Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Chronic obstructive pulmonary disease, COPD
Brief summary
This study is designed to assess the effect of QVA149 (110/50 ug q.d.) versus placebo on pulmonary function and average physical activity levels in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD).
Interventions
DRUGQVA149
QVA149 (110/50 µg) once a day via Breezhaler® device
DRUGPlacebo
Placebo once a day via Breezhaler® device
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients with stable COPD according to the current GOLD guidelines (GOLD 2013). Current or ex-smokers who have a smoking history of at least 10 pack years (e.g. 10 pack years = 1 pack /day x 10 yrs, or ½ pack/day x 20 yrs).. Patients with airflow limitation indicated by a post-bronchodilator FEV1 ≥40% and \<80% of the predicted normal, and a post-bronchodilator FEV1/FVC \<0.70
Exclusion criteria
Patients with conditions contraindicated for treatment with, or having a history of reactions/hypersensitivity to any of the following inhaled drugs, drugs of a similar class or any component thereof, anticholinergics, long and short acting beta2 agonists, sympathomimetic amines, lactose or any of the other excipients Patients who have a clinically significant ECG abnormality at Visit 1, who in the judgment of the investigator would be at potential risk if enrolled into the study. Patients with paroxysmal (e.g. intermittent) atrial fibrillation are excluded. 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., beta blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, atrial fibrillation must be present at baseline and screening visits, with a resting ventricular rate \< 100/min. Patients with Type I or uncontrolled Type II diabetes and patients with a history of blood glucose levels consistently outside the normal range Patients with narrow-angle glaucoma, symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention. Patients with a history of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. Patients with non-melanoma skin carcinoma may be considered for the study. Patients with a body mass index (BMI) of more than 40 kg/m2. Women who are pregnant or breast feeding Patients requiring long term oxygen therapy on a daily basis for chronic hypoxemia. Patients who have had a COPD exacerbation that required treatment with antibiotics and/or oral corticosteroids and/or hospitalization in the 6 weeks prior to screening. Patients who have had a respiratory tract infection within 4 weeks prior to screening. Patients with any history of asthma. Patients with concomitant pulmonary disease Patients with clinically significant bronchiectasis. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak Inspiratory Capacity (IC) Comparison Between QVA149 and Placebo | Baseline, day 22, baseline day 36, day 57 | Inspiratory capacity (IC) will be measured with spirometry conducted according to internationally accepted standards. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the IC measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36 |
| Change From Baseline in the Comparison of QVA149 Versus Placebo With Respect to Average Physical Activity Level | Baseline, day 22, baseline day 36, day 57 | Average physical activity level is defined by average daily activity-related energy consumption \[Kcal/day\], measured via Actinography device. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the activity measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak IC Comparison Between QVA149 and Placebo on Day 1. | Day 1 or day 36 | Inspiratory capacity (IC) will be measured with spirometry conducted according to internationally accepted standards. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. The IC measurements collected prior to dosing on either Day 1 or 36, respectively, were subtracted from the appropriate peak measures on the same respective days |
| Change From Baseline in the Trough IC Comparison Between QVA149 and Placebo | Baseline, day 22, baseline day 36, day 57 | Inspiratory capacity (IC) will be measured with spirometry conducted according to internationally accepted standards. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the IC measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36 |
| Change in the Comparison of QVA149 vs. Placebo on the Average Number of Steps Per Day | Baseline, day 22, baseline day 36, day 57 | The average number of steps per day will be measured via Actinography device. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the activity measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day 1 or Day 57-Day36 |
| Trough FEV1 Comparison Between QVA149 and Placebo After 22 Days | Baseline, day 22, baseline day 36, day 57 | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the FEV1 measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36 |
| Peak Forced Expiratory Volume 1 (FEV1) Comparison Between QVA149 and Placebo at Day 1 | Day 1 or day 36 | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. The FEV1 measurements collected prior to dosing on either Day 1 or 36, respectively, were subtracted from the appropriate peak measures on the same respective days |
| Change in the Duration of at Least Moderate Activity Per Day Comparison of QVA149 Versus Placebo | Baseline, day 22, baseline day 36, day 57 | Least moderate activity (defined as 3,5-7kcal/min) will be measured via Actinography device. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the activity measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36 |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| QVA149 Then Placebo QVA149 once a day during 22 days cross-over to placebo once a day for up to 22 days | 96 |
| Placebo Then QVA149 Placebo once a day during 22 days cross-over to QVA149 once a day for 22 days | 98 |
| Total | 194 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Severe or moderate (COPD) Exacerbation | 5 | 1 |
Baseline characteristics
| Characteristic | QVA149 Then Placebo | Placebo Then QVA149 | Total |
|---|---|---|---|
| Age, Continuous | 64.3 Years STANDARD_DEVIATION 7.9 | 61.2 Years STANDARD_DEVIATION 7.7 | 62.8 Years STANDARD_DEVIATION 7.9 |
| Sex: Female, Male Female | 32 Participants | 35 Participants | 67 Participants |
| Sex: Female, Male Male | 64 Participants | 63 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 193 | 19 / 188 |
| serious Total, serious adverse events | 4 / 193 | 2 / 188 |
Outcome results
Primary
Change From Baseline in Peak Inspiratory Capacity (IC) Comparison Between QVA149 and Placebo
Inspiratory capacity (IC) will be measured with spirometry conducted according to internationally accepted standards. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the IC measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36
Time frame: Baseline, day 22, baseline day 36, day 57
Population: Full Analysis Set (FAS): all randomized patients who applied at least one dose of study medication during at least one study period. all patients were included in these analyses when baseline and day 22 data plus baseline day 36 and day 57 data were available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline in Peak Inspiratory Capacity (IC) Comparison Between QVA149 and Placebo | 0.3790 Liters | 95% Confidence Interval 0.2747 |
| Placebo | Change From Baseline in Peak Inspiratory Capacity (IC) Comparison Between QVA149 and Placebo | 0.1769 Liters | 95% Confidence Interval 0.1933 |
p-value: <0.000195% CI: [0.1583, 0.246]ANCOVA
Primary
Change From Baseline in the Comparison of QVA149 Versus Placebo With Respect to Average Physical Activity Level
Average physical activity level is defined by average daily activity-related energy consumption \[Kcal/day\], measured via Actinography device. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the activity measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36
Time frame: Baseline, day 22, baseline day 36, day 57
Population: Full Analysis Set (FAS): all randomized patients who applied at least one dose of study medication during at least one study period. Only patients with baseline and day 22 data, plus baseline on day 36 and day 57 data were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline in the Comparison of QVA149 Versus Placebo With Respect to Average Physical Activity Level | 5.1063 kcal/day | 95% Confidence Interval 214.6 |
| Placebo | Change From Baseline in the Comparison of QVA149 Versus Placebo With Respect to Average Physical Activity Level | -31.6063 kcal/day | 95% Confidence Interval 233 |
p-value: 0.039995% CI: [1.7241, 71.7011]ANCOVA
Secondary
Change From Baseline in Peak IC Comparison Between QVA149 and Placebo on Day 1.
Inspiratory capacity (IC) will be measured with spirometry conducted according to internationally accepted standards. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. The IC measurements collected prior to dosing on either Day 1 or 36, respectively, were subtracted from the appropriate peak measures on the same respective days
Time frame: Day 1 or day 36
Population: Full Analysis Set (FAS): all randomized patients who applied at least one dose of study medication during at least one study period. Only patients with baseline and day 1 post treatment initiation were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline in Peak IC Comparison Between QVA149 and Placebo on Day 1. | 0.486 Liters | Standard Deviation 0.2752 |
| Placebo | Change From Baseline in Peak IC Comparison Between QVA149 and Placebo on Day 1. | 0.207 Liters | Standard Deviation 0.2114 |
Secondary
Change From Baseline in the Trough IC Comparison Between QVA149 and Placebo
Inspiratory capacity (IC) will be measured with spirometry conducted according to internationally accepted standards. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the IC measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36
Time frame: Baseline, day 22, baseline day 36, day 57
Population: Full Analysis Set (FAS): all randomized patients who applied at least one dose of study medication during at least one study period. Only patients with baseline and day 20 post treatment initiation were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline in the Trough IC Comparison Between QVA149 and Placebo | 0.210 Liters | Standard Deviation 0.346 |
| Placebo | Change From Baseline in the Trough IC Comparison Between QVA149 and Placebo | -0.035 Liters | Standard Deviation 0.279 |
Secondary
Change in the Comparison of QVA149 vs. Placebo on the Average Number of Steps Per Day
The average number of steps per day will be measured via Actinography device. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the activity measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day 1 or Day 57-Day36
Time frame: Baseline, day 22, baseline day 36, day 57
Population: Full Analysis Set (FAS): all randomized patients who applied at least one dose of study medication during at least one study period. Only patients with baseline and day 22 data, plus baseline on day 36 and day 57 data were included in this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in the Comparison of QVA149 vs. Placebo on the Average Number of Steps Per Day | 30.7 Steps/day | Standard Deviation 1662 |
| Placebo | Change in the Comparison of QVA149 vs. Placebo on the Average Number of Steps Per Day | -320.7 Steps/day | Standard Deviation 1648 |
Secondary
Change in the Duration of at Least Moderate Activity Per Day Comparison of QVA149 Versus Placebo
Least moderate activity (defined as 3,5-7kcal/min) will be measured via Actinography device. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the activity measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36
Time frame: Baseline, day 22, baseline day 36, day 57
Population: Full Analysis Set (FAS): all randomized patients who applied at least one dose of study medication during at least one study period. Only patients with baseline and day 22, plus baseline day 36 and day 57 data were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in the Duration of at Least Moderate Activity Per Day Comparison of QVA149 Versus Placebo | -5.5 Minutes | Standard Deviation 51.8 |
| Placebo | Change in the Duration of at Least Moderate Activity Per Day Comparison of QVA149 Versus Placebo | -13.0 Minutes | Standard Deviation 52.3 |
Secondary
Peak Forced Expiratory Volume 1 (FEV1) Comparison Between QVA149 and Placebo at Day 1
FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. The FEV1 measurements collected prior to dosing on either Day 1 or 36, respectively, were subtracted from the appropriate peak measures on the same respective days
Time frame: Day 1 or day 36
Population: Full Analysis Set (FAS): all randomized patients who applied at least one dose of study medication during at least one study period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Peak Forced Expiratory Volume 1 (FEV1) Comparison Between QVA149 and Placebo at Day 1 | 0.347 Liters | Standard Deviation 0.176 |
| Placebo | Peak Forced Expiratory Volume 1 (FEV1) Comparison Between QVA149 and Placebo at Day 1 | 0.111 Liters | Standard Deviation 0.179 |
Secondary
Trough FEV1 Comparison Between QVA149 and Placebo After 22 Days
FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the FEV1 measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36
Time frame: Baseline, day 22, baseline day 36, day 57
Population: Full Analysis Set (FAS): all randomized patients who applied at least one dose of study medication during at least one study period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Trough FEV1 Comparison Between QVA149 and Placebo After 22 Days | 0.245 Liters | Standard Deviation 0.221 |
| Placebo | Trough FEV1 Comparison Between QVA149 and Placebo After 22 Days | -0.058 Liters | Standard Deviation 0.207 |