Investigation of the Clinical, Radiological and Biological Factors Associated With Disease Progression, Phenotypes and Endotypes of COPD in China
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

TMF-13816843 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
208630 
 
1 
 
TITLE PAGE 
Protocol Title: Investigation of the Clinical, Radiological and Biological factors 
associated with disease progression, phenotypes and endotypes of COPD in China  
Protocol Number: 208630/02  
Short Title: Investigation of COPD disease phenotypes and endotypes in China 
Compound Number: 
GW685698+GW642444+GSK573719 
 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Sponsor Contact Address: 
GlaxoSmithKline R&D Shanghai (China) Co., Ltd. 
Building 18, 999 Huanke Road, Pudong District 
Shanghai, 201203, China. 
 
Regulatory Agency Identifying Number(s): Not applicable 
Approval Date: 17-JUN-2021 
 
 
 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
2 
 
SPONSOR SIGNATORY: 
Protocol Title: Investigation of the Clinical, Radiological and Biological factors 
associated with disease progression, phenotypes and endotypes of COPD in China  
Protocol Number: 208630/02  
Compound Number: 
GW685698+GW642444+GSK573719 
 
 
 
 
 
Chris Compton 
Medical Affairs Lead, Respiratory Medical Franchise 
 
Date 
 
The signed page is a separate document. 
 
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
3 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
For protocol 208630/02 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment. 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study.  
Investigator Name: 
 
Professional 
Qualification 
 
Position 
 
Investigator 
Address: 
 
 
Investigator Phone 
Number: 
 
CRU address 
 
CRU phone number 
 
 
 
Investigator Signature 
Date 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
4 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2  
17-JUN-2021 
Amendment 1 
19-JUN-2019 
Original Protocol 
18-OCT-2018 
 
Amendment 2- 17-JUN-2021 
Overall Rationale for Amendment 2: 
This protocol amendment was created to make some minor changes to the study design, 
add clarity to some sections of the protocol, and to correct typographical errors and 
inconsistencies. Protocol changes are described in the table below. 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
5 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title page 
Authors list removed 
Updated based on template 
instructions 
INVESTIGATOR 
PROTOCOL 
AGREEMENT 
PAGE 
Added the investigator protocol 
agreement page  
To meet GSK SOP requirement  
Section 1. 
Synopsis 
Updated information related to 
overall design and number of 
participants 
Align the synopsis with the 
update of the study design in 
Section 5 of this protocol  
Section 2. 
SCHEDULE of 
ACTIVITIES 
(SoA) 
Added a clear definition of a 
month as 30 days and also 
adjusted the visit window from 
28 days to 30 days for V2, V3 
and V4 
 
Clarified that for the 4 clinic 
visits (V1-V4), all the 
participants should be clinically 
stable with no exacerbation or 
other acute medical event for at 
least 30 days prior to each 
scheduled visit 
 
Edited the timeframe around the 
2 exacerbation visits to “at least 
21 days” instead of “at least 6 
months”  
 
 
Added a statement for the sub-
cohort that the planned clinic 
visits should be scheduled with 
an interval of at least 60 days 
after a completed exacerbation 
visit 
 
Edited the visit window of Visit 
1 to “+7 days” instead of “+3 
days”  
 
 
 
 
 
 
To ensure consistency in study 
operation 
 
 
 
 
Ensure that the schedule visits 
intend to assess participants in 
stable state to avoid 
misunderstanding 
 
 
 
 
To prevent this study from 
missing the exacerbations that 
occurred within 6 months of 
each other or at the start of 
study  
 
To provide an appropriate time 
interval between an 
exacerbation visit and a 
scheduled visit for stable state 
 
 
 
To ensure that all baseline 
procedures can be completed 
within a more reasonable 
window once there is any 
participant who is been required 
to undergo a nucleic acid test of 
COVID-19 before initiating the 
onsite screening procedures.  
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
6 
 
Updated the footnote 6 to the 
procedure of lung HRCT scan 
to ensure “The CT scan for an 
exacerbation visit should only 
be performed if the last study 
CT scan performed was more 
than 14 days.” 
 
Added a footnote to the 
procedure of blood draw and 
sputum respectively to ensure 
“No systemic corticosteroids or 
antibiotics used within 14 days 
before collecting the blood or 
sputum samples 
 
Added a sputum sample point at 
V2 for those who do not have a 
qualified sputum cytology 
sample at baseline (footnote 11) 
To clarify the minimal time 
interval between the CT scan 
for an exacerbation visit and a 
CT scan for a scheduled study 
visit 
 
 
 
To ensure obtain accurate 
sputum and EOS assessment 
data in COMPASS study. Any 
use of systemic corticosteroids 
or antibiotics within 14 days 
may affect their results 
 
 
Provide another chance to 
ensure the collection of sputum 
cytology samples in this study 
Section 3.1. 
Benefit/Risk 
Assessment 
Updated the risk assessment 
related to ionising radiation and 
specified that participants <50 
years of age will not be 
included in the sub-cohort, nor 
will females of child bearing 
potential   
To make information clearer  
Section 5.1. 
Overall Design 
Added study sites in Xiamen 
and the rationale behind it 
Xiamen, another coastal city of 
southeast China, is near 
Guangdong province. We added 
one site (maybe more if needed) 
in Xiamen based on feasibility 
to enhance the enrolment of this 
study  
Section 5.2. 
Number of 
Participants 
Removed the minimum 
requirement (15%) for the 
proportion of never smokers in 
each group of main cohort 
while retained the maximum 
requirement (30%), and updated 
Figure 2 
 
Added flexibility for 
recruitment targets of GOLD I 
and GOLD II in main cohort 
 
 
To add the flexibility for Never-
smoker subgroups based on the 
feasibility considerations 
 
 
 
 
 
To ensure a wide and even 
distribution of airflow 
limitation across the patients 
recruited to this study 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
7 
 
Added flexibility for the target 
number of never smokers in 
each group of sub-cohort and 
updated figure 3 
 
Added flexibility for 
recruitment approach of GOLD 
III never smokers in sub-cohort  
 
 
Adjusted the definition of 
Exacerbator. An exacerbation in 
the previous year is defined by 
the occurrence of an episode of 
increased cough (with or 
without phlegm), shortness of 
breath or chest symptoms (chest 
discomfort or tightness) which 
lasted 48 hours or  more and 
interfered with the Participants 
usual activities. The 
requirement for treatment with 
antibiotic ± oral corticosteroid 
has been removed  
To add the flexibility for Never-
smoker subgroups based on the 
feasibility considerations 
 
 
To ensure that the target of 
enrolment of 50 patients with 
GOLD III was achieved as 
planned 
 
COMPASS is primarily 
designed to study patients with 
mild-moderate airways disease. 
Such patients have fewer 
treated exacerbations than those 
with more severe airflow 
limitation. This does not mean 
that they do not have 
exacerbations, it’s equally 
possible that they may be less 
likely to report them. Studies 
with the EXACT diary have 
shown that there may be 2-5 
more unreported exacerbations 
than those that are reported 
(Jones, 2014; Betsuyaku, 2018). 
Patients with unreported 
exacerbations appear to be less 
symptomatic when they are 
stable than those who do report 
them (Leidy, 2014). To ensure 
that we can identify and recruit 
patients whose exacerbations 
are not troublesome enough to 
make them seek treatment, we 
will use an exacerbation 
definition based on a definition 
used in two population surveys 
(BOLD and CANCOLD) that 
included mild subjects (Buist, 
2007; Tan, 2014) 
Section 6.1. 
Inclusion 
Criteria-COPD, 
Chronic 
Bronchitis and 
healthy 
participants 
Changed the age limit for all 
main cohort participants from 
50 years to 40 years 
 
 
 
 
To involve in participants aged 
40-50 to enable the recruitment 
of more early-stage COPD and 
keep consistent with other large 
COPD epidemiological studies  
 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
8 
 
(common to all 
the group of 
participants) 
Identified the additional criteria 
for each group in the sub-cohort 
to allow participants aged 50-80 
years  
Provide clear criteria for the 
sub-cohort to avoid 
misunderstanding 
Section 6.1. 
Inclusion 
Criteria-COPD, 
Chronic 
Bronchitis 
Reduced the pack-year limit for 
all ever smokers in the main 
cohort from 10 to 1 
Allow the recruitment of ever 
smokers with 1-10 pack-year in 
the main cohort. Pack years 
smoking is very closely related 
to age. The typical patient with 
established moderate-severe 
COPD who is for example 65 
years old will have smoked for 
20 years more than a 45 year 
old. 
Section 6.1. 
Inclusion 
Criteria-COPD 
participants 
Edited “A baseline (post-
bronchodilator) FEV1/FVC 
ratio <70%” to “A baseline 
(post-bronchodilator) 
FEV1/FVC ratio <0.70” 
 
 
 
 
 
 
Removed the requirement for 
the severity of historical 
exacerbation event (moderate or 
severe) in the additional criteria 
for sub-cohort 
Use a fraction to 2 decimal 
places rather than a percentage 
of a whole number to make this 
inclusion criterion more precise 
and keep consistent with other 
COPD studies. This becomes 
especially important for patients 
with mild airflow limitation – 
who are an important subgroup 
in COMPASS  
 
Ensure consistency across the 
protocol  
Section 6.1. 
Inclusion 
Criteria-Chronic 
Bronchitis and 
healthy 
participants 
Edited “Baseline post-
bronchodilator FEV1/FVC 
ratio >70%” to “Baseline post-
bronchodilator FEV1/FVC ratio 
≥0.70” 
To involve in participants 
whose Baseline post-
bronchodilator FEV1/FVC ratio 
is greater than or equal to 0.70 
Section 6.2. 
Exclusion 
Criteria-COPD, 
Chronic 
Bronchitis and 
healthy 
participants 
(common to all 
the group of 
participants) 
Specified that COVID-19 
should be excluded in each 
group  
 
Removed “Mandarin” in the 
No. 13 exclusion criterion 
related to read and understand 
Chinese 
Provide specified information  
 
 
 
To make it clear. There are lots 
of local languages in China. 
Mandarin is the most widely 
used official language. To allow 
the participants to participate in 
the study who can speak other 
local languages except 
Mandarin 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
9 
 
Section 6.2. 
Exclusion 
Criteria-Chronic 
Bronchitis and 
healthy 
participants 
Edited “FVC<80% Predicted” 
to “Post-bronchodilator 
FVC<80% Predicted normal” 
According to GOLD and 
ATS/ERS criteria, clarify the 
requirement of post 
bronchodilator FVC <80% 
Predicted normal.  
Section 6.4. 
Screen Failures  
Added “Only in certain special 
cases, re-screening of 
participants will be allowed. 
Investigator will be asked to 
provide detailed information. 
Special cases will be discussed 
at the EST (Empowered Study 
Team) meeting. After 
permission from the medical 
monitor of this study is granted, 
the participants can only be re-
screened once.” 
Re-screening was allowed for 
certain special cases to prevent 
missing early stage COPD 
participants, especially the 
GOLD 1 COPD participants 
Section 9.1. 
Baseline data 
collection 
Added the item of “Number of 
exacerbations in the previous 12 
months and 24 months” 
 
Added more airway parameters 
for spirometry 
Ensure consistency across the 
protocol 
 
 
To achieve a more 
comprehensive evaluation of 
small airway function – which 
is particularly important in mild 
and early disease 
Section 9.2.3. 
Spirometry 
Specified the same 
measurements as baseline 
spirometry 
 
Removed the requirement of 
“Spirometry will be performed 
after the completion of any 
PRO questionnaires” 
Ensure consistency across the 
protocol 
 
 
To reduce the visit time of 
participants 
Section 9.2.6.  
Patient Reported 
Outcome 
Measures 
Added “All Patient reported 
outcome measures should be 
collected in a nice, quiet setting 
without distractions (e.g., 
television, cell phones).”  
 
Removed the original timing 
and order requirements for 
collecting the CAT, mMRC and 
SGRQ-C assessments. Only 
required to collect CAT at the 
beginning of the study visits 
(before any other procedures).   
To ensure the data quality, the 
most important is to have a 
nice, quiet setting to do the 
assessments. 
 
 
To minimize the visit duration 
of the study participants. It’s 
not necessary to require the 
CAT, mMRC and SGRQ-C 
assessments to be done in a 
fixed order at the beginning of 
the study visits.  

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
10 
 
Section 9.2.6.2. 
Evening Diary 
(sub-cohort only) 
Removed the level 5 headings 
and presented headings in 
bullets. 
• 
Exacerbations of 
Chronic Pulmonary Disease 
Tool (EXACT) and Evaluating 
Respiratory Symptoms in 
COPD (E-RS: COPD) 
• 
Additional questions 
Updated as per template 
requirements 
Section 9.3. 
Exacerbation 
Visits (sub-cohort 
only) 
Updated figure 4: removed X in 
second box and corrected 
spelling of units, as well as 
reflected use of EXACT score 
To correct the typo 
Section 10.2.8. 
Interim Analyses 
Deleted the statement of 
“Scientific steering committee 
will oversee the interim 
analyses”. Add the statement, 
The Scientific Steering 
Committee will have sight of, 
and approve, all requests for 
analyses that come from the 
Working Groups 
Clarify the responsibilities of 
the Scientific Steering 
Committee 
Section 11: 
References 
Added references: Jones, 2014; 
Betsuvaku, 2018; Leidy, 2014; 
Buist 2007; Tan, 2014 
To support the data 
Section 12.3. 
Appendix 3: 
Contraceptive and 
Barrier Guidance 
Added this guidance 
Provided the information 
related to Woman of non-child 
bearing potential 
Throughout 
Corrected spelling errors, added 
abbreviations to abbreviation 
list, added punctuations 
wherever applicable 
For consistency and clarity 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
11 
 
TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 4 
1. 
SYNOPSIS ............................................................................................................. 13 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 18 
3. 
BACKGROUND AND STUDY RATIONALE ........................................................... 21 
3.1. 
Benefit/Risk Assessment ............................................................................ 22 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 27 
5. 
STUDY DESIGN .................................................................................................... 28 
5.1. 
Overall Design ............................................................................................ 28 
5.2. 
Number of Participants ............................................................................... 30 
5.3. 
Participant and Study Completion ............................................................... 32 
5.4. 
Scientific Rationale for Study Design .......................................................... 33 
5.5. 
Dose Justification ........................................................................................ 37 
6. 
STUDY POPULATION ........................................................................................... 38 
6.1. 
Inclusion Criteria ......................................................................................... 38 
6.2. 
Exclusion Criteria ........................................................................................ 40 
6.3. 
Lifestyle Restrictions ................................................................................... 42 
6.4. 
Screen Failures........................................................................................... 42 
7. 
TREATMENTS ....................................................................................................... 43 
7.1. 
Treatments Administered ............................................................................ 43 
7.2. 
Dose Modification ....................................................................................... 43 
7.3. 
Method of Treatment Assignment ............................................................... 43 
7.4. 
Blinding ....................................................................................................... 43 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 43 
7.6. 
Treatment Compliance ................................................................................ 43 
7.7. 
Concomitant Therapy.................................................................................. 43 
7.8. 
Treatment after the End of the Study .......................................................... 43 
8. 
DISCONTINUATION CRITERIA ............................................................................. 44 
8.1. 
Discontinuation of Study Treatment ............................................................ 44 
8.2. 
Withdrawal from the Study .......................................................................... 44 
8.3. 
Lost to Follow Up ........................................................................................ 44 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 45 
9.1. 
Baseline data collection .............................................................................. 45 
9.2. 
Follow up data collection ............................................................................. 47 
9.2.1. 
COPD medications and treatments and concomitant 
medications ................................................................................. 47 
9.2.2. 
Smoking status ............................................................................ 47 
9.2.3. 
Spirometry ................................................................................... 48 
9.2.4. 
COPD exacerbations ................................................................... 48 
9.2.5. 
Clinically important deterioration (CID) components .................... 48 
9.2.6. 
Patient Reported Outcome Measures .......................................... 48 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
12 
 
9.2.6.1. 
COPD Assessment Test (CAT) .................................. 48 
9.2.6.2. 
Evening Diary (sub-cohort only).................................. 49 
9.2.6.3. 
Other PRO assessments ............................................ 50 
9.2.7. 
Computed tomography (CT) (sub-cohort only) ............................. 50 
9.2.8. 
Digital physical activity (sub-cohort only)...................................... 50 
9.2.9. 
Biomarker(s) ................................................................................ 51 
9.2.9.1. 
Blood biomarkers ....................................................... 51 
9.2.9.2. 
Sputum microbiome and sputum cytology (sub-
cohort only) ................................................................ 51 
9.2.10. 
Healthcare Resource Utilization and Cost .................................... 51 
9.2.11. 
Mortality ....................................................................................... 52 
9.3. 
Exacerbation Visits (sub-cohort only) .......................................................... 52 
9.4. 
Adverse Events........................................................................................... 53 
9.5. 
Treatment of Overdose ............................................................................... 54 
9.6. 
Safety Assessments ................................................................................... 55 
9.7. 
Pharmacokinetics ....................................................................................... 55 
9.8. 
Pharmacodynamics .................................................................................... 55 
9.9. 
Genetics ..................................................................................................... 55 
10. STATISTICAL CONSIDERATIONS ........................................................................ 56 
10.1. 
Sample Size Determination ........................................................................ 56 
10.1.1. 
Hypotheses .................................................................................. 56 
10.1.2. 
Study Design Considerations ....................................................... 56 
10.1.3. 
Sample size Considerations......................................................... 56 
10.1.4. 
Sample Size Sensitivity ................................................................ 57 
10.1.5. 
Sample Size Re-estimation .......................................................... 58 
10.2. 
Key Elements of Analysis Plan ................................................................... 58 
10.2.1. 
Populations for Analyses ............................................................. 58 
10.2.2. 
Descriptive Analyses ................................................................... 58 
10.2.3. 
Disease Progression Analyses .................................................... 58 
10.2.3.1. Main Cohort ................................................................ 59 
10.2.3.2. Sub-cohort .................................................................. 59 
10.2.4. 
Phenotypic Analyses ................................................................... 60 
10.2.5. 
Treatment Pattern and Healthcare Resource 
Utilization/Cost ............................................................................. 60 
10.2.6. 
Safety Analyses ........................................................................... 61 
10.2.7. 
Other Analyses ............................................................................ 61 
10.2.8. 
Interim Analyses .......................................................................... 61 
11. REFERENCES ....................................................................................................... 62 
12. APPENDICES ........................................................................................................ 66 
12.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 66 
12.2. 
Appendix 2: Study Governance Considerations .......................................... 68 
12.3. 
Appendix 3: Contraceptive and Barrier Guidance ....................................... 72 
12.3.1. 
Definitions: ................................................................................... 72 
12.4. 
Appendix 4: Protocol Amendment History ................................................... 73 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
13 
 
1. 
SYNOPSIS 
Protocol Title: Investigation of the Clinical, Radiological and Biological factors 
associated with disease progression, phenotypes and endotypes of COPD in China 
Short Title:  Investigation of COPD disease phenotypes and endotypes in China   
Rationale: 
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and 
mortality resulting in significant humanistic and economic burden to patients, healthcare 
system and society worldwide. COPD prevalence in China has been significantly 
increasing. A national screening survey, conducted in 2002-2004, reported that the 
overall prevalence of spirometry-defined COPD among people over 40-year-old was 
8.2% in China.  The recently published China Pulmonary Health study (2018) indicated 
the prevalence of COPD among Chinese over 40 years old had increased to 13.7%. A 
study in 2013 including 634 COPD patients from 83 tertiary hospitals in 17 provinces in 
China estimated the average cost of COPD per patient per year to be RMB 20,107.58. 
Further, COPD led to a large productivity loss of RMB 6,941.33 yuan/per person-year; 
the value of working time loss was RMB 613.86 yuan/per person-year. Although COPD 
management in China has been greatly improved over the past decades, many challenges 
persist. One of them is substantial under-diagnosis: up to 65% of people with airflow 
limitation pattern compatible with COPD were found not to have a clinical COPD 
diagnosis. Further, majority of COPD patients (64.7%) exhibit high symptom burden, 
defined as at least one respiratory symptom (cough, phlegm, wheezing, and 
breathlessness), despite treatment.  
COPD prevalence and disease burden have been well studied in North America and 
Western Europe through large cohort studies. The ECLIPSE study recruited patients with 
moderate-severe airflow limitation from secondary care; COPDGene, COPDMAP and 
SPIROMICS largely recruited patients of a wide range of disease severity from a variety 
of healthcare settings. However, so far there have been no dedicated cohort studies 
conducted in China with a specific focus on high density phenotyping of COPD, 
including biomarkers and clinical features associated with disease activity, severity and 
progression in China. Existing large populational cohorts, like the China Kadoorie 
Biobank, inform on the extent of disease burden of airflow limitation; however, due to its 
general population-based nature, they provide only limited information on clinical and 
humanistic burden and therapeutic management of diagnosed COPD. 
With an aging population and persistent air pollution in China, the humanistic and 
economic burden of COPD is expected to increase and will require more healthcare 
resources in the future. COPD has been identified as a key disease of focus under the 
China government’s Thirteenth Five programme. Therefore, to inform clinical practice 
and aid public health resource allocation, it is important to advance knowledge and 
understanding of disease progression and clinical management of COPD, especially at 
early disease stages, in China.  
Whilst COPD is a common disease across the world, its phenotypes and patterns of 
disease progression may differ geographically, impacting approaches to precision 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
14 
 
medicine in China. Recent international studies showed substantial geographic variations 
in respiratory symptoms and other respiratory illnesses in COPD patients. The disease 
progression of COPD and clinical management in China is largely unknown. Recent 
studies in non-Asians have demonstrated that acute exacerbations of COPD (AECOPD) 
can be subdivided by type: infections (bacterial and/or viral), eosinophilic, and pauci-
inflammatory and each subtype has been associated with increased levels of specific 
blood biomarkers. Moreover, recent data indicate that bacterial and eosinophilic 
exacerbations are likely to repeat within an individual, suggesting endotypic differences 
in Western frequent exacerbators. There is a need to compare and validate findings from 
cohorts conducted in predominantly Caucasian populations to guide clinical development 
of new COPD medicines in China. 
With recent technology advances, Electronic Data Capture (EDC) has steadily increased 
in clinical research. Meanwhile, the Electronic Health Record (EHR) systems are 
becoming essential to routine clinical practice and has the potential to facilitate large-
scale clinical research. Therefore, this study also aims to assess the feasibility of 
integrating EHR, electronic clinical outcome assessments (eCOA), biomarkers and 
physical activity data to support application of Digital Data Analytics (DDA) platform in 
China (e.g. direct digital data capture and integration). 
Objectives and Endpoints: 
Research Questions & Objectives 
Endpoints 
1. Evaluate whether the predictors of 
COPD disease progression identified 
in Western cohorts are applicable in 
China. 
• To evaluate disease 
progression in COPD and non-
COPD participants over 2.5 
years as assessed by lung 
function, exacerbation 
frequency, health status, lung 
high-resolution computed 
tomography (HRCT) scan, and 
changes in physical activity. 
Main cohort 
Change from baseline in forced expiratory 
volume in 1 second (FEV1) and rate of 
decline in FEV1 
Change from baseline in forced vital 
capacity (FVC) and rate of decline in FVC 
Rate of moderate/severe exacerbations*  
Change from baseline in COPD 
Assessment Test (CAT) score 
Assess CAPTURE to identify under 
diagnosed COPD patients in Chinese 
population 
Frequency of Clinically Important 
Deterioration (CID) and its components 
Death 
Additional for sub-cohort 
Change in Evaluating Respiratory 
Symptoms in COPD (E-RS: COPD) 
scores 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
15 
 
Research Questions & Objectives 
Endpoints 
Characterisation of   EXAcerbation of 
COPD Tool (EXACT) events  
Change from baseline in airway thickness 
by lung HRCT  
Change in lung density by lung HRCT  
Change in physical activity measures (e.g. 
Daily steps, bouts of activity per day) 
2. Characterise stable disease and 
exacerbation phenotypes in China 
through assessment of blood 
biomarkers, lung microbiome and 
radiological features of COPD 
 
Main cohort: 
Plasma fibrinogen and high-sensitivity C-
Reactive Protein (hsCRP) 
Differential blood cell count (e.g. 
eosinophils, neutrophils) and haemoglobin 
Additional for sub-cohort 
Blood biomarkers including but not 
limited to Serum interferon- γ -inducible 
protein -10 (IP-10), soluble Receptor for 
Advanced Glycation End Products 
(sRAGE), Club cell protein (CC16) and 
HbA1c 
Sputum microbiome as assessed by 
molecular methods 
Sputum total differential cell counts 
percentage
 
 
3. Characterise treatment pathways and 
healthcare resource utilization and 
costs in COPD  
Frequency of treatment with COPD 
medications; Treatment patterns at the 
time of study entry and during the study 
period 
Count of outpatient visits, emergency 
visits, hospitalizations (overall and 
COPD-specific)  
Direct medical costs associated with 
COPD medications and COPD disease 
management  
Insurance coverage and patient out-of-
pocket payment 
CCI

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
16 
 
Research Questions & Objectives 
Endpoints 
4. Test the feasibility of integrating 
electronic health records, electronic 
clinical outcome assessments (eCOA) 
and physical activity data to support 
application of digital data analytics 
(DDA) platform in China studies (e.g. 
direct digital data capture and 
integration) 
NA 
*Moderate exacerbations are defined as COPD exacerbations that require either systemic 
corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. Severe exacerbations 
are defined as COPD exacerbations requiring hospitalization (including intubation and admittance 
to an ICU) or result in death.  
Overall Design: 
This is a 2.5-year multi-center, prospective, longitudinal, non-drug interventional cohort 
study to investigate the pattern of COPD disease phenotypes, clinical, humanistic and 
healthcare utilization burden, disease progression, and management in China. Participants 
will be recruited from multiple hospitals (excluding tier 1) across Guangdong and Fujian 
province. In this study, hospitals at prefecture-level and above will be categorized as 
Type A hospitals; those below prefecture-level will be Type B hospitals. Site/hospital 
selection will consider pollution level and hospital type representativeness, as well as 
feasibility of applying digital data capture and hospital data integration.  
A wide range of COPD patients across Global Initiative for Chronic Obstructive Lung 
Disease (GOLD) grade I-IV will be included. Participants with chronic mucus 
hypersecretion who don’t meet the criteria of COPD will be recruited in the chronic 
bronchitis group. Never smokers without COPD or chronic mucus hypersecretion or 
chronic respiratory symptoms and without other significant disease burden will be 
recruited in the healthy control group.  
Baseline data will be recorded for all participants at Visit 1 and subjects will be followed 
up at 6 months and then every 12 months for a total of 2.5 years. Study visits will be 
conducted within ±30 days of the planned date. In addition to study visits, COPD and 
chronic bronchitis participants will be contacted by phone on a trimonthly basis within ± 
7 days of the planned date to assess the CAT and collect information on exacerbations 
and COPD medications; healthy controls will be contacted by phone on trimonthly basis 
within ± 7 days of the planned date to assess the CAT only. 
A subset of participants from selected Type A hospitals are planned to receive additional 
assessments including digital monitoring of daily steps; daily digital diary (EXACT/E-
RS: COPD); monthly CAT; collection of blood for study defined biomarkers; lung HRCT 
scanning; sputum collection for molecular methods analysis. If moderate/severe 
exacerbations are reported by the participants or detected by investigators during the 
acute phase of event, this subset of participants will be invited to site hospital for an 
exacerbation visit (no more than twice throughout the study). Participants from this sub-
cohort constitute the Biomarker and Digital sub-cohort.  

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
17 
 
In addition, daily air pollution index throughout the study in each participating city will 
be collected retrospectively from a local environmental monitoring centre. 
This cohort study will not provide or recommend any treatment. Patients’ diagnosis and 
treatment will be left to their physicians’ judgement and routine practice. Data will be 
collected from various sources, including electronic case report forms (CRF), EHR from 
hospital databases, and other electronic sources, such as eCOA, and wearable devices.  
 
Number of Participants: 
A total of 2,000 participants are planned to be enrolled, consisting of 1,700 participants 
with COPD, 180 with chronic bronchitis but without COPD (i.e. without fixed airflow 
limitation), and 120 never smoker non-COPD healthy controls. COPD subjects will be 
further classified using the GOLD grades I – IV (i.e. mild, moderate, severe and very 
severe airflow limitation). To better understand the disease progression of early-stage 
COPD, i.e. GOLD I and II grades, targets will be set for COPD participants will be 
recruited in the following manner: GOLD I: 700, GOLD II: 700, GOLD III: 200, GOLD 
IV: 100. The purpose is to ensure a wide and even spread of the degree of airflow 
limitation across the study population. The number of participants recruited to each 
GOLD grade will be monitored and targets adjusted as necessary to ensure an even 
distribution. Among each GOLD grade and chronic bronchitis group, up to 30% of never 
smokers will be recruited in each group. All patient population sizes are approximate and 
allow  10% for feasibility. 
 
All participants will be recruited from Type A and Type B hospitals in Guangdong and 
Fujian province. To represent the difference in patient profile and practice between 
different hospitals, the ratio of participants from Type A and Type B hospitals will be 
2:1.  Specifically, healthy control participants will be recruited from the physical 
examination department at site hospitals. For the healthy control group to be comparable 
with COPD participants, pre-set criteria on demographic profile (i.e. age, gender) will be 
specified in detail in the SRM based on previous studies or available real-world data. 
When appropriate, matching methods will also be used to adjust for differences in 
baseline factors (e.g. age, gender) in statistical analyses. Matching of the cohorts will be 
considered to address specific questions, e.g. biomarkers analysis. Methods to achieve 
balanced cohorts will be chosen based on a hypothesis and the extent of underlying 
differences between the cohorts and detailed in the main or ad-hoc RAP. 
More assessments will be conducted among the 400 Biomarker & Digital sub-cohort 
participants who will be all recruited only from selected Type A hospitals. The sub-
cohort will consist of 50 never smoker healthy control, 100 chronic bronchitis (N never 
smoker: up to 25), 100 GOLD I (N never smoker: up to 25), 100 GOLD II (N never 
smoker: up to 25) and 50 GOLD III participants (N never smoker: up to 20).  All patient 
population sizes are approximate and subject to feasibility and the same considerations 
apply regarding breadth and evenness of spread of severity as apply to the main study 
cohort. 

TMF-13816843 
CONFIDENTIAL 
 
 
208630 
 
18 
 
2. 
SCHEDULE OF ACTIVITIES (SOA) 
Study participants will be followed up for 2.5 years and a total of 4 clinic visits (baseline, 6, 18, and 30 months) are scheduled for study 
assessments with a visit window of ±30 days (Table 1). Baseline data will be collected at Visit 1. In addition, COPD and chronic 
bronchitis participants will be contacted by phone on trimonthly basis within ± 7 days of the planned date to assess the CAT and to collect 
information on exacerbation rates and COPD medications; healthy controls will be contacted by phone on trimonthly basis within ± 7 
days of the planned date to assess the CAT only. For the 4 clinic visits (V1-V4), all the participants should be clinically stable with no 
exacerbation or other acute medical event for at least 30 days prior to each scheduled visit.  
A subset of participants will receive additional digital and biomarker assessments during the study. If moderate/severe exacerbations are 
reported by the participants or detected by the investigators during the acute phase of event, the participant will be invited to site hospital 
for an exacerbation visit. If multiple moderate/severe exacerbations are reported or detected, the participants will be contacted in 
consecutive manner for an exacerbation visit. The total number of the exacerbation visits should be no more than 2, with an interval of at 
least 21 days. Please note, for the sub-cohort, the planned clinic visits should be scheduled with an interval of at least 60 days after a 
completed exacerbation visit. When any participant in the sub-cohort is implemented an exacerbation visit, then his/her next planned 
clinic visit (V2-V4) should be scheduled at least 60 days after completing this exacerbation visit. In this case, the participant’s clinic visit 
may be scheduled outside of the time window of ±30 days, which will not be considered as a Protocol Deviation (for more information 
please refer to the Protocol Deviation Management Plan [PDMP] for this study). 
Table 1 
Time and event table 
Protocol Activity 
Screen/Baseline 
Study visit 
  
visit 
V1 
V2 
V3 
V4 
EW 
Exacerbation 
visit (≤2)1 
Study month 
M0 
M6 
M18 
M30 
window 
 +7 days 
±30 days 
±30 days 
±30 days 
  
 
Procedures 
  
Informed consent2 
X 
- 
- 
- 
- 
- 
Demography 
X 
- 
- 
- 
- 
- 
Medical history 
X 
- 
- 
- 
- 
- 
Health and lifestyle information/Exposures 
X 
- 
- 
- 
- 
- 

TMF-13816843 
CONFIDENTIAL 
 
 
208630 
 
19 
 
Protocol Activity 
Screen/Baseline 
Study visit 
  
Inclusion/Exclusion Criteria   
X 
- 
- 
- 
- 
- 
COPD and Exacerbation History3 
X 
- 
- 
- 
- 
- 
Concurrent medications 
X 
X 
X 
X 
X 
- 
Smoking status 
X 
X 
X 
X 
X 
- 
Spirometry7 
X 
X 
X 
X 
X 
X 
Reversibility Testing 
X 
 - 
-  
- 
- 
- 
Patient reported  
mMRC  
X 
- 
- 
- 
- 
  
SGRQ-C 
X 
- 
- 
- 
- 
 
 
CAPTURE 
X 
 
X 
 
 
 
Questionnaires 
CAT (on-site visit) 
X 
X 
X 
X 
- 
X 
  
CAT (Phone Call) 
Trimonthly Phone Call4 
  
Healthcare resource utilization and cost 
- 
X 
X 
X 
X 
X 
Assessments 
  
COPD exacerbation assessment (on site visit)5 
-  
X 
X 
X 
X 
X 
COPD exacerbation assessment (Phone Call)5 
Trimonthly Phone Call4 
  
COPD medication and treatment (on site visit)5 
X 
X 
X 
X 
X 
X 
COPD medication and treatment (Phone Call)5 
Trimonthly Phone Call4 
  
Death  
- 
 X  
  
Serious Adverse Event assessment12 
 
X 
X 
X 
X 
X 
Lab 
  
Blood Draw13 for e.g. fibrinogen/hsCRP/Cell count 
X 
- 
- 
X 
X 
X 
Sub-cohort only 
  
Lung HRCT scan6 
X 
- 
- 
X 
X 
X 
Daily steps 
X8 
- 
X8 
- 
- 
- 
Evening diary (EXACT plus additional questions) 
X9 
- 
X9 
- 
- 
- 

TMF-13816843 
CONFIDENTIAL 
 
 
208630 
 
20 
 
Protocol Activity 
Screen/Baseline 
Study visit 
  
Monthly CAT  
X10 
- 
X10 
- 
- 
- 
Blood biomarkers (inclusive of serum sRAGE, CC16, IP-10，
HbA1c) 
X 
- 
- 
X 
X 
X 
Sputum cytology11 
X 
- 
- 
X 
X 
X 
Sputum microbiome11 
X 
- 
- 
X 
X 
X 
CAT=COPD assessment test, COPD=Chronic Obstructive Pulmonary Disease, HRCT=High-resolution computed tomography, EW=Early Withdrawal, EXACT=EXAcerbation of COPD 
Tool; SGRQ-C=St.George’s Respiratory Questionnaire for COPD. CAPTURE=COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk 
1. Exacerbation visits only apply to subjects included in the Biomarker & Digital sub-cohort. Moderate exacerbations are defined as COPD exacerbations that require either systemic 
corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. Severe exacerbations are defined as COPD exacerbations requiring hospitalization or result in death. 
2. Informed consent must be conducted at the screen visit prior to performing any study procedures. 
3. For COPD participants only; 
4. When a trimonthly telephone interview overlaps a clinical visit, the COPD exacerbation assessment, COPD medication and treatment questionnaires will be completed at the clinic 
visit. A month is defined as 30 days in this study. 
5. Data collection of COPD exacerbation assessment, COPD medication and treatment are not required for the healthy control participants. 
6. CT scan should only be performed at withdrawal visit if the last study CT performed was more than a year ago. Inspiratory and expiratory HRCT scans are required at Visit 1 and 
Visit 4, while only inspiratory scan will be conducted on exacerbation visit. The CT scan for an exacerbation visit should only be performed if the last study CT scan performed was 
more than 14 days.  
7. Pre-and post- bronchodilator values of spirometry test will be collected at each site visit.  
8. Physical activity will be evaluated by daily steps as assessed by a wrist band dispensed at baseline.  Participants are required to keep wearing the wrist band for 1 month from 
Visit 1 (baseline) and Visit 3 
9. Daily digital EXACT measurement for 6 months from Visit 1 (baseline) and Visit 3 
10. Monthly digital measurement from baseline for 6 months, and monthly digital measurement from V3 for 6 months 
11. Sputum can be collected spontaneously or can be induced, as per investigator judgement. Sputum sampling should only be done if, in the opinion of the investigator, it is safe for 
the subject. No systemic corticosteroids or antibiotics used within 14 days before collecting the sputum sample. Participants who do not have a qualified sputum cytology sample 
at baseline will be requested to have a sputum cytology sample taken or re-sampled at V2 (Note: for COPD participants, they should be clinically stable and has no exacerbations 
for at least 30 days prior to sampling).  
12. Only SAEs relating to the study procedures are collected.  
13. No systemic corticosteroids or antibiotics used within 14 days before collecting the blood sample. 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
21 
 
3. 
BACKGROUND AND STUDY RATIONALE 
COPD is a leading cause of morbidity and mortality resulting in significant humanistic 
and economic burden to patients, healthcare system and society worldwide. COPD 
prevalence in China has been significantly increasing. A national screening survey, 
conducted in 2002-2004, reported that the overall prevalence of spirometry-defined 
COPD among people over 40-year-old was 8.2% in China [Zhong, 2007].The recently 
published China Pulmonary Health study (2018) indicated the prevalence of COPD 
among Chinese over 40 years old had increased to 13.7% [Wang. 2018]. A study in 2013 
including 634 COPD patients from 83 tertiary hospitals in 17 provinces in China 
estimated the average cost of COPD per patient per year to be RMB 20,107.58. Further, 
COPD led to a large productivity loss of RMB 6,941.33 yuan/per person-year; the value 
of working time loss was RMB 613.86 yuan/per person-year [Li, 2015]. Although COPD 
management in China has been greatly improved over the past decades, many challenges 
persist. One of them is substantial under-diagnosis: up to 65% of people with airflow 
limitation pattern compatible with COPD were found not to have a clinical COPD 
diagnosis [Zhong, 2007]. Further, majority of COPD patients (64.7%) exhibit high 
symptom burden, defined as at least one respiratory symptom (cough, phlegm, wheezing, 
and breathlessness), despite treatment [Zhong, 2007].  
COPD prevalence and disease burden have been well studied in North America and 
Western Europe through large cohort studies. The ECLIPSE study recruited patients with 
moderate-severe airflow limitation from secondary care [Vestbo, 2008; Vestbo, 2014; 
Faner, 2014]; COPDGene [Regan, 2010], COPDMAP [Wang, 2017] and SPIROMICS 
[Couper, 2014] largely recruited patients of a wide range of disease severity from a 
variety of healthcare settings. However, so far there have been no dedicated cohort 
studies conducted in China with a specific focus on high density phenotyping of COPD, 
including biomarkers and clinical features associated with disease activity, severity and 
progression in China. Existing large populational cohorts, like the China Kadoorie 
Biobank, inform on the extent of disease burden of airflow limitation; however, due to its 
general population-based nature, they provide only limited information on clinical and 
humanistic burden and therapeutic management of diagnosed COPD [Kurmi, 2014]. 
With an aging population and persistent air pollution in China, the humanistic and 
economic burden of COPD is expected to increase and will require more healthcare 
resources in the future. COPD has been identified as a key disease of focus under the 
government’s Thirteenth Five programme. Therefore, to inform clinical practice and aid 
public health resource allocation, it is important to advance knowledge and understanding 
of disease progression and clinical management of COPD, especially at early disease 
stages, in China.  
Whilst COPD is a common disease across the world, its phenotypes and patterns of 
disease progression may differ geographically, impacting approaches to precision 
medicine in China. Recent international studies showed substantial geographic variations 
in respiratory symptoms and other respiratory illnesses in COPD patients [Kim, 2017; 
Landis, 2014]. The disease progression of COPD and clinical management in China is 
largely unknown. Recent studies in non-Asians have demonstrated that acute 
exacerbations of COPD (AECOPD) can be subdivided by type: infections (bacterial 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
22 
 
and/or viral), eosinophilic, and pauci-inflammatory and each subtype has been associated 
with increased levels of specific blood biomarkers [Wilkinson, 2017; Wang, 2016; Wang, 
2017; Dickson, 2014; Gomez, 2016]. Moreover, recent data indicate that bacterial and 
eosinophilic exacerbations are likely to repeat within an individual, suggesting endotypic 
differences in Western frequent exacerbators [Mayhew, 2018]. There is a need to 
compare and validate findings from cohorts conducted in predominantly Caucasian 
populations to guide clinical development of new COPD medicines in China. 
With recent technology advances, Electronic Data Capture (EDC) has steadily increased 
in clinical research. Meanwhile, the Electronic Health Record (EHR) systems are 
becoming essential to routine clinical practice and has the potential to facilitate large-
scale clinical research. Therefore, this study also aims to assess the feasibility of 
integrating EHR, electronic clinical outcome assessments (eCOA), biomarkers and 
physical activity data to support application of Digital Data Analytics (DDA) platform in 
China (e.g. direct digital data capture and integration). 
3.1. 
Benefit/Risk Assessment 
This cohort study will not provide or recommend any treatment; thus, detailed 
information on investigational product (IP) is not applicable. The participants’ diagnosis 
and treatment will be left to their physicians’ judgement and routine practice. 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
23 
 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Investigational Product (IP)  
No investigational product (IP) will be 
investigated in this study; thus, detailed 
information on IP is not applicable 
 
Not applicable 
 
Not applicable 
Study Procedures  
Potential risk for injury with phlebotomy 
Risks with phlebotomy include 
bruising, bleeding, infection, and nerve 
damage. 
• Procedures to be performed by trained 
personnel (i.e., study nurse) 
Potential risk for sputum induction 
Risks associated with sputum induction 
include worsened expiratory airflow 
limitation and oxygen desaturation 
• Sputum induction to be conducted in sub-
cohort participants only. 
• Procedures to be performed by trained 
personnel (i.e., study nurse). 
• A standardized sputum induction protocol to 
be applied which have minimal deleterious 
effects on lung function and oxygen 
saturation and safety checks during the 
procedure. 
Subjects exposed to ionising radiation as a 
consequence of participation in this study. 
The ionising radiation exposure comes 
from repeated low dose CT scans of the 
chest.   
Participants with COPD will be subject 
to a maximum of 6 scans, resulting in 
an effective dose of ionising radiation in 
the range 10-16mSv. This is equivalent 
The study has been designed to keep the 
radiation dose as low as reasonably practicable 
(ALARP) whilst obtaining images of sufficient 
quality to meet the objectives. Participants <50 
years of age will not be included in the sub-
cohort, nor will females of child bearing 
potential. Healthy control participants will be 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
24 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
to approximately 4.5-7 times the 
average yearly exposure (2.3 mSv) from 
natural background radiation in China. 
The additional risk of developing a fatal 
malignancy as a result of a 16mSv 
exposure has been estimated as 
approximately 1 in 1250 for an adult in 
normal health. The reduced life 
expectancy of the patient population to 
be studied will result in a lower risk for 
these individuals. 
Healthy control participants will be 
subject to a maximum of 4 scans, 
resulting in an effective dose of ionising 
radiation in the range 8-12mSv. This is 
equivalent to approximately 3.5-5.5 
times the average yearly exposure (2.3 
mSv) from natural background radiation 
in China. The additional risk of 
developing a fatal malignancy as a 
result of a 12mSv exposure has been 
estimated as approximately 1 in 1650 
for an adult in normal health. 
The guidance set out by the 
International Commission on 
Radiological Protection in ICRP 62 is 
generally followed when considering 
subject to fewer CT scans than participants 
with COPD. 
Each CT scan will be optimised, using 
Automatic Exposure Control, to obtain 
sufficient image quality whilst using the least 
possible radiation, hence the ranges of possible 
dose estimates. The highest exposures will be 
required only in larger participants with a BMI 
>30. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
25 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
radiation exposure for research 
purposes. These radiation doses fall 
between Risk Categories IIb 
(intermediate risk) and IIIa (moderate 
risk) and are justified by the expected 
scientific impact of the study which is 
expected to provide information that 
will have a beneficial impact on the 
management of COPD in the target 
population. 
 
Wrist band 
Allergy to wrist strap, belt clip, belt 
strap or device case (if device is put on 
upside down). Worn on broken skin 
If participants allergy to the rubber wrist strap 
or have broken skin around wrist, please do 
not included them in the sub-cohort.   
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
26 
 
Benefit Assessment 
Evidence on disease progression, e.g.; decline in lung function, exacerbation types and 
rates and worsening of physical activity, will allow healthcare professionals in China to 
target innovative medicines to the right patients.  
In this study, participants will be monitored regularly throughout the 2.5-year follow-up. 
This will help their physicians to have a better overview of their disease status, phenotype 
and hence provide holistic disease management reflecting underlying disease severity, its 
progression and the participant’s health status. 
Overall Benefit: Risk Conclusion 
This observational cohort study will provide an opportunity to the participants and their 
physicians to have a comprehensive overview of their disease and to inform 
individualized therapy. There is no investigational drug. Considering the measures taken 
to minimize risk to participants in this study, the potential risk from the study procedures 
is minimal and overall can be justified by the anticipated benefits. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
27 
 
4. 
OBJECTIVES AND ENDPOINTS 
Research Questions & Objectives 
Endpoints 
Evaluate whether the predictors of COPD 
disease progression identified in Western 
cohorts are applicable in China. 
• To evaluate disease progression in 
COPD and non-COPD participants 
over 2.5 years as assessed by lung 
function, exacerbation frequency, 
health status, lung HRCT scan, and 
changes in physical activity. 
Main cohort 
Change from baseline in forced expiratory 
volume in 1 second (FEV1) and rate of 
decline in FEV1 
Change from baseline forced vital 
capacity (FVC) and rate of decline in FVC 
Rate of moderate/severe exacerbations*  
Change from baseline in COPD 
Assessment Test (CAT) score 
Assess CAPTURE to identify under 
diagnosed COPD patients in Chinese 
population 
Frequency of Clinically Important 
Deterioration (CID) and its components 
Death 
Additional for sub-cohort 
Change in Evaluating Respiratory 
Symptoms in COPD (E-RS: COPD) 
scores 
Characterization of EXAcerbation of 
COPD Tool (EXACT) events  
Change from baseline in airway thickness 
by lung HRCT  
Change in lung density by lung HRCT  
Change in physical activity measures (e.g. 
Daily steps, bouts of activity per day) 
Characterise stable disease and 
exacerbation phenotypes in China through 
assessment of blood biomarkers, lung 
microbiome and radiological features of 
COPD 
 
Main cohort: 
Plasma fibrinogen, Serum high-sensitivity 
C-Reactive Protein (hsCRP) 
Differential blood cell count (including 
eosinophils, neutrophils) and hemoglobin 
Additional for sub-cohort 
Blood biomarkers including but not 
limited to Serum interferon- γ -inducible 
protein -10 (IP-10), soluble Receptor for 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
28 
 
Research Questions & Objectives 
Endpoints 
Advanced Glycation End Products 
(sRAGE), Club cell protein (CC16)) and 
HbA1c 
Sputum microbiome as assessed by 
molecular methods  
Sputum total differential cell counts and 
percentage  
Characterise treatment pathways and 
healthcare resource utilization and costs in 
COPD  
Frequency of treatment with COPD 
medication and Treatment patterns at the 
time of study entry and during the study 
period 
Count of outpatient visits, emergency 
visits, hospitalizations (overall and 
COPD-specific, separately)  
Direct medical costs associated with 
COPD medications and COPD disease 
management  
Insurance coverage and patient out-of-
pocket payment 
Test the feasibility of integrating 
electronic health records, electronic 
clinical outcome assessments (eCOA) and 
physical activity data to support 
application of digital data analytics 
(DDA) platform in China studies (e.g. 
direct digital data capture and integration) 
NA 
*Moderate exacerbations are defined as COPD exacerbations that require either systemic 
corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. Severe exacerbations 
are defined as COPD exacerbations requiring hospitalization (including intubation and admittance 
to an ICU) or result in death.  
 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a 2.5-year multi-center, prospective, longitudinal, non-drug interventional cohort 
study to investigate the clinical, radiological and biological factors associated with 
disease progression in COPD in Guangdong and Fujian, China. Guangdong, a coastal 
province of southeast China, is the most populous province in China with 109 million 
people in 2015. The residents in Guangdong are Chinese in ethnicity with a mix of urban 
CCI

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
29 
 
and rural population which is representative of the general Chinese population. 
Guangdong has a similar healthcare system across the province that will enable data 
integration. Xiamen, a coastal city in Fujian province (Fujian is another province of 
southeast China), is near Guangdong province. We added one site (maybe more if 
needed) in Xiamen based on feasibility to enhance the enrolment of this study due to the 
advantages of Xiamen on population screening of COPD.  
This cohort study will not provide or recommend any treatment. During the study period, 
patients’ diagnosis and treatment will be left to their physicians’ judgement and routine 
practice. 
A total of approximately 2,000 subjects will be recruited from multiple hospitals 
(excluding tier 1) across Guangdong & Fujian province. In this study, hospitals will be 
categorized by administrative regions: those at prefecture-level and above will be 
categorized as Type A hospitals; those below prefecture-level will be categorized as Type 
B hospitals. Site/hospital selection will consider the representativeness of pollution level 
and hospital type, as well as the feasibility of being part of an integrated electronic 
system with linked hospital databases and various data sources.  
A wide range of COPD patients across GOLD grades I-IV and chronic bronchitis patients 
will be included. Never smokers with no significant diseases will be recruited as healthy 
control group.  
Baseline data will be recorded for all subjects at Visit 1 and subjects will be followed up 
at 6 months and then every 12 months for a total of 2.5 years (Figure 1).  Study visits will 
be conducted within ±30 days of the planned date. In addition to study visits, COPD and 
chronic bronchitis participants will be contacted by phone on trimonthly basis within ± 7 
days of the planned date to assess the CAT and to collect information on exacerbation 
rates and COPD medications; healthy controls will be contacted by phone on trimonthly 
basis within ± 7 days of the planned date to assess the CAT. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
30 
 
Figure 1 
Study schema 
A subset of participants from selected Type A hospitals are planned to receive additional 
assessments including digital monitoring of daily steps; completion of an evening 
electronic diary (including EXACT/ E-RS: COPD); the monthly CAT; collection of 
blood for study defined biomarkers; lung HRCT scanning; sputum collection for 
microbiome and cytology analysis. If moderate/severe exacerbations are reported by the 
participants or detected by investigators during the acute phase of the event, this subset of 
participants will be invited to the site hospital for an exacerbation visit (no more than 
twice with an interval of at least 21 days throughout the study). Participants from this 
sub-cohort constitute the Biomarker and Digital sub-cohort.  
In addition, daily air pollution index throughout the study in each participating city will 
be collected retrospectively from a local environmental monitoring center.  
5.2. 
Number of Participants 
A total of approximate 2,000 participants are planned to be enrolled, consisting of 1,700 
participants with COPD, 180 with chronic bronchitis but without fixed airflow limitation, 
and 120 never smoker healthy control. Specifically, COPD subjects will be classified 
using the GOLD grades I – IV (i.e. mild, moderate, severe and very severe). To better 
understand the disease progression of early stage COPD, i.e. GOLD I and II grades, 
COPD participants will be recruited in the following manner: GOLD I: 700, GOLD II: 
700, GOLD III: 200, GOLD IV: 100 (Figure 2). Among each GOLD category and 
chronic bronchitis group, up to 30% of never smokers will be recruited in each group.  
We set the target number for each grade group (GOLD I- IV) based on the study 
operational perspective, to ensure a wide and even distribution of airflow limitation 
across the participants recruited to this study. During recruitment, we will closely monitor 
the enrolment progress and post-bronchodilator FEV1 distribution, especially the GOLD 
I and GOLD II groups. If necessary, the recruitment targets for  GOLD I and GOLD II in 
the main cohort may be adjusted to achieve an even distribution of participants between 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
31 
 
mild and severe. This may include combining targets for specific GOLD grades to ensure 
that total recruitment numbers are achieved. 
All participants will be recruited from Type A and Type B hospitals in Guangdong 
province.  To represent the difference in patient profile and practice between different 
hospitals, the ratio of participants from Type A and Type B hospitals will be 2:1.  
Specifically, healthy control participants will be recruited from the physical examination 
department at site hospitals. For the healthy control group to be comparable with COPD 
participants, pre-set criteria on demographic profile (i.e. age, gender) will be specified in 
detail in SRM based on previous studies or available real-world data. During the 
recruitment, we will closely monitor the demographic profile (i.e. age, gender) of 
enrolled participants of both groups and adjust the demographic distribution of the 
healthy controls. When feasible, matching methods will be used to adjust for differences 
in baseline factors (e.g. age, gender, smoking status) in statistical analyses. Various 
matching approaches (e.g. pair-wise matching) will be considered depending on specific 
questions to be addressed, e.g. biomarkers analysis, and the extent of underlying 
differences between the cohorts. Details will be specified in the main or ad-hoc RAP.  
Figure 2 
Study Population Schematic 
 
More assessments will be conducted among the 400 Biomarker & Digital sub-cohort 
participants who will be recruited from selected Type A hospitals. The sub-cohort 
consists of 50 never smoker healthy control, 100 chronic bronchitis (N never smoker: up 
to 25), 100 GOLD I (N never smoker: up to 25), 100 GOLD II (N never smoker: up to 
25) and 50 GOLD III participants (N never smoker: up to 20) (Figure 2). Given the 
GOLD III never smokers are rare [Wang. 2018], based on feasibility, when necessary, a 
recruitment approach of combining Ever smoker and Never smoker will be implemented 
to ensure that the target of enrolment of 50 patients with GOLD III is achieved as 
planned. During the recruitment, the enrolment progress will be closely monitored.  
 
In GOLD I-III grades, certain number of COPD participants with previous exacerbation 
history (i.e. exacerbators) will be recruited (target number of subjects are as follows - 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
32 
 
GOLD I: 60 exacerbators, GOLD II: 60 exacerbators, GOLD III: 30 exacerbators). 
Further, a proportion of those who are maintenance inhaler treatment naïve will be 
recruited, aiming for: 10 participants who are maintenance inhaler treatment naive will be 
recruited among exacerbators and non-exacerbators in each GOLD I, II, III groups 
respectively (Figure 3). All patient population sizes are approximate and allow  10% for 
feasibility. 
 
Figure 3 
Sub-cohort Population Schematic 
 
For subjects included in COPD groups, Non-exacerbator is defined as a patient who has 
not had an exacerbation (see definition of exacerbation below) in the 2 years before entry 
into the study; Exacerbator is a patient who has 1 or more exacerbations in the 2 years 
before recruitment. In this study, an exacerbation is defined by the occurrence of an 
episode of increased cough (with or without phlegm), shortness of breath or chest 
symptoms (chest discomfort or tightness) which lasted 48 hours or more and interfered 
with the participant’s usual activities (with or without treatment).  
Inhaled maintenance treatment naïve patients will be defined as not being treated in at 
least prior 12 months with any long-acting inhaled medications inclusive of inhaled 
corticosteroids, long-acting antimuscarinic or long-acting beta2-agonists. 
To minimize selection bias, study investigators are encouraged to follow their routine 
clinical practice and consecutively recruit all eligible patients at their practice. The 
investigator will maintain a screening log to collect details (e.g. age, sex, smoking status, 
presence of chronic mucus hypersecretion (CMH) and maintenance inhaler treatment) of 
all participants screened, to confirm eligibility, and to record reasons for study exclusion, 
as applicable. Recruitment process will be closely monitored to ensure the proper number 
of participants within each subgroup. A patient informed consent will be obtained from 
all participants to allow their past, current and follow-up period information to be 
collected and used. Sub-cohort participants are required to provide a separate consent for 
additional assessments. 
5.3. 
Participant and Study Completion 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit (Visit 4). 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
33 
 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
 
5.4. 
Scientific Rationale for Study Design 
To reflect the real-world management and patient outcomes of COPD in China, a non-
drug interventional study design was chosen. Patient diagnosis and treatment will be left 
to their physicians’ judgement and routine practice. This study will not provide or 
recommend any treatment. By capturing the prospective and longitudinal patient-level 
data in a real-world clinical setting, the study will fulfil the needs to understand the 
phenotypes and their disease progression, and current disease management more 
comprehensively and in depth. Study results will inform clinical practice and may 
improve patient outcomes. 
This study will use COPD and non-COPD cohorts to provide cross-sectional and 
longitudinal data on multiple clinical, radiological and biological evaluations. Study 
participants will mostly represent mild to moderate airflow limitation grades of COPD 
and symptomatic non-COPD (i.e. chronic bronchitis) populations, whose disease 
progression is not well understood in China.  
Air pollution and increased biomass exposure are likely to be key contributors to the 
development of COPD in China. Previous nation-wide studies showed a large proportion 
of COPD patients (20-40%) in China are never smokers. Kurmi et al. reported that 5.4% 
of never smokers had airflow obstruction (AFO) among Kadoorie cohort [Kurmi, 2014]. 
The prevalence of COPD was estimated to be 5.2% among never smokers in Zhong et al 
[Zhong, 2007].This suggested that factors other than smoking (e.g. biomass, occupational 
exposure, and air pollution) may also play an important role in COPD progression. 
However, there is a lack of data on phenotypes and disease progression in never smokers 
with COPD. Differing from the Western cohorts in which participants were required to 
have at least 10-pack year smoking history, never smokers with diagnoses of COPD or 
chronic bronchitis (with respiratory symptoms who don’t meet the spirometric criteria of 
COPD) are also recruited. In addition, air pollution data will be collected retrospectively 
to explore the association between air pollution and COPD natural history. 
Healthy subjects who are never smokers and without a diagnosis of respiratory condition 
and other significant diseases will also be recruited to this study as controls, e.g. 
providing data on baseline natural lung function decline and lung structural damage in a 
general population.  
This study will also set up a Biomarker and Digital sub-cohort aiming to identify early 
disease and rapid progression and associated endotypes among Chinese COPD patients 
through enhanced repeated collection and analysis of biological samples and chest 
computer tomography. COPD is characterised by abnormal spirometric results, with a 
focus on FEV1. Decline in FEV1 is currently the gold standard for assessment of COPD 
progression. However, disease burden and worsening are also inextricably linked with 
disease activity represented by symptom load and exacerbations of COPD. This study 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
34 
 
will aim to evaluate multifactorial framework of disease severity in Chinese population 
similar to work by Agusti and colleagues [Agusti, 2016]. 
The selected 2.5-year follow up is required as a minimum period to achieve sufficient 
precision on the rate of decline in key study measures balanced against any perceived 
burden this study may impose on participants which could result in early withdrawal 
from the study.   
The clinical, radiological and biological factors identified to be associated with disease 
progression in Western cohorts will be investigated to test the hypotheses whether these 
predictors are applicable in China and characterise the exacerbator phenotype in China. 
Healthcare resource utilization and costs in COPD will be assessed to evaluate the 
economic impact of COPD for the different groups of COPD patients in Guangdong 
province. The following table lists all study endpoints and summarizes the rationale of 
including them.   

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
35 
 
Study Outcomes 
Rationale 
• Change from baseline and rate 
of decline in FEV1 and FVC
 
  
• Change in FEV1 is currently the gold standard for 
assessment of COPD progression.  
• Rate of moderate/severe 
exacerbations  
o Healthcare resource 
utilization definition 
o EXACT events (sub-
cohort only) 
• Exacerbations are important events influencing 
disease severity, disease progression, health-
related quality of life, and mortality and are also 
contributing significantly to healthcare resource 
utilization. The characterisation of exacerbation 
frequency, type and duration could be of 
significant importance to clinical practice and 
medical resource allocation. Acute exacerbations 
of COPD (AECOPD) will be collected using: 
o Healthcare resource utilization definition 
where moderate events are classified as 
managed by antibiotics (ATB) and/or 
systemic (intramuscular (IM), intravenous, 
or oral corticosteroid (OCS)) and severe as 
hospital admission or resulting in death 
[EMA, 2010]. 
o In a sub-cohort, EXACT, a daily diary 
evaluating symptoms of exacerbations will 
be employed to collect EXACT events 
[Leidy, 2013]. 
• Clinically Important 
Deterioration (CID) 
composite outcome 
 
CID is a new composite outcome (developed by GSK; 
Singh, 2016; Naya, 2018) for the risk prediction of 
long-term adverse outcomes of COPD. In this study, 
the CID will be derived from three key clinical 
assessments, which are 1) moderate/severe 
exacerbations, 2) worsening of FEV1, and 3) 
worsening of health status using the CAT 
questionnaire.  
• Change from baseline in CAT 
score  
• Change in E-RS: COPD score 
(sub-cohort only) 
 
• COPD-related health status including respiratory 
symptom level is a predictor of long-term adverse 
outcomes of COPD. 
o The CAT questionnaire will capture the 
well-being and health-related quality of 
life of COPD patients and also will be 
used to calculate CID [Jones, 2009]. 
o E-RS: COPD (a subset of the EXACT 
assessment) will be used to capture the 
impact of COPD symptoms in a sub-
cohort [Leidy, 2014]. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
36 
 
Study Outcomes 
Rationale 
• Assess CAPTURE to identify 
under diagnosed COPD 
patients in Chinese population 
 
• To assess the sensitivity and specificity of the 
CAPTURE questionnaire as a case finding tool in 
obstructive lung disease 
• Daily Activity as measured by 
number of steps (sub-cohort 
only). 
• This will be measured by using digital mobility 
device worn by participants. 
• Mortality 
Vital status will be collected 
• Plasma fibrinogen 
•  high-sensitivity C-reactive 
protein (hsCRP) 
 
 
 
• Airway inflammation is a key component of the 
pathogenesis of COPD. The inflammation can be 
characterised by various differential cell profiles in 
induced sputum and the blood.  The systemic 
component of COPD may be reflected by raised 
mean values of blood fibrinogen, CRP. CRP and 
fibrinogen are associated with GOLD stage of 
disease and are elevated during exacerbations. 
Elevated levels of CRP and fibrinogen have also 
been associated with increased risk for 
hospitalization and death from this disease. CRP 
shows significant variability in COPD while 
fibrinogen is much more stable. Because of its 
stability, association with COPD-related outcomes 
(exacerbation, hospitalization and death) and 
sensitivity to intervention, fibrinogen was assumed 
to be a very promising biomarker. Fibrinogen has 
been qualified as a biomarker for patient 
population stratification for clinical trials [Miller, 
2016]. 
CCI

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
37 
 
Study Outcomes 
Rationale 
• Total and Differential blood 
cell counts including 
eosinophils, neutrophils and 
hemoglobin 
• Blood eosinophil measurements is a surrogate 
biomarker for sputum eosinophils both in stable 
COPD patients and during exacerbations. 
Eosinophilic inflammation is a distinctive 
phenotype of AECOPD. Further, it provides a 
measure of the probability of benefit from inhaled 
corticosteroids. 
• Other blood biomarkers 
inclusive of sRAGE, CC16, 
IP-10(sub-cohort only), 
HbA1c 
• sRAGE is a marker for emphysema and its 
progression 
• CC16 is a potential marker for lung function 
decline 
• IP-10 is a biomarker of Human Rhinovirus 
Infection at Exacerbation of COPD 
• HbA1c is a biomarker used in the diagnosis and 
progression of diabetes, it often reflects the average 
level of blood sugar over the past 2 to 3 months. 
•  Sputum microbiome (sub-
cohort only) 
• Changes in lung microbiome are associated with 
COPD disease severity: airflow limitation (and 
CAT) 
• Lung microbiome differs between exacerbation 
subtypes 
• Sputum cytology (sub-cohort 
only) 
• Sputum total differential cell counts and percentage 
in stable COPD patients predicted the clinical 
response to systemic corticosteroids 
Frequency of treatment with 
COPD medication and Treatment 
patterns at the time of study entry 
and during the study period 
Count of outpatient visits, 
emergency visits, hospitalizations, 
(overall and COPD-specific, 
separately)  
Direct medical costs associated 
with COPD medications and 
COPD disease management  
Insurance coverage and patient 
out-of-pocket payment 
• Quantifying the medical costs aids COPD clinical 
management and public health resource allocation 
decision-making. 
• Hospital Information Systems (HIS) will be tested 
for feasibility to provide granular information 
 
5.5. 
Dose Justification 
Not applicable. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
38 
 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.  
Participants will be eligible for inclusion in the main cohort only if all inclusion criteria 
apply and none of the exclusion criteria apply.  
Eligible participants in the main cohort from selected Type A hospitals, consented with 
willingness to use electronic devices for daily patient-reported outcomes collection (e.g. 
logpads), attend more frequent visits and receive additional assessments will be recruited 
to the Biomarker and Digital sub-cohort.   
It is planned to enrol approximately 1,700 COPD subjects in the study, approximately 
180 controls with chronic bronchitis, and approximately 120 never smoker healthy 
controls. 
COPD subjects will fall into the GOLD categories I - IV.  It is intended to recruit the 
COPD subjects in the following manner: 700 GOLD I, 700 GOLD II, 200 GOLD III and 
100 GOLD IV. 
All patient population sizes are approximate and subject to feasibility. 
6.1. 
Inclusion Criteria 
COPD Participants 
A COPD subject will be eligible for inclusion in this study only if all the following 
criteria apply: 
1. Male or female participants, aged 40-80 years inclusive.  
A female is eligible to enter and participate in the study if she is of non-child bearing 
potential. 
2. A baseline (post-bronchodilator) FEV1/FVC ratio ＜0.70 
3. Clinically stable and has no exacerbations for at least 1 month prior to recruitment. 
All courses of oral corticosteroids or antibiotics must be completed at least 2 weeks 
before study start. 
4. Ever smoker (with a lifetime exposure of ≥1 pack-year) or never smoker (with a 
lifetime exposure of <1 pack-year) 
5. A signed and dated written informed consent is obtained prior to participation 
6. Additional criteria for sub-cohort COPD participants to be recruited:  
• Only include participants aged 50-80 years (inclusive)  
• BMI<35 kg/m2 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
39 
 
• Only include ever smoker with a lifetime exposure of ≥10 pack-year or never 
smoker with a lifetime exposure of <1 pack-year 
• About 150 COPD participants with a history of at least 1 exacerbation event(s) 
within the past 2 years at the entry of the study 
• About 60 COPD participants without inhaler maintenance treatment history for 
at least 12 months prior to the entry of the study (including inhaled 
corticosteroids, inhaled long-acting antimuscarinics, and inhaled long-acting 
beta2-agonists). 
 
Chronic Bronchitis Participants 
A chronic bronchitis participant will be eligible for inclusion in this study only if all of 
the following criteria apply: 
1. Male or female participants, aged 40-80 years inclusive, who are free from 
significant disease as determined by history, physical examination and screening 
investigations. 
A female is eligible to enter and participate in the study if she is of non-child bearing 
potential. 
2. Baseline post-bronchodilator FEV1/FVC ratio ≥0.70. 
3. Chronic bronchitis is defined as at least 3 months of cough and phlegm in a year in 
the past 2 years.  
The definition of chronic bronchitis is used for recruiting subjects to Chronic 
Bronchitis group. This would be identified by asking two questions such as: “How 
many MONTHS in the past 12 months have you had bronchitis or chronic coughing 
with phlegm or sputum from the chest?” AND “For how many years have you had 
bronchitis or chronic coughing with phlegm or sputum from the chest?” with at least 
3 months in past year and for at least past 2 years representing a minimum qualifying 
criteria. 
4. Clinically stable and has no exacerbations for at least 1 month prior to recruitment. 
5. Ever smoker (with a lifetime exposure of ≥1 pack-year) or never smoker (with a 
lifetime exposure of <1 pack-year) 
6. A signed and dated written informed consent is obtained prior to participation. 
7. Additional criteria for sub-cohort Chronic Bronchitis participants to be recruited:  
• Only include participants aged 50-80 years (inclusive)  
• BMI <35 kg/m2 
• Only include ever smoker with a lifetime exposure of ≥10 pack-year or never 
smoker with a lifetime exposure of <1 pack-year 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
40 
 
Healthy Participants 
1. Male or female participants, aged 40-80 years inclusive, who are free from significant 
disease as determined by history, physical examination and screening investigations. 
A female is eligible to enter and participate in the study if she is of non-child bearing 
potential. 
2. Baseline post-bronchodilator FEV1/FVC ratio ≥0.70 
3. A CAT score <10 
4. Never smoker with a lifetime exposure of <1 pack-year. Passive smoker is not 
eligible 
5. A signed and dated written informed consent is obtained prior to participation. 
6. Additional criteria for sub-cohort Healthy participants to be recruited:  
• Only include participants aged 50-80 years (inclusive)  
• BMI <35 kg/m2 
6.2. 
Exclusion Criteria 
COPD Participants 
A COPD participant will not be eligible for inclusion in this study if any of the following 
criteria applied: 
1. In the opinion of the investigator, there was a current primary diagnosis of asthma 
(patients with a primary diagnosis of COPD but who also had asthma could be 
included). 
2. Known respiratory disorders, or disorders identified at screening/visit 1(including 
identification on the first CT scan), other than COPD (e.g. COVID-19, lung cancer, 
sarcoidosis, active tuberculosis, lung fibrosis, cystic fibrosis) that may significantly 
impact clinical assessments according to investigator judgement 
3. Having undergone lung surgery (e.g. lung reduction, lung transplant)  
4. Known history of significant inflammatory disease, other than COPD (e.g. 
rheumatoid arthritis and Lupus) 
5. Serious, uncontrolled disease (including serious psychological disorders) likely to 
interfere with the study or impact on subject safety 
6. Diagnosis of cancer: included current and within the last 5 years (patients in 
remission for ≥ 5 years could be included).  
7. Participants who were concurrently participating in any clinical studies where 
investigational drugs were tested within 4 weeks prior to Visit 1 (baseline), or who 
were scheduled to start any during the study period or enrolled in a study where there 
is significant radiation exposure (e.g. CT scans).  

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
41 
 
8. Unable or unwilling to use required digital devices, e.g. wrist band, digital diary 
(sub-cohort only) 
9. Have, in the opinion of the investigator, evidence of alcohol or drug abuse 
10. Have received a blood transfusion in the 4 weeks prior to study start 
11. Is on long term oral corticosteroids (long term is considered use for more than 3 
consecutive months) 
12. Unable to walk 
13. Unable to read and understand Chinese 
Chronic Bronchitis Participants 
A chronic bronchitis participant will not be eligible for inclusion in this study if any of 
the following criteria applied: 
1. Known respiratory disorders, or disorders identified at screening/visit 1(including 
identification on the first CT scan), (e.g.: COVID-19, COPD, current asthma, lung 
cancer, sarcoidosis, active tuberculosis, lung fibrosis, cystic fibrosis) that may 
significantly impact clinical assessments according to investigator judgement 
2. Post-bronchodilator FVC<80% Predicted normal 
3. Having undergone lung surgery (e.g. lung reduction, lung transplant)  
4. Known history of significant inflammatory disease, other than COPD (e.g. 
rheumatoid arthritis and Lupus) 
5. Serious, uncontrolled disease (including serious psychological disorders) likely to 
interfere with the study or impact on subject safety 
6. Diagnosis of cancer – included current and within the last 5 years (patients in 
remission for ≥ 5 years could be included).  
7. Participants who were concurrently participating in any clinical studies where 
investigational drugs were tested within 4 weeks prior to Visit 1 (baseline), or who 
were scheduled to start any during the study period, or enrolled in a study where 
there is significant radiation exposure (e.g. CT scans). 
8. Unable or unwilling to use required digital devices, e.g. wrist band, digital diary 
(sub-cohort only) 
9. Have, in the opinion of the investigator, evidence of alcohol or drug abuse 
10. Have received a blood transfusion in the 4 weeks prior to study start 
11. Is on long term oral corticosteroids (long term is considered use for more than 3 
consecutive months) 
12. Unable to walk 
13. Unable to read and understand Chinese 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
42 
 
Healthy Participants 
A healthy participant will not be eligible for inclusion in this study if any of the following 
criteria applied: 
1. Known respiratory disorders or disorders identified at screening/visit 1(including 
identification on the first CT scan) (e.g. COVID-19, COPD, current asthma, lung 
cancer, sarcoidosis, active tuberculosis, lung fibrosis, cystic fibrosis) that may 
significantly impact clinical assessments according to investigator judgement 
2. Post-bronchodilator FVC<80% Predicted normal 
3. Having undergone lung surgery (e.g. lung reduction, lung transplant)  
4. Known history of significant inflammatory disease, other than COPD (e.g. 
rheumatoid arthritis and Lupus) 
5. Serious, uncontrolled disease (including serious psychological disorders) likely to 
interfere with the study or impact on subject safety 
6. Diagnosis of cancer – included current and within the last 5 years (patients in 
remission for ≥ 5 years could be included).  
7. Participants who were concurrently participating in any clinical studies where 
investigational drugs were tested within 4 weeks prior to Visit 1 (baseline), or who 
were scheduled to start any during the study period, or enrolled in a study where 
there is significant radiation exposure (e.g. CT scans). 
8. Unable or unwilling to use required digital devices, e.g. wrist band, digital diary 
(sub-cohort only) 
9. Have, in the opinion of the investigator, evidence of alcohol or drug abuse 
10. Have received a blood transfusion in the 4 weeks prior to study start 
11. Is on long term oral corticosteroids (long term is considered use for more than 3 
consecutive months) 
12. Unable to walk 
13. Unable to read and understand Chinese 
6.3. 
Lifestyle Restrictions 
No lifestyle restrictions are required.  
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the study but are 
not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants. Minimal 
information includes demography, screen failure details, eligibility criteria. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened. Only in certain special cases, re-screening of participants will be 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
43 
 
allowed. Investigator will be asked to provide detailed information. Special cases will be 
discussed at the EST (empowered study team) meeting. After permission from the 
medical monitor of this study is granted, the participants can only be re-screened once. 
 
7. 
TREATMENTS 
This cohort study will not provide or recommend any treatment. Patients’ diagnosis and 
treatment will be left to their physicians’ judgement and routine practice. This section is 
not applicable. 
7.1. 
Treatments Administered 
Not applicable. 
7.2. 
Dose Modification 
Not applicable 
7.3. 
Method of Treatment Assignment 
Not applicable 
7.4. 
Blinding 
Not applicable 
7.5. 
Preparation/Handling/Storage/Accountability 
Not applicable  
7.6. 
Treatment Compliance 
Not applicable  
7.7. 
Concomitant Therapy 
Not applicable 
7.8. 
Treatment after the End of the Study 
Not applicable 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
44 
 
8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
Not applicable. This cohort study will not provide or recommend any treatment. Patients’ 
diagnosis and treatment will be left to their physicians’ judgement and routine practice.  
8.2. 
Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. 
• 
A subject will be considered withdrawn from the study if he/she joins any clinical 
studies where investigational drugs are tested. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.  If a participant withdraws consent for disclosure, the site may use any 
publicly information to determine vital status at the end of the study and this 
information would be included in the final analyses. 
• 
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
8.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she is unreachable and fails to 
come back for both Visit 3 and 4.  

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
45 
 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in schedule of activities (Table 1) 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue the study.  
Site staff will make every effort to work with participants to collect all study 
assessments. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
Procedures conducted as part of the participant’s routine clinical management (eg, 
spirometry) and obtained before signing of informed consent form (ICF) may be 
utilized for screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA. 
 
9.1. 
Baseline data collection 
A specifically designed baseline survey will be used to collect the following information 
at baseline from all participants, including: 
Informed consent 
Inclusion/exclusion criteria assessment  
Socio-demographics 
o Age  
o Race/ethnicity 
o Gender 
o Education 
o Economic status 
o Occupation  
o Insurance information (basic, commercial) 
Health and lifestyle information 
o Height, weight, body mass index (BMI)  
o Blood pressure, heart rate  
o Smoking status: Never smokers are defined as those with a lifetime exposure of 
<1 package/year in their life (excluding passive smoker). Ever smokers (current 
or former) are defined as those with a lifetime exposure of ≥10 package/year. 
Former smokers are those who have stopped smoking for at least 6 months. 
Current smokers are those who are currently smoking. Passive smokers are 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
46 
 
defined as those with the presence of smokers living in the same household, or 
co-workers smoking nearby while indoors  
o Smoking history including Pack-years of smoking: Number of pack years = 
(number of cigarettes per day / 20) x number of years smoked, e.g., 10 pack-
years means 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 
years) 
o Biomass exposure: refer to the biomass exposure questionnaire  
o Occupational exposures: Whether had the participant worked in occupations 
known or suspected to be associated with the risk of COPD ≥6 months， e.g. 
organic/inorganic dust, irritant gases, fumes, or vapors chef，traffic police   
Toxic and harmful jobs（eg.in pollution factory or chemical work, etc)  
 
COPD Medical history (for COPD participants only) 
o Disease duration  
o Treatment history (e.g. the time of initiating maintenance treatment, current 
treatment) 
o Number of exacerbations in the previous 12 months and 24 months 
o Number of moderate and severe exacerbations in the previous 12 months and 24 
months and their management with oral corticosteroids and/or antibiotics and/or 
hospitalization 
o Family history of COPD or other respiratory diseases 
Lower respiratory infections including chest colds (for chronic bronchitis patients 
only) 
Medical history (including previous asthma history)   
Current co-morbid conditions and childhood respiratory disease 
Concomitant medications: Respiratory medications, antibiotics, oral steroids, anti-
diabetic， anti-hypertension gastroesophageal reflux disease (GERD) therapy, 
cardiovascular disease therapy and whether taking traditional Chinese medicines  
Patient reported outcomes: CAT, SGRQ-C and mMRC, CAPTURE 
Spirometry (pre- and post-bronchodilator)  
o FEV1  
o Forced vital capacity (FVC) & Percent Predicted FVC and FEV1/FVC ratio & 
Percent Predicted FEV1/FVC 
o Forced expiratory volume in 6 seconds (FEV6) 
o Forced expiratory flow between 25% and 75% of vital capacity (FEF 25-75) & 
Percent Predicted FEF 25-75, Forced Expiratory Flow 25% (FEF25), Forced 
Expiratory Flow 50% (FEF50) and Forced Expiratory Flow 75% (FEF75) 
o Peak Expiratory Flow (PEF) & Percent Predicted PEF, time to Peak Expiratory 
Flow (tPEF) and Maximal Mid-Expiratory Flow (MMEF) 
o Forced Expiratory Time (FET) and Volume back extrapolation (VEXT) 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
47 
 
o FEV1 percent of predicted and reversibility test  
o Reversibility will be assessed at Visit 1 (baseline) by measurement of FEV1 
before and 10 to 30 minutes after administration of a short-acting 
bronchodilator (e.g. 400μg β2-agonist or up to 160μg anticholinergic). Prior 
to testing, the patients should not have taken inhaled short-acting 
bronchodilators in the previous six hours, long-acting bronchodilator in the 
previous 12 hours or sustained-release theophylline in the previous 24 hours. 
o Reversibility will be calculated as follows: % Reversibility = 
 
Collection of blood samples for protocol defined analysis (plasma fibrinogen and  
hsCRP, total and differential blood cell count)  
In addition, the following assessments will be conducted among the Biomarker & Digital 
sub-cohort participants only: 
Blood biomarkers (including serum sRAGE, CC16, IP-10，HbA1c)  
Sputum sample collection for protocol defined analyses (microbiome through 
molecular methods, cytology)  
Lung HRCT  
Issue and training in use of electronic diary: EXACT questionnaire (start after clinic 
visit at baseline) 
Digital steps (start after clinic visit at baseline) 
 
9.2. 
Follow up data collection 
9.2.1. 
COPD medications and treatments and concomitant medications 
COPD medications and treatments will be derived from medical records in site hospitals’ 
Hospital Information System (HIS) complemented by site interview at each clinic visit 
including exacerbation visits and trimonthly telephone interviews including those not 
captured in HIS (e.g. purchased in pharmacies, prescribed by HCPs outside the research 
site hospitals). Pictures of COPD medication will be provided to assist patient recall 
during telephone interviews and clinic interviews. 
Concomitant medications collected in this study will include: respiratory medications, 
antibiotics, oral steroids, gastroesophageal reflux disease (GERD) therapy, cardiovascular 
disease therapy and whether taking traditional Chinese medicines. 
9.2.2. 
Smoking status 
Smoking status will be reassessed at each scheduled clinic visit evaluated by participants’ 
self-report (e.g. never smoker, current smoker, former smoker).  
100
 x 
FEV
ator 
bronchodil
-
pre
Highest 
FEV
ator 
bronchodil
-
pre
Highest 
 -
FEV
ator 
bronchodil
-
post
Highest 
 
1
1
1

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
48 
 
9.2.3. 
Spirometry 
Spirometry (same measurements as baseline spirometry, refer to Section 9.1) will be 
performed in triplicate at time points listed in the SoA Table 1. Spirometry assessments 
should be performed in accordance with ATS/ERS guidelines as outlined in the SRM. 
Predicted values will be based upon the spirometric reference values for Chinese [Jian, 
2017].   
9.2.4. 
COPD exacerbations 
COPD subjects will be asked for a history of AECOPD using components of 
moderate/severe exacerbation definition at each clinic visit including exacerbation visits.  
Additionally, COPD subjects will be contacted by phone every 3 months by the study 
staff and asked about their exacerbation details for the previous 3 months. Study staff will 
check Hospital Information System (HIS) during the interview to confirm the event of 
exacerbation wherever possible.  
9.2.5. 
Clinically important deterioration (CID) components 
Clinically important deterioration (CID) is a new composite outcome (developed by 
GSK) for the prediction of future risk of long-term adverse outcomes. In this study, the 
CID will be derived from three key clinical assessments, which are 1) count of 
moderate/severe exacerbations, 2) worsening of FEV1, and 3) change in the CAT score 
measured over 6 months. CID was defined as: decrease of ≥100 mL in post-
bronchodilator FEV1, or increase of ≥2 units in the CAT, or an occurrence of a 
moderate/severe exacerbation.  
9.2.6. 
Patient Reported Outcome Measures 
All Patient reported outcome measures should be collected in a nice, quiet setting without 
distractions (e.g., television, cell phones). 
The COPD Assessment Test (CAT) will be collected at the beginning of study visits 
where applicable, before any other procedure. 
The modified Medical Research Council (mMRC) Dyspnea Scale and St. George’s 
Respiratory Questionnaire for COPD (SGRQ-C) will be administered at baseline.  
The EXAcerbation of COPD Tool (EXACT) will be administered each evening among 
sub-cohort participants using an electronic diary.   
COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and 
Exacerbation Risk (CAPTURE) will be administered at baseline and Visit3. 
9.2.6.1. 
COPD Assessment Test (CAT) 
The COPD Assessment Test (CAT) is a validated, short and simple patient completed 
questionnaire which has been developed for use in routine clinical practice to measure the 
health status of patients with COPD [Jones, 2009; Jones, 2012]. The CAT is an 8-item 
questionnaire suitable for completion by all patients diagnosed with COPD. When 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
49 
 
completing the questionnaire, participants rate their experience on a 6-point scale, 
ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0-
40. Higher scores indicate greater disease impact [Jones, 2009, CAT website]. 
For all participants, CAT will be completed at baseline, each follow up clinic visit, and 
tri-monthly phone interviews. Interviewer-administered approach (face-to-face or over 
the phone) will be used.  
Additionally, for monitoring purpose, monthly CAT will be interviewer-administered 
over phone call in the sub-cohort for 6 months after baseline visit and 6 months after 
Visit 3.CAT will also be assessed in the sub-cohort at exacerbation visits.  
9.2.6.2. 
Evening Diary (sub-cohort only) 
Participants in the sub-cohort will complete an eDiary each evening consisting of the 14 
item EXACT and additional questions as described below. Participants will be trained to 
use the eDiary at baseline visit and will complete the diary each evening in line with 
SOA. 
• Exacerbations of Chronic Pulmonary Disease Tool (EXACT) and Evaluating 
Respiratory Symptoms in COPD (E-RS: COPD) 
The Exacerbation of Chronic Pulmonary Disease Tool-Patient Reported Outcomes 
(EXACT) is a 14-item participant reported outcome instrument designed to capture 
information on the occurrence, frequency, severity, and duration of symptoms suggestive 
of an exacerbation of disease in participants with COPD. EXACT captures information 
on the severity of the respiratory and systemic manifestations of a COPD exacerbation as 
reported by the participant [Leidy, 2013].   
The Evaluating Respiratory Symptoms in COPD (E-RS: COPD) consists of 11 items 
from the 14-item EXACT instrument. The E-RS: COPD is intended to capture 
information related to the respiratory symptoms of COPD, i.e. breathlessness, cough, 
sputum production, chest congestion, and chest tightness. The E-RS: COPD has a scoring 
range of 0-40, with higher scores indicating more severe symptoms [Leidy, 2014]. Three 
subscales of the E-RS: COPD are used to describe different symptoms: breathlessness, 
cough and sputum, and chest symptoms.  
The EXACT questionnaire will be completed each day at bedtime in the daily digital 
diary during the pre-defined study period. EXACT events will be identified from the 14 
EXACT questions. Changes in overall symptoms and in the subscales of breathlessness, 
cough and sputum, and chest symptoms will be measured using the E-RS: COPD subset 
of EXACT. 
• Additional questions 
In addition to the collection of EXACT, participants will also complete 5 additional daily 
diary questions to provide the information on other symptoms suggestive of an 
exacerbation:  sputum purulence (color), wheezing, sore throat, colds (nasal discharge 
and/or nasal congestion) and fever without other cause. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
50 
 
The additional symptoms questions, combined with EXACT responses to questions on 
dyspnea, cough and sputum quantity will be assessed in stream and used to trigger 
prompts to both site and patients about symptom changes that may be indicative of an 
exacerbation. 
9.2.6.3. 
Other PRO assessments 
Chronic mucus hypersecretion (CMH) is defined as: At least 3 months of cough & 
phlegm in past year. This will be identified by asking a question as “How many months 
in the past 12 months have you had bronchitis or chronic coughing with phlegm or 
sputum from the chest?” Meanwhile, SGRQ-C and the CAT will be used for 
identification of CMH in this study. This would be identified by cough and phlegm 
related questions in SGRQ-C or CAT (details to be specified in the RAP).   
The SGRQ-C is a disease-specific questionnaire designed to measure the impact of 
respiratory disease and its treatment on a COPD patient’s HRQL [Meguro, 2007]. The 
SGRQ-C is a recent adaptation of the SGRQ instrument and the resulting SGRQ-C scores 
is transformed into the one equivalent to the original instrument. 
The CATPURE is a short, five-item questionnaire that can be easily completed by 
patients and are used to identify individuals who may have undiagnosed, clinically 
significant COPD. 
9.2.7. 
Computed tomography (CT) (sub-cohort only) 
Inspiratory and expiratory HRCT scans are required at Visit 1(baseline) and Visit 4 (the 
end of study), while only inspiratory scan will be conducted on exacerbation visit. 
HRCT on the study participants may reveal the presence of previously undiagnosed 
malignant or other suspicious lesions (nodules). A local radiologist will review the HRCT 
scans solely for this purpose and notify the PI of any such observations.   The radiologist 
should notify the PI of any observations within a week of the HRCT.  The PI will then 
notify the subject’s own doctor, who will be responsible for referral to further medical 
care.  The follow up care will be in line with local hospital or clinic procedures for 
dealing with nodules.  
9.2.8. 
Digital physical activity (sub-cohort only) 
Daily digital steps will be collected in sub-cohort only. Participants are required to keep 
wearing the wrist band for 1 month from visit 1 and 3 as outlined in the time and event 
table. 
CCI

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
51 
 
9.2.9. 
Biomarker(s) 
9.2.9.1. 
Blood biomarkers 
Blood samples will be taken at Visit 1 and throughout the study as defined in the Time 
and Events Table. (Table 1) 
• Plasma fibrinogen, hsCRP, total/differential blood cell count measurements and 
haemoglobin will be conducted at central lab for all participants 
• Additional protein analysis will be conducted at central lab for the sub-cohort 
using validated assays.  Analytes chosen will include serum sRAGE, CC16 and 
IP-10，HbA1c.  
The blood biomarker assessments will be conducted according to the study reference 
manual. 
9.2.9.2. 
Sputum microbiome and sputum cytology (sub-cohort only) 
Sputum samples for microbiome and sputum cytology will be collected in sub-cohort 
only as defined in the Time and Events Table (Table 1). Sputum can be collected 
spontaneously or can be induced, as per investigator judgement, induced sputum is 
preferred. Sputum sampling should only be done if, in the opinion of the investigator, it is 
safe for the subject. The sputum microbiome and sputum cytology assessments will be 
conducted according to the sputum assessment procedure (Refer to study reference 
manual). 
Additional analyses may include the measurement of viruses and fungi. 
9.2.10. 
Healthcare Resource Utilization and Cost 
To reflect the routine medical care, the information on COPD-related healthcare resource 
utilization and cost occurred within site hospitals will be captured on the study 
questionnaire form where possible using the HIS (based on site feasibility). Information 
collected include: 
• Unscheduled COPD outpatient visits and emergency visits    
o Number of visits, date of visit, diagnosis of visit, cost 
• COPD hospitalization (including intensive care) 
o Number of hospitalization, date and length of stay, diagnosis of visit, cost   
• Prescribed COPD medications  
o Medication name, date of prescription, dosage, administration, cost, whether the 
prescription is picked up at hospital, etc. 
• Other COPD treatment, e.g. oxygen therapy, nebulizers 
o Treatment name, date, cost, etc 
• Lab tests, image tests, surgeries, and other tests and procedures (e.g., spirometry, 
Chest X-Ray, CT) 
o Test or procedure, date of operation, cost, etc. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
52 
 
• Healthcare cost if feasible, e.g. general service usage, consultation fee 
o  Item, date of charge 
• Insurance coverage and patient out-of-pocket payment if feasible 
In addition, healthcare resource utilization could occur in other places outside of the site 
hospitals including: (1) hospitals other than the site hospital where the subject is 
recruited; (2) retail pharmacy stores; (3) subjects’ home. Healthcare resource utilized and 
associated costs will be collected using standard questionnaires at trimonthly subjects’ 
phone interviews. Information collected include COPD-related diagnosis and treatment in 
the above sources:   
• Outpatient visit, emergency visit, and hospitalization 
o Date, reason, length of stay (for hospitalization) 
• Prescribed medications 
• Over-the-counter (OTC) medications  
• Other therapies, e.g. oxygen therapy, nebulizers 
• Associated costs if feasible 
• Lab tests, image tests, surgeries, and other tests and procedures (e.g., spirometry, 
Chest X-Ray, CT) 
Given the high co-morbidities among COPD patients, non-COPD healthcare resource 
utilization will also be captured by extracting data from the HIS/EMR complimented by 
tri-monthly patient interviews. Information collected include: 
• Non-COPD outpatient visits and emergency visits    
o Number of visits, date of visit, diagnosis of visit  
• Non-COPD hospitalization (including intensive care) 
o Number of hospitalization, date and length of stay, diagnosis of visit  
9.2.11. 
Mortality 
Details of any patient deaths, including date of death, will be recorded in the CRF. 
Information will be obtained from the telephone interview and from medical records in 
HIS. Cause of death will be recorded if available.  Data from publicly available source 
will be used if participant is not contactable at the end of the study. 
9.3. 
Exacerbation Visits (sub-cohort only) 
Exacerbation visits only apply to subjects included in the Biomarker & Digital sub-
cohort. Exacerbations that occur during the study will be detected through several 
pathways of reporting, including: direct contact with the study site or using a process of 
screening questions triggering a site alert and follow-up consultation, at which the 
investigator will determine whether the worsening of symptoms identified by evening 
diary meets the definition of a moderate/severe exacerbation and if it does then an 
exacerbation visit is scheduled. This triggering process is described in Section 9.2.6.2. 
Visit will be scheduled to occur within 72 hours of the alert (symptom onset) (Figure 4). 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
53 
 
At the exacerbation Visit, the following study procedures will be completed: (1) PROs: 
e.g. the CAT, (2) blood sampling, (3) spirometry, (4) sputum sampling including induced 
sputum if required, (5) chest imaging, (6) healthcare resource utilization and cost 
including COPD medication and treatment. The sputum samples must be collected before 
the subjects receive antibiotics and/or systematic corticosteroids. 
Figure 4 
Exacerbation Detection Through Evening Diary Questions 
 
After completion of study procedures at the AECOPD Visit, the investigator will 
administer treatment for the exacerbation. Follow-up phone call(s) will be made by the 
investigator to the participant at least every 2 weeks until the AECOPD has resolved. No 
more than 2 AECOPD experienced during the study will be evaluated. If a participant 
experiences another exacerbation while on study, then they are to contact their regular 
physician for treatment. 
9.4. 
Adverse Events 
No study drug will be given in this study, only study procedure related serious adverse 
events (SAE) will be recorded. All SAEs will be collected from the signing of the ICF 
until the follow-up visit at the time points specified in the SoA (Table 1). 
The investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an SAE, provided in this protocol. During the study when there 
is a safety evaluation, the investigator or site staff will be responsible for detecting, 
documenting and reporting SAEs. 
Adverse Events (AE) will not be captured in the study. It is possible that participants 
could spontaneously describe potential adverse events that occurred during the course of 
study visits. As part of the site orientation process, study team members will be trained in 
the recognition of potentially-reportable adverse events. If an AE (serious or non-serious) 
or complaint with any specifically named GSK product is reported spontaneously by a 
subject during the course of the study, the site staff will complete the AE reporting form 
and transmit the report to the GSK China within 24 hours of being made aware of the AE. 
AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a medicinal product. For marketed 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
54 
 
medicinal products, this also includes failure to produce expected benefits (i.e., lack of 
efficacy), abuse or misuse.   
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:  
• Results in death,  
• Is life-threatening, 
• Requires hospitalization or prolongation of existing hospitalization,  
• Results in disability/incapacity, 
• Is a congenital anomaly/birth defect? 
• Other: medical or scientific judgement should be exercised in deciding whether 
reporting is appropriate in other situations, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalisation but 
may jeopardise the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These should also 
be considered serious. 
• Possible drug-induced liver injury 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).  
See study Pharmacovigilance Plan (sPVP) for details. sPVP will include the following 
elements to ensure a comprehensive approach to safety event collection and reporting:  
Supplier pharmacovigilance training 
Investigator and site staff pharmacovigilance training  
Safety-specific roles 
SAEs collection and reporting processes 
SAEs collection forms 
Frequency of data review 
Reporting process and timelines  
Interim reports 
Study-specific PVP monitoring process 
 
9.5. 
Treatment of Overdose 
This cohort study will not provide or recommend any treatment. Patients’ diagnosis and 
treatment will be left to their physicians’ judgement and routine practice. Thus, this 
section is not applicable. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
55 
 
9.6. 
Safety Assessments 
This cohort study will not provide or recommend any treatment. No safety assessment is 
scheduled.  
9.7. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
9.8. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
9.9. 
Genetics 
Genetics are not evaluated in this study. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
56 
 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Sample Size Determination 
10.1.1. 
Hypotheses 
This study is mainly descriptive with no formal inference associated with the study 
objectives. Confidence intervals will accompany all effect estimates.    
10.1.2. 
Study Design Considerations 
This is a longitudinal study in subjects with COPD and controls. The follow-up period is 
2.5 years with scheduled clinic visits at study entry, 6 months, 18 months, and 30 months. 
10.1.3. 
Sample size Considerations 
Sample size was decided based on practical consideration; however, some justification of 
GOLD I and II Grades and for sample size for all COPD patients is provided below. 
There is no formal inference planned, meaning no powered hypothesis test for overall 
study will be performed. Sample size justification is based on precision of effect 
estimates for rate of decline in FEV1 over 2.5 years. 
A review of data from Study HZC113782 FEV1 was collected at 3-month intervals on 
moderate COPD subjects suggests that a within subject standard deviation (model based 
residual error estimate) as 155 mL, and a standard error of the rate of decline in FEV1 as 
2.5 mL/year from placebo group. Those variability estimates were increased to 50% 
higher as 233 mL and 3.8 mL/year, respectively, for the following sample size 
calculation; this is mainly based on the consideration that a more heterogeneous study 
population and non-drug interventional cohort nature by design will yield higher 
variability comparing to those observed in a randomized clinical trial.   
To make simple calculation, it is assumed within subject’s standard deviation and 
standard error of the rate of decline in control groups (Chronic Bronchitis, Healthy 
Control) are the same as the assumption for COPD subjects.  
To detect a difference of  units between the mean rate of decline in two groups, 
Schlesselman [Schlesselman, 1973] proposed the following formula to calculate , 
 
where 
 is an estimate of the variance associated with the rate of decline in FEV1,
 is 
an estimate of the variation about the regression line within a person,  is the duration of 
the study,  is the number of measurements collected during the study, 
 is the upper 
 critical value for the standard normal distribution, and 
 is the upper 
 
critical value for the standard normal distribution. It can be adapted to determine  for a 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
57 
 
 two-sided confidence interval for the difference between the rates of 
decline in FEV1 of two groups that has precision  as 
 
where 
 , 
, and 
 and 
are the 
sample sizes associated with each of the two groups. 
In this study, it is planned to collect P=4 measurements of FEV1 over D=2.5 years.  One 
of interest is an estimate of the rate of decline in FEV1 between subjects GOLD I and II. 
Under the above assumptions with 95% confidence and a 25% drop out, the following 
table gives sample sizes necessary to attain the levels of precision of Gold I vs. Gold II 
comparison.  
Table 2 
Sample size for Gold I vs. Gold II under given precision 
Interested comparison 
Precision* 
(ml/yr) 
Subgroup 
Completers 
Total sample size 
including 25% 
drop out 
Gold I vs. Gold II 
 
15 
Gold I 
525 
700 
Gold II 
525 
700 
*: half width of a 95% confidence interval 
 
Based on the total completed 
 COPD subjects, a 95% two-sided confidence 
interval for the rate of decline in FEV1 of all COPD subjects will have a total width of  
 
where 
 
10.1.4. 
Sample Size Sensitivity 
The width of any confidence interval will be wider than expected, if the true standard 
deviation of an endpoint is larger than assumed.  For example, if the within subject 
standard deviation of the rate of decline in FEV1 is 250ml/year, then the 95% confidence 
interval for COPD subjects overall rate of decline in FEV1 will have width 14.7ml/year.  
Conversely, actual standard deviations that are smaller than assumed will result in 
narrower confidence intervals. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
58 
 
10.1.5. 
Sample Size Re-estimation 
Sample size maybe re-estimated during the conduct of study.  
10.2. 
Key Elements of Analysis Plan 
The high-level analytic approaches and methods are described for each objective. Further 
details and exploratory analyses will be described in the Reporting and Analysis Plan 
(RAP).  
10.2.1. 
Populations for Analyses 
For purposes of analysis, the following populations will be defined: 
Population 
Description 
Full population 
The Full Population will consist of all subjects who are enrolled in 
the study and attend Visit 1.   
Sub-cohort population 
Subjects who are enrolled in the Biomarker & Digital sub-cohort 
and who provided a least one additional sub-cohort assessment.  
Completer Population 
The Completer Population will consist of all subjects in the Full 
Population who complete all scheduled clinic visits over 2.5 years. 
 
Other sub-populations may be defined based on disease severity, co-morbidities, age, 
gender, or subject phenotypes. This will be detailed in RAP. 
10.2.2. 
Descriptive Analyses 
Each endpoint collected during the study that represents a continuous measure will be 
summarized with descriptive statistics with mean, median, min, max and SD at each 
clinic visit as actual values and as change from baseline (Visit 1), if appropriate.  
Endpoints that are discrete in nature will be summarized as frequencies and percentages 
at each clinic visit. Counts (e.g. exacerbations of COPD) will be expressed as event rates 
per person-year. 
mMRC dyspnea score will be summarized using descriptive statistics for the Full 
population. Wilcoxon-rank sum test will be used to analyse mMRC dyspnea score among 
different type of subjects, if data permit. 
SGRQ-C score will be transformed into SGRQ score and summarized using descriptive 
statistics. 
10.2.3. 
Disease Progression Analyses 
Disease progression in clinical, radiological and biological measurements will be 
described based on longitudinal data.   

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
59 
 
10.2.3.1. 
Main Cohort 
• Change from baseline and Rate of decline in FEV1 in millilitres (mL): 
Descriptive statistics of FEV1 and change from baseline FEV1 will be reported for 
baseline and all subsequent visits. The raw mean change from baseline at each visit 
will be presented graphically. 
Rates of decline in FEV1 will be estimated for each type of COPD subjects, overall 
COPD subjects, chronic bronchitis group and healthy control group.   
In order to obtain rate of decline in FEV1, particular from a mixed effects model, a 
random coefficients model, will be used. FEV1 after baseline will be fitted as the 
response variable with the proposed selection of predictors including type of subjects 
(i.e. GOLD I-IV, chronic bronchitis, healthy control), age, gender, smoking status, 
baseline FEV1, count of COPD exacerbations, site, time on study and type of subjects 
by time interaction. Participants and time on study will be random effects. Further 
details will be included in RAP. 
Rates of decline in other endpoints may also be estimated in a similar fashion, if 
warranted. 
• Rate of moderate/severe exacerbations: 
Exacerbations separated by less than 7 days will be treated as a continuation of the 
same exacerbation. The exacerbation frequency, type and duration will be 
summarized using descriptive statistics for Full population.  
A generalized linear model assuming the negative binomial distribution will be used 
to analyze the exacerbations rate among different type of subjects.  Additional 
methods including time to event analysis will be considered as appropriate. 
• Change from baseline in CAT score:  
CAT score and change from baseline value will be summarized using descriptive 
statistics for the Full population. 
If appropriate, Mixed Models Repeated Measures (MMRM) model will be used to 
analyze CAT score among different type of subjects. 
• Clinically important deterioration (CID) components:  
CID will be summarized for Full population using descriptive statistics. 
If data permit, generalized linear mixed model will be used to analyze CID among 
different type of subjects and time to CID will be assessed using time to event 
models. 
10.2.3.2. 
Sub-cohort 
General summary/analysis information for each sub-cohort endpoints are listed as below.  
More details will be included in RAP. 
• EXACT events: the analysis will summarize N of events, their onset, duration and 
severity. EXACT events will be derived according to the EXACT manual [Leidy, 
2013] with any alternative considerations detailed in the RAP.   

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
60 
 
• E-RS: COPD total and domain scores: each 4-week interval summary/analysis will be 
done. If data permit, mean weekly scores will be considered for the analysis; this 
assumption will be tested prior starting data analysis. Relationships between mean E-
RS scores and other study variables will be evaluated using a range of analysis of 
variance and analysis of covariance. Changes from baseline in Total and domain 
scores at pre-defined time points will be analysed using a mixed model for repeated 
measures, adjusted for baseline E-RS scores and other key variables. 
• 
• Daily Activity: summary/analysis with appropriate statistics will be done based on the 
data extracted from wrist band.  
10.2.4. 
Phenotypic Analyses 
The data available at Visit 1 will assist in determination of participant phenotypes in 
disease manifestation.  Phenotypes associated with progression of disease will be based 
on longitudinal data.  Phenotype identification will also refer to the findings of previous 
Western cohorts. Complete details will be included in the RAP. 
10.2.5. 
Treatment Pattern and Healthcare Resource Utilization/Cost 
For COPD-related treatment, the following endpoints will be described using frequency 
and percentage:  
• Each type of treatment for COPD patients  
• Initiation of maintenance treatment 
• Switches to another maintenance treatment  
• Addition of other maintenance treatment  
• Stepping up to triple therapy 
• Discontinuation of treatment 
COPD-related and non-COPD healthcare resource utilization and cost will be described 
with appropriate descriptive statistics: 
• Total medical cost, pharmacy cost, and other costs 
• Number of outpatient visit and cost 
• Number of emergency visit and cost 
• Number of hospitalization, length of stay, and cost 
• Treatment of exacerbation and cost  
CCI

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
61 
 
10.2.6. 
Safety Analyses 
Length of Time in Study 
Length of time in study will be calculated as the number of days from enrollment to study 
completion or study discontinuation (i.e., the span of time between Visit 1 and final visit:  
Final visit date – Visit 1 date + 1).  This will be summarized as a discrete variable based 
on ranges of days.  The number of subjects that attend each visit will also be tabulated. 
Adverse Event Assessments 
Study procedure-related SAEs will be summarized using descriptive statistics. SAEs will 
be assigned preferred terms and categorized into body systems according to the MedDRA 
classification of the World Health Organisation terminology.  
10.2.7. 
Other Analyses 
10.2.8. 
Interim Analyses 
Interim analyses will be conducted at various points during the conduct of the study. At 
the end of Visit 1, data from subjects in the Full Population will be used to address 
questions associated with subject phenotypes, characterisation of disease severity, and 
inter-individual variability of each endpoint. At the end of visit 2, 3 and 4, available 
clinical, radiological, biomarker, PRO, and health economics endpoints will be assessed 
based on the appropriate population. Scientific Steering Committee will have sight of, 
and approve, all requests for analyses that come from the Working Groups. 
Summaries of the interim analyses will be described in RAP. 
CCI

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
62 
 
11. 
REFERENCES 
Agusti A, Bel E, Thomas M, Vogelmeier C, Brusselle G, Holgate S, et al. Treatable 
traits: toward precision medicine of chronic airway diseases. Eur Respir J 2016; 47: 359–
361. 
Bestall JC, Paul EA, Garrod R, et al. Usefulness of the Medical Research Council (MRC) 
dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary 
disease. Thorax. 1999;54(7):581-586 
Betsuyaku T, Kato M, Fujimoto K, Kobayashi A, Hayamizu T, Jones PW. A randomized 
trial of symptom-based management in Japanese patients with COPD. Int J Chron 
Obstruct Pulmon Dis. 2018 Aug 13; 13: 2409-2423. 
Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM, et al. 
International variation in the prevalence of COPD (the BOLD Study): a population-based 
prevalence study. Lancet. 2007 Sep 1;370(9589):741-50. 
Couper D, LaVange LM, Han M, Barr RG, Bleecker E, Hoffman EA, et al. Design of the 
Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS). Thorax. 
2014;69(5):491-4.  
Dickson RP, Martinez FJ, Huff nagle GB. The role of the microbiome in exacerbations of 
chronic lung diseases. Lancet 2014; 384: 691–702. 
European Medicines Agency (EMA). Guideline on clinical investigation of medicinal 
products in the treatment of Chronic Obstructive Pulmonary Disease (COPD). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/
WC500096769.pdf 
Faner R, Tal-Singer R, Riley JH, Celli B, Vestbo J, MacNee W, et al. Lessons from 
ECLIPSE: a review of COPD biomarkers. Thorax 2014; 69: 666–672. 
Gomez C, Chanez P. The lung microbiome: the perfect culprit for COPD exacerbations? 
Eur Respir J 2016; 47: 1034–1036. 
ICRP, 2007. 2007 Recommendations of the International Commission on Radiological 
Protection. ICRP Publication 103, Ann. ICRP 37 (2-4). 
Jian W, Yi Gao, Hao C, Wang N, Ai T, Liu C, et al. Reference values for spirometry in 
Chinese aged 4–80 years. J Thorac Dis 2017;9(11):4538-4549. 
Jones P., Harding G, Berry P, Wiklund I, Chen WH, Kline LN, et al. Development and 
first validation of the COPD Assessment Test. Eur Respir J. 2009 Sep;34(3):648-54. 
Jones PW, Lamarca R, Chuecos F, Singh D, Singh D, Gil EG, et al. Characterisation and 
impact of reported and unreported exacerbations: results from ATTAIN. Eur Respir J. 
2014 Nov;44(5):1156-65.  

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
63 
 
Jones, P., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., Leidy, N. Tests of 
the Responsiveness of the Chronic Obstructive Pulmonary Disease (COPD) Assessment 
Test (CAT) Following Acute Exacerbation and Pulmonary Rehabilitation Chest (2012) 
142 134-140 
Kim WJ, Yim JJ, Kim DK, Lee MG, Fuhlbridge AL, Sliwinski P, et al. Severe COPD 
cases from Korea, Poland, and USA have substantial differences in respiratory symptoms 
and other respiratory illnesses. Int J Chron Obstruct Pulmon Dis. 2017:12 3415–3423. 
Kurmi OP, Li L, Smith M, Augustyn M, Chen J, Collins R, et al. Regional variations in 
the prevalence and misdiagnosis of air flow obstruction in China: baseline results from a 
prospective cohort of the China Kadoorie Biobank (CKB). BMJ Open Resp Res 
2014;1:e000025. doi:10.1136/bmjresp-2014-000025. 
Landis SH, Muellerova H, Mannino DM, Menezes AM, Han MK, van der Molen T, et al. 
Continuing to confront COPD international patient survey: methods, COPD prevalence, 
and disease burden in 2012–2013. Int J Chron Obstruct Pulmon Dis. 2014; 9:597–611. 
Leidy NK,  Murray LT, Monz BU, Nelsen L, Goldman M, Jones PW, et al. Measuring 
respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms 
Tool (E-RS) in three clinical trials. Respir Res. 2014; 15(1): 124. 
Leidy NK, Murray LT, Jones P, Sethi S. Performance of the EXAcerbations of chronic 
pulmonary disease tool patient-reported outcome measure in three clinical trials of 
chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014 Mar;11(3):316-25. 
Leidy NK, Murray LT. Patient-reported outcome (PRO) measures for clinical trials of 
COPD: the EXACT and E-RS. Journal of Chronic Obstructive Pulmonary Disease, 2013; 
10:393-398. 
Li J, Feng B, Cui Y, Liu S, Zeng S, Wand X, et al. Analysis on the Affordability and 
Economic Risk for Using Medicine to Treat Patients with Chronic Obstructive 
Pulmonary Disease in Tier 3 Hospitals in China. Chinese Health Economics. 2015, 34(9): 
66-68. 
Mayhew D, Devos N, Lambert C, Brown JR, Clarke SC, Kim VL, Magid-Slav M, et al. 
Longitudinal profiling of the lung microbiome in the AERIS study demonstrates 
repeatability of bacterial and eosinophilic COPD exacerbations. Thorax 2018;0:1–9. 
Meguro M, Barley EA, Spencer S et al. Development and validation of an improved 
COPD-Specific Version of the St. George Respiratory Questionnaire. Chest. 2007; 132: 
456-463 
Miller BE, Tal-Singer R, Rennard SI, Furtwaengler A, Leidy N, Lowings M, et al. 
Plasma Fibrinogen Qualification as a Drug Development Tool in Chronic Obstructive 
Pulmonary Disease. Perspective of the Chronic Obstructive Pulmonary Disease 
Biomarker Qualification Consortium.Am J Respir Crit Care Med. 2016;193(6):607-13. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
64 
 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J, 2005; 26:319-338 
Naya, I, Birk, R, Brealey, N, Tabberer, M, Zhu, C-Q, Lipson, D. Clinically important 
deterioration in advanced COPD patients using single inhaler triple therapy: results from 
the FULFIL study. ERJ Open Res 2018; 4: 00047-2018 
Newton MF, O’Donnell DE, Forkert L. Response of lung volumes to inhaled salbutamol 
in a large population of patients with severe hyperinflation. Chest 2002;121(4):1042-
1050. 
O’Donnell DE, D’Arsigny C, Fitzpatrick M, Webb KA. Exercise hypercapnia in 
advanced chronic obstructive pulmonary disease: the role of lung hyperinflation. Am J 
Respir Crit Care Med 2002;166(5):663-668.  
Regan EA, Hokanson JE, Murphy JR, Genetic epidemiology of COPD (COPDGene) 
study design. COPD. 2010;7(1):32-43. 
Schlesselman JJ. Planning a Longitudinal Study: II. Frequency of Measurement and 
Study Duration. J Chron Dis 1973; 26:561-570. 
Singh D, Maleki-Yazdi MR, Tombs L, Igbal A, Fahy WA, Naya I. Prevention of 
clinically important deteriorations in COPD with umeclidinium/vilanterol. Int J Chron 
Obstruct Pulmon Dis. 2016; 11: 1413–1424. 
Tan WC, Bourbeau J, Hernandez P, Chapman KR, Cowie R, FitzGerald JM, et al. 
Exacerbation-like respiratory symptoms in individuals without chronic obstructive 
pulmonary disease: results from a population-based study. Thorax. 2014 Aug;69(8):709-
17. 
Vestbo J, Agusti A, Wouters EFM, Bakke P, Calverley PM, Celli B, et al. Should We 
View Chronic Obstructive Pulmonary Disease Differently after ECLIPSE? A Clinical 
Perspective from the Study Team. Am J Respir Crit Care Med 2014; 189: 1022–1030. 
Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards L, et al. Evaluation of 
COPD longitudinally to identify predictive surrogate end-points (ECLIPSE). Eur Respir 
J. 2008;31(4):869-73. 
Wang C, Xu J, Yang L, XuY, Zhang X, Bai C, et al. Prevalence and risk factors of 
chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] 
study): a national cross-sectional study. Lancet. 2018;391(10131):1706-1717. 
Wang Z, Bafadhel M, Haldar K, Spivak A, Mayhew D, Miller BE, et al. Lung 
microbiome dynamics in COPD exacerbations. Eur Respir J 2016; 47: 1082–1092. 
Wang Z, Singh R, Miller BE, Tal-Singer R, Van Horn S, Tomsho L, et al. Sputum 
microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease 
exacerbations: an analysis of the COPDMAP study. Thorax. 2017 Dec 21. doi: 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
65 
 
10.1136/thoraxjnl-2017-210741. [Epub ahead of print]. Available at 
http://europepmc.org/abstract/med/29269441. 
Wilkinson TMA, Aris E, Bourne S, Clarke SC, Peeters M, Pascal TG, et al. A 
prospective, observational cohort study of the seasonal dynamics of airway pathogens in 
the aetiology of exacerbations in COPD. Thorax 2017; 72: 919–927. 
Zhong N, Wang C, Yao W, Chen P, Kang J, Huang S, et al. Prevalence of chronic 
obstructive pulmonary disease in China: a large, population-based survey. Am J Respir 
Crit Care Med. 2007; 176(8):753-60. 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
66 
 
12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
ACT 
Asthma Control Test 
AE 
Adverse Event 
AECOPD 
Acute exacerbations of COPD 
CAT 
COPD Assessment Test 
CC16 
Club cell protein 
CID 
Clinically Important Deterioration 
CMH 
Chronic Mucus Hypersecretion 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID 
Coronavirus disease 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CAPTURE 
COPD Assessment in Primary Care to 
Identify Undiagnosed Respiratory Disease 
and Exacerbation Risk 
DDA 
Digital Data Analytics 
eCOA 
electronic Clinical Outcome Assessment 
EDC 
Electronic Data Collection 
EHR 
Electronic Health Record 
ePRO 
Electronic Patient-reported Outcomes  
E-RS: COPD 
Evaluating Respiratory Symptoms in 
COPD (subset of EXACT) 
EST 
Empowered Study Team 
EXACT 
EXAcerbation of COPD Tool 
FEF 
Forced Expiratory Flow 
FET 
Forced Expiratory Time 
FEV1 
Forced Expiratory Volume in one second 
FEV6 
Forced Expiratory Volume in six second 
FRC 
Functional residual capacity 
FSH 
Follicle stimulating hormone 
FVC 
Forced Vital Capacity 
GERD 
Gastroesophageal Reflux Disease  
GOLD 
Global Initiative for Chronic Obstructive 
Lung Disease 
GIRH 
Guangzhou Institute of Respiratory Health 
HbA1c 
Glycated haemoglobin A1c 
HIS 
Hospital Information System 
hsCRP 
High-sensitivity C-Reactive Protein 
HRCT 
High-resolution computed tomography 
HRT 
Hormonal replacement therapy 
HRQoL 
Health-related Quality of Life 
ICF 
Informed Consent Form 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
67 
 
IP 
Investigational Product 
MMEF 
Maximal Mid-Expiratory Flow 
mMRC 
modified Medical Research Council 
dyspnea scale 
PRO 
Patient reported outcome 
SAE 
Serious Adverse Events 
SGRQ-C 
St. George’s Respiratory Questionnaire 
for COPD 
sRAGE 
soluble Receptor for Advanced Glycation 
End Products 
sPVP 
study-specific Pharmacovigilance Plan 
SoA 
Schedule of Activity 
TLC 
Total Lung Capacity 
tPEF 
time to Peak Expiratory Flow 
OTC 
Over-the-counter 
VEXT 
Volume back extrapolation 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
CAT 
 
MedDRA  
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
68 
 
12.2. 
Appendix 2: Study Governance Considerations 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
 
Financial Disclosure 
 Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
69 
 
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
Data from eCRF, ePROs and mobile devices will be encrypted and 
automatically transmitted to vendor’s server for integration.  HIS data will be 
de-identified and be encrypted and transferred via secured portal for data 
integration.   
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
70 
 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
• 
GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate. 
• 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy. 
• 
A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
Data Quality Assurance 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
The sponsor and the third-party vendors are responsible for the data 
management of this study including quality checking of the data.  
• 
Study monitors will perform ongoing monitoring activities to ensure that the 
safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.  
Source Documents 
• 
Digital data collection from electronic CRF, electronic medical records in 
hospital databases, ePROs, and wearable device along with CT and biomarker 
data are the key sources for data analysis.  The study database will be housed on 
a third-party vendor’s secure network.   Datasets from various sources will be 
delivered in CDISC ODM standards for integration. 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
71 
 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
Inadequate recruitment of participants by the Investigator 
 
 
 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
72 
 
12.3. 
Appendix 3: Contraceptive and Barrier Guidance 
12.3.1. 
Definitions: 
Definitions 
Woman of Childbearing Potential 
 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
 
Women in the following categories are not considered to be Woman of Childbearing 
Potential 
 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
• Females on HRT and whose menopausal status is in doubt will be excluded unless 
they agree to discontinue HRT to confirm their postmenopausal status 
 
 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
73 
 
12.4. 
Appendix 4: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 1 19-JUN-2019 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Authorship has been 
changed: added external 
SC members, 
Yongchang Sun,Fuqiang 
Wen and Qianli Ma. 
Removed people who 
have left GSK,including 
Lihong Zhuang,Na 
Guo,Wela Huang and 
Hana Mullerova. 
According to ICMJE criteria, 
people who left do not meet the 
authorship criteria for this version 
of amendment. 
Section 6.1. 
Inclusion Criteria-
COPD Participants 
Edited “A baseline 
(post-bronchodilator) 
FEV1/FVC ratio ≤70%
”to “A baseline (post-
bronchodilator) 
FEV1/FVC ratio ＜
70%” 
Should be consist with GOLD. 
Section 6.1. 
Inclusion Criteria-
COPD 
Participants/Chronic 
Bronchitis 
Participants 
Section 9.1. Baseline 
data collection 
Redefined smoking 
status as “Ever smoker 
(with a lifetime exposure 
of ≥10 pack-year or 
never smoker (with a 
lifetime exposure of <1 
pack-year” 
The original protocol defined 
smoking status as 100 cigarettes 
which are not as commonly used in 
clinical practice and treatment 
guideline. 
Section 6.1. 
Inclusion Criteria-
COPD Participants, 
CMH participants 
and healthy 
participants 
Added “BMI＜35” on 
additional criteria for 
sub-cohort COPD 
participants,CMH 
participants and healthy 
participants 
To ensure patient’s safety in doing 
CT scan, and also to obtain 
sufficient image quality whilst 
using the least possible radiation, 
hence the ranges of possible dose 
estimates. The highest exposures 
will be required only in larger 
participants with a BMI >30. 
Therefore, only patients with BMI 
＜35 will be included. 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
74 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1 Synopsis 
Section 2 SOA 
Section 4.Objectives 
and Endpoints 
Section 5.4. 
Scientific Rationale 
for study design 
Section 9.1. Baseline 
and data collection 
Section 9.2.6 Patient 
Reported Outcome 
Measures 
Section 9.2.6.3 Other 
PRO assessments 
Added CAPTURE 
questionnaire 
To assess the utility of the 
CAPTURE questionnaire as a case 
finding tool in obstructive lung 
disease 
Section 9.1. Baseline 
data collection 
Added “Biomass 
questionnaire”and 
removed the “Biomass 
definition and detailed 
information including 
ventilation in the kitchen
” 
Combined biomass related 
information to make it clear for 
better understanding of  the 
relationship between Biomass in 
Guangdong region and COPD 
development, 

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
75 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1. Synopsis; 
Section 2. Schedule 
of Activities 
Section 4. Objectives 
and Endpoints 
Section 5.4. 
Scientific Rationale 
for Study Design 
Section 9.1. Baseline 
data collection 
Section 9.2.9.1. 
Blood Biomarkers 
Section 12.1. 
Appendix1 
Added HbA1c test and 
its rationale for sub 
cohort as an endpoint. 
In order to explore the relationship 
between glycaemic control and 
AECOPD/mortality/Hospitalization, 
etc 
Section 1. Synopsis; 
Section 4. Objectives 
and Endpoints 
Section 5.4. 
Scientific Rationale 
Section 9.2.7. 
Computed 
tomography (CT) 
(sub-cohort only) 
Section 10.2.3.2. 
Sub-cohort 
Lung HRCT endpoints have been 
changed to a general description so 
that all the analyses for this 
objective could be conducted. 
Section 2. Schedule 
of activities (SOA) 
Added +3 days window 
for baseline visit 
It may be hard for patients to 
complete all examination in one day 
and according to study as there will 
be  
Section 3.1. 
Benefit/Risk 
assessment 
Potential risk for HRCT 
scans has been refined to 
exposure to ionising 
radiation as a 
consequence of 
participation 
Justified the current dose of ionising 
radiation which will do no harm to 
participants whose BMI is ＜35. 
CCI

TMF-13816843 
CONFIDENTIAL 
 
 
 
208630 
 
76 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 3.1. 
Benefit/Risk 
assessment 
Added Potential risk for 
wrist band 
Include the description of wrist 
band. 
Section 9.2.9.2 
Sputum microbiome 
and sputum cytology 
(sub-cohort only) 
 
Added Additional 
analyses may 
measurement of viruses 
and fungi 
To explore on how respiratory 
microbiota can influence the 
efficacy of common therapies for 
chronic respiratory disease in 
Chinese population. 
Section 9.2.3. 
Spirometry 
Removed central read 
procedure by GIRH. 
Updated equation and 
procedure.  
To perform the lung function in a 
standardized way in order to ensure 
the data quality.     
Section 1 Synopsis 
Section 5.2. Number 
of participants 
Edited “All patient 
population sizes are 
approximate and allow 
subject to feasibility” to 
“All patient population 
sizes are approximate 
and allow  10% for 
feasibility” 
Since the sample size in this study 
is justified by feasibility, no formal 
hypotheses will be tested. 
Therefore, allowing a range    10% 
will not have impact about the 
analysis. 
Throughout 
Minor editorial and 
document formatting 
revisions