Investigation of Chronic Obstructive Pulmonary Disease (COPD) Phenotypes and Endotypes in China

FEV1 is a measure of lung function and is defined as the volume of air that can be forced out in one second after taking a deep breath. FEV1 was measured electronically by spirometry. Baseline value was the assessment with a non-missing value at Day 1 of Month 1. Change from Baseline was calculated as the value at Month 30 minus the value at Baseline. Change from Baseline in pre- and post-bronchodilator FEV1 was assessed and summarized. Also, yearly rate of change in FEV1 (pre- and post-bronchodilator) was analyzed using random coefficients models.

FVC is the total amount of air exhaled during FEV test and is a lung function test that is measured during spirometry. Baseline value was the assessment with a non-missing value at Day 1 of Month 1. Change from Baseline was calculated as the value at Month 30 minus the value at Baseline. Change from Baseline in pre- and post-bronchodilator FVC was assessed and summarized. Also, yearly rate of change in FVC (pre- and post-bronchodilator) was analyzed using random coefficients models.

Moderate exacerbations are defined as COPD exacerbations that require either systemic corticosteroids (intramuscular, intravenous, or oral) and/or antibiotics. Severe exacerbations are defined as COPD exacerbations requiring hospitalization (including intubation and admittance to an intensive care unit) or result in death. Exacerbation rate = number of moderate or sever exacerbation divided by total participants-years. Analysis performed using a generalized linear model assuming a negative binomial distribution with covariates of type of participants (i.e. GOLD I-IV and chronic bronchitis), gender, smoking status, exacerbation history (moderate/severe), site (type of hospital), maintenance therapy (Y/N) and inhaled corticosteroid (ICS) containing (Y/N), Childhood chest disease (Y/N) and biomass fuel exposure (Y/N), age, and with offset logarithm of time on study.

The CAT is a validated 8-items questionnaire developed for use in routine clinical practice to measure the health status of participants with COPD. Participants rate their experience on a 6-point scale, ranging from 0 (no impairment) to 5 (maximum impairment), higher score indicates greater impairment. A total CAT score was calculated by summing the non-missing scores of the eight items with a scoring range of 0 (no disease impact) to 40 (maximum disease impact). Higher scores indicated greater disease impact. Baseline value was the assessment with a non-missing value at Day 1 of Month 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

The CAT is a validated 8-items questionnaire developed for use in routine clinical practice to measure the health status of participants with COPD. Participants rate their experience on a 6-point scale, ranging from 0 (no impairment) to 5 (maximum impairment), higher score indicates greater impairment. A total CAT score was calculated by summing the non-missing scores of the eight items with a scoring range of 0 (no disease impact) to 40 (maximum disease impact). Higher scores indicated greater disease impact.

The CATPURE is a short, five-item questionnaire that can be easily completed by participants and are used to identify individuals who may have undiagnosed, clinically significant COPD. The algorithm is a simple summation of participants responses to each of the five items. For Question 1-4: Score 0 for 'No' and Score 1 for 'Yes'; Question 5: Score 0 for 'None', 1 for 'Once' and 2 for '2 or more'. Total score is ranging from 0 to 6, higher score means higher risk of COPD (0-1 is at low risk, 2-6 is at high risk). Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

The CATPURE is a short, five-item questionnaire that can be easily completed by participants and are used to identify individuals who may have undiagnosed, clinically significant COPD. The algorithm is a simple summation of participants responses to each of the five items. For Question 1-4: Score 0 for 'No' and Score 1 for 'Yes'; Question 5: Score 0 for 'None', 1 for 'Once' and 2 for '2 or more'. Total score is ranging from 0 to 6, higher score means higher risk of COPD (0-1 is at low risk, 2-6 is at high risk).

CID was defined as decrease of greater than or equal to (>=) 100 milliliter (mL) in post-bronchodilator FEV1 or increase of >=2 units in the CAT, or an occurrence of a moderate/severe exacerbation. CID was derived from three key clinical assessments: 1. moderate/severe exacerbations, 2. worsening of FEV1, and 3. worsening of health status using the CAT questionnaire. Baseline value was the assessment with a non-missing value at Day 1 of Month 1. A participant may have more than one CID components, hence total of participants with individual CID components may not match with participants with 'Any CID' category. Number of participants with any CID event and its components (Exacerbation CID, FEV1 CID and CAT CID) observed from Baseline to Month 6 have been presented.

CID was defined as: decrease of greater than or equal to (>=) 100 milliliter (mL) in post-bronchodilator FEV1 or increase of >=2 units in the CAT, or an occurrence of a moderate/severe exacerbation. CID was derived from three key clinical assessments: 1. moderate/severe exacerbations, 2. worsening of FEV1, and 3. worsening of health status using the CAT questionnaire. A participant may have more than one CID components, hence total of participants with individual CID components may not match with participants with 'Any CID' category. Number of participants with any CID event and its components (Exacerbation CID, FEV1 CID and CAT CID) observed from Months 6 to 18 have been presented.

CID was defined as: decrease of greater than or equal to (>=) 100 milliliter (mL) in post-bronchodilator FEV1 or increase of >=2 units in the CAT, or an occurrence of a moderate/severe exacerbation. CID was derived from three key clinical assessments: 1. moderate/severe exacerbations, 2. worsening of FEV1, and 3. worsening of health status using the CAT questionnaire. A participant may have more than one CID components, hence total of participants with individual CID components may not match with participants with 'Any CID' category. Number of participants with any CID event and its components (Exacerbation CID, FEV1 CID and CAT CID) observed from Months 18 to 30 have been presented.

Number of participants who died during study have been presented.

E-RS: COPD is a subset of Exacerbations of Chronic pulmonary Disease Tool (EXACT). E-RS: COPD is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: respiratory symptoms-breathlessness (RS-BRL) comprised of 5 items (2 items scored from 0-4 and 3 items scored from 0-3); RS-cough and sputum (RS-CSP) comprised of 3 items(2 items scored from 0-4 and 1 item scored from 0-3);and RS-chest symptoms (RS-CSY) comprised of 3 items (scored from 0-4). The total score was calculated by taking sum of all individual 11 item scores, which ranges between 0-40 and higher score indicates more severe symptoms. Baseline value was the assessment with a non-missing value at Day 1 of Month 1. The 1 to 6 month E-RS:COPD total score value was derived by calculating the average of E-RS:COPD total scores collected between month 1 and 6. Change from Baseline was calculated by subtracting Baseline value from 1-6 month average total score value.

E-RS: COPD is a subset of Exacerbations of Chronic pulmonary Disease Tool (EXACT). E-RS: COPD is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: respiratory symptoms-breathlessness (RS-BRL) comprised of 5 items (2 items scored from 0-4 and 3 items scored from 0-3); RS-cough and sputum (RS-CSP) comprised of 3 items(2 items scored from 0-4 and 1 item scored from 0-3);and RS-chest symptoms (RS-CSY) comprised of 3 items (scored from 0-4). The total score was calculated by taking sum of all individual 11 item scores, which ranges between 0-40 and higher score indicates more severe symptoms. Baseline value was the assessment with a non-missing value at Day 1 of Month 1. The 18 to 24 month E-RS:COPD total score value was derived by calculating the average of E-RS:COPD total scores collected between month 18 and 24. Change from Baseline was calculated by subtracting Baseline value from 18-24 month average total score value.

The EXACT is a 14-item daily diary designed to provide a measure of patient-reported symptoms of COPD exacerbation. An EXACT Total Score, ranging from 0 to 100, where higher scores indicate a more severe condition. EXACT events were defined as magnitude of responder for symptomatic events defined as acute, sustained symptomatic worsening of COPD, defined as an increase in EXACT score >=9 points for 3 days or >=12 points for 2 days, above Baseline (Baseline value is average of 7-day period [Day 1 to 7]). Number of participants with EXACT events observed from Months 1 to 6 have been presented.

The EXACT is a 14-item daily diary designed to provide a measure of patient-reported symptoms of COPD exacerbation. An EXACT Total Score, ranging from 0 to 100, where higher scores indicate a more severe condition. EXACT events were defined as magnitude of responder for symptomatic events defined as acute, sustained symptomatic worsening of COPD, defined as an increase in EXACT score >=9 points for 3 days or >=12 points for 2 days, above Baseline (Baseline value is average of 7-day period [Day 1 to 7]). Number of participants with EXACT events observed from Months 18 to 24 have been presented.

Digital physical activity was evaluated by daily steps as assessed by a wrist band dispensed at Baseline. Participants were required to keep wearing the wrist band. The daily step data was based on the daily average steps (steps per day) for each participant. Baseline value was derived as the average value of first 7 days (Days 1 to 7 at Month 1).

Digital physical activity was evaluated by daily steps as assessed by a wrist band dispensed at Baseline. Participants were required to keep wearing the wrist band. The daily step data was based on the daily average steps (steps per day) for each participant. Month 1 value was derived as the average of daily step data up to 30 days from study Day 8.

Digital physical activity was evaluated by daily steps as assessed by a wrist band dispensed at Baseline. Participants were required to keep wearing the wrist band. The daily step data was based on the daily average steps (steps per day) for each participant. Month 18 value was derived as the average of daily step data up to 30 days from Month 18.

Fibrinogen is a protein, specifically a clotting factor (factor I), that is essential for proper blood clot formation. Blood samples were collected to evaluate the amount of fibrinogen. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Fibrinogen is a protein, specifically a clotting factor (factor I), that is essential for proper blood clot formation. Blood samples were collected to evaluate the amount of fibrinogen.

Blood samples were collected for the analysis of C-Reactive Protein. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Blood samples were collected for the analysis of C-Reactive Protein.

Blood samples were collected for the analysis of eosinophils and neutrophils. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Blood samples were collected for the analysis of eosinophils and neutrophils.

Blood samples were collected for the analysis of hemoglobin. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Blood samples were collected for the analysis of hemoglobin.

Blood samples were collected at Baseline for the analysis of blood biomarkers serum IP-10 and serum sRAGE. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Blood samples were collected at Month 30 for the analysis of blood biomarkers serum IP-10 and serum sRAGE.

Blood samples were collected for the analysis of blood biomarker CC16. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Blood samples were collected for the analysis of blood biomarker CC16.

Blood samples were collected for the analysis of HbA1c. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Blood samples were collected for the analysis of HbA1c.

Sputum microbiome evaluation involves extraction of deoxyribonucleic acid from sputum samples and analyzing it to identify the microbial community present in the samples using molecular methods. There were not enough samples for analysis. Consequently, data was not analyzed, and data will never be analyzed for this outcome measure in the future.

Sputum samples were collected from the participants for assessment of total cell count. Baseline value was the assessment with a non-missing value at Day 1 of Month 1. Data was not collected for "Never Smoker Healthy Control" arm as sputum samples were not collected at Baseline visit for healthy control group as per the Protocol.

Sputum samples were collected from the participants for assessment of total cell count.

Number of participants with COPD medications received have been presented in separate categories. Data was collected in following categories: Naïve, long-acting muscarinic antagonist (LAMA), long-acting beta agonist (LABA), inhaled corticosteroid (ICS)/LABA, LAMA/LABA, Triple (open), and Triple (closed).

Data was collected in following categories: Step-up (the treatment pattern grade become larger than previous visit), Switch (the treatment pattern changed within a same grade (except grade 0), Stable (the treatment pattern remain the same (except grade 0), Step-down (participants receive treatment and the grade goes down compared with the previous visit), Stop/Missing (No treatment record in the period), and Naïve with respect to their treatment received. Baseline value was the assessment with a non-missing value at Day 1 of Month 1. Number of participants with change from Baseline in treatment pattern have been presented.

Number of participants with COPD related outpatient visits have been presented.

Number of participants with non-COPD related outpatient visits have been presented.

Number of participants with COPD related emergency visits have been presented.

Number of participants with non-COPD related emergency visits have been presented.

Number of participants with COPD related hospitalizations visits have been presented.

Number of participants with non-COPD related hospitalizations visits have been presented.

Direct medical costs of out-of-pocket payment and basic insurance were included for following items: Hospital, Outpatient, Emergency, Participant check, Participant therapy and Prescribing costs.

Airway wall area, in ratio, at Baseline is calculated by dividing airway wall area by total airway area, using low-dose high-resolution computed tomography (HRCT) acquired at Baseline. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Airway wall area, in ratio, at Month 30 is calculated by dividing airway wall area by total airway area, using low-dose HRCT acquired at Month 30.

Average of airway major inner diameter at Baseline is the averaged longest axis of the airway's cross-section in low-dose HRCT acquired at Baseline. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Average of airway major inner diameter at Month 30 is the averaged longest axis of the airway's cross-section in low-dose HRCT acquired at Month 30.

Average of airway minor inner diameter at Baseline is the averaged shortest axis of the airway's cross-section in low-dose high-resolution Computed Tomography (HRCT) acquired at Baseline. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Average of airway minor inner diameter at Month 30 is the averaged shortest axis of the airway's cross-section in low-dose HRCT acquired at Month 30.

Total airway count at Baseline is derived by summing the number of airway segments identified on low-dose HRCT acquired at Baseline. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Total airway count at Month 30 is derived by summing the number of airway segments identified on low-dose HRCT acquired at Month 30.

Pi10 at Baseline is a measure of airway wall thickness, which is calculated by the square root of wall area for a theoretical airway with an internal perimeter of 10 millimeter, using low-dose HRCT acquired at Baseline. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Pi10 at Month 30 is a measure of airway wall thickness, which is calculated by the square root of wall area for a theoretical airway with an internal perimeter of 10 millimeter, using low-dose HRCT acquired at Month 30.

Perc15 in residual volume (RV) at Baseline is the cut-off value, in Hounsfield Unit (HU), below which are distributed the 15 percent of the voxels with the lowest density in low-dose HRCT, acquired at full expiration at Baseline. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Perc15 in residual volume (RV) at Month 30 is the cut-off value, in Hounsfield Unit (HU), below which are distributed the 15 percent of the voxels with the lowest density in low-dose HRCT, acquired at full expiration at Month 30.

Perc15 in total lung capacity (TLC) at Baseline is the cut-off value, in Hounsfield Unit (HU), below which are distributed the 15 percent of the voxels with the lowest density in low-dose HRCT, acquired at full inspiration at Baseline. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Perc15 in total lung capacity (TLC) at Month 30 is the cut-off value, in Hounsfield Unit (HU), below which are distributed the 15 percent of the voxels with the lowest density in low-dose HRCT, acquired at full inspiration at Month 30.

LAA-950 at Baseline is percentage (%) of voxels with attenuation less than or equal to (<=)-950 Hounsfield Unit (HU), which is associated with the extent of emphysema, computed using low-dose HRCT acquired at Baseline. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

LAA-950 at Month 30 is percentage (%) of voxels with attenuation <=-950 Hounsfield Unit (HU), which is associated with the extent of emphysema, computed using low-dose HRCT acquired at Month 30.

Percentage of whole lung associated with gas trapping (GT) as measured by DPM at Baseline. DPM uses low-dose HRCT acquired at both full inspiration (total lung capacity [TLC]) and full expiration (residual volume [RV]) for calculating the percentage of lung volume associated with gas trapping. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Percentage of whole lung associated with gas trapping (GT) as measured by DPM at Week 30. DPM uses low-dose HRCT acquired at both full inspiration (total lung capacity [TLC]) and full expiration (residual volume [RV]) for calculating the percentage of lung volume associated with gas trapping.

Percentage of whole lung associated with emphysema as measured by DPM at Baseline. DPM uses low-dose HRCT acquired at both full inspiration (total lung capacity [TLC]) and full expiration (residual volume [RV]) for calculating the percentage of lung volume associated with emphysema. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Percentage of whole lung associated with emphysema as measured by DPM at Month 30. DPM uses low-dose HRCT acquired at both full inspiration (total lung capacity [TLC]) and full expiration (residual volume [RV]) for calculating the percentage of lung volume associated with emphysema.

Percentage of whole lung associated with normal tissue (NT) as measured by DPM at Baseline. DPM uses low-dose HRCT acquired at both full inspiration (total lung capacity [TLC]) and full expiration (residual volume [RV]) for calculating the percentage of lung volume associated with normal tissue. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Percentage of whole lung associated with normal tissue (NT) as measured by DPM at Month 30. DPM uses low-dose HRCT acquired at both full inspiration (total lung capacity [TLC]) and full expiration (residual volume [RV]) for calculating the percentage of lung volume associated with normal tissue.

Air volume ratio at Baseline is defined as air volume at full expiration (FE) (residual volume [RV]) divided by air volume at full inspiration (FI) (total lung capacity [TLC]) multiplied by 100 (expressed as percentage), measured using low-dose HRCT acquired at Baseline. Baseline value was the assessment with a non-missing value at Day 1 of Month 1.

Air volume ratio at Month 30 is defined as air volume at full expiration (FE) (residual volume [RV]) divided by air volume at full inspiration (FI) (total lung capacity [TLC]) multiplied by 100 (expressed as percentage), measured using low-dose HRCT acquired at Month 30.