Triple thErapy in paTients With COPD Under Real lIve Setting (the TETRIS Study)
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

Protocol  Amendment 2
Study ID:  214468
Official Title of Study: Triple thErapy in paTients With COPD 
Under Real lIve Setting (the TETRIS Study)
NCT ID: NCT04657211
Date of Document: 16-Feb-2022

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NON-INTERVENTIONAL STUDY PROTOCOL 
UNIQUE IDENTIFIER 
214468  
TITLE 
Triple thErapy in paTients with COPD under Real lIve 
Setting (the TETRIS study) 
STUDY ACCOUNTABLE 
PERSON 
Dr. med.
GSK 
CONTRIBUTING 
AUTHORS 
Dr.
 Medical Advisor, GSK 
Dr. 
Medical Advisor, IDS 
Steering Committee: 
Prof. Dr. med 
University Hannover (MHH, Hannover) 
Prof. Dr. med.
for 
Internal Medicine Center of Pulmonology, University 
Medical Center Marburg 
PD. Dr. med.
Research Institute (PRI) at LungenClinic Großhansdorf 
PD. Dr. med.
insaf Respiratory Research Institute, Wiesbaden  
PD. Dr. med.
settled pulmonologist, 
Frankfurt 
 
ASSET ID 
GSK2834425 
GSK ASSET 
Fixed-dose combination of fluticasone furoate / 
umeclidinium / vilanterol (Trelegy Ellipta)  
INDICATION 
Moderate to severe chronic obstructive pulmonary disease 
(COPD)  
PHASE OF 
DEVELOPMENT 
Post-launch  
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
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REVISION CHRONOLOGY   
Date   
Version 
Change(s) since last version 
25-Aug-2020 
Version 1.0 final 
N/A 
08-Dec-2020 
Version 1.1 final 
Various specifications in Section 6.4 (Adverse Event, 
Pregnancy Exposure and Incident Reporting) 
Addition of appendix 4 and 5 
Number of patients were changed from 2300 to 2050 in 
total 
Removal of physical activity tracking by fitness 
wristband 
29-July-2021 
Version 1.2 final 
Extension of SITT or MITT treatment period prior to 
enrolment from 6-18 weeks to at least 6 but not longer 
than 48 weeks (inclusion criterion) 
Extension of the maximum study population per study 
site to 50 
14-Feb-2022 
Version 2.0 final 
Extension of SITT or MITT treatment period prior to 
enrolment from 6-48 weeks to at least 2 but not longer 
than 48 weeks (inclusion criterion) 
Sample size was changed from 2050 to 1100 in total 
Extension of the maximum study population per study 
site to 100 
Removal of Cohort C (patients from outpatient lung 
centres) and total patient number per physician group 
Revision and adaptation of chapters: 3.5, (3.6), 4 and 9 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  Unauthorized 
copying or use of this information is prohibited. 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ..................................................................................................... 4 
1. 
BACKGROUND AND RATIONALE ............................................................................. 7 
2. 
OBJECTIVES ........................................................................................................... 11 
2.1. 
Primary Objectives ........................................................................................ 11 
2.2. 
Secondary Objectives ................................................................................... 11 
3. 
RESEARCH METHODOLOGY ................................................................................. 12 
3.1. 
Study Design ................................................................................................. 12 
3.2. 
Data Source / Data Collection ....................................................................... 14 
3.3. 
Study Population ........................................................................................... 17 
3.4. 
Eligibility Criteria ............................................................................................ 18 
3.4.1. 
Inclusion Criteria............................................................................. 18 
3.4.2. 
Exclusion Criteria ........................................................................... 19 
3.5. 
Endpoints ...................................................................................................... 19 
3.6. 
Sample Size / Power Calculations ................................................................. 21 
4. 
DATA ANALYSIS CONSIDERATIONS ..................................................................... 22 
5. 
LIMITATIONS ........................................................................................................... 23 
6. 
STUDY CONDUCT, MANAGEMENT & ETHICS ...................................................... 24 
6.1. 
Legal Basis for Processing Individual Human Data ....................................... 25 
6.2. 
Monitoring & Data Quality .............................................................................. 25 
6.3. 
Study discontinuation .................................................................................... 26 
6.4. 
Adverse Event (AE), Pregnancy Exposure, and Incident Reporting ............... 26 
6.4.1. 
Definition of adverse events ........................................................... 26 
6.4.2. 
Data collected for adverse events .................................................. 27 
6.4.3. 
Reporting of AEs and timelines ...................................................... 27 
6.4.4. 
Reporting of COVID-19 cases ........................................................ 28 
6.4.5. 
Reporting of pregnancy exposures ................................................. 28 
7. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .......... 28 
8. 
REFERENCES ......................................................................................................... 29 
APPENDIX 1: SAMPLE SIZE CALCULATION ................................................................. 32 
APPENDIX 2: CODE LISTS ............................................................................................. 36 
APPENDIX 3: TABLES AND FIGURES ........................................................................... 40 
 

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Abbreviations 
AE 
Adverse Event 
AMG 
German Medicines Act (Deutsches Arzneimittelgesetz) 
BMI 
Body Mass Index 
CAT 
COPD Assessment Test 
COPD 
Chronic Obstructive Pulmonary Disease 
COPD* 
COPD with or without comorbid comorbid asthma 
CRO 
Contract Research Organisation 
CT 
Computed Tomography 
DLCO 
Diffusing capacity of lung for carbon monoxide 
DR 
Dropout Rate 
eCRF 
Electronic Case Report Form 
EOS 
Eosinophils 
EQ-5D / VAS 
European Quality of Life 5 Dimensions / Visual Analogue Scale 
FeNO 
Fraction Exspiratory Nitric Oxide 
FEV1 
Forced Expiratory Volume in 1 second 
FF/UMEC/VI 
Fluticasone Furoate / Umeclidinium / Vilanterol 
FSA 
Voluntary self-control of pharmaceutical industry (freiwillige 
Selbstkontrolle der Arzneimittelindustrie) 
FVC 
Forced Vital Capacity 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
GP 
General Practitioner 
HCP  
Healthcare Professional 
HRQoL 
Health-related Quality of Life 
HRU 
Healthcare Resource Utilisation 
hsCRP 
High-sensitivity C-reactive protein 
ICF 
Informed Consent Form 
ICS 
Inhaled Corticosteroids 
ICU 
Intensive Care Unit 
IHD 
Individual Human Data 
LABA 
Long-Acting Beta 2 Agonist 
LAMA 
Long-Acting Muscarinic Antagonist 

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MITT 
Multiple Inhaler Triple Therapy 
OCS 
Oral Corticosteroids 
PROs 
Patient-Reported Outcomes 
QoL 
Quality of Life 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Events 
SD 
Standard Deviation 
SITT 
Single-Inhaler Triple Therapy 
WBC count 
White Blood Cell count 
WBC differential 
White Blood Cell Count differential test 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 
 
 
Trademark Information 
Trademarks of the GlaxoSmithKline group 
of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
Trelegy Ellipta 
 
None 
Elebrato Ellipta 
 
 
 
 
 
 
 
 
 

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1. 
BACKGROUND AND RATIONALE 
Burden of chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is a disabling respiratory disease characterised 
by airflow obstruction and associated symptoms, including breathing difficulties caused by 
shortness of breath and wheezing, airway hyperactivity, chronic cough, sputum production, 
exercise intolerance, and poor quality of life [Global Initiative for Chronic Obstructive Lung 
Disease (GOLD) 2020]. The main risk factor for COPD is tobacco smoking but other 
environmental exposures such as biomass fuel exposure and air pollution may contribute. 
Besides exposures, host factors predispose individuals to develop COPD. These include genetic 
abnormalities, abnormal lung development and accelerated aging [GOLD 2020]. 
According to [World Health Organization (WHO)] over 251 million people worldwide suffer 
from COPD [WHO 2016]. According to prevalence estimates, in Germany ten to twelve percent 
of adults older than 40 years are affected by COPD [Umweltbundesamt 2020]. While in 2010, 
6.8 million people suffered from COPD in Germany, this number is expected to increase up to 
7.9 million by 2030 [Umweltbundesamt 2020]. 
COPD is currently the third leading cause of death worldwide [Lozano 2012], with over 3 
million reported deaths in 2016 (5.4% of all global deaths) [WHO 2016]. In contrast to coronary 
heart disease and stroke, it is the only leading cause of death with still increasing number [May 
2015]. COPD is moreover, the second leading cause of (avoidable) hospitalizations: The 
admission rates are expected to exceed that of ischemic heart diseases within the next five years 
[Khakban 2017]. This underlines the unmet medical need for early COPD diagnosis and 
treatment optimisation. It is therefore of paramount importance to provide these patients with 
effective and safe medication to control symptoms and improve quality of life. It is also crucial 
to slow down the progression of the disease by preventing exacerbations and hospital stays, 
thereby reducing mortality rate [GOLD 2020].  
The mainstay of pharmacological therapy for COPD is bronchodilation with a long-acting 
muscarinic antagonist (LAMA), a long-acting beta 2 agonist (LABA), or a combination of both, 
depending on the severity of breathlessness and the patient's risk of exacerbations [GOLD 
2020]. Combinations of inhaled corticosteroids (ICS), long-acting beta 2 agonists (LABAs), and 
long-acting muscarinic antagonists (LAMAs) are also recommended for COPD maintenance 
therapy [GOLD 2020]. 
GOLD recommendations for triple therapy 
At least 50% of patients with COPD fails to achieve adequate control of symptoms or 
exacerbation risk reduction while receiving only a single long-acting bronchodilator, such as a 
LAMA or LABA[Dransfield 2011]. Escalation to multiple bronchodilators with or without an 
inhaled corticosteroid (ICS) will depend on the patient's symptom burden (including dyspnoea, 
cough, sputum production as assessed by the COPD assessment test or modified Medical 
Research Council breathlessness scores) and risk of exacerbations [GOLD 2020]. Fixed-dose 
LAMA/LABA is relatively new to the market and the LAMA/LABA treatment recommendation 
was included in the GOLD report from 2017 onwards [Bogart 2018, GOLD 2020]. Current 
treatment guidelines recommend the use of triple therapy with an ICS/LAMA/LABA for 

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patients currently on bronchodilators with persistent symptoms and/or at risk for future 
exacerbations [Bogart 2018, GOLD 2020]. 
In addition to multiple inhaler triple therapy (MITT) with multiple inhalers, single inhaler triple 
therapy (SITT) is currently available. The first SITT product for the treatment of COPD 
(Trimbow, a twice-daily SITT) was approved in the European Union in July 2017, followed by 
Trelegy Ellipta (a once-daily SITT) in  November 2017. The approval of another SITT product 
(Breztri Aerosphere) is expected in the near future. 
Several recent studies have demonstrated the efficacy of SITT for the treatment of COPD 
patients with moderate-to-severe exacerbations [Ferguson 2018, Lipson 2017, Lipson 2018, 
Singh 2016, Vestbo 2017]. COPD exacerbations are common occurrences that cause a major 
burden of illness [GOLD 2020, Halpin 2017, McDonald 2019 (b)]. They are associated with 
impaired health status, decrease in lung function, hospitalization and increased risk of death. 
Exacerbation avoidance is therefore a major priority [GOLD 2020, McDonald 2019 (b)]. 
The use of SITT resulted in reduced rates of moderate-to-severe exacerbations compared with 
monotherapy [Vestbo 2017] and dual therapy [Lipson 2017, Singh 2016]. The IMPACT study 
evaluated the effects of SITT in comparison to therapy with either a LAMA/LABA or an 
ICS/LABA in symptomatic patients with risk of exacerbations. The results of this study 
demonstrated that SITT significantly reduced the rate of moderate-to-severe exacerbations, 
improved lung function and health-related quality of life scores, when compared with both dual 
therapies at 52 weeks timepoint [Lipson 2018]. A secondary analysis from the IMPACT trial 
proved that treatment of symptomatic patients with COPD and a history of exacerbation with a 
once-daily SITT significantly reduced the risk of all-cause mortality compared with a dual 
bronchodilator (LAMA/LABA) combination [Lipson 2020]. 
Triple therapy forCOPD in routine clinical practice 
The GOLD recommendations suggest escalation to triple therapy for patients with a high 
symptom burden and high exacerbation risk, who develop further exacerbations while being 
treated with maximum bronchodilator therapy [GOLD 2020]. However, prescription behavior 
is not always aligned with these recommendations [Visentin 2016]. Treatment decisions in 
routine clinical practice may be different and can deviate from treatment recommendations. A 
retrospective survey in clinical routine found that approximately 10% of patients received triple 
therapy without prior bronchodilator use or exacerbation history [Bogart 2018]. Possible 
rationales could have been based on persistent symptoms reported by the patients, mild or 
unobserved exacerbations, or spirometry results [Bogart 2018]. 
A retrospective German study from 2018 revealed that treatment of COPD patients by 
experienced lung specialists seemed also to diverge from GOLD recommendations, probably 
leading to widespread under-treatment [Greulich et al., GSK data on file]. A significant number 
of patients under triple therapy received five or more different COPD medications during one 
year of treatment. Furthermore, data from this trial revealed that de-escalation of triple therapy 
in symptomatic COPD patients with a recent history of exacerbations via step-down to 
LAMA/LABA or ICS/LABA was common practice by many lung specialists [Greulich et al., 
data on file]. 

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So far, limited data is available on how decisions regarding escalation to triple and de- or re-
escalation are actually taken in COPD treatment reality in Germany and based on which 
rationale. 
For further treatment optimisation, it is crucial to evaluate which patients with their individual 
disease characteristics particularly benefit from an escalation or de-escalation of therapy. This 
requires long-term data, which needs to last beyond a one-year observation period that is often 
chosen in controlled clinical trials. 
Individualising COPD therapy: phenotyping and treatable traits 
Obstructive lung diseases such as COPD and asthma have diverse aetiology and disease 
mechanisms, and manifest with a range of symptoms. The impact of each disease on individual 
patients is also heterogeneous. This heterogeneity and complexity have led to the recognition 
that treatment approaches cannot be ‘one size fits all’, but individualised treatment regimens are 
needed for chronic airway diseases [McDonald 2019 (a)]. Chronic bronchitis versus 
predominant emphysema as well as COPD with concomitant asthma are well recognized 
phenotypes in COPD [GOLD 2020]. GOLD does not longer refer to asthma & COPD overlap 
(ACO), instead it is emphasized that asthma and COPD are different disorders, although they 
may share common traits and clinical features (e.g., increase in eosinophilia level) [GOLD 
2020].  
A concept of treatable traits has developed over the last decade following recognition that 
chronic airway diseases are complex syndromes which require individualised assessment, 
investigation and treatment [Agusti 2016, Gibson 2010, Fingleton 2018]. Treatable traits are 
disease characteristics that are clinically relevant, identifiable and modifiable [McDonald 2019 
(a)]. The treatable trait strategy was initially proposed in 2016 [Agusti 2016], building on 
previous work that proposed multidimensional assessment and treatment approaches for 
individual respiratory diseases [Gibson 2010]. Subsequent international workshops have been 
convened to seek expert consensus on how to apply and progress a treatable traits strategy for 
clinical management [Agusti 2017, McDonald 2019 (b)]. 
The treatable traits strategy incorporates a number of elements. Inherent to its approach is a 
multidimensional assessment of each individual patient to determine which traits exist in that 
patient. Multidimensional assessment can be used to identify the range of traits within an 
individual and involves a clinical history and examination, an evaluation of risk factors, and 
measurement of spirometry and blood eosinophils. The treatable traits strategy aims to support 
an individualised and targeted treatment approach [McDonald (a)]. Some of the treatable traits 
in COPD include airflow limitation, cachexia, reduced mobility, smoking, and eosinophilic 
airway inflammation [Sin 2020].    
Poor mobility and impaired physical activity are major concerns in COPD patients, and reduced 
mobility is an underestimated clinical feature of COPD [Sin 2020]. Smoking is related to a rapid 
decline in lung function in COPD patients [Sin 2020]. Increased concentrations of blood 
eosinophils (EOS) in patients with COPD have been associated with increased frequency of 
exacerbation and reduction in lung function [Bafadhel 2011]. There is substantial evidence that 
a raised blood EOS count could be a biomarker for predicting patient response to inhaled 
corticosteroids (ICS) in COPD [DiSantostefano 2016, Zysman 2017]. In a clinical trial, a greater 

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decline in forced expiratory volume in 1 second (FEV1) was observed in COPD patients with 
high blood EOS counts who were not treated with ICS [Barnes 2016]. 
Scientific Rationale for the TETRIS study 
In accordance with the GOLD recommendations, it is important to assess the characteristics and 
treatment patterns of patients prior to triple therapy initiation, in order to determine adherence 
to these guidelines and understand how patients progress to triple therapy. Despite a clearly 
defined guidance from GOLD treatment recommendations for the initiation and maintenance of 
triple therapy, treatment changes in Germany, including de-escalation, are often seen in 
treatment reality. The TETRIS study is intended to provide information on how many COPD 
patients remain continuously on triple therapy in Germany. The reasons for treatment changes 
are hardly known, as are possible clinical consequences. Therefore, this observational study will 
also retrospectively capture the reasons in Germany to put the patients on MITT or SITT 
considering existing treatment recommendations. When evaluating all information that is 
collected about the therapy and patient environment, SITTs and MITTs will be looked at both 
separately and combined. 
TETRIS will observe patients with COPD with or without comorbid asthma (hereinafter 
summarized as COPD*) who are on an existing combined treatment of LAMA, LABA and ICS. 
The study is intended to gain a better understanding of what influences the treatment decision 
of German physicians in primary and secondary care under real life conditions. TETRIS is also 
designed to elicit the reasons for treatment changes and to describe long-term outcomes with 
patients initiated on triple therapy over a period of two years. Another goal is to describe the 
temporal dynamics of treatment pattern and to unravel potentially complex patient journeys§ in 
different German regions. Research investigating the patient journey is required to better 
understand the individualized treatment regime of a patient over time with COPD* in Germany 
and to address the limitations faced by health care professionals when aiming to optimise 
treatment according to current GOLD COPD recommendations. 
A further aim of TETRIS is to identify and follow-up a variety of ‘treatable traits’ in COPD 
patients, which - when modified - may lead to improved health outcomes. Therefore, COPD 
patients with signs of asthma or an asthma history will also be included to gain a better 
understanding of this phenotype. Recognition of certain patient characteristics may already be 
directly or indirectly linked to treatment decisions and therefore are of particular interest to be 
further explored in clinical practice. 
In order to be able to map treatment reality in Germany as comprehensively as possible, the 
TETRIS study will collect all relevant data. The results may guide the medical community to 
provide a more targeted medical education approach of the unmet medical need in COPD. The 
data will enable the medical community to ensure that patients receive optimised therapy for 
their COPD by driving better informed treatment decisions. In addition, analysis comparing 
patient characteristics in the event of maintenance or interruption of triple therapy could provide 
further valuable insights that contribute to an understanding of the treatment reality in Germany. 
§ Patient journey means the ongoing sequence of care events which a patient follows from the 
point of access into the health system, continuing towards diagnosis and care and ending in 
outpatient care. 

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2. 
OBJECTIVES 
This section provides an overview of the study goals and objectives. Details on related 
variables and times of documentation are tabulated in Section 3.2 (Table 1) and Section 
3.5 (Table 2). Questionnaires referred to can be found in Appendix 2, together with references 
and comments on validation. 
When evaluating the information gathered for primary and secondary objectives, SITTs and 
MITTs will be looked at both separately and combined. 
2.1. 
Primary Objectives 
The primary objective is to describe the percentage of participants with diagnosed COPD with 
or without comorbid asthma (hereinafter summarized as COPD*) who continuously receive 
triple therapy for 6, 12 and 24 months after study enrolment. 
2.2. 
Secondary Objectives 
Secondary objectives are to (for details see Table 2): 
 Describe profiles of COPD* patients who initiated or are on triple therapy 
(LAMA/LABA/ICS) in Germany, for example 
- patient and disease characteristics when initiating triple therapy 
 Describe the distribution and frequency of combined treatable traits in COPD* patients.   
 Describe the percentage of participants with at least one switch from triple therapy to 
LAMA/LABA or to ICS/LABA after 6, 12 and 24 months 
 Describe COPD* treatment decisions of German physicians who have either initiated 
patients on triple or decided to change actual therapy, for example 
- distribution and frequency of prespecified reasons† to initiate or change triple therapy 
 Describe clinical outcomes in COPD* patients initiated on triple therapy, for example 
- annual rate of moderate and/or severe exacerbations 
 Describe the patient journey§ of COPD* patients initiated on triple therapy, for example 
- annual rate of COPD* related primary and secondary care contacts   
 Describe safety with focus on pneumonia and cardiovascular events 
 
† The prespecified reasons were defined by leading medical experts within the Steering 
Committee.A drop-down list will be offered to the investigator including but not limited to: 
 patient is continuous symptomatic under current maintenance treatment 
 patient asked for help because of disease worsening 
 patient asked to change medication or device 

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 patient experienced 2 or more exacerbations treated with antibiotics and/or OCS 
 patient was hospitalized for a severe exacerbation / others (including freetext windows) 
§ Patient journey means the ongoing sequence of care events which a patient follows from the 
point of access into the health system, continuing towards diagnosis and care and ending in 
outpatient care. 
 
3. 
RESEARCH METHODOLOGY 
3.1. 
Study Design 
This study is a multi-centre, prospective observational cohort study. Participants with COPD* 
have already been treated with triple therapy for at least 2 but not longer than 48 weeks will be 
enrolled into two cohorts: 
 Cohort A: treatment by settled general practitioners (“GPs”, primary care, practitioner / 
registered doctor) 
 Cohort B: treatment by settled pulmonologists (“specialists”, primary or secondary care) 
The involvement of these two German physician groups is an important basis to ensure that real 
everyday treatment conditions will be depicted for this observational cohort study. 
About 30-35% of COPD drugs in Germany are prescribed through primary care physicians 
(mostly GPs). About 55-60% are prescribed by settled pneumologists and the remainder from 
outpatient lung centres. . 
In general there is a high level of standardization in the education of HCPs (pneumologists, 
generalists)and in the processes in the private practices (treatment, documentation, visits, 
diagnostic methods). Thus, a generalizability of patient recruitment and study conduct can be 
assumed. The site feasibility performed in line with the study and the site managment processes 
also assure comparable patient recruitment and study conduct. General practitioners (GPs) 
usually serve as primary care sites, settled pneumologists as secondary care specialists. 
Nevertheless there is considerable interchangeability since GPs often serve as secondary care 
centre after hospitalizations due to severe exacerbations and patient with moderate/advanced 
disease may directly be referred to pneumonologists depending on the region in Germany. 
As this is a non-interventional study, the protocol will not interfere with the physicians’ 
management of the patients, i.e. this study does not include treatment interventions. Participants 
will continue to use medication prescribed by their regular treating physician. Data collection 
follows routine clinical practice, i.e. the study does not require additional visits to the physician.  
Data will be collected at patients' routine visits and only questionnaires recommended in 
guidelines and questions used in daily practice will be applied. Participants’ regular treating 
physician will be informed of the results of study assessments following each of the four main 
on-study visits. 

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Non-interventional studies shall not have the potential to incentivise physicians to prescribe any 
specific product. For this reason, the TETRIS study includes only patients who have been treated 
with triple therapy for at least 2 weeks. TETRIS does not intend to confirm the efficacy and 
tolerability of Trelegy in comparison to a control group, as efficacy and tolerability have already 
been well established in the clinical development programme [Lipson 2017, Lipson 2018, 
Lipson 2020]. 
The data collection in the study includes two parts (see Figure 1 below): 
Part 1 involves the cross-sectional phenotyping of participating COPD* patients at study 
enrolment (hereinafter referred to as “visit 1”). 
Part 2 involves a two-year longitudinal follow-up period to monitor / document all visits of the 
study participants during the 24-months observation period. The goal is to understand how 
physicians assess and treat patients with COPD* in clinical practice in Germany. The study 
assumes that most COPD* patients see their doctor every 3 months (at least to get a new 
prescription). Further data should therefore be provided in the clinical routine after 
approximately 
6 
(-3/+2) 
months 
(hereinafter 
referred 
to 
as 
“visit 
2”),  
12 (-3/+5) months (hereinafter referred to as “visit 3”) and for the last visit after approximately 
24 (-6/no upper limit) months (hereinafter referred to as “visit 4”). There should be a minimum 
interval of 3 months between each of these visits, otherwise the visit is counted as an interim 
visit. 
For each additional patient visit to the treatment centre between study visits 1 and 4, safety data, 
exacerbations, hospital stays as well as treatment changes and reasons for this are recorded. 
Patients will participate in the study for approximately two years from enrolment to the last 
study contact (visit 4). 
Two interim analyses are planned: 
 The first interim analysis is intended to collect and analyse cross-sectional data / baseline 
characteristics and is planned after at least 825 patients (~75%) of the total study 
population have been recruited. 
 The second interim analysis is intended to include 6 and 12 months data for a subset of the 
study population and is planned after full recruitment or after 2 years from study start, 
whatever occurs earlier.  
 
The final analysis will be performed after a 24-month follow-up from study enrolment for all 
patients. Participants may be withdrawn from the study if they become pregnant or enrol in 
another study with treatment intervention. Furthermore, patients may discontinue study 
participation – with or without formal withdrawal of their informed consent and with or without 
giving reasons – at any time during the study. 
 It is essential for the study objectives to obtain as complete follow-up of patients as is 
possible in a non-interventional study. An example in the patient journey where a patient 
may get lost to follow-up could be:Patients may move to another outpatient care physician 
for personal reasons. 

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A supporting concept with mitigation measures will be provided to avoid loss of patients at the 
risk points above. The concept provides that physicians as well as patients can refer to a change 
of doctor via a central homepage. The new supervising physician has the opportunity to also 
participate in the study. With these measures we expect to be able to reduce the dropout rate to 
5-10%. 
Figure 1: Assessment and follow-up study schematic 
 
3.2. 
Data Source / Data Collection 
The prospective observation period is scheduled for 24 months from study enrolment. This 
period is required to obtain information on the long-term maintenance of triple therapy, the long-
term development of treatable traits and to meet clinical endpoints. So far, there has been limited 
data available that go beyond a one-year observation period for patients treated with single 
inhaler triple therapy for COPD with or without comorbid asthma (COPD*). Long-term data 
that provide information over a period of at least two years are therefore of great clinical interest. 
As this is a non-interventional study, the protocol will not interfere with the physicians’ 
management of the patients.  
For each additional patient visit to the treatment centre between study visits 1 and 4, safety data, 
exacerbations, hospital stays, deaths and treatment changes and reasons for this are recorded. 
Patients will participate in the study for approximately two years from enrolment to the last 
study contact (visit 4). 
Data will be collected in electronic case report forms (eCRFs). Table 1 (see below) illustrates 
data collection over time. Three eCRF variants will be used for the data collection, depending 
on the study visits (visit 1, visits 2-4, on-site visits at any time in between): 
 An extended eCRF (“extended eCRF part 1”) will be used for part 1 of study data 
collection. The extended eCRF part 1 documents the cross-sectional phenotyping of 
participants at study enrolment, including the recording of socio-demographic and 
comorbidity data. 
 Another extended eCRF that is based on the extended eCRF part 1 (“extended eCRF part 
2”) will be used for part 2 of the study. The extended eCRF part 2 will document a two-
year longitudinal follow-up consisting of three study visits (visits 2 to 4) during routine 
clinical practice. These are scheduled after approximately 6, 12 and 24 months. The 
2–48  
weeks 
6 (-3/+2)  
months 
12 (-3/+5)  
months 
Pulmonologists 
General 
practitioners 
Study 
Start 
24 (-6/no  
upper limit)  
months 
Dual or Mono bronchodilation 
Triple therapy (SITT or MITT) 

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extended eCRF part 2 largely corresponds to the extended eCRF part 1 but does not 
involve the baseline questions on demographic data and comorbidities. 
 For each additional patient visit to the treatment centre between study visits 1 and 4, safety 
data, events3 including exacerbations, hospital stays as well as treatment changes and 
reasons for this will be recorded on a short eCRF (“short eCRF”). 
All information relevant for the study is expected to be routinely documented in the patients' 
charts, which will serve as source data. However, questionnaires collect information in a 
specific, unified and validated structure and with specified response options, which may differ 
not in extent, but in details from routine practice in study centres. Thus, the patients' charts may 
not be suitable source data for questionnaires, especially HRQoL and symptoms questionnaires, 
and the questionnaires themselves or suitable worksheets will serve as source data here and be 
stored with the patients' charts. For centre related information collected in this study, the eCRF 
itself will serve as source data, and an electronic copy or printout will be provided for the 
investigator site files. 
Since an eCRF is used, all the patient has to do is complete the EQ-5D/VAS questionnaire 
remotely. All other data can be recorded by the attending doctor or nurse. In the case of 
telemedicine visits, the attending physician is asked to collect the completed questionnaire from 
the patients in order to transfer the data into the eCRF form. 
Patients will participate in the study for approximately two years from enrolment to the last 
study contact (visit 4). 
Data will be used in anonymized form conforming to data protection regulations (General Data 
Protection Regulation of the European Union and related German law on data protection). 
3 Event includes: unstable COPD, cold requiring antibiotics, and exacerbation 
 
 
 

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Table 1: 
Data collection schedule (data will be collected as per clinical routine). 
EW: Early withdrawal. 
Procedure 
Screening  
(up to 14 days 
before visit 1) 
Part 1 
Part 2 
EW 
 
 
Visit 1: Month 0 
Intermediate visits 
Visit 2§:  
Month 6 (-3/+2) 
Intermediate visits 
Visit 3§:  
Month 12 (-3/+5) 
Intermediate visits 
Visit 4§: Month 24 
(-6/no upper limit) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
Patient's sociodemo-graphic 
characteristics 
X 
 
 
 
 
 
 
 
 
Height, weight, BMI 
 
X 
 
X 
 
X 
 
X 
X 
Medical history and 
comorbidities 
X 
X 
 
 
 
 
 
 
 
COPD* medication history 
before initiating triple therapy 
 
X 
 
 
 
 
 
 
 
Maintenance medication for 
COPD*  
X 
X 
 
X 
 
X 
 
X 
X 
Concomitant COPD* medication  
X 
 
X 
 
X 
 
X 
X 
Reasons for initiating triple 
therapy 
 
X 
 
 
 
 
 
 
 
Reasons for changing 
maintenance medication for 
COPD*  
 
 
 
X 
 
X 
 
X 
X 
Smoking status 
 
X 
X 
X 
X 
X 
X 
X 
X 
Narratives of any lung CT 
scansa) 
 
X 
 
X 
 
X 
 
X 
X 
Spirometry testing (FEV1, FVC, 
FEV1/FVC ratio) (if routinely 
collected) 
X 
X 
 
X 
 
X 
 
X 
X 
Body-plethysmo-graphie (if 
performed routinely)  
 
X 
 
X 
 
X 
 
X 
 
DLCO (if routinely collected) 
 
X 
 
X 
 
X 
 
X 
 
FeNO (if routinely collected) 
 
X 
 
X 
 
X 
 
X 
 
Eosinophils (EOS) in blood  
(if routinely collected) 
X 
X 
 
X 
 
X 
 
X 
X 
WBC count (if routinely 
collected) 
 
X 
 
X 
 
X 
 
X 
X 
WBC differential (if routinely 
collected) 
 
X 
 
X 
 
X 
 
X 
X 
hsCRP (if routinely collected) 
 
X 
 
X 
 
X 
 
X 
X 

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Procedure 
Screening  
(up to 14 days 
before visit 1) 
Part 1 
Part 2 
EW 
 
 
Visit 1: Month 0 
Intermediate visits 
Visit 2§:  
Month 6 (-3/+2) 
Intermediate visits 
Visit 3§:  
Month 12 (-3/+5) 
Intermediate visits 
Visit 4§: Month 24 
(-6/no upper limit) 
Healthcare resource utilisation 
(HRU)c) 
 
X 
 
X 
 
X 
 
X 
X 
Eventsb) during study 
 
 
X 
X 
X 
X 
X 
X 
X 
CAT 
X 
X 
 
X 
 
X 
 
X 
X 
EQ-5D (incl. VAS) 
 
X 
 
X 
 
X 
 
X 
X 
AE/SAE review 
 
X 
 
X 
 
X 
 
X 
X 
The eCRF will additionally capture surrogate markers for compliance (e.g. "Did the patient regularly/every 3 
months ask for a new prescription?"). 
 
§ There should be a minimum interval of 3 months between each of the visits (visit 2, 3, 4), otherwise the visit is 
counted as an interim visit. 
 
AE: adverse event; BMI: body mass index; CAT: COPD Assessment Test; COPD: chronic obstructive pulmonary 
disease; COPD*: COPD with or without comorbid asthma; CT: computed tomography; DLCO: diffusing capacity; 
EOS, eosinophils; EQ-5D, European Quality of Life 5 Dimensions; EW: early withdrawal; FeNO, Fraction 
Exspiratory Nitric Oxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; hsCRP, high-
sensitivity C-reactive protein; HRU, healthcare resource utilisation; SAE: serious adverse event; VAS, Visual 
Analogue Scale; WBC, white blood cell; WOCBP: woman of child bearing potential. 
a. 
The radiologist’s narrative will be collected for any historical lung CT scans performed in the year prior to 
the study or any lung CT scans performed as part of routine clinical management during the study. 
b. 
Event includes: unstable COPD, cold requiring antibiotics, exacerbation and hospitalizations. 
c. 
HRU includes: hospitalization, hospitalization in intensive care unit, number of physicians treating the 
patient (primary and secondary care), number of physician goups treating the patient (2 groups), change 
of treating physician, returning from secondary care to primary care physician, returning from acute care 
to primary or secondary care  
 
 
Patient characteristics can be identified in a number of ways. Determination of blood eosinophils and hsCRP may 
aid identification in the same way that DLCO measurements and CT images can help detect persistent lung inflation. 
Sputum secretion, dry cough, or FeNO determinations can also help identify important patient characteristics. The 
detection of "rapid declines" (loss of> 100 ml lung volume per year) may be another important patient characteristic. 
 
3.3. 
Study Population 
This study plans to recruit a population of approximately 1100 patients with moderate to severe 
COPD with or without comorbid asthma (COPD*) who have been on triple therapy for at least 
2 and for a maximum of 48 weeks (see sample size estimation in Section 3.6). 
The TETRIS study participants will be enrolled by two different physician groups covering all 
German regions: a) settled general practitioners (“GPs”, primary care) and b) settled 

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pulmonologists (“specialists”, primary or secondary care. This is in order to get a better 
representation of the treatment reality in Germany. The patients will be recruited from the 
following  physician groups: 
 COPD* patients should be included by settled pulmonologists (“specialists”, primary or 
secondary care). Depending on the regional distribution of the centres, patients within each 
centre of cohort B who meet the inclusion criteria will be considered. If a single centre has 
recruited the maximum number of patients, the study management will decide whether 
further patients may be recruited (up to a maximum of 100 patients). 
 COPD* patients should be included by settled general practitioners (“GPs”, primary care). 
Depending on the regional distribution of GPs, patients who meet the inclusion criteria will 
be considered within each centre of cohort A. If a single centre has recruited the maximum 
number of patients, the study management will decide whether further patients may be 
recruited (up to a maximum of 100 patients).  
It is assumed that around 15% of the study population were hospitalized for exacerbations. 
Continous crossfunctional recruitment management (lead by the CRO and the GSK study head) 
will be a key element to ensure proper regional distribution of centres and patients enrollment.  
3.4. 
Eligibility Criteria 
3.4.1. 
Inclusion Criteria 
Study participants may be male or female. Participants are only eligible to be included in the 
TETRIS study if all of the following criteria apply: 
 Participant is at least 18 years of age at the time of signing the informed consent 
 Participant is on a single or multiple inhaler triple therapy (SITT or MITT) for treatment of 
an obstructive respiratory disease for a period of 2 to 48 weeks prior enrolment with a 
combination of inhaled LAMA, LABA and ICS either on 
- a triple maintenance treatment or 
- an intermediate triple therapy regime (ICS “on/off” or LAMA “on/off”) 
 Only applies to Cohort A (treatment by settled general practitioners): Participants are 
treated according to a physicians diagnosis of COPD*. 
 Only applies to Cohorts B (treatment by settled pulmonologists): Participants have a 
confirmed physician’s diagnosis (diagnosis based on spirometry or body plethysmography) 
of COPD*. 
 Participants need to give and be capable of giving signed informed consent (ICF) which 
includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol. 
 

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3.4.2. 
Exclusion Criteria 
Participants are ineligible to be included in the study if any of the following criteria apply: 
 Participant has a diagnosis of pure asthma, without clinical features of COPD 
 Participant has a current diagnosis of lung cancer or lung metastasis 
 Participant has a current primary diagnosis of diffuse pan-bronchiolitis, or a primary 
diagnosis of bronchiectasis or pulmonary fibrosis or cystic fibrosis or other significant 
respiratory disorders 
 Participant is currently enrolled or has participated in a study within the last 90 days before 
signing of consent involving investigational study treatment intervention. If, while enrolled 
in the present study, the participant enrols in another study involving investigational study 
treatment intervention, he/she will be withdrawn from the present study 
 Recent (≤ 3 months) major cardiac or pulmonary event (e.g. myocardial infarction, 
pulmonary embolism) 
3.5. 
Endpoints 
Endpoints of the study are outlined in Table 2 below, with associated objectives. 
The non-interventional concept of this study does not demand visits or examinations outside of 
clinical routine. The Statistical Analysis Plan (SAP) will define the allocation of data to time 
points of analysis, if required and non-obvious ("time windows"). 
Table 2: 
Listing of objectives and associated endpoints 
Objective 
Endpoints 
Evaluate the percentage of patients who 
continuously receive triple therapy 
 Patients who continuously receive triple therapy for 6, 12 and 24 months 
(including stratification by SITT vs. MITT) 
 Time to stop triple therapy 
Describe profiles of COPD patients who 
initiated or are on triple therapy (LAMA/ 
LABA/ICS) in Germany 
Patient and disease characteristics when initiating triple therapy: 
 Percentage of COPD patients with diagnosis of asthma at the age of <40 
years 
 Percentage of patients with peripheral blood EOS of <100 cells/µl, 100-200 
cells/µl, 200-300 cells/µl and > 300 cells/µl 
 Percentage of participants with a physician’s diagnosis of COPD by site 
localization and physician´s group 
 Percentage of participants with different symptom and risk classes (GOLD) 
 Medications received by COPD patients (including OCS), split by physician 
group and site localization 
 Time on triple therapy before study start (<3 months / 3 - <6 months / >=6 
months) 
Describe the distribution and frequency 
of combined treatable traits in COPD 
patients 
 Percentage of patients presenting with a smoking history (when initiating 
triple therapy and at different time points during a 24-month observation 
period) 
 Percentage of patients with a non-smoking history when initiating triple 
therapy 

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Objective 
Endpoints 
 Percentage of patients with a FEV1/FVC ratio <0.7 at study enrolment and at 
a 6, 12 and 24 months documentation 
 Percentage of patients with any moderate/severe exacerbation in the 24 
months prior to study enrolment or 3 months prior to each subsequent on-
study visit during a 24-month observation period 
 Percentage of patients with a CAT score ≤10 / 11-19 / ≥20 at baseline and at 
a 6, 12 and 24 months documentation 
 Percentage of patients with peripheral blood eosinophil (EOS) count ≥100 
cells/µl at baseline and at a 6, 12 and 24 months documentation 
 Percentage of patients with chronic bronchitis phenotype  
Describe the percentage of participants 
with at least one switch from triple 
therapy to LAMA/LABA or to ICS/LABA 
after 6, 12 and 24 months 
 Patients with at least one switch from triple therapy to LAMA/LABA after 6, 12 
and 24 months 
 Patients with at least one switch from triple therapy to ICS/LABA after 6, 12 
and 24 months 
Describe COPD treatment decisions of 
German physicians who have initiated 
patients on triple therapy 
 Distribution (by physician group) and frequency of prespecified reasons to 
initiate triple therapy (either MITT or SITT) 
 Percentage of patients changing from triple to dual therapy and back to triple 
therapy (re-escalation) during a 24-month observation period after study 
enrolment (split by SITT and MITT and split by LAMA/LABA and ICS/LABA) 
 Percentage of patients with at least one re-escalation from LAMA/LABA or 
ICS/LABA or LAMA to triple therapy during the 24-month observation period 
 Percentage of patients with at least one change from MITT to SITT or SITT to 
MITT during a 24-month observation period 
 Percentage of patients with at least one change from SITT to SITT or MITT to 
MITT during a 24-month observation period 
 Percentage of patients changing from once daily to twice daily medication or 
vice versa or between different inhaler types 
 Percentage of patients changing between different inhaler types 
 Distribution (by physician group) and frequency of prespecified reasons to 
change a triple therapy (either MITT or SITT) 
 Distribution and frequency of prespecified reasons to change triple therapy to 
another triple therapy 
 Distribution and frequency of prespecified reasons† to change triple therapy 
to therapy de-escalation 
 Distribution and frequency of prespecified reasons to change de-escalataed 
therapy back to triple therapy (re-escalation) 
Describe clinical outcomes in COPD 
patients initiated on triple therapy 
 Mean annual rate of moderate and/or severe exacerbations over a 24-month 
observation period (including subgroup analysis by peripheral blood 
eosinophil count, smoking status and asthma history) 
 Mean annual rate of hospitalizations due to severe exacerbations 
 Change of lung function parameters during a 24-month observation period 
(including subgroup analysis by peripheral blood eosinophil count, smoking 
status and asthma history) 
 Change of COPD symptoms during a 24-month observation period  
 Change in HRQoL during a 24-month observation period  
 Percentage of COPD patients experiencing a clinically important 
deterioration2 during a 24-month observation period 

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Objective 
Endpoints 
 Time to first moderate or severe exacerbation during a 24-month observation 
period 
 Time to first hospitalization / hospitalization during a 24-month observation 
period 
 Time to death during a 24-months observation period 
Describe the patient journey of COPD 
patients initiated on triple therapy 
 Mean annual rate of COPD related primary and secondary care contacts 
 Number of different documenting physicians per patient during a 24-month 
observation period (also split by patients with a severe or moderate or severe 
exacerbation and split by site localization)   
 Mean number of treating physicians per patient over a 24-month observation 
period (also split by site localization and diagnosis) 
 Percentage of patients treated by 1, 2 or all 3 physician groups addressed in 
the study (settled general practitioners, settled pulmonologists, outpatient 
lung centres) 
Describe safety with triple therapy 
 Safety with focus on pneumonia and cardiovascular events 
 Benefit-harm profiles for single-inhaler triple therapies (SITTs, including 
Trelegy, Trimbow and Breztri) 
 Benefit-harm profiles for major multiple inhaler triple therapy (MITT) 
combinations 
 Benefit-harm profiles for triple therapies interrupted by ICS and/or LAMA 
“off/on” periods 
 Benefit-harm profiles for triple therapies switching between SITT and MITT 
 
3.6. 
Sample Size / Power Calculations 
See Appendix 1 for further details and various scenarios. 
In order to obtain information about the long-term maintenance of triple therapy, a total 
observation period of 24 months was chosen for this non-interventional study. Within the co-
primary endpoint “description of the percentage of participants with a physician's diagnosis of 
COPD* who continuously receive triple therapy for 6, 12 and 24 months after study enrolment”, 
we therefore focused on the percentage of patients on a continuous triple therapy regime for 24 
months. 
The sample size calculation is based on the precision of the estimate for this endpoint. Based on 
research data we assume the rate of patients continuously being on triple therapy of around 35% 
of all patients two years after study enrolment on triple therapy. With a target width of 7%, the 
corresponding 95% confidence interval ranges from 31.6% to 38.65% for a sample size of 740 
patients. As for this planned analysis data are necessary for two years, we determine the sample 
size to a total of approximately 1,100 patients to consider about 30% study drop-outs.  
Based on the current market mix of MITTs and SITTs and including the anticipated market 
dynamics towards more SITT usage during the next two years in Germany it is expected to enrol 
around 50 up to 60% of patients with COPD* on SITT (with shares of Trelegy/Trimbow/Breztri 
of approximately 2:2:1).  

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4. 
DATA ANALYSIS CONSIDERATIONS  
This is a descriptive study which is designed to estimate the primary endpoint with a specific 
precision. The study is not powered to detect differences and no formal statistical hypothesis 
testing will be performed for any of the endpoints.  
Two interim analyses are planned (see also Section 3.1): 
 The first interim analysis is intended to collect and analyse cross-sectional data/ baseline 
characteristics and is planned when at least 825 patients (~75%) of the total study 
population have been recruited. 
 The second interim analysis is intended to include 6 and 12 months data for a subset of the 
study population and is planned after full recruitment or after 2 years from study start, 
whatever occurs earlier.  
The final analysis will be performed after a 24-month follow-up from study enrolment for all 
patients. Participants may be withdrawn from the study if they become pregnant or enrol in 
another study with treatment intervention. Furthermore, patients may discontinue study 
participation – with or without formal withdrawal of their informed consent and with or without 
giving reasons – at any time during the study. 
In order to get a more detailed idea of how therapy and outcome parameters develop during the 
24-month observation period, the following subgroups will be investigated separately: 
 triple therapy once daily vs. twice daily 
 SITT vs. MITT and SITT vs. SITT  
 continuous vs. interrupted triple therapy 
 physician cohorts  
 COPD vs. COPD with asthma 
further exploratory subgroups (i.e. by exacerbation history / by ± ICS containing pre-treatment 
/ by smoking status) before study start. 
The population enrolled in the data analysis will include all participants who sign the ICF and 
who complete both the screening visit and visit 1. This population will be the primary analysis 
population for all endpoints, including safety data. 
Missing Data / Sensitivity analysis 
Analyses will be based on available data. Missing data will not be imputed and will be 
displayed as a separate category. The number of dropouts will be analysed descriptively 
and their impact on the primary endpoint will be investigated. 
If a variable is completely or systematically missing, it is excluded from the analyses. If 
a variable is missing for only some of the patients or arbitrarily missing, a missing data 

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category will be added and used in the analyses. However in case of a considerable 
amount of missing data (1/3 or more)  for one variable, the impact of this missing data 
will be investigated by conducting the analysis without the corresponding variable – as 
a sensitivity analysis. If a variable is missing but equivalent information can be inferred 
using available variables, the corresponding information will be used instead. 
According to the descriptive study design all endpoints will be analysed descriptively.  
Endpoints with continuous measures will be analysed by mean, median, minimum, maximum 
and standard deviation [SD], discrete and categorical endpoints by frequencies and  percentages 
and event/survival-endpoints counts will be analysed by providing event rates per participant-
year and Kaplan-Meier estimates). Full details including a list of exploratory endpoints will be 
provided in the SAP as an additional document to this study protocol. 
 
5. 
LIMITATIONS 
This is a real-life, prospective, non-interventional study. Availability of data for collected 
variables may be limited due to the non-interventional character of the study, and variables may 
not be comprehensively recorded for all patients. Therefore, availability of data for collected 
variables may not be complete, which can lead to a bias due to missing data. 
There may be an enrolment bias, though sites will be expected to enrol all eligible patients that 
present at their site and maintain screening logs of all patients meeting eligibility criteria, along 
with reasons for non-enrolment of otherwise eligible patients. 
Because of recruitment strategies in this study (recruitment from “GPs”and “specialists; 
accessibility limitations to GPs) there may also be a potential bias in generalizing to overall 
patient population in Germany. 
There are different inclusion/exclusion criteria for cohort A (physician diagnosis) vs. cohort B 
(confirmed diagnosis). This potential selection bias is unavoidable since general practitioners 
do not always use spirometry or body plethysmography to diagnose COPD. 
Selecting patients who have received triple therapy for at least 2 weeks may limit the population 
to adherent patients and those who do not experience significant AEs after initiating triple 
therapy. This can limit the generalizability of the collected data. 
There also may be inconsistent interpretation of eCRF by participating centres. Therefore, all 
centres/sites will undergo standardised training and utilise standardised documentation for 
completing of case report forms at enrolment and for each assessment during the observation 
period. 
By participating in a study, the investigators may feel more obliged to follow treatment 
recommendations. Therefore, there may be deviations from “real world” treatment when making 
therapy decisions (Hawthorne effect). 

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Another point to consider is that patients can drop out in follow-up care for various reasons. To 
mitigate this risk, a supporting concept to follow-up patients (see 3.1.) will be provided as an 
additional document to this study protocol. 
Furthermore, non-interventional studies and studies without a control group can only describe 
correlations but cannot establish causality. 
 
6. 
STUDY CONDUCT, MANAGEMENT & ETHICS  
The study is intended to provide insights into the use of an authorized medicinal products. It is 
therefore a non-interventional study ("Anwendungsbeobachtung", observational study) 
according to § 4 (23) and § 67 (6) of the German Medicines Act (AMG). The study considers 
the 
International 
Society 
for 
Pharmacoepidemiology's 
Guidelines 
for 
Good 
Pharmacoepidemiology Practices of 2015. To the extent relevant, the study also submits to the 
principles set out in the current version of the Declaration of Helsinki of the World Medical 
Association. 
Prior to its launch, this study will be registered to the relevant authorities and professional and 
payers' associations and entered in a publicly accessible study register. The study register will 
disclose consenting centres, and the study will be conducted in accordance with the codex of 
the “freiwillige Selbstkontrolle der Arzneimittelindustrie” (FSA Codex, German voluntary self-
control of pharmaceutical industry). Fees paid to centres and investigators will be reported to 
authorities and professional and payers' associations in accordance with the AMG. Authorities 
may publish information received within the framework of the AMG. Centres may only 
participate, if required permissions are obtained, e.g. of hospital operators. 
The study will be submitted to the ethics committee of the Hannover Medical School 
(Medizinische Hochschule Hannover, MHH) for professional advice. It will only start, after 
queries have been resolved and the ethics committee has issued a positive vote. Subsequent 
changes to the protocol will be communicated to the ethics committee. Any changes that affect 
the Informed Consent Form (ICF) beyond editorial aspects or the scientific value of the project 
or relevantly increase the amount of data collected, will be submitted to the ethics committee as 
an amendment. Like the original protocol and ICF, amendments may only be installed, after the 
ethics committee has issued a positive vote. Locally responsible ethics committees of centres 
are involved as required by the local investigator's professional code (Ärztliche Berufsordnung). 
An ICF must be signed by the participant before his or her participation in the study. The medical 
file for each participant must document the informed consent process and that written informed 
consent was obtained prior to participation in the study. A copy of each signed ICF must be 
provided to the participant. 
The ICF must be revised whenever there are changes to procedures outlined in the informed 
consent or when new information becomes available that may affect the willingness of the 
participant to participate. For any updated or revised ICFs, the medical file for each participant 
must document the informed consent process and that written informed consent was obtained 
for the updated/revised ICF for continued participation in the study. 

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In order to maintain participant confidentiality, each participant will be assigned a unique 
participant identifier upon study enrolment. This participant identifier will be used in place of 
participant name for the purpose of data analysis and reporting. Medical record number or other 
local reference identifiers are not collected as part of the study database. 
All parties will ensure protection of participant personal data and will not include participant 
names on any study forms, reports, publications, or in any other disclosures, except where 
required by law. In accordance with local regulations in Germany, participants will be informed 
about data handling procedures and asked for their consent. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing participant data. Every effort will be made to protect participant confidentiality in 
compliance with Safe Harbour privacy principles, if data are transferred to countries outside the 
European Union. 
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system meets approved established standards 
for the security of health information and is validated. The system also meets the standards of 
the International Conference on Harmonisation (ICH) guideline E6R2 regarding electronic 
study data handling and is available for audit upon request. 
This study will comply with all applicable laws regarding subject privacy. No direct subject 
contact or primary collection of individual human subject data will occur. Study results will be 
in tabular form and aggregate analyses that omits subject identification, therefore informed 
consent, ethics committee or IRB approval are not required. Any publications and reports will 
not include subject identifiers. 
6.1. 
Legal Basis for Processing Individual Human Data 
The authors confirm that study data is Individual Human Data (IHD) owned by GSK and that:  
 The proposed use of the IHD is Study Use* as outlined in the patient consent. 
 The research participants consented to their IHD being processed for Further Research and 
have NOT submitted an Individual Rights Management (IRM) request that limits the use 
of their IHD      
 
* Study Use means - the use of IHD is as stated in the original study protocol and/or aligned with the informed 
consent form to answer the study objectives and satisfy regulatory requirements and learn more about the product 
studied and the disease/condition studied. This includes bringing the product to market or maintaining market 
access which includes working with government agencies, insurers or health care payers and aiding GSK’s 
understanding of clinical efficacy, safety, or effectiveness of the product. 
6.2. 
Monitoring & Data Quality 
To ensure high data quality, it is planned to perform a source data check in 10% of all enrolled 
sites. Sites and patients will be selected through a risk-based algorithm. Details will be described 
in the project plan or the monitoring plan. 

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Before receiving access to the electronic case report form (eCRF) system for data entry, 
participating physicians and/or their study nurses need to participate in a study specific training. 
Furthermore, data entered to the eCRF will undergo data validation at data entry and entries 
violating validation rules will be rejected immediately to be corrected or explained. This assures 
high ad hoc data quality. Further data checks as well as medical reviews of data entered will be 
performed regularly at database level, with incomplete, inconsistent or ambiguous entries 
returned to the sites for clarification. 
6.3. 
Study discontinuation 
Patients may discontinue study participation – with or without formal withdrawal of their 
informed consent and with or without giving reasons – at any time without any detrimental 
effect on their treatment and physician-patient relationship. However, patients discontinuing 
shall be asked to consent to a final data collection ("early withdrawal observation"; see Table 
1). Patients shall also be asked to consent to the further use of their data collected until study 
discontinuation, and this decision shall be documented. If patients do not consent to the further 
use of their data, these data will be deleted or used only in anonymized form conforming to data 
protection regulations (General Data Protection Regulation of the European Union and related 
German law on data protection). 
Furthermore, physicians may also discontinue data collection for specific patients at their own 
discretion, e.g. in cases of non-compliance with treatment or visit schedules agreed upon outside 
the study. For these patients, the physician should fill in all available information to the "early 
withdrawal" forms. 
6.4. 
Adverse Event (AE), Pregnancy Exposure, and Incident 
Reporting 
All clinical safety data will be collected as outlined in the eCRF. Under ICH GCP and all 
applicable local regulations and legal requirements, the Sponsor, is responsible for, and 
undertakes to, assess all clinical safety information arising during the Study (including, but not 
limited to, that set out in the Definition 6.4.1 in order to generate all safety reports as required. 
Definition and reporting of incidents are described in the form "Medical device or combination 
product with device deficiency/incident report form - Investigator Instructions" that can be 
found in the Investigator Site File (ISF). 
6.4.1. 
Definition of adverse events  
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An adverse event (AE) can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medication, whether or not related to the 
medication. 
An adverse drug reaction (ADR) is defined as a noxious and unintended response to a 
medication related to any dose that has at least a reasonable possibility of relationship, with 
facts, evidence and/or arguments that suggest a causal relationship.  

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A serious adverse event (SAE) shall mean any adverse event which meets the following criteria:  
 fatal 
 life threatening 
 disabling or incapacitating 
 requires unplanned in-patient treatment or prolongs existing hospitalization (i.e., 
hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an SAE) 
 is a congenital anomaly in the offspring of a subject 
 medically significant or which may require intervention to prevent the previously stated 
outcomes 
In addition, all occurrences of possible drug-induced liver injury that meet Hy's law criteria must 
be reported as an SAE. These criteria are the following: ALT or AST increase of ≥ 3 x the ULN, 
total bilirubin increase of ≥ 2 x the ULN with absence of initial findings of cholestasis (i.e., no 
AP increase of ≥ 2 x the ULN) and without other explanation for the observed abnormalities. 
For the purposes of this agreement, all ADRs and SAEs will be captured in the eCRF and 
reported to the sponsor as defined in Sections 6.4.2, 6.4.3, and 6.4.4. 
6.4.2. 
Data collected for adverse events 
Investigator completes all data fields of the AE form in the eCRF and sends it to the GSK email 
address below within 24 hours of becoming aware of the event. The address is embedded in the 
EDC system. In case investigator does not actively send AEs fulfilling the minimum case 
criteria, the EDC system will transmit information automatically within 24 hours of entry (see 
also 6.4.4). 
6.4.3. 
Reporting of AEs and timelines 
The study investigator involved is obliged to collect and report from the time of informed 
consent to study termination, all ADRs and SAES, COVID-19 cases, pregnancy exposures, and 
incidents identified as explicitly attributed to any GSK product (including products not covered 
in the specific study objective).   
All ADRs and SAEs will be reported to GSK global safety case management 
(OAX37649@gsk.com) in the form of an electronic safety report within 24 hours of 
documentation via an automated process.  
The safety-related information will be processed according to the legal requirements and 
country specific regulations to the competent authorities. The recording and reporting of safety 
data is in a pseudo anonymous format. 
A study specific Pharmacovigilance  Plan (sPVP) has been approved and provide detailed 
information on the study specific pharmacovigilance processes and procedures. 

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6.4.4. 
Reporting of COVID-19 cases 
COVID-19 cases will be reported based on the WHO criteria using the following categories: 
suspected, probable, and confirmed cases. A COVID-19 form that can also be found in the ISF 
will be used to capture additional COVID case details. COVID-19 infection related SAEs will 
be documented and followed as described in sections 6.4.2 and 6.4.3. 
6.4.5. 
Reporting of pregnancy exposures 
To ensure subject safety, each pregnancy must be reported to the sponsor within 24 hours of 
learning of its occurrence. The pregnancy must be followed up to determine outcome (including 
premature termination) and status of mother and child, which must also be reported to the 
sponsor. Pregnancy complications and elective terminations for medical reasons must be 
reported. 
Investigators will be provided with necessary “pregnancy exposure” and “pregnancy follow up” 
forms and supported by CRA and/or GSK medical affairs in complying with pregnancy 
reporting procedures. 
 
7. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
Based on the objectives and the different timelines of data availability, analyses will be 
performed, and results presented (abstract/poster, full publication). 
Two interim analyses are planned (first interim analysis when at least 825 patients (~75%) of 
the total study population have been recruited, ; second interim analysis after full recruitment or 
after 2 years from study start, whatever occurs earlier). The final analysis will be performed 
after a 24-month follow-up from study enrolment for all patients. 
1. The results of the first interim analysis are planned to be published after all study 
centres have been recruited and all participating patients have completed study visit 1. 
The analysis will describe cross-sectional data of COPD* patients initiated on triple 
therapy in Germany and reasons for initiating triple therapy.  
2. The results of the second interim analysis should be published if the data are available. 
This analysis will focus on the 6 and 12 months data for a subset of the study 
population, covering primarily treatment patterns and reasons for treatment changes as 
well as evolution and patient journey§ of COPD* patients initiated on triple therapy in 
Germany. 
3. The final publication is planned to use data collected until the end of the 24-month 
follow-up. It will concentrate primarily on long-term treatment patterns as well as 
evolution and patient journey of COPD* patients who have initiated triple therapy in 
Germany. 

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Any publication of the results from this study will be consistent with GSK’s publication policy 
and guided by the International Committee of Medical Journal Editors Recommendations for 
the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals (ICMJE 
2018). 
 § Patient journey means the ongoing sequence of care events which a patient follows from the 
point of access into the health system, continuing towards diagnosis and care and ending in 
outpatient care. 
 
8. 
REFERENCES 
Agusti A et al. Precision medicine in airway diseases: moving to clinical practice. Eur Respir J 
2017; 50(4): 1701655. 
Agusti A et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur 
Respir J 2016; 47(2): 410-419. 
Bafadhel M et al. Acute Exacerbations of Chronic Obstructive Pulmonary Disease: 
Identification of Biologic Clusters and Their Biomarkers. Am J Respir Crit Care Med 2011; 
184: 662-671. 
Barnes NC et al. Blood Eosinophils as a Marker of Response to Inhaled Corticosteroids in 
COPD. Eur Respir J 2016; 47(5): 1374-1382. 
Bogart M et al. Clinical Characteristics and Medication Patterns in Patients With COPD Prior 
to Initiation of Triple Therapy With ICS/LAMA/LABA: A Retrospective Study. Respir Med 
2018; 142: 73-80. 
DiSantostefano RL et al. Relationship Between Blood Eosinophils and Clinical Characteristics 
in a Cross-Sectional Study of a US Population-Based COPD Cohort. Respir Med 2016; 112: 
88-96. 
Dransfield MT et al. Disease severity and symptoms among patients receiving monotherapy 
for COPD. Prim Care Respir J 2011; 20: 46-53. 
Ferguson GT et al. Triple combination of budesonide/glycopyrrolate /formoterol fumarate 
using co-suspension delivery technology versus dual therapies in chronic obstructive 
pulmonary disease (KRONOS): a double-blind, parallel-group, randomised controlled trial. 
Lancet Respir Med 2018; 6(10): 747-758. 
Fingleton J et al. Treatable traits of chronic airways disease. Curr Opin Pulm Med 2018; 
24(1): 24-31. 
Gibson PG et al. Asthma in older adults. Lancet 2010; 376(9743): 803-813. 

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Global Initiative for Chronic Obstructive Lung Disease(GOLD) report 2020. Available at 
https://goldcopd.org/gold-reports/. Last accessed May 2020. 
Greulich T et al., GSK data on file (manuscript planned to be submitted to the journal 
‘Pneumology’ in 2020). 
Halpin DM et al. Impact and Prevention of Severe Exacerbations of COPD: A Review of the 
Evidence. Int J Chron Obstruct Pulmon Dis 2017; 12: 2891-2908. 
Jones P et al (a). Improving the Process and Outcome of Care in COPD: Development of a 
Standardised Assessment Tool.  Prim Care Respir J 2009; 18(3): 208-215. 
Jones PW et al (b). Development and First Validation of the COPD Assessment TestEur Resp 
J 2009; 34(3): 648-654. 
Jones PW et al. Tests of the Responsiveness of the COPD Assessment Test Following Acute 
Exacerbation and Pulmonary Rehabilitation. Chest 2012; 142(1): 134-140. 
Khakban A et al. The projected epidemic of chronic obstructive pulmonary disease 
hospitalizations over the next 15 years. A population-based perspective. Am J Resp Crit Care 
2017; 195(3): 287-291. 
Kon SS et al. Minimum Clinically Important Difference for the COPD Assessment Test: A 
Prospective Analysis. Lancet Respir Med 2014; 2(3): 195-203. 
Kurashima K et al. COPD Assessment Test and Severity of Airflow Limitation in Patients 
With Asthma, COPD, and asthma-COPD Overlap Syndrome. Int J Chron Obstruct Pulmon 
Dis 2016; 11: 479-487. 
Lipson DA et al.: FULFIL trial: once-daily triple therapy for patientswith chronic obstructive 
pulmonary disease. Am J Respir Crit Care Med 2017; 196: 438–446. 
Lipson DA et al: Once-daily single-inhaler triple versus dual therapy in patients with COPD. 
N Engl J Med 2018; 378: 1671-1680. 
Lipson DA et al. Reduction in All-Cause Mortality With Fluticasone 
Furoate/Umeclidinium/Vilanterol in Patients With Chronic Obstructive Pulmonary Disease. 
Am J Respir Crit Care Med 2020; 201: 1508-1516. 
Lozano R et al. Global and regional mortality from 235 causes of death for 20 age groups in 
1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet 
2012; 380(9859): 2095-2128. 
May SM et al. Burden of chronic obstructive pulmonary disease: Healthcare costs and beyond. 
Allergy Asthma Proc 2015; 36: 4-10. 
McDonald VM et al (b). Treatable Traits: a new paradigm for 21st century management of 
chronic airway diseases. Eur Respir J 2019; 53:1802058. 

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McDonald VM et al (a). Treatable traits in acute exacerbations of chronic airway diseases. 
Chron Respir Dis 2019, 16: 1479973119867954. 
Sin DD. Contemporary Concise Review 2019: Chronic Obstructive Pulmonary Disease. 
Respirology 2020; 25(4): 449-454. 
Singh D et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β 2-
agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, 
parallel group, randomised controlled trial. Lancet 2016; 388: 963-973. 
Umweltbundesamt. Prevalence of COPD in Germany. Published 05.02.2018. Available from: 
https://www.umweltbundesamt.de/en/topics/health/environmental-medicine/copd. Last 
accessed 07.07.2020. 
Vestbo J et al. Single inhaler extrafine triple therapy versus long-ac-ting muscarinic antagonist 
therapy for chronic obstructive pulmonarydisease (TRINITY): a double-blind, parallel group, 
randomised control-led trial. Lancet 2017; 389: 1919-1929. 
Visentin E et al. An Observation of Prescription Behaviors and Adherence to Guidelines in 
Patients With COPD: Real World Data From October 2012 to September 2014. Curr Med Res 
Opin 2016; 32(9): 1493-1502. 
World Health Organisation (WHO). Disease burden and mortality estimates. Geneva: World 
Health Organisation; 2016. 
https://www.who.int/healthinfo/global_burden_disease/estimates/en/ (accessed 28 May 2020). 
Zysman M et al. Relationship Between Blood Eosinophils, Clinical Characteristics, and 
Mortality in Patients With COPD. Int J Chron Obstruct Pulmon Dis 2017; 12: 1819-24. 
 
 

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APPENDIX 1: SAMPLE SIZE CALCULATION 
This is the original output of the sample size calculation software, in which several scenarios for the 
actual proportion of the primary endpoint (ranging from 0,1 to 0,5) were investigated. Finally the 
sample size was selected based on a proportion of 0,35  
 
PASS 2019, v19.0.1 
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Confidence Intervals for One Proportion 
 
Numeric Results for Two-Sided Confidence Intervals for One Proportion 
─────────────────────── 
Confidence Interval Formula: Exact (Clopper-Pearson) 
 
 
Sample 
 
 
 
 
 
 
Confidence 
Size 
Target 
Actual 
Proportion 
Lower 
Upper 
Width if 
Level 
(N) 
Width 
Width 
(P) 
Limit 
Limit 
P = 0.5 
0,950 
310 
0,070 
0,070 
0,100 
0,069 
0,139 
0,114 
0,950 
427 
0,070 
0,070 
0,150 
0,117 
0,187 
0,097 
0,950 
529 
0,070 
0,070 
0,200 
0,167 
0,237 
0,087 
0,950 
615 
0,070 
0,070 
0,250 
0,216 
0,286 
0,080 
0,950 
685 
0,070 
0,070 
0,300 
0,266 
0,336 
0,076 
0,950 
740 
0,070 
0,070 
0,350 
0,316 
0,386 
0,073 
0,950 
779 
0,070 
0,070 
0,400 
0,365 
0,435 
0,071 
0,950 
803 
0,070 
0,070 
0,450 
0,415 
0,485 
0,070 
0,950 
810 
0,070 
0,070 
0,500 
0,465 
0,535 
0,070 
 
References 
Fleiss, J. L., Levin, B., Paik, M.C. 2003. Statistical Methods for Rates and Proportions. Third Edition. 
John 
   Wiley & Sons. New York. 
Newcombe, R. G. 1998. 'Two-Sided Confidence Intervals for the Single Proportion: Comparison of 
Seven Methods.' 
   Statistics in Medicine, 17, pp. 857-872. 
 
Report Definitions 
Confidence level is the proportion of confidence intervals (constructed with this same confidence level, 
   sample size, etc.) that would contain the population proportion. 
N is the size of the sample drawn from the population. 
Width is the distance from the lower limit to the upper limit. 
Target Width is the value of the width that is entered into the procedure. 
Actual Width is the value of the width that is obtained from the procedure. 
Proportion (P) is the assumed sample proportion. 
Lower Limit is the lower limit of the confidence interval. 
Upper Limit is the upper limit of the confidence interval. 
Width if P = 0.5 is the maximum width for a confidence interval with sample size N. 
 
 
Summary Statements 
───────────────────────────────────────────────────────── 
A sample size of 310 produces a two-sided 95% confidence interval with a width equal to 0,070 
when the sample proportion is 0,100. 
 
 

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PASS 2019, v19.0.1 
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Confidence Intervals for One Proportion 
 
Dropout-Inflated Sample Size 
──────────────────────────────────────────────────── 
 
 
 
Dropout- 
 
 
 
Inflated 
Expected 
 
 
Enrollment 
Number of 
 
Sample Size 
Sample Size 
Dropouts 
Dropout Rate 
N 
N' 
D 
30% 
310 
443 
133 
30% 
427 
610 
183 
30% 
529 
756 
227 
30% 
615 
879 
264 
30% 
685 
979 
294 
30% 
740 
1058 
318 
30% 
779 
1113 
334 
30% 
803 
1148 
345 
30% 
810 
1158 
348 
 
Definitions 
Dropout Rate (DR) is the percentage of subjects (or items) that are expected to be lost at random 
during the 
   course of the study and for whom no response data will be collected (i.e. will be treated as 
"missing"). 
N is the evaluable sample size at which the confidence interval is computed. If N subjects are 
evaluated out 
   of the N' subjects that are enrolled in the study, the design will achieve the stated confidence interval. 
N' is the total number of subjects that should be enrolled in the study in order to end up with N 
evaluable 
   subjects, based on the assumed dropout rate. After solving for N, N' is calculated by inflating N using 
the 
   formula N' = N / (1 - DR), with N' always rounded up. (See Julious, S.A. (2010) pages 52-53, or 
Chow, S.C., 
   Shao, J., Wang, H., and Lokhnygina, Y. (2018) pages 32-33.) 
D is the expected number of dropouts. D = N' - N. 
 

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PASS 2019, v19.0.1 
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Confidence Intervals for One Proportion 
 
Chart Section 
─────────────────────────────────────────────────────────── 
 
 

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PASS 2019, v19.0.1 
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Confidence Intervals for One Proportion 
 
Procedure Input Settings 
────────────────────────────────────────────────────── 
 
 
Design Tab 
Solve For: 
Sample Size 
Confidence Interval Formula: 
Exact (Clopper-Pearson) 
Interval Type: 
Two-Sided 
Confidence Level (1 - Alpha): 
0,95 
Confidence Interval Width (Two-Sided): 
0,07 
P (Proportion): 
0,1 to 0,5 by 0,05 
 
 
 
 

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APPENDIX 2: CODE LISTS 
Patient-Reported Outcomes (PROs) 
COPD Assessment Test (CAT) 
The CAT is a validated measure of health status in COPD. The CAT is an 8-item, 
patient-completed instrument that covers symptoms such as cough, phlegm, chest tightness and 
breathlessness, and disease impacts including physical activity, confidence, sleep and energy. 
The CAT asks patients to score each item according to their current experience; there is no 
specific recall period. Items are scored on a 6-point response scale, with a score of 0 representing 
the patient not experiencing the symptom or the impact at all and a score of 5 representing a 
maximal symptom or impact. All items have equal weighting and so the total score is simply 
the sum of all scores and can range from 0 to a maximum of 40, with higher scores indicating a 
worse health state [Jones 2009 (a); Jones et al. 2009 (b)]. A decrease in score indicates an 
improvement in health status and the minimum clinically important difference (MCID) is 
estimated to be between 1.2 to 2.8 units [Jones 2012, Kon 2014].  
The CAT has been translated into many languages including Japanese and has been shown to 
be easy to understand and to complete by patients in many countries worldwide. 
The CAT has been used previously to compare health-related quality of life (HRQoL) and 
severity of airflow limitation in patients with asthma, ACO and COPD [Kurashima 2016]. 
 
Example of the COPD Assessment Test (CAT) (in the TETRIS study, a German language version 
will be provided): 

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CCI

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CCI

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APPENDIX 3: TABLES AND FIGURES 
Table 1 (see also Section 3.2): 
SCHEDULE OF ACTIVITIES 
Table 1:  Data collection schedule (data will be collected as per clinical routine). EW: Early 
withdrawal. 
Procedure 
Screening  
(up to 14 days 
before visit 1) 
Part 1 
Part 2 
EW 
 
 
Visit 1: Month 0 
Intermediate visits 
Visit 2§:  
Month 6 (-3/+2) 
Intermediate visits 
Visit 3§:  
Month 12 (-3/+5) 
Intermediate visits 
Visit 4§: Month 24 
(-6/no upper limit) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
Patient's sociodemo-graphic 
characteristics 
X 
 
 
 
 
 
 
 
 
Height, weight, BMI 
 
X 
 
X 
 
X 
 
X 
X 
Medical history and 
comorbidities 
X 
X 
 
 
 
 
 
 
 
COPD* medication history 
before initiating triple therapy 
 
X 
 
 
 
 
 
 
 
Maintenance medication for 
COPD*  
X 
X 
 
X 
 
X 
 
X 
X 
Concomitant COPD* medication  
X 
 
X 
 
X 
 
X 
X 
Reasons for initiating triple 
therapy 
 
X 
 
 
 
 
 
 
 
Reasons for changing 
maintenance medication for 
COPD*  
 
 
 
X 
 
X 
 
X 
X 
Smoking status 
 
X 
X 
X 
X 
X 
X 
X 
X 
Narratives of any lung CT 
scansa) 
 
X 
 
X 
 
X 
 
X 
X 
Spirometry testing (FEV1, FVC, 
FEV1/FVC ratio) (if routinely 
collected) 
X 
X 
 
X 
 
X 
 
X 
X 
Body-plethysmo-graphie (if 
performed routinely)  
 
X 
 
X 
 
X 
 
X 
 
DLCO (if routinely collected) 
 
X 
 
X 
 
X 
 
X 
 
FeNO (if routinely collected) 
 
X 
 
X 
 
X 
 
X 
 

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Procedure 
Screening  
(up to 14 days 
before visit 1) 
Part 1 
Part 2 
EW 
 
 
Visit 1: Month 0 
Intermediate visits 
Visit 2§:  
Month 6 (-3/+2) 
Intermediate visits 
Visit 3§:  
Month 12 (-3/+5) 
Intermediate visits 
Visit 4§: Month 24 
(-6/no upper limit) 
Eosinophils (EOS) in blood  
(if routinely collected) 
X 
X 
 
X 
 
X 
 
X 
X 
WBC count (if routinely 
collected) 
 
X 
 
X 
 
X 
 
X 
X 
WBC differential (if routinely 
collected) 
 
X 
 
X 
 
X 
 
X 
X 
hsCRP (if routinely collected) 
 
X 
 
X 
 
X 
 
X 
X 
Healthcare resource utilisation 
(HRU)c) 
 
X 
 
X 
 
X 
 
X 
X 
Eventsb) during study 
 
 
X 
X 
X 
X 
X 
X 
X 
CAT 
X 
X 
 
X 
 
X 
 
X 
X 
EQ-5D (incl. VAS) 
 
X 
 
X 
 
X 
 
X 
X 
AE/SAE review 
 
X 
 
X 
 
X 
 
X 
X 
The eCRF will additionally capture surrogate markers for compliance (e.g. "Did the patient regularly/every 3 
months ask for a new prescription?"). 
 
§ There should be a minimum interval of 3 months between each of the visits (visit 2, 3, 4), otherwise the visit is 
counted as an interim visit. 
 
AE: adverse event; BMI: body mass index; CAT: COPD Assessment Test; COPD: chronic obstructive pulmonary 
disease; COPD*: COPD with or without comorbid asthma; CT: computed tomography; DLCO: diffusing capacity; 
EOS, eosinophils; EQ-5D, European Quality of Life 5 Dimensions; EW: early withdrawal; FeNO, Fraction 
Exspiratory Nitric Oxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; hsCRP, high-
sensitivity C-reactive protein; HRU, healthcare resource utilisation; SAE: serious adverse event; VAS, Visual 
Analogue Scale; WBC, white blood cell; WOCBP: woman of child bearing potential. 
a. 
The radiologist’s narrative will be collected for any historical lung CT scans performed in the year prior to 
the study or any lung CT scans performed as part of routine clinical management during the study. 
b. 
Event includes: unstable COPD, cold requiring antibiotics, exacerbation and hospitalizations. 
c. 
HRU includes: hospitalization, hospitalization in intensive care unit, number of physicians treating the 
patient (primary and secondary care), number of physician goups treating the patient (2 groups), change 
of treating physician, returning from secondary care to primary care physician, returning from acute care 
to primary or secondary care  
 
 
Patient characteristics can be identified in a number of ways. Determination of blood eosinophils and hsCRP may 
aid identification in the same way that DLCO measurements and CT images can help detect persistent lung inflation. 
Sputum secretion, dry cough, or FeNO determinations can also help identify important patient characteristics. The 
detection of "rapid declines" (loss of> 100 ml lung volume per year) may be another important patient characteristic. 
 
 
 

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Table 2 (see also Section 3.5): 
LISTING OF OBJECTIVES AND ASSOCIATED ENDPOINTS 
Objective 
Endpoints 
Evaluate the percentage of patients who 
continuously receive triple therapy 
 Patients who continuously receive triple therapy for 6, 12 and 24 months 
(including stratification by SITT vs. MITT) 
 Time to stop triple therapy 
Describe profiles of COPD patients who 
initiated or are on triple therapy (LAMA/ 
LABA/ICS) in Germany 
Patient and disease characteristics when initiating triple therapy: 
 Percentage of COPD patients with diagnosis of asthma at the age of <40 
years 
 Percentage of patients with peripheral blood EOS of <100 cells/µl, 100-200 
cells/µl, 200-300 cells/µl and > 300 cells/µl 
 Percentage of participants with a physician’s diagnosis of COPD by site 
localization and physician´s group 
 Percentage of participants with different symptom and risk classes (GOLD) 
 Medications received by COPD patients (including OCS), split by physician 
group and site localization 
 Time on triple therapy before study start (<3 months / 3 - <6 months / >=6 
months) 
Describe the distribution and frequency 
of combined treatable traits in COPD 
patients 
 Percentage of patients presenting with a smoking history (when initiating 
triple therapy and at different time points during a 24-month observation 
period) 
 Percentage of patients with a non-smoking history when initiating triple 
therapy 
 Percentage of patients with a FEV1/FVC ratio <0.7 at study enrolment and at 
a 6, 12 and 24 months documentation 
 Percentage of patients with any moderate/severe exacerbation in the 24 
months prior to study enrolment or 3 months prior to each subsequent on-
study visit during a 24-month observation period 
 Percentage of patients with a CAT score ≤10 / 11-19 / ≥20 at baseline and at 
a 6, 12 and 24 months documentation 
 Percentage of patients with peripheral blood eosinophil (EOS) count ≥100 
cells/µl at baseline and at a 6, 12 and 24 months documentation 
 Percentage of patients with chronic bronchitis phenotype  
Describe the percentage of participants 
with at least one switch from triple 
therapy to LAMA/LABA or to ICS/LABA 
after 6, 12 and 24 months 
 Patients with at least one switch from triple therapy to LAMA/LABA after 6, 12 
and 24 months 
 Patients with at least one switch from triple therapy to ICS/LABA after 6, 12 
and 24 months 
Describe COPD treatment decisions of 
German physicians who have initiated 
patients on triple therapy 
 Distribution (by physician group) and frequency of prespecified reasons to 
initiate triple therapy (either MITT or SITT) 
 Percentage of patients changing from triple to dual therapy and back to triple 
therapy (re-escalation) during a 24-month observation period after study 
enrolment (split by SITT and MITT and split by LAMA/LABA and ICS/LABA) 
 Percentage of patients with at least one re-escalation from LAMA/LABA or 
ICS/LABA or LAMA to triple therapy during the 24-month observation period 
 Percentage of patients with at least one change from MITT to SITT or SITT to 
MITT during a 24-month observation period 

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Objective 
Endpoints 
 Percentage of patients with at least one change from SITT to SITT or MITT to 
MITT during a 24-month observation period 
 Percentage of patients changing from once daily to twice daily medication or 
vice versa or between different inhaler types 
 Percentage of patients changing between different inhaler types 
 Distribution (by physician group) and frequency of prespecified reasons to 
change a triple therapy (either MITT or SITT) 
 Distribution and frequency of prespecified reasons to change triple therapy to 
another triple therapy 
 Distribution and frequency of prespecified reasons† to change triple therapy 
to therapy de-escalation 
 Distribution and frequency of prespecified reasons to change de-escalataed 
therapy back to triple therapy (re-escalation) 
Describe clinical outcomes in COPD 
patients initiated on triple therapy 
 Mean annual rate of moderate and/or severe exacerbations over a 24-month 
observation period (including subgroup analysis by peripheral blood 
eosinophil count, smoking status and asthma history) 
 Mean annual rate of hospitalizations due to severe exacerbations 
 Change of lung function parameters during a 24-month observation period 
(including subgroup analysis by peripheral blood eosinophil count, smoking 
status and asthma history) 
 Change of COPD symptoms during a 24-month observation period  
 Change in HRQoL during a 24-month observation period  
 Percentage of COPD patients experiencing a clinically important 
deterioration2 during a 24-month observation period 
 Time to first moderate or severe exacerbation during a 24-month observation 
period 
 Time to first hospitalization / hospitalization during a 24-month observation 
period 
 Time to death during a 24-months observation period 
Describe the patient journey of COPD 
patients initiated on triple therapy 
 Mean annual rate of COPD related primary and secondary care contacts 
 Number of different documenting physicians per patient during a 24-month 
observation period (also split by patients with a severe or moderate or severe 
exacerbation and split by site localization)   
 Mean number of treating physicians per patient over a 24-month observation 
period (also split by site localization and diagnosis) 
 Percentage of patients treated by 1, 2 or all 3 physician groups addressed in 
the study (settled general practitioners, settled pulmonologists, outpatient 
lung centres) 
Describe safety with triple therapy 
 Safety with focus on pneumonia and cardiovascular events 
 Benefit-harm profiles for single-inhaler triple therapies (SITTs, including 
Trelegy, Trimbow and Breztri) 
 Benefit-harm profiles for major multiple inhaler triple therapy (MITT) 
combinations 
 Benefit-harm profiles for triple therapies interrupted by ICS and/or LAMA 
“off/on” periods 
 Benefit-harm profiles for triple therapies switching between SITT and MITT