Einweisung veranlasst (Anzahl)
COPD-related referral / admission arranged 
(number of)
COP_EINWEISUNG.NEIN
Integer2
COPD-bezogene Über- bzw. 
Einweisung nicht veranlasst 
(Anzahl)
No COPD-related referral / admission arranged 
(number of)
COP_EXA
Integer2
Häufigkeit der COPD 
Exazerbation 
Number of COPD-related hospitalizations
COP_SCHULUNG.NICHT_EMPF
Boolean1
Schulung nicht empfohlen
COPD-related training not recommended
COP_SCHULUNG.NM
Boolean1
Schulung nicht möglich (Fehlende 
Schulungskapazität, 
Krankenhausaufenthalt, private 
Gründe, …)
COPD-related training not possible
COP_SCHULUNG.NW
Boolean1
Schulung nicht wahrgenommen
COPD-related training not participated
COP_SCHULUNG.OK
Boolean1
Empfohlene Schulung(en) 
wahrgenommen
Participated in recommended COPD-related 
training
1Boolean variables represent one of two possible values (e.g. “1” or “0”, “yes” or “no”),
2Integer variables are variables that must take an integer value (0, 1, 2, …)

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Supplemental Table 2: COPD medications available in the German market
Medication class
Agents
ATC-Codes
SABA
Salbutamol
R03AC02
Terbutaline
R03AC03
Fenoterol
R03AC04; R03CC04
Reproterol
R03CC14; R03AC15
LABA
Salmeterol
R03AC12
Formoterol
R03AC13
Indacaterol
R03AC18
Olodaterol
R03AC19
Bambuterol
R03CC12
Clenbuterol
R03CC13
LABA-combi
Clenbuterol, combinations
R03CC63
SABA-combi
Fenoterol and sodium cromoglycate
R03AK03
Salbutamol and sodium 
l
R03AK04
Reproterol and sodium 
l
R03AK05
ICS+LABA
Salmeterol and fluticasone
R03AK06; R03AK61
Formoterol and budesonide
R03AK07; R03AK28; 
R03AK72
Formoterol and beclometasone
R03AK08; R03AK27; 
R03AK71
Vilanterol and fluticasone furoate
R03AK10
Formoterol and fluticasone
R03AK11
SABA+SAMA
Fenoterol and ipratropium bromide
R03AL01
Salbutamol and ipratropium 
b
id
R03AL02
LABA+LAMA
Vilanterol and umeclidinium 
R03AL03
Indacaterol and glycopyrronium 
b
id
R03AL04
Formoterol and aclidinium bromide
R03AL05
Olodaterol and tiotropium bromide
R03AL06
ICS
Beclometasone
R03BA01; R01AD01
Budesonide
R03BA02; R01AD05
Fluticasone
R03BA05; R01AD08
SAMA
Ipratropium bromide
R03BB01; R01AX03
LAMA
Tiotropium bromide
R03BB04
Aclidinium bromide
R03BB05
Glycopyrronium bromide
R03BB06
Umeclidinium
R03BB07
LAMA+LABA+ICS
Glycopyrronium and Formoterol 
d B
l
R03AL09

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Medication class
Agents
ATC-Codes
Methylxanthine
Theophylline
R03DA04
Aminophylline
R03DA05
PDE-4
Roflumilast
R03DX07
Systemic/oral corticosteroids 
1
Prednisolone
R01AD02
Methylprednisolone
D07AA01; D10AA02; 
1for exacerbations

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Supplemental Table 3: Calculation of the Charlson Comorbidity Index (CCI)
No
Comorbidity
Charlson 
Score
ICD-10 Code
1
Coronary artery disease
1
I20.-, I21.-, I22.-, I23.-, I24.-, I25.-
2
Congestive heart failure
1
I11.-, I50.-
3
Peripheral vascular disease
1
I73.-, I74.-, I77.-
4
Cerebrovascular disease
1
G45.-, G46.-, I6.-
5
Dementia
1
F00.-, F01.-, F02.-, F03.-, G30.-
6
Chronic pulmonary disease
1
J4.-, J6.- w/o J67.-, J68.-, J69.-
7
Connective tissue disorder
1
M05.-, M06.-, M07.-, M08.-, M3.-
8
Peptic ulcer disease
1
K25.-, K26.-, K27.-, K28.-
9
Mild liver disease
1
B18.-, K70.-, K73.-, K75.-
10
Diabetes mellitus without complications
1
E109.-, E119.-, E129.-, E139.-, 
E149.-
11
Hemiplegia
2
G81.-, G82.-
12
Moderate or severe renal disease
2
N17.-, N18.-, N19.-
13
Diabetes mellitus with end-organ damage
2
E10.-, E11.-, E12.-, E13.-, E14.- w/o 
[No 10]
14
Tumor without metastases, leukemia, 
lymphoma, multiple myeloma
2
C% w/o [No 16]
15
Moderate or severe liver disease
3
K72.-, K74.-, I85.-
16
Metastatic solid tumor
6
C77.-, C78.-, C79.-, C80.-
17
AIDS
6
B20.-, B21.-, B22.-, B23.-, B24.-
18
Age factor (was excluded from index)
For each decade ≥50 years of age, 1 point was 
added to the score