The Cohort Study for Chronic Obstructive Pulmonary Diseases (COPD) in China---- Observation of the Disease Outcome and Identification of Prognostic Biomarkers for the Disease Outcome
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Beijing Chao Yang Hospital

Clinical Study Protocol  
Study Code 
ESR-16-12485 
Edition Number 
1.0 
Date 
16 Nov 2016 
The cohort study for chronic obstructive pulmonary diseases (COPD) in 
China ---- Observation of the disease outcome and identification of 
prognostic biomarkers for the disease outcome 
Principal Investigator: Chen Wang/Kewu Huang  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Contents 
TITLE PAGE ............................................................................................................................ 1 
1. 
INTRODUCTION ................................................................................................... 3 
1.1 
Background .............................................................................................................. 4 
1.2 
Rationale .................................................................................................................. 4 
2. 
OBJECTIVES .......................................................................................................... 5 
2.1 
Primary Objective & Outcome Measure .................................................................. 5 
2.2 
Secondary Objectives & Outcome Measure ............................................................ 6 
2.3 
Exploratory Objectives & Outcome Measure .......................................................... 6 
3. 
METHODOLOGY .................................................................................................. 7 
3.1 
Funding ..................................................................................................................... 7 
3.2 
Study PopulationDesign ........................................................................................... 7 
3.3 
Study Population ...................................................................................................... 8 
3.4 
Data Sources  ........................................................................................................... 8    
3.5 
Inclusion Criteria ..................................................................................................... 8 
3.6 
Exclusion Criteria .................................................................................................. 99 
3.7 
Study Plan ................................................................................................................ 9 
3.7.1         Intensive Follow-up Study Plan .............................................................................. 9 
3.7.2         Extensive Follow-up Study Plan ........................................................................... 10 
4. 
VARIABLES AND EPIDEMIOLOGICAL MEASUREMENTS ........................ 12 
4.1 
Exposures ............................................................................................................... 12 
4.2 
Variables ................................................................................................................ 12 
5. 
DATA PROCESSING ........................................................................................... 13 
5.1 
Sample Size Determination .................................................................................... 13 
5.2 
Statistical Analyses ................................................................................................ 14 
5.3 
Data Management .................................................................................................. 15 
6. 
MONITORING OF THE STUDY ......................................................................... 15 
7.  
COLLECTION AND REPORTING OF ADVERSE EVENTS/ADVERSE 
DRUG REACTIONS ............................................................................................. 16 
7.1 
Definition of Adverse Events (AE) .......................................................................... 16 
7.2           DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  .................................. 16 
7.3 
DEFINITION OF ADVERSE DRUG REACTIONS (ADR) ............................... 16 
7.4 
Reporting of Adverse Events ................................................................................. 17 
8. 
STUDY TIMETABLE ......................................................................................... 177 

9. 
STUDY AGREEMENT ......................................................................................... 18 
10. 
LIST OF REFERENCES ....................................................................................... 18 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS 
 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Events 
ADR 
Adverse Drug Reactions 
BD 
Bronchodilator 
CAT 
COPD Assessment Test 
COPD 
Chronic Obstructive Pulmonary Disease  
FEV1 
Forced Expiratory Volume in 1 second  
FVC 
Forced Vital Capacity  
GOLD 
Global Initiative for Chronic Obstructive Lung 
Disease  
HRQoL 
Health-related Quality of Life  
mMRC 
Modified British Medical Research Council  
SAE 
Serious Adverse Events 
SGRQ 
the St George’s Respiratory Quesionnaire 
 
 

1. 
INTRODUCTION 
1.1 
Background 
Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable 
disease, is characterized by persistent airflow limitation that is usually progressive and 
associated with an enhanced chronic inflammatory response in the airways, which is 
diagnosed based on chronic cough, sputum, wheeze & exposure to harmful factors, and 
confirmed by spirometry(1). 
COPD is a leading cause of morbidity and mortality worldwide. In China, respiratory 
diseases (of which COPD is a major component) are the third leading cause of death in rural 
areas and the fourth leading cause of death in urban areas and rank second among the burdens 
of diseases. 
The overall prevalence of COPD was 8.2%(men, 12.4%; women, 5.1%) (40 y) in China. 
It seems the prevalence is still growing concerning the high smoking rate, increasing aging 
population and serious air pollution in China(2). 
Currently, COPD is largely treated symptomatically using bronchodilators to improve 
airflow, reduce dyspnea and prevent exacerbations. One major barrier to novel therapies is the 
heterogeneity of COPD pathogenesis. Although COPD is characterized by airflow limitation, 
the molecular processes that drive the airflow limitation are thought to be highly variable. To 
capture this heterogeneity, there has been a focused effort on finding simple biomarkers of 
disease activity. 
1.2 
Rationale 
Chronic obstructive pulmonary disease (COPD) is a complex clinical entity. In contrast 
to previously limited diagnostic definitions, it is now apparent that COPD is a clinically and 
biologically heterogeneous disease process, overlapping with other airways diseases like 
chronic asthma. As such, symptomatic response to current standard treatment practices is 
variable. Thus phenotype and endotype are need to be identified to figure out the way to 
predict the disease course, treatment responses and prognosis. Recently, some big cohort 
studies about COPD have been conducted in the world, such as COPDgene, Eclipse and 
Spiromics(3-5). And some specific phenotypes and valuable biomarker have been identified in 
patients with strict definition of COPD.  
However, currently there is few COPD studies to describe the biomarkers of the COPD 
patients longitudinally and few biological database established in China. Furthermore, there is 
very limited availability of emerging biomarker data (especially linked to other data types), 
which are key to understanding novel phenotypes and endotypes, disease mechanism, and 
disease progression, and to drive scientific discovery in obstructive lung disease. 
Novelty, a Global sponsored study by AstraZeneca, aims to identify phenotypes and 
endotypes based on biomarkers and/or clinical parameters that are associated with differential 
outcomes over 3 years. But due to HGRAC restriction, China made the Specific Protocol 

Amendment: No biobanking of any samples and remove collection of: DNA & RNA; urine; 
plasma. 
In China, the phenotype / endotype of COPD patients might be unique for the following 
reasons, passive smoking is very common in China; air-pollution is public health issue in 
China; exposure to bio-fuel is not uncommon, especially in rural areas of China.  
This study aims to clearly understand the Chinese COPD patients as below:  
1. What’s clinical outcome of COPD patients, including mortality, lung function 
decline, QOL, COPD exacerbation? 
2. What’s the different biomarkers to predict clinical outcomes in COPD patients? 
3. What’s the longitudinal clinical features and clinical practice of COPD patients to 
guide the future treatment pattern? 
4. What’s the relationship between high risk population (GOLD 0) with COPD patients 
and identify specific biomarkers to predict the disease progress? 
This study is co-fuding with National Key Research and Development Program of China 
(No: 2016YFC0901102) and AstraZeneca's clinical research project (ESR-16-12485). 
2. 
OBJECTIVES 
2.1 
Primary Objective & Outcome Measure 
Primary Objective: 
Outcome Measure: 
 
To observe the disease outcome and 
identify sub-populations (phenotype& 
biomarker) of COPD patients to know the 
clinical outcome 
  
 
COPD-related mortality and all-cause mortality 
in COPD individuals and GOLD 0 individuals 
respectively 
 
Clinical characteristics* and biomarkers* to 
identify phenotype*  
 
Use different phenotypes /biomarkers to predict 
clinical outcomes* of COPD 
 
Phenotypes and biomarkers of COPD patients to 
know the clinical outcome from specific 
treatment regimen* 
* Clinical characteristics: allergic history, smoking history/ passive smoking history, 
occupational exposure, bio-fuel exposure, current respiratory symptoms, pulmonary function 
test, presence or absence of emphysema or chronic bronchitis on CT scan 
* Biomarkers: blood sample tested for biomarkers such as IL-4, IL-5, IL6, IL-8, IL-13, IL-33, 
TNF-α, CRP, EOS, etc. 
* Phenotype: COPD without asthma/asthmatic characteristic population, COPD overlapping 
asthma/ asthmatic population, passive-smoking population, bio-fuel exposure population, 

bronchitis-dominant COPD sub-population, emphysema-dominant COPD sub-population, 
more inflammatory COPD sub-population, less inflammatory COPD sub-population, 
neutrophilic inflammatory COPD sub-population, eosinophilic inflammatory COPD sub-
population, etc.  
* Clinical outcomes: COPD-related mortality and all-cause mortality, exacerbation rate, QOL, 
FEV1, 6MWT decline. 
* Specific treatment regimen: such as ICS+LABA vs LABA. e.g. inflammatory cytokine to 
predict clinical outcomes assessed by acute exacerbation rate, COPD-related mortality and all-
cause mortality with different treatment regimen. 
2.2 
Secondary Objectives & Outcome Measure 
Secondary Objective: 
Outcome Measure : 
 
To identify the risk factor of progressing 
to COPD in population with high risk 
factors (GOLD 0). 
 
To describe the association between 
specified biomarkers, at enrolment and 
over time and evaluate their stability over 
time, factors affecting their variability, 
and their relationship with clinical 
features. 
 
Baseline summary of patients in GOLD 0 & 
COPD I~IV: demographic data, medical history, 
risk factors, acute exacerbation history in 12 
months before the visit. Pulmonary function, CT 
results, QOL 
 
Longitudinal summary of patients in GOLD 0 & 
COPD I~IV: mortality, exacerbation* and 
treatment regimen modification* and reseasons 
for modifications,  comorbidities morbidity, 
pulmonary function(FEV1) , QOL and ability of 
activity ecaluated by 6MWT decline, 
biomarkers* at baseline and annually at each 
visit. 
* Exacerbation: the number of exacerbations, severity of exacerbation: using systemic 
hormones/antibiotics/emergency /hospitalization and days of hospitalization or emergency 
room visit 
* Treatment regimen modification: non-medicine treatment and medicine treatment including 
type/duration/dosage/frequency/discontinuation 
* Biomarkers: blood sample tested for biomarkers such as IL-4, IL-5, IL6, IL-8, IL-13, IL-33, 
TNF-α, CRP, EOS, etc. 
2.3 
Exploratory Objectives & Outcome Measure 
Exploratory Objective: 
Outcome Measure : 

 
To investigate the factors of exacerbation 
of COPD patients. 
 
To investigate the factors to predict 
treatment response. 
 
 
Multiple-factor analysis about the COPD 
exacerbation number (biomarkers, demographics 
data, drug compliance, visit compliance, 
smoking status, drug class, comorbidity, disease 
severity, QOL, etc.) 
 
Treatment regimen modification and reseasons 
for modifications: medicine  
(type/duration/dosage/frequency/discontinuation)  
between each follow-up assessment. 
 
Correlation between biomarkers, disease severity 
and/ or control and different measures of 
response to treatment. 
 
Levels of biomarker parameters, lung function, 
and risk factors at each follow-up assessment, 
and variability in these measures 
 
3. 
METHODOLOGY 
3.1 
National Program ---- Co-Funding 
This study is co-fuding with National Key Research and Development Program of China 
(No: 2016YFC0901102) and AstraZeneca's clinical research project (ESR-16-12485). 
3.2 
Study Design 
This is a multi-center observational prospective longitudinal cohort study. The study is 
designed to observe 3800 subjects for more than 5 years, including COPD subjects (n = 3000) and 
GOLD 0 subjects (n = 800) from 20 study sites, with baseline visit and Visit 1 in the first year and 
Visit 2 to Visit 5 in the next consecutive years. Each site will recruit about 150 COPD patients and 
25 GOLD 0 subjects successively. 
Blood sample will be collected at sites and transported to central lab to test for 
biomarkers such as IL-4, IL-5, IL6, IL-8, IL-13, IL-33, TNF-α, CRP, EOS, etc. Blood sample 
will then be preserved in central lab. 
 
 

3.3 
Study Population 
The study population will recruit about 3800 subjects, men or women, between 40-75 
yrs, with or without persistent airflow limitation (post-BD FEV1/FVC < 0.7) in China. There 
are 2 cohorts in this study: COPD group and GOLD 0 group. 
3000 patients will be recruited in COPD group. The post-bronchodilator FEV1/FVC 
ratio < 0.70 was used as definition of COPD, which was proposed by the Global Initiative for 
Chronic Obstructive Lung Disease (GOLD). According to the real distribution of COPD 
patients, the sample size for different GOLD level was assigned as 500 (I), 2000 (II/III), 500 
(IV). 
800 individuals will be recruited in GOLD 0 group. GOLD 0 is defined as having 
chronic respiratory symptoms and/or high risk factors, but without airflow (post-BD 
FEV1/FVC ≥ 0.7). Chronic respiratory symptoms is defined as chronic cough, phlegm 
production, chest tightness, short of breath, dyspnea, wheeze, ect. High risk factors is defined 
as cigarette smoking, passive smoking, occupational exposures, bio-fuels exposures ect. 
 
GOLD 0  
GOLD I 
GOLD II/III 
GOLD IV 
Sample 
800 
500 
2000 
500 
post-BD FEV1/FVC 
≥ 0.7 
< 0.7 
< 0.7 
< 0.7 
FEV1 % Pred 
 
＞ 80% 
80 – 30% 
< 30% 
 
3.4 
Data Sources 
Sites must be tier 2 or tier 3 hospitals in China, with the equipment and ability to 
conduct pulmonary function test, HRCT. Investigators will be respiratory physicians working 
in the respiratory department of tier 2 or tier 3 hospitals. Physicians should have patients’ 
spirometric data with 12 months before baseline in the patient’s medical files (post-BD 
FEV1%pred and post-BD FEV1/FVC). 
3.5 
Inclusion Criteria 
Subject population that will be observed in this study must meet all of the following criteria: 
• Aged 40-75 years 
• COPD group: baseline post-bronchodilator FEV1/FVC ＜ 0.7 
• GOLD 0 group: individuals with chronic respiratory symptoms and/or high risk factors 
• Signed informed consent obtained prior to participations with the ability to comply 
with protocol and be available for study visits over more than 5 years 

3.6 
Exclusion Criteria 
Subject population that will be observed in this study must meet none of the following criteria: 
• Acute exacerbation in the past 3 months 
• Having other repiratory diseases with massive lung tissue destruction such as severe 
bronchiectasis and tuberculosis, etc 
• The usual criteria of serious uncontrolled diseases 
• thoracic or abdominal surgery in the last 3 months 
• eye surgery in the last three months 
• retinal detachment 
• myocardial infarction in the last 3 months 
• admission to hospital for any cardiac condition in the last month 
• heart rate over 120 beats per minute 
• antibacterial chemotherapy for tuberculosis 
• pregnant or breast feeding 
3.7 
Study Plan 
3.7.1 
Intensive Follow-up Study Plan 
 
V0 
V1
（12mo
nths±
30d） 
V2
（24mo
nths±
30d） 
V3
（36mo
nths±
30d） 
V4
（48mo
nths±
30d） 
V5
（60mo
nths±
30d） 
TC* 
（Every 3 
months 
after 
enrolled） 
Informed 
consent 
√ 
 
 
 
 
 
 
Inclusion/excl
usion criteria 
√ 
 
 
 
 
 
 
Demographic
s, medical 
history, etc 
√ 
 
 
 
 
 
 
Disease 
outcome 
 
√ 
√ 
√ 
√ 
√ 
√ 

Physical 
examination 
√ 
√ 
√ 
√ 
√ 
√ 
 
Spirometry 
√ 
√ 
√ 
√ 
√ 
√ 
 
Lung volume 
measurement 
√ 
 
√ 
 
√ 
 
 
Diffusion 
function 
√ 
 
√ 
 
√ 
 
 
FENO 
√ 
√ 
√ 
√ 
√ 
√ 
 
Chest X-ray 
 
√ 
 
√ 
 
√ 
 
Chest 
CT(inspirator
y and 
expiratory 
phase) 
√ 
 
√ 
 
√ 
 
 
6MWT 
√ 
√ 
√ 
√ 
√ 
√ 
 
Blood RT 
√ 
√ 
√ 
√ 
√ 
√ 
 
Phadiatop 
√ 
√ 
√ 
√ 
√ 
√ 
 
Total IgE 
√ 
√ 
√ 
√ 
√ 
√ 
 
Questionnaire 
(SGRQ/CAT/
mMRC/GERD 
Q/GAD-
7/PHQ-9) 
√ 
√ 
√ 
√ 
√ 
√ 
 
Daily 
activities 
√ 
√ 
√ 
√ 
√ 
√ 
 
Blood 
samples 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
* TC: Every 3 months after enrolled, interview participates by phone focusing on acute 
exacerbations, visits to hospitals, hospitalization and data about mortality 
 
3.7.2 
Extensive Follpw-up Study Plan 
3.7.2.1 COPD Cohort Extensive Follpw-up 
 
V0 
V1
（12mon
ths±
30d） 
V2
（24mon
ths±
30d） 
V3
（36mont
hs±
30d） 
V4
（48mont
hs±
30d） 
V5
（60mont
hs±
30d） 
Informed 
consent 
√ 
 
 
 
 
 

Inclusive/excl
usive criteria 
√ 
 
 
 
 
 
Demographics, 
medical 
history, etc 
√ 
 
 
 
 
 
Disease 
outcomes 
 
√ 
√ 
√ 
√ 
√ 
Physical 
examination 
√ 
√ 
√ 
√ 
√ 
√ 
Spirometry 
√ 
√ 
√ 
√ 
√ 
√ 
Chest X-ray 
√ 
√ 
√ 
√ 
√ 
√ 
Blood RT 
√ 
 
 
 
 
 
Questionnaire 
(CAT/mMRC) 
√ 
√ 
√ 
√ 
√ 
√ 
Blood samples 
√ 
 
 
 
 
 
 
 
3.7.2.2 GOLD 0 Cohort Extensive Follow-up 
 
V0 
（0 月） 
V1
（12mon
ths±
30d） 
V2
（24mon
ths±
30d） 
V3
（36mon
ths±
30d） 
V4
（48mo
nths±
30d） 
V5
（60mon
ths±
30d） 
Informed 
consent 
√ 
 
 
 
 
 
Inclusive/excl
usive criteria 
√ 
 
 
 
 
 
Demographics, 
medical 
history, etc 
√ 
 
 
 
 
 
Disease 
outcomes 
 
 
 
 
 
√ 
Physical 
examination 
√ 
 
 
 
 
√ 
Spirometry 
√ 
 
 
 
 
√ 
Chest X-ray 
√ 
 
 
 
 
√ 
Blood RT 
√ 
 
 
 
 
 
Questionnaire 
(CAT/mMRC) 
√ 
 
 
 
 
√ 
Blood samples 
√ 
 
 
 
 
 

4. 
VARIABLES AND EPIDEMIOLOGICAL MEASUREMENTS 
4.1 
Exposures 
The treatments will be determined by their treating physicians and no additional 
investigational drugs will be applied to the patients included in this study. Current medications 
and dosages to treat these diseases and some specific concomitant medications (steroids) will 
be collected at the visit. 
4.2 
Variables 
• Demographic Data: gender, date of birth, height, weight, living environment, 
educational level/ years of formal education 
• Medical history or Family history 
• Allergic history 
• Smoking history/ Passive smoking history 
• Occupational exposure 
• Bio-fuel exposure 
• Current respiratory symptoms: breathlessness, chest tightness, coughing, wheezing, 
sputum production 
• Years of COPD/chronic bronchitis/emphysema diagnosis and age of onset 
• Acute exacerbation 
× 
Acute exacerbation history in 12 months before the visit (the number of exacerbations, 
severity of exacerbation (using systemic hormones / antibiotics / emergency / 
hospitalization) and days of hospitalization or emergency room visit 
× 
Acute exacerbation and treatment information during intervals of visits: the number of 
exacerbations, severity of exacerbation (using systemic hormones / antibiotics / emergency / 
hospitalization) and days of hospitalization or emergency room visit 
• Comorbidities 
× Fromer comorbidities before baseline 
× New-developed comorbidities during intervals of visits 
• COPD-related mortality and all-cause mortality during intervals of visits 
• Teatment 
× Current used medications prescribed by physicians to treat COPD/ chronic respiratory 
symptoms (type/duration/dosage/frequency) 
× Treatment regimen modification and reseason for modifications during intervals of 
visits: medicine (type/duration/dosage/frequency) and non-medicine treatment 
× Specific concomitant medications: steroids 
• Pulmonary function: 
× The latest pulmonary function results at non-acute stage in 12 months before baseline 
× Spirometry and bronchial dilation test: pre/post/pred - FEV1, pre/post/pred - FVC, 
post - FEV1/FVC 

× Lung volume measurement: absolute/pred - IC, absolute/pred - VCmax, absolute/pred 
- RV, absolute/pred - TLC 
× Diffusion function: absolute/pred DLCO SB, absolute/pred VA 
• Chest X-Ray 
• HRCT scan: Chest high-resolution computed tomography at inspiratory and expiratory: 
presence or absence of emphysema /chronic bronchitis/pulmonary bulla or other 
abnormities; bronchial wall thickening 
• Blood sample: IL-4, IL-5, IL6, IL-8, IL-13, IL-33, TNF-α, CRP, EOS 
• Health-Related Quality of Life (QOL) evaluated by questionnaires: CAT*, mMRC*, 
SGRQ* 
• Daily activity: monitored by pedometer for consecutive 7 days 
• 6 minute walk test 
*Patient Reported Outcomes(PRO) Measures 
CAT / mMRC / SGRQ will be completed by patients themselves independently. If patients have any 
questions, investigator can help to explain the content of every item. The investigator should review the 
questionnaires to avoid any uncompleted responses. It is recommended that the investigators perform the 
clinical evaluation following completion of the questionnaire. 
*CAT (COPD Assessment Test ): CAT has been developed by Jones et al. CAT is a validated, short and 
simple questionnaire used to assess COPD symptom and the COPD impact on patients’ daily life and well-
being. It has good measurement properties, is sensitive to differences in state and should provide a valid, 
reliable and standardised measure of COPD health status with worldwide relevance. CAT comprises eight 
questions, each presented as a semantic six-point (0–5) differential scale, providing a total score out of 40. 
Scores of 0–10, 11–20, 21–30 and 31–40 represent mild, moderate, severe, or very severe clinical impact, 
respectively. 
*mMRC (Modified British Medical Research Council): mMRC is a modified respiratory questionnaire 
designed by British Medical Research Council. It is used to assess the severity of breathlessness of COPD 
patients according to the different activities when dyspnea occurrs. mMRC is divided into 5 grades from 0 
to 4 grade. 
*SGRQ (the St George’s Respiratory Quesionnaire): The SGRQ is designed to measure health impairment 
in patients with asthma and COPD. It is in two parts. Part  I produces the Symptoms score, and Part 2 the 
Activity and Impacts scores. A Total score is also produced. 
5. 
DATA PROCESSING  
5.1 
Sample Size Determination 
This study is co-fuding with National Key Research and Development Program of China 
(No: 2016YFC0901102). The sample size has been determined as 3000 COPD individuals and 
800 GOLD 0 subjects.. 

Sample size of the surney is 3800, including 3000 COPD patients and 800 GOLD 0 
subjects. The sample size of COPD corhort was calculated considering the mortality of COPD 
as the primary outcome. With the assumption of average mortality in COPD population is 
15%(6)，3000 enrolled subjects (assume a drop-out rate of 30%)  will provide a precision of 
1.5% for the estimate of the 95% confidence interval for the mortality rate.   
According to the real distribution of COPD patients, the number of enrolled subjects for 
different GOLD level was assigned as 800 (GOLD I), 2000 (GOLD II/III) and 800 (GOLD 
IV). Assume the mortality for GOLD IV will be the highest, 25%, 800 subjects considering 
30% drop-out rate still provide a precision of 4.5%. There’s no exact assumption for the 
mortality rate in GOLD (0) population. It’s assumed less than 25%, then 800 subjects will still 
provide a precision less than 4.5% which can fulfil the study need. 
5.2 
Statistical Analyses 
Full analysis set (FAS) will be used for all analyses, which includes all enrolled subjects 
who fulfil the inclusion/exclusion criteria. Missing data will be analysed as it is, no imputation 
method will be utilized.  
Statistical analysis will be conducted by epidemiology & statistics work group from 
Chinese Academy of Sciences, using SAS and SUDAAN software. 
The analysis method will be primarily descriptive. For continuous variables, summary 
statistics including n, mean, median, standard deviation, min and max will be presented. For 
categorical variables, frequency and percentage of subjects at each category level will be 
presented. The variable with missing values will be analysed as is, that is, no imputation 
method will be utilized.  
The primary variable, mortality rates inlucding COPD related mortality and all-cause 
mortality overall and by GOLD group will be summarized using the frequency and 
percentage, a 95% confidence interval for the percentage will be constructed.  The mortality 
per patient-year (defined as the number of patients in whom an event occurs divided by the 
sum of person-time) may be provided if applicable 
The other primary and secondary variables will be analysed descriptively overall and by 
sub-population: gender, year of birth, height, weight, living environment, educational level/ 
years of formal education, data of medical history, allergic history, smoking history/ passive 
smoking history, occupational exposure, bio-fuel exposure, current respiratory symptoms, 
pulmonary function test, HRCT scan (presence or absence of emphysema /chronic 
bronchitis/pulmonary bulla or other abnormities; bronchial wall thickening); blood sample 
(IL-4, IL-5, IL6, IL-8, IL-13, IL-33, TNF-α, CRP, EOS) .  
The pre-planned sub-populations are: COPD without asthma/asthmatic characteristic 
population, COPD overlapping asthma/ asthmatic population, passive-smoking population, 
bio-fuel exposure population, bronchitis-dominant COPD sub-population, emphysema-
dominant COPD sub-population, more inflammatory COPD sub-population, less 

inflammatory COPD sub-population, neutrophilic inflammatory COPD sub-population, 
eosinophilic inflammatory COPD sub-population, etc. 
Risk factor analyses will be performed using linear regression or logistic regression 
method to explore the relationship between phenotypes /biomarkers (IL-4, IL-5, IL-6, IL-8, 
IL-13, IL-33, TNF, CRP, EOS), different treatment regimen and clinical outcomes (COPD-
related mortality and all-cause mortality, exacerbation rate, QOL, FEV1 decline, 6MWT) in 
the whole population of COPD and different sub-populations mentioned above. 
The multiple-factor analyses will be further performed to explore if different phenotypes 
/biomarkers (IL-4, IL-5, IL-6, IL-8, IL-13, IL-33, TNF, CRP, EOS) , different treatment 
regimen are pragnostic factors of clinical outcomes (COPD-related mortality and all-cause 
mortality, exacerbation rate, QOL, FEV1 decline, 6MWT) in the whole population of COPD 
and different sub-populations mentioned above. 
The analyses will be further detailed in a statistical analysis plan (SAP).   
5.3 
Data Management 
An electronic data capture (EDC) system will be used in this study. A password-
protected web-based data entry platform was used to enter data of each site. Meanwhile, 
paper-based questionnaire administration was also used in order to ensure the validity of the 
computer-based system. The PFTs data from spirometry was transmitted daily to the web-
based data entry platform. Researchers in each site graded the quality of PFTs (FEV1, FVC, 
and diffusing capacity of the lung for carbon monoxide) in 48 hour intervals according to a 
scholastic-type grading system: A, B, C, D, or E. Researchers at the central site checked the 
quality grade among 20% of PFT data selected randomly each week. If more than 10% of PFT 
data in a sample site was graded D or E, PFTs was conducted again. If researcher grading 
differs between a site and central site, PFTs was also conducted again at that site. 
Questionnaire variables was checked for completeness and accuracy. Any apparent 
errors and omissions in the data that require clarification will be resolved with the interviewer 
before data entry. All paper questionnaire administration was transmitted to the central site 
and was entered into the electronic database as well. Currently, double-entered data needed to 
be checked for consistency before statistical analysis, while the paper questionnaires needed to 
be scanned and properly documented. 
6. 
MONITORING OF THE STUDY 
During the study, PI will be in charge of the monitoring of the whole procedure. Two 
working group will be recruited, focusing on data cleaning and data analysis respectively. 
They will be led by Prof. Kewu Hang from Beijing Institute of Respiratory Medicine. The 
leader will report the progress of the study to the PI every week. 

7. 
COLLECTION AND REPORTING OF ADVERSE 
EVENTS/ADVERSE DRUG REACTIONS 
7.1 
Definition of Adverse Events (AE) 
An AE is any untoward medical occurrence in a patient or clinical study subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An adverse event can therefore be any unfavourable and unintended sign 
(e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs. 
7.2 
Definition of Serious Adverse Events (SAE) 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfills one or more of the following criteria: 
• 
Results in death 
• 
Is life-threatening (life-threatening in this context refers to a reaction in which the patient 
was at risk of death at the time of the reaction; it does not refer to a reaction that 
hypothetically might have caused death if more severe) 
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality/birth defect 
• 
Is an important medical event that may jeopardise the subject or may require intervention 
to prevent one of the outcomes listed above. Medical and scientific judgement should be 
exercised in deciding whether other situations should be considered an SAE. 
Any suspected transmission via a medicinal product of an infectious agent is also considered 
an SAE and may be subject to expedited reporting requirements in some countries. Any 
organism, virus or infectious particle (for example Prion Protein Transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent. 
7.3 
Definition of Adverse Drug Reactions (ADR) 
An Adverse Drug Reaction (ADR) is an Adverse Event suspected to be causally related to the 
medicinal product. 
An ADR is a response to a medicinal product which is noxious and unintended.  Adverse 
reactions may arise from use of the product within or outside the terms of the marketing 
authorization or from occupational exposure. 

The term ADR is used to include both serious and non-serious ADRs.  
7.4 
Reporting of Adverse Events 
The investigator is responsible for ensuring that all staff involved in the study is familiar with 
the content of this section.  
The investigator is responsible for reporting adverse events to regulatory authorities according 
to China related regulation.  
The investigator is also responsible for reporting serious ADRs related to AZ products within 
24 hours after awareness to AZ Data Entry Site and copy to AZ China pharmacovigilance 
department, and reporting non-serious ADRs related to AZ products to AZ Data Entry Site 
and copy to China pharmacovigilance department within the same timeline as investigator 
reports to ADR center.  
Contact information of AZ Data Entry Site: 
Fax: +1 302 886 4114; 
Email: AEmailboxclinicaltrialTCS@astrazeneca.com;  
Contact information of AZ China Pharmacovigilance department:  
Fax: +86 21 38683551;  
E-mail: China.AZDrugSafety@astrazeneca.com;  
Tel: +86 21 52929866. 
For ADRs related to non-AZ products, the investigator can report to the marketing 
authorisation holder of the products if he/she consider it is appropriate. 
8. 
STUDY TIMETABLE  
The study is expected to start in 2017-Q3 and to be completed by 2025-Q4. 
The end of the study is definite as “completing all related analysis of the study” 
Study period 
Estimated Time 
Protocol approved 
Dec. 2016 
First subject in 
Mar. 2017 
Last subject in 
Feb. 2020 
Last subject last visit 
Mar. 2025 
Database lock 
Jun. 2025 

Study period 
Estimated Time 
Completion of Final Study Report  
Sep. 2025 
Final Study Report to Publication  
Dec. 2025  
 
9. 
STUDY AGREEMENT  
The principal investigator must comply with all the terms, conditions and obligations 
of the protocol for this study. In the event of any inconsistency, the study protocol shall 
prevail.  
10. 
LIST OF REFERENCES 
1. 
World Health Organization. The top 10 causes of death.  (Accessed May 5, 2016 at 
http://www.who.int/mediacentre/factsheets/fs310/en/) 
2.         Department of disease prevention and control of the Ministry of health of People's 
Republic of China, The Chinese Center for Disease Control and Prevention. China chronic 
disease report. 2006.5 (Accessed May 5, 2016 at http://www.gov.cn/gzdt/2006- 
05/12/content_ 279061. htm) 
3.         Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. 
4. 
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. American journal 
of respiratory and critical care medicine. 2007;176(8):753-60. 
5. 
Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, et al. Genetic 
epidemiology of COPD (COPDGene) study design. Copd. 2010;7(1):32-43. 
6. 
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). The 
European respiratory journal. 2008;31(4):869-73. 
7. 
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. 
8. 
McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA, Committee TCE. 
Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical 
Endpoint Committee. Thorax. 2007;62(5):411-5.