Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD, Dyspnea, QVA149, tiotropium
Brief summary
This study assessed the effect of QVA149 on patient-reported dyspnea in moderate to severe Chronic Obstructive Pulmonary Disease (COPD) patients.
Detailed description
This study used a multi-center, randomized, blinded, double-dummy placebo controlled, three-period crossover design to assess the effect of once daily QVA149 q.d vs. placebo and tiotropium 18 μg q.d. in terms of patient reported dyspnea as assessed by Baseline Dyspnea Index (BDI)/Transient Dyspnea Index (TDI)(SAC version) in patients with moderate to severe COPD.
Interventions
DRUGQVA149
QVA149 110/50 μg hard non-gelatin capsule, inhalation/blister once a day via SDDPI
DRUGTiotropium
Tiotropium 18 ug hard gelatin capsule, inhalation/ blister once a day via HandiHaler® device
Placebo 0 mg hard non-gelatin capsule, inhalation/ blister once a day via SDDPI
Placebo 0 mg hard gelatin capsule, inhalation/ blister once a day via HandiHaler® device
salbutamol/albuterol (containing CFC-free propellant -HFA 134a) inhaler used as rescue medication when needed.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with moderate to severe stable chronic obstructive pulmonary disease * Smoking history of 10 pack years * Post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) between 30 - 80% * Patients must be able to use computer mouse and display * mMRC grade\>2
Exclusion criteria
* Patients with a history of long QT syndrome * Patients with Type I or uncontrolled Type II diabetes * Patients who have had a COPD exacerbation or respiratory tract infection within 6 weeks prior to screening * Patients with any history of asthma * Patients with pulmonary lobectomy, lung volume reduction surgery, or lung transplantation * Patients with concomitant pulmonary disease * Patients requiring long term oxygen therapy (\>15 h a day) Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Placebo | Baseline and 6 weeks | Total Transient Dyspnea Index (TDI) is part of the BDI/TDI questionnaire where participants indicated whether they improved or deteriorated since their Baseline Dyspnea Index (BDI). The BDI and TDI each had 3 domains: activities, tasks, and effort. BDI domains were rated from 0 (very severe) to 4 (none) and the rates summed for the total BDI score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. TDI domains were rated from -6 (major deterioration) to 6 (major improvement) and the rates summed for the total TDI score ranging from -18 to 18. However, to ensure comparability with the TDI paper version, all TDI values were divided by 2 before the analysis. If data was missing or insufficient for any one of the domains a BDI/TDI was calculated. BDI = Baseline Dyspnea Index taken 75 min prior to the first dose in each treatment period. TDI = Transition Dyspnea Index taken after 6 weeks of treatment 75 min prior to the last dose in each treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Tiotropium | Baseline and 6 weeks | Total Transient Dyspnea Index (TDI) is part of the BDI/TDI questionnaire where participants indicated whether they improved or deteriorated since their Baseline Dyspnea Index (BDI). The BDI and TDI each had 3 domains: activities, tasks, and effort. BDI domains were rated from 0 (very severe) to 4 (none) and the rates summed for the total BDI score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. TDI domains were rated from -6 (major deterioration) to 6 (major improvement) and the rates summed for the total TDI score ranging from -18 to 18. However, to ensure comparability with the TDI paper version, all TDI values were divided by 2 before the analysis. If data was missing or insufficient for any one of the domains a BDI/TDI was calculated. BDI = Baseline Dyspnea Index taken 75 min prior to the first dose in each treatment period. TDI = Transition Dyspnea Index taken after 6 weeks of treatment 75 min prior to the last dose in each treatment period. |
| Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 5min-4h After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | 5min-4hr at day 1 and week 6 post-dose | Forced Expiratory Volume in 1 second (FEV1) was measured with spirometry conducted according to internationally accepted standards. Measurements were taken at 5 min- 4hr post-dose of day 1 and week 6. The standardized FEV1 Area under the curve (AUC) was calculated as the sum of trapezoids divided by the length of time. |
| Standardized Forced Vital Capacity (FVC) Area Under the Curve (AUC) 5min-4 Hrs After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | 5min-4hr at day 1 and week 6 post-dose | Forced Vital Capacity (FVC) is the total amount of air that can be exhaled by the patient after a full inhalation. The FVC was measured via spirometry conducted according to internationally accepted standards at 5 min-4 hr post dose of day 1 and week 6. |
| Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Used Over the 6 Weeks of Treatment | Baseline and 6 weeks | The number of puffs of rescue medication taken by participants, were collected each day during the study via entries in e-diaries |
| Change From Baseline in The Capacity of Daily Living During the Morning (CDLM) Score Averaged Over 6 Weeks of Treatment | Baseline and 6 weeks | The Capacity of Daily Living during the Morning (CDLM) is a self-administered daily assessment. The CDLM asks COPD patients to (i) report their ability to carry out 6 morning activities and (ii) rate the difficulty in performing those activities on a five point Likert-type scale ranging from not at all difficult to extremely difficult. For each of the six morning activities a score ranging from 0 (=so difficult that they could not carry out the activity by themselves) to 5 (not at all difficult to carry out the activity by themselves) is calculated by using the responses from the two questions for each activity. Daily CDLM is calculated using the scores average from the 6 morning activities. CDLM is calculated as the average daily CDLM score over 6 weeks of treatment. The change from baseline in CDLM score over 6 weeks is analyzed using a MIXED model with baseline CDLM score as a covariate. A CDLM score of 0.20 is considered to be a minimal clinically important difference. |
Countries
Belgium, Canada, Germany, Spain, United Kingdom
Participant flow
Recruitment details
247 patients were randomized. Of these 247, one patient was misrandomized, did not receive study treatment and was excluded from any analysis set. Of 246 patients, 191 completed the study. This is a crossover study; therefore, participants are counted more than once depending on their dosing sequences.
Pre-assignment details
Participants were randomized to 1 of 6 treatment sequences to receive 1 of 3 treatment combinations; then, crossed to the other 2 possible treatment combinations for a total of 3 treatment periods. Each treatment combination period was followed by a 14 day washout.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants who entered the study and were randomized to any of the 3 treatment combinations: QVA149 plus placebo to tiotropium; tiotropium plus placebo to QVA149 or placebo to QVA149 plus placebo to tiotropium. | 246 |
| Total | 246 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period I | Adverse Event | 4 | 1 | 1 | 3 | 2 | 4 |
| Period I | Protocol Violation | 1 | 1 | 1 | 1 | 0 | 0 |
| Period I | Withdrawal by Subject | 1 | 3 | 2 | 1 | 2 | 1 |
| Period II | Adverse Event | 2 | 3 | 2 | 2 | 4 | 2 |
| Period II | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Period II | Protocol Violation | 0 | 0 | 1 | 1 | 0 | 0 |
| Period II | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 |
| Period III | Adverse Event | 3 | 1 | 0 | 1 | 0 | 0 |
| Period III | Death | 0 | 0 | 0 | 1 | 0 | 0 |
| Period III | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age Continuous | 62.8 years STANDARD_DEVIATION 8.19 |
| Sex: Female, Male Female | 73 Participants |
| Sex: Female, Male Male | 173 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 51 / 223 | 58 / 220 | 70 / 218 |
| serious Total, serious adverse events | 6 / 223 | 6 / 220 | 5 / 218 |
Outcome results
Primary
Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Placebo
Total Transient Dyspnea Index (TDI) is part of the BDI/TDI questionnaire where participants indicated whether they improved or deteriorated since their Baseline Dyspnea Index (BDI). The BDI and TDI each had 3 domains: activities, tasks, and effort. BDI domains were rated from 0 (very severe) to 4 (none) and the rates summed for the total BDI score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. TDI domains were rated from -6 (major deterioration) to 6 (major improvement) and the rates summed for the total TDI score ranging from -18 to 18. However, to ensure comparability with the TDI paper version, all TDI values were divided by 2 before the analysis. If data was missing or insufficient for any one of the domains a BDI/TDI was calculated. BDI = Baseline Dyspnea Index taken 75 min prior to the first dose in each treatment period. TDI = Transition Dyspnea Index taken after 6 weeks of treatment 75 min prior to the last dose in each treatment period.
Time frame: Baseline and 6 weeks
Population: The analysis set includes all randomized patients who received at least one dose of study drug and for whom data are available. Data was analyzed according to the treatment they were randomized. In this cross-over design the number of patients on each treatment does not add up to the total number of patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 + Placebo to Tiotropium | Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Placebo | BDI | 7.34 Units on a scale | Standard Deviation 2.033 |
| QVA149 + Placebo to Tiotropium | Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Placebo | TDI | 0.98 Units on a scale | Standard Deviation 2.666 |
| Placebo | Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Placebo | BDI | 7.33 Units on a scale | Standard Deviation 2.206 |
| Placebo | Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Placebo | TDI | -0.38 Units on a scale | Standard Deviation 2.308 |
Secondary
Change From Baseline in The Capacity of Daily Living During the Morning (CDLM) Score Averaged Over 6 Weeks of Treatment
The Capacity of Daily Living during the Morning (CDLM) is a self-administered daily assessment. The CDLM asks COPD patients to (i) report their ability to carry out 6 morning activities and (ii) rate the difficulty in performing those activities on a five point Likert-type scale ranging from not at all difficult to extremely difficult. For each of the six morning activities a score ranging from 0 (=so difficult that they could not carry out the activity by themselves) to 5 (not at all difficult to carry out the activity by themselves) is calculated by using the responses from the two questions for each activity. Daily CDLM is calculated using the scores average from the 6 morning activities. CDLM is calculated as the average daily CDLM score over 6 weeks of treatment. The change from baseline in CDLM score over 6 weeks is analyzed using a MIXED model with baseline CDLM score as a covariate. A CDLM score of 0.20 is considered to be a minimal clinically important difference.
Time frame: Baseline and 6 weeks
Population: The analysis set includes all randomized patients who received at least one dose of study drug and for whom data are available. Data was analyzed according to the treatment they were randomized. In this cross-over design the number of patients on each treatment does not add up to the total number of patients.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 + Placebo to Tiotropium | Change From Baseline in The Capacity of Daily Living During the Morning (CDLM) Score Averaged Over 6 Weeks of Treatment | 0.09 Units on a scale | Standard Error 0.02 |
| Tiotropium + Placebo to QVA149 | Change From Baseline in The Capacity of Daily Living During the Morning (CDLM) Score Averaged Over 6 Weeks of Treatment | 0.08 Units on a scale | Standard Error 0.02 |
| Placebo | Change From Baseline in The Capacity of Daily Living During the Morning (CDLM) Score Averaged Over 6 Weeks of Treatment | -0.01 Units on a scale | Standard Error 0.02 |
Secondary
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Used Over the 6 Weeks of Treatment
The number of puffs of rescue medication taken by participants, were collected each day during the study via entries in e-diaries
Time frame: Baseline and 6 weeks
Population: The analysis set includes all randomized patients who received at least one dose of study drug and for whom data are available. Data was analyzed according to the treatment they were randomized. In this cross-over design the number of patients on each treatment does not add up to the total number of patients.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 + Placebo to Tiotropium | Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Used Over the 6 Weeks of Treatment | -1.02 puffs | Standard Deviation 0.202 |
| Tiotropium + Placebo to QVA149 | Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Used Over the 6 Weeks of Treatment | -0.57 puffs | Standard Deviation 0.202 |
| Placebo | Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Used Over the 6 Weeks of Treatment | 0.41 puffs | Standard Deviation 0.203 |
Secondary
Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 5min-4h After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium
Forced Expiratory Volume in 1 second (FEV1) was measured with spirometry conducted according to internationally accepted standards. Measurements were taken at 5 min- 4hr post-dose of day 1 and week 6. The standardized FEV1 Area under the curve (AUC) was calculated as the sum of trapezoids divided by the length of time.
Time frame: 5min-4hr at day 1 and week 6 post-dose
Population: The analysis set includes all randomized patients who received at least one dose of study drug and for whom data are available. Data was analyzed according to the treatment they were randomized. In this cross-over design the number of patients on each treatment does not add up to the total number of patients.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 + Placebo to Tiotropium | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 5min-4h After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Day 1 (n=220,219,2117) | 1.564 Liters | Standard Error 0.0082 |
| QVA149 + Placebo to Tiotropium | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 5min-4h After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Week 6 (n=205,209,206) | 1.636 Liters | Standard Error 0.0122 |
| Tiotropium + Placebo to QVA149 | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 5min-4h After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Day 1 (n=220,219,2117) | 1.496 Liters | Standard Error 0.0082 |
| Tiotropium + Placebo to QVA149 | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 5min-4h After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Week 6 (n=205,209,206) | 1.529 Liters | Standard Error 0.0122 |
| Placebo | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 5min-4h After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Day 1 (n=220,219,2117) | 1.352 Liters | Standard Error 0.0082 |
| Placebo | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 5min-4h After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Week 6 (n=205,209,206) | 1.302 Liters | Standard Error 0.0122 |
Secondary
Standardized Forced Vital Capacity (FVC) Area Under the Curve (AUC) 5min-4 Hrs After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium
Forced Vital Capacity (FVC) is the total amount of air that can be exhaled by the patient after a full inhalation. The FVC was measured via spirometry conducted according to internationally accepted standards at 5 min-4 hr post dose of day 1 and week 6.
Time frame: 5min-4hr at day 1 and week 6 post-dose
Population: The analysis set includes all randomized patients who received at least one dose of study drug and for whom data are available. Data was analyzed according to the treatment they were randomized. In this cross-over design the number of patients on each treatment does not add up to the total number of patients.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 + Placebo to Tiotropium | Standardized Forced Vital Capacity (FVC) Area Under the Curve (AUC) 5min-4 Hrs After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Day 1 (n=210,219,217) | 3.340 Liters | Standard Error 0.019 |
| QVA149 + Placebo to Tiotropium | Standardized Forced Vital Capacity (FVC) Area Under the Curve (AUC) 5min-4 Hrs After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Week 6 (n= 205,209,206) | 3.393 Liters | Standard Error 0.0254 |
| Tiotropium + Placebo to QVA149 | Standardized Forced Vital Capacity (FVC) Area Under the Curve (AUC) 5min-4 Hrs After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Day 1 (n=210,219,217) | 3.249 Liters | Standard Error 0.0191 |
| Tiotropium + Placebo to QVA149 | Standardized Forced Vital Capacity (FVC) Area Under the Curve (AUC) 5min-4 Hrs After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Week 6 (n= 205,209,206) | 3.269 Liters | Standard Error 0.0253 |
| Placebo | Standardized Forced Vital Capacity (FVC) Area Under the Curve (AUC) 5min-4 Hrs After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Day 1 (n=210,219,217) | 3.020 Liters | Standard Error 0.0191 |
| Placebo | Standardized Forced Vital Capacity (FVC) Area Under the Curve (AUC) 5min-4 Hrs After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium | Week 6 (n= 205,209,206) | 2.957 Liters | Standard Error 0.0253 |
Secondary
Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Tiotropium
Total Transient Dyspnea Index (TDI) is part of the BDI/TDI questionnaire where participants indicated whether they improved or deteriorated since their Baseline Dyspnea Index (BDI). The BDI and TDI each had 3 domains: activities, tasks, and effort. BDI domains were rated from 0 (very severe) to 4 (none) and the rates summed for the total BDI score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. TDI domains were rated from -6 (major deterioration) to 6 (major improvement) and the rates summed for the total TDI score ranging from -18 to 18. However, to ensure comparability with the TDI paper version, all TDI values were divided by 2 before the analysis. If data was missing or insufficient for any one of the domains a BDI/TDI was calculated. BDI = Baseline Dyspnea Index taken 75 min prior to the first dose in each treatment period. TDI = Transition Dyspnea Index taken after 6 weeks of treatment 75 min prior to the last dose in each treatment period.
Time frame: Baseline and 6 weeks
Population: The analysis set includes all randomized patients who received at least one dose of study drug and for whom data are available. Data was analyzed according to the treatment they were randomized. In this cross-over design the number of patients on each treatment does not add up to the total number of patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 + Placebo to Tiotropium | Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Tiotropium | BDI | 7.34 Units on a scale | Standard Deviation 2.033 |
| QVA149 + Placebo to Tiotropium | Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Tiotropium | TDI | 0.98 Units on a scale | Standard Deviation 2.666 |
| Tiotropium + Placebo to QVA149 | Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Tiotropium | BDI | 7.31 Units on a scale | Standard Deviation 2.199 |
| Tiotropium + Placebo to QVA149 | Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Tiotropium | TDI | 0.47 Units on a scale | Standard Deviation 2.184 |