Chronic Obstructive Pulmonary Disease, COPD
Conditions
Keywords
COPD,, chronic bronchitis,, inflammation,, airway,, LCI,, pulmonary function test,, lung function,, controlled clinical trial,, randomized,, airflow,, smoker
Brief summary
To evaluate the efficacy, safety and tolerability of multiple doses of QBW251 vs placebo administered orally, on airway function, lung volume, and quality of life in patients with chronic obstructive pulmonary disease (COPD)
Interventions
DRUGQBW251
QBW251 capsule(s) taken orally twice per day
DRUGPlacebo
Matching placebo capsule(s) taken orally twice per day
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Must have a diagnosis of GOLD II-III chronic obstructive pulmonary disease (COPD); Must have clinical diagnosis of chronic bronchitis; Must be either a current smoker (smoked ≤ 1 pack per day on average for the last 3 months with at least a 10 pack year smoking history) OR an ex-smoker with at least a 10 pack year smoking history;
Exclusion criteria
Must not be receiving chronic, daily, systemic steroids; Must not have severe emphysema (determined by HRCT); Must not have had a COPD exacerbation or respiratory tract infection requiring antibiotics or oral steroids or hospitalization within 6 weeks of screening; Must not be pregnant or nursing or a woman of child bearing potential; Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Lung Clearance Index (LCI) | Baseline and Day 29 | Change from baseline to Day 29 in LCI as measured by multiple breath nitrogen washout (MBNW) technique. MBNW is the time taken to wash out nitrogen while breathing 100% oxygen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FEV1 Post-bronchodilator | Day 29 | Change From Baseline to Day 29 in FEV1 will be measured by spirometer after bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. |
| Change From Baseline in FVC Pre Bronchodilator | Day 29 | Change From Baseline to Day 29 in FVC will be measured by spirometer before bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured before bronchodilator |
| Change From Baseline in FVC Post- Bronchodilator | Day 29 | Change From Baseline to Day 29 in FVC will be measured by spirometer after bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured after bronchodilator |
| Change From Baseline in TLC | Day 29 | Change From Baseline to Day 29 in TLC will be measured by spirometry. Total lung capacity (TLC) is the volume in the lungs at maximal inflation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. |
| Change From Baseline in RV | Day 29 | Change From Baseline to Day 29 in RV will be measured by spirometry. Residual volume (RV) is the volume of air remaining in the lungs after a maximal exhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. |
| Change From Baseline in FEV1 Pre-bronchodilator | Day 29 | Change From Baseline to Day 29 in FEV1 will be measured by spirometer before bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. |
| Change From Baseline in DLCO | Day 29 | Diffusing capacity of the lung for carbon monoxide (DLCO) is the extent to which oxygen passes from the lung to the blood. |
| Plasma Concentration of QBW251 by TMax (0-8hours) | Day 1, Day 28 | Tmax is the time to reach the maximum concentration after drug administration. |
| Plasma Concentration of QBW251 by CMax (0-8hours) | Day 1, Day 28 | Cmax is the observed maximum plasma concentration following drug administration. |
| Plasma Concentration of QBW251 by AUClast (0-8hours) | Day 1, Day 28 | AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. |
| Plasma Concentration of QBW251 by AUC0-12h | Day 1, Day 28 | AUC 0-12h is the area under the plasma concentration-time curve from time zero to 12 hours. |
| Change From Baseline in FRC | Day 29 | Change From Baseline to Day 29 in FRC will be measured by spirometry. Functional residual capacity (FRC) is the volume in the lungs at the end-expiratory position. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. |
Countries
Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| QBW251 QBW251(28 day treatment period) and placebo (42 days, run-in and wash-out periods) | 64 |
| Placebo Placebo (70 days, run-in, treatment and wash-out periods) | 28 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value | 0 | 1 |
| Overall Study | Administrative problems | 1 | 0 |
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | Patient decision | 2 | 0 |
| Overall Study | Protocol deviation | 4 | 0 |
Baseline characteristics
| Characteristic | QBW251 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63.6 Years STANDARD_DEVIATION 6.61 | 64.9 Years STANDARD_DEVIATION 7.55 | 64.0 Years STANDARD_DEVIATION 6.89 |
| Sex: Female, Male Female | 31 Participants | 9 Participants | 40 Participants |
| Sex: Female, Male Male | 33 Participants | 19 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 64 |
| other Total, other adverse events | 5 / 28 | 6 / 64 |
| serious Total, serious adverse events | 0 / 28 | 4 / 64 |
Outcome results
Primary
Change From Baseline in Lung Clearance Index (LCI)
Change from baseline to Day 29 in LCI as measured by multiple breath nitrogen washout (MBNW) technique. MBNW is the time taken to wash out nitrogen while breathing 100% oxygen.
Time frame: Baseline and Day 29
Population: Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QBW251 | Change From Baseline in Lung Clearance Index (LCI) | -0.03 Days | Standard Deviation 1.28 |
| Placebo | Change From Baseline in Lung Clearance Index (LCI) | -0.16 Days | Standard Deviation 1.15 |
p-value: 0.1390% CI: [-0.24, 0.79]ANCOVA
Secondary
Change From Baseline in DLCO
Diffusing capacity of the lung for carbon monoxide (DLCO) is the extent to which oxygen passes from the lung to the blood.
Time frame: Day 29
Population: Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBW251 | Change From Baseline in DLCO | -0.91 ml/min/mmHg | Standard Error 0.24 |
| Placebo | Change From Baseline in DLCO | -0.25 ml/min/mmHg | Standard Error 0.34 |
Secondary
Change From Baseline in FEV1 Post-bronchodilator
Change From Baseline to Day 29 in FEV1 will be measured by spirometer after bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time frame: Day 29
Population: Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QBW251 | Change From Baseline in FEV1 Post-bronchodilator | 0.05 Liters | Standard Deviation 0.21 |
| Placebo | Change From Baseline in FEV1 Post-bronchodilator | -0.02 Liters | Standard Deviation 0.16 |
Secondary
Change From Baseline in FEV1 Pre-bronchodilator
Change From Baseline to Day 29 in FEV1 will be measured by spirometer before bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time frame: Day 29
Population: Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QBW251 | Change From Baseline in FEV1 Pre-bronchodilator | 0.04 Liters | Standard Deviation 0.24 |
| Placebo | Change From Baseline in FEV1 Pre-bronchodilator | -0.02 Liters | Standard Deviation 0.23 |
Secondary
Change From Baseline in FRC
Change From Baseline to Day 29 in FRC will be measured by spirometry. Functional residual capacity (FRC) is the volume in the lungs at the end-expiratory position. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time frame: Day 29
Population: Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBW251 | Change From Baseline in FRC | 0.01 Liters | Standard Deviation 0.07 |
| Placebo | Change From Baseline in FRC | -0.02 Liters | Standard Deviation 0.09 |
Secondary
Change From Baseline in FVC Post- Bronchodilator
Change From Baseline to Day 29 in FVC will be measured by spirometer after bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured after bronchodilator
Time frame: Day 29
Population: Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBW251 | Change From Baseline in FVC Post- Bronchodilator | 0.03 Liters | Standard Deviation 0.04 |
| Placebo | Change From Baseline in FVC Post- Bronchodilator | 0.01 Liters | Standard Deviation 0.05 |
Secondary
Change From Baseline in FVC Pre Bronchodilator
Change From Baseline to Day 29 in FVC will be measured by spirometer before bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured before bronchodilator
Time frame: Day 29
Population: Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBW251 | Change From Baseline in FVC Pre Bronchodilator | 0.07 Liters | Standard Deviation 0.05 |
| Placebo | Change From Baseline in FVC Pre Bronchodilator | 0.01 Liters | Standard Deviation 0.07 |
Secondary
Change From Baseline in RV
Change From Baseline to Day 29 in RV will be measured by spirometry. Residual volume (RV) is the volume of air remaining in the lungs after a maximal exhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time frame: Day 29
Population: Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBW251 | Change From Baseline in RV | 0.03 Liters | Standard Deviation 0.07 |
| Placebo | Change From Baseline in RV | -0.02 Liters | Standard Deviation 0.1 |
Secondary
Change From Baseline in TLC
Change From Baseline to Day 29 in TLC will be measured by spirometry. Total lung capacity (TLC) is the volume in the lungs at maximal inflation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time frame: Day 29
Population: Pharmacodynamics (PD): analysis set included all patients with available PD data and no major protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBW251 | Change From Baseline in TLC | 0.01 Liters | Standard Deviation 0.07 |
| Placebo | Change From Baseline in TLC | -0.07 Liters | Standard Deviation 0.1 |
Secondary
Plasma Concentration of QBW251 by AUC0-12h
AUC 0-12h is the area under the plasma concentration-time curve from time zero to 12 hours.
Time frame: Day 1, Day 28
Population: PK analysis set: included all patients with at least one available valid PK concentration measurement. Due to practicalities of study conduct PK samples were collected only up to 8 hours. As a result, from noncompartmental analysis AUClast was not calculated up to 12 hours after dosing So this data is not available.
Secondary
Plasma Concentration of QBW251 by AUClast (0-8hours)
AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration.
Time frame: Day 1, Day 28
Population: Pharmacokinetics (PK): all patients with at least one available valid PK concentration measurement, who received study drug, and no protocol deviations with relevant impact on PK data. 3 patients had no sufficient concentration data on Day 1 and 2 patients had no concentration data on Days 1 and 28. 7 patients had no concentration data on Day 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 | Plasma Concentration of QBW251 by AUClast (0-8hours) | Day 1 | 3830 hr×ng/mL | Standard Deviation 3280 |
| QBW251 | Plasma Concentration of QBW251 by AUClast (0-8hours) | Day 28 | 6840 hr×ng/mL | Standard Deviation 4490 |
Secondary
Plasma Concentration of QBW251 by CMax (0-8hours)
Cmax is the observed maximum plasma concentration following drug administration.
Time frame: Day 1, Day 28
Population: Pharmacokinetics (PK): all patients with at least one available valid PK concentration measurement, who received study drug, and no protocol deviations with relevant impact on PK data. 3 patients had no sufficient concentration data on Day 1 and 2 patients had no concentration data on Days 1 and 28. 7 patients had no concentration data on Day 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBW251 | Plasma Concentration of QBW251 by CMax (0-8hours) | Day 1 | 1250 ng/mL | Standard Deviation 840 |
| QBW251 | Plasma Concentration of QBW251 by CMax (0-8hours) | Day 28 | 1640 ng/mL | Standard Deviation 916 |
Secondary
Plasma Concentration of QBW251 by TMax (0-8hours)
Tmax is the time to reach the maximum concentration after drug administration.
Time frame: Day 1, Day 28
Population: Pharmacokinetics (PK): all patients with at least one available valid PK concentration measurement, who received study drug, and no protocol deviations with relevant impact on PK data. 3 patients had no sufficient concentration data on Day 1 and 2 patients had no concentration data on Days 1 and 28. 7 patients had no concentration data on Day 28
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| QBW251 | Plasma Concentration of QBW251 by TMax (0-8hours) | Day 28 | 1.98 hr |
| QBW251 | Plasma Concentration of QBW251 by TMax (0-8hours) | Day 1 | 1.27 hr |