Primary Outcomes

Description: Bacterial pathogens, as identified by bacteriological methods, including (but not necessarily limited to) Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii.

Measure: Occurrence of potential bacterial in sputum of stable COPD patients.

Time: Over the course of 1 year

---

Description: Bacterial pathogens, as identified by bacteriological methods, including (but not necessarily limited to) Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii.

Measure: Occurrence of potential bacterial in sputum during AECOPD.

Time: Over the course of 1 year

---

Description: Viral pathogens, as identified by PCR, including (but not necessarily limited to) Respiratory syncytial virus (RSV), parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza virus, adenovirus, bocavirus and coronavirus and by rhinovirus quantitative RT-PCR.

Measure: Occurrence of viral pathogens in sputum of stable COPD patients.

Time: Over the course of 1 year

---

Description: Viral pathogens, as identified by PCR, including (but not necessarily limited to) Respiratory syncytial virus (RSV), parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza virus, adenovirus, bocavirus and coronavirus and by rhinovirus quantitative RT-PCR.

Measure: Occurrence of viral pathogens in sputum during AECOPD.

Time: Over the course of 1 year

---

Secondary Outcomes

Description: Including (but not necessarily limited to) H. influenzae, M. catarrhalis, S. pneumoniae, S. aureus and P. aeruginosa. The proportion of sputum samples obtained at each confirmed stable/AECOPD visit and positive for specific bacterial pathogens by PCR will be computed with 95% confidence intervals.

Measure: Occurrence of potential bacterial pathogens in sputum of stable COPD patients and during AECOPD, as measured by real-time qualitative PCR/ quantitative PCR and compared to data from bacteriological methods.

Time: Over the course of 1 year

---

Description: The proportion of sputum samples obtained at each AECOPD visit and positive for specific bacterial/viral pathogens by bacteriological methods and PCR, respectively (overall and by bacterial/viral species) will be computed with 95% confidence intervals by any severity (mild, moderate and severe).

Measure: Occurrence of potential bacterial and viral pathogens (overall and by species) in sputum during AECOPD by severity of AECOPD.

Time: Over the course of 1 year

---

Description: The proportion of sputum samples obtained at each confirmed stable visit and positive for bacterial/viral pathogens by bacteriological methods and PCR, respectively (overall and by bacterial / viral species) will be computed with 95% confidence intervals by Gold grade at enrolment.

Measure: Occurrence of potential bacterial and viral pathogens (overall and by species) in sputum of stable COPD patients by GOLD grade.

Time: Over the course of 1 year

---

Description: The following incidence rates will be computed, with 95% confidence intervals (CI): All-cause AECOPD. AECOPD having sputum containing bacterial pathogens found by PCR or by bacteriological methods or by both methods (overall and by, but not limited to, the following bacterial species: H. influenzae, M. catarrhalis, S. pneumoniae, S. aureus, and P. aeruginosa). The 95% CI of the incidence rate will be computed using a model which accounts for repeated events. The incidence rates described above will also be computed for mild, moderate severe AECOPD and by GOLD grade at enrolment.

Measure: Incident rate (per subject per year) of any AECOPD overall and by GOLD grade.

Time: Over the course of 1 year

---

Description: Classification of severity according to the intensity of medical intervention required: mild: controlled with an increase in dosage of regular medications; moderate: requires treatment with systemic corticosteroids and/ or antibiotics; severe: requires hospitalisation.

Measure: Number of mild, moderate or severe AECOPD overall and by GOLD grade.

Time: Over the course of 1 year

---

Description: Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) on the number of days of AECOPD episodes will be presented.

Measure: Number of days of AECOPD episodes overall and by AECOPD severity.

Time: Over the course of 1 year

---

Description: Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) on the CAT scores will be tabulated at each respective visit.

Measure: COPD assessment test (CAT) score in stable COPD patients and during AECOPD.

Time: Over the course of 1 year

---

Description: Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) on the SGRQ-C scores will be tabulated at each respective visit.

Measure: St. George's Respiratory Questionnaire (SGRQ-C) score in stable COPD patients.

Time: Over the course of 1 year

---

Description: The spirometric classification of airflow limitation in COPD patients is based on post-bronchodilator FEV1. Summary statistics (mean, median, standard deviation, maximum and minimum) on post bronchodilator FEV1% of predicted normal value will be tabulated at each respective visit.

Measure: Forced expiratory volume in 1 second (FEV1%) of predicted normal value in stable COPD patients.

Time: At Pre-Month 0 and Month 12

---

Description: Healthcare use for each COPD patient will be obtained through review of the subject's medical record (aided by subject self-reporting). Healthcare utilisation includes all unscheduled visits to a physician office, visits to urgent care, visits to emergency department, and hospitalizations.

Measure: Assessment of the Healthcare utilization.

Time: Over the course of 1 year

---

Primary Outcomes

Description: The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies.

Measure: The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies.

Time: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic.

---

Secondary Outcomes

Description: The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies

Measure: The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies

Time: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic.

---

Description: The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies

Measure: The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies

Time: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic.

---

Description: The change in number of airway submucosal inflammatory cells per mm2 from baseline, across the spectrum of T2 status, determined by microscopic evaluation of bronchoscopic biopsies

Measure: The change in number of airway submucosal inflammatory cells per mm2 from baseline, across the spectrum of T2 status, determined by microscopic evaluation of bronchoscopic biopsies

Time: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic.

---

Primary Outcomes

Description: The exacerbation rate is based on exacerbations reported by the investigator over 52 weeks.

Measure: Moderate or severe COPD exacerbation rate ratio (tezepelumab vs placebo)

Time: Over 52 Weeks

---

Secondary Outcomes

Description: Time to first occurrence of moderate/severe exacerbation post randomization. Outcome measures: Hazard ratio

Measure: Time to first moderate or severe COPD exacerbation

Time: By Week 52

---

Description: Proportion of subjects with at least one moderate/severe exacerbation reported by the Investigator over 52 weeks Outcome measure: Odds Ratio

Measure: Proportion with at least one moderate/severe COPD exacerbation

Time: Over 52 Weeks

---

Description: The severe exacerbation rate is based on severe exacerbations reported by the Investigator over 52 weeks.

Measure: Severe COPD exacerbation rate ratio (tezepelumab vs. placebo)

Time: Over 52 Weeks

---

Description: Difference in change from baseline in pre-BD forced expiratory volume in 1 second (FEV1) in tezepelumab arm as compared to placebo at Week 52. FEV1 is defined as the volume of air exhaled from the lungs in the first second of forced expiration.

Measure: Change from baseline in pre-bronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1)

Time: Baseline, Week 52

---

Description: Proportion of subjects achieving a decrease of 4 units or more in the St. George's Respiratory Questionnaire (SGRQ) total score at Week 52, i.e. minimum clinically important difference (MCID). Outcome measure: odds ratio

Measure: Change in respiratory health status/health-related quality of life

Time: Baseline, Week 52

---

Description: Difference (tezepelumab vs. placebo) in SGRQ from baseline at Week 52. SGRQ is a 50-item patient reported outcome questionnaire. The SGRQ total score is expressed as a percentage of overall impairment, in which 100% means the worst possible health status and 0% indicates the best possible health status. Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater impairment. Decrease of 4 units is associated with a minimum clinically important difference (MCID).

Measure: Change from baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score

Time: Baseline, Week 52

---

Description: Difference (tezepelumab vs. placebo) in COPD assessment tool (CAT) from baseline at Week 52. CAT is an 8-item patient reported outcome questionnaire developed to measure the impact of COPD on health status. The instrument uses semantic differential six-point response scales. A CAT total score is the sum of item responses. The score ranges from 0 to 40, with higher scores indicating greater COPD impact on health status.

Measure: Change from baseline in the COPD Assessment Test (CAT) Total Score

Time: Baseline, Week 52

---

Description: Serum trough concentration of tezepelumab

Measure: Evaluate pharmacokinetics of tezepelumab

Time: Weeks 0, 4, 12, 24, 36, 52, 64

---

Description: Incidence of anti-drug antibodies (ADA)

Measure: Evaluate immunogenicity of tezepelumab

Time: Over 52 weeks

---

Primary Outcomes

Description: mean rate of recovery in patients with diagnosis of Covid-19 pneumonia, who present with complications at the time of hospital admission (such as diabetes, obesity, cardiovascular disease, hypertension or respiratory failure), with the mean recovery rate in patients without any of the above-mentioned complications.

Measure: rate of recovery

Time: 3 weeks

---

Secondary Outcomes

Description: comparison of the survival curves (times to improvement) in the two groups (patients with and without complications) and among patients presenting with different types of complications

Measure: time to improvement

Time: 3 weeks

---

Description: the efficacy of different pharmaceutical treatment against Covid-19

Measure: efficacy of treatments

Time: 3 weeks

---

Description: liver, kidney or multiorgan failure, cardiac failure

Measure: organ failure

Time: 3 weeks

---

Primary Outcomes

Description: Size of collected audio dataset measured as number of collected cough sounds, targeting ≥10,000 identified coughs.

Measure: Dataset size

Time: 14 days

---

Secondary Outcomes

Description: Identification of cough sounds by the existing mathematical model with ≥ 99% specificity and ≥ 60% sensitivity

Measure: Cough sound identification

Time: 14 days

---

Description: Increase in the sensitivity of the mathematical model to cough sounds to ≥ 70% while retaining the specificity of ≥ 99%

Measure: Improvement of the existing model

Time: 14 days

---

Description: Determination of the level of acceptance and satisfaction of the solution by patients by means of a Standard Usability Questionnaire to provide feedback. The score ranges from 10 to 50, higher score indicating a better usability.

Measure: Evaluate the usability of the application

Time: 14 days

---

Primary Outcomes

Description: The 7-day length of invasive MV for each arm will be estimated with 95% confidence intervals (CIs) using the exact binomial distribution. Their difference by the arms will be tested by Cochran-Mantel-Haenszel (CMH) test stratified by the age group and Sequential Organ Failure Assessment (SOFA) score at significance level of 0.05.

Measure: 7-day length of invasive mechanical ventilation (MV)

Time: Up to 7 days

---

Description: Defined as death within 30-day after randomization. The 30-day mortality rate for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05.

Measure: 30-day mortality rate

Time: Up to 30-day after randomization

---

Secondary Outcomes

Description: The rate of ICU transfer for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05.

Measure: Rate of intensive care (ICU) transfer

Time: Up to 2 years

---

Description: The rate of invasive mechanical ventilation for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05.

Measure: Rate of invasive mechanical ventilation

Time: Up to 2 years

---

Description: The rate of tracheostomy for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05.

Measure: Rate of tracheostomy

Time: Up to 2 years

---

Description: Will first be described by median and inter-quartile, and then compared between two arms by Wilcoxon Sum-Rank test

Measure: Length of ICU stay

Time: Up to 2 years

---

Measure: Length of hospital stay

Time: Up 2 years

---

Primary Outcomes

Description: assess if inpatients who presented with pneumonia but had a negative test for Covid-19 are positive at the serology for SARS-CoV-2.

Measure: Serology

Time: 3 weeks

---

Secondary Outcomes

Description: to find if the combination of CT scan and serology could help us in the identification of those patients who were initially negative at laboratory testing alone.

Measure: Efficacy of CT scan and Serology

Time: 3 weeks

---

Description: the efficacy of different pharmaceutical treatments against Covid-19

Measure: Efficacy of different pharmaceutical treatments

Time: 3 weeks

---

Primary Outcomes

Description: This is set on visit 3 (90 ± 5 days from the date of visit 1). The two groups of vaccination are compared for the primary endpoints which is composite. Patients who meet any of the following will be considered to meet the primary endpoint: Positive for the respiratory questionnaire endpoint when at least one of the following combination is met either at visit 2 and/or at visit 3: One situation definitively related to COVID-19 All four questions of symptoms possibly related to COVID-19 At least two questions of symptoms possibly related to COVID-19 as well as need for admission at the emergency department of any hospital and/or need for intake of antibiotics At least four questions of symptoms probably related to COVID-19 one of which is "need for admission at the emergency department of any hospital and/or need for intake of antibiotics" Positive IgG or IgM antibodies against SARS-CoV-2

Measure: Positive for the respiratory questionnaire consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19 on visit 3.

Time: Visit 3 (90 +/- 5 days)

---

Secondary Outcomes

Description: The two groups of vaccination are compared for the primary endpoints which is composite (as defined at primary study endpoint) and meet a positive respiratory questionnaire endpoint on visit 4

Measure: Positive respiratory questionnaire endpoint consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19 on visit 4

Time: Visit 4 (135 +/- 5 days)

---

Description: The two groups of vaccination are compared for the primary endpoints which is composite (as defined at primary study endpoint) and meet a positive respiratory questionnaire endpoint (as defined at primary study endpoint) on visit 5

Measure: Positive respiratory questionnaire endpoint consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19 on visit 5

Time: Visit 5 (180 +/- 5 days)

---

Description: Prevalence of IgG/IgM against SARS-CoV-2 will be measured among the patients who failed the eligibility procedure and the patients that were eligible and were enrolled

Measure: Prevalence of IgG/IgM against SARS-CoV-2

Time: Screening Visit and Visit 3 (90 +/- 5 days)

---

Description: Itemized analysis of each of the components of the respiratory questionnaire on each study visit

Measure: Analysis of each of the components of the respiratory questionnaire consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19.

Time: Visit 2 (45 +/- 5 days), Visit 3 (90 +/- 5 days), Visit 4 (135 +/- 5 days), Visit 5 (180 +/- 5 days)

---

Description: The impact of new cardiovascular events between the two study groups (placebo and BCG) will be analyzed, though the collection of any cardiovascular events occured to the enrolled patients.

Measure: The impact of new cardiovascular events between the two study groups

Time: Visit 2 (45 +/- 5 days), Visit 3 (90 +/- 5 days), Visit 4 (135 +/- 5 days), Visit 5 (180 +/- 5 days)

---

Description: Differences in repeated measurements of arterial stiffness in visit 3 between the two sub-study groups (placebo or BCG) will be analyzed through the speed of the pulse wave velocity. Pulse wave velocity is measured in m/sec.

Measure: Differences in repeated measurements of angiometric parameters (arterial hardness) between the two sub-study groups in Visit 3

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

---

Description: Differences in repeated measurements of central arterial pressures and reflected waves in visit 3 between the two sub-study groups (placebo or BCG) will be measured non-invasively by pulse wave analysis. Central arterial pressure is measured in mmHg.

Measure: Differences in repeated measurements of angiometric parameters (central arterial pressures and reflected waves) between the two sub-study groups in Visit 3

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

---

Description: Differences in repeated measurements of endothelial function in visit 3 between the two sub-study groups (placebo or BCG) will be measured by ultrasound measurement of endothelium-dependent flow-mediated dilatation and by nitrate-mediated dialatation. Endothelial function will be assessed by Flow Mediated Dilatation (FMD). Endothelium-dependent: diameter of the artery prior and after temporary ischemia in is measured in mm, nitrate-mediated: diameter of the artery prior and after nitrate administration is measured in mm

Measure: Differences in repeated measurements of angiometric parameters (endothelial function) between the two sub-study groups in Visit 3

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

---

Description: Differences in repeated measurements of thickness of the medial carotid sheath in visit 3 between the two sub-study groups (placebo or BCG) will be measured by B-mode ultrasound examination. Intima-Media Thickness is measured in mm

Measure: Differences in repeated measurements of angiometric parameters (thickness of the medial carotid sheath) between the two sub-study groups in Visit 3

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

---

Description: Differences in repeated measurements of arterial stiffness in visit 5 between the two sub-study groups (placebo or BCG) will be analyzed through the speed of the pulse wave velocity. Pulse wave velocity is measured in m/sec.

Measure: Differences in repeated measurements of angiometric parameters (arterial hardness) between the two sub-study groups in Visit 5

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

---

Description: Differences in repeated measurements of central arterial pressures and reflected waves in visit 5 between the two sub-study groups (placebo or BCG) will be measured non-invasively by pulse wave analysis. Central arterial pressure is measured in mmHg.

Measure: Differences in repeated measurements of angiometric parameters (central arterial pressures and reflected waves) between the two sub-study groups in Visit 5

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

---

Description: Differences in repeated measurements of thickness of the medial carotid sheath in visit 5 between the two sub-study groups (placebo or BCG) will be measured by B-mode ultrasound examination. Intima-Media Thickness is measured in mm

Measure: Differences in repeated measurements of angiometric parameters (thickness of the medial carotid sheath) between the two sub-study groups in Visit 5

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

---

Description: Differences in repeated measurements of endothelial function in visit 5 between the two sub-study groups (placebo or BCG) will be measured by ultrasound measurement of endothelium-dependent flow-mediated dilatation and by nitrate-mediated dialatation. Endothelial function will be assessed by Flow Mediated Dilatation (FMD). Endothelium-dependent: diameter of the artery prior and after temporary ischemia in is measured in mm, nitrate-mediated: diameter of the artery prior and after nitrate administration is measured in mm

Measure: Differences in repeated measurements of angiometric parameters (endothelial function) between the two sub-study groups in Visit 5

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

---

Description: Differences in cardiac ultrasound at visit 5 between the two sub-study groups (placebo or BCG) will be assessed using standard measurements from 2-D and Doppler echocardiography.

Measure: Differences in cardiac ultrasound at visit 5 between the two sub-study groups

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

---

Description: Changes in the release of cytokines from blood mononuclear cells at visit 3 between the two sub-study groups (placebo or BCG) will be analyzed

Measure: Changes in the release of cytokines from blood mononuclear cells at visit 3 between the two sub-study groups

Time: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

---

Primary Outcomes

Description: Annual rate of the physiologically adjusted lung density change will be measured as the 15th percentile of the lung density measurements (PD15) as assessed by Computed Tomography (CT) densitometry at total lung capacity (TLC). CT lung density at the 15th percentile (PD15) is the threshold below which 15 percentage (%) of the voxels have lower densities and is used as the parameter for estimating the rate of lung density decline. Annual rate of the physiologically adjusted lung density change will be tested in a fixed comparision sequence 1. ARALAST NP 120 mg/kg BW/week group versus (vs) external placebo group, 2. ARALAST NP120 mg/kg BW/week vs 60 mg/kg BW/week, 3. ARALAST NP 60 mg/kg BW/week group vs external placebo group.

Measure: Annual Rate of the Physiologically Adjusted Lung Density Change

Time: Baseline, up to Week 104

---

Secondary Outcomes

Description: COPD exacerbations are defined as an acute worsening of respiratory symptoms that results in additional therapy and will be assessed according to the classification in GOLD criteria (2020) as follows: Moderate (treated with short acting bronchodilators [SABDs] plus antibiotics and/or oral corticosteroids) and Severe (required hospitalizations or a visit to the emergency room).

Measure: Number of Moderate or Severe Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)

Time: Baseline, up to Week 104

---

Description: Annual rate of change in post-bronchodilator FEV1 will be assessed.

Measure: Annual Rate of Change in Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1)

Time: Baseline, up to Week 104

---

Description: An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this IP or medicinal product. A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment with an IP or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the IP or medicinal product. TEAE's will include related, serious adverse events (SAEs), suspected adverse reactions plus adverse reactions of interest, temporally-associated adverse events (AEs) with onset during infusion or within 24 hours following the end of IP infusion, and AEs resulting in changes to infusion dose.

Measure: Number of Participants with Treatment-Emergent Adverse Events (TEAE's)

Time: From Start of the study drug administration up to End of the study (up to Week 105)

---

Description: Number of participants who develop anti- A1PI antibodies following treatment with ARALAST NP will be assessed.

Measure: Number of Participants Who Develop Anti-A1PI Antibodies Following Treatment With ARALAST NP

Time: From Start of the study drug administration up to End of the study (up to Week 105)

---

Description: Plasma trough level of antigenic and functional A1PI for ARALAST NP at each dose level (ARALAST NP 60 mg/kg BW/week, ARALAST NP 120 mg/kg BW/week) will be assessed.

Measure: Plasma Trough Level of Antigenic and Functional A1PI for ARALAST NP at each dose Level

Time: Pre-dose, Weeks 4, 13, 28, 52, 78, 91, 104, 105

---

Primary Outcomes

Measure: Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo

Time: From Baseline up to average of Weeks 13 and 14

---

Secondary Outcomes

Description: The EXACT (E-RS) scale is a participant-reported outcome (PRO) designed to measure the symptoms of participants with COPD. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms. The E-RS will be collected on the daily e-diary, which will include all 14 items from the EXACT questionnaire.

Measure: Change From Baseline in the EXACT Respiratory Symptoms (E-RS) Daily Symptom Diary to the Primary Time Point

Time: One week prior to first dose through one week after the last dose.

---

Description: The CAT is an eight-item questionnaire that will be completed by the participant and is designed to quantify the impact of COPD symptoms on the health status of participants. The CAT provides a score of 0-40 to indicate the impact of the disease.

Measure: Change From Baseline in the COPD Assessment Test (CAT) to the Week 14 Time Point

Time: From Baseline up to Week 14

---

Description: The SGRQ is a participant completed, a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airway disease. Scores of the SGRQ-C range from 0 to 100, with higher scores indicating more limitations.

Measure: Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) to the Week 14 Time Point

Time: From Baseline up to Week 14

---

Measure: Change from Baseline in Post-Bronchodilator FEV1

Time: From Baseline up to average of Weeks 13 and 14

---

Measure: Cmax: Maximum Observed Plasma Concentration for ION-827359

Time: Up to Week 24

---

Measure: Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359

Time: Up to Week 24

---

Measure: AUC[0-t]: Area Under the Plasma Concentration-Time Curve from Time Zero to t for ION-827359

Time: Up to Week 24

---

Measure: Incidence of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), Graded by Severity

Time: Up to Week 24

---

Measure: Number of Participants With Abnormal Laboratory Values

Time: Up to Week 24

---

Measure: Number of Participants With Abnormal Vital Signs Measurements

Time: Up to Week 24

---

Primary Outcomes

Description: Total number of people enrolled divided by the total number of people invited to participate (multiplied by 100 to calculate a percentage)

Measure: Recruitment Rate

Time: Pre-program (baseline)

---

Description: Percentage of people who completed the full program and all assessments

Measure: Completion Rate

Time: Through study completion, 12 weeks

---

Description: Percentage of people who attended program sessions (exercise and cognitive training components)

Measure: Attendance

Time: Throughout entire intervention (12 weeks, 2 sessions/week per group)

---

Description: Participant and instructors rating of program components and overall program (via hand-written questionnaire). Participants and instructors must rate their level of agreement (1 = strongly disagree, 2 = disagree, 3 = no opinion, 4 = agree, 5 = strongly agree) with various statements. The higher the rating, the greater the satisfaction. They also must rate if the difficulty of the program was optimal, somewhat easy or hard, or too easy or hard. They must also specify how much money they would be willing to spend on the program. They are also given an opportunity to record optional additional comments/recommendation.

Measure: Change in Participant and Instructor Rating of experience, satisfaction, and feasibility of program

Time: Mid-point (6 weeks) and post-program (12 weeks)

---

Description: Financial cost of running program (equipment purchased for study - cognitive training tablet and stands - and YMCA staff pay) as reported by researcher and YMCA staff

Measure: Cost of program

Time: Post-program (12 weeks)

---

Description: Self-reported biological sex (at birth) using basic demographics questionnaire

Measure: Sex

Time: Pre-program (baseline)

---

Description: One-on-one interview with researcher, answering broad questions about their experience in the program and study

Measure: Participant and Instructor perceived program experience and satisfaction

Time: Post-program (at 12 weeks)

---

Description: Experience of participants and instructors will also be observed by the researcher (observational notes will be taken by the researcher during each class). No names of participants and instructors will be recorded.

Measure: Participant and Instructor observer-perceived program experience and satisfaction

Time: Throughout entire intervention (12 weeks, 2 sessions/week per group)

---

Description: Self-reported years of formal education and training (training years for instructors only) using basic demographics questionnaire

Measure: Education

Time: Pre-program (baseline)

---

Description: Self-reported previous and current occupations using basic demographics questionnaire

Measure: Occupation

Time: Pre-program (baseline)

---

Description: Self-reported previous and current medical conditions using basic demographics questionnaire

Measure: Medical Condition

Time: Pre-program (baseline)

---

Description: Self-reported previous and current medications using basic demographics questionnaire

Measure: Medications

Time: Pre-program (baseline)

---

Description: Using the Montreal Cognitive Assessments (brief clinical tool) to assess visual/spatial abilities, working memory, executive functioning, language, abstraction, and orientation). Will be used to describe participants' baseline cognitive status (a score out of 30 is measured).

Measure: Montreal Cognitive Assessment (global cognitive function)

Time: Pre-program (baseline)

---

Description: Using the International Physical Activities Questionnaire (IPAQ) to assess physical activity level based on self-reported frequency and duration of job-related, house work-related, transportation-related, and leisure-related physical activities done in the past week. METS-minutes/week will be calculated and reported (i.e. take the number of minutes doing an activity in the past week and multiply by the appropriate metabolic equivalent, which will vary based on the intensity of the physical activity).

Measure: Physical Activity Level

Time: Pre-program (baseline)

---

Description: Using a cognitive activity scale (score of 0-4 per activity) that requires participants to self-report how often they typically engage in a variety of mentally stimulating activities (i.e. playing card games, reading, cooking, etc.) The more frequently they engage in the activity, the higher the score.

Measure: Participant cognitive activity

Time: Pre-program (baseline)

---

Description: Using a scale (score of 0-3 per group) that requires participants to self-report how often they typically interact (face-to-face or virtually) with different groups of people (i.e. their spouse, family, friends, co-workers, etc.). The more frequently they interact with the group, the higher the score.

Measure: Participant social activity

Time: Pre-program (baseline)

---

Description: Self-reported years of age using basic demographics questionnaire

Measure: Participant and Instructor Age

Time: Pre-program (baseline)

---

Secondary Outcomes

Description: STROOP task which assesses the length of time (seconds) it takes for a participant to correctly name a coloured square (test 1), read the name of a colour (test 2), and say the name of the colour that a word is printed in (test 3). Number of corrected and uncorrected errors are also recorded.

Measure: Change in Stroop Task Performance

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Trails Making Test Part A and B. Part A assesses visual search (participants must connect numbered circles in ascending numerical order (1-2-3-etc). Part B assesses working memory and task-switching (participants must connect circles in ascending numerical and alphabetical order (1-A-2-B- etc.). Time to complete the tests (second) and errors (number) made during the tests are recorded.

Measure: Change in Trail Making Task Performance

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Resting (seated) heart rate (beats per minute) using an automatic blood pressure cuff

Measure: Change in Resting Heart Rate

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Resting (seated) blood pressure (millimeters of mercury) using an automatic blood pressure cuff

Measure: Change in Resting Systolic and Diastolic Blood Pressure

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Using hand dynamometer (assessing grip strength in lbs) for right and left hand (two trials per hand)

Measure: Change in Grip Strength

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Weight (using automatic scale to measure in lbs, converted to kg) and height (measured in feet and inches, converted to meters) measured and combined to provide BMI (kg/m^2)

Measure: Change in Body Mass Index (BMI)

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Divide waist circumference (cm) by hip circumference (cm) to get ratio calculation

Measure: Change in Hip-to-Waist Circumference Ratio

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Agility and functional balance will be assessed using the Timed Up-and-Go (participants stand up from a chair, walk 6 meters, turn around an object, walk back to chair, and sit down). Time to complete test is measured (seconds) and assessor's observational notes of performance are taken.

Measure: Change in Timed Up-and-Go Performance

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Agility and functional balance will be assessed using the Four Square Step Test (participants must step over lines that are set up in a cross formation, creating 4 quadrants. They must step forward, backward, and side to side in a specific pattern (i.e. from quadrant 1 to quadrant 2, to quadrant 3, to quadrant 4). Time to complete test is recorded in seconds.

Measure: Change in Four Square Step Test Performance

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Lower body strength will be assessed using the 5 Time Sit-to-Stand (participants must complete 5 sit-to-stands from a chair as fast as they can). Time to complete all 5 is recorded in seconds.

Measure: Change in Sit-to-Stand Performance

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Functional fitness will be assessed using the 6 minute walk (participants walk along indoor track for 6 minutes). The number of laps achieved in 6 minutes is recorded. Assessor's observational notes of walking performance is also recorded.

Measure: Change in 6-minute walk test Performance

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Well-being will be self-reported using the "Vitality-Plus Scale" (self-reported general health questionnaire - rating of sleep quality, appetite, general energy level, etc.). Participants rate their degree of health on a scale from 1 - 5 (the higher the rating, the better their perceived overall well-being).

Measure: Change in Overall Well-being

Time: Pre-program (baseline) and post-program (12 weeks)

---

Description: Bandura Scale (named after the researcher who developed it) - self-reported rating of confidence (0 - 100%) to continue exercising routinely in various hypothetical situations (i.e. if one is sick, if the weather is poor, etc). The greater the confidence, the higher the score

Measure: Change in Exercise-related Self-Efficacy

Time: Pre-program (baseline) and post-program (12 weeks)

---

Primary Outcomes

Description: Change from baseline of Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h

Measure: Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h

Time: 12 weeks

---

Secondary Outcomes

Description: Change from baseline of Average FEV1 AUC0-4h post-dose at Week 12

Measure: Average FEV1 AUC0-4h post-dose at Week 12

Time: 12 weeks

---

Description: Change from baseline in Peak FEV1 over 4 hours post dose at Week 12

Measure: Peak FEV1 over 4 hours post dose at Week 12

Time: 12 weeks

---

Description: Change from baseline as a weekly average of Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24

Measure: Weekly average of Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24

Time: 24 weeks

---

Description: Change from baseline of SGRQ total score at Week 24

Measure: St. George's Respiratory Questionnaire (SGRQ) total score at Week 24

Time: 24 weeks

---

Description: Change from baseline of Morning trough FEV1 at Week 12

Measure: Morning trough FEV1 at Week 12

Time: 12 weeks

---

Description: The proportion of St. George's Respiratory Questionnaire (SGRQ) responders at Week 24.

Measure: St. George's Respiratory Questionnaire (SGRQ)

Time: 24 weeks

---

Description: Change from baseline of Rescue medication use at Week 24

Measure: Rescue medication use at Week 24

Time: 24 weeks

---

Description: Transitional Dyspnea Index (TDI) at Week 24

Measure: Transitional Dyspnea Index (TDI) at Week 24

Time: 24 weeks

---

Description: Change from baseline Evening trough FEV1 at Week 12

Measure: Evening trough FEV1 at Week 12

Time: 12 weeks

---

Description: Change from baseline Peak FEV1

Measure: Peak FEV1 at Week 6 and Week 24

Time: 6 and 24 weeks

---

Description: Change from baseline morning trough FEV1

Measure: Morning trough FEV1 at Week 6 and Week 24

Time: 6 and 24 weeks

---

Description: Change from baseline evening trough FEV1

Measure: Evening trough FEV1 at Week 6 and Week 24

Time: 6 and 24 weeks

---

Description: Change from baseline FEV1 AUC0-4h

Measure: FEV1 AUC0-4h at Week 6 and Week 24

Time: 6 and 24 weeks

---

Description: Change from baseline E-RS Total Score

Measure: Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 6 and Week 12

Time: 6 and 12 weeks

---

Description: Change from baseline SGRQ responder analysis

Measure: St. George's Respiratory Questionnaire (SGRQ) responder analysis at Week 6 and Week 12

Time: 6 and 12 weeks

---

Description: Change from baseline TDI

Measure: TDI at Week 6 and Week 12

Time: 6 and 12 Weeks

---

Description: Change from baseline of SGRQ total score at Weeks 6 and 12

Measure: St. George's Respiratory Questionnaire (SGRQ) total score at Weeks 6 and 12

Time: 6 Weeks and 12 weeks

---

Description: Change from baseline of Rescue medication use at Weeks 6 and 12

Measure: Rescue medication use at Weeks 6 and 12

Time: 12 weeks

---

Primary Outcomes

Description: Change from baseline of Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h

Measure: Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h

Time: 12 weeks

---

Secondary Outcomes

Description: Change from baseline of Average FEV1 AUC0-4h post-dose at Week 12

Measure: Average FEV1 AUC0-4h post-dose at Week 12

Time: 12 weeks

---

Description: Change from baseline of Peak FEV1 over 4 hours post-dose at Week 12

Measure: Peak FEV1 over 4 hours post-dose at Week 12

Time: 12 weeks

---

Description: Change from baseline as a weekly average of Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24

Measure: Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24

Time: 24 weeks

---

Description: Change from baseline of SGRQ total score at Week 24

Measure: St. George's Respiratory Questionnaire (SGRQ) total score at Week 24

Time: 24 weeks

---

Description: Change from baseline of Morning trough FEV1 at Week 12

Measure: Morning trough FEV1 at Week 12

Time: 12 weeks

---

Description: The proportion of St. George's Respiratory Questionnaire (SGRQ) responders at Week 24.

Measure: St. George's Respiratory Questionnaire (SGRQ) responders at Week 24

Time: 24 weeks

---

Description: Change from baseline of Rescue medication use at Week 24

Measure: Rescue medication use at Week 24

Time: 24 weeks

---

Description: Transitional Dyspnea Index (TDI) at Week 24

Measure: Transitional Dyspnea Index (TDI) at Week 24

Time: 24 weeks

---

Description: Change from baseline Evening trough FEV1 at Week 12

Measure: Evening trough FEV1 at Week 12

Time: 12 weeks

---

Description: Change from baseline Peak FEV1

Measure: Peak FEV1 at Week 6 and Week 24

Time: 6 or 24 weeks

---

Description: Change from baseline morning trough FEV1

Measure: Morning trough FEV1 at Week 6 and Week 24

Time: 6 or 24 weeks

---

Description: Change from baseline evening trough FEV1

Measure: Evening trough FEV1 at Week 6 and Week 24

Time: 6 or 24 weeks

---

Description: Change from baseline FEV1 AUC0-4h

Measure: FEV1 AUC0-4h at Week 6 and Week 24

Time: 6 or 24 weeks

---

Description: Change from baseline E-RS Total Score

Measure: Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 6 and Week 12

Time: 6 or 12 weeks

---

Description: Change from baseline SGRQ responder analysis

Measure: SGRQ responder analysis at Week 6 and Week 12

Time: 6 or 12 weeks

---

Description: Change from baseline TDI

Measure: TDI at Week 6 and Week 12

Time: 6 or 12 weeks

---

Description: Change from baseline of SGRQ total score

Measure: St. George's Respiratory Questionnaire (SGRQ) total score at Weeks 6 and 12

Time: 6 or 12 weeks

---

Description: Change from baseline of Rescue medication use

Measure: Rescue medication use at Weeks 6 and 12

Time: 6 or 12 weeks

---

Primary Outcomes

Description: Evaluation of the relative bioavailability between the test formulations and the reference formulation for fixed dose combinations (FDCs) of BGF when delivered as BGF MDI with 3 different propellants by Cmax.

Measure: Maximum observed concentration (Cmax) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Evaluation of the relative bioavailability between the test formulations and the reference formulation for FDCs of BGF when delivered as BGF MDI with 3 different propellants by AUCinf.

Measure: Area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Evaluation of the relative bioavailability between the test formulations and the reference formulation for FDCs of BGF when delivered as BGF MDI with 3 different propellants by AUClast.

Measure: Area under the plasma concentration- curve from time zero to the time of last quantifiable concentration (AUClast) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Secondary Outcomes

Description: Assessment of the pharmacokinetic (PK) parameters of BGF when administered as 3 different propellant formulations by tmax.

Measure: Time to reach maximum observed concentration (tmax) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by t½λz.

Measure: Terminal elimination half-life (t½λz) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by MRT.

Measure: Mean residence time in the systemic circulation extrapolated to infinity (MRT) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by λz.

Measure: Terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by CL/F.

Measure: Apparent total body clearance of drug after extravascular administration (CL/F) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by Vz/F.

Measure: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by TRCmax.

Measure: Treatment ratio for Cmax derived by dividing the Cmax of the test treatment by the reference treatment (TRCmax) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by TRAUCinf.

Measure: Treatment ratio for AUCinf, derived by dividing the AUCinf of the test treatment by the reference treatment (TRAUCinf) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Assessment of the PK parameters of BGF when administered as 3 different propellant formulations by TRAUClast.

Measure: Treatment ratio for AUClast derived by dividing the AUClast of the test treatment by the reference treatment (TRAUClast) of BGF MDI

Time: Pre-dose and 2, 5, 10, 20, 30, and 45 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post-dose

---

Description: Assessment of the safety and tolerability of a combination of BGF when administered as single doses in 3 different propellant formulations in healthy participants.

Measure: Number of participants with serious adverse events (SAE) and non-serious adverse events

Time: Screening (Only SAE), Days -1, 1, and Day 2 until Follow-up visit (approximately 3 to 7 days post final dose)

---

Primary Outcomes

Description: To assess the effects of MEDI3506 compared with placebo on pulmonary function in participants with COPD and chronic bronchitis.

Measure: Change from baseline to Week 12 in pre-bronchdilator forced expiratory volume in 1 second (FEV1) measured in clinic.

Time: From Baseline to Week 12

---

Secondary Outcomes

Description: To assess the PK of MEDI3506 in participants with COPD and chronic bronchitis.

Measure: Area under the PK concentration- time curve, during the intervention and follow up periods.

Time: From Study Day 1 to Week 36

---

Description: To assess the PK of MEDI3506 in participants with COPD and chronic bronchitis.

Measure: Peak plasma concentration (Cmax) profile during the intervention and follow up periods

Time: From Study Day 1 to Week 36

---

Description: To assess the immunogenicity of MEDI3506 compared with placebo in participants with COPD and chronic bronchitis.

Measure: Anti-drug antibodies during the intervention and follow-up periods.

Time: From Study Day 1 to Week 36

---

Description: To assess the effect of MEDI3506 on COPDCompEx event in participants with COPD and chronic bronchitis

Measure: Time to first COPDCompEx event based on the period from baseline to 4 weeks after last dose (Week 28)

Time: From Baseline to Week 28

---

Description: To assess the effect of MEDI3506 compared with placebo on respiratory symptoms in participants with COPD and chronic bronchitis. Higher score indicates worse outcome. Min Score = 0 Max Score= 40

Measure: Change from baseline to Week 12 in E-RS:COPD

Time: From Baseline to Week 12

---

Description: To assess the effect of MEDI3506 compared with placebo on respiratory symptoms in participants with COPD and chronic bronchitis. Higher score indicates worse outcome. Min Score= 0 Max Score=12

Measure: Change from baseline to Week 12 in Mean Breathless, cough and sputum scale (BCSS) Score

Time: From Baseline to Week 12

---

Description: To assess the effect of MEDI3506 compared with placebo on respiratory symptoms in participants with COPD and chronic bronchitis. Higher score indicates worse outcome. Min Score= 0 Max Score=100

Measure: Change from baseline to Week 12 in Cough Visual Analogue Scale (VAS) item

Time: From Baseline to Week 12

---

Description: To assess the effect of MEDI3506 compared with placebo on disease impact in participants with COPD and chronic bronchitis. Higher score indicates worse outcome. Min Score= 0 Max Score=100

Measure: Change from baseline to Week 12 in St Georges Respiratory Questionnaire (SGRQ) total score

Time: From Baseline to Week 12

---

Description: To assess the effect of MEDI3506 compared with placebo on disease impact in participants with COPD and chronic bronchitis. Responder endpoint 'yes' and 'no'. 'No' is the worse outcome.

Measure: Proportion of participants with a decrease in St Georges Respiratory Questionnaire (SGRQ) total score of ≥ 4 points from baseline to Week 12

Time: From Baseline to Week 12

---

Description: To assess the effect of MEDI3506 compared with placebo on airway resistance and reactance in participants with COPD and chronic bronchitis.

Measure: Change from baseline to Week 12 in Airway Oscillometry parameter difference between R5 and R20 (R5-R20)

Time: From Baseline to Week 12

---

Description: To assess the effect of MEDI3506 compared with placebo on airway resistance and reactance in participants with COPD and chronic bronchitis.

Measure: Change from baseline to Week 12 in Airway Oscillometry parameter Area under Reactance Curve (AX).

Time: From Baseline to Week 12

---

Description: To assess the effect of MEDI3506 compared with placebo on airway resistance and reactance in participants with COPD and chronic bronchitis.

Measure: Change from baseline to Week 12 in Airway Oscillometry parameter resistance at 20Hz (R20) .

Time: From Baseline to Week 12

---

Description: To assess the effect of MEDI3506 compared with placebo on airway resistance and reactance in participants with COPD and chronic bronchitis.

Measure: Change from baseline to Week 12 in Airway Oscillometry parameter resistance at 5Hz (R5)

Time: From Baseline to Week 12

---

Description: To evaluate the effect of MEDI3506 compared with placebo on objective cough measures in participants with COPD and chronic bronchitis.

Measure: At Week 12, ratio to baseline in: Daily (ie, 24 hour) cough frequency, Night time cough frequency, Awake time cough frequency

Time: Week 12

---

Primary Outcomes

Description: it will be measured in plasma

Measure: cortisol

Time: It will be measured after eight weeks of training

---

Description: this a questionnaire that will assess anxiety and depression in COPD patients

Measure: hospital anxiety and depression scale

Time: It will be measured after eight weeks of training

---

Secondary Outcomes

Description: it will be a measurement for lung volume and capacities

Measure: pulmonary function test

Time: It will be measured after eight weeks of training

---

Description: It is an inflammatory marker in plasma

Measure: Interleukin-8

Time: It will be measured after eight weeks of training

---

Description: it will measure body mass changes

Measure: body mass index

Time: It will be measured after eight weeks of training

---

Description: it assess functional capacity

Measure: six minute walking test

Time: It will be measured after eight weeks of training

---

Description: It assess the effect of COPD on general quality of life

Measure: St. George's respiratory questionnaire

Time: It will be measured after eight weeks of training

---

Primary Outcomes

Description: AHI is defined as the average number of apneas and hypopneas per hour of sleep. AHI will be assessed using polysomnography (PSG). The International Classification of Sleep Disorders (ICSD) (American Academy of Sleep Medicine, 2014) defines the severity of OSA according to the AHI: an AHI >5 to <15 is classed as mild, AHI >=15 to <30 as moderate, and AHI >=30 as severe.

Measure: OSA Cohort: AHI on Day 8 of Treatment

Time: Day 8

---

Description: SpO2 is an estimate of the amount of oxygen in the blood. It is the percentage of hemoglobin containing oxygen compared to the total amount of hemoglobin in the blood (that is, oxygenated hemoglobin versus oxygenated and non-oxygenated hemoglobin). SpO2 is monitored by noninvasive method known as transmissive pulse oximetry. TST is defined as the total time asleep in minutes using PSG.

Measure: COPD Cohort: Mean SpO2 During TST on Day 8 of Treatment

Time: Day 8

---

Secondary Outcomes

Description: AHI is defined as the average number of apneas and hypopneas per hour of sleep. AHI will be assessed using PSG. The ICSD (American Academy of Sleep Medicine, 2014) defines the severity of OSA according to the AHI: an AHI >5 to <15 is classed as mild, AHI >=15 to <30 as moderate, and AHI >=30 as severe.

Measure: AHI on Day 1 and Day 8 of Treatment

Time: OSA Cohort: Day 1; COPD Cohort: Day 1 and Day 8

---

Description: SpO2 is an estimate of the amount of oxygen in the blood. It is the percentage of hemoglobin containing oxygen compared to the total amount of hemoglobin in the blood (that is, oxygenated hemoglobin versus oxygenated and non-oxygenated hemoglobin). SpO2 is monitored by noninvasive method known as transmissive pulse oximetry. TST is defined as the total time asleep in minutes using PSG.

Measure: Mean SpO2 During TST on Day 1 and Day 8 of Treatment

Time: OSA Cohort: Day 1 and Day 8; COPD Cohort: Day 1

---

Description: SpO2 is an estimate of the amount of oxygen in the blood. It is the percentage of hemoglobin containing oxygen compared to the total amount of hemoglobin in the blood (that is, oxygenated hemoglobin versus oxygenated and non-oxygenated hemoglobin). SpO2 is monitored by noninvasive method known as transmissive pulse oximetry. TST is defined as the total time asleep in minutes using PSG.

Measure: Percentage of TST During Which the SpO2 is <90 percent (%), <85% and <80% on Day 1 and Day 8 of Treatment

Time: Day 1 and Day 8

---

Description: ODI is defined as (oxygen desaturations >=3%*60)/TST (that is, the average number of oxygen desaturations >=3% per hour of sleep), as defined by the American Academy of Sleep Medicine. ODI will be assessed using PSG.

Measure: Mean Oxygen Desaturation Index (ODI) on Days 1 and 8 of Treatment

Time: Day 1 and Day 8

---

Description: Desaturation is defined as decrease in the mean SpO2 of >=3% (over the last 120 seconds) that lasts for at least 10 seconds. Desaturation will be assessed using PSG.

Measure: Absolute Number of Desaturations (>=3% Reduction From Baseline SpO2) on Days 1 and 8 of Treatment

Time: Day 1 and Day 8

---

Primary Outcomes

Description: Change in forced expiratory volume in one second (FEV1) as compared to baseline, measured by home spirometer.

Measure: Change in forced expiratory volume in one second (FEV1)

Time: Baseline and up to 90 Days

---

Description: Changes in oxygen saturation from baseline as measured by pulse oximeter. Normal oxygen range is 95 to 100 percent and low oxygen range is under 90 percent.

Measure: Change in Oxygen Saturation level

Time: Baseline and up to 90 Days

---

Description: Changes in basal temperature as measured by digital thermometer. Fever is indicated at 100.4 F (38 C) or higher.

Measure: Change in Presence of Fever

Time: Baseline and up to 90 Days

---

Secondary Outcomes

Description: CAP Symptom Questionnaire records how much the patient rated the bothersomeness of the symptom. Each item is scored as "0" (Patient did not have this symptom), "1" (Not at All) to "5" (Extremely). Full range scale from 0 to 90, higher score indicating patient experiencing more frequent or more severe symptoms.

Measure: Change in Presence of pneumonia symptoms via Community Acquired Pneumonia (CAP) Symptom Questionnaire

Time: Baseline and up to 90 Days

---

Description: The QOL-B is a disease-specific questionnaire that measures symptoms, functioning, and health-related quality of life relevant to patients with bronchiectasis. Scores are generated from 37 items that fall on 8 domains: Physical Functioning, Role Functioning, Vitality, Emotional Functioning, Social Functioning, Treatment Burden, Health Perceptions, and Respiratory Symptoms. All subscales and the full range scale are standardized to score from 0 to 100, with higher scores indicating better enjoyment and satisfaction with specific life domains.

Measure: Change in Quality of life via Quality of Life Questionnaire-Respiratory (QOL-B)

Time: Baseline and up to 90 Days

---

Description: The PHQ-8 is the depression module, which scores each of the eight DSM-IV criteria as "0" (not at all) to "3" (nearly every day). Full scale from 0-24, with higher score indicating more severe symptoms.

Measure: Change in Mental health screening via Personal Health Questionnaire Depression Scale (PHQ-8)

Time: Baseline and up to 90 Days

---

Description: The General Anxiety Disorder 7-item questionnaire (GAD-7) is a 7-item questionnaire that asks user to rank how often they have been bothered by seven problems over the past two weeks from "0" (not at all) to "3" (nearly every day). Full scale from 0-21, with higher score indicating more symptoms.

Measure: Change in Mental health screening via General Anxiety Disorder-7 (GAD-7)

Time: Baseline and up to 90 Days

---

Description: Eight questions that are specific to recent literature describing patients' experiences of symptoms during COVID. They are rated on a frequency scale from "never" to "always," using a 1-4 point scale. Full scale range from 8 to 32, with higher scores indicating more frequent symptoms.

Measure: Change in COVID Symptom Checklist

Time: Baseline and up to 90 Days

---

Description: Amount of time used per week in minutes

Measure: AffloVest Usage

Time: 90 Days

---