COPD (Chronic Obstructive Pulmonary Disease)
Conditions
Keywords
COPD, Chronic Obstructive Pulmonary Disease, Pulmonary Function Tests, Current Smoker, Former Smoker, Chronic Obstructive Airway Disease, Respiratory Symptoms
Brief summary
The study hypothesis is that symptomatic current and former smokers with spirometric values within the normal range (post-bronchodilator FEV1/FVC≥0.70 and post-BD FVC ≥ 70% predicted will still derive symptomatic benefit from long-acting bronchodilator therapy even though they are excluded from current GOLD guideline recommendations.
Detailed description
RETHINC is a 12-week multicenter, randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily in symptomatic current and former smokers with respiratory symptoms despite preserved spirometry as defined by CAT ≥ 10 and post-bronchodilator FEV1/FVC ratio ≥0.70, respectively.
Interventions
27.5/15.6 mcg active indacaterol/glycopyrrolate
DRUGPlacebo
27.5/15.6 mcg placebo
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Subject must be able to understand and provide informed consent 2. Age 40-80 3. ≥10 pack-year smoking history 4. Post-bronchodilator FEV1/FVC ratio ≥0.70 5. Baseline CAT≥10
Exclusion criteria
1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol. 2. Subject is pregnant, breast-feeding, or plans to become pregnant. 3. Active pulmonary infection or prior pulmonary infection where antibiotic and/or steroid treatment was completed ≤4 weeks prior to enrollment. 4. Post-BD FVC \< 70% predicted 5. A primary diagnosis of asthma established by each study investigator based on ATS/ERS criteria as previously implemented in the MACRO clinical trial. 6. Known concomitant lung disease, pulmonary tuberculosis (unless confirmed by chest x-ray to be no longer active), or clinically significant bronchiectasis. 7. History (or family history) of long QT syndrome. 8. History of paroxysmal (intermittent) atrial fibrillation will be considered an exclusion. Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, heart rate at enrollment must be \< 100/min. 9. Patients with BMI \< 15 or more than 40 kg/m2. 10. Patients with diabetes Type I or uncontrolled diabetes Type II. 11. Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to) significant renal disease, psychiatric disease, gastrointestinal disease, unstable ischemic heart disease, arrhythmia (excluding chronic stable atrial fibrillation), uncontrolled hypertension or any other condition which in the opinion of investigator might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study. 12. Patients with any history of lung cancer. 13. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck obstruction or severe renal impairment or urinary retention. Benign Prostatic Hyperplasia (BPH) patients who are stable on treatment can be considered. 14. Any other past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study. 15. Patients with a history of hypersensitivity to any of the study drugs or to drugs from similar chemical classification, including untoward reactions to sympathomimetic amines or inhaled medication or any component thereof. 16. Patients unable to successfully use a dry powder inhaler device or perform spirometry measurements. 17. Use of other investigational drugs at the time of enrollment or within 30 days or 5 half-lives of enrollment, whichever is longer. 18. Patients receiving any protocol-specified prohibited medications.. 19. Patients receiving any protocol-specified prohibited COPD related medications (will be required to undergo a required washout period prior to enrollment).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion (Percentage) of Individuals Who Experience a 4 Unit Improvement in St. George's Respiratory Questionnaire (SGRQ) at 12 Weeks and do Not Meet Criteria for Treatment Failure During the 12 Week Treatment Period | Baseline and 12 weeks | Measured by units of improvement in SGRQ scores at Baseline and 12 weeks, as well as review of treatment failure status at 4 weeks and 12 weeks of treatment (treatment failure is defined by an increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics). A 4 unit change is the minimum clinically important difference. SGRQ has a 0 - 100 score; 0 as low symptoms (feeling better) and 100 as high symptoms (feeling worse). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Individuals With a 1 Unit Improvement in the BDI/TDI Without Treatment Failure | 12 weeks | Proportion of individuals with a 1 unit improvement in the BDI/TDI without treatment failure |
| Proportion of Individuals With Both a 4 Unit Improvement in SGRQ and a 1 Unit Improvement in BDI/TDI Without Treatment Failure | 12 weeks | Measured by units of improvement in SGRQ scores at Baseline and 12 weeks, as well as review of treatment failure status at 4 weeks and 12 weeks of treatment (treatment failure is defined by an increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics). |
| Mean Change in St. George's Respiratory Questionnaire (SGRQ) | Baseline, 12 weeks | Value at 12 Weeks Minus Baseline. SGRQ has a 0 - 100 score; 0 as low symptoms (feeling better) and 100 as high symptoms (feeling worse). |
| Mean Change in COPD Assessment Test (CAT) | Baseline, 12 weeks | Value at 12 Weeks Minus Baseline. 0 - 40; 0 as low symptoms (feeling better) and 40 as high symptoms (feeling worse). |
| Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) | 12 Weeks | Value at 12 Weeks Minus Baseline. |
| Area Under the Curve (AUC) 0-3 Hours for FEV1 | At 12 weeks, FEV1 is measured at 1-hour intervals for 3 hours | FEV1 AUC0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in liters. |
| Proportion of Individuals With a 2 Unit Improvement in CAT Without Treatment Failure | 12 weeks | Proportion of individuals with a 2 unit improvement in CAT without treatment failure |
| Change From Baseline in 12 Hour Trough Inspiratory Capacity - Absolute Value | Baseline | Change from baseline in 12 hour trough inspiratory capacity - absolute value |
| Symptoms and Rescue Medication Use Based on Daily Diary | During study follow-up (Baseline to 12 weeks) | Percentage of days with symptoms (shortness of breath, chest tightness, wheezing, cough, or sputum) or use of albuterol |
| Treatment Failure Defined by Increase in Lower Respiratory Symptoms Necessitating Treatment With Active, Long-acting Inhaled Bronchodilator, Corticosteroids or Antibiotics | During study follow-up (baseline to 12 Weeks) | Treatment failure defined by increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics |
| Change From Baseline in Trough FEV1 - % Predicted | Baseline to 12 Weeks | Trough FEV1 at 12 week minus trough FEV1 at baseline. |
| Change in FEF25-75% | Baseline to 12 weeks | FEF25-75%-Forced expiratory flow over the middle one half of the FVC; the average flow from the point at which 25 percent of the FVC has been exhaled to the point at which 75 percent of the FVC has been exhaled. |
| Change From Baseline in Trough Forced Expiratory Volume Per 1 Second (FEV1) - Absolute Value | Baseline to 12 Weeks | Trough FEV1 at 12 week minus trough FEV1 at baseline. |
Countries
United States
Participant flow
Pre-assignment details
Of the 780 consented, 242 were screen fails and 3 dropped out before randomization, so 535 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Indacaterol/Glycopyrrolate indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks
Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate | 261 |
| Placebo Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks
Placebo: 27.5/15.6 mcg placebo | 274 |
| Total | 535 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 25 | 18 |
| Overall Study | Participant withdrawn by investigator | 0 | 1 |
| Overall Study | Unable to complete protocol | 3 | 7 |
Baseline characteristics
| Characteristic | Total | Placebo | Indacaterol/Glycopyrrolate |
|---|---|---|---|
| Age, Continuous | 58.8 years STANDARD_DEVIATION 9.7 | 59.1 years STANDARD_DEVIATION 9.8 | 58.6 years STANDARD_DEVIATION 9.6 |
| COPD Assessment Test (CAT) Score | 17.6 units on a scale STANDARD_DEVIATION 6.4 | 17.6 units on a scale STANDARD_DEVIATION 6 | 17.5 units on a scale STANDARD_DEVIATION 6.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 47 Participants | 22 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 488 Participants | 252 Participants | 236 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Post bronchodilator FEV1 percent predicted | 94.2 percent predicted STANDARD_DEVIATION 13.3 | 94.9 percent predicted STANDARD_DEVIATION 12.6 | 93.8 percent predicted STANDARD_DEVIATION 14 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 191 Participants | 99 Participants | 92 Participants |
| Race (NIH/OMB) More than one race | 12 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 23 Participants | 12 Participants | 11 Participants |
| Race (NIH/OMB) White | 302 Participants | 154 Participants | 148 Participants |
| Region of Enrollment United States | 535 participants | 274 participants | 261 participants |
| Sex: Female, Male Female | 274 Participants | 140 Participants | 134 Participants |
| Sex: Female, Male Male | 261 Participants | 134 Participants | 127 Participants |
| St. George's Respiratory Questionnaire (SGRQ) Score | 38.2 units on a scale STANDARD_DEVIATION 20.2 | 38.4 units on a scale STANDARD_DEVIATION 19.3 | 37.9 units on a scale STANDARD_DEVIATION 21 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 261 | 0 / 274 |
| other Total, other adverse events | 0 / 261 | 0 / 274 |
| serious Total, serious adverse events | 4 / 261 | 8 / 274 |
Outcome results
Primary
Proportion (Percentage) of Individuals Who Experience a 4 Unit Improvement in St. George's Respiratory Questionnaire (SGRQ) at 12 Weeks and do Not Meet Criteria for Treatment Failure During the 12 Week Treatment Period
Measured by units of improvement in SGRQ scores at Baseline and 12 weeks, as well as review of treatment failure status at 4 weeks and 12 weeks of treatment (treatment failure is defined by an increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics). A 4 unit change is the minimum clinically important difference. SGRQ has a 0 - 100 score; 0 as low symptoms (feeling better) and 100 as high symptoms (feeling worse).
Time frame: Baseline and 12 weeks
Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing SGRQ at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243). An additional person did not complete final visit but had treatment failure so are still included in mITT (243 + 1 = 244).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Proportion (Percentage) of Individuals Who Experience a 4 Unit Improvement in St. George's Respiratory Questionnaire (SGRQ) at 12 Weeks and do Not Meet Criteria for Treatment Failure During the 12 Week Treatment Period | 128 Participants |
| Placebo | Proportion (Percentage) of Individuals Who Experience a 4 Unit Improvement in St. George's Respiratory Questionnaire (SGRQ) at 12 Weeks and do Not Meet Criteria for Treatment Failure During the 12 Week Treatment Period | 144 Participants |
p-value: 0.6595% CI: [0.6, 1.37]Generalized Estimating Equation
Secondary
Area Under the Curve (AUC) 0-3 Hours for FEV1
FEV1 AUC0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in liters.
Time frame: At 12 weeks, FEV1 is measured at 1-hour intervals for 3 hours
Population: Not all persons completed their lung function tests.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Area Under the Curve (AUC) 0-3 Hours for FEV1 | 8.09 liters |
| Placebo | Area Under the Curve (AUC) 0-3 Hours for FEV1 | 7.82 liters |
p-value: <0.001Linear Mixed Effects Model
Secondary
Change From Baseline in 12 Hour Trough Inspiratory Capacity - Absolute Value
Change from baseline in 12 hour trough inspiratory capacity - absolute value
Time frame: Baseline
Population: Not all participants had all measures measured.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Change From Baseline in 12 Hour Trough Inspiratory Capacity - Absolute Value | 0.12 Liters |
| Placebo | Change From Baseline in 12 Hour Trough Inspiratory Capacity - Absolute Value | 0.02 Liters |
Secondary
Change From Baseline in Trough FEV1 - % Predicted
Trough FEV1 at 12 week minus trough FEV1 at baseline.
Time frame: Baseline to 12 Weeks
Population: Not all participants had all measures measured.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Change From Baseline in Trough FEV1 - % Predicted | 2.48 percentage of predicted number |
| Placebo | Change From Baseline in Trough FEV1 - % Predicted | -0.09 percentage of predicted number |
Secondary
Change From Baseline in Trough Forced Expiratory Volume Per 1 Second (FEV1) - Absolute Value
Trough FEV1 at 12 week minus trough FEV1 at baseline.
Time frame: Baseline to 12 Weeks
Population: Not all participants had all measures measured.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Change From Baseline in Trough Forced Expiratory Volume Per 1 Second (FEV1) - Absolute Value | 0.04 Liters |
| Placebo | Change From Baseline in Trough Forced Expiratory Volume Per 1 Second (FEV1) - Absolute Value | -0.01 Liters |
Secondary
Change in FEF25-75%
FEF25-75%-Forced expiratory flow over the middle one half of the FVC; the average flow from the point at which 25 percent of the FVC has been exhaled to the point at which 75 percent of the FVC has been exhaled.
Time frame: Baseline to 12 weeks
Population: Not all participants had pulmonary function tests.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Change in FEF25-75% | 0.07 Liters per second |
| Placebo | Change in FEF25-75% | -0.08 Liters per second |
Secondary
Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI)
Value at 12 Weeks Minus Baseline.
Time frame: 12 Weeks
Population: Not all participants had these measures taken.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) | 0.93 ratio |
| Placebo | Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) | 0.92 ratio |
p-value: 0.96Linear Mixed Effects Model
Secondary
Mean Change in COPD Assessment Test (CAT)
Value at 12 Weeks Minus Baseline. 0 - 40; 0 as low symptoms (feeling better) and 40 as high symptoms (feeling worse).
Time frame: Baseline, 12 weeks
Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing CAT at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Mean Change in COPD Assessment Test (CAT) | -4.5 score on a scale |
| Placebo | Mean Change in COPD Assessment Test (CAT) | -4.8 score on a scale |
p-value: 0.49Linear Mixed Effects Model
Secondary
Mean Change in St. George's Respiratory Questionnaire (SGRQ)
Value at 12 Weeks Minus Baseline. SGRQ has a 0 - 100 score; 0 as low symptoms (feeling better) and 100 as high symptoms (feeling worse).
Time frame: Baseline, 12 weeks
Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing SGRQ at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243). .
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Mean Change in St. George's Respiratory Questionnaire (SGRQ) | -7.7 score on a scale |
| Placebo | Mean Change in St. George's Respiratory Questionnaire (SGRQ) | -8.9 score on a scale |
p-value: 0.3Linear Mixed Effects Model
Secondary
Proportion of Individuals With a 1 Unit Improvement in the BDI/TDI Without Treatment Failure
Proportion of individuals with a 1 unit improvement in the BDI/TDI without treatment failure
Time frame: 12 weeks
Population: Not all participants had all measures measured.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Proportion of Individuals With a 1 Unit Improvement in the BDI/TDI Without Treatment Failure | 80 Participants |
| Placebo | Proportion of Individuals With a 1 Unit Improvement in the BDI/TDI Without Treatment Failure | 80 Participants |
Secondary
Proportion of Individuals With a 2 Unit Improvement in CAT Without Treatment Failure
Proportion of individuals with a 2 unit improvement in CAT without treatment failure
Time frame: 12 weeks
Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing SGRQ at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243). An additional person did not complete final visit but had treatment failure so are still included in mITT (243 + 1 = 244).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Proportion of Individuals With a 2 Unit Improvement in CAT Without Treatment Failure | 169 Participants |
| Placebo | Proportion of Individuals With a 2 Unit Improvement in CAT Without Treatment Failure | 166 Participants |
Secondary
Proportion of Individuals With Both a 4 Unit Improvement in SGRQ and a 1 Unit Improvement in BDI/TDI Without Treatment Failure
Measured by units of improvement in SGRQ scores at Baseline and 12 weeks, as well as review of treatment failure status at 4 weeks and 12 weeks of treatment (treatment failure is defined by an increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics).
Time frame: 12 weeks
Population: Not all participants had all measures measured.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Proportion of Individuals With Both a 4 Unit Improvement in SGRQ and a 1 Unit Improvement in BDI/TDI Without Treatment Failure | 55 Participants |
| Placebo | Proportion of Individuals With Both a 4 Unit Improvement in SGRQ and a 1 Unit Improvement in BDI/TDI Without Treatment Failure | 60 Participants |
Secondary
Symptoms and Rescue Medication Use Based on Daily Diary
Percentage of days with symptoms (shortness of breath, chest tightness, wheezing, cough, or sputum) or use of albuterol
Time frame: During study follow-up (Baseline to 12 weeks)
Population: Not all participants submitted complete diaries.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Symptoms and Rescue Medication Use Based on Daily Diary | 67.0 percentage of days |
| Placebo | Symptoms and Rescue Medication Use Based on Daily Diary | 63.6 percentage of days |
Comparison: P Value for percentage of days with any symptoms (shortness of breath, chest tightness, wheezing, cough, or sputum)p-value: 0.35Linear Mixed Effects Model
Comparison: P Value for percentage of days with shortness of breathp-value: 0.61Linear Mixed Effects Model
Comparison: P Value for percentage of days with chest tightnessp-value: 0.48Linear Mixed Effects Model
Comparison: P Value for percentage of days with wheezingp-value: 0.81Linear Mixed Effects Model
Comparison: P Value for percentage of days with coughp-value: 0.17Linear Mixed Effects Model
Comparison: P Value for percentage of days with sputump-value: 0.64Linear Mixed Effects Model
Comparison: P Value for percentage of days with use of albuterol.p-value: 0.84Linear Mixed Effects Model
Secondary
Treatment Failure Defined by Increase in Lower Respiratory Symptoms Necessitating Treatment With Active, Long-acting Inhaled Bronchodilator, Corticosteroids or Antibiotics
Treatment failure defined by increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics
Time frame: During study follow-up (baseline to 12 Weeks)
Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing SGRQ at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243). An additional person did not complete final visit but had treatment failure so are still included in mITT (243 + 1 = 244).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Indacaterol/Glycopyrrolate | Treatment Failure Defined by Increase in Lower Respiratory Symptoms Necessitating Treatment With Active, Long-acting Inhaled Bronchodilator, Corticosteroids or Antibiotics | 5 Participants |
| Placebo | Treatment Failure Defined by Increase in Lower Respiratory Symptoms Necessitating Treatment With Active, Long-acting Inhaled Bronchodilator, Corticosteroids or Antibiotics | 9 Participants |